Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways.

The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered association studies and ancestry-specific effects. In the present study, we performed a succinct review of case-control association studies published prior to April 2015. Meta-analyses were performed for candidate gene variants examined in at least three studies using the Cochrane Mantel-Haenszel fixed-effect model. Secondary analyses were also performed to assess the influences of sex, agoraphobia co-morbidity and ancestry-specific effects on panicogenesis. Meta-analyses were performed on 23 variants in 20 PD candidate genes. Significant associations after correction for multiple testing were observed for three variants, TMEM132D rs7370927 (T allele: odds ratio (OR)=1.27, 95% confidence interval (CI): 1.15-1.40, P=2.49 × 10(-6)), rs11060369 (CC genotype: OR=0.65, 95% CI: 0.53-0.79, P=1.81 × 10(-5)) and COMT rs4680 (Val (G) allele: OR=1.27, 95% CI: 1.14-1.42, P=2.49 × 10(-5)) in studies with samples of European ancestry. Nominal associations that did not survive correction for multiple testing were observed for NPSR1 rs324891 (T allele: OR=1.22, 95% CI: 1.07-1.38, P=0.002), TPH1 rs1800532 (AA genotype: OR=1.46, 95% CI: 1.14-1.89, P=0.003) and HTR2A rs6313 (T allele: OR=1.19, 95% CI: 1.07-1.33, P=0.002) in studies with samples of European ancestry and for MAOA-uVNTR in female PD (low-active alleles: OR=1.21, 95% CI: 1.07-1.38, P=0.004). No significant associations were observed in the secondary analyses considering sex, agoraphobia co-morbidity and studies with samples of Asian ancestry. Although these findings highlight a few associations, PD likely involves genetic variation in a multitude of biological pathways that is diverse among populations. Future studies must incorporate larger sample sizes and genome-wide approaches to further quantify the observed genetic variation among populations and subphenotypes of PD.

Tolerance evaluation of overdosed dietary levels of 25-hydroxyvitamin D3 in growing piglets.

Forty-eight, cross-bred (GL × LW × P) piglets were used in a 42-day tolerance trial to assess the effects of feeding diets supplemented with vitamin D or increasing levels of 25-hydroxyvitamin D3 (25-OH-D3 ). Six-week-old piglets (24 castrate males, 24 females) were used. Two replicate groups of 6 piglets were randomized by weight and allocated to four dietary treatments. The control group (T1) was supplemented with 50 µg vitamin D3 /kg feed. The experimental groups received 25-OH-D3 at the recommended dose (T2: 50 µg/kg = 1x), at 250 µg/kg (T3: 5x) or at 500 µg/kg (T4: 10x) respectively. Feed intake and daily weight gain were measured weekly, and the animals were examined by a veterinarian daily. After 42 days, body mass, blood, urine, bone and tissue samples were analysed and a pathology examination conducted. Dietary treatments had no significant effect on final body mass or daily weight gain. The 25-OH-D3 plasma concentration in T1 was 17 ± 3 ng/ml (mean ± SD) while the respective values of the experimental groups were significantly increased in T2, T3 and T4. Tissue concentrations of 25-OH-D3 were higher in liver and muscle for T3 and T4 and in skin for T4 than in T1. However, neither gross pathology nor histology, nor blood and urine characteristics, nor bone parameters were affected by dietary treatments. Weight of organs as well as dry matter, ash and calcium content of kidneys remained unaffected by dietary 25-OH-D3 intake. Furthermore, no changes were observed for general indicators of health. The results of this study demonstrated that feeding piglets with 25-OH-D3 at 5 or 10 times the recommended level had no adverse effects on any of the biological parameters measured. It was concluded that 25-OH-D3 can be regarded as a supplement with a very high safety margin when used at the recommended level.

Allergic sensitization to pegylated interferon-α results in drug eruptions.

