bluuebunny/crossref_metadata_2025 huggingface dataset:
Allergen databases
Authors: Brusic V. , Millot M. , Petrovsky N. , Gendel S. M. , Gigonzac O. , Stelman S. J.
Published: December 2004

Allergies represent a significant medical and industrial problem. Molecular and clinical data on allergens are growing exponentially and in this article we have reviewed nine specialized allergen databases and identified data sources related to protein allergens contained in general purpose molecular databases. An analysis of allergens contained in public databases indicates a high level of redundancy of entries and a relatively low coverage of allergens by individual databases. From this analysis we identify current database needs for allergy research and, in particular, highlight the need for a centralized reference allergen database.
Allergen‐induced mediator release tests
Authors: Demoly P. , Lebel B. , Arnoux B.
Published: December 2004

The diagnosis of allergic reactions in clinical practice is based on both clinical history and the determination of specific immunoglobulin E (IgE), either in the serum or on skin mast cells. However, for various reasons, identification of the causative factors is not possible in all the cases. Moreover, not all allergies are IgE‐dependent. In an attempt to find sensitive, specific and cost‐effective methods to investigate hypersensitivity reactions, in vitro tests were developed at a very early stage. Allergen‐induced mediator release assays analyze the mediator released from effector cells, mainly peripheral blood cells, when stimulated in vitro with serial dilutions of the putative allergens. Described initially as research tools, they could well become diagnostic tests. However, relatively few high quality reports have been published so far. In this review, we will detail allergen‐dependent histamine, tryptase, arachidonic acid metabolite, e.g. cysteinyl leukotrienes and 15‐hydroxyeicosatetraenoic mediator release tests.
Peanut allergen Ara h 3: Isolation from peanuts and biochemical characterization
Authors: Koppelman S. J. , Knol E. F. , Vlooswijk R. A. A. , Wensing M. , Knulst A. C. , Hefle S. L. , Gruppen H. , Piersma S.
Published: December 2004

Background:  Peanut allergen Ara h 3 has been the subject of investigation for the last few years. The reported data strongly depend on recombinant Ara h 3, since a purification protocol for Ara h 3 from peanuts was not available.

Methods:  Peanut allergen Ara h 3 (glycinin), was purified and its posttranslational processing was investigated. Its allergenic properties were determined by studying IgE binding characteristics of the purified protein.

Results:  Ara h 3 consists of a series of polypeptides ranging from approximately 14 to 45 kDa that can be classified as acidic and basic subunits, similar to the subunit organization of soy glycinin. N‐terminal sequences of the individual polypeptides were determined, and using the cDNA deduced amino‐acid sequence, the organization into subunits was explained by revealing posttranslational processing of the different polypeptides. IgE‐binding properties ofAra h 3 were investigated using direct elisa and Western blotting with sera from peanut‐allergic individuals. The basic subunits, and to a lesser extent the acidic subunits, bind IgE and may act as allergenic peptides.

Conclusions:  We conclude that peanut‐derived Ara h 3, in contrast to earlier reported recombinant Ara h 3, resembles, to a large extent, the molecular organization typical for proteins from the glycinin family. Furthermore, posttranslational processing of Ara h 3 affects the IgE‐binding properties and is therefore an essential subject of study for research on the allergenicity of Ara h 3.
The value of perinatal immune responses in predicting allergic disease at 6 years of age
Authors: Prescott S. L. , King B. , Strong T. L. , Holt P. G.
Published: December 2004

Background:  Characterizing early abnormalities in immune development of allergic individuals provides an important basis for defining disease pathogenesis and future prevention strategies. This study compares patterns of early immune responses in an established cohort based on allergic outcomes and allergen skin prick test (SPT) reactions at 6 years of age.

Methods:  Children from an original birth cohort (n = 60) consisting of 44 high risk (HR) (family history of allergy) and 16 low risk (LR) (no family history) were reassessed at 6 years of age. Detailed clinical information about allergic disease was obtained (n = 53) and a subgroup (n = 31) consented to have allergen SPT to common food and inhalant allergens. Data from previous immunological assessments performed at birth, 1 and 2 years of age, including lymphoproliferation and cytokine [interleukin (IL)‐4, IL‐5, IL‐6, IL‐10, IL‐13 and interferon (IFN)‐γ] responses to ovalbumin (OVA), house dust mite (HDM), cat allergen (Fel d 1), phytohaemaglutinin (PHA) and tetanus toxoid, were re‐analysed based on the 6‐year clinical outcomes.

Results:  Twenty‐eight HR and three LR children had a clinical history of allergic disease at 6 years of age including doctor diagnosed asthma (n = 17) and/or eczema (n = 24). Most children (78%) with atopy at 6 years had positive SPT to the allergens tested, and 70% had symptoms within the last year. Children at genetic risk (family history) of allergy had weaker (P = 0.017) polyclonal T helper 1 (Th1) IFN‐γ responses in the neonatal period compared with LR children. Although children with allergic disease at 6 years also tended to have weaker neonatal IFN‐γ responses compared to those with no symptoms, but this was not quite significant (P = 0.05). A positive SPT to HDM at 6 years was associated with higher IL‐13 responses to HDM at 1 year (P = 0.02), whereas allergic disease at 6 years was associated with higher IL‐5 messenger RNA (mRNA) responses to HDM at 1 year (P = 0.01). Despite these associations, regression analysis demonstrated that the only significant early predictors of allergic sensitization at 6 years of age were a family history of allergic disease, and atopic symptoms at 2 years. Importantly, none of the early immunological parameters measured were significantly predictive of allergic disease or allergic sensitization in these 6‐year‐olds.

