Evidence for secondary 5 alpha-reductase deficiency in genital and supra-pubic skin of subjects with androgen insensitivity syndrome

The activity of 5 alpha-reductase in genital and supra-pubic skin (homogenate or fibroblasts) from subjects with complete or incomplete androgen insensitivity syndrome was low compared with mean activity in samples from normally differentiated male controls. Also, in two subjects with incomplete androgen insensitivity syndrome the ratio of the concentration of testosterone to that of 5 alpha-dihydrotestosterone in plasma was raised after hCG stimulation but normal under basal conditions. In three subjects with complete androgen insensitivity syndrome there was no evidence of raised ratios of testosterone to 5 alpha-dihydrotestosterone in plasma under basal or hCG-stimulated conditions. The activities of other steroid metabolizing enzymes, e.g. 17 beta-hydroxysteroid dehydrogenase, 3 alpha/beta-hydroxysteroid dehydrogenase, were not decreased. The low 5 alpha-reductase activity of androgen insensitive subjects reported here, and by others, may imply that this enzyme in genital skin is in some way androgen dependent, or responsive to other factors associated with androgen insensitivity syndrome.     

Ethnicity and social deprivation independently influence metabolic control in children with type 1 diabetes

AIMS/HYPOTHESIS: This study was performed to evaluate the influence of ethnicity and socioeconomic status (SES) on metabolic control in a population-based cohort of children with type 1 diabetes mellitus, and to evaluate whether any relationship between ethnicity and HbA(1c) is mediated by SES. METHODS: We performed a retrospective review of all patients under age 16 years with type 1 diabetes (n = 555) from 1995 to 2005 in the greater Auckland region, New Zealand. Diabetes care variables and HbA(1c) values were collected prospectively, during clinic visits. RESULTS: The mean population HbA(1c) was 8.3 +/- 1.3%. Maori and Pacific patients had poorer metabolic control than their European counterparts (9.1% and 9.3% vs 8.1%, p < 0.001) and higher rates of moderate to severe hypoglycaemia (31.1 and 24.8 vs 14.9 events/100 patient-years, p = 0.03). In multiple linear regression analysis, both ethnicity and SES were independently associated with HbA(1c) (p < 0.001). Other factors associated with higher HbA(1c) level were longer duration of diabetes, higher insulin dose, lower BMI z score and less frequent blood glucose monitoring (p < 0.001). CONCLUSIONS/INTERPRETATION: Both ethnicity and SES independently influenced metabolic control in a large, unselected population of children with type 1 diabetes. Irrespective of SES, Maori and Pacific youth with type 1 diabetes were at greater risk of both moderate to severe hypoglycaemia and long-term complications associated with poor metabolic control.     

Recent advances and new challenges in travel medicine

Recent advances in travel medicine include the use of computer resources to obtain information on outbreaks and recommendations to travelers, the introduction of atovaquone/proguanil as chemoprophylaxis and treatment for malaria, the use of azithromycin as an alternative in the self-treatment of traveler’s diarrhea, and the combination of hepatitis A and hepatitis B vaccines. At the same time, new challenges continue to appear. Shifts in the distribution of infections, such as West Nile virus and dengue fever, underscore the need for up-to-date information. Well-known infectious diseases, such as polio, meningococcal meningitis, and influenza are appearing in unexpected ways and settings. It is increasingly clear that travelers, while at risk for infections, also play a role in the global dispersal of pathogens, such as certain serogroups of Neisseria meningitidis and influenza. Increasing drug resistance affects the choice of drugs for treatment and chemoprophylaxis, and decisions about use of vaccines. Newly identified adverse events associated with yellow fever vaccine have prompted enhanced surveillance after vaccination and careful scrutiny of appropriate indications for the vaccine.     