BACKGROUND: The introduction of pegylated interferon (PEG-IFN)-α in the treatment of chronic hepatitis C has led to an increase in sustained virological response. Despite reduced immunogenicity of the pegylated form in comparison with native interferon (IFN)-α, a high frequency of adverse cutaneous reactions has been reported with pegylated IFN-α. Here, we aimed to investigate the immunological mechanisms underlying pegylated IFN-α-induced drug eruptions. METHODS: Hepatitis C patients suffering from drug eruptions in association with administration of pegylated interferons were enrolled in the study (n = 22). Subjects were tested for sensitivity to pegylated IFN-α2a , pegylated IFN-α2b , or ribavirin using intradermal, scratch, and/or patch tests, as well as lymphocyte activation tests (LATs). Skin biopsies obtained from pegylated IFN-α-associated exanthemas, as well as from localized inflammatory skin reactions at pegylated IFN-α injection sites, were analyzed for the expression of relevant chemokines by quantitative real-time PCR and immunohistochemistry. RESULTS: A subset of patients suffering from pegylated IFN-α-associated exanthemas displayed positive intradermal tests to PEG-IFNs but not to conventional IFN (11/22). In selected patients, this observation correlated with the presence of pegylated IFN-specific T cells (3/11). Chemokine profiles of inflammatory skin reactions at the injection sites reflected an IFN-α-signature, whereas lesional skin of exanthemas showed induction of TH2-associated chemokines. CONCLUSIONS: Our results indicate that specific sensitizations are one cause of exanthemas under therapy with PEG-IFNs. Clinical proof-of-concept analyses demonstrate that affected patients may benefit from a switch to conventional, nonpegylated drugs, enabling IFN-α therapy continuation without drug-associated skin eruptions.

Development and evaluation of a baseline-event-anticipation score for hepatitis delta.

Hepatitis delta is considered the most severe form of viral hepatitis, but variables associated with disease progression are poorly defined. This study aimed to identify risk factors associated with worse clinical outcome in patients with hepatitis delta and to develop a clinical score to determine their risk of experiencing liver-related morbidity or mortality. We followed 75 HBsAg-anti-HDV-positive patients with hepatitis delta for up to 16 years (median 5 years). The baseline-event-anticipation score (BEA score) was developed based on variables associated with the development of liver-related clinical complications. Age, region of origin, presence of cirrhosis, albumin, INR, hyperbilirubinemia and thrombocytopenia were all associated with the development of an event in the training cohort. The BEA score included age, sex, region of origin, bilirubin, platelets and INR. Points were allocated according to hazard ratios, and three risk groups were defined: BEA-A mild risk, BEA-B moderate risk and BEA-C high risk. Hazard ratios of BEA-B and BEA-C patients for liver-related clinical endpoints were 9.01 and 25.27 vs BEA-A with an area under curve of the receiving operating characteristic curve of 0.88. The accuracy of the BEA score was confirmed in two independent validation cohorts followed in Barcelona (n = 77) and Düsseldorf (n = 62). Delta hepatitis is associated with a very severe long-term outcome. The BEA score is easy to apply and predicts with a very high accuracy the development of liver-related complications in patients with hepatitis delta.

Full genome ultra-deep pyrosequencing associates G-to-A hypermutation of the hepatitis B virus genome with the natural progression of hepatitis B.

Human APOBEC3 (A3) cytosine deaminases are antiviral restriction factors capable of editing the genome the hepatitis B virus (HBV). Despite the importance of the human A3 protein family for the innate immune response little is known about the clinical relevance for hepatitis B. The aim of this study was to utilize ultra-deep pyrosequencing (UDPS) data to analyse the phenomenon of G-to-A hypermutation of the complete HBV genome and to relate it to fundamental characteristics of patients with chronic hepatitis B. By analysing the viral population of 80 treatment naïve patients (47 HBeAg-positive and 33 HBeAg-negative), we identified an unequal distribution of G-to-A hypermutations across the genome. Our data indicate that G-to-A hypermutation occurs predominantly in a region between nucleotide positions 600 and 1800 a region which is usually single stranded in matured HBV particles. This implies that A3 likely edits HBV in the virion. Hypermutation rates for HBeAg-negative patients were more than 10-fold higher than those of HBeAg-positive patients. For HBeAg-negative patients higher hypermutation rates were significantly associated with the degree of fibrosis. Additionally, we found that for HBeAg-positive chronic hepatitis G-to-A hypermutation rates were significantly associated with the relative prevalence of the G1764A mutation, which is related to HBeAg seroconversion. In total, our data imply an important association of hypermutation mediated by A3 deaminases with the natural progression of chronic hepatitis B infections both in terms of HBeAg seroconversion and disease progression towards cirrhosis.

