bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient Risk Factors Do Not Impact 90-Day Readmission and Emergency Department Visitation After Total Ankle Arthroplasty
Authors: Cunningham Daniel , Karas Vasili , DeOrio James , Nunley James , Easley Mark , Adams Samuel
Published: August 2018

Background:

The Comprehensive Care for Joint Replacement (CJR) model provides bundled payments for in-hospital care and care within 90 days following discharge for Medicare beneficiaries undergoing lower-extremity joint replacement involving the hip, knee, or ankle (total hip arthroplasty, total knee arthroplasty, or total ankle arthroplasty [TAA]). The study hypothesis was that patient comorbidities are associated with readmissions, emergency department (ED) utilization, and subspecialist wound-healing consultation, which are examples of costly contributors to postoperative health-care spending.

Methods:

The medical records for 1,024 patients undergoing TAAs between June 2007 and December 2016 at a single academic center in the southeastern United States were reviewed for the outcomes of readmissions, ED visitations, and subspecialist wound-healing consultation within the 90-day post-discharge period. All patients undergoing TAA (n = 1,365) were eligible. Of the 1,037 patients who consented to participation in the study and underwent TAA, 1,024 (98.7%) completed the study. Medical comorbidities according to the Elixhauser and Charlson-Deyo comorbidity indices that were present prior to TAA were recorded. Univariate and multivariable tests of significance were used to relate patient and operative characteristics to outcomes.

Results:

Four hundred and ninety-six (48.4%) of the 1,024 patients were female, and 964 (94.1%) were white/Caucasian, with an average age (and standard deviation) of 63 ± 10.5 years. Hypertension, obesity, solid tumor, depression, rheumatic disease, cardiac arrhythmia, hypothyroidism, diabetes mellitus, and chronic pulmonary disease had a prevalence of >10%. Fifty-three (5.2%) of the 1,024 patients were readmitted for any cause. Thirty-six (3.5%) of the 1,024 returned to the ED but were not admitted to the hospital. Readmission or ED visitation was most commonly for a wound complication, followed by deep venous thrombosis (DVT) and pulmonary embolism (PE) evaluation, while urgent medical evaluations composed the majority of non-TAA-related ED visitations. No patient comorbidities were significantly associated with 90-day readmission, ED visitation, or wound complications in multivariable models.

Conclusions:

Patient comorbidities were not associated with 90-day hospital readmissions or ED visitation for patients undergoing TAA. Readmissions were dominated by evaluation of wound compromise as well as DVT and PE. These data suggest that there may be considerable differences between TAA and total hip arthroplasty or total knee arthroplasty that cause surgeons to question the inclusion of TAA in CJR bundled payment models.

Level of Evidence:

Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Early Surgical Stabilization of Complex Chest Wall Injuries Improves Short-Term Patient Outcomes
Authors: Iqbal Hafiz J. , Alsousou Joseph , Shah Sohan , Jayatilaka Lara , Scott Sharon , Scott Simon , Melling David
Published: August 2018

Background:

This study aimed to assess the outcome of patients undergoing internal fixation of complex rib fractures in a U.K. major trauma center.

Methods:

A retrospective analysis was performed on all patients undergoing operative fixation of rib fractures from March 2014 to May 2016. Outcome measures included hospital length of stay, intensive care unit (ICU) admission, mechanical ventilation, infection, and mortality.

Results:

One hundred and two patients (66 male patients and 36 female patients, with a median age of 62 years) underwent rib fracture fixation during the study period. The causes of trauma were road traffic accidents in 39 patients (38%), a fall from a substantial height in 38 patients (37%), and a fall down stairs in 21 patients (21%). Thirty-eight patients (37%) had isolated chest trauma, and 64 patients (63%) had additional injuries. Fifty-three patients (52%) required ICU admission with a mean ICU stay of 4.7 days (range, 1 to 34 days). The median hospital length of stay was 10.6 days (range, 3 to 51 days). Patients with additional injuries (p = 0.01) and those requiring mechanical ventilation (p < 0.0001) stayed significantly longer. Sixty-five patients (64%) underwent rib fixation within 48 hours of the injury, and 37 patients (36%) underwent the surgical procedure after 48 hours. A surgical procedure within 48 hours resulted in a shorter ICU stay (p = 0.01), fewer cases of pneumonia (p = 0.001), reduced duration of mechanical ventilation (p = 0.03) and fewer tracheostomies (p = 0.02), and shorter hospital length of stay (11.5 compared with 17.3 days; p = 0.008).

Conclusions:

Surgical stabilization of multiple rib fractures may improve the outcome in patients with multiple injuries and isolated chest wall trauma. Early surgical fixation leads to shorter length of stay and better outcomes.

Level of Evidence:

Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Cross-Linked Polyethylene for Total Hip Arthroplasty Markedly Reduces Revision Surgery at 16 Years
Authors: de Steiger R. , Lorimer M. , Graves S.E.
Published: August 2018

Background:

Total hip arthroplasty (THA) is an effective operation for the management of end-stage hip osteoarthritis, but long-term success can be limited by wear of the polyethylene bearing surface. Cross-linking conventional polyethylene has resulted in lower wear rates and a reduction in bone lysis in both laboratory and clinical studies. The aim of this study was to compare the rates of revision between cross-linked polyethylene (XLPE) and conventional non-cross-linked polyethylene (CPE) at 16 years after THAs performed for the treatment of osteoarthritis.

