Cytokines and chemokines involved in the defense reaction against HIV-1 and hepatitis B virus: isn't it time to use a standardized nomenclature of the involved mediators?

Discovery of new mediators of immune cell activation and interaction facilitated elucidation of the various ways of defense against infectious agents and happened some 40 years ago. Each involved group of researchers named the mediators according to their scope of investigation; often the same molecules were published at the same time with different names. To avoid confusion resulting from using different names for the same mediators and to prevent a Babylonian confusion, standardization was implemented-as in the field of metrics, music, or science including virology. For cytokines and chemokines a standard nomenclature was proposed some 10 years ago and in conclusion it should be used. In this paper the most relevant biomarkers in HIV-1 and HBV infection and their contribution during viral pathogenesis are listed.

What happens with schizophrenia patients after their discharge from hospital? Results on outcome and treatment from a "real-world" 2-year follow-up trial.

Aim of the study was to examine the course of schizophrenia patients within 2 years after discharge. Within a multicenter study of the German Competence Network on Schizophrenia, patients suffering from a schizophrenia spectrum disorder were examined regarding their psychopathological improvement, tolerability, and the treatment regime applied during hospitalization and a 2-year follow-up period. Response, remission, the level of everyday functioning, and relapse were furthermore evaluated during the follow-up period using established definitions for these outcome domains. The psychopharmacological treatment was specifically evaluated in terms of a potential association with relapse. 149 patients were available for analysis, with 65% of the patients being in response, 52% in symptomatic remission, and 64% having a satisfiable everyday functioning 2 years after their discharge from hospital. Despite these favorable outcome rates, 63% of the patients suffered from a relapse within the 2-year follow-up period with 86% of these patients being rehospitalized. Discharge non-responder and non-remitter were twice as likely to relapse during follow-up. A significant decrease of side-effects was observed with negligible rates of extrapyramidal side-effects, sedation, and weight gain during follow-up. Patients receiving treatment with atypical antipsychotics were found to have the lowest risk to relapse (p < 0.0001). The results highlight the natural and unsteady course of schizophrenia in most patients underlining the need to develop more specific treatment strategies ensuring ongoing stability and preventing relapse.

Aspects on the history of transmission and favor of distribution of viruses by iatrogenic action: perhaps an example of a paradigm of the worldwide spread of HIV.

Transmission of infectious agents might be associated with iatrogenic actions of charitable help in health care. An example is the vaccination against yellow fever in USA that transmitted hepatitis B virus. Another example is injections of praziquantel for treatment and cure of schistosomiasis in Central and Northern Africa, with a focus in Egypt that has spread hepatitis C virus. There is no indication that human T-lymphotropic virus type 1 was spread by injection treatment for African trypanosomiasis, syphilis and treponematosis, but these treatments might have contributed to the early spread of human immunodeficiency virus type 1 (HIV-1) in Central Africa. Slave trade contributed as well to the spread of viruses from Africa to the Americas; it was stopped in 1850. Until that date HIV-1 was not transported to the Americas. By analysis of nucleic acid sequence data it can be concluded that the continental spread of HCV and HIV-1 might have started around 1920 with an exponential phase from 1940 to 1970. Further iatrogenic actions that promoted the spread of HCV and HIV-1 might be vaccinations to prevent deadly diseases. The successful vaccination was followed by diminution of the infectious agent in the population such as small pox, yellow fever and measles. Measurements to reduce the spread of plague and cholera were further benefits increasing survival of diseased subjects in a population. Thus, the reduction of exposure to deadly infectious agents might have given a chance to HIV-1 infected subjects to survive and for HIV-1 to be distributed around the world starting from Central Africa in the 1950s.

Validity of remission and recovery criteria for schizophrenia and major depression: comparison of the results of two one-year follow-up naturalistic studies.

