FIZIOLOGIA
physiology
FOUNDING EDITORCHIEF EDITOR
CO-CHIEF EDITORSASSOCIATE EDITORSEXECUTIVE EDITORSFRANCISC SCHNEIDERCARMEN PANAITESCUCARMEN TATUFLORINA BOJINMIHAI NECHIFORSORIN RIGAGABRIELA TANASIEDACIANA NISTORCALIN MUNTEANEDITORIAL BOARD
ARDELEAN AURELBĂDĂRĂU ANCA
BENEDEK GYORGYBENGA GHEORGHECOJOCARU MANOLEGĂLUȘCAN ATENAIANCAU MARIAMIHALAŞ GEORGETA
MUNTEAN DANINAMUREŞAN ADRIANANESTIANU VALERIUOPREA TUDORPANAITESCU CARMEN(Arad)(Bucureşti)(Szeged)(Cluj)(Bucureşti)(Timișoara)(Craiova)(Timişoara)(Timişoara)(Cluj)(Craiova)(New Mexico)(Timişoara)PĂUNESCU VIRGILPETROIU ANAPODARIU ANGELA CODRUTA
RÂCZ OLIVERRIGA DANSABĂU MARIUS
SAULEA I. AURELSIMIONESCU MAIASWYNGHEDAUW BERNARDTANGUAY M. ROBERTTATU ROMULUS FABIANVLAD AURELIANVOICU VICTORZĂGREAN LEON

ACCREDITED BY CNCSIS - B+CATEGORY ■ CODE 240
http://www.ebscohost.com/titleLists/a9h-journals.pdf

Fiziologia (Physiology) is issued quarterly
Printed at Editura EUROSTAMPA
www.eurostampa.ro
Bd. Revoluţiei din 1989 nr. 26, Timişoara
Tel/fax: 0256-204816

ISSN 1223-2076(Timişoara)(Timişoara)(Timișoara)(Kosice)(Bucureşti)(Tg. Mureş)(Chişinău)(Bucureşti)(Paris)(Canada)(Timişoara)(Timişoara)(Bucureşti)(Bucureşti)Instructions to Authors
Submission: Only original papers in English areconsidered and should be sent to the following
address: carmen.tatu@umft.ro
Manuscripts should be submitted by e-mail only,
written in Microsoft Word 97 or later versions.
Conditions: AII manuscripts are subject to editorial
review. Manuscripts are received with the explicit
understanding that they are not under simultaneousconsideration by any other publication. Submission ofan article for publication implies the transfer of the
Copyright from the author the publisher upon
acceptance. Accepted papers become the permanent
property of "Fiziologia" (Physiology) and may not be
reproduced by any means, in-whole or in part, without
the written consent of the publisher. It is the author's
responsibility to obtain permission to reproduce
illustrations, tables, etc. from other publications.
Arrangement:
Title page: The first of each paper should indicate
the title, the authors' names and their affiliation(s).
A short title for use as running head is also required.
Keywords: for indexing purposes, a list of 3-5
keywords in English and Romanian is essential.
Corresponding author: Indicate the full name, theemail address and the phone number.
Abstract: Each paper needs abstract and title in
Romanian and English language, fonts size 9, Arial
Narrow.
Body text: fonts size 10, Arial Narrow.
Small type: Paragraphs which can or must be set
in smaller type (case histories, test methods, etc.)
should be indicated with a „p" (petit) in the margin on
the left-hand side.
Footnotes: Avoid footnotes. When essential, they
are numbered consecutively and typed at the foot of
the appropriate page, fonts size 8, Arial Narrow.
Tables and illustrations: Tables (numbered in
Roman numerals) and illustrations (numbered in
Arabic numerals) should be prepared on separate
sheets, fonts size 9, Arial Narrow. Tables require aheading, and figures a legend, also prepared on a
separate sheet. For the reproduction of illustrations,only good drawings and original photographs can be
accepted; negatives or photocopies cannot be used.
When possible, group several illustrations on one
block for reproduction (max. size 140x188 mm) or

2

provide crop marks. On the back of each illustration
indicate its number, the author's name, and article
title.
References: In the text identify references by
Arabic figures, (in brackets), fonts size 9, Arial Narrow.
Material submitted for publication but not yet
accepted should be noted as "unpublished data" andnot be included in the reference list. The list ofreferences should include only those publications
which are cited in the text. The references should benumbered and arranged alphabetically by the authors'names. The surnames of the authors followed byinitials should be given. There should be nopunctuation signs other than a comma to separate theauthors. When there are more than 3 authors, thenames of the 3 only are used, followed by "et al"abbreviate journal names according to the Index
Medicus system. (also see International Committee ofMedical Journal Editors: Uniform Requirements formanuscripts submitted to biomedical journals. Ann
Intern Med 1982; 96: 766-771).
Examples:(a) Papers published in periodicals: Kauffman
HF, van der Heide S, Beaumont F, et al: Class-specificantibody determination against Aspergillus fumigatus
by mean of the enzyme-linked immunosorbent assay.
III. Comparative study: IgG, IgA, IgM, ELISA titers,
precipitating antibodies and IGE biding after
fractionation of the antigen. Int Arch Allergy Appl
Immunol 1986; 80:300 - 306.
(b) Monographs; Matthews DE, Farewell VT:
Using and Understanding Medical Statistics. Basel, Karger,
1985.
(c) Edited books: Hardy WD Jr, Essex M:.FeLVinducted feline acquired immune deficiency syndrome: A
model for human AIDS; in Klein E(ed): Acquired
Immunodeficiency Syndrome. Prag Allergy, Busel,
Karger, 1986, vol 37,353 - 376.
Galley proofs: unless indicated otherwise, galley
proofs are sent to the first-named author and should
be returned with the least possible delay. Alternations
made in galley proofs, other than the corrections ofprinter's errors, are charged to the author. No page
proofs are supplied.

Fiziologia - Physiology • 2018.28.1(95)CONTENTS
1. CAR T Cells Therapy vs. TILs Therapy: The Future of Cancer Immunotherapy ........................................ 4
Szekely FAE, Zogorean R, Anghel S, Paunescu V

2. Faculty Perception for the Need of Change in I Year MBBS Indian Physiology Practical Curriculum ....... 16
Smita R Sorte, Sachin B Rathod

3. Impact of Isotonic Hand Grip Exercise on Blood Pressure and Sympathetic Response
in Prehypertensives ..................................................................................................................................... 21
Saravanan Murugan, Singh S K

4. Misdiagnosis of Aspirated Bronchial Foreign Body. A Case Report ......................................................... 31
Cioboata R, Bazavan I, Nitu M, Georgescu M, Olteanu M

5. Clinical and Etiological Aspects of the Confusional Syndrome ................................................................ 35
Albu VC, Sandu RE, Pirscoveanu D, Bumbea AM, Parvulescu OC, Bogdan C, Florescu AO,
Balseanu TA, Enescu A, Mirea CS, Barbulescu AL

6. Clinical Patterns of Neuropsychiatric Systemic Lupus Erythematosus ................................................... 40
Sandu RE, Barbulescu AL, Florescu AO, Pirscoveanu D, Bumbea AM, Parvulescu OC,
Tartea AE, Bogdan C, Balseanu TA, Enescu A, Mirea CS, Albu VC, Burada E

CUPRINS
1. Terapia cu celule CAR-T vs. TIL: Viitorul imunoterapiei în cancer .............................................................. 4
Szekely FAE, Zogorean R, Anghel S, Paunescu V

2. Percepția academică referitoare la nevoia de schimbare a curriculum de fiziologie practică
pentru studenții MBBs din anul I ................................................................................................................ 16
Smita R Sorte, Sachin B Rathod

3. Impactul exercițiilor isotonice hand grip privind presiunea de sânge și răspunsul simpatic
la pre-hipertensivi ........................................................................................................................................ 21
Saravanan Murugan, Singh S K

4. Diagnostic greșit al unui corp strain aspirat bronșic. Raport de caz ....................................................... 31
Cioboata R, Bazavan I, Nitu M, Georgescu M, Olteanu M

5. Aspecte clinico-etiologice ale sindromului confuzional ............................................................................ 35
Albu VC, Sandu RE, Pirscoveanu D, Bumbea AM, Parvulescu OC, Bogdan C, Florescu AO,
Balseanu TA, Enescu A, Mirea CS, Barbulescu AL

6. Afectarea neuropsihiatrică în lupus eritematos sistemic - aspecte clinice .............................................. 40
Sandu RE, Barbulescu AL, Florescu AO, Pirscoveanu D, Bumbea AM, Parvulescu OC,
Tartea AE, Bogdan C, Balseanu TA, Enescu A, Mirea CS, Albu VC, Burada E

Fiziologia - Physiology • 2018.28.1(95)3CAR T CELLS THERAPY VERSUS TILs THERAPY:
THE FUTURE OF CANCER IMMUNOTHERAPYSZEKELY FLAVIA ANNE-ELISE1,2, ZOGOREAN ROXANA1, ANGHELSIMONA1,3, GAVRILIUC OANA1,3, BOJIN FLORINA1,3, PĂUNESCU VIRGIL1,3
1Clinical Emergency County Hospital “Pius Brînzeu” Timișoara, Centre for Cellular and Gene Therapies in the Treatment of Cancer –OncoGen2Emergency Hospital for Children Louis Țurcanu Timișoara
3”Victor Babes” University of Medicine and Pharmacy Timisoara, Department of Functional Sciences, Immunology Discipline

ABSTRACTWorldwide, cancers are one of the main leading causes of death and the conventional treatment has its own limits.
Researches from immunotherapy field are focusing on discovering feasible alternative therapeutic approaches for treating
this disorder.
In cancers, immunotherapy has the role to enhance anti-tumor effect of the immune cells involved in the process.
Depending on the type of targeted antigens, side effects of this therapy may vary from local and mild to systemic and more
severe reactions.
The principle of CAR T cells and TILs immunotherapies is based on using T cells that are specific for a certain antigen andre-infusing back to the patient after those cells were expended ex vivo, in order to cause tumor destruction. Association ofthese therapies with a lymphodepleting regime and T cell growth factor IL-2 leads to a potent effect on patients.
Within this article, we make an overview of the CAR T cell therapy and TILs therapy, by describing the principles of thisimmunotherapies, their clinical applications, as well as their advantages, disadvantages and future perspectives.
Key words: CAR T cells, TILs, immunotherapies, cancer

INTRODUCTION
An overview of cancer immunotherapy strategies
During the last decades, cancer has become one of the
primary diseases that threaten human lives, metastatic
cancers remaining an incurable disease for the mostpatients. Each year, approximately 8,8 million people aredying of cancer, this disease having the highest frequency
in low-income and middle-income countries (LMICs), where
the number of cancer cases is rising most rapidly. By 2035,
the cancer incidence is estimated to double, especially in
LMICs because of the population aging and the increasing
exposure to risk factors [1, 2].
The conventional therapy strategies against cancer
have incorporated surgery, chemotherapeutic agents andradiotherapy to eliminate the tumor mass. Although many ofthese therapies offered substantial benefits, the high relapse
rate associated with poor prognosis, continues to be a major
challenge [3, 4]. Because of the limited effectiveness ofthese conventional antitumor treatments, there is a need forcancer treatments with favorable benefits and toxicity
profiles that can potentially result in long-term survival [5].
In last years, researchers and clinicians have focusedon discovering therapeutic alternatives designed to induce a
potent anti-tumor response and to eliminate the resistanttumor cells, with fewer side effects. One alternative strategy
that opened the door to new cancer therapies isimmunotherapy [6]. Cancer immunotherapy is becoming an
attractive strategy to induce anti-tumor response, focusing
on the host’s immune system to recognize and eliminate thecancer cells [1].
Even though the idea of using immune system in fighting
cancer was novel in the 1980s, its practice wasn’t. The firstsuccessful immunotherapy to treat cancer was developed
by William B. Coley, using toxins from Streptococcus
erysipelas and Bacillus prodigious. Two decades later, after
the Coley’s death in 1936, was the advent of theReceived April 16th 2018. Accepted May 20th 2018. Address for correspondence: Gavriliuc Oana, PhD, ”Victor Babes” University of Medicine
and Pharmacy Timisoara, Department of Functional Sciences, Immunology Discipline, Clinical Emergency County Hospital “Pius Brînzeu”
Timișoara, Centre for Cellular and Gene Therapies in the Treatment of Cancer – OncoGen; Eftimie Murgu Square No. 2A, RO-300041,
Timisoara, Romania; phone: +40728301083; e-mail: gavriliuc.oana@umft.ro4

Fiziologia - Physiology • 2018.28.1(95)immunology modern era. This new era in medicine beganwith discovering of interferon in 1957 and continued with:publishing the first ever cancer vaccine study, a 114 patient
cohort of gynecologic cancer patients in 1959, discovery andcharacterization of dendritic cells in 1973, description of
MHC restriction in 1974 and continued with many moreother discoveries. Since our understanding of immune
mechanisms has expended, there have been identified awide array of immune pathways useful to promote an
antitumor response in cancer patients [6,7].
Due to the research of the last decades, could havebeen developed different immunotherapy strategies aiming
to enhance the immune system for a potent anti-tumor
response. For this, a wide range of immunotherapy
approaches have been developed and we are going todiscuss them in the following [8].
Monoclonal antibodies-based treatment, which isone of the most successful immunotherapy used for solid
tumor and hematologic malignancies. Monoclonal
antibodies are modified antibodies used to target in different
ways tumor cell. There are four types of monoclonal
antibodies: murine, chimeric, humanized and humanchemotherapeutic monoclonal antibodies. Once themonoclonal antibodies are attached to the targeted antigen
tumor, cell destruction can be caused through three main
mechanisms:
x induction of apoptosis, inhibition of cell survival
signaling, or through the direct delivery of cytotoxic
drugs.
x immune mediated tumor cell killing by activation ofcellular phagocytosis and engaging antibodydependent-cell-mediated-cytotoxicity, complementmediated-cytotoxicity.
x vascular ablation and disruption of stromalinteraction with cancer cells [9].
Cytokines are immune modulators of the innate andadaptive immune system which helps cells of the immune
system to communicate with one another. These immune
regulators, such as interleukin (IL)-2, IL-12, IL-15, IL-21,
granulocyte macrophage colony-stimulating factor (GMCSF), interferon (IFN)- α have been explored in thetreatment of cancer, showing their effectiveness in
preclinical murine cancer models [10,11].
Cancer vaccines are designed to strength patient’s
own immune system in order to eradicate cancer cells.
During the last decades, several therapeutic vaccination
strategies have been developed or are currently evaluatedin clinical trials. Based on their format, they are classified
into several major categories, presented below:- autologous cell vaccines, one of the first types ofvaccines to be tasted, are using patient-derived
tumor cells. Once these types of cells are obtained,
they irradiated and then administrated to the patientalone, or in combination with an adjuvant.
Fiziologia - Physiology • 2018.28.1(95)allogenic tumor cell vaccines would be a better
option because may overcome some limitations ofautologous tumor cell vaccines such as a varied
source of antigens of cancer cells, easier expression
manipulation of immunostimulatory molecules, large
scale production of this vaccine type.
- dendritic cells are cells specialized in presenting theantigen, having an important role in taking,processing, presenting tumor antigens, inducing an
immune system. This type of therapy is based on
injecting patients with in vitro matured autologous
monocytes, treated with antigen right before
administration.
- protein based cancer vaccines are based on
generation an immune- mediated response against
a single cell tumor antigen, associated with an HLA
complex from its surface.
- genetic vaccines are used to trigger on immunemediated response by injecting the patient with
vectors that carries genetic information of theantigen. Thereby, dendritic and somatic cells aretransfected, generating an immune-response [8,12].
Cell based immunotherapy is an adoptive cell therapy(ACT) used for hematologic malignancies and solid cancers.
This treatment involves use of autologous lymphocytes withantitumor activity, or lymphocytes genetically engineered toexpress antitumor TCRs [8].
With this review, our goal is to present the molecularbasis of adoptive T cell therapy, discuss the clinicalapplication in different types of cancers, with presentation of
the latest result from clinical trials. Using all this data, we
hope to identify the best immunotherapy solution incompliance with different types of cancers.
-

CAR T CELLS THERAPY
Adoptive T cell therapy (ACT) is one of the main
treatment approaches, using genetically modified
lymphocytes in order to fight against cancer cells fromhematological malignancies and solid tumors. There arethree main adaptive T cell therapies such as chimericantigen receptors (CAR-T), T cell receptor engineered T
cells (TCR) and tumor infiltrating lymphocytes (TILs). In thefollowing we will focus on adaptive T cell transfer using
genetically modified lymphocytes [3].
1. Chimeric antigen receptors: production,
structure, generations of CARs
Chimeric antigen receptor (CAR-T) is an immunotherapy
based on using genetically engineered T cells in order torecognize and eliminate specific tumor cells [13].

5Production of CARs
Autologous T-cells are collected from patients’
peripheral blood, isolated through leukapheresis andfollowed by apheresis to obtain the T-cells. After the
purification, T-cells are genetically modified using a viral(retroviral or lentiviral) or non-viral vector. The viral vector
used (which encode the CAR), will integrate its genetic
material into the genome of the patient cells. Thus, CARsexpressing lymphocytes will be produced and will be
expended in culture. When the cell expansion process isfinished and passed all the quality control testing, the final
cell product will be infused into the patient. In order to havea better T cell expansion, a lymphodepleting treatment
should be done two days prior the CAR-T cells
administration [13, 14].
Structure of CARs
Genetically modifications of T lymphocytes used to
produce CAR T-cells, determine reconstruction of thereceptor region to recognize specific antigens of the cancer
cells that are to be destroyed.
The CAR T receptor has three primary domains:
extracellular domain, a transmembrane domain (TMD) anda signal transduction domain (STD) (Figure 1).
The extracellular domain is represented by antigenbinding single-chain variable fragment domain (scFv) from amonoclonal antibody, which is designed to recognize a
specific surface molecule on B cells. It consists of signal
peptide, antigen recognition region and spacer.
The TMD is the linkage between scFv region andintracellular signaling/activation domain and its structure isrepresented by a hydrophobic alpha helix that spans themembrane.
The functional end of the receptor is represented by theendodomain, containing a CD3ζ domain and a costimulatory
domain (usually 4-1BB or CD28) [15,16].

Generations of CARs
In 1989 was developed this concept therapy,
represented by the first generation of CART cells. First
generation of CARs had the extracellular domain (scFV)
attached to a cytoplasmic domain represented by zeta chain
CD3 complex (CD3 ζ). Because of a low proliferation rate,
short life duration and insufficient cytokines secretion, has
led to an improvement of the CAR-T cells. A new type ofcells was developed represented by the second generationof CARs. This new type of CARs had incorporated a costimulatory protein receptor (CD28 or CD137) attached tothe cytoplasmic tail. This co-stimulatory protein receptor has
the role to provide a supplementary signal to the T cell, inorder to improve the CAR-T cells features and responses.
Third generation of CARs is characterized by combining
sequences of multiple stimulatory signals (OX40 (CD134),
CD28, 4-1BB (CD137), CD27, DAP10 or other molecules)
with CD3ζ. The role of multiple co-stimulatory signals is toincrease the cytokine production, T-cell proliferation rate
and to improve killing ability [3,17].
The desire to broaden the anti-tumor response byrecruiting other immune cells due to the cancer cells
heterogeneity from solid tumors, has led to creation of the
fourth generation of CAR-T cells, called TRUCKs(universal cytokine-mediated killing). TRUCK cells are
CAR-T cells modified to produce a cytokine (IL-12), using
as base the second-generation construct. The role of the
IL-12 is to enhance T-cell function, stimulate additional
immune cells to fight against tumor cells and to influence
the immunological and vascular tumor environment(Figure 2) [18].

Fig. 2. Generations of CARs

2. Risk factors of CAR T cells therapy

Fig. 1. Structure of CAR T receptor

6

Even though there are and will be introduced new
targets for CAR-T cells immunotherapy, for achieving better
results in treating a larger variety of cancers, there are somechallenges to overcome such as factors that may affect in anegative way safety and efficiency of this therapy (Table I)[16,17; 19-21].
Fiziologia - Physiology • 2018.28.1(95)Table I. Risk factors that may affect therapy with CAR T cells.
Factors that may affectefficacy
lymphodepletion (because
it can reduce the number ofcirculating T cells)
cell dose of CAR-T cells

Factors that may affectsafetyon target off-tumor activity

tumor microenvironment(tumor cells, vasculature,
immune-cells)

cytokine release syndrome(CRS-which is a major side
effect observed after CAR-T
cell therapy)
sterility of the vector(potential for insertionalmutagenesis caused by the
integration of vector DNA
into the host cells)
types and concentration ofcytokines released during
the CAR T cell
immunotherapy
autoimmune disease(caused by elimination ofpotential healthy cellularantigens)
CAR-T cell-related
encephalopathy syndrome(CRES)

administration of a defined
number of CAR-T cells

long term safety of viral
vectors used

(CD3γ and CD3ε; CD3δ and CD3ε; CD3ζ). For an efficient
activation of the cell, also there is required an accessory
adhesion molecules expressed by T cell (CD4 for MHC
class II and CD8 for MHC class I) (Figure 3) [19,24].

off-target reactivity

Legend: adapted from Sharma P et al. Cell.
2017;168(4):707-723. (1)

3. TCR and UCART therapies
TCR therapy
T cell receptors (TCR) engineering technologies are
based on producing tumor antigen-specific TCR throughaltering specificity of lymphocytes T by modifying expressionof alpha and beta chains. Thereby this type of cells will beable to target specific cancer antigen presented by the major
histocompatibility complex proteins. In order to that, first, T
cells must be isolated from the patient blood or tissue
affected by the tumor. Clones of TCR α and β chain genes
are inserted into a vector (lentivirus or retrovirus) and thentransduced into the T cells. All this process allows genemodification in order to obtain modified T cells with a specific
TCR sequences. After the new T cells are expended, in vitro,enough to have a sufficient number of cells, will be reinfused to the patient [22, 23].
Normally, a T-cell receptor is a protein of the adaptive
immune response and has in its structure α and β chains.
Each chain has two extracellular domains, a variabledomain (VR – which binds to the peptide/MHC complex) anda constant region (C). The constant region is associatedtransmembrane with a CD3 complex with three dimers
Fiziologia - Physiology • 2018.28.1(95)Fig. 3. T cell receptor

Even though TCRs and CARs therapies obtained
promising results in cancer treatment, CARs therapy ispreferred because those type of cells recognize antigens
structure which are not associated with major
histocompatibility complex (MHC) [4].
UCART therapy
Universal Chimeric Antigen Receptor T-cells are a newgeneration of modified CAR T cells, using cells fromallogenic healthy donor. UCARTS are considered to be thefuture of cancer immunotherapy, even though there aresome issues that need to be fixed in the practical utilization.
The common base of this new system of UCARTS is tomodify allogenic T cells using genome-editing techniquesand generating universal T cells, in order to obtain universal
T cells for a specific antigen.
The principle of genome-editing methods used to
produce universal T cells, is to eliminate graft-versus-hostdisease (GVHD) by abrogating at the genomic level the TCR
expression or antigen of HLA class 1. Therefore, T cells are
not able to recognize and target allogenic antigens and
GVHD is abolished. Gene-editing methods used to generate
universal T cells are [25]:- zinc finger nuclease (ZNF): is a type of enzyme
which has two main domains. A DNA – binding
domain has the role to target the DNA sequence wewant to replace/modify. Cleavage domain is used for
double-strand breaking of the DNA molecule [26].
- transcription activator like effector nuclease(TALEN), another gene-editing tool, may beengineered to target any desired sequence. Like
7

-

ZFN, TALEN has in its structure two domains, aDNA-cleaving nuclease which is bind to a DNAbinding domain. Attaching of the TALEN molecule tothe desired DNA sequence, will induce doublestrand-breaks (DSBs). Although TALENs and ZFNs
are similar and equally effective, TALEN is a moresuitable editing tool because of the wide range oftargeting genes and its simplicity [27].
clustered regularly interspaced short palindromic
repeat – associated protein 9 (CRISPR/CAS 9) is
the newest generation of gene-editing tool, used toinactivate the target gene, through deletion or
insertion of DNA. CRISPR/CAS9 uses an RNA
guide which hybridize to the target sequence andCas 9 nucleases that generates a double-strand
break. This new technology was successfully usedin production of the universal T cells and have been
initiated clinical trials in order to see the efficiency ofthis new method [25, 28].