Methods:

We performed an observational study of data, from a national registry, on all patients who underwent THA for osteoarthritis in Australia from 1999 through December 31, 2016. The outcomes of THAs performed with CPE were compared with those of THAs performed with XLPE, along with an analysis of the effect of age, sex, femoral head size, the method of acetabular and femoral component fixation, and the reasons and types of revision. The principal outcome measure was the time to the first revision, determined using Kaplan-Meier estimates of survivorship.

Results:

CPE was used in 41,171 procedures, and XLPE was used in 199,131. The mean ages of the men and women treated with CPE were 70.0 years (standard deviation [SD] = 9.9 years) and 72.5 years (SD = 9.7 years), respectively, whereas the men and women who received XLPE were slightly younger (mean age, 68.6 years [SD = 10.3 years] and 70.7 years [SD = 9.9 years], respectively. XLPE was associated with a lower rate of revision than CPE at 6 months, and this difference became more apparent with time. The 16-year cumulative percentage of revisions of the primary THAs was 11.7% (95% confidence interval [CI] = 11.1% to 12.3%]) in the CPE group and 6.2% (95% CI = 5.7% to 6.7%) in the XLPE group. The hazard ratio at 9 years was 3.02 (p = 0.001).

Conclusions:

The use of XLPE has resulted in a significant reduction in the rate of revision at 16 years following THA for osteoarthritis. This evidence suggests that the longevity of THA is likely to be improved, which may enable younger patients to undergo surgery, confident of a reduced need for revision in the long term.

Level of Evidence:

Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Risk Factors and Pooled Rate of Prolonged Opioid Use Following Trauma or Surgery
Authors: Mohamadi Amin , Chan Jimmy J. , Lian Jayson , Wright Casey L. , Marin Arden M. , Rodriguez Edward K. , von Keudell Arvind , Nazarian Ara
Published: August 2018

Background:

Prolonged use of opioids initiated for surgical or trauma-related pain management has become a global problem. While several factors have been reported to increase the risk of prolonged opioid use, there is considerable inconsistency regarding their significance or effect size. Therefore, we aimed to pool the effects of risk factors for prolonged opioid use following trauma or surgery and to assess the rate and temporal trend of prolonged opioid use in different settings.

Methods:

Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched Embase, PubMed, Web of Science, EBM (Evidence-Based Medicine) Reviews - Cochrane Database of Systematic Reviews, and ClinicalTrials.gov from inception to August 28, 2017, without language restriction. Observational studies reporting risk factors for, or the rate of, prolonged opioid use among adult patients following surgery or trauma with a minimum of 1 month of follow-up were included. Study and patient characteristics, risk factors, and the rate of prolonged opioid use were synthesized.

Results:

Thirty-seven studies with 1,969,953 patients were included; 4.3% (95% confidence interval [CI] = 2.3% to 8.2%) of patients continued opioid use after trauma or surgery. Prior opioid use (number needed to harm [NNH] = 3, odds ratio [OR] = 11.04 [95% CI = 9.39 to 12.97]), history of back pain (NNH = 23, OR = 2.10 [95% CI = 2.00 to 2.20]), longer hospital stay (NNH = 25, OR = 2.03 [95% CI = 1.03 to 4.02]), and depression (NNH = 40, OR = 1.62 [95% CI = 1.49 to 1.77]) showed some of the largest effects on prolonged opioid use (p < 0.001 for all but hospital stay [p = 0.042]). The rate of prolonged opioid use was higher in trauma (16.3% [95% CI = 13.6% to 22.5%]; p < 0.001) and in the Workers’ Compensation setting (24.6% [95% CI = 2.0% to 84.5%]; p = 0.003) than in other subject enrollment settings. The temporal trend was not significant for studies performed in the U.S. (p = 0.07) while a significant temporal trend was observed for studies performed outside of the U.S. (p = 0.014).

Conclusions:

To our knowledge, this is the first meta-analysis reporting the pooled effect of risk factors that place patients at an increased chance for prolonged opioid use. Understanding the pooled effect of risk factors and their respective NNH values can aid patients and physicians in developing effective and individualized pain-management strategies with a lower risk of prolonged opioid use.

Level of Evidence:

Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Saturated Salt Solution Cadaver-Embalming Method Improves Orthopaedic Surgical Skills Training
Authors: Burns David M. , Bell Ian , Katchky Ryan , Dwyer Tim , Toor Jay , Whyne Cari M. , Safir Oleg
Published: August 2018

Background:

Human cadaver surgical skills training offers the highest-fidelity simulation of the operative environment, with the potential to enhance surgeon training and to reduce operative risks to patients. Embalming extends the duration that a cadaveric specimen may be used for surgical skills training and reduces the risk of disease transmission, but it can alter the properties of the cadaver tissue, reducing the simulation fidelity and training quality. The purpose of this controlled laboratory study was to evaluate 3 embalming methods, formaldehyde solution, alcohol-glycol solution, and saturated salt solution, and to compare their relative performance in a 2-week orthopaedic surgical skills training course.