The objective of the present study was the application and comparison of common remission and recovery criteria between patients with the diagnosis of schizophrenia and major depressive disorder (MDD) under inclusion of other outcome parameters. Patients with schizophrenia and MDD who were treated as inpatients at the beginning of the study were examined within two naturalistic follow-up trials from admission to discharge of an inpatient treatment period and the one-year follow-up assessment. PANSS criteria of the Remission in Schizophrenia Working Group (RSWG) for schizophrenia and HAMD criteria of the ACNP Task Force in MDD for depressive patients as well as the Clinical Global Impression-Severity Scale (CGI-S) were applied as symptomatic outcome measures additionally to functional outcome parameters. Data of 153 schizophrenia patients and 231 patients with a MDD episode have been included in the analysis. More depressive than schizophrenia patients reached a threshold score of ≤3 on the CGI-S, indicating symptomatic remission at discharge and at the one-year follow-up. In contrast similar proportions of patients reaching symptomatic remission at discharge from inpatient treatment and at the one-year follow-up in the schizophrenia and in the MDD group were found when disease-related consensus criteria (RSWG vs. ACNP Task Force) were used. Functional remission and recovery rates were significantly lower in schizophrenia than in depressive patients at the one-year follow-up visit. Common outcome criteria for remission and recovery in schizophrenia and major depression were not directly comparable. However, our results indicated a significantly poorer outcome in schizophrenia than in depressive patients according to terms of remission and recovery.

Add-on Antidepressants in the Naturalistic Treatment of Schizophrenia Spectrum Disorder - When, Who, and How?

The aim of this study was to evaluate antidepressant add-on treatment within the acute treatment of schizophrenia spectrum disorder patients. Antidepressant add-on was evaluated in 365 patients within a naturalistic multicenter study. Patients with/without antidepressant add-on were compared regarding clinical and treatment-related variables, response and remission, and remission of depressive and negative symptoms. The efficacy of antidepressant add-on treatment was furthermore analyzed applying marginal structure models. Twenty-three percent of the patients received antidepressant add-on for a mean duration of 50.28 (33.42) days. Patients with the diagnosis of a schizoaffective disorder, multiple illness episodes, and a longer duration of their illness as well as those with significantly fewer baseline positive symptoms, more negative and depressive symptoms, more side effects, and less subjective well-being were augmented with antidepressants. At discharge no significant effect of antidepressant add-on treatment was observed in terms of a 25% improvement (p=0.2623), a 50% improvement (p=0.3946), remission (p=0.0552), or remission of depressive (p=0.6336) and negative symptoms (p=0.8756). Also, when analyzing marginal structure models considering the diagnostic subgroups, no significant effect was found. Add-on with antidepressants is common. A final recommendation in terms of this strategy's efficacy cannot be given.

Towards a consensus on how to diagnose and quantify female pattern hair loss - The 'Female Pattern Hair Loss Severity Index (FPHL-SI)'.

BACKGROUND: Female pattern hair loss (FPHL) is a common non-scarring alopecia characterized by widening of the midline hair part at the crown (vertex). In 1977, Ludwig developed a scale that graded the degree of visible vertex hair thinning from I (least severe) to III (most severe). However, by the time patients exhibit the full manifestations of 'Ludwig I', they have already lost a significant volume of hair. Although current therapies may realistically halt progression of hair loss, improvements in hair density is often more limited. Identification and grading of FPHL at an earlier stage is desirable to institute appropriate therapy before significant hair loss has occurred and to enable monitoring over time. AIM: To generate consensus guidance for the recognition and quantification of FPHL that can be used in the clinic. METHODS: Nine clinicians from Europe, North America and Australia experienced in the management of FPHL developed this scale by consensus. RESULTS: We propose a three-point severity scale (termed the FPHL Severity Index (FPHL-SI)) that combines validated measures of hair shedding, midline hair density and scalp trichoscopy criteria to produce a total FPHL-SI score (maximum score = 20). The score is designed to grade FPHL severity over time, while being sufficiently sensitive to identify early disease. A score of 0-4 makes FPHL unlikely; a score of 5-9 would indicate early-stage FPHL, with higher scores indicating greater disease severity. CONCLUSIONS: As a starting point for further public debate, we employ criteria already used in clinical practice to generate a pragmatic FPHL grading system (FPHL-SI) of sufficient sensitivity to identify and monitor early FPHL changes. This may have to be further optimized after systematic validation in clinical practice.

