Guided self-help for binge eating/purging anorexia nervosa before inpatient treatment

Abstract

The goal of this study was to develop a cognitive–behavioral self-help manual for anorexia nervosa. Patients diagnosed with anorexia nervosa (N=102), binge eating/purging type (AN-B/P), were consecutively assigned to one of two conditions: 6-week manualized guided self-help or a wait-list control. All patients thereafter received inpatient treatment in a hospital for behavioral medicine. The primary outcome variable was the number of days in inpatient treatment. Secondary outcome variables were measures of psychopathology. Results showed that duration of inpatient treatment was significantly shorter (by 5.2 days) among participants receiving guided self-help. Body image, slimness ideal, general psychopathology, and some bulimic symptoms improved significantly during self-help. The authors conclude that, to increase effects of therapist-guided self-help in AN-B/P, additional variants of a self-help manual should be tried in different therapeutic settings.     

Role of Cytochrome P450 3A4 and 1A2 Phenotyping in Patients with Advanced Non‐small‐Cell Lung Cancer Receiving Erlotinib Treatment

Erlotinib is metabolized by cytochrome p450 (CYP) 3A and CYP1A. This study assessed CYP3A4 (midazolam) and CYP1A2 (caffeine) phenotyping in plasma and dried blood spots (DBS) for predicting the pharmacokinetics and toxicity of erlotinib in 36 patients with advanced NSCLC. On day 1, erlotinib 150 mg OD was initiated, and the two oral probe drugs midazolam (2 mg) and caffeine (100 mg) were added on day 1. Plasma and DBS were collected for erlotinib, OSI‐420 and probe drugs for up to 6 hr on day 1 and 2‐weekly up to week 10. Probe drugs, erlotinib and OSI‐420 were analysed using LC‐MS‐MS, and PK data were processed using population modelling. A high correlation was found between plasma and DBS concentrations for erlotinib (R² = 0.960, p < 0.0001), OSI‐420 (R² = 0.971, p < 0.0001), midazolam (R² = 0.995, p < 0.0001) and caffeine (R² = 0.968, p < 0.0001). Apparent oral caffeine clearance was significantly correlated with erlotinib clearance (R² = 0.33, p = 0.048), while midazolam clearance was not (R² = ?0.09, p = 0.596). Erlotinib clearance was lower in patients experiencing grade 2 or 3 rash as compared to patients experiencing grade 0 or 1 rash (3.15 versus 3.93 L/hr, p = 0.086 for Student's t‐test). The results suggest that probe drug phenotyping is unlikely to substitute therapeutic drug monitoring of erlotinib in patients with advanced NSCLC, but erlotinib PK sampling from DBS may replace more invasive venous sampling and facilitate TDM in patients with cancer.     

Recreational marijuana use is not associated with worse outcomes after renal transplantation

As marijuana (MJ) legalization is increasing, kidney transplant programs must develop listing criteria for marijuana users. However, no data exist on the effect of MJ on kidney allograft outcomes, and there is no consensus on whether MJ use should be a contraindication to transplantation. We retrospectively reviewed 1225 kidney recipients from 2008 to 2013. Marijuana use was defined by positive urine toxicology screen and/or self‐reported recent use. The primary outcome was death at 1 year or graft failure (defined as GFR<20 mL/min/1.73 m²). The secondary outcome was graft function at 1 year. Using logistic regression analyses, we compared these outcomes between MJ users and non‐users. Marijuana use was not associated with worse primary outcomes by unadjusted (odds ratio 1.07, 95% CI 0.45–2.57, P=.87) or adjusted (odds ratio 0.79, 95% CI 0.28–2.28, P=.67) analysis. Ninety‐two percent of grafts functioned at 1 year. Among these, the mean creatinine (1.52, 95% CI 1.39–1.69 vs 1.46, 95% CI 1.42–1.49; P=.38) and MDRD GFR (50.7, 95% CI 45.6–56.5 vs 49.5, 95% CI 48.3–50.7; P=.65) were similar between groups. Isolated recreational MJ use is not associated with poorer patient or kidney allograft outcomes at 1 year. Therefore, recreational MJ use should not necessarily be considered a contraindication to kidney transplantation.     

