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Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10−6), and rs7700147, an intergenic variant (P=2.93 × 10−5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

Purpose Adjuvant chemotherapy improves survival of patients with gastric cancer. Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) was a phase III study comparing sequential FOLFIRI followed by docetaxel/cisplatin versus 5-fluorouracil monotherapy. The intensive regimen was not superior in terms of disease-free survival (DFS) and overall survival (OS).Methods The treatment was to be started within 8 weeks from surgery. This analysis evaluates the impact of time from surgery to chemotherapy start (TSC) on outcomes.Results Out of 1,106 randomized, 1,072 patients without major violations of eligibility criteria and receiving at least one treatment cycle were analyzed. Median TSC was 50 days. Chemotherapy was interrupted in 201 (18.8%) cases, whereas it was completed without or with modifications in 277 (25.8%) and 594 (55.4%), respectively. At a median follow-up of 56.9 months, 513 progressions and 472 deaths occurred. A longer TSC was significantly associated with longer DFS (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.89-1.00; p = 0.05) and OS (HR 0.91; 95% CI 0.86-0.97; p = 0.004), after adjustment for treatment arm, age, sex, primary tumor site, number of resected nodes, and tumor stage. Better treatment compliance was associated with improved survival.Conclusions Our findings suggest that longer TSC had at least no detrimental effect on DFS and OS, whereas treatment completion had a protective effect. Our findings need to be confirmed prospectively.

Pharmacogenetic studies investigating the 40bp VNTR polymorphism at SLC6A3and methylphenidate response have shown conflicting results and large differences in study design and efficacy endpoints. Our objective was to investigate the relation between the 3′VNTR at SLC6A3and variability in methylphenidate response in a sample of 141 ADHD children and adolescents, assessed before and after methylphenidate treatment with both clinical and neuropsychological outcome measures. 10R homozygotes were significantly overrepresented in the low response group, but no genotype effect was shown in cognitive variables improvement. A metaanalysis of pharmacogenetic studies with comparable data responders vs. nonresponders on a total of 475 subjects showed a significant association between the 1010 genotype and low rates of methylphenidate response mean Odds Ratio  0.46; 95 CI 0.28–0.76. Heterogeneity between these studies did not reach a significant level but, as publications with different endpoints were excluded from this metaanalysis, our results do not rule out a possible influence of study design. © 2008 WileyLiss, Inc.

The purpose of this study was to evaluate the activity and the toxicity of the combination of gemcitabine with ifosfamide and cisplatin (GIP) in chemonaive patients with advanced non small cell lung cancer (NSCLC). Eighty chemonaive patients with Stage IIIB-IV NSCLC were treated with the combination of gemcitabine 1 g/m² on Days 1 and 8, ifosfamide 2 g/m² on Day 1 and cisplatin 80 mg/m² on Day 2. Cycles were administered on an outpatient basis every 3 weeks. Hematologic toxicity was the main side effect; Grade III-IV thrombocytopenia was observed in 54 (67%) patients and Grade III-IV leucopenia in 44 (55%) patients, with 4 episodes of febrile neutropenia and 1 toxic death. Thirteen patients received platelet transfusions and 38 were transfused with packed red cells. All patients were evaluable for response. The overall response rate was 54% (95% confidence interval 43 to 65%) with 1 complete response. In patients with Stage IIIB and IV disease, response rates were 58% and 52%, respectively. Median time to progression was 40 weeks (range 0–114) and median overall survival was 12 months (16.6 months for stage IIIB and 10.4 months for stage IV). Median and minimum follow-up were 19 and 12 months, respectively. The GIP combination shows a response rate and overall survival of clinical interest. Hematologic toxicity was the main toxic effect, especially in patients with low performance status. This regimen will be tested in a Phase III randomized trial. Int. J. Cancer 87:724–727, 2000. © 2000 Wiley-Liss, Inc.

The aim of the trial was to compare efficacy and safety of the aromatase inhibitor formestane (250 mg i.m. given every 2 weeks) with the progestin megestrol acetate (160 mg administered orally once daily), as second-line therapy in postmenopausal patients with advanced breast cancer previously treated with tamoxifen. A total of 547 patients were enrolled. Analyses revealed no statistically significant or clinically relevant difference between treatments with respect to time endpoints. In the intent-to-treat analysis, the median values for time to failure and overall survival for formestane were 169 and 561 days, respectively. The corresponding values for megestrol acetate were 169 days and 597 days, respectively. Overall response rates were comparable for formestane and megestrol acetate (16.3% vs 20.3%).