What are residual symptoms in schizophrenia spectrum disorder? Clinical description and 1-year persistence within a naturalistic trial.

The aim of this study was to evaluate residual symptoms in patients achieving remission according to the consensus criteria and to analyze their potential influence on the patient's outcome one year after discharge. In total, 399 patients suffering from a schizophrenia spectrum disorder were evaluated within a naturalistic study. Remission status was examined using the consensus criteria. Residual symptoms were defined as any symptom present at the time-point of remission following analogous analyses performed in depressed patients. Therefore, a PANSS item with a symptom severity of >1 (= at least borderline mentally ill) was defined to be a residual symptom. Remitters with and without residual symptoms were compared regarding psychopathology, functioning and side effects. In total, 236 patients (59%) were remitters at discharge with 94% of them suffering from at least one residual symptom. The most common residual symptoms were blunted affect (49%), conceptual disorganization (42%) and social withdrawal (40%). A significant association was found between the presence of residual symptoms and the severity of side effects (p < 0.0001) and functioning (p = 0.0003) at discharge as well as between residual symptoms and the risk of relapse and chance of remission one year after discharge. Residual symptoms were highly prevalent in remitted schizophrenia inpatients following the suggested definition. Most residual symptoms were persistent baseline symptoms suggesting an ongoing illness severity. Also, the necessity to re-evaluate the consensus criteria questioning the status of remission in these patients is also pointed out.

Effect of antiretroviral HIV therapy on hepatitis B virus replication and pathogenicity.

Coinfections with hepatitis B virus (HBV) and HIV are very frequent. Although HBV is a DNA virus, it replicates via reverse transcription like HIV. Structural similarities between the enzymatic pocket of the HBV DNA polymerase and HIV-1 reverse transcriptase are the basis that certain drugs inhibit both enzymes and thus the replication of both viruses. HBV components increase the pathogenic action of HIV and vice versa directly by certain proteins like HBsAg in the case of HBV and HIV-encoded Tat and Vpr and by disturbing the cytokine balance in affected cells. Antiretroviral therapy is highly beneficial for HIV/HBV-coinfected patients, but carries the risk of drug-induced resistance development and hepatotoxicity. Even with restoration of the immune capacity, signs of hepatic inflammation may develop even after 10 years of treatment.

[Nail diseases in routine practice]. / Nageldermatosen in der Praxis.

BACKGROUND: Nail problems are common reasons for patients presenting to dermatological and general practitioners practices. PROBLEM: Which nail diseases should be known and recognized in routine daily practice? MATERIAL AND METHODS: This article presents the most common nail alterations experienced by the authors from clinics and routine practices with guidelines on the diagnostics, therapy and additional literature. RESULTS: Nail alterations can be designated as inflammatory nail dermatoses or neoplasms. Depending on the local nail findings, clinical investigations, patient history, histology if necessary and additional procedures, concrete indications can be derived for the correct diagnosis and therapy. CONCLUSION: Knowledge of the most commonly occurring nail diseases allows a targeted classification and additional diagnostics which can help to alleviate pain, improve aesthetics and adequately treat malignant alterations.

Microvascular retinal abnormalities in acute intracerebral haemorrhage and lacunar infarction.