4. CAR T cells therapy in blood cancer
The immunotherapy based on chimeric antigen receptor
T cells (CAR-T cells) have shown their effectiveness over the
past years, especially in treating patients with hematologicalmalignancies in preclinical and clinical trials [29, 16]. Anti
CD19 CAR-T cells therapies have demonstrated their utility inpatients’ treatment (pediatric and adult) with diverse
hematological malignancies such as lymphoma, acutelymphoblastic leukemia (ALL), chronic lymphocytic leukemia(CLL) and multiple myeloma (MM) (Figure 4) [14, 3].

Fig. 4. Chimeric antigen receptor of T cell binding to an antigen
on cancer cell

Acute lymphoblastic leukemia (ALL)
Acute lymphoblastic leukemia is a hematologicalmalignant disease caused by genetic or chromosomal
abnormalities which determines a pathological proliferation8and differentiation of precursor cells of the lymphoid cell line.
World Health Organization proposed a classification of ALL
in B-cells ALL and T-cells ALL, B-cells ALL being further
classified based on the genetic modifications [30].
In ALL, CAR-T cells therapy is targeting CD19 cells,
which is the most important biomarker of B cells lines and ishighly expressed in B-cell ALL [14].
Grupp et al. described CAR-T cells as a potential
therapy for B- cells ALL. They presented cases of 2 young
patients which had an active ALL associated with multiple
relapses after chemotherapies. These patients were infusedwith modified T cells in order to present anti CD19 antibody.
After infusion, the number of CAR T cells were higher thaninitially, and persisted for at least 6 months in the
cerebrospinal fluid. Both patients presented side effects(aplasia of B cells, cytokine release syndrome) and went into
remission 11 months from the treatment [31].
In their review, Zijuan Zhao et al. highlights the utility of
CAR-T cell therapy in ALL, especially for patients (bothchildren and adults) with relapsed/refractory (r/r) B-ALL. Allof those patients showed partial and complete remission
rates. In other clinical trials, was suggested receiving a
conditioning treatment (fludarabine and cyclophosphamide)
one week after infusion with CAR-T cells. Also, it issuggested the importance of correlation between used
doses of CAR-T cells, in vivo expansion of the cells and risksof side effects such as cytokine release syndrome,neurotoxicity [14].
Same aspects were confirmed by Tawilliger and AbdulHay. Also, they describe a new type of modified CAR-T cells
specific for CD 22 against CD22 positive B-ALL [30,32]. A
dual infusion of anti CD22 and anti-CD19 CAR-Ts are taken
into consideration as a better alternative for the control ofthis disease [33].
Chronic lymphocytic leukemia (CLL)In North America and Western Europe chronic
lymphocytic leukemia is the most common type of leukemia,
being present in 4,5/100000 persons. Because the medianage when this disease is frequently diagnosed is around 6772 years, these hematological malignancies are considered
to be diseases of elderly people.
Accumulation of mature CD5 positive B cells in spleen,
lymph nodes, blood and bone marrow is a characteristicfeature for CLL. Recent studies highlighted a genetic
component as cause of this pathology, additions or deletionsof chromosomal material being detected (deletion of 13q –which is the most frequently genetic aberration, deletion of
11q, trisomy 12, and deletion of 17p). Also, additional
mutations may influence the gravity of CLL [34, 35].
Even if immunochemotherapy is the first line therapy in
CLL [34], there are clinical studies which demonstrate the
CAR-T cell therapy as an alternative therapy. CAR-T cells
therapy has become an important part in treatment of therelapsed and refractory (r/r) CLL [36].
Fiziologia - Physiology • 2018.28.1(95)Zou Y et al. presented different clinical trials which
confirmed the potential of CAR-T cells as a valid therapy
for treatment of chronic lymphocytic leukemia [36].
In a study published in 2018, Fraiette and his teamhave tried to use this novel immunotherapy in order toovercome tumor mediated rejection and tolerance of theimmune system, for patients diagnosed with chronic
lymphocytic leukemia (CLL). 41 patients with advanced
CLL were included in the study and some of them
responded to the CD19-targeted T cells (CTL019)
treatment, with a dramatic expansion of the number of
CAR T cell, associated with B cell aplasia. Other patientsdisplayed limited response. Also, there were a small groupof patients that had a high number of active T cells but later
relapsed into an aggressive form of B cell Lymphoma.
Efficiency of the treatment wasn’t related to the age ofpatient, therapies followed prior CART cells, or any otherfactors. All these different patients’ responses to thetreatment have been attributed to the innate immune
system [37].
Porter and his colleagues present a clinical trial where
14 patients were infused with CAR-modified T cell, with
monitoring the evolutions of patients. All patients who took
part of this trial presented a refractory-relapsed (r/r) formof CLL. From all those 14 patients, just 8 of them presenteddifferent rates of response towards the treatment. Half of
those cases presented a complete remission, while theother four patients presented a partial remission. All thepatients that responded to the treatment developed side
effects such as B cell aplasia and cytokine release
syndrome [38].

light chain in order to kill tumor cells. The clinical trial result
showed the potential of N CAR T cells as an alternative
therapy.
Because of the highly expressed CD 138 on MM cells,
a new series of anti CD138-CAR T cells were developed. In
the presented clinical trial, 4 of 5 patients had a stabledisease, while the other patients presented a number
reduction of MM cells.
Last, but not least, CAR-T cells targeting B cellmaturation antigen, which is highly expressed by all oftumor plasma cells, is another therapeutic strategy in order
to treat patients with MM. All trials conducted to see theefficiency of this new treatment, showed a dramatic response
toward this new treatment. Besides CD 138 CAR-T cells,
patients received a treat also received a conditioning
chemotherapy like fludarabine, cyclophosphamide prior theinfusion [40].
Berahovich and his team showed the potential antitumor activity of BCMA 4C8A CAR T cells. BCMA CAR T
cells are a novel type of CAR T cells in order to be used forpatients with MM. For creation of this cells, a BCMA specificmAb, clone 4C8A was generated. Clone 4C8A was used inconstruction of single chain variable fragments (scFv), which
was inserted into a second generation of CARs. These
modified CAR T cells were infused to the mice with xenograft
tumor model, to measure their reaction against the tumor[41]. In order to establish the utility of this novel treatment,
is necessary to test their utility in clinical trials. Some studies
have showed or are about to presents their results regarding
the potential anti-tumor function of BCMA CAR T cells[42,43].

Multiple myeloma (MM)In the Western World, multiple myeloma represents 10%
from all of hematological cancers, being presents in
5,6/100000 persons. It is defined by an accumulation inside
the bone marrow of plasmatic clonal cells.
Conventional therapies are focused to prolong thesurvival rate of the patient with a number reduction ofmalignant plasmatic cells, followed by a therapy in order tomaintain therapeutic effectiveness. During the last years,
have been developed novel immunotherapies in order toimprove the curative potential and disease management,
CAR-T cells therapy being one of the most recent
therapeutic alternatives, with successful results in ALL and
CLL treatment [49,40].
With their review article, Ghosh et al focuses on CD 19
CAR T cells therapy which targets multiple myeloma, putting
on spot other CAR T cells that target different tumor antigen.
CD 19 CAR T cells therapy has been studied as analternative treatment for patients with relapse-refractorydisease, without satisfactory results. They also proposed N
CAR T cells, CD 138 CAR T cells and BCMA CAR T cells.
Usage N CAR T cells is a new strategy developed to eliminate
in a more selective way malignant B cells, by targeting kappa

Lymphoma
In 1832, this malignancy was described for the first timeby Thomas Hodgkin which described six cases, of which
only three were proven to be right later [44].
Lymphomas have been classified in two groups: NonHodgkin lymphoma and Hodgkin Lymphoma. Humanlymphoma is caused by a clonal expansion of NK (naturalkiller) cells, T cells, B cells, derived from different
development stages of these cells (Table II) [45].

Fiziologia - Physiology • 2018.28.1(95)Table II. Types of lymphomas and origin of cells foundin lymphomas
Types of Lymphomas
B cell lymphomas
T cell lymphomas
NK cell lymphomas

The origin of the cells
germinal or post-germinal center B
cells
normal T cells regardless of thestage of lymphopoiesis
normal NK cells regardless of thestage of lymphopoiesis

Legend: adapted from Knochelmann HM et al.
Front Immunol. 2018; 9:1740. (46)9Organs which are rich in lymphoid immune tissue,
represent the starting point for Hodgkin (HL) and NonHodgkin (NHL) lymphomas and represents a very easy
access for antibodies. Because of that, immunotherapy
represent a useful tool in lymphoma treatment [45].
Besides anti CD 19 CAR-T cells, have been studied
the utility of other potential target antigens like CD 20, CD
30, ĸ light chain. Ramos et al. [45] reviewed the results ofclinical trials in order to identify a better treatment
alternative for patients with lymphoma. Even though, therate of disease remissions from the reviewed clinical trials
was not as expected, CAR T cells still remain a valid
therapy as the “one and done” treatment. I order toincrease the efficiency of CAR T cells, it is necessary toadopt alternative solutions to improve CAR T cells
function. Targeting checkpoint inhibition, inhibitory
cytokines or cells from tumor stroma may enhance are thealternative strategies used to inhibit the tumor immunesuppression.
Zhao, Chen et al. highlights the superior qualities ofsecond and third generations of T cells, associated with
CD28 or with a cytoplasmic signaling domain 4-1BB; thisassociation causing a higher proliferation rate andpersistence of T cells. Also, CD20 CAR T cells usage forpatients with DLBCC (diffuse large B cell lymphoma),showed promising results. In regard to CD30 CAR T cells,
there is clinical trial that reports a regression of disease
after receiving a conditioning chemotherapy prior CD30
CAR T cells infusion. CD30 is an antigen expressed in
DLBCL, in lymphoma with anaplastic large cells, primary
mediastinal B cell and peripheral T cell lymphoma, HL [44].
5. CAR T cells therapy in solid tumor
Even if adoptive cell therapy using chimeric antigen
receptor has encouraging results in treating hematologicalmalignancies, especially B cell malignancies, we cannot talkabout the same results when it comes to CAR T cells
treatment of solid tumor [46].
Because desired antigens aren’t often expressed just intumors, CAR T cells therapy determine severe toxicities.
Knochelmann and his colleagues described several clinical
trials and case reports regarding this type of immunotherapy
for solid tumor, focusing on side effects like liver toxicity inrenal cell carcinoma, the multi organ failure in CAR T cell
treatment against ERB2. Also, poor results were obtained ina trial with CEACAM5- CAR T cells for gastrointestinal
cancer, EGFR VIII in glioblastoma, HER2-based CAR insarcoma. Despite these challenging cases, recently has
been recorded success in treatment of glioblastoma withCAR T cell therapy [46].
Schmidts and Maus present in their review, article
studies that shows promising results in treatment of phase I
clinical trial of pediatric neuroblastoma with CART T cells
specific for GD2, phase II/III clinical studies for treatment
10with CAR T cells specific for HER2. Currently there are morethan 270 CAR T cells clinical trials registered at U.S.
National Library of Medicine, third of these studies
researching the use of solid tumors in solid tumor of CAR T
cells therapies [47].
Same results as Knochelmann, Schmidts and Maus was
described by Newick and his team [48].
Because of this poor results of CAR T cells therapy insolid tumor treatment, was identified some berriers involved in
failure of CAR T cells, such as structure of CARs, choice of
desired antigen, doses, frequency and way of administrationof CARs, survival on long-term in the environment of tumor
tissue, lymphodepletion treatment [49].

TILs THERAPY
1. What is TIL therapy?
Tumor infiltrating lymphocytes therapy is an adoptive
cell therapy, being an alternative approach to the CAR T
cells therapy [50].
For the first time, in 1863, was described the presenceof lymphoid cells in the structure of neoplastic tissue by
Rudolf Virchow, who hypothesized a link between tumor andthe presence of inflammation [51]. Years later, in 1969, thenotion of tumor infiltrating lymphocytes was introduce for the
first time by Wallace H. Clark Jr, to describe the immune
response of the host against cancer [50,52]. Tumor
infiltrating lymphocytes are considered to be lymphocytes
cells that are leaving the bloodstream and infiltrate thetumor, being into a direct contact with cancer cells. TILs
which are involved into this “defensive response” are formed
by T cells, B cells, natural killer cells, T regulatory cells,
dendritic cells, myeloid-derived suppressor cells andmacrophages [52,53]. Even though TILs are presented
inside the tumor, they are inactivated by the
immunosuppressive tumor environment. In vivo,
immunosuppressive factors such as cytotoxic T lymphocyte
antigen 4 (CTLA4), lymphocyte activation gene 3 protein(LAG 3), programmed cell death protein 1 (PD1), T cell
immunoglobulin and mucin domain-containing protein 3(LAG3), enables TILs expansion and antitumor activity [54].
Because of their property of recognizing tumor cells
antigens, TILs are used as an alternative immunotherapy,
especially in treating melanoma [24]. Doctor Steven
Rosenberg and his colleagues from Surgery Branch of the
National Cancer Institute were the pioneers who introduced
the benefit of TILs as adoptive cell therapy, especially intreatment of melanoma. During years of clinical trials
coordinated by Rosenberg and his team, have beenhighlighted the importance of this novel immunotherapy forthe treatment of patients with melanoma, which will be
detailed later [55].
Fiziologia - Physiology • 2018.28.1(95)In order to administrate TILs as an adoptive cell therapy,
first, this type of lymphocytes must be isolated andexpended. Tumor masses are surgically resected,
fragmented and the cells are placed into enriched T cell
growth factors well, such as interleukin – 2 (IL-2). After
activation, T cells that present the desired TCR are selected,
transferred into another culture medium for their expansion
and then, infused back to the patient [23,54]. This type ofT cells has the ability to recognize the antigen expressedon the surface of tumor cells, which is associated with
MHC class I and II molecules, the first antigen associatedwith tumor described was melanoma associated antigen 1(MAGEA1) (Figure 5) [54].

Fig. 5. TILs therapy

The combination of TILs therapy with a preparative
lymphodepletion prior infusion with transferred with T cells,
showed an enhanced persistence of TILs. Lymphodepletion
may be accomplished using chemotherapy or total body
irradiation (TBI) [54]. There are many studies that shows theimportance of this treatment, having the role to eliminate
regulatory T cells and competing immune elements(cytokine sinks) having as purpose enhancing the efficiency
of TILs immunotherapy; preparative lymphodepletion having
an important role in clinical results of all adoptive T cells
therapies [51,56]. Also, the association with interleukin-2 cell
growth factor determined a longer eradication of cancer [54].
There are many clinical trials that shows promising
results of this TILs therapy in eradicating tumor cells in many
types of cancer such as cervical tumor, colorectal cancer,
breast cancer [24], but, its potential utility has been
analyzed, especially, in clinical trials involving patients withmelanoma. Also, there are studies that shows the role of
TILs as a predictive and prognostic biomarker in tumors [52].
2. TILs therapy in solid tumor
Malignant Melanoma
Even though have been developed therapeutic strategies
which are currently used in melanoma treatment (ipilinumab,
nivolumab, pembrolizumba), there is an increasing need to
Fiziologia - Physiology • 2018.28.1(95)research alternative therapies with better results. The firstattempt was made by Doctor Rosenberg [57].
Rosenberg with his team were the pioneers in using
TILs as an alternative therapy. They showed the possibility
to determine regression of tumors by using antigen specific
T cells that are found infiltrated in solid tumor tissues (3).
They used this principle in order to study the efficiency ofthis therapy on patients with melanoma, by conducting aclinical trial between 1988 and 1994. In this study a numberof 86 patients were enrolled. All of them were infused with
TILs cells and high dose of IL-2 after a lymphodepleting
conditioning. From 86 patients, 34% of them exhibited
partial or complete remissions. Of the 29 patients thatshowed an objective response, only five of them achieved
complete remission [56, 58].
Another study has been conducted in 2008 for a bettercharacterization of the efficiency of different
lymphodepletion techniques, used in combination with TILs
and IL-2 therapy. Total body irradiation (TBI) andchemotherapy were analyzed. Best results were associatedwith using 12 Gy TBI. The toxic effects were associated toIL-2 and TBI therapies [59].
Side effects of TILs therapy are caused by the
myeloablative chemotherapy or by the Interleukin-2 (IL-2).
In general, these adverse effects appear during or after
treatment [59].
Ellebeak and her colleagues conducted a clinical trial from
June 2009 to June 2011 and 11 patients with metastaticmelanoma were included in the study. Out of 11 patients, justfor one patient TILs culture wasn’t successful, 2 patientsdeveloped brain metastases during TIL culture and other 2
patients had a rapid progression of the disease after thesurgical intervention of tumor resection. Therefore, only 6
patients remained eligible for the study. Of these 6 patients, acomplete response achieved 2 patients, for another 2 theirdisease remained stable and for other 2 patients, tumor
progressed in a rapid way. Prior infusion with TILs, all patients
received a treatment based on administration of IL-2. Due tolymphodepleting chemotherapy received, toxicity related
symptoms were described [60].
There are many other clinical trials that shows promising
results in melanoma treatment with tumor infiltrating
lymphocytes, these aspects have been highlighted in otherclinical trials (such as: Dudley et all in 2008, Basser and hiscolleagues in 2010 and 2013, another clinical trial conductedby Rosenberg in 2011) [6,52,61-63].
Because of these results obtained for melanoma, there
is encouraged using this immunotherapy in other types oftumors [52].
TILs role in renal carcinoma
During the last decades, have been published several
reviews and clinical trials which presented results that
couldn’t demonstrate the antitumor function of TIL [64]. Also,at the same conclusions, reached Baldan and his team andSchachted et al. [52].
11Even though it has been difficult to prove the efficiency
anti-tumor activity of TILs, there are studies that shows theutility of TIL in prediction of the disease evolution, bystudying the immune profile of immune cells which infiltrated
the tumor [65,66].
Overall, TIL therapy can be take into consideration as
an alternative therapy, but more clinical trials are necessary
in order to prove its success in treatment of renal cell
carcinoma [52].
TILs in breast cancer
In their study, Lee et al., successful isolated and expended,
ex vivo, TIL cells which derived from all types of breast cancer
tissues. Also, expended TIL cells have been shown anti-tumor
reaction, in vivo, in a xenograft mouse model [53].
Many other studies presented by Badalamenti in his
review, showed the potential role of TIL as a predictive
biomarker in breast cancers [66].
TILs and gastrointestinal cancers
Even though gastrointestinal cancer is a rare type ofcancer, several studies have been conducted in order toobtain more biological information for a better prognosis,
diagnosis of this tumor [66].
Also, Turcotte et al. demonstrated in their studies theachievement of a successful TILs culture and expansion toa sufficient number of cells which can be used in clinical
trials [67, 68].
3. TILs immunotherapy limitations
Even though all studies have shown promising results inusing TIL as an alternative immunotherapy, there are someissues (Table III) to overcome in order to make thistreatment a feasible one [69].
Table III. Limitations of TILs immunotherapy
Variable successful rates
Relatively high costs for production of this treatment
because it is personalized for every patient
Too long production time (> 1 month), especially when
there are patients with a rapidly progressive type of tumor
Highly specialized facilities that requires highly trained
specialists and extensive investments
Legend: adapted from Rohaan MW et al. J Immunother Cancer.
2018;6(1):102. (71)

CONCLUSIONS AND FUTURE PERSPECTIVES
Cancer is one of the most complex, frequent disease and,because of this, there are under development a series of novel
immunotherapies in order to improve patient’s condition [58].
12

Because of the limited effect of the classical therapies,
there is a great desire in searching alternatives treatmentswith a better outcome. One of the alternative strategies thatprove its efficiency is immunotherapy, is using the patient
immune system in order to make fight against tumor cells.
Adoptive T cells therapy, cancer vaccines, immune
checkpoint blockade, immunomodulatory agents may
represent an alternativein cancer treatment and theiruses in clinical trials [55].
In order to obtain the desired results using
immunotherapy as main treatment it is important to take inconsideration the patient status, type of tumor, the purposeof the therapy, as well as tumor classification that dictates
the available time to obtain desired clinical results [58].
From all those immunological therapeutic strategies, we
tried to highlight the importance of adoptive cell therapy(CAR T cells, TILs) in treating patients with blood
malignancies and solid tumor.
Evan if CAR T cells therapy is making steps in changing
the management of blood malignancies, there are someissues in applying successfully this therapy to solid tumors[24].
In 2018, have been successful approved by USA FDA
two types of CAR-T cell therapies: YESCARTA andKYMRIAH. Both of them have the role to attack B – cells
malignancies (leukemia and lymphoma) [70].
In conclusion, with this review article, we wanted tofocus on the potential benefits of treating various types oftumors using novel immunotherapies such as adoptive celltransfer and, also, we expect a faster improvement of thesetechnologies in order to solve the problems we are now
facing in clinical trials.
In future, it will be important to explore other methods todetermine an improvement of the ablation of immune
system in order to obtain promised results in cancer studies,by using ACT technologies. Also, the ability to identify
patient specific tumor antigens, through DNA sequencing
techniques, will revolutionize the immunotherapy in cancer[50].
Acknowledgement: This work was supported by the grant“Chimeric Antigen Receptor Targeted Oncoimmunotherapy with
Natural Killer Cells (CAR-NK)”, POC 92/09/09/2016, ID: P_37_786,
MySMIS code: 103662.

