Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly

Unlike some other childhood neurodevelopmental disorders, no diagnostic biochemical marker has been identified in all individuals with an autism spectrum disorder (ASD). This deficit likely results from genetic heterogeneity among the population. Therefore, we evaluated a subset of individuals with ASDs, specifically, individuals with or without macrocephaly in the presence or absence of PTEN mutations. We sought to determine if amino or organic acid markers could be used to identify individuals with ASDs with or without macrocephaly in the presence or absence of PTEN mutations, and to establish the degree of macrocephaly in individuals with ASDs and PTEN mutation. Urine, blood and occipital–frontal circumference (OFC) measurements were collected from 69 individuals meeting DSM-IV-TR criteria. Urine and plasma samples were subjected to amino and organic acid analyses. PTEN was Sanger-sequenced from germline genomic DNA. Germline PTEN mutations were identified in 27% (6/22) of the macrocephalic ASD population. All six PTEN mutation-positive individuals were macrocephalic with average OFC+4.35 standard deviations (SDs) above the mean. No common biochemical abnormalities were identified in macrocephalic ASD individuals with or without PTEN mutations. In contrast, among the collective ASD population, elevation of urine aspartic acid (87% 54/62), plasma taurine (69% 46/67) and reduction of plasma cystine (72% 46/64) were observed. PTEN sequencing should be carried out for all individuals with ASDs and macrocephaly with OFC ≥2SDs above the mean. A proportion of individuals with ASDs may have an underlying disorder in sulfur amino acid metabolism.     

Clinical Supervision in Effectiveness and Implementation Research

The role of clinical supervision in the larger‐scale implementation of effective mental health treatments has begun to attract attention in effectiveness research and implementation science. Clinical supervision approaches demonstrated to support the implementation of effective treatments could provide a fruitful basis for adaptation to the contours and implementation of other interventions. The adaptation of the Multisystemic Therapy supervision model to support the implementation of an innovative, experimental mental health service model called Links to Learning is described. An observational study provides the platform for consideration of the extent to which the Links supervision model was implemented as intended and of challenges to Links implementation illuminated by the supervision process. Implications are considered for research on supervision as a tool to effect the implementation and outcomes of effective treatment and service models in community practice contexts.     

Methods and Findings from the National Violent Death Reporting System for Identifying Gang-Like Homicides, 2005–2008

Background

The National Violent Death Reporting System (NVDRS) captures homicides that law enforcement or coroner/medical examiners deem as gang-related but the criteria used may vary across locations. Also, the existing gang-related variable likely underestimates the number of homicides that are associated with gang activity. This study utilizes NVDRS data to identify “gang-like” homicides which are not currently captured as “gang-related.”

Constitutive macropinocytosis allows TAP-dependent major histocompatibility compex class I presentation of exogenous soluble antigen by bone marrow-derived dendritic cells

Dendritic cells expanded from mouse bone marrow (BMDC) with granulocyte/macrophage-colony-stimulating factor have potent T cell-stimulatory properties both in vitro and in vivo. This has been well documented for major histocompatibility complex (MHC) class II-restricted responses, and more recently using peptide-loaded and protein-pulsed DC for CD8 responses following adoptive transfer in mice. An unresolved question concerns the capacity of BMDC to present exogenous antigen on MHC class I molecules, an unconventional mode of MHC class I loading for which there is now considerable evidence, particularly in macrophages. Here, we show that BMDC exhibit high levels of macropinocytosis driven by constitutive membrane ruffling activity. Up to one-third of actively ruffling and macropinocytosing BMDC transferred pinocytosed horseradish peroxidase into the cytosol following a 15-min pulse, suggesting that they might be capable of presenting exogenous soluble antigen on MHC class I molecules. We show that BMDC presented exogenous ovalbumin to a T cell hybridoma more effectively, more rapidly, and at lower exogenous antigen concentrations than BM macrophages on a cell-for-cell basis. Presentation was TAP dependent, brefeldin A sensitive, and blocked by inhibitors of proteasomal processing, demonstrating use of the classical MHC class I pathway. Although effective presentation of exogenous antigen by BMDC occurred in the absence of agents which stimulate macropinocytosis, treatment with phorbol myristate acetate (PMA) enhanced both pinocytosis and MHC class I presentation by BMDC. Finally, PMA-stimulated BMDC exposed to exogenous ovalbumin in vitro were able to prime an antigen-specific cytotoxic T lymphocyte response following adoptive transfer in vivo.     

