Evidence that the retroviral DNA integration process triggers an ATR-dependent DNA damage response

Caffeine is an efficient inhibitor of cellular DNA repair, likely through its effects on ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) kinases. Here, we show that caffeine treatment causes a dose-dependent reduction in the total amount of HIV-1 and avian sarcoma virus retroviral vector DNA that is joined to host DNA in the population of infected cells and also in the number of transduced cells. These changes were observed at caffeine concentrations that had little or no effect on overall cell growth, synthesis, and nuclear import of the viral DNA, or the activities of the viral integrase in vitro. Substantial reductions in the amount of host-viral-joined DNA in the infected population, and in the number of transductants, were also observed in the presence of a dominant-negative form of the ATR protein, ATRkd. After infection, a significant fraction of these cells undergoes cell death. In contrast, retroviral transduction is not impeded in ATM-deficient cells, and addition of caffeine leads to the same reduction that was observed in ATM-proficient cells. These results suggest that activity of the ATR kinase, but not the ATM kinase, is required for successful completion of the viral DNA integration process and/or survival of transduced cells. Components of the cellular DNA damage repair response may represent potential targets for antiretroviral drug development.     

Thoracic aortic aneurysm with aortobronchial fistula: a thirteen-year experience

PURPOSE: This study investigated the causes of aortobronchial fistula, clinical features, diagnostic modalities, and prognostic factors. PARTICIPANTS: A retrospective analysis of 17 patients with aortobronchial fistula secondary to thoracic aortic aneurysm was studied. METHODS: Retrospective chart review was used. RESULTS: Atherosclerosis (47.1%), infection (23.5%), and previous thoracic vascular surgery (17.6%) accounted for most causes. Most patients (94.1%) experienced at least 1 episode of hemoptysis. Chest computer tomography is the most useful tool and revealed hematoma or consolidation around the aneurysm in more than half of our patients. Bronchoscopy and aortoangiogram frequently did not demonstrate an aortobronchial fistula. The 6 patients in the surgery group all survived, in contrast to 100% mortality in the non-surgery group. The average interval between initial presentation of hemoptysis and surgical intervention in the surgery group is 68 days, in contrast to 170 days between initial presentation of hemoptysis and death in the non-surgery group. CONCLUSIONS: A high index of suspicion will decrease delayed diagnosis. Early diagnosis and emergent surgery are 2 prognostic factors for survival.     

Genetics of Somatic Mammalian Cells: Lethal Antigens as Genetic Markers for Study of Human Linkage Groups

The antigen that causes killing of at least 98% of a human cell population treated with a 1% solution of a specific rabbit antiserum in the presence of complement is a sensitive genetic marker. The rapid loss of human chromosomes in human-Chinese hamster cell hybrids makes possible a convenient test of linkage relationships with this marker. Hybrid clones with and without the lethal antigen were isolated and analyzed. In 76 clones and subclones studied, 41 carried both the lethal antigen and the lactic dehydrogenase-A marker, 35 carried neither, and no clones contained only one of the two markers. In contrast to this clear demonstration of linkage, absence of linkage was found between the lethal antigen and the following markers: Lactic dehydrogenase B, NAD-dependent malic dehydrogenase, NADP-dependent malic dehydrogenase, glucose-6-phosphate dehydrogenase, phosphoglucomutase, glutamate oxaloacetate transaminase, indophenol oxidase, glucose phosphate isomerase, proline, inositol, hypoxanthine B, and glycine A. This lethal antigen appears to be carried on a single human autosome.     

A Placebo-Controlled Trial of Dextromethorphan as an Adjunct in Opioid-Dependent Patients Undergoing Methadone Maintenance Treatment

Background:

Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT).

Methods:

Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor–β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect.

Results:

After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different.

Conclusions:

We provide evidence—decreased concomitant heroin use—of low-dose add-on DM’s efficacy for treating opioid-dependent patients undergoing MMT.     

Idiopathic myointimal hyperplasia of mesenteric veins: a rare mimic of idiopathic inflammatory bowel disease

Idiopathic myointimal hyperplasia of mesenteric veins (IMHMV) is a rare and poorly understood disease that occurs in the rectosigmoid colon of predominantly young, previously healthy male patients. IMHMV typically requires segmental resection due to complications after a relatively protracted clinical course. This disease presents a challenging diagnostic dilemma for the clinician because it is initially often confused with chronic idiopathic inflammatory bowel disease. We report a case of IMHMV, illustrate endoscopic and histopathologic features, and review key characteristics of this rare entity.     