ERCC1 mutations impede DNA damage repair and cause liver and kidney dysfunction in patients

ERCC1-XPF is a multifunctional endonuclease involved in nucleotide excision repair (NER), interstrand cross-link (ICL) repair, and DNA double-strand break (DSB) repair. Only two patients with bi-allelic ERCC1 mutations have been reported, both of whom had features of Cockayne syndrome and died in infancy. Here, we describe two siblings with bi-allelic ERCC1 mutations in their teenage years. Genomic sequencing identified a deletion and a missense variant (R156W) within ERCC1 that disrupts a salt bridge below the XPA-binding pocket. Patient-derived fibroblasts and knock-in epithelial cells carrying the R156W substitution show dramatically reduced protein levels of ERCC1 and XPF. Moreover, mutant ERCC1 weakly interacts with NER and ICL repair proteins, resulting in diminished recruitment to DNA damage. Consequently, patient cells show strongly reduced NER activity and increased chromosome breakage induced by DNA cross-linkers, while DSB repair was relatively normal. We report a new case of ERCC1 deficiency that severely affects NER and considerably impacts ICL repair, which together result in a unique phenotype combining short stature, photosensitivity, and progressive liver and kidney dysfunction.     

Cellular,synaptic, and biochemical features of resilient cognition in Alzheimer's disease

Although neuritic plaques and neurofibrillary tangles in older adults are correlated with cognitive impairment and severity of dementia, it has long been recognized that the relationship is imperfect, as some people exhibit normal cognition despite high levels of Alzheimer's disease (AD) pathology. We compared the cellular, synaptic, and biochemical composition of midfrontal cortices in female subjects from the Religious Orders Study who were stratified into three subgroups: (1) pathological AD with normal cognition (“AD-Resilient”), (2) pathological AD with AD-typical dementia (“AD-Dementia”), and (3) pathologically normal with normal cognition (“Normal Comparison”). The AD-Resilient group exhibited preserved densities of synaptophysin-labeled presynaptic terminals and synaptopodin-labeled dendritic spines compared with the AD-Dementia group, and increased densities of glial fibrillary acidic protein astrocytes compared with both the AD-Dementia and Normal Comparison groups. Further, in a discovery-type antibody microarray protein analysis, we identified a number of candidate protein abnormalities that were associated with a particular diagnostic group. These data characterize cellular and synaptic features and identify novel biochemical targets that may be associated with resilient cognitive brain aging in the setting of pathological AD.     

Evaluation of a morphological filter in mean cardiac output determination: application to left ventricular assist devices

A morphological filter (MF) is presented for the determination of beat-to-beat mean rotary left ventricular assist device (LVAD) flow rate, measured using an implanted flow probe. The performance of this non-linear filter was assessed using LVAD flow rate (Q_LVAD) data sets obtained from in silico and in vivo sources. The MF was compared with a third-order Butterworth filter (BWF) and a 10-s moving average filter (MAF). Performance was assessed by calculating the response time and steady state error across a range of heart rates and levels of noise. The response time of the MF was 3.5 times faster than the MAF, 0.5 s slower than the BWF, and had a steady state error of 2.61 %. It completely removed pulsatile signal components caused by residual ventricular function, and tracked sharp transient changes in Q_LVAD better than the BWF. The use of a two-stage MF improved the noise immunity compared to the single-stage MF. This study showed that the good performance characteristics of the non-linear MF make it a more suitable candidate for embedded real-time processing of Q_LVAD than linear filters.     

Evaluation of the Verigene Gram-Positive Blood Culture Nucleic Acid Test for Rapid Detection of Bacteria and Resistance Determinants

Rapid identification of pathogens from blood cultures can decrease lengths of stay and improve patient outcomes. We evaluated the accuracy of the Verigene Gram-positive blood culture (BC-GP) nucleic acid test for investigational use only (Nanosphere, Inc., Northbrook, IL) for the identification of Gram-positive bacteria from blood cultures. The detection of resistance genes (mecA in Staphylococcus aureus and Staphylococcus epidermidis and vanA or vanB in Enterococcus faecium and Enterococcus faecalis) by the BC-GP assay also was assessed. A total of 186 positive blood cultures (in BacT/Alert FA bottles) with Gram-positive cocci observed with Gram staining were analyzed using the BC-GP assay. The BC-GP results were compared with the identification and susceptibility profiles obtained with routine methods in the clinical laboratory. Discordant results were arbitrated with additional biochemical, cefoxitin disk, and repeat BC-GP testing. The initial BC-GP organism identification was concordant with routine method results for 94.6% of the blood cultures. Only 40% of the Streptococcus pneumoniae identifications were correct. The detection of the mecA gene for 69 blood cultures with only S. aureus or S. epidermidis was concordant with susceptibility testing results. For 3 of 6 cultures with multiple Staphylococcus spp., mecA detection was reported but was correlated with oxacillin resistance in a species other than S. aureus or S. epidermidis. The detection of vanA agreed with susceptibility testing results for 45 of 46 cultures with E. faecalis or E. faecium. Comparison of the mean times to results for each organism group showed that BC-GP results were available 31 to 42 h earlier than phenotypic identifications and 41 to 50 h earlier than susceptibility results.     