REFERENCES
1. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary,
Adaptive, and Acquired Resistance to Cancer Immunotherapy.
Cell. 2017;168(4):707-723.
2. Prager GW, Braga S, Bystricky B, et al. Global cancer control:
responding to the growing burden, rising costs and inequalities
in access. ESMO Open. 2018;3(2):e000285.
3. Miliotou AN, Papadopoulou LC. CAR T-cell Therapy: A New
Era in Cancer Immunotherapy. Curr. Pharm. Biotechnol.
2018;19:5-18.
Fiziologia - Physiology • 2018.28.1(95)4. Zhang H, Chen J. Current status and future directions ofcancer immunotherapy. J Cancer. 2018;9(10):1773-81.
5. Ascierto PA, Daniele B, Hammers H, et al. Perspectives in
immunotherapy: meeting report from the "Immunotherapy
Bridge", Napoli, November 30th 2016. J Transl Med.
2017;15(1):205.
6. Borghaei H, Smith MR, Campbell KS. Immunotherapy ofcancer. Eur J Pharmacol. 2009;625(1-3):41-54.
7. Decker WK, da Silva RF, Sanabria MH, et al. Cancer
Immunotherapy: Historical Perspective of a Clinical Revolution
and Emerging Preclinical Animal Models. Front Immunol.
2017;8:829.
8. Ventola CL. Cancer Immunotherapy, Part 1: Current
Strategies and Agents. P&T. 2017;42(6):375-383.
9. Coulson A, Levy A, Gossell-Williams M. Monoclonal
Antibodies in Cancer Therapy: Mechanisms, Successes andLimitations. West Indian Med J. 2015;63(6):650-4.
10. Waldmann TA. Cytokines in Cancer Immunotherapy. Cold
Spring Harb Perspect Biol. 2018 Dec 3;10(12).
11. Lee S, Margolin K. Cytokines in cancer immunotherapy.
Cancers (Basel). 2011;3(4):3856-93.
12. Guo C, Manjili MH, Subjeck JR, Sarkar D, Fisher PB, Wang
XY. Therapeutic cancer vaccines: past, present, and future.
Adv Cancer Res. 2013;119:421-75.
13. Levine BL, Miskin J, Wonnacott K, Keir C. Global
Manufacturing of CAR T Cell Therapy. Mol Ther Methods Clin
Dev. 2016;4:92-101.
14. Zijun Z, Yu C, Ngiambudulu MF, Yuanqing Z, Minhao W. The
application of CAR-T cell therapy in hematologicalmalignancies: advantages and challenges. Acta Pharm Sin B.
2018; 8(4):539-551.
15. Xia AL, Wang XC, Lu YJ, et al. Chimeric-antigen receptor T(CAR-T) cell therapy for solid tumors: challenges andopportunities. Oncotarget. 2017;8(52):90521-90531.
16. Aaron J. Smith, John Oertle, Dan Warren, Dino Prato.
Chimeric antigen receptor (CAR) T cell therapy for malignant
cancers: Summary and perspective. Journal of Cellular
Immunotherapy. 2016; 2(2):59-68.
17. Zhang C, Liu J, Zhong JF, Zhang X. Engineering CAR-T cells.
Biomark Res. 2017; 5:22.
18. Chmielewski M, Abken H. TRUCKs: the fourth generation of
CARs. Expert Opin Biol Ther. 2015; 15(8):1145-1154.
19. Sharpe M, Mount N. Genetically modified T cells in cancer
therapy: opportunities and challenges. Dis Model Mech.
2015;8(4):337-50.
20. Graham C, Hewitson R, Pagliuca A, Benjamin R. Cancer
immunotherapy with CAR-T cells – behold the future. Clin
Med. 2018;18(4):324-328.
21. Chu F, Cao J, Neelalpu SS. Versatile CAR T-cells for cancer
immunotherapy. Contemp Oncol (Pozn). 2018;22(1A):73-80.
22. Ping Y, Liu C, Zhang Y. T-cell receptor-engineered T cells forcancer treatment: current status and future directions. Protein
Cell. 2017;9(3):254-266.
23. Rosenberg SA. Cell transfer immunotherapy for metastatic
solid cancer--what clinicians need to know. Nat Rev Clin
Oncol. 2011;8(10):577-85.

Fiziologia - Physiology • 2018.28.1(95)24. Eisenberg V, Hoogi S, Shamul A, et al. T-cells “à la CAR-T(e)”– Genetically engineering T-cell response against cancer. Adv
Drug Deliv Rev. 2019.
25. Zhao J, Lin Q, Song Y, Liu D. Universal CARs, universal T
cells, and universal CAR T cells. J Hematol Oncol. 2018;
11:132.
26. Carroll D. Genome engineering with zinc-finger nucleases.
Genetics. 2011;188(4):773-82.
27. Joung JK, Sander JD. TALENs: a widely applicable technology
for targeted genome editing. Nat Rev Mol Cell Biol.
2012;14(1):49-55.
28. Tsai SQ, Joung JK. Defining and improving the genome-wide
specificities of CRISPR–Cas9 nucleases. Nat Rev Genet.
2016;17(5):300-12.
29. Tomuleasa C, Fuji S, Berce C, et al. Chimeric Antigen
Receptor T-Cells for the Treatment of B-Cell Acute
Lymphoblastic Leukemia. Front Immunol. 2018;9:239.
30. Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: acomprehensive review and 2017 update. Blood Cancer J.
2017;7(6):e577.
31. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptormodified T cells for acute lymphoid leukemia. N Engl J Med.
2013;368(16):1509-1518.
32. Shah NN, Stetler-Stevenson M, Yuan CM, et al. Minimal
Residual Disease Negative Complete Remissions Following
Anti-CD22 Chimeric Antigen Receptor (CAR) in Children andYoung Adults with Relapsed/Refractory Acute Lymphoblastic
Leukemia (ALL). Blood. 2016;128(22).
33. Huang L, Wang N, Li C, CaoY, et al. Sequential Infusion of
Anti-CD22 and Anti-CD19 Chimeric Antigen Receptor T Cells
for Adult Patients with Refractory/Relapsed B-Cell Acute
Lymphoblastic Leukemia. Blood. 2017;130(1).
34. Hus I, Roliński J. Current concepts in diagnosis and treatmentof chronic lymphocytic leukemia. Contemp Oncol (Pozn).
2015;19(5):361-7.
35. Hallek M. Chronic lymphocytic leukemia: 2017 update on
diagnosis, risk stratification, and treatment. Am J Hematol.
2017;92:946–965.
36. Zou Y, Xu W, Li J. Chimeric antigen receptor-modified T celltherapy in chronic lymphocytic leukemia. J Hematol Oncol.
2018;11(1):130.
37. Fraietta JA, Lacey SF, Orlando EJ, et al. Determinants of
response and resistance to CD19 chimeric antigen receptor(CAR) T cell therapy of chronic lymphocytic leukemia. Nat
Med. 2018;24(5):563-571.
38. Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen
receptor T cells persist and induce sustained remissions in
relapsed refractory chronic lymphocytic leukemia. Sci Transl
Med. 2015;7(303):303ra139.
39. Ormhøj M, Bedoya F, Frigault MJ, Maus MV. CARs in the Lead
Against Multiple Myeloma. Curr Hematol Malig Rep.
2017;12(2):119-125.
40. Ghosh A, Mailankody S, Giralt SA, et al. CAR T cell therapy
for multiple myeloma: where are we now and where are weheaded?. Leuk Lymphoma. 2018;59(9):2056-2067.
41. Berahovich R, Zhou H, Xu S, et al. CAR-T Cells Based on
Novel BCMA Monoclonal Antibody Block Multiple Myeloma
Cell Growth. Cancers (Basel). 2018;10(9):323.
13

42. Xu J, Wang Q, Xu H, et al. Anti-BCMA CAR-T cells fortreatment of plasma cell dyscrasia: case report on POEMS
syndrome and multiple myeloma. J Hematol Oncol.
2018;11(1):128.
43. Cho SF, Anderson KC, Tai YT. Targeting B Cell Maturation
Antigen (BCMA) in Multiple Myeloma: Potential Uses of
BCMA-Based Immunotherapy. Front Immunol. 2018;9:1821.
44. Aisenberg, A. C. Historical review of lymphomas. Br J
Haematol. 2000;109(3):466-476.
45. Ramos CA, Heslop HE, Brenner MK. CAR-T Cell Therapy for
Lymphoma. Annu Rev Med. 2015;67:165-83.
46. Knochelmann HM, Smith AS, Dwyer CJ, et al. CAR T Cells in
Solid Tumors: Blueprints for Building Effective Therapies.
Front Immunol. 2018;9:1740.
47. Schmidts A, Maus MV. Making CAR T Cells a Solid Option for
Solid Tumors. Front Immunol. 2018;9:2593.
48. Newick K, O'Brien S, Moon E, Albelda SM. CAR T Cell
Therapy for Solid Tumors. Annu Rev Med. 2017;68(1):139152.
49. D'Aloia MM, Zizzari IG, Sacchetti B, et al. CAR-T cells: the long
and winding road to solid tumors. Cell Death Dis.
2018;9(3):282.
50. Sackstein R, Schatton T, Barthel SR. T-lymphocyte homing:an underappreciated yet critical hurdle for successful cancer
immunotherapy. Lab Invest. 2017;97(6):669-697.
51. Geukes Foppen MH, Donia M, Svane IM, Haanen JB. Tumorinfiltrating lymphocytes for the treatment of metastatic cancer.
Mol Oncol. 2015;9(10):1918-35.
52. Lee N, Zakka LR, Mihm MC, Jr, Schatton T. Tumour-infiltrating
lymphocytes in melanoma prognosis and cancer
immunotherapy. Pathology. 2016;48(2):177–87.
53. Lee HJ, Kim YA, Sim CK, et al. Expansion of tumor-infiltrating
lymphocytes and their potential for application as adoptive celltransfer therapy in human breast cancer. Oncotarget.
2017;8(69):113345-59.
54. Restifo NP, Dudley ME, Rosenberg SA. Adoptive
immunotherapy for cancer: harnessing the T cell response.
Nat Rev Immunol. 2012;12(4):269-81.
55. Lizée G, Overwijk WW, Radvanyi L, et al. Harnessing thePower of the Immune System to Target Cancer. Annu Rev
Med. 2013;64(1):71-90.
56. Muranski P, Boni A, Wrzesinski C, et al. Increased intensity
lymphodepletion and adoptive immunotherapy--how far can
we go?. Nat Clin Pract Oncol. 2006;3(12):668-81.
57. Lee S, Margolin K. Tumor-infiltrating lymphocytes inmelanoma. Curr Oncol Rep. 2012;14(5):468-74.
58. Alatrash G, Jakher H, Stafford PD, Mittendorf EA. Cancer
immunotherapies, their safety and toxicity. Expert Opin Drug
Saf. 2013;12(5):631-645.

14

59. Dudley ME, Yang JC, Sherry R, et al. Adoptive cell therapy forpatients with metastatic melanoma: evaluation of intensive
myeloablative chemoradiation preparative regimens. J Clin
Oncol. 2008;26(32):5233-9.
60. Ellebaek E, Iversen TZ, Junker N, et al. Adoptive cell therapy
with autologous tumor infiltrating lymphocytes and low-doseInterleukin-2 in metastatic melanoma patients. J Transl Med.
2012;10:169.
61. Besser MJ, Shapira-Frommer R, Treves AJ, et al. Clinicalresponses in a phase II study using adoptive transfer ofshort-term cultured tumor infiltration lymphocytes inmetastatic melanoma patients. Clin Cancer Res.
2010;16(9):2646–2655.
62. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete
responses in heavily pretreated patients with metastaticmelanoma using T-cell transfer immunotherapy. Clin Cancer
Res. 2011;17(13):4550–4557.
63. Besser MJ, Shapira-Frommer R, Itzhaki O, Treves AJ, Zippel
DB, Levy D, Kubi A, Shoshani N, Zikich D, Ohayon Y,
Ohayon D, Shalmon B, et al. Adoptive transfer of tumorinfiltrating lymphocytes in patients with metastaticmelanoma: intent-to-treat analysis and efficacy after failure
to prior immunotherapies.
Clin Cancer Res.
2013;19(17):4792–4800.
64. Shablak A, Hawkins RE, Rothwell DG, Elkord E. T cell-based
immunotherapy of metastatic renal cell carcinoma: modest
success and future perspective. Clin. Cancer Res.
2009;15(21):6503–6510.
65. Geissler K, Fornara P, Lautenschläger C, et al. Immune
signature of tumor infiltrating immune cells in renal cancer.
Oncoimmunology. 2015;4(1):e985082.
66. Badalamenti G, Fanale D, Incorvaia L, et al. Role of tumorinfiltrating lymphocytes in patients with solid tumors: Can adrop dig a stone?. Cell Immunol. 2018.
67. Turcotte S, Gros A, Hogan K, et al. Phenotype and function of
T cells infiltrating visceral metastases from gastrointestinal
cancers and melanoma: implications for adoptive cell transfer
therapy. J Immunol. 2013;191(5):2217-25.
68. Turcotte S, Gros A, Tran E, et al. Tumor-reactive CD8+ T cells
in metastatic gastrointestinal cancer refractory to
chemotherapy. Clin Cancer Res. 2014;20(2):331–343.
69. Rohaan MW, van den Berg JH, Kvistborg P, Haanen JBAG.
Adoptive transfer of tumor-infiltrating lymphocytes inmelanoma: a viable treatment option. J Immunother Cancer.
2018;6(1):102.
70. Salmikangas P, Kinsella N, Chamberlain P. Chimeric
Antigen Receptor T-Cells (CAR T-Cells) for Cancer
Immunotherapy - Moving Target for Industry?. Pharm Res.
2018;35(8):152.

Fiziologia - Physiology • 2018.28.1(95)TERAPIA CU CELULE CAR-T VS. TIL:
VIITORUL IMUNOTERAPIEI ÎN CANCERREZUMATLa nivel mondial, cancerele sunt unele dintre principalele cauze de deces, iar tratamentul convențional are propriile
limitări. Cercetările din domeniul imunoterapiei se concentrează pe descoperirea unor alternative terapeutice fezabile
pentru tratarea acestei patologii.
În cancere, imunoterapia are rolul de a spori efectul antitumoral al celulelor imune implicate în acest proces. În funcție
de antigenul țintă, efectele adverse ale acestei terapii pot varia de la reacții locale și ușoare, la cele sistemice și mai
severe.
Principiul imunoterapiilor cu celule CAR T și TILs se bazează pe folosirea celulelor T, care sunt specifice pentru unanumit antigen și reinfuzarea înapoi în pacient dupa ce aceste celule au fost multiplicate ex vivo, pentru a determina
distrugerea tumorii. Asocierea acestor terapii cu un regim de depleție limfocitară și cu administrarea factorului IL-2 decreștere a celulelor T determină un efect puternic asupra pacienților.
În cadrul acestui articol, vom face o prezentare generală a terapiei cu celule CAR T și a terapiei cu TIL, descriind
principiile acestor imunoterapii, aplicațiile clinice, precum și avantajele, dezavantajele și perspectivele acestora.
Key words: celule CAR-T, TILs, imunoterapii, cancer

Fiziologia - Physiology • 2018.28.1(95)15FACULTY PERCEPTION FOR THE NEED OF CHANGE
IN I YEAR MBBS INDIAN PHYSIOLOGY PRACTICALCURRICULUMSMITA R SORTE1, SACHIN B RATHOD2
1Assistant Professor, Department of Physiology, Shri Shankaracharya Institute of Medical Sciences, Bhilai, Chhattisgarh, India

2Assistant Professor, Department of Physiology, Shri Shankaracharya Institute of Medical Sciences, Bhilai, Chhattisgarh, India.

ABSTRACT
Indian medical curriculum differs from other foreign universities. In India, Bachelor of Medicine and Bachelor of Surgery(MBBS) is 5½ year professional course, in which physiology is 1 st-year MBBS subject. Physiology deals with teaching thebasic principles of functioning of various system of body. Indian physiology Practical syllabus includes four sections Haematology, Experimental-Amphibian practical, human experiments and basic clinical examination. This syllabus wasformulated many years back which has not been revised. Physiology is the base of medicine, so physiology curriculum
should be well-designed to build basic clinical concept that can be applied in medicine practice. Graduate medical education
regulation, long-term goal is to get the qualified doctor for the better patient care health system. But alignment is not seenin curriculum and the physiology practical syllabus. So this study was conducted on 330 teaching faculty of India to know
their perspective about the need of change in I year MBBS Indian physiology practical curriculum. Our study found thatmany topics have no clinical relevance. Student gained irrelevant knowledge which has no future clinical use. Those
topics should be replaced by newer practicals and demonstration. Teaching faculty staff suggested early clinical exposure,
simulation experiments, basic of research and healthy lifestyle practice should be inculcated in the newer syllabus.
Short Running Title: Faculty perception for the need of change in I year MBBS Indian physiology practical curriculum
Keywords: curriculum, physiology syllabus, medical education, MBBS.

INTRODUCTION
Curricula” is two wheeled chariot drawn by horse andcurriculum is the path or the course. The curriculum isplanned educational experience [1]. Indian medical
curriculum differs from other foreign universities. Indian
medical council act was established in 1933 under which
Medical Council of India was established in 1934 [2]. The
act was reconstituted in 1956 [3] and its first, second andthird schedule was formed later on. The amendment wasadded in 1993 [4], 2011 [5], 2012 [6] and 2016 [7]. In 1997,
Graduate medical education regulation (GMER) was
published in part III, section- 4 [8] which was modified manytimes, and the latest modification was done in May 2018.
In India, Bachelor of Medicine and Bachelor of Surgery(MBBS) is a 5½ year professional course. In the first year,
the preclinical subjects – Anatomy, Physiology, andBiochemistry are taught for the duration of 1 year. The

Second year includes – Pathology, Microbiology,
Pharmacology and Forensic Medicine and toxicology
covered in the duration of 1 and ½ year. The third year
includes PSM, Ophthalmology, and ENT in the duration of 1
year and final year includes Medicine, Surgery, Pediatrics
and Obstetrics & Gynecology in the duration of 1 year. It isfollowed by 1 year of compulsory clinical rotator internship.
Physiology is basic science subject taught in 1st MBBS.
It teaches the basic principles of functioning of the various
system of the body. Graduate medical curriculum is oriented
towards training students to undertake the responsibilities ofa physician of first contact who is capable of looking after
the preventive, promotive, curative & rehabilitative aspect of
medicine. According to GME regulation goal of teaching
physiology is to providing the student comprehensive
knowledge of the normal functions of the organ systems of
the body to facilitate an understanding of the physiologicalbasis of health and disease [8].

Received April 15th 2018. Accepted May 21st 2018. Address for correspondence: Dr Sachin B Rathod, Department of Physiology, Shri
Shankaracharya Institute of Medical Sciences, Junwani, Bhilai, India; Phone: +91-9407796105, +91-9423409931, e-mail:drsuchinrat10@gmail. Name of department to which work is attributed: Department of Physiology, Rural Medical College, Loni, PIMS,
Ahmednagar, Maharashtra, India

16

Fiziologia - Physiology • 2018.28.1(95)Process objectives of teaching physiology are - at theend of the course, the student will be able to: (1) Explain
the normal functioning of all the organ systems and theirinteractions for well-coordinated total body function. (2)Assess the relative contribution of each organ system to themaintenance of the milieu interior. (3) Elucidate thephysiological aspects of normal growth and development.
(4) Describe the physiological response and adaptations toenvironmental stresses. (5) List the physiological principles
underlying pathogenesis and treatment of disease [8].
Indian physiology Practical syllabus includes four
sections - Haematology, Experimental-Amphibian practical,
human experiments and basic clinical examination. Thissyllabus was formulated many years back which has notbeen revised. Curriculum hypertrophy or curriculomegaly is
the disease of curriculum described by Stephen
Abrahamson in 1978 [9]. It is caused due to the addition ofnewer knowledge in pre-existing knowledge. Ever
expanding syllabus has to be taught in limited duration ofteaching hours. So some part of older outdated syllabus
must be removed while newer syllabus should be regularly
added in the curriculum at some time intervals.
The curriculum should be aligned with the specificlearning objectives, the syllabus, teaching-learning
methods, and assessment. But this alignment is not seen inphysiology practical part of the curriculum. According to
GMER, learners objectives in practical skills are at the endof the course the student will be able to i) conduct
experiments designed for the study of physiologicalphenomena; ii) Interpret experimental/investigative data; iii)
Distinguish between normal and abnormal data derived asa result of tests which he/she has performed and observedin the laboratory.
The government of India had banned animal experiments
in 2012 [10] due to which animal dissection is not conductedin the teaching of experimental amphibian practicals. The
amphibian graphs are taught theoretically on basis ofexperiments conducted in past. This government rule leads tomisalignment of the curriculum with the skill learning objective(that students should be able to conduct experiments
designed for the study of physiological phenomena). This
makes it necessary to formulate new a skill learning objective
to fulfill the physiology curriculum need.
Physiology is the base of medicine, so physiology
curriculum should be well-designed to build basic clinicalconcept that can be applied in medical practice. Somestudies were conducted from students’ perspective of MBBS
curriculum which found many topics of physiology
curriculum to be irrelevant and obsolete [11, 12]. Anotherstudy was conducted on faculty perception of only
experimental physiology curriculum which also found thatamphibian experimental physiology is outdated and need tobe replaced by newer practicals. Our study was conducted
to find faculty perception about the need to change I year
MBBS physiology practical curriculum in India.

Fiziologia - Physiology • 2018.28.1(95)

METHOD AND MATERIALA descriptive cross-sectional study was conducted in the
Department of Physiology, RMC Loni, Ahmednagar,
Maharashtra, India. The study was approved by IEC. The
structured organized online survey was conducted on
website- Survey Monkey. The questionnaire was validated
by experts. Qualitative questions were evaluated by 3 points
Likert scale. Internal reliability of question was evaluated by
Cronbach’s alpha. Open-ended question to obtain theopinion of faculty regarding new physiology topics to be
added in practical syllabus was also asked.
Physiology faculty of different cadre from various
colleges of India was informed about the survey bytelephones and emails, where the link of the survey was
attached. Consent of participant was taken as the firstquestion and then they were allowed to participate in thesurvey. Data was collected from 330 physiology faculty inthe duration of 6 months.
Statistical analysis
Data was analyzed and the result was calculated aspercentage. No statistical test was applied.