Background & Aims: Cytotoxic T cells have been suggested to be responsible for lysis of hepatitis B virus (HBV)-infected hepatocytes and control of virus infection. The frequency, kinetics, phenotype, and capacity for clonal expansion of circulating HBV-specific CD8 cells were analyzed directly in patients with acute HBV infection to clarify their pathogenetic role. Methods: Three HLA-A2 peptide tetramers able to visualize HBV core, envelope, and polymerase epitope-specific cytotoxic T lymphocytes were synthesized and used for flow cytometric analysis of antigen-specific populations. Results: Tetramer-positive cells specific for the core 18-27 epitope were found at a higher frequency than those specific for polymerase 575-583 and envelope 335-343 epitopes in most patients with acute HBV. The number of HBV-specific CD8 cells was highest during the clinically acute stage of infection and decreased after recovery. These cells expressed an activated phenotype and had an impaired capacity to expand in vitro and to display cytolytic activity in response to peptide stimulation. Recovery of these functions was observed when the frequency of specific CD8 cells decreased, coincident with a progressive decrease in their expression of activation markers. Conclusions: This study provides the first ex vivo evidence that the highest frequency of circulating HBV-specific CD8 cells coincides with the clinically acute phase of hepatitis B. These cells exhibit an activated phenotype with limited further proliferative capacity that is restored during recovery. GASTROENTEROLOGY 1999;117:1386-1396

1. Injury is known to be associated with variable degrees of tissue insensitivity to insulin. We measured insulin resistance in a group of non-obese, glucose-tolerant patients undergoing major elective surgery with an uncomplicated post-operative course. 2. Shortly after surgery, hyperglycaemia (7.3 ±0.6 versus 4.2 ± 0.3 mmol/l glucose pre-surgery, mean ± sem, P < 0.01) with normal insulin concentrations (73 ±15 versus 64 ± 18 pmol/l) suggested the presence of insulin resistance. Counter-regulatory hormones were raised, whole-body protein oxidation was doubled (P < 0.01) and energy expenditure was up by 18% (P < 0.01). 3. Insulin sensitivity was quantified by clamping plasma glucose concentrations at 5.6 mmol/l during 24 h of total parenteral nutrition (15% protein, 55% glucose and 30% fat, supplying 1.25 times the measured resting energy expenditure) with a variable infusion of exogenous insulin. After surgery, eight times more insulin was needed than before surgery (14.14±1.15 versus 1.78±0.29 pmol min−1 kg−1, P < 0.001) to maintain euglycaemia. 4. After surgery, stimulation of net carbohydrate oxidation (18.8 ±1.4 versus 17.2 ± 1.8μmol min−1 kg−1 pre-operatively, not significant), suppression of lipolysis and lipid oxidation and inhibition of ketogenesis occurred to the same extent as before surgery. Of the infused nutrients, the glucose was all oxidized, amino acids replaced endogenous protein losses (= neutral nitrogen balance) and lipids were stored. Insulin administration caused no further increment in oxygen consumption or energy expenditure. 5. We conclude that: (a) uncomplicated surgery causes severe insulin resistance, the effects of which insulin can reverse; and (b) with an energy supply only slightly in excess of demand, insulin supplementation preserves body protein and energy stores effectively.

BACKGROUND & AIMS: The cytokine pattern secreted by T cells at the site of viral replication may influence the final outcome of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. The aim of this study was to assess whether a cytokine imbalance oriented toward T helper (Th) 1 or Th2-type responses may play a role in chronic hepatitis B or C. METHODS: Production of interferon (IFN)-gamma, interleukin (IL)-4, and IL-5 by wide series of T-cell clones derived from the liver of 6 patients with chronic hepatitis B (291 clones) and 9 patients with chronic hepatitis C (260 clones) was studied. T-cell clones were generated by limiting dilution from freshly isolated mononuclear cells derived from liver tissue to give a reliable representation of the intrahepatic inflammatory infiltrates. RESULTS: The majority of liver-infiltrating T cells in chronic hepatitis C were Th1 cells able to secrete IFN-gamma but unable to secrete IL-4 or IL-5, whereas in hepatitis B, most CD4+ and CD8+ liver T cells were ThO-like cells able to produce not only IFN-gamma but also IL-4 and IL-5. CONCLUSIONS: The different cytokine profiles of T cells within the liver in chronic HBV and HCV infections illustrate a different behavior of the local immune response in these two infections that may have pathogenetic implications. (Gastroenterology 1997 Jan;112(1):193-9)