Nicotinic receptors on local circuit neurons in dentate gyrus: a potential role in regulation of granule cell excitability

Although the dentate gyrus is one of the primary targets of septo-hippocampal cholinergic afferents, relatively little is known about the cholinergic physiology of neurons in the area. By combining whole cell patch-clamp recording with brief local application of exogenous agonists in horizontal slices, we found that there is robust expression of functional somatic alpha 7-containing nicotinic acetylcholine receptors (nAChRs) on molecular layer interneurons, hilar interneurons, and the glutamatergic mossy cells of the dentate hilus. In contrast, the principal neurons of the dentate gyrus, the granule cells, are generally unresponsive to focal somatic or dendritic application of ACh in the presence of atropine. We also demonstrate that cholinergic activation of alpha 7-containing nAChRs on the subgranular interneurons of the hilus can produce methyllycaconitine-sensitive GABAergic inhibitory postsynaptic currents (IPSCs) in nearby granule cells and enhance the amplitude of an electrically evoked monosynaptic IPSC. Further, activation of alpha 7-containing nAChRs on subgranular interneurons that is timed to coincide with synaptic release of glutamate onto these cells will enhance the functional inhibition of granule cells. These findings suggest that a complex interplay between glutamatergic afferents from the entorhinal cortex and cholinergic afferents from the medial septum could be involved in the normal regulation of granule cell function. Such a relationship between these two afferent pathways could be highly relevant to the study of both age-related memory dysfunction and disorders involving regulation of excitability, such as temporal lobe epilepsy.     

Partial Left Ventriculectomy and Limited Heart Transplantation Availability

BACKGROUND AND AIM: Partial left ventriculectomy, a novel cardiac volume reduction operation, is applied in countries without a developed heart transplantation program. We sought to determine its impact in our population of patients. METHODS: Partial left ventriculectomy was performed in 38 patients during the last 4 years. Basic inclusion criteria were nonischemic dilated cardiomyopathy and poor response to medical therapy for heart failure. Hemodynamic evaluation was carried out before and after operation. A modified surgical technique of mitral valve repair and ventricle suturing was applied. RESULTS: Thirty-day, 6-month, and 2-year survival rates were 82% +/- 7%, 65% +/- 8%, and 61% +/- 9%, respectively. Duration of heart failure symptoms was the only predictor of survival (p = 0.042). A high proportion of noncardiac causes of death was noted. Functional capacity in surviving patients improved at every successive measurement up to 1 year postoperatively. CONCLUSIONS: The introduction of partial left ventriculectomy in a country with limited heart transplantation availability had a great impact on the management of end-stage heart failure and may represent the only surgical option for some patients. The average cost per patient was substantially lower when compared to heart transplantation.     

A randomized phase II pharmacokinetic and pharmacodynamic study of indisulam as second-line therapy in patients with advanced non-small cell lung cancer.

PURPOSE: The primary aim of this study was to measure the objective tumor response rate following treatment with indisulam [E7070; N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide] as second-line therapy in patients with advanced non-small cell lung cancer. The secondary aims were to determine progression-free survival, to assess the safety and tolerability of indisulam, and to study its pharmacokinetic and pharmacodynamic profile. EXPERIMENTAL DESIGN: Patients were randomized to receive indisulam every 3 weeks either as a single i.v. dose of 700 mg/m(2) on day one (dx1) or 130 mg/m(2) given on days 1 to 5 inclusive as a daily infusion (dx5). All patients had previously received platinum-based chemotherapy. RESULTS: Forty-four patients were randomized. Only minor responses were seen. Myelosuppression, gastrointestinal symptoms, and lethargy were the most common toxicities and were more frequent in the dx1 arm. The pharmacokinetics of indisulam in each treatment schedule were adequately described using a previously developed population pharmacokinetic model and were mostly consistent with the results of the phase I program. Flow cytometric analysis of endobronchial and metastatic disease revealed a reduction in the fraction of cycling cells and an increase in apoptosis following indisulam compared with pretreatment levels. CONCLUSIONS: We conclude that, despite evidence of tumor-specific indisulam-induced apoptosis, neither of these treatment schedules has single-agent activity as second-line treatment of non-small cell lung cancer.     

Child abuse and smoking among young women: the importance of severity, accumulation, and timing.