RESULTS
Total 330 teaching faculty participated in the study.
Table I shows the academic cadre or rank of participants.
Table I. The academic personnel or rank of participants

1
2
3
4
5

Academic personnel
Dean / Principal /HODProfessor
Associate Professor /ReaderAssistant Professor /Lecturer
Tutor / demonstrator
Total

Percentage

Number

11.63

57

4.65

22

11.63

48

55.81

138

16.28
100%

65
330

Importance of Haematology Practicals was asked toteaching faculty (Q. No 2 Do u thinks Haematology
Practical’s should be removed from Physiology Practical
Syllabus?). According to 12.24% (40) teaching staff feelsthat all Haematology tests are done by automated machines
in clinical practice so Haematology Practicals should be
removed from Physiology Practical Syllabus.
According to 34.69% faculty Haematology Practical’s
should not be removed from Physiology Practical Syllabus
as they are of clinical significance. Faculty feels that in
Haematology practical we are not emphasizing the17techniques but we teach the students to correlate thehaematological finding with clinical scenario. In
Haematology, the student can appreciate blood cell which
can be utilized to understand and diagnose the abnormalityof blood cell in pathology. So the applied aspect ofHaematology should be the part of physiology practicals.
When student (future doctor) practice in rural areas where
automated machines are not available, these oldhaematological test and techniques are useful for diagnosis
of certain diseases.
While 53.06% teaching faculty thinks that, newer
Haematology techniques should replace older techniques.
They suggested the addition of platelet count and genetic
practical’s like extraction of chromosomes from WBC for
mapping. The principle of research and curiosity should be
inculcated by Haematology practical’s.
The significance of amphibian experimental physiology
was asked in Question no 3 (Do u think Experimental
Physiology (Amphibian Graphs) should be removed from
Syllabus?)
40.63 % teaching staff consider that Experimental
Physiology (Amphibian Graphs) should be removed fromsyllabus as it is of no clinical significance. The relevance of
these practicals is decreased as the dissection of animal isbanned. 31.25 % teaching staffs think that Experimental
Physiology (Amphibian Graphs) should not be removed
from syllabus but its marks weight-age should bedecreased, or it should be integrated with Pharmacology.
28.13% teaching staff think that Experimental
Physiology (Amphibian Graphs) should not be removed
from the practical syllabus. Amphibian experiments show
the basic invented of Physiology subject. “I hear and I forget.
I see and I remember. I do and I understand.” Is a common
Chinese proverb, which can be also applicable inexperimental Physiology. Unless animal (frog) dissections
are done, mere graphs are not understood by I year MBBS
students. As animal dissection is banned by the governmentof India, Physiology society should seriously consult withanimal protection organization and get permission todissection animal for medical and research centers. Though
animal killing should not be practiced, Frogs may bereplaced with other easily replaceable lab animals. As it
forms the basis of the physiology, newer animation and soft
copy of the experiment can be shown to the students or it
can be replaced with computer simulations. Good software’s
like COMPU FROG can be used and faculties should betrained to use such software.
The implication of human experiments was asked inquestion no 3.(Are human practical’s like Ergography/
stethography/ Pulmonary function test etc required in
Human physiology practical’s?)
11 % teaching staff thinks that Human physiology
practical’s syllabus requires no modifications. 5% teaching
staff thinks that Human physiology practicals are outdated
practical’s of no clinical significance. Some experiments like
perimetry, spirometry should be removed. But 84% faculty
18

appreciates the significance of human experiments but
suggest modification in experiments, like the use ofcomputerized / simulation techniques. Some faculty
suggests the addition of exercise physiology related
experiments in this section.
Opinion regarding addition of Neurophysiology
experiments was asked in question no 4 (Do u think that
Neurophysiology experiments like NCV, BERA, VEP, EMG
etc should be included in physiology practical?)
79.79% teaching staff thinks that Neurophysiology
experiments like NCV, BERA, VEP, EMG etc should be
included in physiology practicals. With the progressive
scope of research for neurophysiology, yoga, andmeditation, it becomes essential to learn basics in I MBBS.
Some staff suggested it should be taught in form of
demonstration or integrated with theory teachings.
Demonstration in the clinical setting would expose students
to the patients which will help to understand their clinicalrelevance. 13.83% teaching staff thinks that
Neurophysiology experiments like NCV, BERA, VEP, EMG
etc should not be included in physiology practical’s, whereas
6.38% teaching staff did not express their view in thiscontext.
The open-ended question was asked (What otherexperiments can be added to Physiology practical syllabus forfirst yr MBBS students?). Results were tabulated in Table II.
Table II. The answers of open ended questions
Topics1

Hematology

2

Amphibian

3

Human

4

ClinicalOpinions for adding topics in physiology
practical curriculum
Clinically oriented experiments should
be added. Discussion of Computerizedhaemogram should be done. Visit toblood banks and pathology labs should
be done.
Replace amphibian experiments byother experiments
Computerized
perimetry,
Computerized PFT, pulse oximetry,
Blood pressure alteration with stress,
cold etc. Vision test, Memory/cognitive
test, Tonometry, Endoscopy, effect ofhypoxia on body functions, and otherenvironmental practical’s should beconsidered
More emphasis should be given toclinical examination and early exposure
to patients. It must be given more
marks distribution. In Early clinicalexposure students can learn todifferentiate normal from abnormal.
Comprehensive clinical history taking
and clinical examination of clinicalcases should include. They should bemaster of clinical examinations e.g.
General, CVS, RS, CNS and abdomen
Fiziologia - Physiology • 2018.28.1(95)5Experimentson yoga andmeditation

6

Radiology

7

Exercisephysiology

7

Neuro
physiology

8

Simulation
experiments

9Biochemical
experiments

10Diet and
Healthy
lifestyle11

Endocrine

12Biophysics

13
14

Reproductive
Assessment

examination. Examination of heartsound by electronic stethoscope,Phonocardiogram, Murmurs should be
added. Communication skills should be
included.
Compulsion of yoga and meditation to
students for thirty days to establish thebenefits and implementation among
students to better citizens of our country
Brief introduction and principles ofxrays,
ultrasound,
Doppler,
Echocardiography,CT
scan,Radionucleotide imaging and MRI.
There demonstration should beconsidered.
Treadmill test, bicycle Ergography,
cardiorepiratory fitness assessment,
exercise stress test.
Demonstration of Reaction time, ECG,
EEG, EMG, NCV, Autonomic function
testing- HRV and sleep study.
Simulation lab with latest equipments
for clinical skills, First aid techniques,
Cardio-Pulmonary
Resuscitation,
simulators for artificial respiration.
Simulation lab for renal physiology,
nerve muscle physiology, transport
across cell membrane.
Experiments based on Resting
membrane potentials e.g voltageclamp
technique.
Biochemical
Estimations using standard kitscomparing normal and patient samples.
Automated ELISA, colorimetric, PCR,
electrophoresis Hormonal assay, tests
based on Antigen-antibody reactions
may be included in the Physiology
curriculum
Basal Metabolic Rate calculation,
Estimation nutrition /diet prescriptions,caloric requirement and daily calories
burn.
Endocrine photos in form of cases tofind pathophysiology could increase theapplication of their knowledge
Calculation based biophysics logicalgraph/chart/photograph
Semen analysis
More problems based clinical learning;
less weightage should be given on
memorizing facts than learning
concepts, and increase viva andobjective questions marks while
decreasing theory marks.

Fiziologia - Physiology • 2018.28.1(95)DISCUSSION
Physiology curriculum must be designed with a longterm goal of better patient care and health practice system.
Even graduate medical education regulation aims to makestudents better doctors of tomorrow. But alignment is notseen in physiology curriculum and its syllabus which is also
perceived by the faculty members in our study. Due to thedaily addition of newer information and techniques, there iscurriculomegaly or hypertrophy which should be included in
the syllabus by time to time amendments.
The cadre of most of the faculty in our study is Assistantprofessor> tutors> HOD> Associate professor> Professor.
So we can consider the results are the opinion of young
budding teachers and researchers generation. According toour study, most part of physiology curriculum is outdated
and obsolete, which should be replaced by newer practicals
and demonstration. Study on faculty perspective by Dr.
paralikar [13], Dr. Narlawar [11] suggested parallel findings
whereas study on student’s perspective by Dr. Goyal [14]and Dr. Chawla [15] also suggested similar findings, thus
supports our study. Students complained that though they
have gained basic knowledge they had also learned too
much irrelevant knowledge in some areas.
The government of India had banned animal experiments,
due to which amphibian experimental syllabus has lost its
charm, making it a dull and bore section of the practicalsyllabus. Certain topics have no clinical relevance. Physiology
societies should find an alternative (simulation/videos) or
remove this section from the practical syllabus.
Majority of teaching faculty (53.06%) thinks that newer
hematology techniques should replace older techniques.
The principle of research should be inculcated byhematology practicals. A good number of teaching faculties(84%) appreciates the significance of human experiments
but suggest modification in experiments, like the use ofcomputerized / simulation techniques. 79.79% teaching staff
feels that Neurophysiology experiments like NCV, BERA,
VEP, EMG etc should be included in physiology practical’s.
Teaching faculty staff suggested early clinical exposureand many newer topics that should be added in the newer
curriculum. These topics are mostly clinically oriented
experiments. They are computerized perimetry,computerized PFT, pulse oximetry, Blood pressure
alteration with stress, vision test, Memory/cognitive test,
Tonometry, Endoscopy, effect of hypoxia on body functions,and other environmental practical’s, simulators for first aid
techniques, Cardio-Pulmonary Resuscitation, Brief
introduction of x rays, ultrasound, Doppler,
Echocardiography, CT scan and MRI. Treadmill test, bicycle
ergography cardiorespiratory fitness assessment, exercise
stress test, Reaction time, ECG, EEG, EMG, NCV,
Autonomic function testing- HRV and sleep study.
As lifestyle diseases are one of the major causes ofmortality and morbidity, one should also focus on practicing
a healthy lifestyle and healthy diet. The basic principle and19practice should be included in I year MBBS. Yoga andmeditation should also be taught and practiced. The doctor
is a researcher and so the seed of research should also be
sowed in IST year MBBS.

CONCLUSION
In fact practical’s help in understanding the underlying
physiological phenomenon. We learn faster and better byperforming the experiments. Thus the entire physiologicalphenomenon must be taught with practical demonstration.
Many of physiology practicals are outdated and useless. We
should focus on the current clinical scenario to teachstudents. SPICES model of curriculum organization should
be used in formulating the newer curriculum. It should beStudent-centered, Problem based learning, Integrated
teaching, Community based education, Elective andSystematic. It should facilitate horizontal and vertical
integration to link disparity between theory and practical.
Clinical training, research and principles of a healthy lifestyleand diet should start in first MBBS focusing on
professionalism, basic clinical skills and communication
skills. It is the responsibility of physiological bodies andsociety to consider the opinion of young teaching faculty anddevelop a new modified physiology practical curriculum forbetter future doctors.

REFERENCES
1. Curriculum Development for Medical Education [Internet].
Availablefrom:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074744/
2. Introduction | MCI India [Internet]. Available from:https://www.mciindia.org/CMS/about-mci/introduction
3. The Indian Medical Council Act, 1956 | MCI India [Internet].
Available from: https://www.mciindia.org/CMS/acts-amendments/
the-indian-medical-council-act-1956

20

4. Amendment to the Act | MCI India [Internet]. Available from:https://www.mciindia.org/CMS/actsamendments/amendment-to-the-act
5. IMC Amendment Act 2011 | MCI India [Internet]. Available
from: https://www.mciindia.org/CMS/acts-amendments/imcamendment-act-2011
6. IMC Amendment Act 2012 | MCI India [Internet]. Available
from: https://www.mciindia.org/CMS/acts-amendments/imcamendment-act-2012
7. IMC Amendment Act 2016 | MCI India [Internet]. Available
from: https://www.mciindia.org/CMS/acts-amendments/imcamendment-act-2016
8. Graduate Medical Education Regulations, 1997 | MCI India[Internet].
Availablefrom:https://www.mciindia.org/
CMS/rules-regulations/graduate-medical-educationregulations-1997
9. Abrahamson S. Diseases of the curriculum. J Med Educ. 1978
Dec; 53(12):951–7.
10. Govt bans use of live animals for education, research | India
News - Times of India [Internet]. Available from:https://timesofindia.indiatimes.com/india/Govt-bans-use-oflive-animals-for-education-research / articleshow / 12696452.cms
11. Perception of medical teachers towards existing graduate
medical education regulations 1997 | Narlawar | International
Journal of Community Medicine and Public Health [Internet].
Availablefrom:
http://www.ijcmph.com/index.php/ijcmph/article/view/499
12. Need for Changes in the Practical Physiology Curriculum of
Medical Undergraduates [Internet]. Available from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535342/
13. Paralikar S, Shah C. Faculty perceptions of the strengths,
weaknesses and future prospects of the current medical
undergraduate experimental physiology curriculum in Gujarat,
India. Indian J Physiol Pharmacol. 2015 Mar; 59(1):109–16.
14. TS H. Need for changes in the practical pharmacology
curriculum of medical undergraduates. Indian J Pharmacol.
2004 May 1;36(3):181.
15. Chawla O, Bhattacharjee M, Kansal NK. Students’ perspectiveof the MBBS Physiology curriculum. 2012;6:5.

Fiziologia - Physiology • 2018.28.1(95)IMPACT OF ISOTONIC HAND GRIP EXERCISE ON
BLOOD PRESSURE AND SYMPATHETIC RESPONSEIN PREHYPERTENSIVESSARAVANAN MURUGAN1, SINGH SK2
1Associate Professor, The Sarvajanik College of Physiotherapy, Rampura, Surat, Gujarat, India

2Head, Department of Physiology, Pramukh Swami Medical College, Gokulnagar, Karamsad, Gujarat, India

ABSTRACT
Background of the study: Physical exercise is one of the essential elements for controlling blood pressure. However,certain constraints like feasibility of exercise equipment and time have reduced the compliance of people towards
exercising. Isotonic hand grip (IHG) exercise can be considered an alternative to other forms of exercise if it could bestudied for the effects it has on blood pressure (BP). Hence, this study was conducted to determine and compare the shortterm effect of IHG exercise versus brisk walking (BW) on BP and cardiovascular reactivity in prehypertensives.
Methods: 60 volunteers with prehypertension (male–30; female–30) participated in this study. The study was conductedon three consecutive days: Day 1- Control or non-exercise, Day 2 –IHG exercise and Day 3 – BW. Baseline pre exercise
systolic (SBP) and diastolic blood pressure (DBP) and pulse rate (PR) of the participants were recorded on arrival followedby cold pressor test (CPT). This was followed by no exercise, isotonic hand grip exercise or brisk walking for 20 minutes
on day 1, 2 and 3 respectively. BP was recorded immediately after 20 minutes followed by CPT. Measurements were again
recorded after 1 hour in the same sequence on all three days. Repeated measures ANOVA (p<0.05) was used for analyzing
differences between pre exercise, immediate post exercise and 60 minutes post exercise BP, PR, mean arterial pressure(MAP) and Pulse pressure (PP). CPT measurements were also analyzed to find out the differences in response of
cardiovascular system to IHG exercise and BW.
Results: Among the female participants, significant differences were found in BP and PR measurements immediately after
exercise. IHG exercise showed significant reduction in PR (mean ±SD; -0.36±5.09), SBP (-0.33±4.87), DBP (-0.53±4.49),
MAP (-0.24±3.74) and PP (-0.86±5.75) as compared to BW which showed an increase in PR (20.20±11.75), SBP(12.00±5.88), DBP (3.76±4.85), MAP (6.51±4.01) and PP (8.23±7.06). However, after 60 minutes of exercise, no significant
differences in SBP, DBP, MAP and PP were observed to IHG exercise and BW, with only PR showing a significant reduction
to IHG exercise (-4.26±5.34) than BW (0.33±4.45). CPT response measured at baseline and 60 minutes post exercises
were not statistically significant on the two experiment days. However, immediate post exercise CPT response to BW wassignificantly higher (15.33±4.42) than IHG exercise (11.10±4.07)
Significant differences were found in PR, SBP, MAP and PP measurements immediately after exercise and that of preexercise baseline in male participants. IHG exercise showed significant reductions in SBP (-1.93±4.65), MAP (-0.82±4.07)
and PP (-1.66±4.43) as compared to BW which showed an increase in SBP (18.16±5.47), MAP (7.52±3.18) and PP(15.96±7.60). An increase in PR was observed on both exercise conditions with BW (14.73±4.51), significantly higher than
IHG exercise (2.20±3.77). No significant difference was found in DBP on both exercise days. Similarly, after 60 minutes of
exercise, no significant differences were observed in DBP and MAP to IHG exercise and BW. PR showed a significant
reduction to IHG exercise (-2.70±4.00) than BW (2.23±4.36). Significant reduction was also observed in SBP (-6.10±4.18)
and PP (-3.83±4.44) to IHG exercise than SBP (-2.96±3.47) and PP (-0.43±5.69) to BW.
CPT response measured at baseline and 60 minutes post exercises were not statistically significant on the two experimentdays. However, immediate post exercise CPT response to BW was significantly higher (17.00±4.26) than IHG exercise(12.03±4.27).
Conclusions: The findings suggest that 20 minutes of IHG exercise can be used as a cost effective and less time
consuming method for reducing BP levels in both male and female prehypertensive adolescents as compared to BW. It isalso found that acute IHG exercise appears to have a significant impact on BP responses to cold stress. Further studies toinvestigate the long term training effects of IHG exercise on BP are required.
Short Title: Blood pressure and sympathetic response to Hand grip exercise in Prehypertensives
Key words: Isotonic hand grip exercise, Cold pressor test, Prehypertension

Received April 26th 2018. Accepted May 22nd 2018. Address for correspondence: Dr. Saravanan Murugan, Associate Professor, The
Sarvajanik College of Physiotherapy, Rampura, Surat, Gujarat, India; phone: + 91-937 598 5609; e-mail: saravananmurugan77@gmail.com

Fiziologia - Physiology • 2018.28.1(95)21INTRODUCTION
Physical exercise is one of the essential elements forcontrolling BP. Physical exercise controls BP throughmultiple long-term mechanisms which include decrease insympathetic nerve traffic, potentiation of baroreceptor reflex,
reduced arterial stiffness, increase total systemic arterial
compliance, increase release of endothelium-derived nitricoxide and increase insulin sensitivity [1-3]. Recent evidence
also suggest that acute dynamic exercise result in transientchanges in physiological variables that lead to reduction in
BP for 12 to 16 hours following the exercise act [4]. However,the compliance of people towards exercise has not beenvery encouraging for healthcare professionals due to anumber of reasons like time, space and economic
constraints [5-9]. It is therefore necessary to provide an
exercise therapy which is feasible for people. Isotonic
handgrip exercise is a simple, cheap and feasible form ofphysical exercise which can be performed at the person’s
convenience at any time or place using simple equipment
like handgrip dynamometer. But, before we prescribe IHG
exercise to population it is essential to determine whether
IHG exercise actually tends to lower blood pressure to an
extent that is at least equivalent to the common form of
exercises like brisk walking which is prescribed and known
to have beneficial effect in reducing BP.
Cardiovascular reactivity hypotheses [10] have beenclosely associated with BP reactivity and individual
differences in such reactivity are prospectively related to
hypertension and coronary artery indices [11 12]. The coldpressor test (CPT), which measures the response of BP to
the stimulus of external cold, has long been a standard test
for characterization of sympathetic function and has been
documented to predict the subsequent risk of hypertension
in normotensive persons [12-14]. However, scant literature
is available which indicates the short term or long term
effects of IHG exercise on BP and cardiovascular reactivity
neither in normotensives nor in prehypertensives.
The current study is therefore designed to study andcompare the short-term effects of IHG exercise on BP andcold pressor response with the short term effects of BW in
Prehypertensives.

METHODSThis repeated measures study design included 60
volunteers (30 males and 30 females) in the age group of
18-25, diagnosed with prehypertension; those in the 120–
139/80–89 mmHg BP [15], from The Sarvajanik College ofPhysiotherapy, Surat. Untrained participants of all socioeconomic class and falling under the normal Body Mass
Index (BMI) range, with prehypertension were included in
the study. Participants were excluded from the study if they
were smokers or present with any chronic illness or chronic
22

usage of medical drugs. Pregnant females were also
excluded. A written informed consent was obtained from allparticipants prior to their participation in the study. The
Human Research Ethics committee (HREC) of Pramukh
Swami Medical College, Karamsad approved this study.
ProtocolDuring a pre testing session, the maximal voluntary
contraction (MVC) of hand grip strength was performed.
30% MVC was set and was used as an appropriatemagnitude of contraction during intervention. The study
protocol required participants to be present for threeconsecutive days. The participants were asked to avoid theintake of any stimulant (drugs, coffee etc) for a period of atleast 30 min before the measurement. The participants werealso asked to empty the bladder before the measurement
and relax quietly in sitting position for a period of at least
5 minutes prior to measurement of BP.
Procedure for BP and Pulse Rate (PR) measurements:
Systolic, Diastolic BP (SBP, DBP) and PR were
measured in the left arm in sitting position with arm and backsupport, uncrossed legs and feet on the floor using theOmron HEM 711 DLX Automatic BP instrument (Accuracy,
BP: ±4 mm Hg, Pulse: ±5, validated by Association for the
Advancement of Medical Instrumentation, AAMI andEuropean Society of Hypertension). BP was recorded atintervals of 1 minute till the difference between two
consecutive BP readings is less than 5 mm Hg. The averageof the two consecutive readings was used for statisticalanalysis. Pulse pressure (PP) was calculated as SBP – DBP
and Mean Arterial Pressure (MAP) was calculated from theaverage values of SBP and DBP using the formula, MAP =DBP + 1/3(PP) respectively.
Procedure of CPT
For the CPT, the right hand of the participant was immersed
above the wrist for 1 minute in a custom made thermocole box
filled with ice water at 10° C, during which time the BP and PR
were measured in the opposite arm at 60 seconds andrecorded. Three measures of cold pressor reactivity were
calculated: the maximum changes in SBP, DBP and PR fromthe control values during the cold stimulus [12 16].
Experimental Procedure
On day two, pre exercise baseline SBP, DBP and PR of
the participants were recorded on arrival. This was followed
by CPT procedure. Participants were asked to perform IHG
exercise of the dominant hand at 30% of MVC for a periodof 20 minutes at a cadence of 2 seconds of contraction / 3
seconds of release. (Rate of contraction: 12/ min) [17]. Aftercompletion of 20 minutes of IHG exercise, BP and PR were
measured and recorded as post exercise measurements.
CPT responses were recorded following 20 minutes of
exercise. The same sequence of procedures was followed
after 60 minutes of exercise and the measurements
Fiziologia - Physiology • 2018.28.1(95)recorded as post exercise 60 minutes. The procedure
explained above was same on Day 1 and Day 3, exceptthat day 1 involved no exercise and day 3 had theparticipants perform BW on a treadmill for a duration of 20
minutes at an intensity of 60% Heart Rate Reserve (HRR).
Heart rate (HR) and BP were monitored at intervals of
every 5 minutes and exercise was stopped if the heart raterose above 85% Maximum HR or BP above 180/ 110
mmHg. The time for recording BP and PR after the
exercise on day 2 and day 3 coincided with the time forrecording the BP and PR on day 1 so as to reduce thepossibilities of circadian variation.
Since gender differences were observed in BP response
to isotonic handgrip exercise among prehypertensives [18],the collected data were analyzed separately for male andfemale participants.

Statistical Analysis
A repeated measure ANOVA (General Linear Model)
with a LSD post hoc analysis to determine specificdifferences was used to analyze the data. SPSS v 20.0 wasused and an alpha level of less than 5% (p ≤ 0.05) was
considered statistically significant. All data are presented asmeans ± SD.

RESULTSThe results of the present study are represented intables I - VI for female participants and tables VII-XII
represent the results of male participants.

