A segregation and linkage study of classical and nonclassical 21-hydroxylase deficiency.

The segregation of classical and nonclassical 21-hydroxylase deficiency (21-OHD) and its linkage to HLA-B was investigated in 220 families. First, the surprisingly high frequency of the nonclassical 21-OHD gene estimated elsewhere was confirmed using a different methodology which avoided particular assumptions concerning the classification of an individual''s genotype. In the present study the gene frequency was found to be .103 +/- .020 in an ethnically pooled sample and was as high as .223 +/- .062 among Ashkenazi Jews. Second, the segregation analysis of families ascertained through a nonclassical 21-OHD proband and those ascertained through a classical 21-OHD proband showed essentially identical results. A partial recessive model with no recombination between 21-OHD and HLA-B fitted the data better than did a complete recessive model with approximately 0.5% recombination between 21-OHD and HLA-B. The support for the partial over the complete recessive model depended on the assumed ascertainment probability, an unknown parameter in these data. Four families provided most of the evidence against the complete recessive model. All these included an unaffected sib who shared both HLA-B specificities in common with the affected proband. Possible explanations for the condition in these families include recombination, gene conversion, mutation in one of the parental gametes, or technical errors.     

Colonization and emergence of midges (Chironomidae: Diptera) in slow sand filter beds

Colonization by midges, and temporal changes in their community structure, were examined in slow sand filter beds. The replicated beds allow the development of communities to be traced from a known starting point.The filter beds (rectangular concrete containers filled with water) have a substratum of sand on which a rich coating of organic particles develops during passage of the water through the bed. The containers (ponds) are drained from time to time and the organic layer is then scraped off the sand surface. This occurs on average, once a month. The length of time the ponds were filled with water (bed run) during the present study ranged from 16 to 77 days.In long bed runs small midges with a short aquatic phase (Cricotopus sylvestris, Psectrocladius limbatellus, Tanytarsus fimbriatus) produced adults after 16–20 days; other, larger midges,e.g. Psectrocladius barbimanus and the Tanypodinae required a longer aquatic phase. Of the Tanypodinae, the smallAblabesmyia phatta, had the shortest duration of the four species found, and was much the most numerous member of this subfamily. Some Chironomini only appeared when the organic coating had developed over the sand surface. Midges of this tribe frequently failed to complete their larval development within the duration of bed runs and were thus trapped on the substratum at the time of cleaning. When ponds were drained after short bed runs the succession in community structure observed in long runs was arrested.Three small midgesC. sylvestris, P. limbatellus andT. fimbriatus, were collected in high numbers throughout the life of all beds, except towards the end of the longest runs in the study. This suggests that small size, short life cycles, and the ability to colonize clean substrata, are important characteristics for the development of primary chironomid communities in short-lived temporary habitats.     

Intercellular communication in the rat anterior pituitary gland: an in vivo and in vitro study

The concept of "stimulus-secretion coupling" suggested by Douglas and co-workers to explain the events related to monamine discharge by the adrenal medulla (5, 7) may be applied to other endocrine tissues, such as adrenal cortex (36), pancreatic islets (4), and magnocellular hypothalamic neurons (6), which exhibit a similar ion-dependent process of hormone elaboration. In addition, they share another feature, that of joining neighbor cells via membrane junctions (12, 26, and Fletcher, unpublished observation). Given this, and the reports that hormone secretion by the pars distalis also involves a secretagogue-induced decrease in membrane bioelectric potential accompanied by a rise in cellular [Ca++] (27, 34, 41), it was appropriate to test the possibility that cells of the anterior pituitary gland are united by junctions.     

Scale‐dependent spatial patterns in benthic communities around a tropical island seascape

Understanding and predicting patterns of spatial organization across ecological communities is central to the field of landscape ecology, and a similar line of inquiry has begun to evolve sub‐tidally among seascape ecologists. Much of our current understanding of the processes driving marine community patterns, particularly in the tropics, has come from small‐scale, spatially‐discrete data that are often not representative of the broader seascape. Here we expand the spatial extent of seascape ecology studies and combine spatially‐expansive in situ digital imagery, oceanographic measurements, spatial statistics, and predictive modeling to test whether predictable patterns emerge between coral reef benthic competitors across scales in response to intra‐island gradients in physical drivers. We do this around the entire circumference of a remote, uninhabited island in the central Pacific (Jarvis Island) that lacks the confounding effects of direct human impacts. We show, for the first time, that competing benthic groups demonstrate predictable scaling patterns of organization, with positive autocorrelation in the cover of each group at scales < ~1 km. Moreover, we show how gradients in subsurface temperature and surface wave power drive spatially‐abrupt transition points in group dominance, explaining 48–84% of the overall variation in benthic cover around the island. Along the western coast, we documented ten times more sub‐surface cooling‐hours than any other part of the coastline, with events typically resulting in a drop of 1–4°C over a period of < 5 h. These high frequency temperature fluctuations are indicative of upwelling induced by internal waves and here result in localized nitrogen enrichment (NO₂ + NO₃) that promotes hard coral dominance around 44% of the island's perimeter. Our findings show that, in the absence of confounding direct human impacts, the spatial organization of coral reef benthic competitors are predictable and somewhat bounded across the seascape by concurrent gradients in physical drivers.     

