Spontaneous luteinizing hormone surges can be reliably prevented by the timely administration of a gonadotrophin releasing hormone antagonist (Nal-Glu) during the late follicular phase.

A new gonadotrophin releasing hormone antagonist (Nal-Glu) was used during the late follicular phase of the natural cycle in order to prevent spontaneous surges of luteinizing hormone (LH). Eight regularly ovulating women (group 1) received two injections of Nal-Glu (5 mg) administered 48 h apart when plasma oestradiol levels exceeded 125 pg/ml. Human menopausal gonadotrophin (HMG, 225 IU) was administered simultaneously with Nal-Glu and repeated every 12 h thereafter until either a spontaneous LH surge occurred or human chorionic gonadotrophin (HCG, 5000 IU) was administered. HCG was arbitrarily administered 48 h after the second Nal-Glu injection. Six other women (group 2) receiving only HMG served as controls. In seven of the eight women in group 1, LH and progesterone remained low for 96 h following Nal-Glu, i.e. until HCG administration. In the remaining woman in this group, LH started to rise 12 h before HCG injection. In this group, Nal-Glu did not interfere with follicular development or the plasma profile of oestradiol. All women developed one single dominant follicle with the exception of one subject who had already spontaneously developed two dominant follicles prior to administration of Nal-Glu and HMG. In group 2, LH rose spontaneously in all women before the planned HCG injection. The luteal phase was apparently not altered by Nal-Glu. These results suggest that Nal-Glu administration during the late follicular phase of natural cycles supported by HMG, can prevent the spontaneous LH surge while not interfering with follicular growth.(ABSTRACT TRUNCATED AT 250 WORDS)     

A man with the combination of dry and wet beriberi

A 34-year-old alcoholic man had neurological and cardiac symptoms. The patient was admitted to the hospital for acute painful sensory disturbances and severe weakness of the feet. Neurological and electrophysiological investigation revealed axonal sensorimotor polyneuropathy that was most prominent in the legs. Cardiac assessment showed signs and symptoms of heart failure due to a high-output state. Blood analysis showed a low thiamine concentration of 58 nmol/l (lower reference limit: 80). Therefore, a diagnosis of combined wet beriberi with cardiomyopathy and dry beriberi with axonal polyneuropathy was made. The treatment of beriberi is simple and effective and consists of thiamine supplementation in conjunction with diuretic treatment. With this approach, the patient recovered fully. Patients with beriberi have a good prognosis, particularly when the diagnosis is made at an early stage.     

SEM-EDX study of prepared human dentine surfaces exposed to gingival retraction fluids

OBJECTIVES: To evaluate the effects of gingival retraction fluids (GRF) on prepared dentine surfaces, and to test the null-hypothesis that prior exposure of dentine surfaces for prolonged period to any of the fluids evaluated does not influence acid-etching of the exposed surfaces. METHODS: The investigation was carried out using SEM and energy-dispersive X-ray analysis (EDX). The GRF studied were Hemodent (HMDT), Astringedent (AST) and Ultradent buffered 25% Aluminium Chloride (ULTB). Longitudinal sections of 220-grit ground dentine surfaces were exposed to GRF for 0.5-, 1-, 2- and 5-min (n=4 each). Another group of samples was produced by 20s application of 35% phosphoric acid (PA) on GRF-pretreated dentine. Control samples were not exposed to GRF. Differences in etching effect-a function of the Ca-contents detected by EDX, were analysed using Friedman's and Wilcoxon's rank test (P<0.05). RESULTS: The SEM demonstrated the presence of a relatively non-porous amorphous dentine matrix, but many of the dentine tubule orifices remained occluded. Granular precipitates, which remained even after acid-etching, were noted on surfaces exposed to Hemodent for 5 min. Characteristic crystal growth was observed on surfaces exposed to Astringedent for 1- or 2-min prior to acid-etching. The EDX data demonstrated that there were differences in resulting Ca-content; ULTB >AST>HMDT>ULTB+PA>HMDT+PA>AST+PA>PA, but AST and HMDT were not significantly different. CONCLUSIONS: The exposure of dentine prepared surfaces to these three GRF altered its morphology and reduced the dentine's susceptibility to acid-etching, thus the null-hypothesis is rejected.     

