Apoptosis of Merkel cells in neurotrophin-3 null mice

Postnatal mice lacking neurotrophin-3 (NT3) are deficient in Merkel cells of touch domes and whisker follicles. We examined the mechanism of Merkel cell loss by immunocytochemistry and electron microscopy. Merkel cell of whisker follicles of NT3 null newborns exhibited decreased immunoreactivity for cytokeratin 8 and contained apoptotic bodies that were positive for cleaved caspase-3, a marker of active apoptosis. By electron microscopy, the Merkel cells displayed aggregation of chromatin along the nuclear membrane, with the marginated chromatin forming caps at the periphery of the nucleus. Ribosomes aggregated in the cytoplasm, while dense core granules characteristic of Merkel cells were still discernible. Finally, the Merkel cells and their nuclei fragmented into apoptotic bodies. None of the apoptotic Merkel cells were contacted by nerve fibers, and their desmosomal contacts with surrounding keratinocytes disappeared. After postnatal day 6 apoptotic Merkel cells were no longer observed, and the number of surviving Merkel cells was severely reduced. They were flat and contained few osmiophilic granules. We conclude that perinatal apoptosis is responsible for the loss of Merkel cells lacking innervation in NT3 null mice.     

Krill Oil Supplementation Reduces Exacerbated Hepatic Steatosis Induced by Thermoneutral Housing in Mice with Diet-Induced Obesity

Preclinical evidence suggests that n-3 fatty acids EPA and DHA (Omega-3) supplemented as phospholipids (PLs) may be more effective than triacylglycerols (TAGs) in reducing hepatic steatosis. To further test the ability of Omega-3 PLs to alleviate liver steatosis, we used a model of exacerbated non-alcoholic fatty liver disease based on high-fat feeding at thermoneutral temperature. Male C57BL/6N mice were fed for 24 weeks a lard-based diet given either alone (LHF) or supplemented with Omega-3 (30 mg/g diet) as PLs (krill oil; ω3PL) or TAGs (Epax 3000TG concentrate; ω3TG), which had a similar total content of EPA and DHA and their ratio. Substantial levels of TAG accumulation (~250 mg/g) but relatively low inflammation/fibrosis levels were achieved in the livers of control LHF mice. Liver steatosis was reduced by >40% in the ω3PL but not ω3TG group, and plasma ALT levels were markedly reduced (by 68%) in ω3PL mice as well. Krill oil administration also improved hepatic insulin sensitivity, and its effects were associated with high plasma adiponectin levels (150% of LHF mice) along with superior bioavailability of EPA, increased content of alkaloids stachydrine and trigonelline, suppression of lipogenic gene expression, and decreased diacylglycerol levels in the liver. This study reveals that in addition to Omega-3 PLs, other constituents of krill oil, such as alkaloids, may contribute to its strong antisteatotic effects in the liver.     

Dietary Supplementation with Selenium and Coenzyme Q10 Prevents Increase in Plasma D-Dimer While Lowering Cardiovascular Mortality in an Elderly Swedish Population

A low intake of selenium is associated with increased cardiovascular mortality. This could be reduced by supplementation with selenium and coenzyme Q₁₀. D-dimer, a fragment of fibrin mirroring fibrinolysis, is a biomarker of thromboembolism, increased inflammation, endothelial dysfunction and is associated with cardiovascular mortality in ischemic heart disease. The objective was to examine the impact of selenium and coenzyme Q₁₀ on the level of D-dimer, and its relationship to cardiovascular mortality. D-dimer was measured in 213 individuals at the start and after 48 months of a randomised double-blind placebo-controlled trial with selenium yeast (200 µg/day) and coenzyme Q₁₀ (200 mg/day) (n = 106) or placebo (n = 107). The follow-up time was 4.9 years. All included individuals were low in selenium (mean 67 μg/L, SD 16.8). The differences in D-dimer concentration were evaluated by the use of T-tests, repeated measures of variance and ANCOVA analyses. At the end, a significantly lower D-dimer concentration was observed in the active treatment group in comparison with those on placebo (p = 0.006). Although D-dimer values at baseline were weakly associated with high-sensitive CRP, while being more strongly associated with soluble tumour necrosis factor receptor 1 and sP-selectin, controlling for these in the analysis there was an independent effect on D-dimer. In participants with a D-dimer level above median at baseline, the supplementation resulted in significantly lower cardiovascular mortality compared to those on placebo (p = 0.014). All results were validated with a persisting significant difference between the two groups. Therefore, supplementation with selenium and coenzyme Q₁₀ in a group of elderly low in selenium and coenzyme Q₁₀ prevented an increase in D-dimer and reduced the risk of cardiovascular mortality in comparison with the placebo group. The obtained results also illustrate important associations between inflammation, endothelial function and cardiovascular risk.     