Table I. As compared to the control day, ' PR (Post Exercise -Pre Exercise Baseline) was found to be significantly lower on
IHG exercise day. However, BW day showed a significantly larger ' PR (Post Exercise -Pre Exercise Baseline) in comparison
to control and IHG day. Similarly as compared to the control day, ' PR (Post Exercise 60 min- Pre Exercise Baseline) was
found to be significantly lower on IHG day. However in comparison to control day, BW day had significantly larger ' PR (Post
Exercise 60 min- Pre Exercise Baseline)
Table I. Effect of IHG & BW Exercise on PR – Female
Control (n=30)
Pre Exercise Baseline PR
87.23±6.59
Post Exercise PR
83.63±6.12-3.60±4.48' (Post Exercise PR - Pre
Exercise Baseline PR)
Post Exercise 60 min PR
79.50±7.77-7.73±4.94' (Post Exercise 60 min PR-Pre
Exercise Baseline PR)
PR: Pulse Rate
Control: Non Exercise Day
IHG: Isotonic Hand Grip Exercise – Dominant Hand
BW: Brisk Walking

IHG (n=30)
85.07±7.1584.70±7.66*-0.36±5.09*

BW (n=30)
84.33±5.53
104.53±15.19*#
20.20±11.73*#

F
3.287
40.81872.494p value
0.054
0.00
0.00

80.80±6.55-4.26±5.34*

84.67±8.15#
0.33±4.45*#

6.745
20.8250.006
0.00* - Control v/s IHG or BW# - IHG v/s BW

Table II. No significant difference was found on IHG day as compared to the control day on ' SBP (Post Exercise -Pre Exercise
Baseline). BW day showed a significantly larger ' SBP (Post Exercise -Pre Exercise Baseline) in comparison to control and IHG
day. As compared to the control day, ' SBP (Post Exercise 60 min-Pre Exercise Baseline) was significantly larger on IHG day.
Table II. Effect of IHG & BW Exercise on SBP- Female
Control (n=30)
Pre Exercise Baseline SBP
121.93±3.92
Post Exercise SBP
119.50±4.19-2.43±3.46' (Post Exercise SBP -Pre
Exercise Baseline SBP)
Post Exercise 60 min SBP
119.77±4.19-2.16±2.30' (Post Exercise 60 min SBP -Pre
Exercise Baseline SBP)
SBP: Systolic Blood Pressure
Control: Non Exercise Day
IHG: Isotonic Hand Grip Exercise – Dominant Hand
BW: Brisk Walking

Fiziologia - Physiology • 2018.28.1(95)

IHG (n=30)
122.13±2.76
121.80±4.80-0.33±4.87

BW (n=30)
121.43±4.04
133.43±7.35*#
12.00±5.88*#

F
0.511
73.89875.132p value
0.603
0.00
0.00

117.70±3.32*-4.66±3.45*

117.67±4.55-3.76±3.43

3.851
4.960

0.031
0.012

* - Control v/s IHG or BW# - IHG v/s BW

23

Table III. As compared to control and IHG days, ' DBP (Post Exercise -Pre Exercise Baseline) was significantly larger on BW
day. There was no significant difference in ' DBP (Post Exercise 60 min-Pre Exercise Baseline) between the control, IHG and
BW days.
Table III. Effect of IHG & BW Exercise on DBP- Female
Control (n=30)
Pre Exercise Baseline DBP
82.60±2.28
Post Exercise DBP
80.27±4.69-2.33±5.10' (Post Exercise DBP -Pre Exercise
Baseline DBP)
Post Exercise 60 min DBP
80.57±5.55-2.03±5.36' (Post Exercise 60 min DBP -Pre
Exercise Baseline DBP)
DBP: Diastolic Blood Pressure
Control: Non Exercise Day
IHG: Isotonic Hand Grip Exercise – Dominant Hand
BW: Brisk Walking

IHG (n=30)
82.80±3.66
83.33±5.62-0.53±4.49

BW (n=30)
82.47±2.66
86.23±5.92*
3.76±4.85*#

F
0.137
11.04514.971

p value
0.873
0.00
0.00

81.53±5.75-1.26±5.49

79.63±4.54-2.83±4.20

1.512
1.048

0.229
0.357

* - Control v/s IHG or BW# - IHG v/s BW

Table IV. As compared to the control day, ' MAP (Post Exercise -Pre Exercise Baseline) was significantly lower on IHG day.
However, in comparison to control and IHG days, ' MAP (Post Exercise -Pre Exercise Baseline) was significantly larger on
BW day. There was no significant difference in ' MAP (Post Exercise 60 min-Pre Exercise Baseline) between the control, HGE
and BW days.
Table IV. Effect of IHG & BW Exercise on MAP- Female
Control (n=30)
Pre Exercise Baseline MAP
95.71 ±1.93
Post Exercise MAP
93.34±3.82' (Post Exercise MAP -Pre Exercise -2.36±3.59
Baseline MAP)
Post Exercise 60 min MAP
93.63±4.58-2.07±3.88' (Post Exercise 60 min MAP -Pre
Exercise Baseline MAP)
MAP: Mean Arterial Pressure
Control: Non Exercise Day
IHG: Isotonic Hand Grip Exercise – Dominant Hand
BW: Brisk Walking

IHG (n=30)
95.91±2.60
96.15±4.70*-0.24±3.74*

BW (n=30)
95.45 ±2.40
101.96±4.96*#
6.51±4.01 *#F
0.432
39.86958.711

p value
0.651
0.00
0.00

93.58 ±4.22-2.32 ±3.9292.31±3.86-3.14 ±3.16

1.537
0.900

0.224
0.412

* - Control - v/s IHG or BW# - IHG v/s BW

Table V. As compared to the control day and IHG day, ' PP (Post Exercise -Pre Exercise Baseline) was found to be significantly
larger on BW day. There was no significant difference in ' PP (Post Exercise 60 min-Pre Exercise Baseline) between thecontrol, IHG and BW days.
Table V. Effect of IHG & BW Exercise on PP- Female
Control (n=30)
Pre Exercise Baseline PP
39.33±4.67
Post Exercise PP
39.23±5.17-0.10±6.17' (Post Exercise PP - Pre
Exercise Baseline PP)
Post Exercise 60 min PP
39.20±4.96' (Post Exercise 60 min PP - Pre -.13±5.13
Exercise Baseline PP)
PP: Pulse Pressure
Control: Non Exercise Day
IHG: Isotonic Hand Grip Exercise – Dominant Hand
BW: Brisk Walking

24

IHG (n=30)
39.33±4.5938.47±5.46-0.86±5.75

BW (n=30)
38.97 ±4.4247.20 ±8.68 *#8.23 ±7.06 *#F
0.098
17.09317.156p value
0.907
0.00
0.00

36.17 ±5.94-3.16 ±5.89

38.03±5.08-0.93 ±5.04

3.326
3.834

0.049
0.035

* - Control - v/s IHG or BW# - IHG v/s BW

Fiziologia - Physiology • 2018.28.1(95)Table VI. There was no significant difference in ' DBP (1R Pre Exercise -Pre Exercise Baseline) between the control, IHG and
BW days. As compared to the control day and IHG days, ' DBP (1R Post Exercise-Post Exercise) was found to be significantly
larger on BW day. It was also significantly larger on IHG day than control day. There was no significant difference in ' DBP(1R Post Exercise 60 min-Post Exercise 60 min) between the control, IHG and BW days.
Table VI. CPT recovery to IHG & BW Exercise- Female
Control (n=30)
Pre Exercise Baseline DBP
82.60±2.28
1R Pre Exercise DBP
89.83±2.63
7.23±2.54' DBP (1R Pre Exercise DBP- Pre
Exercise Baseline DBP)
Post Exercise DBP
80.27±4.69
1R Post Exercise DBP
87.63±3.49
7.36±2.72' DBP (1R Post Exercise DBPPost Exercise DBP)
Post Exercise 60 min DBP
80.57±5.55
1R Post Exercise 60 min DBP
87.90±4.01
7.33±3.29' DBP (1R Post Exercise 60 min
DBP - Post Exercise 60 min DBP)
DBP: Diastolic Blood Pressure
Control: Non Exercise Day
IHG: Isotonic Hand Grip Exercise – Dominant Hand
BW: Brisk Walking

IHG (n=30)
82.80±3.66
90.10±5.20
7.30±3.91

BW (n=30)
82.47±2.66
88.47±2.17
6.00±2.51

F
0.137
1.929
1.448

p Value
0.873
0.155
0.243

83.33±5.62
94.43±5.16*
11.10±4.07*

86.23±5.92*
101.57±3.97*#
15.33±4.42*#

11.04591.40933.465

0.000
0.000
0.000

81.53±5.75
88.37±4.67
6.83±2.79

79.63±4.5488.37±3.79
8.73±4.20

1.512
0.168
3.070

0.229
0.846
0.063

* - Control v/s IHG or BW# - IHG v/s BW

Table VII. As compared to the control day, ' PR (Post Exercise -Pre Exercise Baseline) was not found to be significantly
different on IHG day. However, BW day showed a significantly larger ' PR (Post Exercise -Pre Exercise Baseline) incomparison to control and IHG days. As compared to the control day, there was no significant difference in ' PR (Post Exercise
60 min- Pre Exercise Baseline) of the IHG day. However in comparison to control day, BW day had significantly larger ' PR
(Post Exercise 60 min- Pre Exercise Baseline).
Table VII. Effect of IHG & BW Exercise on PR – MaleControl (n=30)
Pre Exercise Baseline PR
78.80±5.69
Post Exercise PR
78.90±5.57-0.10±4.92' (Post Exercise PR - Pre
Exercise Baseline PR)
Post Exercise 60 min PR
77.23±4.60-1.56±4.03' (Post Exercise 60 min PR-Pre
Exercise Baseline PR)
PR: Pulse Rate
Control: Non Exercise Day
IHG: Isotonic Hand Grip Exercise – Dominant Hand
BW: Brisk Walking

IHG (n=30)
78.63±5.63
80.83±4.97
2.20±3.77

BW (n=30)
78.50±4.68
93.23±6.22*#
14.73±4.51*#

F
0.038
77.855118.185

p value
0.962
0.000
0.000

75.93±5.17-2.70±4.00

80.73±5.71#
2.23±4.36*#

8.596
12.377

0.001
0.000

* - Control v/s IHG or BW# - IHG v/s BW

Table VIII. As compared to the control day, ' SBP (Post Exercise -Pre Exercise Baseline) was not found to be significantly
different on IHG day. However, BW day showed a significantly larger ' SBP (Post Exercise -Pre Exercise Baseline) incomparison to control and IHG days. As compared to the control day, ' SBP (Post Exercise 60 min-Pre Exercise Baseline)
was significantly larger on IHG day. It was also found to be significantly larger on the IHG day as compared to BW day.
Table VIII. Effect of IHG & BW Exercise on SBP-MalePre Exercise Baseline SBP
Post Exercise SBP

Fiziologia - Physiology • 2018.28.1(95)Control (n=30)
123.13±5.02120.37±3.94

IHG (n=30)
123.30±1.80
121.37±4.61

BW (n=30)
122.70±3.45140.87±7.17*#

F
0.413
174.283

p value
0.664
0.000

25

' (Post Exercise SBP -Pre

-2.76±4.35
Exercise Baseline SBP)
Post Exercise 60 min SBP
118.77±2.22-4.36±4.42' (Post Exercise 60 min SBP -Pre
Exercise Baseline SBP)
SBP: Systolic Blood Pressure
Control: Non Exercise Day
IHG: Isotonic Hand Grip Exercise – Dominant Hand
BW: Brisk Walking-1.93±4.65

18.16±5.47*#

165.4350.000

117.20±2.39*-6.1±4.18*

119.73±2.82#-2.96±3.47#

9.256
29.469

0.001
0.000

* - Control v/s IHG or BW# - IHG v/s BW

Table IX. There was no significant difference in ' DBP (Post Exercise -Pre Exercise Baseline) between the control day and IHG
day. However, in comparison to control, ' DBP (Post Exercise -Pre Exercise Baseline) was significantly larger on BW day. There
was no significant difference in ' DBP (Post Exercise 60 min-Pre Exercise Baseline) between the control, IHG and BW days.
Table IX. Effect of IHG & BW Exercise on DBP-MaleControl (n=30)
Pre Exercise Baseline DBP
80.40±2.22
Post Exercise DBP
79.23±3.49-1.16±3.42' (Post Exercise DBP -Pre
Exercise Baseline DBP)
Post Exercise 60 min DBP
77.53±3.86' (Post Exercise 60 min DBP -Pre -2.86±4.03
Exercise Baseline DBP)
DBP: Diastolic Blood Pressure
Control: Non Exercise Day
IHG: Isotonic Hand Grip Exercise – Dominant Hand
BW: Brisk Walking

IHG (n=30)
79.97±2.73
79.70±5.19-0.26±4.54

BW (n=30)
80.23±2.8182.43±5.42*
2.20±4.41*

F
0.296
4.692
5.646

p value
0.745
0.013
0.006

77.70±5.30-2.26±4.07

77.70±4.28-2.53±3.83

0.018
0.177

0.982
0.838

* - Control v/s IHG or BW# - IHG v/s BW

Table X. There was no significant difference in ' MAP (Post Exercise -Pre Exercise Baseline) between the control days and
IHG days. However, in comparison to control and IHG days, ' MAP (Post Exercise -Pre Exercise Baseline) was significantly
larger on BW day. There was no significant difference in ' MAP (Post Exercise 60 min-Pre Exercise Baseline) between thecontrol, IHG and BW days.
Table X. Effect of IHG & BW Exercise on MAP-MaleControl (n=30)
Pre Exercise Baseline MAP
94.64±2.22
Post Exercise MAP
92.94±2.77' (Post Exercise MAP -Pre Exercise -1.70±3.06
Baseline MAP)
Post Exercise 60 min MAP
91.27±2.87-3.36±2.98' (Post Exercise 60 min MAP -Pre
Exercise Baseline MAP)
MAP: Mean Arterial Pressure
Control: Non Exercise Day
IHG: Isotonic Hand Grip Exercise – Dominant Hand
BW: Brisk Walking

IHG (n=30)
94.41±2.1193.58±4.40-0.82±4.07

BW (n=30)
94.38±2.47101.91±4.36*#
7.52±3.18 *#F
0.208
63.07770.32

p value
0.813
0.000
0.000

90.86 ±3.74-3.54 ±3.05

91.71±2.83-2.67 ±2.58

0.690
0.861

0.506
0.428

* - Control - v/s IHG or BW# - IHG v/s BW

Table XI. As compared to the control and IHG days, ' PP (Post Exercise -Pre Exercise Baseline) was found to be significantly
larger on BW day. As compared to the control day, there was no difference in ' PP (Post Exercise 60 min-Pre Exercise
Baseline) on the IHG and BW days. ' PP (Post Exercise 60 min-Pre Exercise Baseline) was found to be significantly lower on
the BW day as compared to IHG day.

26

Fiziologia - Physiology • 2018.28.1(95)Table XI. Effect of IHG & BW Exercise on PP-MaleControl (n=30)
Pre Exercise Baseline PP
42.73±5.50
Post Exercise PP
41.13±5.01-1.60±4.62' (Post Exercise PP - Pre
Exercise Baseline PP)
Post Exercise 60 min PP
41.23±3.88-1.50±6.17' (Post Exercise 60 min PP - Pre
Exercise Baseline PP)
PP: Pulse Pressure
Control: Non Exercise Day
IHG: Isotonic Hand Grip Exercise – Dominant Hand
BW: Brisk Walking

IHG (n=30)
43.33±2.67
41.67±5.03-1.66±4.43

BW (n=30)
42.47±3.73
58.43 ±8.93 *#15.96 ±7.60 *#

F
0.49
75.86
83.92

p value
0.613
0.000
0.000

39.50 ±5.46-3.83±4.4442.03±5.55-0.43 ±5.69 #

2.65
3.50

0.083
0.041

* - Control - v/s IHG or BW# - IHG v/s BW

Table XII. As compared to the control and IHG days, ' DBP (1R Pre Exercise -Pre Exercise Baseline) was found to besignificantly larger on BW day. As compared to the control and IHG days, ' DBP (1R Post Exercise-Post Exercise) was
found to be significantly larger on BW day. There was no significant difference in ' DBP (1R Post Exercise 60 min-Post
Exercise 60 min) between the control, IHG and BW days.
Table XII. CPT recovery to IHG & BW Exercise – MaleControl (n=30)
Pre Exercise Baseline DBP
80.40±2.22
1R Pre Exercise DBP
85.97±2.87
5.56±2.73' DBP (1R Pre Exercise DBP- Pre
Exercise Baseline DBP)
Post Exercise DBP
79.23±3.49
1R Post Exercise DBP
88.83±3.38
9.60±3.13' DBP (1R Post Exercise DBPPost Exercise DBP)
Post Exercise 60 min DBP
77.53±3.86
1R Post Exercise 60 min DBP
83.93±3.61
6.40±3.55' DBP (1R Post Exercise 60 min
DBP - Post Exercise 60 min DBP)
DBP: Diastolic Blood Pressure
Control: Non Exercise Day
IHG: Isotonic Hand Grip Exercise – Dominant Hand
BW: Brisk Walking

DISCUSSION
Recent studies have proven that small reductions of BP in
prehypertensive or hypertensive population could havesignificant health benefits. Studies suggest that a 2mm Hg dropin DBP would lead to a 17% decrease in Hypertension, 6%
reduction in Coronary Heart Disease and 15% reduction in
Stroke related events[19]. The results of the present study
shows that 20 minutes of IHG exercise reduces BP in
prehypertensive young male and females. Immediately after 20
minutes of IHG exercise, mean reduction in PR, SBP, DBP,
MAP and PP were observed both in female (Tables: 1-5) andmale (Tables: 7-11) participants whereas there was an increase
in mean of all the above parameters after BW. The mean
reductions of PR, SBP and PP of females were higher in IHG
exercise as compared to BW. However, mean DBP (Fiziologia - Physiology • 2018.28.1(95)

IHG (n=30)
79.97±2.7386.40±4.44
6.43±3.50

BW (n=30)
80.23±2.8188.10±3.55*
7.86±3.21*

F
0.296
3.547
4.185

p Value
0.745
0.041
0.022

79.70±5.19
91.73±4.48*
12.03±4.2782.43±5.42*
99.43±3.90*#
17.00±4.26*#

4.692
61.962
32.46

0.014
0.000
0.000

77.70±5.30
84.80±4.38
7.10±4.02

77.70±4.2886.17±4.03
8.46±4.80

0.018
2.947
1.705

0.982
0.067
0.191

* - Control v/s IHG or BW# - IHG v/s BW

2.83±4.20) and MAP (-3.14±3.16) of BW were higher than IHG
exercise. Similarly, the mean reductions of PR, SBP, MAP and
PP of males were higher in IHG exercise as compared to BW
except for reductions in DBP which was higher in BW.
Earlier studies reported variations in reductions of SBP
and DBP to various forms of exercise. Quinn TJ [20]observed 4 mm Hg and 5 mm Hg reductions in SBP and
DBP to treadmill walking for 30 minutes at 75% VO2 max,
whereas Wallace et al [21] observed 8 mm Hg and 6 mm Hg
in SBP and DBP respectively, after treadmill exercise of 5
sessions of 10 minutes at 50% VO2 max. Pescatello et al[22 23], Lehmkuhl et al [24], Hara et al [25], Rueckert et al[26], in their studies found no significant changes in BP after
various intensities of treadmill walking and running.
Differences in reductions of BP and PR of this present
study from past studies can be attributed to the different
duration and intensities of the exercise, as the present study

27

had focused on the benefits of only 20 minutes of exercising,which was the least of all the above mentioned studies.
Various studies in the past have postulated numerous
potential mechanisms responsible for the reduction in BP
following handgrip exercises, most of these studies focusing
on isometric handgrip exercises [27 28]. Some of the factors
include oxidative stress [29], improved endotheliumdependent vasodilatation [30 31], and modulation ofAutonomic Nervous system [32 33]. Despite the fact that thepresent study recommending IHG exercise to reduce BP in
prehypertensives, the exact mechanisms responsible for BP
reductions following IHG exercise remains elusive.
CPT response immediately after IHG exercise and BW
showed a rise in DBP in both female and male participants,
however this increase was quite larger on BW day (Tables 6
and 12). At 60 minutes post exercise, DBP response to CPT
returned close to baseline resting values on IHG as
compared to BW day, where the DBP stayed higher thanbaseline values.
Once stimulated by a stressor, the sympathetic systemsets off a rise in heart rate and blood pressure, but usuallythese effects return to normal levels within a very short periodof time (5 minutes) after the withdrawal of the stressor.
Diastolic blood pressure is the index of peripheral resistance.
Higher diastolic pressure even after the withdrawal of the cold
stimulus indicated that once constricted through sympathetic
stimulation, vessels took longer to return to their normal
original diameters [34]. Persons with higher cardiovascular
reactivity to a stressor show slower rate of recovery after thewithdrawal of the stressor responsible for sympathetic
stimulation, indicating that the autonomic control system is notcompetent enough to lower heart rate and blood pressure to
the baseline quickly.

LIMITATIONS OF THE STUDYThis study had some limitations: First, our inclusion
criteria were purposely restrictive so as to limit the strong
confounding effects of age, BMI, and training, but they also
limit the generalization of our findings to the population
studied. Secondly, being a repeated measures study
design, the practice effects on participants on threeconsecutive days were not controlled. Finally, it focused only
on the acute effect of IHG exercise on BP and PR
parameters, hence further studies should advance thefindings of this research by taking into consideration, thelong term training effects of IHG exercise.

CONCLUSION
One of the common barrier to exercise among patientand normal population is time. The present study protocol
requires very little adjustments in day to day routine and at28

the same time is effective to yield a better reduction in
resting SBP and PP in comparison to treadmill walking. Thismight increase the adherence of prehypertensives toexercise as the IHG exercise can be considered as
participation in leisure time. The clinical benefits of IHG
exercise found out from this study, which is least explored
till date, can be considered as a novel therapy intranscending time and cost and might be provided as analternative method for prehypertensive population to control
BP by improving exercise adherence.