Calcium signaling in Alzheimer's disease & therapies

Alzheimer's disease (AD) is the most common type of dementia and is characterized by the accumulation of amyloid (Aβ) plaques and neurofibrillary tangles in the brain. Much attention has been given to develop AD treatments based on the amyloid cascade hypothesis; however, none of these drugs had good efficacy at improving cognitive functions in AD patients suggesting that Aβ might not be the disease origin. Thus, there are urgent needs for the development of new therapies that target on the proximal cause of AD. Cellular calcium (Ca²⁺) signals regulate important facets of neuronal physiology. An increasing body of evidence suggests that age-related dysregulation of neuronal Ca²⁺ homeostasis may play a proximal role in the pathogenesis of AD as disrupted Ca²⁺ could induce synaptic deficits and promote the accumulation of Aβ plaques and neurofibrillary tangles. Given that Ca²⁺ disruption is ubiquitously involved in all AD pathologies, it is likely that using chemical agents or small molecules specific to Ca²⁺ channels or handling proteins on the plasma membrane and membranes of intracellular organelles to correct neuronal Ca²⁺ dysregulation could open up a new approach to AD prevention and treatment. This review summarizes current knowledge on the molecular mechanisms linking Ca²⁺ dysregulation with AD pathologies and discusses the possibility of correcting neuronal Ca²⁺ disruption as a therapeutic approach for AD.     

Regional co-ordinator for haemophilia in domiciliary practice.

The North-east Thames Region has appointed a nursing sister to co-ordinate the organisation of care for haemophiliacs in the region. As a result of the appointment, facilities for home treatment have expanded rapidly. Several associate centres providing care to haemophiliacs have been set up around the region in addition to the four main haemophilia centres, which are all in the south-west corner of the region. As well as providing support and supervision of patients on home treatment, the co-ordinator helps to place haemophiliac children in suitable schools, maintains the regional register of haemophiliacs, and has a more general role in ensuring that services are available where they are needed throughout the region.     

Clinical implications of sperm DNA damage in IVF and ICSI: updated systematic review and meta-analysis

The clinical effect of sperm DNA damage in assisted reproduction has been a controversial topic during recent decades, leading to a variety of clinical practice recommendations. While the latest European Society of Human Reproduction and Embryology (ESHRE) position report concluded that DNA damage negatively affects assisted reproduction outcomes, the Practice Committee of the American Society for Reproductive Medicine (ASRM) does not recommend the routine testing of DNA damage for in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Herein, our aim was to perform a systematic review and meta-analysis of studies investigating whether sperm DNA damage affects clinical outcomes in IVF and ICSI, in order to contribute objectively to a consistent clinical recommendation. A comprehensive systematic search was conducted according to PRISMA guidelines from the earliest available online indexing year until March 2020, using the MEDLINE-PubMed and EMBASE databases. We included studies analysing IVF and/or ICSI treatments performed in infertile couples in which sperm DNA damage was well defined and assessed. Studies also had to include information about pregnancy, implantation or live birth rates as primary outcomes. The NHLBI-NIH quality assessment tool was used to assess the quality of each study. Meta-analyses were conducted using the Mantel–Haenszel method with random-effects models to evaluate the Risk Ratio (RR) between high-DNA-damage and control groups, taking into account the 95% confidence intervals. Heterogeneity among studies was evaluated using the I² statistic. We also conducted sensitivity analyses and post-hoc subgroup analyses according to different DNA fragmentation assessment techniques. We identified 78 articles that met our inclusion and quality criteria and were included in the qualitative analysis, representing a total of 25639 IVF/ICSI cycles. Of these, 32 articles had sufficient data to be included in the meta-analysis, comprising 12380 IVF/ICSI cycles. Meta-analysis revealed that, considering IVF and ICSI results together, implantation rate (RR = 0.74; 95% CI = 0.61–0.91; I² = 69) and pregnancy rate (RR = 0.83; 0.73–0.94; I² = 58) are negatively influenced by sperm DNA damage, although after adjustment for publication bias the relationship for pregnancy rate was no longer significant. The results showed a non-significant but detrimental tendency (RR = 0.78; 0.58–1.06; I² = 72) on live birth rate. Meta-analysis also showed that IVF outcomes are negatively influenced by sperm DNA damage, with a statistically significant impact on implantation (RR = 0.68; 0.52–0.89; I² = 50) and pregnancy rates (RR = 0.72; 0.55–0.95; I² = 72), although the latter was no longer significant after correction for publication bias. While it did not quite meet our threshold for significance, a negative trend was also observed for live birth rate (RR = 0.48; 0.22–1.02; I² = 79). In the case of ICSI, non-significant trends were observed for implantation (RR = 0.79; 0.60–1.04; I² = 72) or pregnancy rates (RR = 0.89; 0.78–1.02; I² = 44), and live birth rate (RR = 0.92; 0.67–1.27; I² = 70). The current review provides the largest evidence to date supporting a negative association between sperm DNA damage and conventional IVF treatments, significantly reducing implantation and pregnancy rates. The routine use of sperm DNA testing is therefore justified, since it may help improve the outcomes of IVF treatments and/or allow a given couple to be advised on the most suitable treatment. Further well-designed controlled studies on a larger number of patients are required to allow us to reach more precise conclusions, especially in the case of ICSI treatments.     