Diverging associations of an intended early invasive strategy compared with actual revascularization, and outcome in patients with non-ST-segment elevation acute coronary syndrome: the problem of treatment selection bias

AIMS: In several observational studies, revascularization is associated with substantial reduction in mortality in patients with non-ST-segment elevation acute coronary syndrome (nSTE-ACS). This has strengthened the belief that routine early angiography would lead to a reduction in mortality. We investigated the association between actual in-hospital revascularization and long-term outcome in patients with nSTE-ACS included in the ICTUS trial. METHODS AND RESULTS: The study population of the present analysis consists of ICTUS participants who were discharged alive after initial hospitalization. The ICTUS trial was a randomized, controlled trial in which 1200 patients were randomized to an early invasive or selective invasive strategy. The endpoints were death from hospital discharge until 4 year follow-up and death or spontaneous myocardial infarction (MI) until 3 years. Among 1189 patients discharged alive, 691 (58%) underwent revascularization during initial hospitalization. In multivariable Cox regression analyses, in-hospital revascularization was independently associated with a reduction in 4 year mortality and 3 year event rate of death or spontaneous MI: hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.37-0.96] and 0.46 (95% CI 0.31-0.68). However, when intention-to-treat analysis was performed, no differences in cumulative event rates were observed between the early invasive and selective invasive strategies: HR 1.10 (95% CI 0.70-1.74) for death and 1.27 (95% CI 0.88-1.85) for death or spontaneous MI. CONCLUSION: The ICTUS trial did not show that an early invasive strategy resulted in a better outcome than a selective invasive strategy in patients with nSTE-ACS. However, similar to retrospective analyses from observational studies, actual revascularization was associated with lower mortality and fewer MI. Whether an early invasive strategy leads to a better outcome than a selective invasive strategy cannot be inferred from the observation that revascularized patients have a better prognosis in non-randomized studies.     

Couples’ experiences with expanded carrier screening: evaluation of a university hospital screening offer

Preconception carrier screening offers couples the possibility to receive information about the risk of having a child with a recessive disorder. Since 2016, an expanded carrier screening (ECS) test for 50 severe autosomal recessive disorders has been available at Amsterdam Medical Center, a Dutch university hospital. This mixed-methods study evaluated the experiences of couples that participated in the carrier screening offer, including high-risk participants, as well as participants with a general population risk. All participants received genetic counselling, and pre- (n = 132) and post-test (n = 86) questionnaires and semi-structured interviews (n = 16) were administered. The most important reason to have ECS was to spare a future child a life with a severe disorder (47%). The majority of survey respondents made an informed decision (86%), as assessed by the Multidimensional Measure of Informed Choice. Among the 86 respondents, 27 individual carriers and no new carrier couples were identified. Turn-around time of the test results was considered too long and costs were perceived as too high. Overall, mean levels of anxiety were not clinically elevated. High-risk respondents (n = 89) and pregnant respondents (n = 13) experienced higher levels of anxiety before testing, which decreased after receiving the test result. Although not clinically significant, distress was on average higher for carriers compared to non-carriers (p < 0.0001). All respondents would opt for the test again, and 80.2% would recommend it to others. The results suggest that ECS should ideally be offered before pregnancy, to minimise anxiety. This study could inform current and future implementation initiatives of preconception ECS.Subject terms: Genetic testing, Human behaviour     

Spatiotemporal dynamics of gene flow and hybrid fitness between the M and S forms of the malaria mosquito,Anopheles gambiae