Conclusions:  Although our observations suggest that subtle differential alterations in cytokine responses during early immune development are associated with different aspects of subsequent atopy, there are still no early predictive biomarkers of disease. A positive family history of allergy remains the dominant predictive factor.
Safety of rush insect venom immunotherapy. The results of a retrospective study in 178 patients
Authors: Wenzel J. , Meissner‐Kraemer M. , Bauer R. , Bieber T. , Gerdsen R.
Published: December 2004

Background: Venom immunotherapy (VIT) is regarded as an established and efficient treatment of Hymenoptera venom allergy. Different frequencies of side‐effects have been reported in the literature, depending on the hyposensitization regimen (conventional outpatient programme, rush immunotherapy, ultra rush immunotherapy) and the venom preparation. Aim of this study was to evaluate safety and tolerance of rush VIT in patients treated with a 7‐day protocol in our department.

Methods: VIT protocols of 178 patients treated at the Department of Dermatology and Allergy of the University of Bonn were analysed retrospectively. All patients had been treated with a standardized venom preparations (ALK‐SQTM). We used a modified VIT‐protocol with a 2‐day break to reduce systemic side‐effects.

Results: During the course of VIT in 15 patients (8.4%) systemic reactions grade I (Mueller scale) were observed, in seven (3.9%) grade II, in six (3.4%) grade III and in four (2.2%) grade IV. A total of 146 patients (82.1%) had no or only local reactions.

Conclusions: The rate of systemic adverse reactions Mueller Grade I–IV of 17.9% of the ‘Bonn rush VIT protocol’ appears to be relatively low compared with the data in the literature.
Immunochemical characterization of Russian thistle (Salsola kali) pollen extracts. Purification of the allergen Sal k 1
Authors: Carnés J. , Fernández‐Caldas E. , Marina A. , Alonso C. , Lahoz C. , Colás C. , Lezaun A.
Published: December 2004

Background: Salsola kali (Russian thistle) is a weed which belongs to the Chaenopodiacea family. It is widely distributed along the coasts of Europe, North Africa, USA and Australia. The objectives of this study were to study the allergenic composition of S. kali pollen and to purify an important allergen from the pollen extracts of this plant.

Methods: A population of 66 individuals with specific IgE‐mediated allergic symptoms and positive skin tests to S. kali were included in the study. Specific IgE to S. kali was determined by direct enzyme‐linked immunosorbent assay (ELISA). The antigenic and allergenic profile of S. kali was evaluated by sodium dodecyl sulphate‐polyacrylamide gel electrophoresis (SDS‐PAGE), isoelectric focussing (IEF) and immunoblot. Allergen purification was conducted by preparative SDS‐PAGE. The allergenicity of the protein was evaluated by skin testing, direct ELISA, ELISA inhibition and immunoblots.

Results: Specific IgE to S. kali was detected in 39 of the 66 individuals (59%). An allergen with a molecular weight of approximately 43 kDa was purified. This allergen was termed Sal k 1. A partial sequencing was obtained and no homology was found with other known proteins/allergens. The allergenicity of Sal k 1 was tested in vitro and in vivo. Of the 39 individuals with a positive specific IgE determination to S. kali, 26 (66.6%) had detectable specific IgE to Sal k 1. Twenty of these 39 individuals were skin‐prick tested with the purified allergen (0.5 mg/ml) and all of them had a positive skin test to the purified allergen. Ten additional individuals, used as negative controls, had a negative response.

Conclusions: Sal k 1, an important allergen of S. kali, is recognized, in vitro, by approximately 67% of the patients sensitized to S. kali. Twenty patients with a positive skin test to a standardized S. kali extract had a positive reaction to the purified allergen.
The monocyte‐derived chemokine is released in the bronchoalveolar lavage fluid of steady‐state asthmatics
Authors: Lezcano‐Meza D. , Negrete‐Garcia M. C. , Dante‐Escobedo M. , Teran L. M.
Published: December 2004

Infiltration of the airways by T helper type 2 (Th2) lymphocytes is a well‐recognized feature of bronchial asthma. Monocyte‐derived chemokine (MDC) is a potent attractant which activates Th2 lymphocytes via the chemokine receptor CCR4. We have investigated both leukocyte recruitment and MDC release into the airways of asthmatic patients. Differential cell counts in bronchoalveolar lavage (BAL) fluid showed that numbers of lymphocytes and eosinophils were elevated in asthmatics compared with normal subjects (median, 6.1 vs. 1.0 × 103/ml, P < 0.005 and 1.4 vs. 0.24 × 103/ml, P = 0.001, respectively). By enzyme‐linked immunosorbent assay it was demonstrated that MDC concentrations were significantly elevated in BAL fluid from asthmatics compared with normals (medians 282 pg/ml, range 190–780 pg/ml vs. median 29 pg/ml range 17–82 pg/ml, P < 0.001). Interestingly, there was a significant correlation between MDC levels and the bronchoconstrictive response to methacholine [PC20 forced expiratory volume (FEV)1, r = −0.78, P = 0.001], suggesting that MDC may be involved in the severity of the disease. By immunohistochemistry, MDC was localized predominantly to the bronchial epithelium in bronchial biopsies derived from stable asthmatics. Moreover, primary human airway epithelial cells were found to release MDC upon cytokine stimulation. These findings suggest that MDC may play a major role in the pathogenesis of bronchial asthma.
Characterization of a novel Candida albicans 29 kDa IgE‐binding protein – purification, cDNA isolation and heterologous expression of Cand a 3
Authors: Chou H. , Tam M. F. , Chang C.‐Y. , Lai H.‐Y. , Huang M.‐H. , Chou C.‐T. , Lee S.‐S. , Shen H.‐D.
Published: December 2004

Background: Candida albicans has been implicated in human allergic disorders. However, many of its immunoglobulin E (IgE)‐reacting components have not yet been identified. The purpose of the present study is to characterize a novel 29 kDa IgE‐binding protein from C. albicans.