BACKGROUND: Retinal microvascular changes have been previously associated with cerebral MRI markers of small vessel disease (SVD). Whether retinal changes differ between patient with intracerebral haemorrhage (ICH) and patients with lacunar infarction (LI) caused by small vessel disease has been poorly investigated. OBJECTIVE: The study aims to compare the frequency of retinal changes between patients with LI and patients with ICH at the acute stage of stroke-related SVD. METHODS: Microvascular wall signs (arteriolar occlusion, arteriovenous nicking, focal arterial narrowing) and retinopathy lesions (microanevrysms, cotton wool spots, retinal haemorrhages, hard exudates) were assessed by retinography up to three months after stroke onset. RESULTS: Forty-eight non-diabetic patients with acute stroke-related to SVD (26 LI, 22 ICH) were recruited prospectively in the study. Retinal wall signs (arteriovenous nicking, and focal arterial narrowing) were found in more than three quarters of subjects and most often bilaterally in both groups. Retinopathy lesions (cotton wool spots, retinal haemorrhages) were found more frequently in ICH patients than in LI patients (22.2% vs. 15.4%, 50% vs. 34% respectively, P>0.005). The frequency of bilateral cotton wool spots and of bilateral retinal haemorrhages was significantly higher in ICH patients than in LI patients (12.5% vs. 0%, P=0.012, 41.2% vs. 7.7%, P=0.029 respectively). CONCLUSION: These results confirm the high frequency of microvascular alterations in patients with hypertension-related SVD leading to LI or ICH and suggest that retinal tissue alterations are more frequent in ICH than in LI. Further investigations are needed to investigate the mechanisms underlying this difference.

Novel surface-based methodologies for investigating GH11 xylanase-lignin derivative interactions.

The recalcitrance of lignocellulose to bioprocessing represents the core problem and remains the limiting factor in creating an economy based on lignocellulosic ethanol production. Lignin is responsible for unproductive interactions with enzymes, and understanding how lignin impairs the susceptibility of biomass to enzymatic hydrolysis represents a significant aim in optimising the biological deconstruction of lignocellulose. The objective of this study was to develop methodologies based on surface plasmon resonance (SPR), which provide novel insights into the interactions between xylanase (Tx-xyn11) and phenolic compounds or lignin oligomers. In a first approach, Tx-xyn11 was fixed onto sensor surfaces, and phenolic molecules were applied in the liquid phase. The results demonstrated weak affinity and over-stoichiometric binding, as several phenolic molecules bound to each xylanase molecule. This approach, requiring the use of soluble molecules in the liquid phase, is not applicable to insoluble lignin oligomers, such as the dehydrogenation polymer (DHP). An alternative approach was developed in which a lignin oligomer was fixed onto a sensor surface. Due to their hydrophobic properties, the preparation of stable lignin layers on the sensor surfaces represented a considerable challenge. Among the various chemical and physico-chemical approaches assayed, two approaches (physisorption via the Langmuir-Blodgett technique onto self-assembled monolayer (SAM)-modified gold and covalent coupling to a carboxylated dextran matrix) led to stable lignin layers, which allowed the study of its interactions with Tx-xyn11 in the liquid phase. Our results indicated the presence of weak and non-specific interactions between Tx-xyn11 and DHP.

Investigation of selected cytokine genes suggests that IL2RA and the TNF/LTA locus are risk factors for severe alopecia areata.

BACKGROUND: Alopecia areata (AA) is the second most common cause of hair loss in humans, and has a genetically complex inheritance. The hypothesis that AA is autoimmune in nature is supported by previous studies. These report an association with specific HLA alleles, as well as genetic variants of other genes implicated in autoimmunity, such as various cytokine genes. However, these cannot yet be considered proven susceptibility loci, as many of these association findings were derived from small patient samples. OBJECTIVES: To investigate the association between AA and selected cytokine genes using a sample of 768 patients with AA and 658 controls of Central European origin. METHODS: Eleven single-nucleotide polymorphisms (SNPs) from cytokine genes implicated in previous AA studies were genotyped. These genes were IL1B, IL1A, IL1RN, MIF, IFNG and the TNF/LTA gene region. We also genotyped 15 SNPs selected from cytokine genes that have shown significant association with other autoimmune diseases. These genes were IL10, IL36RN, IL12B, IL6, IL2, IL23, IL2RA and IL4R. RESULTS: Significant association was found for two variants within both IL2RA and TNF/LTA. In the overall sample, the most significant results were obtained for the IL2RA variant rs706778 (P = 0·00038) and the TNF/LTA locus variant rs1800629 (P = 0·0017). In subgroup analyses, according to severity, age at onset and family history these effects were stronger in the severely affected patients, with the lowest P-values being obtained for rs706778 (P = 3·8 × 10(-6) ). CONCLUSIONS: Our results point to the involvement of IL2RA and the TNF/LTA region in the aetiology of AA, in particular severe AA, and provide further support for the hypothesis that AA is autoimmune in nature.