The M and S forms of Anopheles gambiae have been the focus of intense study by malaria researchers and evolutionary biologists interested in ecological speciation. Divergence occurs at three discrete islands in genomes that are otherwise nearly identical. An “islands of speciation” model proposes that diverged regions contain genes that are maintained by selection in the face of gene flow. An alternative “incidental island” model maintains that gene flow between M and S is effectively zero and that divergence islands are unrelated to speciation. A “divergence island SNP” assay was used to explore the spatial and temporal distributions of hybrid genotypes. Results revealed that hybrid individuals occur at frequencies ranging between 5% and 97% in every population examined. A temporal analysis revealed that assortative mating is unstable and periodically breaks down, resulting in extensive hybridization. Results suggest that hybrids suffer a fitness disadvantage, but at least some hybrid genotypes are viable. Stable introgression of the 2L speciation island occurred at one site following a hybridization event.The M and S forms of the African malaria vector Anopheles gambiae have been the subject of intense study over the past decade. The focus has centered on models of the evolution and maintenance of genetic divergence between the two forms in relation to speciation (reviewed in ref. 1). A. gambiae has become a model, described in a number of recent reviews on speciation (2–5).The two forms occur in sympatry throughout West and Central Africa (6). They were initially described on the basis of several single nucleotide polymorphisms (SNPs) in the X-linked ribosomal DNA locus (7, 8). Heterozygotes were rarely found in nature and studies of reproductive isolation (RI) confirmed strong assortative mating with interform matings occurring at a frequency of ∼1% (9). Progeny of laboratory crosses and backcrosses show no signs of reduced fitness (10). However, it is widely held that, in nature, some degree of ecologically dependent postzygotic isolation, in addition to assortative mating, contributes to divergence between the two forms (11, 12).Studies of the genetic structure of M and S based on microsatellite markers revealed little between-form differentiation outside the centromeric region of the X chromosome and a few regions associated with inversions (13–15). This overall lack of divergence was attributed to the homogenizing effect of gene flow between the forms (16).In 2008, several reports of much higher frequencies of M/S hybrids, as high as 24%, appeared (17–19). These were all observed in populations in coastal West Africa, an area now thought to represent a zone of secondary contact (20, 21). These reports resulted in the emergence of this species as the focus of research aimed at exploring the evolution and maintenance of genetic divergence with gene flow (11, 12, 22, 23).The first genome-wide comparison of the M and S forms by Turner et al. (24) was consistent with earlier observations that divergence overall is low, but there are small, discrete regions of divergence representing about 3% of the genome. They identified three diverged regions: one near the centromere on the X chromosome, one on the left arm of chromosome 2 (2L), and one on the right arm of chromosome 2 (2R). A number of genome-wide scans comparing M and S have been conducted since. These have applied several methods, including the same microarray used by Turner et al. (25, 26), high-density SNP arrays (12, 21, 23, 27), and whole-genome sequencing (28). These studies likewise revealed little divergence except in a few discrete regions of the genome characterized by high levels of differentiation (islands of divergence).This body of work has culminated in two opposing models aimed at describing the evolution of M and S (1, 11). The “islands of speciation” model supposes that (i) small regions of divergence contain genes responsible for RI because they are directly associated with assortative mating and/or are under strong ecologically dependent divergent selection, and (ii) the rest of the genome is either neutral with respect to differentiation or close enough to neutral so that contemporary gene flow overwhelms selection. The alternative “incidental island” model recognizes the presence of islands of divergence, but suggests that (i) these are not related to RI and the remainder of the genome is less differentiated due to segregating ancestral polymorphism, not gene flow, and (ii) F₁ hybrids are effectively sterile, therefore the amount of “realized” gene flow between M and S is near zero and that M and S are in fact “good species.” Indeed, the M form has recently been elevated to species status and provided the formal species name Anopheles coluzzii (29). We continue to refer to M and S forms to facilitate discussion with reference to the recent literature.Limitations in the genome-wide scans described above may have contributed to disparate views of the evolution of divergence between A. gambiae subgroups. All comparisons of natural populations to date used single-locus, X-linked genotypes (7, 30–32) to identify M and S form specimens used in downstream analyses. These single-locus assays misidentify a significant proportion of backcross individuals. In addition, assessment of hybridization frequencies and comprehensive tests for introgression are precluded from these studies because DNA pools were used (21, 23, 27), sample sizes were too small (24, 26), or such assessments may be irrelevant because M and S laboratory colony mosquitoes were used (28). Finally, there are strong limitations in relying on genome scans alone for detecting selection, gene flow, and recombination that occurs during speciation (33, 34).In this study, we used a simple multilocus SNP genotype approach to distinguish M, S, F₁ hybrids, and backcross individuals (35), which we call the “divergence island SNP” (DIS) assay (SI Appendix). We describe the spatial and temporal distribution of hybridization frequencies, the extent to which hybridization results in introgression, and the fitness of hybrid genotypes in nature. Assumptions concerning these between-form interactions have played a central role in the interpretation of comparative genomics data as applied to understanding speciation in this system. The results we report challenge a number of these assumptions and they provide unique information about temporal dynamics in the way in which M and S forms interact that suggests new avenues for future research.