Impact of the SARS-CoV-2 virus on male reproductive health

The coronavirus 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to more than 160 million infections and 3.5 million deaths globally. Men are disproportionately affected by COVID-19, having more severe disease with higher mortality rates than women. Androgens have been implicated as the underlying cause for more severe disease, as the androgen receptor has been noted to upregulate the cell surface receptors that mediate viral cell entry and infection. Unfortunately, despite testosterone’s potential role in COVID-19 prognosis, androgen deprivation therapy is neither protective nor a treatment for COVID-19. Interestingly, the male reproductive organs have been found to be vulnerable in moderate to severe illness, leading to reports of erectile dysfunction and orchitis. COVID-19 viral particles have been identified in penile and testis tissue, both in live patients who recovered from COVID-19 and post mortem in men who succumbed to the disease. Although sexual transmission remains unlikely in recovered men, moderate to severe COVID-19 infection can lead to germ cell and Leydig cell depletion, leading to decreased spermatogenesis and male hypogonadism. The objective of this review is to describe the impact of SARS-CoV-2 on male reproductive health. There are still many unanswered questions as to the specific underlying mechanisms by which COVID-19 impacts male reproductive organs and the long-term sequelae of SARS-CoV-2 on male reproductive health.     

Dimensional complexity of the neuronal activity in a rat model of depression

The Flinders sensitive line of rats is a widely accepted and validated model of depression. These rats demonstrate abnormalities in limbic dopamine neurotransmission, suggesting disturbed neuronal activity in the ventral tegmental area. Interspike interval time-series were recorded from the ventral tegmental area of control Sprague-Dawley and Flinder sensitive line rats. These data were analyzed using standard measures (mean firing rate, bursting activity and spectral analysis) as well as the pointwise correlation dimension, a nonlinear measurement characterizing the complexity degree of dynamic systems. Pointwise correlation dimension, but not standard analysis revealed a significant difference between the animal lines. Our results suggest that nonlinear analyses can detect dysregulation of the mesolimbic dopaminergic system and shed light on the pathophysiology of depression.     

Chronic clomipramine alters presynaptic 5-HT(1B) and postsynaptic 5-HT(1A) receptor sensitivity in rat hypothalamus and hippocampus, respectively

Clomipramine is a tricyclic antidepressant drug with a high affinity for the serotonin (5-HT) uptake site or transporter. Electrophysiological experiments have provided evidence that repeated administration of clomipramine induces an increase in the sensitivity of postsynaptic 5-HT(1A) receptors in the hippocampus. We have studied the effects of clomipramine, administered to rats at a dose of 10mg/kg/day for 28 days by osmotic minipumps, on presynaptic 5-HT(1A) and 5-HT(1B) autoreceptors in the hypothalamus, and on postsynaptic 5-HT(1A) receptors in the hippocampus, by using in vivo microdialysis to measure 5-HT and cyclic adenosine monophosphate (cAMP) levels. Postsynaptic 5-HT(1A) receptor sensitivity in the hypothalamus was determined by means of a neuroendocrine challenge procedure. Although the sensitivity of presynaptic 5-HT(1A) autoreceptors, as measured by the effect of a subcutaneous (s.c.) injection of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.2mg/kg or 50 microg/kg) to reduce 5-HT levels, did not change, there was a reduction in sensitivity of presynaptic 5-HT(1B) receptors, as measured by the effect of an injection of the 5-HT(1B/1D) antagonist GR 127935 (5mg/kg, s.c.) to increase 5-HT levels. This effect probably accounted for the increase in basal 5-HT levels observed in the hypothalamus after chronic clomipramine administration. Postsynaptic 5-HT(1A) receptor sensitivity in the hippocampus, measured by the effect of 8-OH-DPAT to increase cAMP levels in the dialysate, was increased after chronic clomipramine. Animals that had received daily intraperitoneal injections of 10mg/kg clomipramine for 28 days did not show a change in postsynaptic 5-HT(1A) receptor sensitivity in the hypothalamus as measured by the ability of 8-OH-DPAT (50 microg/kg, s.c.) to stimulate secretion of corticosterone. Taken together with the results of previous experiments involving the cerebral cortex, these in vivo results show that chronic clomipramine exerts effects on both pre- and postsynaptic serotonin receptors, but that these effects are highly region-specific.     