Expanding the clinical spectrum of the ‘HDAC8‐phenotype’ – implications for molecular diagnostics,counseling and risk prediction

Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous disorder characterized by typical facial dysmorphism, cognitive impairment and multiple congenital anomalies. Approximately 75% of patients carry a variant in one of the five cohesin‐related genes NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Herein we report on the clinical and molecular characterization of 11 patients carrying 10 distinct variants in HDAC8. Given the high number of variants identified so far, we advise sequencing of HDAC8 as an indispensable part of the routine molecular diagnostic for patients with CdLS or CdLS‐overlapping features. The phenotype of our patients is very broad, whereas males tend to be more severely affected than females, who instead often present with less canonical CdLS features. The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X‐inactivation, observed in seven out of eight female patients. Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children. This further supports the urgent need for an integration of highly sensitive sequencing technology to allow an appropriate molecular diagnostic, genetic counseling and risk prediction.     

Nerve growth factor in serum is a marker of the stage of alcohol disease

Long-term alcohol abuse has deleterious effects on the peripheral and central nervous system. Nerve growth factor (NGF) is a pleiotropic neurotrophic protein involved in development, maintenance of function and regeneration of nerve cells. We examined patients in different stages of alcohol disease and measured their NGF serum concentrations based on the hypothesis that these reflect the state of disease. We examined 57 patients suffering from alcohol-dependence for more than 2 years (DSM IV) on day 8 of a qualified withdrawal, 18 patients with Korsakoff's syndrome and 40 healthy controls. In addition to clinical examination, careful history taking and a standard neuropsychological test battery, serum NGF concentrations were measured by a highly sensitive enzyme-immunoassay. Of the 57 patients 9 had suffered from severe withdrawal delirium in the past, other clinical parameters were alike. Cognitive test performance did not differ from the control group. Mean NGF levels of controls amounted to 42.1pg/ml (S.D. 68.0); mean levels of patients with alcohol dependence were raised significantly to 401.5pg/ml (S.D. 932.6) without delirium in the past and even further to 3292.5pg/ml (S.D. 4879.6) with former withdrawal delirium. By contrast, patients with persistent amnestic disorder (Korsakoff's syndrome) showed values identical to the controls. NGF serum levels were significantly elevated in alcohol-dependent patients, more so in those with prior delirium. Their cognitive tests being normal, this possibly reflects the activity of NGF as an endogenous repair mechanism for damaged neurons. In accordance with this hypothesis, NGF values are "normal" in patients with persistent alcohol-related cognitive decline.     

The intracellular sites of early replication and budding of SARS-coronavirus

In this study, we analyzed the replication and budding sites of severe acute respiratory syndrome coronavirus (SARS-CoV) at early time points of infection. We detected cytoplasmic accumulations containing the viral nucleocapsid protein, viral RNA and the non-structural protein nsp3. Using EM techniques, we found that these putative viral replication sites were associated with characteristic membrane tubules and double membrane vesicles that most probably originated from ER cisternae. In addition to its presence at the replication sites, N also accumulated in the Golgi region and colocalized with the viral spike protein. Immuno-EM revealed that budding occurred at membranes of the ERGIC (ER-Golgi intermediate compartment) and the Golgi region as early as 3 h post infection, demonstrating that SARS-CoV replicates surprisingly fast. Our data suggest that SARS-CoV establishes replication complexes at ER-derived membranes. Later on, viral nucleocapsids have to be transported to the budding sites in the Golgi region where the viral glycoproteins accumulate and particle formation occurs.     

SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome

Background

Heterozygous gain‐of‐function mutations in various genes encoding proteins of the Ras‐MAPK signalling cascade have been identified as the genetic basis of Noonan syndrome (NS) and cardio‐facio‐cutaneous syndrome (CFCS). Mutations of SOS1, the gene encoding a guanine nucleotide exchange factor for Ras, have been the most recent discoveries in patients with NS, but this gene has not been studied in patients with CFCS.

Methods and results

We investigated SOS1 in a large cohort of patients with disorders of the NS–CFCS spectrum, who had previously tested negative for mutations in PTPN11, KRAS, BRAF, MEK1 and MEK2. Missense mutations of SOS1 were discovered in 28% of patients with NS. In contrast, none of the patients classified as having CFCS was found to carry a pathogenic sequence change in this gene.

Conclusion

We have confirmed SOS1 as the second major gene for NS. Patients carrying mutations in this gene have a distinctive phenotype with frequent ectodermal anomalies such as keratosis pilaris and curly hair. However, the clinical picture associated with SOS1 mutations is different from that of CFCS. These findings corroborate that, despite being caused by gain‐of‐function mutations in molecules belonging to the same pathway, NS and CFCS scarcely overlap genotypically.