Pneumatosis intestinalis: a rare cause of lower gastrointestinal bleeding.

Pneumatosis intestinalis is an uncommon condition characterized by the presence of gas in the bowel wall. We present the case of a 49-year-old man admitted to our Clinic for his 4 day long haematochezia. Colonoscopy revealed pneumatosis coli as a cause of the lower gastrointestinal bleeding. A wide range of diagnostic methods didn't show any underlying disease related to the bleeding, other than the presence of gas. Patient is reported in order to draw attention to the primary pneumatosis coli presented as a rare cause of haematochezia.

Renal function during treatment with adefovir plus peginterferon alfa-2a vs either drug alone in hepatitis B/D co-infection.

Long-term safety of treatment with hepatitis B virus (HBV) polymerase inhibitors is a concern. Adefovir dipivoxil (ADV) therapy has previously been associated with impairment of renal function. Limited data are available on the safety of combination therapy with nucleos(t)ide analogues and interferon alfa (IFNα). The aim of this analysis was to assess the renal function during combination therapy with peginterferon alfa-2a (PegIFNα-2a) plus ADV vs either drug alone in patients with hepatitis B/D co-infection. We performed a retrospective analysis of renal function data of patients treated in the Hep-Net/International Delta Hepatitis Intervention Trial 1(HIDIT-1-trial), a European multicenter study to investigate the efficacy of 48 weeks of therapy with PegIFNα-2a+ADV vs either drug alone in 90 patients with chronic hepatitis B/D co-infection. Glomerular filtration rates (GFR) were calculated by Cockcroft-Gault (CG), abbreviated Modification of Diet in Renal Disease (MDRD) study and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. After 48 weeks of therapy GFR values were significantly lower in patients receiving adefovir-containing treatment vs PegIFNα-2a alone [mean difference 16.1 mL/min (CG) and 10.2 mL/min (MDRD), respectively, P < 0.05] while no differences were observed between patients receiving adefovir alone vs combination treatment. Twenty-four weeks after treatment GFR values did not differ between treatment arms. A decrease in GFR ≥ 20% was observed more often in patients during adefovir-containing treatment vs PegIFNα-2a alone (P < 0.05) which was confirmed by Kaplan-Meier analysis. Adefovir-containing but not PegIFNα-2a treatment was associated with a decrease in GFR values in about one-fifth of patients. Combination treatment of PegIFNα-2a+ADV in chronic hepatitis B/D co-infection did not lead to any further impairment of kidney function.

TMEM132D, a new candidate for anxiety phenotypes: evidence from human and mouse studies.

The lifetime prevalence of panic disorder (PD) is up to 4% worldwide and there is substantial evidence that genetic factors contribute to the development of PD. Single-nucleotide polymorphisms (SNPs) in TMEM132D, identified in a whole-genome association study (GWAS), were found to be associated with PD in three independent samples, with a two-SNP haplotype associated in each of three samples in the same direction, and with a P-value of 1.2e-7 in the combined sample (909 cases and 915 controls). Independent SNPs in this gene were also associated with the severity of anxiety symptoms in patients affected by PD or panic attacks as well as in patients suffering from unipolar depression. Risk genotypes for PD were associated with higher TMEM132D mRNA expression levels in the frontal cortex. In parallel, using a mouse model of extremes in trait anxiety, we could further show that anxiety-related behavior was positively correlated with Tmem132d mRNA expression in the anterior cingulate cortex, central to the processing of anxiety/fear-related stimuli, and that in this animal model a Tmem132d SNP is associated with anxiety-related behavior in an F2 panel. TMEM132D may thus be an important new candidate gene for PD as well as more generally for anxiety-related behavior.