Methods: The 29 kDa protein was partially purified and its tryptic digests subjected to mass spectrometric analysis. The cDNA encoding this protein was isolated and heterologously expressed in Escherichia coli. Monoclonal antibodies (MoAbs) were raised against the 29 kDa protein purified from C. abicans extracts.

Results: We isolated a 29 kDa IgE‐reacting component from C. albicans. The protein was digested on‐gel with trypsin and the masses of the resulting fragments were determined in a MALDI‐TOF mass spectrometer. The data were searched against protein sequences deduced from the C. albicans genome. An open reading frame that possibly encodes the 29 kDa IgE‐reacting component was identified. The cDNA corresponding to the open reading frame was isolated. It encodes a 236 residues protein that has 62% sequence identity to that of a hypothetical protein (YDR533c) from Saccharomyces cerevisiae. Conserved domain search suggests that the encoded protein belongs to the ThiJ/PfpI family. The cDNA isolated was inserted into a pQE‐30 vector for protein expression in Escherichia coli. The recombinant protein can react with IgE antibodies in sera from asthmatic patients and two MoAbs that were generated against the purified native 29 kDa protein from C. albicans.

Conclusions: We identified and cloned a novel 29 kDa IgE‐reacting component (Cand a 3) from C. albicans. The recombinant proteins produced from this clone and the MoAbs prepared may be useful in the standardization of diagnostic extracts. They are also instrumental in elucidating the role of C. albicans in clinical allergy.
RANTES, eotaxin and eotaxin‐2 expression and production in patients with aspirin triad
Authors: Pods R. , Ross D. , van Hülst S. , Rudack C. , Maune St.
Published: December 2004

Background:  Polyposis, asthma, aspirin‐intolerance and aspirin‐triad are mostly accompanied with eosinophilia of mucosal airways. Chemotactic cytokines, the CC‐chemokines regulated on activation, normal T‐cell expressed (RANTES), eotaxin, and eotaxin‐2 activate and attract eosinophilic leukocytes to the site of inflammation. This points to the implication of CC‐chemokines in eosinophilia of nasal tissue of these diseases.

Methods:  Therefore, nasal polypous tissue specimens of patients suffering from chronic nasal polypous sinusitis (NP), intrinsic asthma (ATA), aspirin‐intolerance (AINA), and aspirin‐triad (TRIAD) were investigated. The amount of mRNA and protein of CC‐chemokines was analyzed using semi‐quantitative reverse transcriptase polymerase chain reaction and chemokine‐specific enzyme‐immuno‐assays. The patterns of CC‐chemokines were compared.

Results:  The mRNA‐expression as well as protein synthesis of CC‐chemokines was quantified in all tissues investigated. The expression of RANTES‐mRNA in NP, ATA, AINA, and TRIAD (averaging 148–324%d‐glyceraldehyde‐3‐phosphate dehydrogenase) and protein synthesis (0.13–0.15 ng/mg tissue weight) did not differ significantly. But the protein synthesis of eotaxin‐ and eotxin‐2‐mRNA was significantly (P < 0.05) higher in TRIAD (3.3 pg/mg and3.4 ng/mg tissue weight) (4 ng/mg tissue weight), than in NP, ATA, or AINA (1.8 pg/mg and 2.1 ng/mg, 2.1 pg/mg and 1.6 ng/mg, or 1.7 pg/mg and2.2 ng/mg tissue weight, respectively).

Conclusion:  Patients suffering from TRIAD in association with tissue eosinophilia were characterized by elevated eotaxin and eotaxin‐2 mRNA‐expression as well as protein‐synthesis. This pointed to the implication of eotaxins and RANTES in eosinophilia‐associated diseases. Further studies will have to prove, whether the analysis of these chemokines might improve the diagnosis of eosinophilia associated polyposis and initiate the development of new therapeutic strategies.
Nasal inflammation and bronchial reactivity to methacholine in atopic children with respiratory symptoms
Authors: Sale R. , Silvestri M. , Battistini E. , Defilippi A.‐C. , Sabatini F. , Pecora S. , Rossi G. A.
Published: December 2004

Background: In atopic subjects, dysfunctions of the upper and lower airways frequently coexist and allergic rhinitis seems to constitute a risk factor for the occurrence of asthma in predisposed individuals.

Aim of the study: To evaluate whether in atopic subjects nasal inflammation could reflect changes in respiratory functions, 11 allergic children, sensitized to house dust mites (HDM), with rhinoconjunctivitis and asthma and 10 nonatopic controls (ctrs) were studied.

Methods: All subjects underwent nasal brushing to detect percentages of nasal eosinophils (Eos %) and intercellular adhesion molecule‐1 (ICAM‐1) expression by nasal epithelial cells. In the same day pulmonary function tests, i.e. forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), forced expiratory flows at 25–75% of the vital capacity (FEF25−75%) and methacholine (MCh) bronchial inhalation challenge were also evaluated.

Results: Pulmonary function parameters were not significantly different in allergic children and in ctrs (P > 0.05), while a significant increase in bronchial reactivity to MCh, expressed as Pd20 MCh, was detected in the former population (P < 0.05). As compared with ctrs, allergic children showed elevated Eos % and ICAM‐1 expression (P < 0.05). When nasal inflammation and pulmonary function parameters were compared, a significant correlation was found between nasal Eos % and bronchial reactivity to MCh (P = 0.002).