Mental health of adolescents associated with sexual and reproductive outcomes: a systematic review

ObjectiveTo systematically review the literature on the mental health of adolescents associated with sexual and reproductive outcomes, and compare the mental health outcomes with that of other age groups.MethodsWe searched seven databases for relevant peer-reviewed articles published between 1 January 2010 and 25 April 2019. Our inclusion criteria required that the study included age-disaggregated data on adolescents, and focused and assessed mental health outcomes associated with pregnancy or sexually transmitted infections. We extracted data on the specific health event, the mental health outcome and the method of measuring this, and comparisons with other age groups.FindingsAfter initially screening 10 818 articles by title and abstract, we included 96 articles in our review. We observed that a wide-ranging prevalence of mental ill-health has been reported for adolescents. However, most studies of mental health during pregnancy did not identify an increased risk of depression or other mental disorders among adolescents compared with other age groups. In contrast, the majority of studies conducted during the postpartum period identified an increased risk of depression in adolescents compared with other age groups. Three studies reported on mental health outcomes following abortion, with varying results. We found no studies of the effect of sexually transmitted infections on mental health among adolescents.ConclusionWe recommend that sexual and reproductive health services should be accessible to adolescents to address their needs and help to prevent any adverse mental health outcomes.     

Neurotensin-like Peptides in the CNS of Lampreys: Chromatographic Characterization and Immunohistochemical Localization with Reference to Aminergic Markers

Neurotensin (NT)-like peptides in the CNS of the lamprey Lampetra fluviatilis were studied by radioimmunoassay (C-terminal specific NT antiserum), reverse-phase HPLC and immunohistochemistry. Multiple peaks of NT-immunoreactive (-ir) material were observed upon HPLC, of which a major peak eluted in the position of bovine NT. Immunofluorescence histochemistry showed that a monoclonal antibody recognizing the N-terminal (1 - 11) fragment of NT, as well as two polyclonal NT antisera labelled a large number of cell bodies in the periventricular area of hypothalamus, including the postinfundibular commissural nucleus and the ventral and dorsal hypothalamic nuclei. Additional groups of NT-ir cells were observed in the preoptic nucleus, the postoptic commissural nucleus, the mesencephalic tegmentum (L.fluviatilis), and in the spinal cord (L.fluviatilis and Ichtyomyzon unicuspis). Dense NT-ir fibre plexuses were present in the caudal hypothalamus, corpus striatum, ventral mesencephalon, and in the dorsal horn and lateral margin of the spinal cord. At the ultrastructural level the lateral spinal margin showed NT-ir terminal structures, which in most cases were not associated with synaptic specializations, although occasional synaptic contacts with unlabelled elements were found. The relation between NT-ir and monoamine-containing cells was examined with immunofluorescence double-staining, using antisera to tyrosine hydroxylase (TH), 5-hydroxytryptamine (5-HT), and histamine respectively. In the periventricular nuclei of hypothalamus numerous TH-, 5-HT-, as well as histamine-ir cells were located in close association with NT-ir cells, but none of the aminergic markers could be detected within NT-ir neurons. The chemical properties as well as the anatomical distribution of lamprey NT-like peptides show several similarities with those present in mammals, suggesting that NT-containing neuronal systems in the CNS developed early in vertebrate phylogeny.     

Cancer patients who refuse treatment

The value of cancer treatment was assessed using a natural experiment where patients who refused treatment served as no-treatment controls in a situation where withholding treatment to form a control group is unethical. Each cancer patient who refused treatment in Alberta, Canada between 1975 and 1988 was compared with five subjects who accepted treatment, matched on cancer site, age, number of cancers, and time period. Variables associated with treatment-refusal were included in Cox's proportional hazards model of survival, with death from cancer as the endpoint and deaths from other causes as censored observations. Treatment was refused at a rate of 7.5 per 1,000. One-third of patients who refused treatment had lung cancer and most had unstaged disease. Treatment refusal was associated with a difference in median survival of approximately nine months. Site-specific analyses showed a range of effects. Case fatality among the treated patients fell by approximately 10 percent during the 14-year study period. Even in advanced disease, treatment can result in improved survival. However, the results of this study must be interpreted with caution and cannot be generalized to all cancer patients.Dr Huchcroft and Mr Snodgrass are with the Alberta Cancer Board, Calgary, Alberta, Canada. Address correspondence to Dr Shirley Huchcroft, Senior Scientist, Division of Epidemiology and Preventive Oncology, Alberta Cancer Board, Calgary, Alberta, Canada T2N 4N2.