Methods:

The 3 embalming methods were applied to 3 cadavers each. Joint range of motion and joint stiffness were measured prior to dissection. The cadavers were assessed by 4 orthopaedic surgeons on the first and last days of the training course in 4 domains: tissue visual fidelity, tissue tactile fidelity, odor, and overall suitability for surgical skills training using 7-point Likert scales. Sterile specimens for bacterial and fungal culture were obtained from cadaver muscle tissue on the fourth and fifteenth days of use.

Results:

All cadaver groups were successfully preserved without putrefaction and were utilized over the duration of the training course. The saturated salt solution cadavers had supple joints with excellent motion and were rated highly across all domains. The saturated salt solution cadaver joint motion, stiffness, visual and tactile tissue fidelity, odor, and suitability for surgical skills training were significantly superior (p < 0.05) to the formaldehyde solution and alcohol-glycol solution cadavers.

Conclusions:

The saturated salt embalming method is inexpensive and logistically straightforward and preserves human cadavers at room temperature in a state suitable for high-fidelity orthopaedic surgical skills training.
Computer-Assisted Compared with Conventional Total Knee Replacement
Authors: Petursson Gunnar , Fenstad Anne Marie , Gøthesen Øystein , Dyrhovden Gro Sævik , Hallan Geir , Röhrl Stephan M. , Aamodt Arild , Furnes Ove
Published: August 2018

Background:

We previously reported the short-term radiographic and functional results of a randomized controlled trial (RCT) comparing computer-assisted and conventionally performed total knee replacement. We currently report the 2-year clinical results from this trial.

Methods:

One hundred and ninety patients were randomly allocated to undergo either computer-assisted or conventional total knee replacement. One hundred and seventy-two patients were available for clinical evaluation at 2 years, and 167 (97%) of those answered all patient-reported outcome measures (PROMs), including the Knee Injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Society Score (KSS), visual analog scale (VAS), and EuroQol-5 Dimensions (EQ-5D). Patients and clinical evaluators were blinded to the method of surgery. Surgical outcome was assessed using the Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) criteria to calculate responder rates, divided into high responders, moderate responders, and nonresponders.

Results:

The computer-assisted group had significantly more improvement than the conventional group in the mean scores for 2 subscales of the KOOS (7.4 for symptoms [p = 0.02] and 16.2 for sport and recreation [p < 0.01]) and in 1 subscale of the WOMAC (8.8 for stiffness [p = 0.03]).The computer-assisted group also had significantly more high responders (82.8%) than the conventional group (68.8%; p = 0.03) at 2 years, with the number needed to treat determined to be 8.

Conclusions:

In this study, the use of computer navigation provided better pain relief and restored better function than the use of the conventional surgical technique at 2 years after total knee replacement.

Level of Evidence:

Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
Differences in the Radius of Curvature Between Femoral Condyles
Authors: Du Peter Z. , Markolf Keith L. , Levine Benjamin D. , McAllister David R. , Jones Kristofer J.
Published: August 2018

Background:

The radius of curvature (ROC) is an important variable related to potential cartilage incongruities in the transplantation of a large femoral osteochondral allograft. The anterior-posterior length (APL) of a condyle is used as a criterion for donor-graft acceptance. We hypothesized that there would be a linear correlation between the ROC and APL of a condyle, that the ROC and APL would differ significantly between the medial femoral condyle (MFC) and the lateral femoral condyle (LFC), and that a donor graft from the LFC would be suitable for an MFC defect.

Methods:

Knee magnetic resonance imaging scans of 147 patients with no cartilage defects were analyzed. Best-fit circles in the sagittal plane were determined at standardized locations on each condyle. Assuming the use of a 20-mm graft that was flush to the edges of the native cartilage, the central graft prominence was calculated for potential donor-host differences in the ROC.

Results:

There was a linear correlation between the ROC and APL. There were significant differences in the mean ROC and APL between the MFC and LFC. Based on calculations of the central graft prominence among all ROC combinations within the patient group, 100% of potential medial-to-medial, 97.8% of lateral-to-lateral, and 92.5% of lateral-to-medial transplantations would produce a central graft prominence of <1 mm. On average, an allograft harvested from an LFC (mean ROC, 25.7 mm; mean APL, 69.8 mm) implanted into an MFC defect site (mean ROC, 31.9 mm; mean APL, 66.6 mm) would have a central graft prominence of 0.4 ± 0.3 mm.

Conclusions:

Assuming a maximum central graft prominence tolerance of +1 mm, our findings demonstrate that matching the ROC or APL would not be necessary for potential medial-to-medial or lateral-to-lateral allograft transplants within this patient group. Implantation of an LFC donor allograft into an MFC defect is also supported by our findings.
A Novel Method for the Approximation of Humeral Head Retrotorsion Based on Three-Dimensional Registration of the Bicipital Groove
Authors: Vlachopoulos Lazaros , Carrillo Fabio , Dünner Celestine , Gerber Christian , Székely Gábor , Fürnstahl Philipp
Published: August 2018

Background:

The accurate restoration of premorbid anatomy is key for the success of reconstructive surgeries of the proximal part of the humerus. The bicipital groove has been proposed as a landmark for the prediction of humeral head retrotorsion. We hypothesized that a novel method based on bilateral registration of the bicipital groove yields an accurate approximation of the premorbid anatomy of the proximal part of the humerus.