Neuropeptide S receptor gene -- converging evidence for a role in panic disorder.

Animal studies have suggested neuropeptide S (NPS) and its receptor (NPSR) to be involved in the pathogenesis of anxiety-related behavior. In this study, a multilevel approach was applied to further elucidate the role of NPS in the etiology of human anxiety. The functional NPSR A/T (Asn¹°7Ile) variant (rs324981) was investigated for association with (1) panic disorder with and without agoraphobia in two large, independent case-control studies, (2) dimensional anxiety traits, (3) autonomic arousal level during a behavioral avoidance test and (4) brain activation correlates of anxiety-related emotional processing in panic disorder. The more active NPSR rs324981 T allele was found to be associated with panic disorder in the female subgroup of patients in both samples as well as in a meta-analytic approach. The T risk allele was further related to elevated anxiety sensitivity, increased heart rate and higher symptom reports during a behavioral avoidance test as well as decreased activity in the dorsolateral prefrontal, lateral orbitofrontal and anterior cingulate cortex during processing of fearful faces in patients with panic disorder. The present results provide converging evidence for a female-dominant role of NPSR gene variation in panic disorder potentially through heightened autonomic arousal and distorted processing of anxiety-relevant emotional stimuli.

Proteomic-based genotyping in a mouse model of trait anxiety exposes disease-relevant pathways.

In our biomarker identification efforts, we have reported earlier on a protein that differs in its electrophoretic mobility between mouse lines bred either for high or low trait anxiety. The altered electrophoretic behavior of enolase phosphatase (EP) is now identified to be caused by two single-nucleotide polymorphisms. In both cases, the genetic polymorphism introduces an amino acid change in the protein's sequence resulting in differential mobility on SDS gels. This was shown by recombinantly expressing the two EP isoforms. Functional studies indicate that the EP isoform from the high anxiety mouse line has a lower enzymatic activity than does its low anxiety mouse counterpart. EP is a member of the methionine salvage pathway that is responsible for the synthesis of S-adenosyl-L-methionine, a natural compound with potential antidepressant activities. In addition, it is linked to the polyamine pathway whose members have functions in anxiety/depression-related behaviors. In a freely-segregating F2 panel, both single-nucleotide polymorphisms were significantly associated with locomotion-independent trait anxiety, further supporting a functional role of EP for this phenotype. The study shows that proteomic analysis can reveal genotypic differences relevant for the phenotype. The identified protein alterations, in turn, can expose metabolic pathways pertinent to the behavioral phenotype.

The norepinephrine transporter gene is a candidate gene for panic disorder.

Panic disorder (PD) is an anxiety disorder characterized by recurrent panic attacks with a lifetime prevalence of 4.7%. Genetic factors are known to contribute to the development of the disorder. Several lines of evidence point towards a major role of the norepinephrine system in the pathogenesis of PD. The SLC6A2 gene is located on chromosome 16q12.2 and encodes the norepinephrine transporter (NET), responsible for the reuptake of norepinephrine into presynaptic nerve terminals. The aim of the present study was to analyze genetic variants located within the NET gene for association with PD. The case-control sample consisted of 449 patients with PD and 279 ethnically matched controls. All cases fulfilled the ICD-10 diagnostic criteria for PD. Genotyping was performed using the Sequenom platform (Sequenom, Inc, San Diego, USA). To test for allelic and haplotypic association, the PLINK software was used, and COMBASSOC was applied to test for gene-wise association. After quality control 29 single nucleotide polymorphisms (SNPs) spanning the gene-region were successfully analyzed. Seven SNPs located within the 5' end of the gene were significantly associated with PD. Furthermore, the NET gene showed overall evidence for association with the disease (P = 0.000035). In conclusion, the present study indicates that NET could be a susceptibility gene for PD.

Sunitinib induced pyoderma gangrenosum-like ulcerations.