Investigation of the male pattern baldness major genetic susceptibility loci AR/EDA2R and 20p11 in female pattern hair loss.

BACKGROUND: The aetiology of female pattern hair loss (FPHL) is largely unknown. However, it is hypothesized that FPHL and male pattern baldness (AGA) share common susceptibility alleles. The two major susceptibility loci for AGA are the androgen receptor (AR)/ectodysplasin A2 receptor (EDA2R) locus on the X-chromosome, and a locus on chromosome 20p11, for which no candidate gene has yet been identified. OBJECTIVES: To examine the role of the AR/EDA2R and 20p11 loci in the development of FPHL using 145 U.K. and 85 German patients with FPHL, 179 U.K. supercontrols and 150 German blood donors. METHODS: Patients and controls were genotyped for 25 single nucleotide polymorphisms (SNPs) at the AR/EDA2R locus and five SNPs at the 20p11 locus. RESULTS: Analysis of the AR/EDA2R locus revealed no significant association in the German sample. However, a nominally significant association for a single SNP (rs1397631) was found in the U.K. sample. Subgroup analysis of the U.K. patients revealed significant association for seven markers in patients with an early onset (P = 0·047 after adjustment for the testing of multiple SNPs by Monte Carlo simulation). No significant association was obtained for the five 20p11 variants, either in the overall samples or in the analysis of subgroups. CONCLUSIONS: The observed association suggests that the AR/EDA2R locus confers susceptibility to early-onset FHPL. Our results do not implicate the 20p11 locus in the aetiology of FPHL.

Evaluating depressive symptoms in schizophrenia: a psychometric comparison of the Calgary Depression Scale for Schizophrenia and the Hamilton Depression Rating Scale.

BACKGROUND: The aim of this study was to compare two measures of depression in patients with schizophrenia and schizophrenia spectrum disorder, including patients with delusional and schizoaffective disorder, to conclude implications for their application. SAMPLING AND METHODS: A total of 278 patients were assessed using the Calgary Depression Scale for Schizophrenia (CDSS) and the Hamilton Depression Rating Scale (HAMD-17). The Positive and Negative Syndrome Scale (PANSS) was also applied. At admission and discharge, a principal component analysis was performed with each depression scale. The two depression rating scales were furthermore compared using correlation and regression analyses. RESULTS: Three factors were revealed for the CDSS and HAMD-17 factor component analysis. A very similar item loading was found for the CDSS at admission and discharge, whereas results of the loadings of the HAMD-17 items were less stable. The first two factors of the CDSS revealed correlations with positive, negative and general psychopathology. In contrast, multiple significant correlations were found for the HAMD-17 factors and the PANSS subscores. Multiple regression analyses demonstrated that the HAMD-17 accounted more for the positive and negative symptom domains than the CDSS. CONCLUSIONS: The present results suggest that compared to the HAMD-17, the CDSS is a more specific instrument to measure depressive symptoms in schizophrenia and schizophrenia spectrum disorder, especially in acutely ill patients.

Remission and recovery and their predictors in schizophrenia spectrum disorder: results from a 1-year follow-up naturalistic trial.