Methods:

Three-dimensional (3D) triangular surface models were created from computed tomographic data of 100 paired humeri (50 cadavers). Segments of the distal part of the humerus and the humeral shaft of prespecified lengths were defined. A surface registration algorithm was applied to superimpose the models onto the mirrored contralateral humeral model based on the defined segments. We evaluated the 3D proximal humeral contralateral registration (p-HCR) errors, defined as the difference in 3D rotation of the humeral head between the models when superimposed. For comparison, we quantified the landmark-based retrotorsion (LBR) error, defined as the intra-individual difference in retrotorsion, measured with a landmark-based 3D method.

Results:

The mean 3D p-HCR error using the most proximal humeral shaft (bicipital groove) segment for the registration was 2.8° (standard deviation [SD], 1.5°; range, 0.6° to 7.4°). The mean LBR error of the reference method was 6.4° (SD, 5.9°; range, 0.5° to 24.0°).

Conclusions:

Bilateral 3D registration of the bicipital groove is a reliable method for approximating the premorbid anatomy of the proximal part of the humerus.

Clinical Relevance:

The accurate approximation of the premorbid anatomy is a key for the successful restoration of the premorbid anatomy of the proximal part of the humerus.
Substance use in Spanish adolescents: The relationship between depression and social support seeking
Authors: Espada Sánchez José Pedro , Gonzálvez Maestre María Teresa , Orgilés Mireia
Published: August 2018

The lack of family or social support and social circles are risk factors for the onset of substance use and teen depression. In turn, depression is a risk factor for substance consumption itself. Although there is evidence on the relationship between coping strategies and substance abuse, there are few data on adolescents. The present study aimed to analyze the relationship between coping based on social support and depression, with reference to tobacco, alcohol, and cannabis consumption in a sample of Spanish adolescents. Various measures were administered to 1,522 adolescent students in the province of Alicante. The results showed a significant relationship between social support, depression, and consumption of tobacco and alcohol, and a marginally significant relationship with the frequency of tobacco consumption. Although the models were significant, there was not an interaction effect of coping and depression, due to the simple effects of both the variables, which may have accounted for the results. The lack of interaction may be due to previous studies examine the relationship between coping and stress, finding the same effect with depression.
Validación del Cuestionario de Clasificación de Fumadores C4 en América Latina
Authors: Londoño Constanza , Velasco Salamanca Ruth Marcela , Pardo Adames Carlos Antonio
Published: August 2018

Este estudio psicométrico tenía como objetivo validar el Cuestionario de Clasificación de Consumidores de Cigarrillo (C4) en América Latina, en una muestra no probabilística de 2280 fumadores hombres y mujeres mayores de edad provenientes de 6 países (Cuba, México, Argentina, Ecuador, Perú y Colombia). Se aplicó un cuestionario de exposición a humo y el C4. Se analizaron las condiciones psicométricas de validez, confiabilidad, funcionamiento diferencial del ítem de acuerdo con el nivel de consumo y el contexto sociocultural. Previo a su aplicación, por país, expertos analizaron la validez de presentación y el lenguaje del Cuestionario C4, posteriormente se hizo un encuentro internacional para definir las condiciones definitivas de presentación del instrumento. Adicionalmente, se presenta un panorama de consumo de Tabaco en América Latina con comparación del consumo por país, y un formato de aplicación por medios electrónicos con un aplicativo de auto calificación y mensajes promotores de la cesación de acuerdo con el nivel de consumo declarado. Se concluye que no existe funcionamiento diferencial por país de los ítems y el cuestionario cumple los requisitos psicométricos mínimos, por ello es utilizable para evaluar el consumo en población procedente de los países participantes y de otros países con población homóloga.
Digital banking impact on Turkish deposit banks performance
Authors: Kahveci Eyup , Wolfs Bert
Published: August 2018

The technological developments in the banking sector have significant implications for banks and are dramatically changing the way retail banks conduct their business. Banks can invest in digital banking (DB) services either to acquire a strategic advantage or because doing so has become a strategic necessity. This study is organized to examine if DB service channels have any positive or negative impact on Turkish deposit banks’ performance. With this aim in mind, in the first stage of the proposed DEA model, physical assets are used. Then, in the second stage, DB service channels are added to see if they have any impact on banks’ performance. The results show that the banks are investing in DB services just to keep the competition as it is. In other words, they invest in DB services as a strategic necessity. DB services do not provide any strategic advantage to any banks in terms of financial performance or efficiency since the banks are already efficient. Investing in DB only helped to preserve their strategic positions. The Turkish deposit banking industry is very competitive and very profitable, and it is necessary to invest in DB services just to keep the competition as it is.
Cellular Communication in Bone Homeostasis and the Related Anti-osteoporotic Drug Development
Authors: Zhang Yi , Luo Guojing , Yu Xijie
Published: August 2018

Background:

Intercellular crosstalk among osteoblast, osteoclast, osteocyte and chondrocyte is involved in the precise control of bone homeostasis. Disruption of this cellular and molecular signaling would lead to metabolic bone diseases such as osteoporosis. Currently a number of anti-osteoporosis interventions are restricted by side effects, complications and long-term intolerance. This review aims to summarize the bone cellular communication involved in bone remodeling and its usage to develop new drugs for osteoporosis.