Conclusions: These data support the concept of significant links between upper and lower respiratory tract involvement in atopic children sensitized to HDM.
Nuclear transport factor 2 represents a novel cross‐reactive fungal allergen
Authors: Weichel M. , Schmid‐Grendelmeier P. , Flückiger S. , Breitenbach M. , Blaser K. , Crameri R.
Published: December 2004

Background: Ubiquitously occuring moulds are important allergenic sources known to elicit IgE‐mediated allergic diseases and to share cross‐reactive allergens. Limited information is available about the molecular structures involved in cross‐reactivity. We aimed to clone and characterize cross‐reactive mould allergens.

Methods: Phage surface‐displayed Alternaria alternata and Cladosporium herbarum cDNA libraries were screened using sera from Aspergillus fumigatus‐sensitized patients. Inserts encoding putative allergens were sequenced, and recombinant proteins used to demonstrate cross‐reactivity by inhibition experiments and skin test. Three‐dimensional homology models of cloned putative nuclear transport factor 2 (NTF2) were constructed based on known NTF2 structure to corroborate the functional and structural properties of the novel allergens.

Results: After six rounds of affinity selection, the libraries were enriched for clones displaying allergens. Sequencing of inserts showed that some clones derived from Alternaria alternata and Cladosporium herbarum contain open reading frames predicting proteins of 124 and 125 amino acids corresponding to NTF2. The recombinant proteins were able to bind and cross‐inhibit IgE binding and to elicit type I skin reactions in mould‐sensitized individuals, demonstrating the allergenicity of the proteins.

Conclusions: NTF2 represents a novel cross‐reactive fungal allergen as demonstrated by sequence homology, three‐dimensional modelling, inhibition experiments and skin test reactivity.
Validation of the classification of ARIA (allergic rhinitis and its impact on asthma)
Authors: Demoly P. , Allaert F.‐A. , Lecasble M. , Bousquet J. ,   PRAGMA
Published: December 2004

Background: Allergic rhinitis is commonly divided into seasonal and perennial rhinitis. The recent Allergic Rhinitis and its Impact on Asthma (ARIA) workshop proposes to replace these terms by intermittent vs persistent rhinitis.

Methods: In order to test the new ARIA classification against the classical one used in medical practice in France, we designed two cross‐sectional surveys: (i) a spring survey, where 1321 general practitioners enrolled 3026 patients consulting for seasonal allergic rhinitis and (ii) an autumn–winter survey, where 1346 doctors enrolled 3507 patients for perennial allergic rhinitis. Both doctors and patients filled out a specific questionnaire on allergic rhinitis.

Results: Focusing on the number of days per week and consecutive weeks per year, the patients described the duration of their symptoms (based on an auto‐questionnaire). About 43.7% of the patients, classified by their doctor as seasonal, did in fact have persistent rhinitis, whereas 44.6% classified as perennial had intermittent rhinitis.

Conclusions: The proposal of the ARIA expert panel defining the chronology of allergic rhinitis as number of days per week and consecutive weeks per year is likely to change daily physician practice.
Comparison of standard and modified SPT method
Authors: Zawodniak A. , Kupczyk M. , Górski P. , Kuna P.
Published: December 2004

Background: The aim of our study was to compare clinical significance and economical factors of commonly used standard skin prick tests (SPT) method with new, modified and more handy way of performing SPT.

Methods: Twenty‐one subjects [with an average age of 23 years (SD ± 2.72)] with known sensitivity to examined allergen extracts were tested with histamine, negative control solution and standard allergen extracts (Allergopharma, Reinbeck, Germany). SPT were applied to the volar surface of randomly assigned forearm with two methods: standard technique using lancet needle to prick the epidermis under small drop of extract and tested method using lancet needle which was dipped in extract before prick. In this method all extracts were placed in marked, small, plastic chambers.

Results: Mean wheal to histamine was 5.49 (standard method) and 5.01 (modified method). There was no statistical difference between the standard and modified method for size of wheal to histamine (P = 0.654) and to allergen extracts (n = 36, P = 0.824, Wilcoxon test). Economical analysis revealed that examined SPT technique is cheaper than standard method.

Conclusion: Examined method may be considered to be an alternative for performing SPT as it is safe, cheaper and more convenient than standard technique. Summary statement: Comparison of standard and modified SPT method revealed the new method to be more economical.
Discontinuing lithium maintenance treatment in bipolar disorders: risks and implications
Authors: Baldessarini Ross J , Tondo Leonardo , Viguera Adele C
Published: December 2004

Objective:

To review research findings on clinical effects of discontinuing lithium maintenance treatment.

Methods:

Data from studies reported since 1970 plus our recent findings were updated.

Results:

Discontinuing lithium maintenance treatment led to marked increases of early affective morbidity and suicidal risk. Gradual discontinuation markedly reduced early recurrences of mania or depression, did so more in bipolar II than I disorder patients, and also tended to reduce suicidal risk. Similar effects were found in pregnant and nonpregnant women after lithium discontinuation. Long‐term retreatment with lithium following discontinuation was only slightly less effective than in initial trials.