Remission and recovery are major outcome goals in schizophrenia yet their predictors have not been studied in detail. Therefore, 186 patients were examined regarding remission and recovery including their potential sociodemographic and clinical predictors 1 year after discharge. Remission was defined according to the consensus remission criteria and recovery following the definition by Liberman et al. (2002). Of the 186 patients 54% achieved remission and 26% recovery at the 1-year follow-up. The remission status at discharge was found to significantly influence remission and recovery at follow-up. A higher SOFAS score (P = 0.0002) as well as a positive attitude towards treatment at discharge (P = 0.0038) were identified to be significant predictors of remission at 1-year follow-up. Having a job (P = <0.0001) and being without pharmacological treatment at follow-up (P = 0.0113) were found to be significantly predictive of recovery. Our results underline the need to implement more specific treatment strategies to improve long-term outcome.

Search for sub-eV mass solar axions by the CERN Axion Solar Telescope with 3He buffer gas.

The CERN Axion Solar Telescope (CAST) has extended its search for solar axions by using (3)He as a buffer gas. At T=1.8 K this allows for larger pressure settings and hence sensitivity to higher axion masses than our previous measurements with (4)He. With about 1 h of data taking at each of 252 different pressure settings we have scanned the axion mass range 0.39 eV≲m(a)≲0.64 eV. From the absence of excess x rays when the magnet was pointing to the Sun we set a typical upper limit on the axion-photon coupling of g(aγ)≲2.3×10(-10) GeV(-1) at 95% C.L., the exact value depending on the pressure setting. Kim-Shifman-Vainshtein-Zakharov axions are excluded at the upper end of our mass range, the first time ever for any solar axion search. In the future we will extend our search to m(a)≲1.15 eV, comfortably overlapping with cosmological hot dark matter bounds.

Agrin regulation of alpha3 sodium-potassium ATPase activity modulates cardiac myocyte contraction.

Drugs that inhibit Na,K-ATPases, such as digoxin and ouabain, alter cardiac myocyte contractility. We recently demonstrated that agrin, a protein first identified at the vertebrate neuromuscular junction, binds to and regulates the activity of alpha3 subunit-containing isoforms of the Na,K-ATPase in the mammalian brain. Both agrin and the alpha3 Na,K-ATPase are expressed in heart, but their potential for interaction and effect on cardiac myocyte function was unknown. Here we show that agrin binds to the alpha3 subunit of the Na,K-ATPase in cardiac myocyte membranes, inducing tyrosine phosphorylation and inhibiting activity of the pump. Agrin also triggers a rapid increase in cytoplasmic Na(+) in cardiac myocytes, suggesting a role in cardiac myocyte function. Consistent with this hypothesis, spontaneous contraction frequencies of cultured cardiac myocytes prepared from mice in which agrin expression is blocked by mutation of the Agrn gene are significantly higher than in the wild type. The Agrn mutant phenotype is rescued by acute treatment with recombinant agrin. Furthermore, exposure of wild type myocytes to an agrin antagonist phenocopies the Agrn mutation. These data demonstrate that the basal frequency of myocyte contraction depends on endogenous agrin-alpha3 Na,K-ATPase interaction and suggest that agrin modulation of the alpha3 Na,K-ATPase is important in regulating heart function.

Does clinical judgment of baseline severity and changes in psychopathology depend on the patient population? Results of a CGI and PANSS linking analysis in a naturalistic study.

BACKGROUND: Linking of the Clinical Global Impression (CGI) Scale and the Positive and Negative Syndrome Scale (PANSS) was performed within a naturalistic sample. Furthermore, these linking results were compared with those derived from randomized controlled trials to examine if the baseline severity might influence the linking results. METHODS: Biweekly PANSS and CGI ratings were performed from admission to discharge in 398 schizophrenia patients treated within a naturalistic study. Equipercentile linking was performed using the statistical program, R 2.8.1. To evaluate how the naturalistic study design would influence linkage results, a so-called study sample was computed with patients of the naturalistic study fulfilling common inclusion criteria of randomized controlled trials (n = 199). Patients not fulfilling these criteria (less ill sample) and those fulfilling the criteria (study sample) were compared using confidence intervals. RESULTS: We found a considerable difference between the linking of the CGI severity score and the PANSS total score comparing the less ill sample and the study sample. Being considered "mildly ill" at admission in the less ill sample corresponded to a PANSS total score of 47 points and to a PANSS total score of 67 points in the study sample. Considering the linking of the CGI improvement score and PANSS changes, similar results were found for CGI improvement ratings ranging from "very much improved" to "minimally improved". CONCLUSIONS: Despite considerable differences, a 50% PANSS reduction was found to correspond to a clinical rating of much improved, which seems to be a suitable definition for response in clinical drug trials.