Methods:

We searched PubMed for publications from 1 January 1980 to 1 January 2018 to identify relevant and latest literatures, evaluation and prospect of osteoporosis medication were summarized. Detailed search terms were ‘osteoporosis’, ‘osteocyte’, ‘osteoblast’, ‘osteoclast’, ‘bone remodeling’, ‘chondrocyte’, ‘osteoporosis treatment’, ‘osteoporosis therapy’, ‘bisphosphonates’, ‘denosumab’, ‘Selective Estrogen Receptor Modulator (SERM)’, ‘PTH’, ‘romosozumab’, ‘dkk-1 antagonist’, ‘strontium ranelate’.

Results:

A total of 170 papers were included in the review. About 80 papers described bone cell interactions involved in bone remodeling. The remaining papers were focused on the novel advanced and new horizons in osteoporosis therapies.

Conclusion:

There exists a complex signal network among bone cells involved in bone remodeling. The disorder of cell-cell communications may be the underlying mechanism of osteoporosis. Current anti-osteoporosis therapies are effective but accompanied by certain drawbacks simultaneously. Restoring the abnormal signal network and individualized therapy are critical for ideal drug development.
Bacterial Polyphosphate Kinases Revisited: Role in Pathogenesis and Therapeutic Potential
Authors: Gautam Lalit Kumar , Sharma Prince , Capalash Neena
Published: August 2018

Bacterial infections have always been an unrestrained challenge to the medical community due to the rise of multi-drug tolerant and resistant strains. Pioneering work on Escherichia coli polyphosphate kinase (PPK) by Arthur Kornberg has generated great interest in this polyphosphate (PolyP) synthesizing enzyme. PPK has wide distribution among pathogens and is involved in promoting pathogenesis, stress management and susceptibility to antibiotics. Further, the absence of a PPK orthologue in humans makes it a potential drug target. This review covers the functional and structural aspects of polyphosphate kinases in bacterial pathogens. A description of molecules being designed against PPKs has been provided, challenges associated with PPK inhibitor design are highlighted and the strategies to enable development of efficient drug against this enzyme have also been discussed.
Recent Advances in Computational Methods for Identifying Anticancer Peptides
Authors: Feng Pengmian , Wang Zhenyi
Published: August 2018

Anticancer peptide (ACP) is a kind of small peptides that can kill cancer cells without damaging normal cells. In recent years, ACP has been pre-clinically used for cancer treatment. Therefore, accurate identification of ACPs will promote their clinical applications. In contrast to labor-intensive experimental techniques, a series of computational methods have been proposed for identifying ACPs. In this review, we briefly summarized the current progress in computational identification of ACPs. The challenges and future perspectives in developing reliable methods for identification of ACPs were also discussed. We anticipate that this review could provide novel insights into future researches on anticancer peptides.
Targeting the Cardiomyocyte Cell Cycle for Heart Regeneration
Authors: Locatelli Paola , Giménez Carlos Sebastián , Vega Martín Uranga , Crottogini Alberto , Belaich Mariano Nicolás
Published: August 2018

Adult mammalian cardiomyocytes (CMs) exhibit limited proliferative capacity, as cell cycle
activity leads to an increase in DNA content, but mitosis and cytokinesis are infrequent. This
makes the heart highly inefficient in replacing with neoformed cardiomyocytes lost contractile cells as
occurs in diseases such as myocardial infarction and dilated cardiomyopathy. Regenerative therapies
based on the implant of stem cells of diverse origin do not warrant engraftment and electromechanical
connection of the new cells with the resident ones, a fundamental condition to restore the physiology
of the cardiac syncytium. Consequently, there is a growing interest in identifying factors playing relevant
roles in the regulation of the CM cell cycle to be targeted in order to induce the resident cardiomyocytes
to divide into daughter cells and thus achieve myocardial regeneration with preservation of
physiologic syncytial performance.

Despite the scientific progress achieved over the last decades, many questions remain unanswered, including
how cardiomyocyte proliferation is regulated during heart development in gestation and neonatal
life. This can reveal unknown cell cycle regulation mechanisms and molecules that may be manipulated
to achieve cardiac self-regeneration.

We hereby revise updated data on CM cell cycle regulation, participating molecules and pathways recently
linked with the cell cycle, as well as experimental therapies involving them.
Influence of Early Life Lead (Pb) Exposure on α-Synuclein, GSK-3β and Caspase-3 Mediated Tauopathy: Implications on Alzheimer’s Disease
Authors: Bihaqi Syed Waseem , Alansi Bothaina , Masoud Anwar M. , Mushtaq Foqia , Subaiea Gehad M. , Zawia Nasser H.
Published: August 2018

Background:

Previously we have shown that developmental exposure to the heavy metal lead
(Pb) resulted in latent cognitive impairment, upregulation of biomarkers and pathology associated with
both the tau and amyloid pathways, however, the impact on Alpha Synuclein (α-Syn) and its relationship
to these pathways and their connection to cognitive performance warrant further elucidation.

Objective:

The present study determined the impact of developmental Pb exposure on the α-Syn pathways
in a mouse model knock-out (KO) for murine tau gene and in differentiated human neuroblastoma
SHSY5Y cell line exposed to a series of Pb concentrations.

Methods:

Western blot analysis and RT-PCR were used to assess the levels of intermediates in the tau
and α-Syn pathways following postnatal Pb exposure on aged mice lacking tau gene and in differentiated
SHSY5Y cells on day 3 and day 6 after the Pb exposure had ceased.