REFERENCES
1. Hamer M. The effects of exercise on haemodynamic function in
relation to the familial hypertension risk model. Journal of human
hypertension 2006;20(5):313-9.
2. Md. Shahidur Rahman AKMS. Role of Exercise as a
Therapeutic Intervention for Hypertension. University Heart
Journal 2009;5(1):36-39.
3. Peter F. Kokkinos A, Athanasios Manolis, Andreas Pittaras.
Physical Activity in the Prevention and Management of High
Blood Pressure. Hellenic J Cardiol 2009;50:52-59.
4. Fagard R, Vanhees L. Twenty-four hour blood pressure after
exercise in patients with coronary artery disease. Journal of
human hypertension 2000;14(4):231-4.
5. Arikawa AY, O'Dougherty M, Kaufman BC, et al. Attrition andadherence of young women to aerobic exercise: lessons fromthe WISER study. Contemporary clinical trials 2012;33(2):298301.
6. Irwin ML TS, Yasui Y, Rajan B, McVarish L, LaCroix K, et al.
Influence of demographic, physiologic, and psychosocial
variables on adherence to a yearlong moderateintensity
exercise trial in postmenopausal women. . Prev Med
2004;39:1080-6.
7. King AC BS, Bild DE, Dishman RK, Dubbert PM, Marcus BH, etal. Determinants of physical activity and interventions in adults.
Med Sci Sports Exerc 1992;24:S221-36.
8. Martin KA SA. Who will stay and who will go? A review of older
adults’ adherence to randomized controlled trials of exercise.
JAPA 2001;9:91-114.
9. Perri MG AS, Durning PE, Ketterson TU, Sydeman SJ, Berlant
NE, et al.nAdherence to exercise prescriptions: effects ofprescribing moderate versus higher levels of intensity andfrequency. Health Psychol 2002;21:452-58.
10. Krantz DS, Manuck SB. Acute psychophysiologic reactivity andrisk of cardiovascular disease: a review and methodologic
critique. Psychological bulletin 1984;96(3):435-64.
11. Jennings JR, Kamarck TW, Everson-Rose SA, et al.
Exaggerated blood pressure responses during mental stress areprospectively related to enhanced carotid atherosclerosis in
middle-aged Finnish men. Circulation 2004;110(15):2198-203.
12. Menkes MS, Matthews KA, Krantz DS, et al. Cardiovascular
reactivity to the cold pressor test as a predictor of hypertension.
Hypertension 1989;14(5):524-30.
13. Victor RG, Leimbach WN, Jr., Seals DR, et al. Effects of the coldpressor test on muscle sympathetic nerve activity in humans.
Hypertension 1987;9(5):429-36.
14. Wood DL, Sheps SG, Elveback LR, et al. Cold pressor test as apredictor of hypertension. Hypertension 1984;6(3):301-6.
Fiziologia - Physiology • 2018.28.1(95)15. NM. K. Kaplan’s Clinical Hypertension. 9th ed: Lippincott
Williams & Wilkins, 2006.
16. Vivek Verma SKS, S. Ghosh. Identification of susceptibility tohypertension by the cold pressor test. Indian J Physiol
Pharmacol 2005;49(1):119-20.
17. Brian A. Batman Jch UAL, Michael B. Smith, Qing X. Yang,
Lawrence I. Sinoway. . Sympathetic nerve activity during
prolonged rhythmic forearm exercise. The American
Physiological Society 1994:1077-81.
18. Saravanan Murugan SKS, Wasim Sheikh. Does gender affectthe response of blood pressure to isotonic hand grip exercise inprehypertensives? Sch J App Med Sci 2016;4(5(D)):1693-97.
19. Cook NR, Cohen J, Hebert PR, et al. Implications of small
reductions in diastolic blood pressure for primary prevention.
Archives of internal medicine 1995;155(7):701-9.
20. TJ Q. Twenty-four hour, ambulatory blood pressure responses
following acute exercise: impact of exercise intensity. J Hum
Hypertens 2000;14:547-53.
21. Wallace JP, Bogle PG, King BA, et al. A comparison of 24-h
average blood pressures and blood pressure load following
exercise. American journal of hypertension 1997;10(7 Pt 1):72834.
22. Pescatello LS, Kulikowich JM. The aftereffects of dynamic
exercise on ambulatory blood pressure. Medicine and science insports and exercise 2001;33(11):1855-61.
23. Thompson PD, Crouse SF, Goodpaster B, et al. The acuteversus the chronic response to exercise. Medicine and sciencein sports and exercise 2001;33(6 Suppl):S438-45; discussion
S52-3.
24. Lehmkuhl LA, Park S, Zakutansky D, et al. Reproducibility of
postexercise ambulatory blood pressure in Stage I hypertension.
Journal of human hypertension 2005;19(8):589-95.
25. Hara K, Floras JS. Influence of naloxone on muscle sympathetic
nerve activity, systemic and calf haemodynamics andambulatory blood pressure after exercise in mild essential
hypertension. Journal of hypertension 1995;13(4):447-61.
26. Rueckert PA, Slane PR, Lillis DL, et al. Hemodynamic patterns
and duration of post-dynamic exercise hypotension in
hypertensive humans. Medicine and science in sports andexercise 1996;28(1):24-32.
27. Mortimer J, McKune AJ. Effect of short-term isometric handgrip
training on blood pressure in middle-aged females.
Cardiovascular journal of Africa 2011;22(5):257-60.
28. Millar PJ, Bray SR, McGowan CL, et al. Effects of isometrichandgrip training among people medicated for hypertension: amultilevel analysis. Blood pressure monitoring 2007;12(5):30714.
29. Peters PG, Alessio HM, Hagerman AE, et al. Short-term
isometric exercise reduces systolic blood pressure in
hypertensive adults: possible role of reactive oxygen species.
International journal of cardiology 2006;110(2):199-205.
30. McGowan CL, Visocchi A, Faulkner M, et al. Isometric handgrip
training improves local flow-mediated dilation in medicatedhypertensives. European journal of applied physiology
2007;99(3):227-34.
31. McGowan CL, Levy AS, Millar PJ, et al. Acute vascularresponses to isometric handgrip exercise and effects of training
in persons medicated for hypertension. American journal ofphysiology
Heart
and
circulatory
physiology
2006;291(4):H1797-802.
32. Millar PJ, MacDonald MJ, Bray SR, et al. Isometric handgrip
exercise improves acute neurocardiac regulation. European
journal of applied physiology 2009;107(5):509-15.
33. Taylor AC, McCartney N, Kamath MV, et al. Isometric training
lowers resting blood pressure and modulates autonomic control.
Medicine and science in sports and exercise 2003;35(2):251-6.
34. LeBlanc J, Dulac S, Cote J, et al. Autonomic nervous system
and adaptation to cold in man. J Appl Physiol 1975;39(2):181-6.

IMPACTUL EXERCIȚIILOR ISOTONICE HAND GRIPPRIVIND PRESIUNEA DE SÂNGE ȘI RĂSPUNSULSIMPATIC LA PRE-HIPERTENSIVIREZUMAT
Contextul studiului: Exercițiul fizic este unul dintre elementele esențiale pentru controlul tensiunii arteriale. Cu toate
acestea, anumite constrângeri, cum ar fi fezabilitatea echipamentului de exerciții fizice și a timpului, au redus respectarea
oamenilor față de exerciții fizice. Exercitarea izotonică a mâinii (IHG) poate fi considerată o alternativă la alte forme de
exercițiu dacă ar putea fi studiată pentru efectele pe care le are asupra tensiunii arteriale (BP). Prin urmare, acest studiu afost realizat pentru a determina și compara efectul pe termen scurt al exercițiului IHG față de mersul brusc (BW) asupra
BP și a reactivității cardiovasculare la prehypertensive.
Metode: 60 de voluntari cu prehypertensiune (bărbați-30; femei-30) au participat la acest studiu. Studiul a fost efectuat pe
trei zile consecutive: Ziua 1- Control sau non-exercițiu, Ziua 2 - exercițiu IGG și Ziua 3 - BW. La sosire s-au înregistrat
valorile presiunii sistolice (SBP) și tensiunii arteriale diastolice (DBP) și frecvența pulsului (PR), urmate de testul de presiune
la rece (CPT). Acest lucru a fost urmat de nici un exercițiu, exercițiu izotonic de prindere pe mâini sau o plimbare intensă
timp de 20 de minute în ziua 1, 2 și respectiv 3. BP a fost înregistrată imediat după această perioadă de 20 de minuteurmată de CPT. Măsurătorile au fost înregistrate din nou după o oră în aceeași ordine în toate cele trei zile. Măsuri repetate
Fiziologia - Physiology • 2018.28.1(95)29

ANOVA (p <0,05) a fost utilizată pentru analiza diferențelor dintre exercițiul prealabil de bază, exercițiul imediat post și 60
de minute după exercițiul BP, PR, presiunea arterială medie (MAP) și presiunea pulsului (PP). Măsurătorile CPT au fost,de asemenea, analizate pentru a afla diferențele de răspuns ale sistemului cardiovascular la exercițiile IHG și BW.
Rezultate: În rândul participanților feminini, s-au constatat diferențe semnificative în măsurătorile BP și PR imediat dupăexercițiu. Exercițiul IHG a evidențiat o reducere semnificativă a PR (media ± SD, -0,36 ± 5,09), SBP (-0,33 ± 4,87), DBP(-0,53 ± 4,49), MAP (-0,24 ± 3,74) și PP (-0,86 ± 5,75) comparativ cu BW care au prezentat o creștere a PR (20,20 ±
11,75), SBP (12,00 ± 5,88), DBP (3,76 ± 4,85), MAP (6,51 ± 4,01) și PP (8,23 ± 7,06). Cu toate acestea, după 60 deminute de exercițiu, nu s-au observat diferențe semnificative în SBP, DBP, MAP și PP la exercițiul IHG și BW, numai PR
prezentând o reducere semnificativă a exercițiilor IHG (-4,26 ± 5,34) decât BW (0,33 ± 4,45) . Răspunsul CPT măsurat la
momentul inițial și 60 de minute după exerciții nu a fost statistic semnificativ în cele două zile de experiment. Cu toate
acestea, răspunsul CPT exercițiu imediat la BW a fost semnificativ mai mare (15,33 ± 4,42) decât exercițiul IHG (11,10 ±4,07)
S-au constatat diferențe semnificative în măsurătorile PR, SBP, MAP și PP imediat după exercițiu și cea a pre-exercițiului
fizic la participanții de sex masculin. Exercițiul IHG a arătat o reducere semnificativă a SBP (-1,93 ± 4,65), MAP (-0,82 ±4,07) și PP (-1,66 ± 4,43) comparativ cu BW care au prezentat o creștere a SBP (18,16 ± 5,47), MAP (7,52 ± 3,18 ) și PP(15,96 ± 7,60). O creștere a PR a fost observată în ambele condiții de efort cu BW (14,73 ± 4,51), semnificativ mai maredecât exercițiul IHG (2,20 ± 3,77). Nu sa constatat nici o diferență semnificativă în DBP în ambele zile de exerciții fizice. În
mod similar, după 60 de minute de exercițiu, nu s-au observat diferențe semnificative în exercițiul DBP și MAP la exercițiul
IHG și BW. PR a prezentat o reducere semnificativă a exercițiului IHG (-2,70 ± 4,00) decât BW (2,23 ± 4,36). O reducere
semnificativă a fost observată și la SBP (-6,10 ± 4,18) și PP (-3,83 ± 4,44) la efortul IHG decât SBP (-2,96 ± 3,47) și PP (0,43 ± 5,69) la BW.
Răspunsul CPT măsurat la momentul inițial și 60 de minute după exerciții nu a fost statistic semnificativ în cele două zilede experiment. Cu toate acestea, răspunsul CPT imediat la exercițiul BT a fost semnificativ mai mare (17,00 ± 4,26) decât
exercițiul IHG (12,03 ± 4,27).
Concluziile: Constatările sugerează că 20 de minute de exercițiu IHG pot fi utilizate ca o metodă eficientă din punct devedere al costurilor și mai puțin consumatoare de timp pentru reducerea nivelurilor de BP la adolescenții prehypertensivi
masculi și femele în comparație cu BW. De asemenea, sa constatat că exercițiul IHG acut pare să aibă un impact
semnificativ asupra răspunsurilor BP la stresul rece. Sunt necesare studii suplimentare pentru a investiga efectele petermen lung ale antrenamentului IHG asupra BP.
Cuvinte cheie: exercițiu isotonic, test de presor rece, pre-hipertensiune

30

Fiziologia - Physiology • 2018.28.1(95)MISDIAGNOSIS OF ASPIRATED BRONCHIAL
FOREIGN BODY. A CASE REPORTRAMONA CIOBOATA1, ILEANA BAZAVAN1, MIMI NITU1,MARIUS GEORGESCU2, MIHAI OLTEANU 1
1Internal Medicine - Pulmonology Department, University of Medicine and Pharmacy Craiova, Romania
2Physiology Department, University of Medicine and Pharmacy “Victor Babes”, Timisoara, Romania

ABSTRACT
Aspiration of foreign bodies is an often severe medical condition which demands both timely recognition and rapid action.
When diagnosis is delayed, the subsequent delay to treatment associates with severe complications.
Material and method: A 52 year old Caucasian male patient, suffering from recurrent pneumonia, the cause of which was
difﬁcult to pinpoint, especially in the absence of typical risk factors. He was admitted to the emergency ward presenting
dyspnea, chronic productive cough, chest pain, low grade fever and weight loss, which initially debuted 12 months earlier
but was heightened in the 7 days previous to admission.
The diagnosis of foreign body aspiration has been established after performing bronchoscopy due to the suspicion of abronchioloalveolar carcinoma.
Short title: Aspirated bronchial foreign body - a case report
Key words: foreign body, adult pneumonia, bronchoscopy

INTRODUCTION
Foreign-body aspiration is often a serious medical
condition and a potentially life-threatening event demanding
timely recognition and prompt action.
Foreign body aspiration is more common in children
than in adults. Data from the National Security Council
reported that approximately 80 percent of cases occur inpatients younger than 15 years of age, with the remaining
20 percent over the age of 15 years [1].
The most common symptoms of foreign body aspirationin the airways include chronic cough, dyspnea, andhemoptysis, which are often misdiagnosed as obstructive
airway disease. Risk factors for aspiration include
neurological dysfunctions such as stroke, encephalopathy,
alcoholism, seizures, Parkinson’s disease, sedatives, andmental retardation, and also dental procedurecomplications, facial trauma, intubation, and abnormalitiesof the pharynx and esophagus [2,3,4]
Delayed diagnosis and the subsequent delayed
treatment is associated with serious complications. Flexible
and rigid bronchoscopy has become the cornerstone of both

the diagnosis and treatment of patients with suspected
foreign body aspiration [2].

CASE REPORTWe present the case of a 52 year old male patient witha history of high blood pressure and recurrent pneumonia.
He presented to the emergency ward with chronic
productive cough, dyspnea, chest pain, weight loss and low
grade fever which had initially started 12 months earlier butheightened in the last 7 days previous to admission.
Since 12 months before he had been treated withmultiple courses of oral antibiotics for recurrent communityacquired pneumonia, which initially improved the symptoms,
however after a few weeks symptoms recurred. Antibiotic
treatment was then resumed, most recently 1 month prior topresentation but at this time without effect, and the patient
was admitted to the hospital.
He denied history of seizures as well as alcohol,
sedatives or illicit drug use.

Received March 14th 2018. Accepted May 31st 2018. Address for correspondence: Marius Georgescu, MD, PhD, Assistant Teaching
Professor, Department of Functional Sciences, Discipline of Physiology, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu
Square No. 2A, Timisoara, RO-300041. Phone: 0040765527318; e-mail: georgescu.marius@umft.roFiziologia - Physiology • 2018.28.1(95)31Physical examination revealed an underweight patient(IMC value 0f 19.50) with pale and sweaty skin, presenting
the following vital parameters measurements: a bodytemperature of 38.6 Celsius degrees; a heart rate of 97
beats/minute; oxygen saturation was 95% on room air;respiratory rate was 17 /minute and blood pressure was
135/85 mmHg.
His physical exam was remarkable for pulmonary
findings of increased tactile fremitus, dullness to percussion
and crackles on the lower zones of his right lung.
Blood tests showed normochromic normocytic anaemia(haemoglobin 11.2 g/dL, red blood cells 2.97×106/mmc, andmean corpuscular volume 100) elevated white blood cells
count (9800/mm3) and sedimentation rate (125/90 mm).
Renal and liver function tests and electrolytes were normal.
The sputum smear and culture for TB were negative,
with no other pathogens found.
Chest radiography showed a right lower lobe infiltrates
and reticular densities (Figure 1). Computer tomographyscan showed ground glass opacity with right lower lobe
predominance and bronchial wall thickening without
excluding a bronchioloalveolar carcinoma.

Fig. 2. Bronchoscopy image of an object occluding
the right lower bronchus

Fig. 3. Bronchoscopy closer view of the object occluding
the right lower bronchus.

Fig.1. Poasteroanterior chest radiography showed a right lower
lobe infiltrates and reticular densities.

A bronchoscopy was performed the following day withvisualization of an object completely occluding the rightlower bronchus, which appeared to be a foreign body or
mucous concretion (Figures 2, 3, 4). The obstruction wasremoved and the foreign body was in fact a chicken vertebra(Figure 5).

32

Fig.4. Bronchoscopy image after the obstruction
was removed and bronchial lavage was carried out.

Fiziologia - Physiology • 2018.28.1(95)Bronchoscopy is frequently the diagnosis method of
choice [2].
Bronchoscopy was performing with the visualization ofan object completely occluding the right lower bronchus
which appeared to be either a foreign body or mucous
concretions. The obstruction was removed and the foreign
body was in fact a chicken vertebra, with dimensions of
20x15x5mm.
In addition to diagnosis, bronchoscopy remains theprocedure of choice for asphyxiating foreign bodies because
it offers superior airway control, suction and extraction
capabilities [7].
Fig.5. Foreign body which was occluding
the right lower bronchus.

After removal of the foreign body, the patient
symptomatically improved. On follow-up in clinic, the patientunderwent continuous improvement of symptoms and thechest radiography showed complete resorption, with no
opacities in the right lower lobe area.

DISCUSSION
The source of the recurrent pneumonia was difﬁcult to
pinpoint in a 52-year-old Caucasian male patient without
typical risk factors.
Unlike foreign body aspiration in young children and in
the elderly, this occurrence is uncommon in adults. In theadult population, such aspiration is most commonly
secondary to accidental ingestion during generalanesthesia, neurologic disorders, and sedation [5]. In eachcase, time passed from aspiration to diagnosis andsubsequent removal of the foreign body can range fromhours to years. In most cases, late diagnosis is due to subtle
symptoms like cough, sputum production, fever, chill,wheezing, recurrent pneumonia and shortness of breath [2].
In most cases, the diagnosis is confirmed by chest
radiography [6]. Our patient presented with pneumonia like
symptoms which had initially started 12 months earlier andtreated as a repeated infectious episodes until 7 days before
presentation when the treatment was ineffective.
The chest radiography of this patient showed a rightlower lobe infiltrates and reticular densities but couldn’t
highlight the presence of a foreign body.
The computer tomography scan of the thorax was
performed showed ground glass opacity with right lower
lobe predominance and bronchial wall thickening without
excluding a bronchioloalveolar carcinoma.
In such a case, diagnostic tools like chest X-rays andcomputer tomography are of very limited use.

Fiziologia - Physiology • 2018.28.1(95)

CONCLUSION
What makes this case unusual is the rather delayed andinnocuous presentation after aspiration.
A foreign body aspirated within the tracheobronchial tree
is a rare occurrence in adults and is often misdiagnosed as
an obstructive airway disease or other more common
conditions.
Chronic cough and dyspnea with persistent pulmonary
infiltrate should prompt further diagnostic studies.
Bronchoscopy is safe and effective for diagnosis andtreatment when performed by experienced physicians.

REFERENCES
1. National Safety Council. Report on injuries. Injury Facts. 2011
information online: www.nsc.org/library/report injury usa.htm(Accessed on January 23, 2014).
2. Baharloo F, Veyckemans F, Francis C, et al. Tracheobronchialforeign bodies: presentation and management in children andadults. Chest 1999;115: 1357-62.
3. Al-Majed SA, Ashour M, Al-Mobeireek AF, Al-Hajjaj MS,
Alzeer AH, Al-Kattan K. Overlooked inhaled foreign bodies:late sequelae and the likelihood of recovery. Respiratory
Medicine, 1997; 91(5): 293-296.
4. Limper AH, Prakash UBS. Tracheobronchial foreign bodies inadults. Annals of Internal Medicine, 1990; 112(8): 604-609.
5. Baharloo F, Veyckemans F, Francis C, et al. Tracheobronchialforeign bodies: presentation and management in children andadults. Chest 1999; 115:1357-62.
6. Pinto A, Scaglione M, Pinto F, et al. Tracheobronchialaspiration of foreign bodies: current indications for emergency
plain chest radiography. Radiol Med (Torino) 2006;111: 497506.
7. Rafanan AL, Mehta AC. Adult airway foreign body removal.
What’s new? Clin Chest Med 2001; 22:319.