A Driver Training Program Intervention for Student Drivers with Autism Spectrum Disorder: A Multi-site Randomised Controlled Trial

The purpose of this multi-site randomised controlled trial was to evaluate the effectiveness of a Driving Training Program, an intervention designed for student drivers with autism spectrum disorder (ASD). Participants were 72 student drivers with ASD (ages 16–31) who were randomly assigned to an intervention or control group. Student drivers received ten driving lessons with a professional driving instructor via a standardised driving route. The Driving Performance Checklist was used as the outcome measure to evaluate the driving performance of student drivers during on-road pre- and post-observational drives. Both groups showed an improvement in driving performance, however, the extent of improvement between groups was not significant. Findings showed promising intervention efficacy for training student drivers with ASD to drive.

     

Granulocyte-Colony Stimulating Factor Reduces Cocaine-Seeking and Downregulates Glutamatergic Synaptic Proteins in Medial Prefrontal Cortex

Psychostimulant use disorder is a major public health issue, and despite the scope of the problem there are currently no Food and Drug Administration (FDA)-approved treatments. There would be tremendous utility in development of a treatment that could help patients both achieve and maintain abstinence. Previous work from our group has identified granulocyte-colony stimulating factor (G-CSF) as a neuroactive cytokine that alters behavioral response to cocaine, increases synaptic dopamine release, and enhances cognitive flexibility. Here, we investigate the role of G-CSF in affecting extinction and reinstatement of cocaine-seeking and perform detailed characterization of its proteomic effects in multiple limbic substructures. Male Sprague Dawley rats were injected with PBS or G-CSF during (1) extinction or (2) abstinence from cocaine self-administration, and drug seeking behavior was measured. Quantitative assessment of changes in the proteomic landscape in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were performed via data-independent acquisition (DIA) mass spectrometry analysis. Administration of G-CSF during extinction accelerated the rate of extinction, and administration during abstinence attenuated cue-induced cocaine-seeking. Analysis of global protein expression demonstrated that G-CSF regulated proteins primarily in mPFC that are critical to glutamate signaling and synapse maintenance. Taken together, these findings support G-CSF as a viable translational research target with the potential to reduce drug craving or seeking behaviors. Importantly, recombinant G-CSF exists as an FDA-approved medication which may facilitate rapid clinical translation. Additionally, using cutting-edge multiregion discovery proteomics analyses, these studies identify a novel mechanism underlying G-CSF effects on behavioral plasticity.SIGNIFICANCE STATEMENT Pharmacological treatments for psychostimulant use disorder are desperately needed, especially given the disease''s chronic, relapsing nature. However, there are currently no Food and Drug Administration (FDA)-approved pharmacotherapies. Emerging evidence suggests that targeting the immune system may be a viable translational research strategy; preclinical studies have found that the neuroactive cytokine granulocyte-colony stimulating factor (G-CSF) alters cocaine reward and reinforcement and can enhance cognitive flexibility. Given this basis of evidence we studied the effects of G-CSF treatment on extinction and reinstatement of cocaine seeking. We find that administration of G-CSF accelerates extinction and reduces cue-induced drug seeking after cocaine self-administration. In addition, G-CSF leads to downregulation of synaptic glutamatergic proteins in medial prefrontal cortex (mPFC), suggesting that G-CSF influences drug seeking via glutamatergic mechanisms.