Result:

Early life Pb exposure is accompanied by latent up-regulation in α-Syn in these mice. Furthermore,
prior exposure to Pb in-vitro also resulted in an increase in α-Syn, its phosphorylated forms, as
well as an increase in glycogen synthase kinase 3β (GSK-3β) and Caspase-3.

Conclusion:

An environmental agent can act as a latent inducer of both α-Syn and associated kinases
that are involved in tau hyperphosphorylation and may allude to the interactive nature of these two neurodegenerative
pathways.
Anti-α4β1 Integrin Antibodies Attenuated Brain Inflammatory Changes in a Mouse Model of Alzheimer’s Disease
Authors: Manocha Gunjan , Ghatak Atreyi , Puig Kendra , Combs Colin
Published: August 2018

Background:

Alzheimer’s disease (AD) is associated with age-associated central nervous
system degeneration and dementia. This decline in the function correlates with deposition of Aβ peptide
containing plaques and associated reactive gliosis. The inflammatory phenotype of microglia, in particular,
is often considered detrimental to cognitive function in AD. In addition to the changes in the CNS,
altered immune changes in the periphery have recently been observed in AD suggesting a critical immune-
related communication between the periphery and the brain.

Objective:

We hypothesized that modulating the peripheral immune system may alter the proinflammatory
gliosis associated with AD. Therapeutic antibodies against the α4β1 integrin receptor have been
used clinically to attenuate the ability of various immune cells to adhere to endothelium and migrate into
target tissues such as the intestines (Crohn’s disease) or brain (multiple sclerosis). We hypothesized that
a similar peripheral antibody-based therapy would attenuate gliosis by altering immune cell infiltration
or phenotype in peripheral organs and the brain using an APP/PS1 mouse model of Alzheimer’s disease.

Method:

Littermate control wild-type and APP/PS1 mice were tail vein injected with either saline, isotype
control (IgG2b), or an antibody recognizing α4-integrin, anti-CD49d, once a week for 4 consecutive
weeks. To understand CNS and peripheral immune changes, brains and spleen were used.

Results/Conclusion:

Our data suggests that the antibody therapy was able to reduce microgliosis, astrogliosis,
and synaptic changes in the APP/PS1 mice compared to isotype control injections without
changing amyloid-β plaque load. Interestingly, both isotype control and antibody therapy also reduced
the number of proinflammatory cytokines in the spleen although changes in the brain were less robust.
The anti-CD49d and isotype control treatments also reduced CD4 immunoreactivity in the brains, suggesting
a possible mechanism for attenuation of inflammation in the brain. This data suggests that it is
indeed feasible to alter the immune component of AD brain changes using a clinically feasible strategy
of delivering a particular subtype of IgG or epitope selective antibodies that target infiltration of the
peripheral immune system.
Covalent Inhibition in Drug Discovery: Filling the Void in Literature
Authors: Bjij Imane , Olotu Fisayo A. , Agoni Clement , Adeniji Emmanuel , Khan Shama , El Rashedy Ahmed , Cherqaoui Driss , Soliman Mahmoud E.S.
Published: August 2018

The serendipitous discovery of covalent inhibitors and their characteristic potency of inducing
irreversible and complete inhibition in therapeutic targets have caused a paradigm shift from the use of
non-covalent drugs in disease treatment. This has caused a significant evolution in the field of covalent
targeting to understand their inhibitory mechanisms and facilitate the systemic design of novel covalent
modifiers for ‘undruggable’ targets. Computational techniques have evolved over the years and have
significantly contributed to the process of drug discovery by mirroring the pattern of biological occurrences
thereby providing insights into the dynamics and conformational transitions associated with biomolecular
interactions. Moreover, our previous contributions towards the systematic design of selective
covalent modifiers have revealed the various setbacks associated with the use of these conventional
techniques in the study of covalent systems, hence there is a need for distinct approaches. In this review,
we highlight the modifications and development of computational techniques suitable for covalent systems,
their lapses, shortcomings and recent advancements.
Computational Approaches in Antibody-drug Conjugate Optimization for Targeted Cancer Therapy
Authors: Melo Rita , Lemos Agostinho , Preto Antonio J. , Almeida Jose G. , Correia Joao D.G. , Sensoy Ozge , Moreira Irina S.
Published: August 2018

Cancer has become one of the main leading causes of morbidity and mortality worldwide.
One of the critical drawbacks of current cancer therapeutics has been the lack of the target-selectivity, as
these drugs should have an effect exclusively on cancer cells while not perturbing healthy ones. In addition,
their mechanism of action should be sufficiently fast to avoid the invasion of neighbouring healthy
tissues by cancer cells. The use of conventional chemotherapeutic agents and other traditional therapies,
such as surgery and radiotherapy, leads to off-target interactions with serious side effects. In this respect,
recently developed target-selective Antibody-Drug Conjugates (ADCs) are more effective than traditional
therapies, presumably due to their modular structures that combine many chemical properties simultaneously.
In particular, ADCs are made up of three different units: a highly selective Monoclonal
antibody (Mab) which is developed against a tumour-associated antigen, the payload (cytotoxic agent),
and the linker. The latter should be stable in circulation while allowing the release of the cytotoxic agent
in target cells. The modular nature of these drugs provides a platform to manipulate and improve selectivity
and the toxicity of these molecules independently from each other. This in turn leads to generation
of second- and third-generation ADCs, which have been more effective than the previous ones in terms
of either selectivity or toxicity or both. Development of ADCs with improved efficacy requires knowledge
at the atomic level regarding the structure and dynamics of the molecule. As such, we reviewed all
the most recent computational methods used to attain all-atom description of the structure, energetics
and dynamics of these systems. In particular, this includes homology modelling, molecular docking and
refinement, atomistic and coarse-grained molecular dynamics simulations, principal component and
cross-correlation analysis. The full characterization of the structure-activity relationship devoted to
ADCs is critical for antibody-drug conjugate research and development.
Evaluation of the in vitro Antitumor Activity of Nanostructured Cyclotides in Polymers of Eudragit® L 100-55 and RS 30 D
Authors: Silva Osmar N. , Pinto Michelle F.S. , Viana Juliane F.C. , Freitas Camila G. , Fensterseifer Isabel C.M. , Craik David J. , Franco Octavio L.
Published: August 2018