33

DIAGNOSTIC GREȘIT AL UNUI CORP STRĂIN
ASPIRAT BRONȘIC. RAPORT DE CAZ
REZUMAT
Aspirarea corpilor străini este de cele mai multe ori o condiție medicală severă, care necesită recunoaștere la timp șiintervenție rapidă. Atunci când diagnosticul este întârziat, întârzierea consecutivă în aplicarea tratamentului este asociată
cu complicații severe.
Materiale și metode: Un pacient caucazian de sex masculin, care suferă de pneumonie recurentă de cauză necunoscută,în absența factorilor de risc tipici; este internat la Secție de Urgențe prezentând dispnee, tuse cronică productive, dureri
toracice, febră moderată și scădere ponderală, care au debutat cu 12 luni înainte, dar au crescut ca intensitate în ultimele
7 zile, înainte de internare.
Diagnosticul de corp strain de aspirație a fost stabilit după efectuarea bronhoscopiei, procedură efectuată datorită
suspiciunii de carcinoma bronhoalveolar.
Cuvinte cheie: corp străin, pneumonia la adult, bronhoscopie

34

Fiziologia - Physiology • 2018.28.1(95)CLINICAL AND ETIOLOGICAL ASPECTS
OF THE CONFUSIONAL SYNDROMEALBU VALERIA CARMEN1*, SANDU RALUCA ELENA2*, PIRSCOVEANUDENISA1, BUMBEA ANA-MARIA3, PARVULESCU OCTAVIA CORINA4, BOGDANCATALIN5, FLORESCU ANDREEA OANA6, BALSEANU TUDOR ADRIAN5,ENESCU AURELIA7, MIREA CECIL SORIN8, BARBULESCU ANDREEA LILI9
1Departament of Neurology, University of Medicine and Pharmacy of Craiova, Romania
2Departament of Biochemistry, University of Medicine and Pharmacy of Craiova, Romania
3Department of Medical Rehabilitation, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania
4Neuropsychiatry Hospital of Craiova, Romania
5Department of Functional Sciences, University of Medicine and Pharmacy of Craiova, Romania
6Departament of Radiology, University of Medicine and Pharmacy of Craiova, Romania
7Department of Medico-Surgical Emergencies, University of Medicine and Pharmacy of Craiova
8Department of Surgery, University of Medicine and Pharmacy of Craiova, Romania
9Departament of Pharmacology, University of Medicine and Pharmacy of Craiova, Romania

ABSTRACT
Background: Acute confusional syndrome, also known as delirium, is one of the common reasons for hospital admission,
especially among the elderly population. The aim of the study consisted in highlighting the demographic, clinical andlaboratory characteristics of the patients admitted with the diagnosis of confusional syndrome.
Methods: The observational retrospective study was conducted based on the analysis of the observation sheets of the 63
patients included in the study. Demographic, anamnestic laboratory data as well as, data obtained by clinical examinationand information on the treatment and evolution of these patients were extracted. The analyzed paraclinic parameters
included biological parameters (Complete blood count, erythrocyte sedimentation rate, C-reactive protein, lipidograma,
glucose, total proteins, transaminase, urea, creatinine, urinalysis exam) and imagistics parameters, the latter being provided
by the computer tomography exam.
Results: The onset age of the confusional syndrome is between decade 6-7, reaching a peak in the range 70-80 years.
The calculated average age of the study group is 71.5 ± 10 being slightly higher than the one reported by other studies (IDest 65 ± 10 years.). Gender distribution highlights the predominance of female patients: 57% compared to 43% for malegender. A third of the patients have fulfilled on the admission only the classical criteria of the confusional status (35%). As
regards the comorbidities of patients included in this study, the majority presented one or more associated conditions. We
identified the following in a descending order as frequency: hypertension, mainly of the second degree, found at more thanhalf of the patients (59%), atrial fibrillation, with a prevalence of 27% and dyslipidemia, an important cardiovascular risk
factor, found in 24% of cases. In terms of imaging changes, a significant proportion of 37% of patients did not show
pathological changes, this result is similar to the results obtained in other studies. In what laboratory parameters areconcerned, the most frequent change was hyperglycemia, recorded in 37 patients (58.7%), followed by anemic syndrome,found in 34 patients (53.9%) and hypercholesterolemia, situated on the third place, a change that corresponds to 26
patients.
Conclusions: The spectrum of clinical symptoms presented by the patients with confusional syndrome is extremely variable
and includes, in addition to classical symptoms, nonspecific symptoms such as: gait and balance disorders, dizziness,headache. From the imaging point of view, the main change observed in the patients included in the study was cortical
atrophy, which is also a common neuroimaging characteristic found in elderly patients with confusional syndrome
Keywords: Acute confusional state, delirium, risk factor, elderly patients, comorbidities
Received May 9th 2018. Accepted May 21st 2018. Address for correspondence: Cecil Sorin Mirea, Lecturer, MD, PhD, Department of Surgery,
University of Medicine and Pharmacy of Craiova,2 Petru Rareş Street, 200349 Craiova, Romania; Phone +40351–443 500, e-mail:mirea_cecil@yahoo.com

Fiziologia - Physiology • 2018.28.1(95)35INTRODUCTION
Acute confusional syndrome, also known as delirium, is
one of the common reasons for hospital admission,
especially among the elderly population. It is characterized
by the alteration of the state of consciousness and by thedegradation of cognition, centered on the inability toorientation, support and modular attention [4].As all
cognitive processes are carried out based on the clarity andlucidity of the state of consciousness, they will bequantitatively and/or qualitatively affected in proportion to
the degree of consciousness impairment. Hence it results
the diversity of clinical presentation forms of this syndrome.
Diagnosis is essentially clinical and it is based on detecting
the following clinical elements:‐ Hypoprosexia: deficit of targeting, concentration,
maintenance and mobility attention to the most severe
form of aprosexia.
‐ Deterioration of consciousness: obtundation,
characterized by a state of apathy, drowsiness that
increases the perceptive threshold, diminishes contact
with the environment and causes disorientation in
space and time.
‐ Perceptive disorders: distortions such as illusions or
hallucinations most commonly visual type
‐ Sleep-wake cycle disorders such as partial or total
insomnia, dyssomnia with fragmented sleep, daytime
sleepiness or reversal of sleep-wake rhythm [13].
‐ Nevertheless speech disorders starting from mutism toincreased verbal flow with incoherent speech, memory
disturbances in particular recent memory, behavioral
affective disorders with rapid and unpredictablefluctuations between anxious, depressed and euphoricstates have to be taken into account.
This highly complex spectrum of clinical elements isdetermined by the interdependence of the cognitive
functions so affecting any of them destabilizes the others.
As generally accepted scientific instruments to support thediagnosis of acute confusional syndrome can be used: CAM(Assesment Method) or DSM 5 (Diagnostic and statistical
Manual of Mental disorders) which contains the essential
diagnostic criteria and the severity assessment can be
performed by Delirium Rating Scale.
The defining elements are the sudden onset (hours,
days), polymorphism and intermittent of clinicalmanifestations, acute evolution with daytime fluctuations andnocturnal global worsening [2, 13].
There are three clinical forms:- Hyperactive form (20% of cases): characterized bypsychomotor agitation predominates, psychotic
symptoms.

36

Hypoactive form (29%): characterized by apathy,
lethargy, absence of cooperation.
- Mixed form (43%): having elements characteristic for
hyper and hypoactive forms [13, 14].
From the pathophysiological point of view, acuteconfusional syndrome derives from metabolic disturbanceand neurotransmission at diffuse brain level, under theaction of intrinsic local factors or systemic extrinsic factors.
The imbalance generated involves a variety ofneurotransmitters, most commonly incriminated being
acetylcholine and dopamine [9]. The etiology is extremely
varied and can be classified as follows:a) Metabolic causes:‐ hypo/hyperglycemia,
hypercapnia,
hypoxia(secondary to a pulmonary pathology, hypotension,congestive heart failure).
‐ electrolyte and acid-base balance disorders:
hypo/hypernatremia, hypercalcemia, diabetic
ketoacidosis.
‐ hepatic
encephalopathy/uremic,
porphyria,
endocrinopathies (hypo-/hyperfunction of thyroid,
adrenal glands, parathyroid glands), hypo/
hyperthermia.
‐ hypovitaminosis: B12, niacin (pellagra), thiamine(Wernicke encephalopathy).
b) Infectious causes with extra-cerebral onset:
pneumonia, endocarditis, peritonitis, sepsis.
c) Alcoholic or drug intoxication: opiates, anticoagulants,
barbiturates, sedatives, corticosteroids, anticonvulsants,
serotonin antidepressants, dopamine agonists.
d) Alcohol, barbiturates, sedative-hypnotics withdrawal.
e) Psychiatric causes: acute manic state, depression or
extreme anxiety, schizophrenia, hysterical fugue states.
f) Toxic exposure: heavy metals (copper, mercury),
carbon monoxide, pesticides, cyanides, solvents,
various industrial substances.
Neurological pathology (commonly associated with theclinical and focal signs):a) Vascular disorders: ischemic stroke, intracranial/subdural
hemorrhage, hypertensive encephalopathy, vasculitis(systemic erythematosus lupus, arteritis with gigantic
cells, periarteria nodosa), gas embolism.
b) Tumors: primary cerebral tumors, cerebral metastases(which generate cerebral edema, hydrocephalus orcompression of the brainstem) meningeal
carcinomatosis, paraneoplastic syndromes.
c) Infections: meningitis and encephalitis of viral, fungal orparasitic origin, abscesses, progressive multifocal
leukoencephalopathy.
d) Epilepsy: postictal state, temporal lobe epilepsy(partially complex epilepsy)- anamnesis andelectroencephalogram can establish the diagnose[6, 7, 12]-

Fiziologia - Physiology • 2018.28.1(95)This study was conducted in the Neurology Clinic of the
Neuropsychiatry Hospital of Craiova, on a group of 63
patients who were admitted to the hospital between
01.01.2017 and 31.12.2017 having the diagnosis ofconfusional syndrome

OBJECTIVES
The aim of the study consisted in highlighting thedemographic, clinical and laboratory characteristics of thepatients admitted with the diagnosis of confusional
syndrome.

MATERIALS AND METHODSThe observational retrospective study was conductedbased on the analysis of the observation sheets of the 63
patients included in the study. Demographic, anamnestic
laboratory data as well as, data obtained by clinicalexamination andinformation on the treatment andevolution of these patients were extracted. The analyzed
paraclinic parameters included biological parameters(Complete blood count, erythrocyte sedimentation rate,
C-reactive protein, lipidograma, glucose, total proteins,transaminase, urea, creatinine, urinalysis exam) andimagistics parameters, the latter being provided by thecomputer tomography exam. The data was collected andprocessed by using Windows Microsoft excell 2013
program.

Fig. 1. Graphic representation with age of patientsover decades of age

Another aspect that we submitted to the statisticalanalysis was represented by the reasons for hospital
admission. So, also as stated in literature, we noticed thatthe spectrum of subjective symptoms of the patients with
confusional syndrome can be multiple and varied. A third of
the patients have fulfilled on the admission only the classicalcriteria of the confusional status (35%), the rest associatedmore or less specific symptoms of this syndrome,
represented as frequency in the following image (Figure 2).

RESULTS
From a demographic point of view, the analyzed grouppresented the following characteristics:As stated in literature[8], the diagnosis of acute confusional syndrome is mostcommonly found in the elderly population. This feature canbe found in our study, where the onset age of theconfusional syndrome is between decade 6-7, reaching apeak in the range 70-80 years. The calculated average ageof the study group is 71.5 ± 10 being slightly higher than the
one reported by other studies (ID est 65 ± 10 years) [11].
The predominance of this diagnosis to the elderly population
has as a pathophysiological hypothesis the association ofmultiple comorbidities specific to this age group [5,15,12].
Gender distribution highlights the predominance of female
patients: 57% compared to 43% for male gender.
Also,women have a tendency to lately develop thispathology, their average age is 72.3 ± 8.5 compared to 70.3
± 11.9 in men (Figure 1).

Fiziologia - Physiology • 2018.28.1(95)Fig. 2. Graphic representation -the reasonsfor hospitalization of the patients in the studied groupAs regards the comorbidities of patients included in thisstudy, the majority presented one or more associatedconditions. Thus, in the studied group, cardiovascularpathology occupied the first position as prevalence, being
represented by: congestive heart failure, valvularinsufficiency (mitral/aortic), myocardial infarction, chronic
ischemic cardiopathy, hypertension, atrial fibrillation. We
identified the following in a descending order as frequency:
hypertension, mainly of the second degree, found at morethan half of the patients (59%), atrial fibrillation, with aprevalence of 27% and dyslipidemia, an important37

cardiovascular risk factor, found in 24% of cases. All thiscontributes to primary or secondary damage, via cardiac
dysfunction of the cerebral activity. There are studies thatprove that cerebrovascular pathology represents a common
precipitating factor in the confusion state (25% of the cases),
being on the second position as frequency after infectious
causes [10].
A significant percentage of the patients experienced
glucose metabolism disorders, unbalanced glycemic
status being one of the pathophysiological causes of brain
activity disruption. Thus, 24% had type II diabetes and
16% had elevated blood glucose levels. Chronic kidneydisease can also lead to neurological complications byfailing to treat substances that may act as false
neurotransmitters or interfere with ion pump activity. In the
study group 7 patients with chronic kidney disease wereidentified. As we have shown in the introduction, liver
pathology can generate metabolic imbalances with impact
on cerebral homeostasis by favoring neuroinhibition. In thestudied group we found hepatic dysfunction at different
stages: hepatitis (HCV viral etiology in 5 cases or HBV in
2 cases), liver cirrhosis (3 cases) and decompensatedstage with the installation of hepatic encephalopathy (2cases). Also in the spectrum of metabolic disorders withcerebral, chronic alcoholism, found in patients of our study
was included (7 patients).
Computer tomography is a reliable method of imaging
exploration in terms of cost-benefit ratio. In terms of imaging
changes, a significant proportion of 37% of patients did notshow pathological changes, this result is similar to theresults obtained in other studies. Both recent and older
studies have shown that confusional syndrome has apositive and significant neuroimaging correlation withcortical atrophy (Figure 3).

Fig. 3. Graphic representation of CT performed in patientsin the studied group.

This clinical-imaging aspect was also found in thepresent study, in which, for cortical atrophy, we obtained thehighest prevalence, the only imaging change in most cases(32%) or in combination with stroke sequelae (24 %).
38

In the category entitled other detected changes
meningioma, cerebral meningoangiopathy, temporo-parietal
tumor with cavern appearance, subarachnoid cyst andrecent stroke are included.
In what laboratory parameters are concerned, the mostfrequent change was hyperglycemia, recorded in 37 patients(58.7%), followed by anemic syndrome, found in 34 patients(53.9%) and hypercholesterolemia, situated on the third
place, a change that corresponds to 26 patients (Figure 4).

Fig. 4. Graphic representation of paraclinical characteristics.

CONCLUSIONS
1. From the demographic point of view, the studied grouprespects the characteristic of the confusional
syndrome, that of being found among the elderly
population
2. Etiology is in the majority of the cases multifactorial,
being generated by the combination of imbalances
caused by multiple and varied comorbidities of theelderly patients. In the studied group, cardiovascularpathology was predominant, followed by diabetes
mellitus, dyslipidemia, renal, hepatic andcerebrovascular pathology (ishemic sechelar stroke).
3. The spectrum of clinical symptoms presented by thepatients with confusional syndrome is extremely
variable and includes, in addition to classicalsymptoms, nonspecific symptoms such as: gait andbalance disorders, dizziness, headache
4. From the imaging point of view, the main change
observed in the patients included in the study wascortical atrophy, which is also a common
neuroimaging characteristic found in elderly patientswith confusional syndrome
AUTHOR CONTRIBUTION
Albu Valeria Carmen and Sandu Raluca Elena have equallycontributed to this paper

Fiziologia - Physiology • 2018.28.1(95)REFERENCES
1.

2.
3.

4.
5.
6.
7.

8.

Adamis D, Treloar A, McDonal AJ, et al. Concurrent validityof two instruments (the Confusion Asessment Method andDelirium Rating Scale) in the detection of delirium amongolder medical inpatients. Age Ageing, 2005, 34:72.
Akunne A, O’Mahony R. Guideline Development Group:
Diagnosis, prevention and management of delirium:
Summary of NICE guidance. BMJ, 2010; 341:c3704.
M D Cavallari M, PhD Hshieh TT, M D Guttmann C, et al.
Brain atrophy and white matter hyperintensities are notsignificantly associated with incidence and severity of
postoperative delirium in older persons without dementia.
Neurobiol Aging. 2015; 36(6): 2122-2129.
Francis J, Aminoff M,Schmader EK. Delirium and acuteconfusional states, 2013 UpToDate
George J, Bleasdale S, Singleton SJ. Causes and prognosis
of delirium in elderly patients admitted to a district general
hospital. Age Ageing, 2006, 35:350-64.
Goldman-Rakic PS. Working memory and the mind, 1992,
Sci Am, 267:110
Kopelman MD. Disorders of memory, 2002, Brain 125:2152

9.
10.

11.
12.
13.
14.
15.

Lorenzl S, Fusgen I, Noachtar S. Acute Confusional States inthe Elderly - Diagnosis and Treatment, Deutsches Arzteblatt,2012 ,109(21): 391-400.
O Keeffe ST, Ni CA. Postoperative delirium in elderly.
Anaesthesia Br J , 1994,73:673-87.
Rahkonen T, Makel H, Paanila S, et al. Delirium in elderly
people without severe predisposing disordrs: etiology andone year prognosis after discharge. Psychogeriatric,
2000,12:473-81
Raj D, Garg RK, Malhotra HS, et al. Acute confusional
state/delirium: An etiological and prognostic evaluation. Ann
Indian Acad Neurol, 2014; 17(1): 30-34.
Ropper AH, Samuels MA, Klein JP. Adams and Victor s
Principles of Neurology, tenth edition, 2014, section5,
chapter 20.
Saxena S, Lawley D. Delirium in elderly: a clinical review.
Postgrad Med J, 2009, 85: 405-413.
Singler B. Das postoperative Delir. Geriatrie Journal, 2010;
2:41-42.
Schorl JD, Levkoff SE, Lipsitz LA, et al. Risk factors fordelirium in hospitalized elderly. JAMA, 1992, 267:827-31.

ASPECTE CLINICO-ETIOLOGICE ALE SINDROMULUICONFUZIONALREZUMAT
Sindromul confuzional acut, cunoscut și ca delir în literatura de specialitate, este unul dintre motivele frecvente de internare
în spital, mai ales în rândul populației vârstnice. Scopul studiului a constat în evidențierea caracteristicilor demografice,clinice și paraclinice ale pacienților internați cu diagnosticul de sindrom confuzional.
Metode: Studiul de tip retrospectiv observațional a fost realizat pe baza analizei foilor de observație ale celor 63 de pacienți
inclusi în studiu. Au fost extrase date de ordin demografic, anamnestic, de examen clinic și paraclinic, precum și informații
cu privire la tratamentul și evoluția acestor pacienti. Elementele paraclinice analizate au fost de ordin biologic(Hemoleucograma, Viteza de sedimentare a hematiilor, Proteina C reactiva, lipidograma, glicemie, proteine totale,transaminaze, uree, creatinină, examen sumar de urină) și imagistic, acestea din urmă fiind furnizate de examenul
computer tomograf.
Rezultate: Vârsta de debut a sindromului confuzional se situează în decadele 6-7, atingând un vârf în intervalul 70-80 deani. Vârsta medie calculată a lotului de studiu este de 71,5±10 fiind ușor mai ridicată față de cea raportată de alte studii (idest 65±10 ani.). Distribuția pe sexe pune în evidență predominanța pacienților de sex feminin: 57% față de 43% pentru
sexul masculin. O treime dintre pacienti au indeplinit la internare doar criteriile clasice ale stării confuzionale (35%). Am
identificat în ordine descrescătoare ca frecvență: hipertensiune arterială, preponderent de gradul II, regăsită la mai mult dejumătate dintre pacienți (59%), fibrilație atrială, cu o prevalență de 27% și dislipidemia, important factor de risc
cardiovascular, regăsită în 24% din cazuri. Din punct de vedere al modificărilor imagistice, un procent considerabil de 37%
dintre pacienți nu au prezentat modificări patologice, ponderea acestui grup fiind asemănătoare cu cea obținută în altestudii. Din punct de vedere al parametrilor de laborator, cea mai frecventă modificare decelată este hiperglicemia,înregistrată la un număr de 37 de pacienți (58,7%), urmată de sindromul anemic, regăsit la 34 de pacienți (53,9%) și pelocul trei de hipercolesterolemie, modificare ce corespunde unui număr de 26 pacienți.
Concluzii: Spectrul acuzelor clinice ale pacienților internați cu diagnosticul de sindrom confuzional este extrem de variabil
și cuprinde, pe lângă simptomele clasice, simptome nespecifice de tipul: tulburări de mers și echilibru, amețeală, cefalee.
Din punct de vedere imagistic, principala modificare decelată la pacienții din studiu a fost atrofia corticală, aceasta fiind
dealtfel o caracteristică neuroimagistică frecvent identificată la pacienții vârstnici cu sindrom confuzional
Cuvinte cheie: sindrom confuzional acut, delir, factorii de risc, populatie vârstnică, comorbidități

Fiziologia - Physiology • 2018.28.1(95)39CLINICAL PATTERNS OF NEUROPSYCHIATRICSYSTEMIC LUPUS ERYTHEMATOSUSSANDU RALUCA ELENA1*, BARBULESCU ANDREEA LILI2*, FLORESCU
ANDREEA OANA3*, PIRSCOVEANU DENISA 4, BUMBEA ANA-MARIA5,PARVULESCU OCTAVIA CORINA6, TARTEA ANCA ELENA6, BOGDANCATALIN7, BALSEANU TUDOR ADRIAN7, ENESCU AURELIA8, MIREA CECIL
SORIN9, ALBU VALERIA CARMEN4, BURADA EMILIA7
1Departament of Biochemistry, University of Medicine and Pharmacy of Craiova, Romania
2Departament of Pharmacology, University of Medicine and Pharmacy of Craiova, Romania
3Departament of Radiology, University of Medicine and Pharmacy of Craiova, Romania
4Departament of Neurology, University of Medicine and Pharmacy of Craiova, Romania
5Department of Medical Rehabilitation, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania
6Neuropsychiatry Hospital of Craiova, Romania
7Department of Functional Sciences, University of Medicine and Pharmacy of Craiova, Romania
8Department of Medico-Surgical Emergencies, University of Medicine and Pharmacy of Craiova
9Department of Surgery, University of Medicine and Pharmacy of Craiova, Romania

ABSTRACT
Systemic lupus erythematosus is an autoimmune, systemic, chronic disease with relapsing-remitting episodes whose
etiology is unknown and with heterogeneous manifestations. It includes various manifestations, both in the neurologicaland psychiatric spheres. Neuropsychiatric manifestations may embrace various aspects such as headaches, seizures,
psychosis, acute confusional state and cognitive impairment. These neuropsychiatric manifestations are called systemic
neuropsychiatric lupus erythematosus (NPSLE). The risk factors consistently associated with neuropsychiatricmanifestations of the systemic lupus erythematosus are (1) the general activity of the disease, in particular the damage
caused by seizure disorders and severe cognitive impairment (2) previous events or other NPSLE intercurrent
manifestations and (3) antiphospholipid antibodies (persistently moderate-to-high increased titre of anticardiolipin, antiβ2-glycoprotein IgG/IgM or lupus anticoagulant), especially for cerebrovascular disease (CVD), seizure disorder,
moderate-to-severe cognitive impairement, myelopathy and movement disorder. This article provides a comprehensive
and critical review of the literature on the pathophysiology, diagnosis, and management of NPSLE.
Keywords: neuropsychiatric systemic lupus erythematosus (NPSLE); immunosuppressive treatment; antiphospholipid
antibodies; treatment of neuropsychiatric systemic lupus erythematosus

CLINICAL PATTERNSSystemic lupus erythematosus is an autoimmune,systemic, chronic disease with relapsing-remitting episodes
whose etiology is unknown and with heterogeneous
manifestations. It includes various manifestations, both in
the neurological and psychiatric spheres [15].
Neuropsychiatric manifestations may embrace various

aspects such as headaches, seizures, psychosis, acuteconfusional state and cognitive impairment. Renal andneuropsychiatric involvements are associated with a higher
mortality and morbidity rate [38].
These neuropsychiatric manifestations are calledsystemic neuropsychiatric lupus erythematosus (NPSLE)(Figure 1).