The TRAF1/C5 locus confers risk for familial and severe alopecia areata.

BACKGROUND: Alopecia areata (AA) is a common hair loss disorder with a complex mode of inheritance. Autoimmune mechanisms are presumed to be crucial aetiologically. It is plausible that a number of autoimmune disorders may share a common genetic background. This phenomenon has been demonstrated in previous studies, which have shown an overlap of susceptibility alleles between AA and other autoimmune disorders. Recent studies have shown that genetic variants on the TRAF1/C5 (tumor necrosis factor receptor-associated factor 1, complement component 5) locus confer susceptibility to rheumatoid arthritis (RA). OBJECTIVES: To examine the role of the TRAF1/C5 locus in the development of AA using a large sample of 1,195 patients with AA and 1280 controls. METHODS: We genotyped the two most significant single nucleotide polymorphisms (SNPs) (rs10818488, rs2416808) from a former RA candidate gene study. After having obtained evidence for association, we performed a fine-mapping study and genotyped the locus with an additional 27 SNPs. RESULTS: While no significant result was obtained for the overall sample, rs2416808 showed significant associations in the analysis of the subgroups with severe AA and with a positive family history. The most significant P-value for rs2416808 was in familial cases (P = 0.004, P(corr) = 0.026). The fine mapping revealed significant associations for four additional SNPs in the analysis of subgroups, with rs2416808 remaining the most significant marker. CONCLUSIONS: Our results point to the involvement of the TRAF1/C5 locus in the aetiology of familial and severe AA, and provide further support for a shared aetiology between AA and other autoimmune disorders.

Serotonin transporter promoter polymorphism and dopaminergic sensitivity in alcoholics.

The central serotonin (5-HT) system plays an important role in the rewarding and addictive properties of alcohol by a direct activation of the mesolimbic dopamine (DA) system. An insertion/deletion (L/S) promoter polymorphism (5-HTTLPR) of the 5-HT transporter (5-HHT) gene (SLC6A4) has been shown to influence transcriptional activity. It is predicted that reduced transynaptic 5-HT neurotransmission in alcoholics with the L/L genotype of 5-HTTLPR would result in a change in DA function compared to the S/S genotype. Thus the present study has tested whether dopaminergic sensitivity is influenced by the 5-HTTLPR genotype. Dopaminergic sensitivity, 5-HTTLPR genotype and smoking status were assessed in 121 alcoholics. Dopaminergic sensitivity as an indicator of the functional state of the dopaminergic system was measured by the amount of growth hormone (GH) secretion after subcutaneous administration of apomorphine (APO, 0.01 mg/kg). 5-HTTLPR genotype was significantly associated with dopaminergic sensitivity (P = 0.004) explaining 9.2% of the variance of GH response. Subjects homozygous for the L allele (with high 5-HTT expression) showed the lowest GH response, whereas those homozygous for the S allele (with low 5-HTT expression) showed the highest GH response (this was intermediate in heterozygous participants). Furthermore smoking was associated with a significantly reduced GH response (P = 0.006). Our findings indicate that the postsynaptic dopaminergic sensitivity is influenced by the 5-HTTLPR genotype. It is hypothesized that the reduction of sensitivity of the central DA receptors in alcoholics with the L/L genotype might be due to their higher vulnerability to the neurotoxic effects of chronic alcohol consumption than the S carriers.