Background:

Cancer is a major cause of mortality and morbidity and given the limitations
of many current cancer drugs, there is great need to discover and develop novel treatments. An
alternative to the conventional drug discovery path is to exploit new classes of natural compounds
such as cyclotides. This peptide family is characterized by linked C- and N-termini and a structural
fold called the cyclic cystine knot (CCK). The CCK fold is responsible for the exceptional enzymatic,
chemical and thermal stability of cyclotides.

Methods:

In the present study, an alternative to traditional cancer treatments, involving new nanomaterials
and nanocarriers allowing efficient cyclotide delivery, is proposed. Using the polymers
Eudragit® L 100-55 and RS 30 D, the cyclotides kalata B2 and parigidin-br1 (PBR1) were nanocapsulated,
and nanoparticles 91 nm and 188 nm in diameter, respectively, were produced.

Results:

An encapsulation rate of up to 95% was observed. In vitro bioassays showed that the
nanostructured cyclotides were partially able to control the development of the colorectal adenocarcinoma
cell line CACO2 and the breast cancer cell line MCF-7.

Conclusion:

Data reported herein indicate that nanoformulated cyclotides exhibit antitumor activity
and sustained drug release. Thus, the system using Eudragit® nanocapsules seems to be efficient for
cyclotide encapsulation and probably could be used to target specific tumors in future studies.
Novel Automated Method for the Detection of White Matter Hyperintensities in Brain Multispectral MR Images
Authors: Chen Hsian-Min , Chen Clayton Chi-Chang , Wang Hsin Che , Chang Yung-Chieh , Pan Kuan-Jung , Chen Wen-Hsien , Chen Hung-Chieh , Wu Yi-Ying , Chai Jyh-Wen , Ouyang Yen-Chieh , Lee San-Kan
Published: August 2018

Background:

According to the Standards for Reporting Vascular Changes on Neuroimaging,
White Matter Hyperintensities (WMHs) are cerebral white matter lesions that are characterized
by abnormal tissues of variable sizes and appear hyperintense in T2-weighted Magnetic
Resonance (MR) measurements without cavitation (i.e., their tissue signals differ from those of
Cerebrospinal Fluid or CSF). Such abnormal tissue regions are typically observed in the MR images
of brains of healthy older adults and are associated with a number of geriatric neurodegenerative
diseases. Explanations of the exact causes and mechanisms of these diseases remain inconclusive.
Moreover, WMHs are typically identified by visual assessment and manual examination, both
of which require considerable time. This brings up a need of developing a method for detecting
WMHs more objectively and enabling patients to be treated early. As a consequence, damages on
nerve cells can be limited and the severity of patients’ conditions can be contained.

Aims:

This paper presents a computer-aided technique for automatically detecting and segmenting
anomalies in MR images.

Methods:

The method has two steps: (1) a Band Expansion Process (BEP) to expand the dimensions
of brain MR images nonlinearly and (2) anomaly detection algorithms to detect WMHs. Synthesized
MR images provided by BrainWeb were used as benchmarks against which the detection
performance of the algorithms was determined.

Results:

The most notable findings are as follows: Firstly, compared with the other anomaly detection
algorithms and the Lesion Segmentation Tool (LST), BEP-anomaly detection is shown to be
the most effective in detecting WMHs. Secondly, across all levels of background noise and inhomogeneity,
the mean Similarity Index (SI) produced by our proposed algorithm is higher than that
produced by LST, indicating that the algorithm is more effective than LST in segmenting WMHs
from brain MR images.

Conclusion:

Experimental results demonstrated a significantly high accuracy of the BEP-K/R-RX
method in detection of synthetic brain MS lesion data. In the meantime, it also effectively enhances
the detection of brain lesions.
A Comprehensive Review on Nature Inspired Neural Network based Adaptive Filter for Eliminating Noise in Medical Images
Authors: Kumar Manish , Mishra Sudhansu Kumar
Published: August 2018

Background:

Various kind of medical imaging modalities are available for providing
noninvasive view and for analyzing any pathological symptoms of human beings. Different noise
may appear in those modalities at the time of acquisition, transmission, scanning, or at the time of
storing. The removal of noises from the digital medical images without losing any inherent features
is always considered a challenging task because a successful diagnosis relies on them. Numerous
techniques have been proposed to fulfill this objective, and each having their own benefits and
limitations.