Received April 14th 2018. Accepted May 2nd 2018. Address for correspondence: Albu Valeria Carmen, Lecturer, MD, PhD, Department of
Neurology, University of Medicine and Pharmacy of Craiova,2 Petru Rareş Street, 200349 Craiova, Romania; Phone +40351–443 500, email: carmenvaleriaalbu@yahoo.com

40

Fiziologia - Physiology • 2018.28.1(95)Fig.1. Neuropsychiatric syndromes in SLE as per ACR
classification

The risk factors consistently associated withneuropsychiatric manifestations of the systemic lupus
erythematosus are (1) the general activity of the disease, inparticular the damage caused by seizure disorders andsevere cognitive impairment [1, 24, 41]; (2) previous eventsor other NPSLE intercurrent manifestations [2, 8, 25]; and(3) antiphospholipid antibodies (persistently moderate-tohigh increased titre of anticardiolipin, anti-β2-glycoprotein
IgG/IgM or lupus anticoagulant), especially for
cerebrovascular disease (CVD), [24, 8] seizure disorder,
moderate-to-severe cognitive impairement, myelopathy andmovement disorder [34, 27].
In terms of headache as a manifestation ofneuropsychiatric lupus, caution is important in excluding
septic or aseptic meningitis, sinus thrombosis (in particularin patients with positive antiphospholipid antibodies),
cerebral or subarachnoid haemorrhage.
In the absence of the risk factors from medical history
and physical examination (including intercurrent infections,fever, positive antiphospholipid antibodies, administration of
anticoagulants, immunosuppresion, focal neurologicaldeficits, altered cognitive status, meningismus and generaldisease activity in systemic lupus erythematosus),
headaches not accompanied by other manifestations in a
SLE patient do not require any investigations, other thanevaluation, compared to those made for non – SLE patients.
Regarding cerebrovascular disease, ischemic stroke
and/or TIA include over 80% of CVD cases, while CNS
vasculitis is rare.
Cognitive impairment is widespread among patientswith SLE, but heterogeneous in this type of patient
population was reported in 20 to 80 percent of the patientswith SLE [14, 39,43]. It is a subtle manifestation that occurs
with a high frequency and which could be present before any
neuropsychiatric manifestations in systemic lupus
erythematosus. Patients affected by neuropsychiatricmanifestations in systemic lupus erythematosus usually
Fiziologia - Physiology • 2018.28.1(95)complain about having problems with memory andexecutive skills such as attention, visual-spatial function,verbal fluency, motor function as well as planning,organizing and sequencing information. It is often difficult todifferentiate NPSLE form other independent psychologicaldisorders. Moreover, the drug-induced cognitive dysfunction
associated with corticosteroids is another consideration in
the diagnosis of NPSLE. In 1999 the American College of
Rheumatology (ACR) provided nomenclature to determine
the [35] neuropsychiatric syndromes seen in SLE [42].
Cognitive impairment in NPSLE is in close touch withhippocampal atrophy caused by autoantibodies [31],cytokines, hormones [20] and vascular pathologies such as
microvasculopathy or thrombosis [33]. Zimmermann et al.
demonstrated through imaging studies lower volume of theleft hippocampus, amygdala and right hippocampus inpatients with cognitive impairment suffering from SLE
compared to their counter parts [47]. The performance ofcognition may be affected by the local anatomic
heterogeneity of the white matter damage. Language
deficiency is one of the first deficiencies that develops underneurological conditions. The specific brain language areas
represented by both Broca’s and Wernike’s areas are
deficient in non-symptomatic SLE patients [21]. There by,
DiFrancesco et al. noticed a more pronounced involvementof the Broca’s area compared to Wernike during verb
generation in SLE. Memory is a complex entity, wich
involves many different brain areas. DiFrancesco et al.
demonstrated in his studies a greater activation of the
hippocampus and prefrontal regions associated withmemory in SLE patients.
Vitamin D deficiency is a potential risk factor forcognitive impairment within the general population. [4,10,46]
as first observed in animal studies. Low levels of serum
25(OH) D are associated with poor cognitive functions [36],while others do not report such an association.[3][10]. In ourstudy there was a significant correlation between vitamin D
and the reduced executive functioning, also demonstrated
by Tay et al in patients with SLE [40]. The 25(OH) D3
crosses the blood-brain barrier to reach vitamin D receptors(VDRs), which are present on neurons and glial cells of the
CNS, often co-localized in cells expressing 1α-hydroxylase.
This is necessary for conversion of 25(OH) D3 to the
biologically active 1,2 (OH) 2D3 in the CNS, which facilitates
proper cognitive brain functioning [23,17]. Vitamin D
deficiency influences the prognosis of patients with SLE andappears to have a significant negative impact on cognitive
function in the general population.
Convulsive disorders in SLE may embrace various
aspects from generalised tonic-clonic seizures (67-88%) topartial (complex) seizures. Most of them are single isolated
events, while recurrent seizures (epilepsy) account for 1222% with a significant impact on mortality and morbidity.
Movement disorders like chorea (irregular, involuntaryand jerky movements involving any part of the body in41

unnatural order) is the most common movement disorder in
SLE, and it is also associated with antiphospholipid
antibodies.
Acute confusional state is characterised by fluctuatinglevel of consciousness with acut onset and decreased
attention.
Lupic psychosis can dress the appearance of
hallucinations (perceptions in the absence of external
stimuli) or delusions (false beliefs refuted by objective
evidence). Cortisone psychosis is common in 10% of
patients treated with prednisone 1 mg/kg or more and it
manifests primarily as a mood disorder (93%) more thanpsychosis [9]. In prospective studies anti-ribosomal-P
antibodies have been associated with psychiatric SLE(sensitivity 25–27%, specificity 75–80%) [7,13].
Lupus myelopathy is manifested either as a transverse
myelitis with rapid progressive development or as anischemic/thrombotic myelopathy. Patients usually present
with symptoms due to lesions of lower motor neuron suchas flaccid paralysis, loss of muscle tone, hyporeflexia or
upper motor neuron wich often presents with spastic
paralysis, severe hipertonia and hyperreflexia. The lattercan rather be associated with neuromyelitis optica (NMO)
and antiphospholipid syndrome [6].
Most frequent cranial neuropathies involve the eighth,
the oculomotor (third, fourth and sixth), and less commonly
the fifth and seventh nerves. Optic neuropathy includes
inflammatory optic neuritis and ischaemic/thrombotic optic
neuropathy.
Peripheral nervous system disorders include
polyneuropathy(2-3%)
andlesscommonlymononeuropathy (single, multiplex), acute inflammatory
demyelinating polyradiculopathy, myastenia gravis,
plexopathy which are characterized by painful sensations,muscle weakness and atrophy. When focal neurologicalsigns as gait disturbance, visual or urinary disorder,
increased tendon reflexes and/or muscle tone are present,
neuroimaging is necessary to exclude the involvement of thecentral nervous system.
Autoantibodies orientated against certain receptors
found in the brain and against proteins found in the cellular
membranes. Interferons and cytokines may also be
involved. Some of the antibodies that may be involved are
mentioned in Figure 2.

Fig. 3. Autoantibodies associated with cognitive dysfunction,
psychosis and depression in SLE

Certainantibodies
including
antiphospholipid
antibodies, anti-ribosomal P antibodies, anti-N-methyl-Daspartate (NMDA) receptor antibodies and anti-endothelial
cell antibodies can be related to central nervous system(CNS) symptoms such as seizures and stroke. NMDA
receptors play a role in maintaining the synapse conduction
and the plasticity of the central nervous system. These
receptors being ligand-gated ion channels are important inmemory, cognition and also in neural function.

Fig. 4. Pathopsysiology of neuropsychiatric SLE
Fig. 2. Autoantibodies in neuropsychiatric SLE

42

Fiziologia - Physiology • 2018.28.1(95)In patients suffering from fever or presenting signs and
GENERAL TREATMENT
symptoms that are suggestive for infection, theexamination of the cerebrospinal fluid (CSF) (meaning
Treatment with aspirin should be initiated for all patients
performing PCR for herpes simplex virus (HSV) and JC
excepting those who can undergo a surgical or thrombolytic
virus) can be useful in order to exclude CNS infection. CSF
therapy. Control of the cardiovascular risk factors, therapy
mild abnormalities may be noticed but they are not specificwith antiplatelet agents as well as carotid endarterectomy
for NPSLE. Nevertheless, EEG studies may be useful inare indicated as secondary prevention. Glucocorticoids
diagnosing an underlying seizure disorder. Neuroimaging
together with immunosuppressive therapy are used as atherapy for lupus. In patients presenting moderate-to-highmay detect NPSLE involvement and exclude otherlevels of antiphospholipid antibodies, chronic oral
(neurosurgical, infectious) causes. In active NPSLE MRI
anticoagulation therapy has to be taken into account [18,28].
has an average sensitivity of 57% (64% in the major form
compared to 30% in the minor form of
NPSLE, 76% in the focal form compared to
51% in the diffuse form of NPSLE). Small
hyperintense T2-weighted focal lesions found in
the subcortical and periventricular white matter(WM), mainly in the frontal and parietal regions
are considered a pathological pattern. But, on
the other hand, thes lesions described on the
MRI can also be seen in patients not having
neuropsychiatric symptoms (specificity 60–82%) [19,29,37].
Imagistic explorations including
MRI
angiography, CT angiography, or conventional
angiography proved to be useful in detecting
vascular lesions, aneurysms in subarachnoid
haemorrhage. Moreover, MRI/DWI excludes
haemorrhage, and identifies vascular regions inacute stroke [16].
In patients suffering from SLE with seizure
disorder abnormalities on the EEG are often
found (60-70%), certain EEG patterns
suggestive for epilepsy and predictive forseizure recurrence are only found in 24–50%
of the cases (positive predictive value 73%,
negative predictive value 79%) [2,11].
Bilateral optic nerve damage can behighlighted before it becomes clinicallyobserved by using the visual-evoked
potentials. Contrast-enhanced MRI shows an
optic nerve enhancement in 60–70% of thecases.
Nerve-conduction-studies (NCS) andneedle-electromyography proved to be
useful in identifying mononeuropathies, as
Fig. 5. Management of Neuropsychiatric Systemic Lupus Erythematosus
well as in differentiating multiple
mononeuropathies from polyneuropathy andit was also useful in highlighting differences
In patients presenting single/infrequent seizures a
between axonal anddemyelinating neuropathies.
treatment with antiepileptic drugs should not be considered,
Moreover,in the inflammatory demyelinating
excepting the presence of high-risk recurrence featurespolyradiculoneuropathy the CSF analysis was very useful.
including two or more unprovoked seizures within the last 24
In certain cases when the electrodiagnostic studies arehours, severe brain damage and MRI brain abnormalities
normal skin biopsy illustrating a loss of intraepidermal
related to seizures and partial seizures on EEG.
nerve fibres is useful in diagnosing small-fibre neuropathy,
A second AED in order to control seizure activity will be
nerve biopsy is rarely used nowadays [45].
needed for a quarter of the patients. Glucocorticoids alone
Fiziologia - Physiology • 2018.28.1(95)43or combined with immunosuppressive drugs may be needed
if seizures are a reflection of an acute inflammatory event or
lupus flare is present. Refractory seizures responded well to
the treatment combining intravenous methylprednisolone
with cyclophosphamide [5].
For controlling NPSLE activity dopamine antagonists areused as a symptomatic therapy as well as immunosuppressive
agents (azathioprine, cyclophosphamide) in combination withglucocorticoids for movement disorders.
Antidepressive and antipsychotic agents are included in
the management of psychiatric disorders, as well as
biofeedback-assisted cognitive behavioral treatment, thatproved useful in treating depressive symptoms [12].
Glucocorticoids and immunosuppressive drugs proved
significant results (60–80% response) in treating psychiatricdisorders. Relapses were also stated (up to 50%)
[32,22,26,30]. Rituximab showed a significant improvementin psychiatric refractory manifestations [44].
Only 20% of SLE patients develop in time chronic
psychotic disorder.
25 SLE-related optic neuritis accompanied by weakvisual outcome, only a percentage of 30% of the patients
have a visual acuity greater than 20/25. Treatment for thistype of neuropathy consists of a combination between
methylprednisolone and cyclophosphamide, both withintravenous administration. In antiphospholipid-positive
patients that do not respond to immunosuppressive drugs
anticoagulants may be a solution.
In treating peripheral nervous system disorders
glucocorticoids alone or in combination withimmunosuppressive drugs had good results (60–75%
response rate). In severe cases plasma exchange, rituximab
and immunoglobulin with intravenous administration proved
good results.
AUTHOR CONTRIBUTION
Sandu Raluca Elena, Barbulescu Andreea Lili and Florescu
Andreea Oana have equally contributed to this paper

REFERENCES
1. Andrade RM, Alarcón GS, González LA et al: Seizures inpatients with systemic lupus erythematosus. LUMINA, amultiethnic cohort (LUMINA LIV). Ann Rheum Dis 2008; 67:
829–34.
2. Appenzeller S, Cendes F, Costallat LT: Epileptic seizures insystemic lupus erythematosus. Neurology 2004; 63: 1808-12 .
3. Aung K, Burnett J, Smith SM et al: Vitamin D deficiency
associated with self-neglect in the elderly. J Elder Abuse Negl.
2006;18(4):63–78.
4. Balion C, Griffith LE, Strifler L et al: Vitamin D, cognition, anddementia: A systematic review and meta-analysis. Neurology.
2012;79(13): 1397–1405.
5. Barile-Fabris L, Ariza-Andraca R, Olguín-Ortega L et al:Controlled clinical trial of IV cyclophosphamide versus IV
methylprednisolone in severe neurological manifestations in

44systemic lupus erythematosus. Ann Rheum Dis 2005; 64:
620–5.
6. Birnbaum J, Petri M, Thompson R et al: Distinct subtypes ofmyelitis in systemic lupus erythematosus. Arthritis Rheum
2009; 60 : 3378 – 87.
7. Briani C, Lucchetta M, Ghirardello A et al: Neurolupus isassociated with anti-ribosomal P protein antibodies: an
inception cohort study. J Autoimmun 2009; 32 : 79 – 84.
8. Buján S, Ordi-Ros J, Paredes J et al: Contribution of the initialfeatures of systemic lupus erythematosus to the clinicalevolution and survival of a cohort of Mediterranean patients.
Ann Rheum Dis 2003; 62 : 859–65.
9. Chau SY, Mok CC. Factors predictive of corticosteroid
psychosis in patients with systemic lupus erythematosus.
Neurology 2003; 61: 104-7.
10. Etgen T, Sander D, Bickel H et al: Vitamin D deficiency, cognitive
impairment and dementia: a systematic review and metaanalysis. Dement Geriatr Cogn Disord. 2012;33(5):297–305.
11. González-Duarte A, Cantú-Brito CG, Ruano-Calderón L et al:
Clinical description of seizures in patients with systemic lupus
erythematosus. Eur Neurol 2008; 59: 320–3.
12. Greco CM, Rudy TE, Manzi S: Effects of a stress-reduction
program on psychological function, pain and physical functionof systemic lupus erythematosus patients: a randomized
controlled trial. Arthritis Rheum 2004; 51: 625–34.
13. Hanly JG, Urowitz MB, Siannis F et al: Autoantibodies andneuropsychiatric events at the time of systemic lupus
erythematosus diagnosis: results from an international
inception cohort study. Arthritis Rheum 2008; 58: 843 – 53.
14. Harrison MJ, Ravdin LD: Cognitive dysfunction inneuropsychiatric systemic lupus erythematosus. Curr Opin
Rheumatol. 2002;14(5):510–514.
15. Hoda AH MD, Lamiaa ID MD, Nermeen AF MD et al. Does
Vitamin D Deficiency Contribute to Cognitive Dysfunction in
Patients with Systemic Lupus Erythematosus? Innov Clin
Neurosci 2018:15(9–10):25–29.
16. Ioannidis JPA, Aringer M, Bollen E et al: EULAR
recommendations for the management of systemic lupus
erythematosus with neuropsychiatric manifestations: report ofa task force of the EULAR standing committee for clinicalaffairs.
Dis
2010;69:2074–2082.
doi:10.1136/ard.2010.130476.
17. Johansson P, Almqvist EG, Johansson J-O et al:
Cerebrospinal fluid (CSF) 25-hydroxyvitamin D concentration
and CSF acetylcholinesterase activity are reduced in patientswith Alzheimer’s disease. PLoS One. 2013;8(11):e81989.
18. Khamashta MA, Cuadrado MJ, Mujic Fet al:The managementof thrombosis in theantiphospholipid-antibody syndrome. N
Engl J Med 1995; 332 : 993 –7.
19. Kozora E, West SG, Kotzin BL et al Magnetic resonanceimaging abnormalities and cognitive deficits in systemic lupus
erythematosus patients without overt central nervous systemdisease. Arthritis Rheum 1998; 41: 41–7.
20. Kozora E, Laudenslager M, Lemieux A et al: Inflammatory andhormonal measures predict neuropsychological functioning insystemic lupus erythematosus and rheumatoid arthritis
patients. J Int Neuropsychol Soc. 2001;7(6):745-54.
21. Maeshima E, Yamada Y, Yukawa S: Higher corticaldysfunction, antiphospholipid antibodies and neuroradiologicalexaminations in systemic lupus erythematosus. Intern Med.
1992;31(10):1169-74.
Fiziologia - Physiology • 2018.28.1(95)22. Martin-Suarez I, D’Cruz D, Mansoor Met al:Immunosuppressive
treatmentin severe connective tissue diseases: effects of low
dose intravenouscyclophosphamide. Ann Rheum Dis 1997;
56 481–7.
23. McGrath J, Feron F, Eyles D et al: Vitamin D: the neglected
neurosteroid? Trends Neurosci. 2001;24(10):570–572.
24. Mikdashi J, Handwerger B: Predictors of neuropsychiatricdamage in systemic lupus erythematosus. Maryland lupus
cohort. Rheumatology (Oxford) 2004; 43: 1555–60 .
25. Mikdashi J, Krumholz A, Handwerger B: Factors at diagnosis
predict subsequent occurrence of seizures in systemic lupus
erythematosus. Neurology 2005; 64: 2102–7.
26. Mok CC, Lau CS, Wong RW: Treatment of lupus psychosis
with oralcyclophosphamide followed by azathioprinemaintenance: an open-label study. Am J Med 2003; 115:
59–62.
27. Mok MY, Chan EY, Fong DY et al: Antiphospholipid antibody
profi les and their clinical associations in Chinese patientswith systemic lupus erythematosus. J Rheumatol 2005; 32:
622–8.
28. Muñoz-Rodriguez FJ, Font J, Cervera R et al: Clinical study
and follow-up of 100 patients with the antiphospholipid
syndrome. Semin Arthritis Rheum 1999; 29: 182–90.
29. Nomura K, Yamano S, Ikeda Y et al: Asymptomatic
cerebrovascular lesions detected by magnetic resonanceimaging in patients with systemic lupus erythematosus
lacking a history of neuropsychiatric events. Intern Med
1999; 38: 785–95.
30. Pego-Reigosa JM, Isenberg DA: Psychosis due to systemic
lupus erythematosus:characteristics and long-term outcomeof this rare manifestation of the disease. Rheumatology(Oxford) 2008; 47: 1498–502.
31. Peretti CS, Peretti CR, Kozora E et al: Cognitive impairment
in systemic lupus erythematosus women with elevatedautoantibodies and normal single photon emission
computerized tomography. Psychother Psychosom.
2012;81(5):276-85.
32. Rahman P, Humphrey-Murto S, Gladman DD et al: Cytotoxic
therapy in systemic lupus erythematosus. Experience from asingle center. Medicine (Baltimore)1997; 76: 432–7.
33. Sankowski R, Mader S, Valdes-Ferrer SI: Systemic
inflammation and the brain: novel roles of genetic, molecular,
and environmental cues as drivers of neurodegeneration.
Front Cell Neurosci. 2015;9:28.
34. Sanna G, Bertolaccini ML, Cuadrado MJ et al: Neuropsychiatricmanifestations in systemic lupus erythematosus: prevalence
and association with antiphospholipid antibodies. J Rheumatol
2003; 30: 985– 92.

Fiziologia - Physiology • 2018.28.1(95)35. Sarbu N, Alobeidi F, Toledano P et al: Brain abnormalities
in newly diagnosed neuropsychiatric lupus: systematic
MRI approach and correlation with clinical and laboratory
data in a large multicenter cohort. Autoimmun Rev.
2015;14(2):153-9.
36. Sato Y, Honda Y, Hayashida N et al: Vitamin K deficiency
and osteopenia in elderly women with Alzheimer’s disease.
Arch Phys Med Rehabil. 2005;86(3):576–581.
37. Sibbitt WL Jr, Sibbitt RR, Griffey RH et al: Magnetic
resonance and computed tomographic imaging in theevaluation of acute neuropsychiatric disease in systemic
lupus erythematosus. Ann Rheum Dis 1989; 48: 1014–22.
38. Tamirou F, Arnaud LTR, et al: Systemic lupus
erythematosus: state of the art on clinical practiceguidelines. RMD Open 2018: 4: e000793. doi:10.1136/
rmdopen-2018-000793.
39. Tay SH, Mak A: Anti-NR2A/B antibodies and other major
molecular mechanisms in the pathogenesis of cognitive
dysfunction in systemic lupus erythematosus. Int J Mol Sci.
2015;16(5): 10281–10300.
40. Tay SH, Ho CS, Ho RC-M et al: 25-Hydroxyvitamin D3
deficiency independently predicts cognitive impairment inpatients with systemic lupus erythematosus. PLoS One.
2015;10(12):e0144149.
41. Tomietto P, Annese V, D’Agostini S et al: General andspecific factors associated with severity of cognitive
impairment in systemic lupus erythematosus. Arthritis
Rheum 2007; 57: 1461–72 .
42. The American College of Rheumatology nomenclature andcase definitions for neuropsychiatric lupus syndromes.
Arthritis Rheum. 1999;42(4):599-608.
43. The American College of Rheumatology nomenclature andcase definitions for neuropsychiatric lupus syndromes.
Arthritis Rheum. 1999;42:599–608.
44. Tokunaga M, Saito K, Kawabata D et al: Efficacy of rituximab(anti-CD20) for refractory systemic lupus erythematosus
involving the central nervous system. Ann Rheum Dis 2007;
66: 470–5.
45. Tseng MT, Hsieh SC, Shun CT et al: Skin denervation andcutaneous vasculitis in systemic lupus erythematosus. Brain
2006; 129: 977–85.
46. Yap KS, Morand EF: Vitamin D and systemic lupus
erythematosus: continued evolution. Int J Rheum Dis.
2015;18(2):242–249.
47. Zimmermann N, Corrêa DG, Kubo TA et al: Global cognitive
impairment in systemic lupus erythematosus patients: astructural MRI study. Clin Neuroradiol. 2017;27(1):23-9.

45

AFECTAREA NEUROPSIHIATRICA IN LUPUS
ERITEMATOS SISTEMIC - ASPECTE CLINICEREZUMAT
Lupusul eritematos sistemic este o boală sistemică,autoimună, cronică, cu episoade recurent-remisive, a cărei etiologie
este necunoscută și cu manifestări heterogene. Această boală include diverse simptome, atât în sfera neurologică, cât șiîn cea psihiatrică. Manifestările neuropsihiatrice pot cuprinde diverse aspecte, cum ar fi dureri de cap, convulsii, psihoze,
stare de confuzie acută și tulburări cognitive. Aceste manifestări neuropsihiatrice fac parte din lupusul eritematos sistemic
neuropsihiatric (NPSLE). Factorii de risc frecvent asociați cu manifestările neuropsihiatrice ale lupusului eritematos sistemic
sunt (1) activitatea generală a bolii, în special leziunile provocate de convulsii și de tulburările cognitive severe (2)evenimentele anterioare sau alte manifestări intercurente ale NPSLE și (3) anticorpiantifosfolipidici (titruri anticardiolipin,
IgG / IgM anti-β2-glicoprotein anti-β2 sau anticoagulant lupus), în special pentru boala cerebrovasculară (CVD), tulburări
convulsive, tulburări cognitive moderate până la severe, mielopatie și tulburări de mișcare. Ne propunem o trecere în revistă
a principalelor aspecte referitoare la fiziopatologia, diagnosticul și managementul manifestarilor neuropsihiatrice dinlupusului eritematos sistemic.
Cuvinte cheie: manifestări neuropsihiatrice în Lupus eritematos sistemic; tratament imunospresiv, anticorpi
antifosfolipidici; tratamentul lupusului eritematos sistemic cu manifestări neuropsihiatrice46

Fiziologia - Physiology • 2018.28.1(95)