Antisperm Antibody Levels After Vasectomy Reversal Are Not Associated With Pregnancy Rates or Method of Conception.

OBJECTIVE: To examine the relationship between antisperm antibody (ASA), pregnancy rates, and method of conception following vasectomy reversal, given that before and after vasectomy reversal, patients wonder if ASAs will prevent them from achieving pregnancy and American Urological Association vasectomy guidelines call for additional research to answer this question. METHODS: We performed retrospective chart review and phone interview of patients who underwent vasectomy reversal at our institution from 1/1/2000 to 12/31/2018. We excluded patients who underwent vasectomy reversal for pain, or without postoperative semen analysis with ASA. We categorized patients as having low (<50%) or high (≥50%) ASA levels using the first postoperative semen analysis. Our primary outcome was pregnancy rate, including method of conception. Differences in pregnancy rates were tested using Fisher exact test. RESULTS: Two hundred and four patients were chart reviewed. Median age at time of surgery was 40years and median obstruction interval was 7.3years. Median partner age was 32years. One hundred sixty-four (80%) patients underwent bilateral vasovasostomy. Eighty-five patients (42%) had low (<50%) ASA levels and 119 (58%) had high (≥50%) ASA levels. Sixty-seven patients completed phone interviews. Of 27 men with low ASA levels, 19 (70%) achieved a pregnancy with 16 (59%) spontaneous pregnancy. Of 40 men with high ASA levels, 30 (75%) achieved a pregnancy with 16 (40%) spontaneous pregnancy. The Fisher exact test P-value was .2. CONCLUSION: ASA levels are not associated with pregnancy rate or method of conception after vasectomy reversal. These findings can improve patient counseling before and after vasectomy reversal.

Urinary MyProstateScore (MPS) to Rule out Clinically-Significant Cancer in Men with Equivocal (PI-RADS 3) Multiparametric MRI: Addressing an Unmet Clinical Need.

OBJECTIVE: To evaluate the complementary value of urinary MyProstateScore (MPS) testing and multiparametric MRI (mpMRI) and assess outcomes in patients with equivocal mpMRI. MATERIALS AND METHODS: Included patients underwent mpMRI followed by urine collection and prostate biopsy at the University of Michigan between 2015 -2019. MPS values were calculated from urine specimens using the validated model based on serum PSA, urinary PCA3, and urinary TMPRSS2:ERG. In the PI-RADS 3 population, the discriminative accuracy of PSA, PSAD, and MPS for GG≥2 cancer was quantified by the AUC curve. Decision curve analysis was used to assess net benefit of MPS relative to PSAD. RESULTS: There were 540 patients that underwent mpMRI and biopsy with MPS available. The prevalence of GG≥2 cancer was 13% for PI-RADS 3, 56% for PI-RADS 4, and 87% for PI-RADS 5. MPS was significantly higher in men with GG≥2 cancer [median 44.9, IQR (29.4 -57.5)] than those with negative or GG1 biopsy [median 29.2, IQR (14.8 -44.2); P <.001] in the overall population and when stratified by PI-RADS score. In the PI-RADS 3 population (n = 121), the AUC for predicting GG≥2 cancer was 0.55 for PSA, 0.62 for PSAD, and 0.73 for MPS. MPS provided the highest net clinical benefit across all pertinent threshold probabilities. CONCLUSION: In patients that underwent mpMRI and biopsy, MPS was significantly associated with GG≥2 cancer across all PI-RADS scores. In the PI-RADS 3 population, MPS significantly outperformed PSAD in ruling out GG≥2 cancer. These findings suggest a complementary role of MPS testing in patients that have undergone mpMRI.

Genomic non-redundancy of the mir-183/96/182 cluster and its requirement for hair cell maintenance.

microRNAs are important regulators of gene expression. In the retina, the mir-183/96/182 cluster is of particular interest due to its robust expression and studies in which loss of the cluster caused photoreceptor degeneration. However, it is unclear which of the three miRNAs in the cluster are ultimately required in photoreceptors, whether each may have independent, contributory roles, or whether a single miRNA from the cluster compensates for the loss of another. These are important questions that will not only help us to understand the role of these particular miRNAs in the retina, but will deepen our understanding of how clustered microRNAs evolve and operate. To that end, we have developed a complete panel of single, double, and triple mir-183/96/182 mutant zebrafish. While the retinas of all mutant animals were normal, the triple mutants exhibited acute hair cell degeneration which corresponded with impaired swimming and death at a young age. By measuring the penetrance of this phenotype in each mutant line, we determine which of the three miRNAs in the cluster are necessary and/or sufficient to ensure normal hair cell development and function.