Discussion:

In this comprehensive review article, more than 65 research articles are investigated to
illustrate the applications of Artificial Neural Networks (ANN) in the field of biomedical image
denoising. In particular, the zest of this article is to highlight the hybridized filtering model using
nature-inspired algorithms and artificial neural networks for suppression of noise. Various other
techniques, such as fixed filter, linear adaptive filters and gradient descent learning based neural
network filter are also included.

Conclusion:

This article envisages how to train ANN using derivative free nature-inspired algorithms,
and its performance in various medical images modalities and noise conditions.
Current Status of Stem Cell Therapies in Tissue Repair and Regeneration
Authors: Giri Tapan Kumar , Alexander Amit , Agrawal Mukta , Saraf Swarnalata , Saraf Shailendra , Ajazuddin
Published: August 2018

Tissue engineering is a multi-disciplinary field such as material science, life science, and bioengineering that are necessary to make artificial tissue or rejuvenate damaged tissue. Numerous tissue repair techniques and substitute now exist even though it has several shortcomings; these shortcomings give a good reason for the continuous research for more acceptable tissue-engineered substitutes. The search for and use of a suitable stem cell in tissue engineering is a promising concept. Stem cells have a distinctive capability to differentiate and self-renew that make more suitable for cell-based therapies in tissue repair and regeneration. This review article focuses on stem cell for tissue engineering and their methods of manufacture with their application in nerve, bone, skin, cartilage, bladder, cardiac, liver tissue repair and regeneration.
Protective Effect of Alpha-Tocopherol in Deltamethrin Induced Immunotoxicity
Authors: Kumar Anoop , Sharma Ruchika , Rana Divya , Sharma Neelima
Published: August 2018

Background and Objective: α-Tocopherol is the active form of vitamin E which has various
biological functions. However, the exact molecular mechanism of its action is not fully understood.
Thus, the main objective of the current study is to determine the contribution of α-tocopherol in
counteraction of the apoptogenic signaling pathways induced by deltamethrin in murine thymocytes
and splenocytes.

Methods and Results: Deltamethrin (25 µM) induces apoptosis at 18 h through the activation of
reactive oxygen species, caspases and depletion of glutathione in thymocytes and splenocytes. MTT
assay results have shown that α-tocopherol (10 and 50 µg/ml) when added along with Deltamethrin
(25µM), increases the viability of thymocytes and splenocytes in a concentration-dependent manner.
The α-tocopherol treatment reduces the early markers of cell death (ROS and caspase3 activation)
significantly. Further, the depleted GSH by deltamethrin has also been restored by α-tocopherol. At 18
h, α-tocopherol (50 µg/ml) significantly reduced the Deltamethrin induced cell death. In additional,
phenotyping and cytokines assay have demonstrated that alpha-tocopherol significantly ameliorated
the altered immune functions.

Conclusion:

These findings indicate that α-tocopherol shows immunoprotective effects in
Deltamethrin induced splenic and thymic apoptosis by inhibiting oxidative stress and caspasedependent
apoptogenic pathways.
The Effect of Rhizobia Isolates Against Black Root Rot Disease of Faba Bean (Vicia faba L) Caused by Fusarium solani
Authors: Tamiru Gedyon , Muleta Diriba
Published: August 2018

Objective:

Evaluate for potential biocontrol agent by assessing isolates forin vitroinhibitory efficacy, probable mechanisms to inhibit fungal pathogen and effect on growth of Faba bean infected withF. solani.

Methods:

The effect of Rhizobium isolates on the development of radial mycelium ofF. solaniin PDA medium were testedin vitro. The experiments were carried out using the dual culture technique. Isolates that showed inhibitory effect againstF. solaniin vitrowere tested to assess hydrolytic enzymes and growth promoting traits. Subsequently, the three Rhizobium isolates that showed the greatest inhibitions and their combinations were tested in the greenhouse againstF. solaniroot rot on seedlings by applying cell suspensions at three different times of exposure to the pathogen.

Results:

In dual culture, 27 rhizobium isolates inhibited the radial growth ofF. solanimycelium more than 25%. Isolates JU26(1), JU15(2) and Ho-1WG, inhibited fungal radial growth by 70.5 %, 64.7% and 63.7%, respectively. Among the 27 Rhizobium isolates tested for hydrolytic enzymes 26.1%, 44.4%, 14.8% were positive for chitinase, protease and lipase production, respectively. Chitinase, protease and lipase positive isolates showed significant fungal mycelia inhibition. Eight (29.6%) were positive for hydrogen cyanide production. Also, 24(88.8%) were positive for IAA production and over 50% formed visible dissolution haloes on PA. Concurrent production of protease, lipases, chitinase, IAA and phosphate solubilization coupled with anti-fungal activity suggests potential plant growth promotion and broad-spectrum bio control of these isolates. Furthermore, combination and Ho-1WG consistently reduced disease incidence and severity; and increased growth parameters on seedling in greenhouse at all times of application compared to diseased (control). Maximum disease severity (73.3%) reduction was observed with application of combination before the pathogen. The combination formulation provided the highest (48 cm/plant) shoot height when applied before the pathogen.

Conclusion:

Beneficial traits strongly assist the efficiency of candidate antagonists for desired biocontrol, emphasizing the value of concerted mechanisms of action. The result indicated the possible use of Rhizobial isolates as an alternative means of BRR management but further study is needed to verify actual use in agricultural production.