Conclusions:

Recurrences increased sharply soon after discontinuing lithium, but were markedly limited and not merely delayed, by slow discontinuation. Similar reactions may follow discontinuation of other drugs, evidently as responses to long‐term pharmacodynamic adaptations. Discontinuing treatment is not equivalent to not‐treating. Post‐discontinuation relapse risk has implications for the design, management, and interpretation of protocols involving discontinuation of long‐term treatments that should be considered in both clinical management and research.
A two‐illness model of bipolar disorder 1
Authors: Joffe Russell T , Young L Trevor , MacQueen Glenda M
Published: December 2004

The current approach to mood disorders is that bipolar disorder, comprising both mania and depression, is a discreet illness distinct from unipolar depression. This formulation has profoundly influenced the approach to understanding the biology and etiology of these disorders, as well as the manner in which the various phases of bipolar disorder are treated. Our new model suggests that bipolar disorder comprises two distinct illnesses, mania and depression, and that bipolar depression is no different from unipolar depression. Studies of clinical syndromes, course of illness, family history and genetics, biological factors, and treatment response data directly or indirectly support this new model.
Gabapentin in the acute treatment of refractory bipolar disorder
Authors: Altshuler Lori L , Keck Jr Paul E , McElroy Susan L , Suppes Trisha , Brown E Sherwood , Denicoff Kirk , Frye Mark , Gitlin Michael , Hwang Sun , Goodman Robyn , Leverich Gabriele , Nolen Williem , Kupka Ralph , Post Robert
Published: December 2004

Background:

Gabapentin, a new anti‐epileptic agent, has been anecdotally reported to be effective in the treatment of mania. We systematically assessed the response rate in bipolar patients being treated adjunctively with gabapentin for manic symptoms, depressive symptoms, or rapid cycling not responsive to standard treatments.

Method:

Twenty‐eight bipolar patients experiencing manic (n=18), depressive (n=5), or rapid‐cycling (n=5) symptoms inadequately responsive to at least one mood stabilizer were treated in an open fashion with adjunctive gabapentin. Illness response was assessed using the Clinical Global Impression Scale modified for bipolar disorder (CGI‐BP). A ‘positive response’ was operationalized as a CGI response of much or very much improved.

Results:

Fourteen of the 18 (78%) treated for hypomania or mania had a positive response to a dosage range of 600–3600 mg/day. Patients with hypomania responded fastest, with a positive response achieved in 12.7±7.2 days. Patients with classic mania had a mean time to positive response of 25±12 days, and in patients with mixed mania it was 31.8±20.9 days. All of the five patients treated for depression had a positive response within 21±13.9 days. Only one of five patients with rapid cycling had a positive response. Gabapentin was well tolerated by all patients, with the most common side‐effect being sedation.

Conclusions:

Gabapentin appears to have acute anti‐manic and anti‐depressant properties as an adjunctive agent for refractory bipolar illness. Prospective double‐blind studies are needed to further delineate its acute efficacy when used as monotherapy and its prophylactic efficacy as monotherapy or in conjuction with other mood stabilizers.
Substance abuse in bipolar disorder
Authors: Cassidy Frederick , Ahearn Eileen P , Carroll Bernard J
Published: December 2004

Background:High rates of substance abuse have been reported in the general population, with males more often affected than females. Although high rates of substance abuse have also been reported in bipolar patients, the relationship between substance abuse and bipolar disorder has not been well characterized.   Methods:Substance abuse histories were obtained in 392 patients hospitalized for manic or mixed episodes of bipolar disorder and rates of current and lifetime abuse calculated. Analyses comparing sex, subtype (manic vs. mixed) and clinical history variables were conducted.   Results:Rates of lifetime substance abuse were high for both alcohol (48.5%) and drugs (43.9%). Nearly 60% of the cohort had a history of some lifetime substance abuse. Males had higher rates of abuse than females, but no differences in substance abuse were observed between subjects in manic and mixed bipolar states. Rates of active substance abuse were lower in older age cohorts. Subjects with a comorbid diagnosis of lifetime substance abuse had more psychiatric hospitalizations.   Conclusions:Substance abuse is a major comorbidity in bipolar patients. Although rates decrease in older age groups, substance abuse is still present at clinically important rates in the elderly. Bipolar patients with comorbid substance abuse may have a more severe course. These data underscore the significance of recognition and treatment of substance abuse in bipolar disorder patients.
Effects of chronic lithium administration on rat brain phosphatidylinositol cycle constituents, membrane phospholipids and amino acids
Authors: Pettegrew Jay W , Panchalingam Kanagasabai , McClure Richard J , Gershon Samuel , Muenz Larry R , Levine Joseph
Published: December 2004

Objective:
There is evidence linking affective disorders and their treatment to alterations in membrane phospholipid metabolism, the phosphatidylinositol (PtdIns) second messenger cycle and brain excitatory and inhibitory amino acids. This study examines lithium effects on rat brain metabolites associated with the above systems and their reversal by myo‐inositol.   Methods: Thirty rats were treated for 14 days with i.p. lithium, saline or lithium plus myo‐inositol. 1H, 31P and 7Li NMR were used to measure brain metabolites.   Results: Lithium, administered alone or with myo‐inositol, resulted in brain lithium concentrations of approximately 0.6 μM/gram brain tissue. Brain myo‐inositol was unchanged when lithium was co‐administered with myo‐inositol.

