The effects of 24 weeks of moderate- or high-intensity exercise on insulin resistance

This study was designed to investigate the effect of exercise intensity on insulin resistance by comparing moderate- and high-intensity interventions of equal energy cost. Maximum oxygen consumption (VO_2max), insulin, glucose and triglycerides were measured in 64 sedentary men before random allocation to a non-exercise control group, a moderate-intensity exercise group (three 400-kcal sessions per week at 60% of VO_2max) or a high-intensity exercise group (three 400-kcal sessions per week at 80% of VO_2max). An insulin sensitivity score was derived from fasting concentrations of insulin and triglycerides, and insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). Data were available for 36 men who finished the study. After 24 weeks, insulin concentration decreased by 2.54±4.09 and 2.37±3.35 mU l⁻¹, insulin sensitivity score increased by 0.91±1.52 and 0.79±1.37, and HOMA-IR decreased by −0.6±0.8 and −0.5±0.8 in the moderate- and high-intensity exercise groups, respectively. When data from the exercise groups were combined, one-way analysis of variance with one-tailed post hoc comparisons indicated that these changes were significantly greater than those observed in the control group (all P<0.05). Twenty-four week changes in insulin concentration, insulin sensitivity score and HOMA-IR were not significantly different between the exercise groups. These data suggest that exercise training is accompanied by a significant reduction in insulin resistance, as indicated by well-validated surrogate measures. These data also suggest that moderate-intensity exercise is as effective as high-intensity exercise when 400 kcal are expended per session.     

Interaction of Dr adhesin with collagen type IV is a critical step in Escherichia coli renal persistence

The pathogenic mechanism of recurrent or chronic urinary tract infection is poorly understood. Escherichia coli cells bearing Dr fimbriae display unique tropism to the basement membrane (BM)-renal interstitium that enables the bacteria to cause chronic pyelonephritis in experimental mice. The renal receptors for Dr-fimbriated E. coli are type IV collagen and decay-accelerating factor (DAF). We hypothesized that type IV collagen receptor-mediated BM-interstitial tropism is essential for E. coli to cause chronic pyelonephritis. To test the role of the type IV collagen tropism of Dr-fimbriated E. coli in renal persistence, we constructed an isogenic mutant in the DraE adhesin subunit that was unable to bind type IV collagen but retained binding to DAF and examined its virulence in the mouse model. The collagen-binding mutant DrI113T was eliminated from the mouse renal tissues in 6 to 8 weeks, while the parent strain caused persistent renal infection that lasted at least 14 weeks (P < or = 0.02). Transcomplementation with the intact Dr operon restored collagen-binding activity, BM-interstitial tropism, and the ability to cause persistent renal infection. We conclude that type IV collagen binding mediated by DraE adhesin is a critical step for the development of persistent renal infection in a murine model of E. coli pyelonephritis.     

Risk of HIV infection attributable to oral sex among men who have sex with men and in the population of men who have sex with men

We examined HIV infection and estimated the population-attributable risk percentage (PAR%) for HIV associated fellatio among men who have sex with other men (MSM). Among 239 MSM who practised exclusively fellatio in the past 6 months, 50% had three partners, 98% unprotected; and 28% had an HIV-positive partner; no HIV was detected. PAR%, based on the number of fellatio partners, ranges from 0.10% for one partner to 0.31% for three partners. The risk of HIV attributable to fellatio is extremely low.     

Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing

As part of a randomised trial [Genetic Risk Assessment for Familial Hypercholesterolaemia (FH) Trial] of the psychological consequences of DNA-based and non-DNA-based diagnosis of FH, 338 probands with a clinical diagnosis of FH (46% with tendon xanthomas) were recruited. In the DNA-based testing arm (245 probands), using single-strand conformation polymorphism of all exons of the low-density lipoprotein receptor (LDLR) gene, 48 different pathogenic mutations were found in 62 probands (25%), while 7 (2.9%) of the patients had the R3500Q mutation in the apolipoprotein B (APOB) gene. Compared to those with no detected mutation, mean untreated cholesterol levels in those with the APOB mutation were similar, while in those with an LDLR mutation levels were significantly higher (None=9.15±1.62 vs LDLR=9.13±1.16 vs APOB=10.26±2.07 mmol/l p<0.001, respectively). Thirty seven percent of the detected mutations were in exon 3/4 of LDLR, and this group had significantly higher untreated cholesterol than those with other LDLR mutations (11.71±2.39 mmol/l vs 9.88±2.44 mmol/l, p=0.03), and more evidence of coronary disease compared to those with other LDLR or APOB mutations (36 vs 13% p=0.04). Of the probands with a detected mutation, 54 first-degree relatives were identified, of whom 27 (50%) had a mutation. Of these, 18 had untreated cholesterol above the 95th percentile for their age and gender, but there was overlap with levels in the non-carrier relatives such that 12% of subjects would have been incorrectly diagnosed on lipid levels alone. In the non-DNA-based testing arm (82 probands) only 19 of the 74 relatives identified had untreated cholesterol above the 95th percentile for their age and gender, which was significantly lower (p<0.0005) than the 50% expected for monogenic inheritance. These data confirm the genetic heterogeneity of LDLR mutations in the UK and the deleterious effect of mutations in exon 3 or 4 of LDLR on receptor function, lipids and severity of coronary heart disease. In patients with a clinical diagnosis of FH but no detectable mutation, there is weaker evidence for a monogenic cause compared with relatives of probands with LDLR mutations. This supports the usefulness of DNA testing to confirm diagnosis of FH for the treatment of hyperlipidaemia and for further cascade screening.     

Surgical pathology in sub-Saharan Africa—volunteering in Malawi

The breadth of material found in surgical pathology services in African countries differs from the common spectrum of “the West”. We report our experience of a voluntary work in the pathology departments of Blantyre and Lilongwe, Malawi. During a 6-week period, 405 cases (378 histology and 27 cytology cases) were processed. The vast majority showed significant pathological findings (n?=?369; 91.1 %): 175 cases (47.4 %) were non-tumoral conditions with predominance of inflammatory lesions, e.g., schistosomiasis (n?=?11) and tuberculosis (n?=?11). There were 39 (10.6 %) benign tumors or tumor-like lesions. Intraepithelial neoplasia of the cervix uteri dominated among premalignant conditions (n?=?15; 4.1 %). The large group of malignancies (n?=?140; 37.9 %) comprised 11 pediatric tumors (e.g., rhabdomyosarcoma, small blue round cell tumors) and 129 adult tumors. Among women (n?=?76), squamous cell carcinomas (SCCs) of the cervix uteri predominated (n?=?25; 32.9 %), followed by breast carcinomas (n?=?12; 15.8 %) and esophageal SCC (n?=?9; 11.8 %). Males (n?=?53) most often showed SCC of the esophagus (n?=?9; 17.0 %) and of the urinary bladder (n?=?7; 13.2 %). Lymphomas (n?=?7) and Kaposi's sarcomas (n?=?6) were less frequent. Differences compared to the western world include the character of the conditions in general, the spectrum of inflammatory lesions, and the young age of adult tumor patients (median 45 years; range 18–87 years). Providing pathology service in a low-resource country may be handicapped by lack of personnel, inadequate material resources, or insufficient infrastructure. Rotating volunteers offer a bridge for capacity building of both personnel and the local medical service; in addition, the volunteer's horizons are broadened professionally and personally.     