Insulin treatment reverses the postreceptor defect in adipocyte 3-O-methylglucose transport in type II diabetes mellitus

The insulin resistance of type II diabetes mellitus is due to both receptor and postreceptor defects of in vivo insulin action, with the postreceptor defect being the predominant abnormality. Diminished glucose transport has been found in adipocytes from patients with type II diabetes, suggesting that decreased cellular glucose transport activity may be responsible in part for the in vivo postreceptor defect observed in these patients. Recent studies have shown that the in vivo postreceptor defect initially present in patients with Type II diabetes is significantly reversed by insulin therapy. For these reasons, we speculated that the defect in adipocyte glucose transport might also be corrected with exogenous insulin therapy. Therefore, we measured adipocyte 3-O-methylglucose transport in cells from five type II diabetic subjects before and after a 2-week period of intensive insulin treatment. Glycemic control was significantly improved by this regimen. The mean (+/- SE) fasting serum glucose level fell from 292 +/- 24 to 135 +/- 29 mg/100 ml (P less than 0.005), and the mean integrated glucose area under a 7-h meal tolerance test curve decreased from 171,212 +/- 20,403 to 72,408 +/- 9,292 mg/min . dl. The mean 3-O-methylglucose transport activity increased after treatment at all insulin concentrations studied, including basal (before, 0.18 +/- 0.05; after, 0.45 +/- 0.09 pmol/2 X 10(5) cells . 10 sec; P less than 0.005) and maximally effective (25 ng/ml) insulin concentrations (before, 0.50 +/- 0.14; after, 1.32 +/- 0.30 pmol/2 X 10(5) cells . 10 sec; P less than 0.025), although the mean maximal glucose transport activity was still 25% decreased compared to normal values, indicating that a residual in vitro postreceptor defect remained. These results corresponded well with the degree of reversal (75%) of the in vivo postreceptor defect, as assessed by the euglycemic glucose clamp technique. These studies demonstrated that the decrease in adipocyte glucose transport activity in type II diabetes is practically reversible by intensive insulin therapy. This closely corresponds to the reversal by insulin therapy of the postreceptor defect expressed in vivo and provides further evidence that a cellular cause of the postreceptor defect in type II diabetes is a decrease in glucose transport system activity in the major insulin target tissues.     

Effects of heterogeneous risk factors on psychological distress in adolescents with autism and victimization experiences in Taiwan

Purpose: To investigate the prevalence of various types of bullying victimization among adolescents with autism spectrum disorder (ASD) and examine the effects of victimization on the mental health of adolescents with ASD.

Methods: The sample was collected from the Special Needs Education Longitudinal Study (SNELS) database released in 2011. Variables comprising seven psychological distress (PD) items and four types of bullying victimization and family-, school-, and peer-related factors were included in a multivariate regression analysis.

Results: Exclusion and verbal bullying were most frequently reported, 72.4% of students with ASD experiencing exclusion bullying and 66% of them experiencing verbal bullying. Among the victims, delayed bedtime, use of medication, and conflicts with parents significantly increased PD. By contrast, good relationships with parents and friends and liking school environments relieved PD symptoms. Furthermore, delayed bedtime after 12 a.m. enhanced the effects of exclusion victimization on PD in the participants.

Conclusions: Our results indicated that bullying victimization among adolescents with ASD was a risk factor for their psychological well-being. Nevertheless, good parent–adolescent and interpeer relationships improved their mental health. Our results can serve as a reference in implementing strategies for motivating parents and teachers to pay more attention to the needs of adolescents with ASD.

• Implications for Rehabilitation

• More than 80% of adolescents with autism experience at least one type of bullying victimization.

• Bullying victimization attributes to a major factor influencing mental health of adolescents with autism.

• Good parent–adolescent and interpeer relationships can play beneficial roles in improving mental health of the adolescents.

     

Mesenchymal stem cells for treating ocular surface diseases

Mesenchymal stem cells (MSC) have become a promising tool for cell therapy in regenerative medicine. They are readily available, demonstrate powerful differentiation capabilities and present immunosuppressive properties that aid them in surviving from host immune rejection for its great potential use in allograft. Currently clinical trials are underway using MSC, both culture-expanded allogeneic and autologous, for the treatment of a range of diseases not treatable by conventional therapies. A vast array of studies has dedicated towards the use of MSC for treating corneal diseases with very promising outcomes. MSC have successfully differentiated into keratocytes both in vitro and in vivo, and corneal epithelial cells in vitro, but it is uncertain if MSC can assume corneal epithelial cells in vivo. However, to date few studies have unequivocally established the efficacy of MSC for treating corneal endothelial defects. Currently, the diversity in protocols of the isolation and expansion of MSC are hindering to the assessment of cell treatment ability and the further development of treatment regimens. Therefore, future studies should develop international standards for MSC isolation and characterization. In this review, we discuss recent advances in MSC for treating ocular surface diseases.