Intravital high-frequency ultrasonography to evaluate cardiovascular and uteroplacental blood flow in mouse pregnancy

ObjectiveThe objective of this study is to define the ultrasonographic changes in the cardiovascular and uteroplacental circulation of normal pregnant mice compared to non-pregnant mice using high-frequency, high-resolution ultrasonography.MethodsTen to twelve-week-old CD-1 mice (six non-pregnant and six pregnant animals) were used for all experiments. Vevo® 2100 (VisualSonics) was used to evaluate the cardiovascular and uteroplacental circulation physiology. Cardiac echocardiogram and uterine artery Doppler studies were performed on all animals. Pregnant animals were evaluated on embryonic day 7 (E7), 13 (E13) and 18 (E18). Fetal heart rate and umbilical artery Doppler flows were obtained on pregnant animals. Three-dimensional ultrasonography imaging was utilized for quantification of placental volumes. All data are presented as median (10th–90th percentiles).ResultsIn pregnant mice on E7 compared to non-pregnant mice, there was an increase in cardiac output (p = 0.008), stroke volume (p = 0.002), ejection fraction (p = 0.02), and fractional shortening (p = 0.02). The maternal heart rate increased throughout gestation (p = 0.009). During pregnancy, a gestational sac was clearly visible on E7. Between E13 and E18, the fetal size and fetal heart rate increased (p = 0.001) and the umbilical artery peak systolic velocity increased (p < 0.001). Minimal diastolic blood flow was observed in the umbilical artery on E13, which increased slightly on day E18 (p = 0.01). There was no change in the uterine artery resistance index between non-pregnant and pregnant mice. The placental volume increased between E13 and E18 (p = 0.03).ConclusionSeveral changes noted in cardiovascular and uteroplacental systems occurring during normal murine pregnancy have striking similarities to humans and can be accurately measured using newer ultrasonographic techniques. Further studies are needed to evaluate changes in these vascular beds in mouse models of diseases such as preeclampsia and intrauterine growth restriction.     

The Q359K/T360K mutation causes cystic fibrosis in Georgian Jews

Background

The Q359K/T360K mutation, described in Jewish CF patients of Georgian decent, is of questionable clinical significance.

Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia

Preeclampsia is a hypertensive disorder of pregnancy in which patients develop profound sensitivity to vasopressors, such as angiotensin II, and is associated with substantial morbidity for the mother and fetus. Enhanced vasoconstrictor sensitivity and elevations in soluble fms-like tyrosine kinase 1 (sFLT1), a circulating antiangiogenic protein, precede clinical signs and symptoms of preeclampsia. Here, we report that overexpression of sFlt1 in pregnant mice induced angiotensin II sensitivity and hypertension by impairing endothelial nitric oxide synthase (eNOS) phosphorylation and promoting oxidative stress in the vasculature. Administration of the NOS inhibitor l-NAME to pregnant mice recapitulated the angiotensin sensitivity and oxidative stress observed with sFlt1 overexpression. Sildenafil, an FDA-approved phosphodiesterase 5 inhibitor that enhances NO signaling, reversed sFlt1-induced hypertension and angiotensin II sensitivity in the preeclampsia mouse model. Sildenafil treatment also improved uterine blood flow, decreased uterine vascular resistance, and improved fetal weights in comparison with untreated sFlt1-expressing mice. Finally, sFLT1 protein expression inversely correlated with reductions in eNOS phosphorylation in placental tissue of human preeclampsia patients. These data support the concept that endothelial dysfunction due to high circulating sFLT1 may be the primary event leading to enhanced vasoconstrictor sensitivity that is characteristic of preeclampsia and suggest that targeting sFLT1-induced pathways may be an avenue for treating preeclampsia and improving fetal outcomes.     

Plasma homocysteine level and functional outcome of patients with ischemic stroke

OBJECTIVE: To investigate the possible relationships between total plasma homocysteine level (tHcy) and functional outcome of stroke patients as evaluated by the FIM instrument. DESIGN: Retrospective chart analysis. SETTING: Inpatient stroke rehabilitation ward of a university-affiliated referral hospital. PARTICIPANTS: Consecutive patients (N=113) presenting with acute ischemic stroke. Patients were divided into 2 groups according to their tHcy levels (< or = 15 micromol/L, >15 micromol/L) and into 3 groups according to their FIM scores (low, < or =40; moderate, 41-80; high, >80). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The tHcy level was determined shortly after stroke onset by a high performance liquid chromatography method with fluorescence detection. Functional outcome was measured by the FIM instrument at admission and discharge. The tHcy level and FIM scores were obtained for all patients. Data outcomes were analyzed by t tests, 1-way analysis of variance, Mann-Whitney U, and Fisher exact tests, as well as by the 2 ordered polytomous logistic regression model. RESULTS: The 2 tHcy groups were similar in demographic, stroke, and comorbidity characteristics, differing only by higher frequency of hypertension in those with a tHcy greater than 15 micromol/L (51.7% vs 80.8%, respectively, P=.01). Compared with patients who had tHcy levels at 15 micromol/L or lower and were discharged from rehabilitation being in the highest FIM score group (>80), higher tHcy levels were not associated with a discharge FIM score of less than 40 (odds ratio [OR]=.77; 95% confidence interval [CI], 0.13-4.65; P=.77) or with a better functional outcome FIM score between 40 and 80 (OR=3.71; 95% CI, 0.73-18.99; P=.11). CONCLUSIONS: Our findings suggest that determination of tHcy level does not correlate with functional outcome in patients presenting for rehabilitation after acute ischemic stroke.