Lithium increased brain inositol‐1‐phosphate (I1P) by 98% compared with saline and this effect was not attenuated by the addition of myo‐inositol. Lithium treatment decreased phosphatidylserine (PtdSer) and PtdIns by 3% and 8%, respectively. Lithium also decreased taurine levels by 8% and increased aspartate levels by 9%. The above effects of lithium on PtdSer, PtdIns and taurine were attenuated or abolished by the co‐administration of myo‐inositol.   Conclusions: Lithium alters levels of key membrane phospholipids and appears to affect the balance between inhibitory and excitatory amino acids in rat brain. Co‐administration of myo‐inositol attenuates some of these lithium effects on brain metabolites.
The evolving role of topiramate among other mood stabilizers in the management of bipolar disorder
Authors: Chengappa KN Roy , Gershon Samuel , Levine Joseph
Published: December 2004

Objectives:Topiramate, a structurally novel anticonvulsant, is being evaluated for other neurological conditions such as migraine, neuropathic pain, and essential tremor, and also for psychiatric conditions such as bipolar disorder, bulimia, post‐traumatic stress disorder, and schizoaffective disorder, in addition to obesity. This article will focus on the use of topiramate for bipolar disorder.   Methods:The pharmacological profile of topiramate is compared to other established and putative mood stabilizers, and a rationale for its use in bipolar disorder is presented. Data from open clinical trials of topiramate for depression, mania, and rapid‐cycling bipolar disorder are summarized. Preliminary data from one pilot dose‐finding, double‐blind, random‐assignment, placebo‐controlled, 3‐week parallel group study of two doses of topiramate for acute bipolar I mania is reported. Safety data regarding topiramate was reviewed. Finally, the potential place of this agent in bipolar illness is considered.   Results:The pharmacological advantages for topiramate are low protein binding, minimal hepatic metabolism and mainly unchanged renal excretion, a 24‐h half‐life, and minimal drug interactions. Open clinical studies suggest a 50–65% response for refractory bipolar mania, and a 40–56% response for refractory bipolar depression in mainly add‐on treatment. Open clinical studies of topiramate for rapid‐cycling subjects and those for comorbid bulimia, substance abuse, post‐traumatic stress, migraine, and obesity report effectiveness. The primary efficacy endpoint data (change from baseline Y‐MRS total scores) of the placebo‐controlled, random assignment parallel group phase II dose‐finding study were not statistically significant. However, once the antidepressant‐associated manias (28 of the sample, of 97 subjects) were excluded from the controlled study, thepost‐hocanalyses indicated the higher dose (512 mg/day) topiramate treatment group showed a statistically significant reduction in endpoint Y‐MRS change scores as compared to placebo (p<0.03). Adverse effects of topiramate in bipolar subjects include attention, concentration and memory problems, fatigue, sedation, transient paraesthesias, nausea, and anorexia. Some subjects experience word‐finding difficulty. Weight loss may be seen in several topiramate‐treated subjects with bipolar disorder.   Conclusions:Topiramate appears to show promise as an addition to the agents available to treat bipolar disorder. More definitive controlled data on the efficacy of topiramate in the acute and continuation phases as well as for the prophylaxis either as monotherapy or as combination treatment of bipolar disorder are ongoing, and the results are awaited.
The effect of previous mood states on switch rates: a naturalistic study
Authors: Gitlin Michael , Boerlin Harold , Fairbanks Lynn , Hammen Connie
Published: December 2004

Objectives:  A recent study suggested that post‐manic depressions (post‐MD) may differ from post‐euthymia depression (post‐ED). The goal of this study was to compare the switch rates and length of depressive episodes stratified by the pre‐depression mood states.

Methods:  The course of 72 prospectively observed depressions in 28 patients with Bipolar I depressions were divided into post‐MD versus ED. The two groups, both all episodes and first observed episode, only were compared in their switch rates and length of episode.

Results:  Almost two‐thirds (65%) of episodes were rated as ED. There was no difference in switch rates between the two groups, whether analysed by all episodes, first episodes only, or episodes not treated with antidepressants. Length of depressive episodes were also not significantly different between the two groups.

Discussion:  These findings do not suggest different switch characteristics between post‐MD and post‐ED.
Anti‐inflammatory cytokine response and the development of multiple organ failure in severe sepsis
Authors: Loisa P. , Rinne T. , Laine S. , Hurme M. , Kaukinen S.
Published: December 2004

Background:  The production of proinflammatory cytokines activates the systemic inflammatory response in sepsis. Patients also develop a compensatory anti‐inflammatory reaction, which may have an important down‐regulatory effect on the overactive inflammation. However, the role of this anti‐inflammatory response in sepsis is not completely clarified. In this prospective study, we investigated the relationship between the pro‐ and anti‐inflammatory cytokine profiles in severe sepsis and their role in the development of multiple organ failure (MOF).

Methods:  Thirty‐eight patients meeting the criteria for severe sepsis were studied. MOF was defined as a maximum SOFA score of 10 or higher. Serial measurements of the proinflammatory IL‐6 and IL‐1β and the anti‐inflammatory IL‐10 and IL‐1ra were used. The cytokine samples were taken at the onset of sepsis and on the third and fifth day during the ICU period.

Results:  The initial IL‐10 and IL‐1ra responses were identical in patients with or without MOF. The anti‐inflammatory cytokine levels remained elevated in the MOF patients, whereas in patients without MOF the levels declined. The IL‐6/IL‐10 ratio was significantly higher in the MOF patients on days 1 and 3 compared with patients without MOF.

Conclusions:  We could not demonstrate overproduction of anti‐inflammatory IL‐10 in MOF patients. On the contrary, the high IL‐6/IL‐10 ratio indicates that IL‐10 deficiency may contribute to the development of MOF in severe sepsis.
Adjusting positive end‐expiratory pressure and tidal volume in acute respiratory distress syndrome according to the pressure–volume curve
Authors: Pestaña D. , Hernández‐Gancedo C. , Royo C. , Uña R. , Villagrán M. J. , Peña N. , Criado A.
Published: December 2004

Background:  Management of acute respiratory distress syndrome (ARDS) patients implies the selection of the adequate ventilatory parameters, essentially PEEP and tidal volume (Vt), to prevent ventilator‐induced lung injury. These parameters should be reset as the lung injury evolves. Among the different methods proposed for the adjustment of the ventilator, the measurement of the P–V curve has emerged as a useful, although debated, tool. Our aim has been to study the relationship between the different inflection points of the P–V curve in ARDS patients, and to assess the changes in the empiric PEEP and Vt (PEEPemp, Vtemp) following its use.

