The major histocompatibility complex region marked by HSP70-1 and HSP70- 2 variants is associated with clozapine-induced agranulocytosis in two different ethnic groups

Genes of the major histocompatibility complex (MHC) have been associated with susceptibility to drug-induced adverse reactions. We previously found that clozapine-induced agranulocytosis (CA) is associated with the HLA-DRB1*0402, DRB4*0101, DQB1*0302, DQA1*0301 haplotype in Ashkenazi Jewish patients and with the HLA-DRB1*1601, DRB5*02, DQB1*0502, DQA1*0102 haplotype in non-Jewish patients. In the present study, we tested the hypothesis that the variants of the heat- shock protein 70 (HSP-70) encoded by the HSP-70 loci located within the MHC region and known to be involved in apoptosis and regulation of cell proliferation could play an important role in molecular mechanisms of CA. First, we analyzed HSP70-2 polymorphism in risk-associated haplotypes from HLA homozygous cells and normal individuals and confirmed that the HSP70-2 9-kb variant was associated invariably with DR4 (HLA-DRB1*0402, DQB1*0302) and DR2 (HLA-DRB1*01601, DQB1*0502, DQA1*0102 and HLA-DRB1*1501, DQB1*0602) haplotypes, which were the haplotypes found increased in Jewish and non-Jewish patients with CA, respectively. The 9.0-kb variant was also found to be associated with HLA-B44, DRB1*0401 and HLA-B44, DRB1*07 haplotypes. Second, in patients with CA (12 Ashkenazi Jewish and 20 non-Jewish patients), HSP70-1 A and HSP70-2 9.0-kb variants were associated with the MHC haplotypes found by us to be markers of susceptibility to CA. The clozapine-treated control group had an excess number of HSP70-1 C and HSP70-2 8.5-kb variants, consistent with genetic resistance to CA associated with those variants. This finding supports our hypothesis that a dominant gene within the MHC region (marked by HSP70-1 and HSP70-2), but not necessarily HLA, is associated with CA in two different ethnic groups.     

“Glass fairies” and “bone children”: Adolescents and young adults with anorexia nervosa show positive reactions towards extremely emaciated body pictures measured by the startle reflex paradigm

In this study, we investigated the emotional processing of extremely emaciated body cues in adolescents and young adults with (n = 36) and without (n = 36) anorexia nervosa (AN), introducing a new picture type, which was taken from websites that promote extreme thinness and is targeted specifically at adolescents interested in extreme thinness. A startle reflex paradigm was used for implicit reactions, while a self‐assessment instrument was used for subjective responses. We found a significant group difference with a startle inhibition (appetitive response) among the patients and a startle potentiation (aversive response) among the controls, whereas no such difference for subjective measures was found. The results are in contrast to previous studies, which proposed a general failure to activate the appetitive motivational system in AN, but in keeping with findings from other addictions, where the same response pattern has been found. Implications for prevention and therapy are discussed.     

Review of current classifications for diverticular disease and a translation into clinical practice

Introduction  

Diverticular disease of the sigmoid colon prevails in Western society. Its presentation may vary greatly per individual patient, from symptomatic diverticulosis to perforated diverticulitis. Since publication of the original Hinchey classification, several modifications and new grading systems have been developed. Yet, new insights in the natural history of the disease, the emergence of the computed tomography scan, and new treatment modalities plead for evolving classifications.     

Effect of primary versus revisional Roux-en-Y gastric bypass: inferior weight loss of revisional surgery after gastric banding