PURPOSE: We examined the association between severity, accumulation, and timing of abuse in childhood and adolescence and smoking status among young women. METHODS: Retrospective self-reported childhood abuse was ascertained with the modified Conflict Tactics Scale from 91,286 Nurses Health Study II participants in 2001 (68,505 returned; 75.0% response rate). Childhood abuse was categorized by severity (mile/moderate/severe), type (physical/sexual), and timing (childhood/adolescence). Smoking status during adolescence was reported at baseline (1989). Logistic regression was used to predict smoking initiation by age 14 and smoking status between the ages of 15 and 19. RESULTS: A graded association between severity of abuse and early initiation of smoking (by age 14 years) was demonstrated (odds ratio [OR] = 1.9, 95% confidence interval [CI] = 1.7-2.1 for severe physical violence). Young women with both physical and sexual abuse were two times more likely to start smoking by age 14 than were those reporting no abuse (OR = 2.0, 95% CI = 1.8-2.3). Although abuse during childhood increased risk for adolescent smoking (OR = 1.7, 95% CI = 1.8-2.1) for those with childhood physical and sexual abuse, inclusion of adolescent physical and sexual abuse (OR = 2.2, 95% CI 2.1-2.4) diminished the impact of childhood abuse (OR = 1.1, 95% CI 1.1-1.2). The degree of familial emotional support was protective against smoking, and reduced the impact of abuse by 40% among those with high emotional support versus those without (p < .0001). CONCLUSIONS: A strong and graded association was observed between both severity and accumulation of abuse and the risk of early initiation of smoking among girls. Smoking status during late adolescence was more strongly associated with adolescent abuse than childhood abuse. Early smoking onset is associated with both heightened risk for disease in adolescence but also increased morbidity and mortality in adulthood. Identifying and intervening in potentially modifiable risk factors for smoking onset in young women, such as early-life physical and sexual abuse, and building familial strengths, such as emotional support, may have significant public health implications.     

Aerobic and anaerobic microbiology of acute suppurative parotitis

Aspirates of pus from acute suppurative parotitis were studied for aerobic and anaerobic bacteria. Bacterial growth was present in 23 specimens. A total of 36 bacterial isolates (20 anaerobic and 16 aerobic and facultative) were recovered, accounting for 1.6 isolates per specimen (0.9 anaerobic and 0.7 aerobic and facultative). Anaerobic bacteria only were present in 10 (43%) patients, aerobic and facultatives in 10 (43%), and mixed aerobic and anaerobic flora in 3 (13%). Single bacterial isolates were recovered in 9 infections, 6 of which were Staphylococcus aureus and 3 were anaerobic bacteria. The predominant bacterial isolates were S. aureus (8 isolates), Bacteroides sp. (6 isolates, including 4 Bacteroides melaninogenicus group), and Peptostreptococcus sp. (5). beta-Lactamase-producing organisms were recovered from 11 (73%) of the 15 specimens tested. This study highlights the polymicrobial nature and importance of anaerobic bacteria in acute suppurative parotitis.     

Aerobic and anaerobic microbiologic factors and recovery of beta-lactamase producing bacteria from obstetric and gynecologic infection

Specimens obtained from 736 patients with obstetric and gynecologic infections were studied for aerobic and anaerobic bacteria. Bacterial growth was present in 714 specimens. These included 53 specimens of infected fallopian tubes, 470 of infected endometrium, 94 of infected amniotic fluid, 57 of aspirates of cul-de-sacs in instances of pelvic inflammatory disease, 14 labial and vaginal abscesses and 26 of Bartholyn's cyst abscess. A total of 2,052 isolates (2.9 per specimen), 1,139 anaerobes (1.6 per specimen) and 913 aerobic or facultative (1.3 per specimen) were recovered. The most commonly isolated anaerobic bacteria was Bacteroides species (566 isolates), which included Bacteroides bivius (151), Bacteroides fragilis group (130), Bacteroides melaninogenicus group (110) and Bacteroides ureolyticus (47). Others included an anaerobic gram-positive cocci (391), Clostridium species (48) and Fusobacterium species (36). The most frequently recovered aerobic and facultative bacteria were Lactobacillus species (169), Escherichia coli (85), Neisseria gonorrhoeae (62), Staphylococcus aureus (59) and Group B streptococcus (55). Three hundred and sixty-five (18 per cent) of the isolates recovered from 276 (39 per cent) patients were beta-lactamase producing organisms (BLPO); 222 (61 per cent) anaerobes and 143 (39 per cent) aerobes or facultatives. The most common BLPO were B. fragilis group, B. bivius, B. melaninogenicus, B. disiens, Enterobacteriaceae and S. aureus. These data illustrate the polymicrobial nature and important role of BLPO in obstetric and gynecologic infection.