Development of a competitive immunoassay for the determination of N-(2-hydroxypropyl)valine adducts in human haemoglobin and its application in biological monitoring

Abstract

Propylene oxide (PO) is an important industrial compound and a directly acting mutagen. Human exposure to PO can be monitored by the determination of haemoglobin adducts. An immunoassay that quantifies the N-terminal adduct N-(2-hydroxypropyl)valine in whole haemoglobin was developed and its potential usefulness as a tool for biologically monitoring occupational exposure was demonstrated. Analytical reliability was confirmed in a comparative study with GC-MS (range 3.7–992 nmol g^?1 haemoglobin (Hb), correlation coefficient 0.99, n=10). The assay has been configured as a competitive enzyme-linked immunosorbent assay to facilitate the rapid throughput of samples. The assay employs a whole blood matrix and has a working range of 2–250 pmol g^?1 Hb. It does not appear to be affected by structurally similar metabolites and has been used to determine adducts in human blood samples. The first results in potentially exposed workers indicate the assay's high potential usefulness in routine occupational biomonitoring of exposure to PO.     

Human Spermatogenic Failure Purges Deleterious Mutation Load from the Autosomes and Both Sex Chromosomes,including the Gene DMRT1

Gonadal failure, along with early pregnancy loss and perinatal death, may be an important filter that limits the propagation of harmful mutations in the human population. We hypothesized that men with spermatogenic impairment, a disease with unknown genetic architecture and a common cause of male infertility, are enriched for rare deleterious mutations compared to men with normal spermatogenesis. After assaying genomewide SNPs and CNVs in 323 Caucasian men with idiopathic spermatogenic impairment and more than 1,100 controls, we estimate that each rare autosomal deletion detected in our study multiplicatively changes a man''s risk of disease by 10% (OR 1.10 [1.04–1.16], p<2×10⁻³), rare X-linked CNVs by 29%, (OR 1.29 [1.11–1.50], p<1×10⁻³), and rare Y-linked duplications by 88% (OR 1.88 [1.13–3.13], p<0.03). By contrasting the properties of our case-specific CNVs with those of CNV callsets from cases of autism, schizophrenia, bipolar disorder, and intellectual disability, we propose that the CNV burden in spermatogenic impairment is distinct from the burden of large, dominant mutations described for neurodevelopmental disorders. We identified two patients with deletions of DMRT1, a gene on chromosome 9p24.3 orthologous to the putative sex determination locus of the avian ZW chromosome system. In an independent sample of Han Chinese men, we identified 3 more DMRT1 deletions in 979 cases of idiopathic azoospermia and none in 1,734 controls, and found none in an additional 4,519 controls from public databases. The combined results indicate that DMRT1 loss-of-function mutations are a risk factor and potential genetic cause of human spermatogenic failure (frequency of 0.38% in 1306 cases and 0% in 7,754 controls, p = 6.2×10⁻⁵). Our study identifies other recurrent CNVs as potential causes of idiopathic azoospermia and generates hypotheses for directing future studies on the genetic basis of male infertility and IVF outcomes.     

Repeated oral administration of capsaicin increases anxiety-like behaviours with prolonged stress-response in rats

This study was conducted to examine the psycho-emotional effects of repeated oral exposure to capsaicin, the principal active component of chili peppers. Each rat received 1 mL of 0.02% capsaicin into its oral cavity daily, and was subjected to behavioural tests following 10 daily administrations of capsaicin. Stereotypy counts and rostral grooming were significantly increased, and caudal grooming decreased, in capsaicin-treated rats during the ambulatory activity test. In elevated plus maze test, not only the time spent in open arms but also the percent arm entry into open arms was reduced in capsaicin-treated rats compared with control rats. In forced swim test, although swimming duration was decreased, struggling increased in the capsaicin group, immobility duration did not differ between the groups. Repeated oral capsaicin did not affect the basal levels of plasma corticosterone; however, the stress-induced elevation of plasma corticosterone was prolonged in capsaicin treated rats. Oral capsaicin exposure significantly increased c-Fos expression not only in the nucleus tractus of solitarius but also in the paraventricular nucleus. Results suggest that repeated oral exposure to capsaicin increases anxiety-like behaviours in rats, and dysfunction of the hypothalamic-pituitary-adrenal axis may play a role in its pathophysiology.