Pyoderma gangrenosum is a non-infectious neutro?philic skin disease commonly associated with underlying systemic diseases. Histopathological and laboratory diagnostics are unspecific in the majority of the cases and the diagnosis is made in accordance with the clinical picture. Here, we report the case of a 69-year old man with progredient pyoderma gangrenosum-like ulcerations under treatment with sunitinib due to hepatocellular carcinoma. A conventional ulcer therapy did not lead to a regression of the lesions. Solely cessation of sunitinib therapy resulted in an improvement of the ulcerations. Sunitinib is a multikinase inhibitor that targets the PDGF-α- and ?ß-, VEGF-1-3-, KIT-, FLT3-, CSF-1- and RET-receptor, thereby impairing tumour proliferation, pathological angiogenesis and metastasation. Here, we demonstrate that pyoderma gangrenosum-like ulcers may represent a serious side effect of sunitinib-based anti-cancer treatment.

The role of neoadjuvant and adjuvant treatment for adenocarcinoma of the upper gastrointestinal tract.

Both locally advanced adenocarcinoma of the stomach and gastro-esophageal junction are associated with poor prognosis due to the lack of effective treatment. Recently multimodal treatment consisting of neoadjuvant chemotherapy in combination with radiotherapy is reported to improve survival when compared to surgery alone. Neoadjuvant therapy in these locally advanced tumors allows for early tumor responses and the extent of tumor regression that can be achieved is considered a significant prognostic factor. This, in turn, increases the resectability of these tumors. Also due to the high frequency of lymph node metastasis, patients with locally advanced adenocarcinoma should undergo a D2 lymphadenectomy. Postoperative chemo?radiation and perioperative chemotherapy have been studied in gastric adenocarcinomas and showed a survival benefit. However, the surgical techniques used in these trials are no longer considered to be standard by today's surgical practice. In addition, there are no standard recommendations for adjuvant chemotherapy or chemoradiation after R0 resection and adequate lymph node dissection.

Trimodal therapy in squamous cell carcinoma of the esophagus.

Patients with ESCC (squamous cell carcinoma of the esophagus) are most commonly diagnosed with locally advanced tumor stages. Early metastatic disease and late diagnosis are common reasons responsible for this tumor's poor clinical outcome. The prognosis of esophageal cancer is very poor because patients usually do not have symptoms in early disease stages. Squamous cell carcinoma of the esophagus frequently complicates patients with multiple co-morbidities and these patients often require interdisciplinary diagnosis and treatment procedures. At present time, neoadjuvant radiation therapy and chemotherapy followed by surgery are regarded as the international standard of care. Meta-analyses have confirmed that this approach provides the patient with better local tumor control and an increased overall survival rate. It is recommended that patients with positive tumor response to neoadjuvant therapy and who are poor surgical candidates should consider definitive radiochemotherapy without surgery as a treatment option. In future, EGFR antibodies may also be administered to patients during therapy to improve the current treatment effectiveness. Positron-emission tomography proves to be an early response-imaging tool used to evaluate the effect of the neoadjuvant therapy and could be used as a predictive factor for the survival rate in ESCC. The percentage proportions of residual tumor cells in the histopathological analyses represent a gold standard for evaluating the response rate to radiochemotherapy. In the future, early response evaluation and molecular biological tests could be important diagnostic tools in influencing the treatment decisions of ESCC patients.

Do insulin-like growth factor associated proteins qualify as a tumor marker? Results of a prospective study in 163 cancer patients.

OBJECTIVE: Insulin-like growth factor (IGF)-1, -2 and Insulin like growth factor binding proteins (IGFBP) are involved in the proliferation and differentiation of cells. It has never been evaluated, if the IGF-system can serve as a tumor marker in neoplasms. METHODS: In our prospective study 163 patients with colorectal cancer (22), prostate cancer (21), head and neck tumors (17), lymphomas (20), lung cancer (34) and other entities (49) were analysed for their IGF and IGFBP serum levels at the beginning and the end of radiotherapy and compared to 13 healthy people. Subgroups of patients with local tumor disease versus metastatic disease, primary and recurrent therapy and curative versus palliative therapy were compared. RESULTS: The serum levels of IGF-2 were significantly elevated in patients with prostate and colorectal cancer. However, sensitivity and specificity were only 70%. IGFBP-2 serum levels were elevated in patients with head and neck tumors. Again sensitivity and specificity were only 73%. A difference between local disease and metastatic disease could not be found. A difference between IGF serum levels before and after radiotherapy could not be detected. CONCLUSION: The IGF-system cannot serve as a new tumor marker. The detected differences are very small, sensitivity and specificity are too low. IGF measurement is not useful for the evaluation of the success of radiotherapy in malignancies.