Metabolic abnormalities occur in biguanide-treated diabetic patients. We investigated the relationship between plasma metformin and phenformin concentrations and metabolic effects. Drug levels were measured in 37 type II diabetic patients by HPLC. The method was sensitive, specific, and linear over a wide range of drug concentrations. Metformin and phenformin values ranged from 236 to 718 ng/ml and from 28 to 114 ng/ml, respectively. The plasma metformin level was correlated with triglycerides (r = −0.55; P < 0.05) but not with drug dosage, plasma glucose, HbA1, creatinine, creatinine clearance, lactate, pyruvate, lipid, and clinical parameters. Plasma phenformin concentrations correlated with lactate (r = 0.49; P < 0.05) and HbA1(r = 0.50; P < 0.05) but not with drug dosage, parameters of diabetes control, creatinine, creatinine clearance, pyruvate, and clinical parameters. The clinical usefulness of this HPLC method, the evidence that the increase of lactate is related to the circulating phenformin levels, and the demonstration that the metformin effect on triglyceride metabolism is correlated to plasma drug levels are the positive findings of this work.

The fortieth author’s name was listed incorrectly. The correct presentation is A Keski-Rahkonen.

Discrepancies in the role of the 40 bp VNTR polymorphism of the dopamine transporter gene DAT1 in attentiondeficit hyperactivity disorder ADHD could be due to various sources of genetic or phenotypical heterogeneity. We therefore analyzed a sample of 146 ADHD children and their parents, with a transmission disequilibrium test TDT design, assessing age, inattention, and hyperactivity dimensions and total score of the ADHD Rating Scale, the number of errors and the total score at Stroop ColorWord test, and the total score at the Trail Making Test. The TDT for 10repeat 10R allele shows a perfect lack of transmission bias Mc Nemar χ2  0 and PBAT analyses showed no role of this polymorphism for any of the studied endophenotypes. Lack of statistical power is always a possibility, but with a sample size above the average of the majority of previous studies, and an odds ratio number of transmitted versus untransmitted 10R allele of 1.00 exactly, this possibility may be considered as not very likely. © 2008 WileyLiss, Inc.

Tyrosine hydroxylase is the rate-limiting enzyme in catecholamine synthesis: the gene has previously been cloned and localised to the short arm of chromosome 11. Because of the interest in tyrosine hydroxylase as a candidate gene for manic-depressive psychosis and other affective disorders, we carried out family studies to determine the linkage of tyrosine hydroxylase with insulin, β-globin, D11S12 and Harvey-ras1, members of a linkage group which has previously been localised to lip. Using DNA from the Centre d'Etude du Polymorphisme Humain (CEPH) and from two large British pedigrees. we show that tyrosine hydroxylase is closely linked to these four loci (2=7.36, θ=0.04 for linkage to insulin) and suggest a gene order based on multipoint mapping.

Formestane (®LENTARON), a synthetic steroid derivative of an-drostenedione is the first selective aromatase inhibitor to become available. The multicentre study of ®LENTARON (250mg i.m. fortnightly) vs megestrol acetate (160mg oral once daily) enrolled 547 patients. All patients had histologically proven advanced breast cancer, had documented relapse of disease while under adjuvant therapy with tamoxifen administered for at least 12 months or had experienced progression of advanced breast cancer after an initial response for at least 3 months while under first-line therapy with tamoxifen and had ER and/or PgR positive or unknown. The primary end-point was time to treatment failure. Secondary endpoints were objective tumour response (in accordance with UICC criteria), time to progression, and overall survival time. Efficacy analysis was performed for the intent to treat patients and for the eligible patients who were evaluable for tumour response and will be presented. Preliminary analysis of safety data indicate a trend of more serious adverse events in the Megace group (pulmonary embolism and vaginal bleeding) in comparison with the ®LENTARON group.