Methods:  P–V curves were measured in 27 patients (lung injury score [LIS] ≥ 2, 69 measurements) by means of the low‐flow continuous inflation method.

Results:  A lower inflection point (LIP) was found in all patients and, although it correlated with the PEEPemp, there was only a fair concordance, so the PEEP was modified in 80% of the cases. The expiratory inflection point (EIP) was significantly lower than the LIP (6.3 ± 1.7 vs. 8.1 ± 3.2, P = 0.008). An upper inflection point was observed in 16 measurements (23%) and the Vt was reset in 20% of the cases. Both PEEP and Vt were readjusted on 10 occasions (14%). Only the EIP was significantly higher on the first 3 days of mechanical ventilation. The LIS was correlated with all the inflection points. There were no differences for any parameter independent of the cause of the ARDS (pulmonary/extrapulmonary).

Conclusions:  The quasi‐static measurement of the P–V curve is a simple method, easy to interpret, for objective adjustment of the ventilatory parameters in ARDS patients as the lung injury evolves. The implementation of this strategy may vary the empiric clinical practice. The role of the EIP for the evaluation of the severity of lung injury deserves further investigation.
Cardiopulmonary resuscitation after near drowning and hypothermia: restoration of spontaneous circulation after vasopressin
Authors: Sumann G. , Krismer A. C. , Wenzel V. , Adelsmayr E. , Schwarz B. , Lindner K. H. , Mair P.
Published: December 2004

Recent animal data have challenged the common clinical practice to avoid vasopressor drugs during hypothermic cardiopulmonary resuscitation (CPR) when core temperature is below 30°C. In this report, we describe the case of a 19‐year‐old‐female patient with prolonged, hypothermic, out‐of‐hospital cardiopulmonary arrest after near drowning (core temperature, 27°C) in whom cardiocirculatory arrest persisted despite 2 mg of intravenous epinephrine; but, immediate return of spontaneous circulation occurred after a single dose (40 IU) of intravenous vasopressin. The patient was subsequently admitted to a hospital with stable haemodynamics, and was successfully rewarmed with convective rewarming, but died of multiorgan failure 15 h later. To the best of our knowledge, this is the first report about the use of vasopressin during hypothermic CPR in humans. This case report adds to the growing evidence that vasopressors may be useful to restore spontaneous circulation in hypothermic cardiac arrest patients prior to rewarming, thus avoiding prolonged mechanical CPR efforts, or usage of extracorporeal circulation. It may also support previous experience that the combination of both epinephrine and vasopressin may be necessary to achieve the vasopressor response needed for restoration of spontaneous circulation, especially after asphyxial cardiac arrest or during prolonged CPR efforts.
Prediction of severity of mean arterial pressure elevation after tracheal intubation in hypertensive patients by preanesthetic recurrence quantification analysis of heart rates
Authors: Yum M. K. , Kim H. S.
Published: December 2004

Background: We tried to determine whether the severity of additional mean arterial pressure (MAP) elevation after endotracheal intubation during general anesthesia could be predicted with preanesthetic recurrence quantification analysis of heart rates in hypertensive and normotensive patients.

Methods: Twenty‐four newly diagnosed hypertensive patients and 34 normotensive patients were included. We defined ΔMAP = maximal mean MAP after endotracheal intubation – average MAP before general anesthesia. We classified each of the hypertensive and normotensive patients into mild (ΔMAP ≤ 35 mmHg [median value of ΔMAP in the hypertensive patients]) and severe group (ΔMAP > 35 mmHg). Using preanesthetic RR interval data, we calculated classical linear and non‐linear indices of RR interval dynamics, and performed recurrence quantification analysis to calculate three preanesthetic recurrence indices, percentage of recurrence (%REC), percentage of determinism (%DET), and maximal length of recurrence (Lmax).

Results: In the hypertensive patients, all preanesthetic classical indices showed no significant difference between the mild and severe group and showed no significant linear correlation with the ΔMAP. However, the Lmax was significantly higher in the severe than in the mild group (16.10 ± 3.79 vs. 7.90 ± 0.73, P < 0.005) and, moreover, linearly correlated with the ΔMAP (r = 0.671, P = 0.001). In the normotensive patients, all preanesthetic classical and recurrence indices showed no significant difference between the two groups.

Conclusion: In hypertensive patients, the severity of additional MAP elevation after tracheal intubation during general anesthesia can be predicted by the preanesthetic recurrence quantification analysis of heart rates.
A new short‐acting non‐depolarizing muscle relaxant (SZ1677) without cardiovascular side‐effects
Authors: Vizi E. S. , Tuba Z. , Mahó S. , Foldes F. F. , Nagano O. , Dóda M. , Takagi S. , Chaudhry I. A. , Saubermann A. J. , Nagashima H.
Published: December 2004

Background:  In order to facilitate rapid tracheal intubation, the development of a rapid onset, short duration, non‐depolarizing muscle relaxant without cardiovascular side‐effects would be a significant accomplishment in the field of anesthesiology. The aim of the present study was to test the action of a new non‐depolarizing muscle relaxant (SZ1677) on neuromuscular transmission, muscarinic (M2, M3) receptors and cardiovascular reactions and to compare it with clinically used muscle relaxants.