[Increasing number and improved survival of patients with hepatocellular carcinoma from 1988 to 2007: data of a German university clinic]. / Zunahme und verbessertes Überleben des hepatozellulären Karzinoms im Zeitraum von 1988 - 2007: Daten einer deutschen Universitätsklinik.

BACKGROUND AND OBJECTIVES: Hepatocellular carcinoma (HCC) ranks sixth regarding prevalence and third regarding mortality among malignant tumours worldwide. The aim of the present study was to determine changes of clinical-epidemiological parameters and survival rates during two decades. PATIENTS AND METHODS: A total of 441 consecutive patients with HCC admitted to the University Clinic Düsseldorf between January 1988 and December 2007 were included. For comparison, this time period was divided into two decades (1988 - 1997 and 1998 - 2007). RESULTS: The number of newly diagnosed HCCs has tripled in the years 1998 - 2007 compared to the years 1988 - 1997. HCV-associated HCCs increased from 28 % in the years 1988 - 1997 to 38 % (p < 0.05) in the years 1998 - 2007. Tumour size, Okuda and BCLC stages decreased during the observation period (both p < 0.001 and p < 0.05). Median overall survival improved during the observation period from 6 [95 % CI: 4.83 - 7.17] to 9 months ]95 % CI: 7.31 - 10.69]; p < 0.0001) as did the 1-year and 5-year survival rates from 22 % to 42 % (p < 0.019) and from 0 % to 9 % (p < 0.001), respectively. The proportion of treated patients compared to patients with best supportive care as well as the proportion of patients receiving a multimodal therapy compared to patients with a single treatment regimen increased in the second decade (55 % vs. 79 %: p < 0.005; 5.4 % vs. 23 %: p < 0.0001). Multimodal therapy was an independent predictor for prolonged survival in a multivariate analysis including Child-Pugh score, BCLC stage, tumour size, and gender (odds ratio 2,77; 95 % CI: 1.44 - 5.31). CONCLUSION: Improved screening as well as broader and improved treatment options may have contributed to the increasing survival rates.

[Diagnosis of focal liver lesions in cirrhotic patients: comparison of contrast-enhanced ultrasound using sulphur hexafluoride (SF6) microbubbles and MRI using Gd-EOB-DTPA]. / Vergleich der kontrastverstärkten Sonografie und der MRT mit Gd-EOB-DTPA zur Diagnostik fokaler Leberläsionen bei Patienten mit Leberzirrhose.

AIM: The diagnostic accuracies of contrast-enhanced sonography and hepatobiliary contrast-enhanced MRI of the liver in evaluating focal liver lesions in patients with liver cirrhosis were compared. MATERIAL AND METHODS: In 33 patients (25 men, 8 women, mean age 63.2 ± 11.2 years) MRI of the liver using Gd-EOB-DTPA (Primovist®, Bayer Schering Pharma, Berlin) was performed. Axial T(2)-weighted, unenhanced T(1)-weighted and enhanced T(1)-weighted scans during arterial, portal venous and late phases were acquired, followed by coronary T(1)-weighted and axial fat-suppressed T(1)-weighted scans 15 minutes post contrast application. In all patients within 4 weeks contrast-enhanced sonography using sulfur hexafluoride microbubbles (SonoVue®, Nycomed, Germany) was obtained. RESULTS: Cirrhosis of the liver was related to viral infection in 45.4% and to alcoholism in 39.4%. All hepatic lesions were confirmed by histologic examination. Sensitivity and specificity of MRI were 90.2% and 83.3%, compared to contrast-enhanced sonography with 92.7 % and 50 %, respectively. Positive and negative predictive values were 97.4% and 55.5 % for MRI and 90.5% and 50% for contrast-enhanced sonography, respectively. DISCUSSION: In this retrospective study MRI using Gd-EOB-DTPA as well as contrast-enhanced sonography using sulfur hexafluoride microbubbles gave excellent results in detecting HCC in patients suffering from liver cirrhosis. Although the specificity was higher for MRI, the accuracy showed no significant difference between these two imaging techniques.