BackgroundLaparoscopic adjustable gastric banding is a popular and effective restrictive bariatric procedure. However, with longer follow-up, it has become clear that a considerable number of patients require revisional surgery, of which Roux-en-Y gastric bypass (RYGB) is the most commonly performed procedure. Studies that compared the outcomes of primary RYGB and revisional RYGB have not been conclusive. Our objective was to determine whether significant differences exist in the 1-year outcomes between primary RYGB (prim-RYGB) and revisional RYGB after laparoscopic adjustable gastric banding (rev-RYGB) at a major training hospital in The Netherlands.MethodsAll prim-RYGB and rev-RYGB procedures performed from 2007 to 2009 were analyzed. Data were collected regarding weight loss, hospitalization, operative time, postoperative complications, and co-morbidities.ResultsA total of 292 RYGB procedures were performed: 66 rev-RYGB and 226 prim-RYGB procedures. The operative time was significantly shorter in the prim-RYGB group (136.6 ± 37.5 versus 167.5 ± 40.6 min; P < .0001). No significant differences were found in hospitalization time (4.4 ± 1.7 versus 4.9 ± 2.4 d; P = .063) or complication rate (14.7% versus 15.2%; P = .962). No deaths occurred in either group. The number of patients with resolved diabetes and hypertension did not differ between the 2 groups (50.1% versus 23.1%; P = .116; and 40.7% versus 25.0%; P = .384, respectively). Weight loss was significantly greater in the prim-RYGB group in terms of excess weight loss (71.6% ± 20.8% versus 48.4% ± 26.8%; P < .0001), body mass index reduction (13.0 ± 3.8 versus 10.2 ± 5.6 kg/m²; P < .0001), absolute weight loss (37.4 ± 11.5 versus 29.3 ± 17.2 kg; P = .001), and percentage of weight loss (29.7% ± 8% versus 21.7% ± 11.5%; P < .0001).Conclusionrev-RYGB is a safe procedure with outcomes similar to those of prim-RYGB in terms of complication rate, hospitalization time, and effect on co-morbidity. Weight loss, however, was significantly less after rev-RYGB than after prim-RYGB.     

Peripartale Blutungen,Diagnostik und Therapie

Die Anaesthesiologie - Anhand einer fiktiven Kasuistik wird die aktuelle Leitlinie „Peripartale Blutungen, Diagnostik und Therapie“ mit einem Schwerpunkt auf die anästhesiologische...     

The novel use of a biodegradable stent placed by percutaneous transhepatic cholangiography for the treatment of a hepaticojejunostomy biliary leak following an extended left hepatectomy and pancreaticoduodenectomy

A 61-year-old man presented with jaundice, and subsequently underwent an extended left hepatectomy and pancreaticoduodenectomy for a cholangiocarcinoma invading the head of the pancreas. The patient developed sepsis due to a biliary leak at the hepaticojejunostomy. We describe the original use of a biodegradable stent, deployed via percutaneous transhepatic cholangiography into the Roux limb, resulting in good drainage and resolution of sepsis. The chief benefit of this procedure is the lack of need for subsequent removal as well as purported reduced biofilm accumulation. We believe this to be the first reported case of this type and the literature surrounding the subject is also discussed.     

Differential responses to JNJ‐37822681, a specific and fast dissociating dopamine D2 receptor antagonist,in cynomolgus monkey and Sprague–Dawley rat general toxicology studies: clinical observations,prolactin levels,mammary histopathology findings and toxicokinetics

JNJ‐37822681 is a potent, specific and fast dissociating dopamine D₂ receptor antagonist intended for the treatment of schizophrenia. Its nonclinical toxicological profile was investigated in a series of general repeat dose toxicity studies in cynomolgus monkeys and Sprague–Dawley rats. The maximum duration of treatment was 9 and 6 months, respectively. Interspecies differences were noted in the response to JNJ‐37822681 in terms of extrapyramidal (EPS)‐like clinical signs and prolactin‐mediated tissue changes in the mammary gland. Monkeys showed severe EPS‐like clinical signs such as abnormal posture, abnormal eye movements and hallucination‐like behavior at relatively low exposures compared to those associated with EPS in patients with schizophrenia. The high sensitivity of the monkey to JNJ‐37822681‐induced EPS‐like signs was unexpected based on the fast dissociating properties of the compound. Rats, however, were not prone to EPS. Elevated serum prolactin levels were found in rats and monkeys. While rats showed slight to moderate prolactin‐related tissue changes upon histopathological examination in all studies, which among others affected the mammary gland, only minor mammary gland tissue changes were noted in monkeys. Prolactin levels were only slightly increased in patients with schizophrenia receiving relatively high dose levels of JNJ‐37822681. The monkey toxicology studies did not provide an exposure‐based safety margin, while in rats adverse effects were only noted at exposures considerably higher than those achieved at efficacious plasma concentrations in the clinic. Overall, the available data suggest that the cynomolgus monkey showed better predictivity towards the nature of JNJ‐37822681‐associated adverse events in humans than the Sprague–Dawley rat. Copyright © 2013 John Wiley & Sons, Ltd.