Phosphorylative respiratory activity of mitochondria isolated from the left and right ventricles of rabbit hearts following partial pulmonary trunk occlusion

Right ventricular hypertrophy was produced by placing a spiral Monel metal clip around the pulmonary trunks of rabbits causing a sustained 67% occlusion of the vessel. The operation produced a doubling of right ventricular weight, by 13 days post-surgery, which persisted throughout the post-operative period studied (13 to 84 days); only a slight increase in left ventricular free wall weight was observed. Isolated mitochondria exhibited region-specific changes with time in state 3 Qo₂. Thirteen days after operation, the state 3 Qo₂ of right ventricular mitochondria was depressed to about 85% of controls. Thereafter, respiration increased fairly sharply, peaking at just above control values by 40 days post-operation. Finally, it declined abruptly to about 70% of controls by 84 days. A very different pattern of change was observed when left ventricular mitochondrial respiratory activities were examined. Thirteen days after the operation, state 3 Qo₂ was elevated somewhat above controls. Thereafter, it declined linearly and gradually, dropping to about 85% of controls by 84 days.     

On control of spontaneous testicular regression in tree sparrows (Spizella arborea)

To clarify whether androgen plays a role in the mechanism of spontaneous testicular regression in chronically photostimulated tree sparrows (Spizella arborea), microgram quantities of testosterone propionate (TP) or the free alcohol of cyproterone, a specific and potent antagonist of androgen, were implanted intracerebrally in separate experiments. Steroids, including cholesterol implanted in controls, were mixed homogeneously with cocoa butter. TP implants in the basal infundibular nucleus of the hypothalamus induced in photostimulated birds regressive changes that frequently culminated in testicular dysfunction and collapse; cholesterol implants in or near the basal infundibular nucleus were ineffective. Contrarily, cyproterone implants terminating in a central portion of the TP-sensitive basal infundibular nucleus inhibited spontaneous testicular regression in birds held 17 wk on 20-hr daily photoperiods. Magnitude of inhibition-assessed by both weight and histological criteria-ranged from complete to partial. Cyproterone implants elsewhere in the basal infundibular nucleus, as well as cholesterol or cocoa-butter implants, did not impede regression. Taken together, our results suggest that androgen-sensitive receptors in or near the basal infundibular nucleus are capable of detecting local concentrations of androgen and of altering pituitary gonadotropin secretion, presumably by varying the rate of neurohormone synthesis and/or release. Confirmation of Wilson's (1970) observation that cyproterone can prevent initiation of spontaneous testicular regression strengthens the notion that androgen plays an important role in the mechanism that terminates testicular function in chronically photostimulated tree sparrows.     

Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings

Activation of presynatic histamine H(3) receptors (H(3)R) down-regulates norepinephrine exocytosis from cardiac sympathetic nerve terminals, in both normal and ischemic conditions. Analogous to the effects of alpha(2)-adrenoceptors, which also act prejunctionally to inhibit norepinephrine release, H(3)R-mediated antiexocytotic effects could result from a decreased Ca(2+) influx into nerve endings. We tested this hypothesis in sympathetic nerve terminals isolated from guinea pig heart (cardiac synaptosomes) and in a model human neuronal cell line (SH-SY5Y), which we stably transfected with human H(3)R cDNA (SH-SY5Y-H(3)). We found that reducing Ca(2+) influx in response to membrane depolarization by inhibiting N-type Ca(2+) channels with omega-conotoxin (omega-CTX) greatly attenuated the exocytosis of [(3)H]norepinephrine from both SH-SY5Y and SH-SY5Y-H(3) cells, as well as the exocytosis of endogenous norepinephrine from cardiac synaptosomes. Similar to omega-CTX, activation of H(3)R with the selective H(3)R-agonist imetit also reduced both the rise in intracellular Ca(2+) concentration (Ca(i)) and norepinephrine exocytosis in response to membrane depolarization. The selective H(3)R antagonist thioperamide prevented this effect of imetit. In the parent SH-SY5Y cells lacking H(3)R, imetit affected neither the rise in Ca(i) nor [(3)H]norepinephrine exocytosis, demonstrating that the presence of H(3)R is a prerequisite for a decrease in Ca(i) in response to imetit and that H(3)R activation modulates norepinephrine exocytosis by limiting the magnitude of the increase in Ca(i). Inasmuch as excessive norepinephrine exocytosis is a leading cause of cardiac dysfunction and arrhythmias during acute myocardial ischemia, attenuation of norepinephrine release by H(3)R agonists may offer a novel therapeutic approach to this condition.     

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.