Myofibrillar myopathy caused by a mutation in the motor domain of mouse MyHC IIb

Ariel is a mouse mutant that suffers from skeletal muscle myofibrillar degeneration due to the rapid accumulation of large intracellular protein aggregates. This fulminant disease is caused by an ENU-induced recessive mutation resulting in an L342Q change within the motor domain of the skeletal muscle myosin protein MYH4 (MyHC IIb). Although normal at birth, homozygous mice develop hindlimb paralysis from Day 13, consistent with the timing of the switch from developmental to adult myosin isoforms in mice. The mutated myosin (MYH4(L342Q)) is an aggregate-prone protein. Notwithstanding the speed of the process, biochemical analysis of purified aggregates showed the presence of proteins typically found in human myofibrillar myopathies, suggesting that the genesis of ariel aggregates follows a pathogenic pathway shared with other conformational protein diseases of skeletal muscle. In contrast, heterozygous mice are overtly and histologically indistinguishable from control mice. MYH4(L342Q) is present in muscles from heterozygous mice at only 7% of the levels of the wild-type protein, resulting in a small but significant increase in force production in isolated single fibres and indicating that elimination of the mutant protein in heterozygotes prevents the pathological changes observed in homozygotes. Recapitulation of the L342Q change in the functional equivalent of mouse MYH4 in human muscles, MYH1, results in a more aggregate-prone protein.     

Extended Broca’s Area in the Functional Connectome of Language in Adults: Combined Cortical and Subcortical Single-Subject Analysis Using fMRI and DTI Tractography

Traditional models of the human language circuitry encompass three cortical areas, Broca’s, Geschwind’s and Wernicke’s, and their connectivity through white matter fascicles. The neural connectivity deep to these cortical areas remains poorly understood, as does the macroscopic functional organization of the cortico-subcortical language circuitry. In an effort to expand current knowledge, we combined functional MRI (fMRI) and diffusion tensor imaging to explore subject-specific structural and functional macroscopic connectivity, focusing on Broca’s area. Fascicles were studied using diffusion tensor imaging fiber tracking seeded from volumes placed manually within the white matter. White matter fascicles and fMRI-derived clusters (antonym-generation task) of positive and negative blood-oxygen-level-dependent (BOLD) signal were co-registered with 3-D renderings of the brain in 12 healthy subjects. Fascicles connecting BOLD-derived clusters were analyzed within specific cortical areas: Broca’s, with the pars triangularis, the pars opercularis, and the pars orbitaris; Geschwind’s and Wernicke’s; the premotor cortex, the dorsal supplementary motor area, the middle temporal gyrus, the dorsal prefrontal cortex and the frontopolar region. We found a functional connectome divisible into three systems—anterior, superior and inferior—around the insula, more complex than previously thought, particularly with respect to a new extended Broca’s area. The extended Broca’s area involves two new fascicles: the operculo-premotor fascicle comprised of well-organized U-shaped fibers that connect the pars opercularis with the premotor region; and (2) the triangulo-orbitaris system comprised of intermingled U-shaped fibers that connect the pars triangularis with the pars orbitaris. The findings enhance our understanding of language function.     

Release of retinal growth hormone in the chick embryo: Local regulation?

The neural retina is an extrapituitary site of growth hormone (GH) production and an autocrine or paracrine site of retinal GH action. Retinal GH is released from retinal tissue and may be secreted into the vitreous. Ontogenetic changes in the abundance of retinal GH during embryogenesis indicate that the amount of GH released may be regulated. The presence of pituitary GH secretagogues (GH-releasing hormone, GHRH; thyrotropin-releasing hormone, TRH; and ghrelin) and pituitary GH inhibitors (somatostatin, SRIF and insulin-like growth factor, IGF-1) within the neural retina may indicate the involvement of these factors in retinal GH release. This possibility is supported by the finding that GHRH is colocalized with GH in chick retinal ganglion cells (RGCs) and in immortalized cells (QNRD) derived from quail neuroretinal cells and by the induction of GH mRNA in incubated QNRD cells. In summary, these results provide evidence for the autocrine or paracrine regulation of retinal GH release in the ganglion cells of the embryonic chick retina.