Cholestatic liver diseases from child to adult: the diversity of MDR3 disease.

The phospholipidfloppase MDR3 (gene symbol: ABCB4) is expressed in the canalicular membrane of hepatocytes and mediates the biliary excretion of phosphatidylcholine, which is required for the formation of mixed micelles in bile. Several mutations of ABCB4 have been identified, which cause cholestatic liver diseases of varying severity including progressive familial intrahepatic cholestasis type 3 (PFIC-3), intrahepatic cholestasis of pregnancy (ICP) and the low phospholipid associated cholelithiasis syndrome (LPAC). Here, we report on four new (S1076N; L 23Hfs16X; c.286 + 1G > A; Q 1181E) and one known (S27G) MDR3 mutations in eight patients of three families. The patients presented with a wide spectrum of liver diseases. The clinical presentation and decisive laboratory findings or the association to a trend-setting family history led to the identification of the genetic background in these patients. Even the same mutation may be associated with varying disease progression.

Retrospective analysis of chronic hepatitis D in a West German University Clinic over two decades: migratory pattern, prevalence and clinical outcome.

BACKGROUND/AIMS: Epidemiology, clinical features and long term-course of chronic hepatitis D were addressed in a non-endemic Central European area. METHODS: Sixty-seven patients with chronic hepatitis D were identified among 1307 HBsAg carriers at the university hospital Düsseldorf during two decades (1989 - 2008) and followed for a mean of 7 +/- 6 years. Forty-one of these were treated with IFN-alfa for at least six months. RESULTS: Hepatitis D prevalence increased from 4.1 to 6.2 % among HBsAg carriers during the two decades (p < 0.06). Patients originating from the former Soviet Union (32.1 vs. 46.2 %) and Africa (0 vs. 17.9 %) became more frequent whereas the prevalence of patients from Southern Europe declined (46.5 vs.17.9 % p < 0.03). The time span between the diagnosis of hepatitis B and D was 4.8 +/- 7 years (p < 0.0001). A sustained virological response to interferon-alfa was achieved in 19.5 % of the patients. The yearly incidence rates for death, HCC and complications were 3.2 %, 2.7 % and 8 % among patients with liver cirrhosis. Estimated survival and complication-free survival during 12 years were 72 % and 45 % in cirrhotic compared to 100 % in non-cirrhotic patients (p < 0.008 and p < 0.0001, respectively). CONCLUSION: Hepatitis D in western Germany appears to be on the increase and has a migration background that should be considered in clinical practice. Clinical outcome and response to IFN are as poor as in endemic regions, indicating the need to improve early diagnosis.

The GABA transporter 1 (SLC6A1): a novel candidate gene for anxiety disorders.

Recent evidence suggests that the GABA transporter 1 (GAT-1; SLC6A1) plays a role in the pathophysiology and treatment of anxiety disorders. In order to understand the impact of genetic variation within SLC6A1 on pathological anxiety, we performed a case-control association study with anxiety disorder patients with and without syndromal panic attacks. Using the method of sequential addition of cases, we found that polymorphisms in the 5' flanking region of SLC6A1 are highly associated with anxiety disorders when considering the severity of syndromal panic attacks as phenotype covariate. Analysing the effect size of the association, we observed a constant increase in the odds ratio for disease susceptibility with an increase in panic severity (OR approximately 2.5 in severely affected patients). Nominally significant association effects were observed considering the entire patient sample. These data indicate a high load of genetic variance within SLC6A1 on pathological anxiety and highlight GAT-1 as a promising target for treatment of anxiety disorders with panic symptoms.