Hypothalamic POMC or MC4R deficiency impairs counterregulatory responses to hypoglycemia in mice.

OBJECTIVE: Life-threatening hypoglycemia is a major limiting factor in the management of diabetes. While it is known that counterregulatory responses to hypoglycemia are impaired in diabetes, molecular mechanisms underlying the reduced responses remain unclear. Given the established roles of the hypothalamic proopiomelanocortin (POMC)/melanocortin 4 receptor (MC4R) circuit in regulating sympathetic nervous system (SNS) activity and the SNS in stimulating counterregulatory responses to hypoglycemia, we hypothesized that hypothalamic POMC as well as MC4R, a receptor for POMC derived melanocyte stimulating hormones, is required for normal hypoglycemia counterregulation. METHODS: To test the hypothesis, we induced hypoglycemia or glucopenia in separate cohorts of mice deficient in either POMC or MC4R in the arcuate nucleus (ARC) or the paraventricular nucleus of the hypothalamus (PVH), respectively, and measured their circulating counterregulatory hormones. In addition, we performed a hyperinsulinemic-hypoglycemic clamp study to further validate the function of MC4R in hypoglycemia counterregulation. We also measured Pomc and Mc4r mRNA levels in the ARC and PVH, respectively, in the streptozotocin-induced type 1 diabetes mouse model and non-obese diabetic (NOD) mice to delineate molecular mechanisms by which diabetes deteriorates the defense systems against hypoglycemia. Finally, we treated diabetic mice with the MC4R agonist MTII, administered stereotaxically into the PVH, to determine its potential for restoring the counterregulatory response to hypoglycemia in diabetes. RESULTS: Stimulation of epinephrine and glucagon release in response to hypoglycemia or glucopenia was diminished in both POMC- and MC4R-deficient mice, relative to their littermate controls. Similarly, the counterregulatory response was impaired in association with decreased hypothalamic Pomc and Mc4r expression in the diabetic mice, a phenotype that was not reversed by insulin treatment which normalized glycemia. In contrast, infusion of an MC4R agonist in the PVH restored the counterregulatory response in diabetic mice. CONCLUSION: In conclusion, hypothalamic Pomc as well as Mc4r, both of which are reduced in type 1 diabetic mice, are required for normal counterregulatory responses to hypoglycemia. Therefore, enhancing MC4R function may improve hypoglycemia counterregulation in diabetes.

Reduced renal sympathetic nerve activity contributes to elevated glycosuria and improved glucose tolerance in hypothalamus-specific Pomc knockout mice.

OBJECTIVE: Hypothalamic arcuate nucleus-specific pro-opiomelanocortin deficient (ArcPomc-/-) mice exhibit improved glucose tolerance despite massive obesity and insulin resistance. We demonstrated previously that their improved glucose tolerance is due to elevated glycosuria. However, the underlying mechanisms that link glucose reabsorption in the kidney with ArcPomc remain unclear. Given the function of the hypothalamic melanocortin system in controlling sympathetic outflow, we hypothesized that reduced renal sympathetic nerve activity (RSNA) in ArcPomc-/- mice could explain their elevated glycosuria and consequent enhanced glucose tolerance. METHODS: We measured RSNA by multifiber recording directly from the nerves innervating the kidneys in ArcPomc-/- mice. To further validate the function of RSNA in glucose reabsorption, we denervated the kidneys of WT and diabetic db/db mice before measuring their glucose tolerance and urine glucose levels. Moreover, we performed western blot and immunohistochemistry to determine kidney GLUT2 and SGLT2 levels in either ArcPomc-/- mice or the renal-denervated mice. RESULTS: Consistent with our hypothesis, we found that basal RSNA was decreased in ArcPomc-/- mice relative to their wild type (WT) littermates. Remarkably, both WT and db/db mice exhibited elevated glycosuria and improved glucose tolerance after renal denervation. The elevated glycosuria in obese ArcPomc-/-, WT and db/db mice was due to reduced renal GLUT2 levels in the proximal tubules. Overall, we show that renal-denervated WT and diabetic mice recapitulate the phenotype of improved glucose tolerance and elevated glycosuria associated with reduced renal GLUT2 levels observed in obese ArcPomc-/- mice. CONCLUSION: Hence, we conclude that ArcPomc is essential in maintaining basal RSNA and that elevated glycosuria is a possible mechanism to explain improved glucose tolerance after renal denervation in drug resistant hypertensive patients.