Methods:  Neuromuscular transmission was studied by recording muscle contractions elicited by indirect electrical stimulation, using (i) in vitro isolated phrenic nerve‐hemidiaphragm preparation of mice, rats and guinea pigs and (ii) in vivo sciatic nerve‐anterior tibial muscle preparation of anesthetized rats, guinea pigs and cats. Cardiovascular effects of muscle relaxants were evaluated on the grounds of their effects on changes of blood pressure and heart rate induced by electrical stimulation of the right vagal nerve in anesthetized cats. To study postsynaptic antimuscarinic affinity of muscle relaxants on M3 receptors, oxotremorine‐induced contractions of longitudinal muscle strip of guinea pig ileum were registered in their presence and absence.

Results:  One of more than 120 newly synthesized non‐depolarizing muscle relaxants compounds, 1‐3[α‐hydroxy‐17β‐acetyloxy‐2β‐(1,4‐dioxa‐8‐azaspiro[4,5]dec‐8‐yl)‐5α‐androstane‐16β‐il] ‐1‐(2‐propenyl)pyrrolidinium bromide (SZ1677), excelled with its advantageous pharmacological properties: relatively short duration of action, no accumulation and lack of unwanted side‐effects. Pharmacodynamic studies show that SZ1677 is a non‐depolarizing neuromuscular blocking agent with a relatively short duration and rapid onset of action in a variety of laboratory animal species. It is without cumulative effect, does not reduce blood pressure, and fails to produce tachycardia. Significant cardiac vagal blocking effects were not observed even at concentrations or dosages of 8 times the ED90. This compound, unlike many other muscle relaxants, does not have atropine‐like effects on human atrial tissue; it does not increase the release of NA from sympathetic innervation in the heart. In all practical ways, at least from the vantage point of the preclinical study, SZ1677 compares favorably with all presently available short‐acting muscle relaxants, including rapacuronium.

Conclusion:  In experiments, SZ1677 proved to be a short‐acting neuromuscular blocking compound having a large safety margin between the doses required to produce neuromuscular block and those likely to lead to cardiovascular side‐effects.
Gender differences in drug effects: implications for anesthesiologists
Authors: Pleym H. , Spigset O. , Kharasch E. D. , Dale O.
Published: December 2004

Background:  The gender aspect in pharmacokinetics and pharmacodynamics of anesthetics has attracted little attention. Knowledge of previous work is required to decide if gender‐based differences in clinical practice is justified, and to determine the need for research.

Methods:  Basis for this paper was obtained by Medline searches using the key words ‘human’ and ‘gender’ or ‘sex,’ combined with individual drug names. The reference lists of these papers were further checked for other relevant studies.

Results:  Females have 20–30% greater sensitivity to the muscle relaxant effects of vecuronium, pancuronium and rocuronium. When rapid onset of or short duration of action is very important, gender‐modified dosing may be considered. Males are more sensitive than females to propofol. It may therefore be necessary to decrease the propofol dose by 30–40% in males compared with females in order to achieve similar recovery times. Females are more sensitive than males to opioid receptor agonists, as shown for morphine as well as for a number of kappa (OP2) receptor agonists. On this basis, males will be expected to require 30–40% higher doses of opioid analgesics than females to achieve similar pain relief. On the other hand, females may experience respiratory depression and other adverse effects more easily if they are given the same doses as males.

Conclusion:  These examples illustrate that gender should be taken into account as a factor that may be predictive for the dosage of several anesthetic drugs. Moreover, there is an obvious need for more research in this area in order to further optimize drug treatment in anesthesia.
Inhibitory effect of propofol on ketamine‐induced c‐Fos expression in the rat posterior cingulate and retrosplenial cortices is mediated by GABAA receptor activation
Authors: Nakao S. , Nagata A. , Miyamoto E. , Masuzawa M. , Murayama T. , Shingu K.
Published: December 2004

Background:  Non‐competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonists, including ketamine, have psychotomimetic activities and cause neuronal damage in the posterior cingulate and retrosplenial cortices (PC/RS), which are suggested to be the brain regions responsible for their psychotomimetic activities. We previously demonstrated that ketamine induced marked c‐Fos (c‐fos protein) expression in the rat PC/RS, which was inhibited by propofol, and the expression was closely related to ketamine‐induced abnormal behavior. In the present study, we investigated whether the inhibition by propofol was mediated by GABAA receptor receptor activation.

Methods:  Using Wistar rats, propofol alone, propofol with bicuculline or propofol with flumazenil was injected intravenously and then continuously infused. Fifteen minutes later, 100 mg kg−1 of ketamine or normal saline was injected intraperitoneally. Two hours after the ketamine or saline injection, the brain was extracted and brain sections were prepared, and c‐Fos expression was detected using immunohistochemical methods.

Results:  Ketamine induced marked c‐Fos expression in the PC/RS (171 ± 9/0.4 mm2), which was significantly inhibited by propofol (5 ± 5/0.4 mm2). The inhibition by propofol was disinhibited dose‐dependently by both bicuculline (0.5 and 1.0 mg kg−1 bicuculline groups: 46 ± 15 and 143 ± 16, respectively) and flumazenil (0.1 and 1.0 mg kg−1 flumazenil groups: 79 ± 6 and 130 ± 15, respectively).

Conclusion:  These results demonstrate that the inhibitory effect of propofol on ketamine‐induced c‐Fos expression in the PC/RS is mediated by GABAA receptor activation, and suggests that ketamine‐induced psychoneuronal adverse effects may be suppressed by propofol via the activation of GABAA receptors.