Carbon monoxide-induced atrial fibrillation resolved with hyperbaric oxygen.

Carbon monoxide (CO) exposure is a prevalent cause of poisoning worldwide. The cardiac effects of CO poisoning are well described and can manifest as angina, myocardial ischemia or infarction, cardiogenic shock, and/or life-threatening arrhythmias. Atrial fibrillation has been associated with severe CO poisoning; however, few cases have described atrial fibrillation in acute CO poisoning with regard to hyperbaric oxygen (HBO2) therapy. Herein, we describe a case of severe CO poisoning that caused atrial fibrillation with successful conversion to sinus rhythm following HBO2 therapy and discuss implications for further research.

Mouse Spermatogenesis Requires Classical and Nonclassical Testosterone Signaling.

Testosterone acts though the androgen receptor in Sertoli cells to support germ cell development (spermatogenesis) and male fertility, but the molecular and cellular mechanisms by which testosterone acts are not well understood. Previously, we found that in addition to acting through androgen receptor to directly regulate gene expression (classical testosterone signaling pathway), testosterone acts through a nonclassical pathway via the androgen receptor to rapidly activate kinases that are known to regulate spermatogenesis. In this study, we provide the first evidence that nonclassical testosterone signaling occurs in vivo as the MAP kinase cascade is rapidly activated in Sertoli cells within the testis by increasing testosterone levels in the rat. We find that either classical or nonclassical signaling regulates testosterone-mediated Rhox5 gene expression in Sertoli cells within testis explants. The selective activation of classical or nonclassical signaling pathways in Sertoli cells within testis explants also resulted in the differential activation of the Zbtb16 and c-Kit genes in adjacent spermatogonia germ cells. Delivery of an inhibitor of either pathway to Sertoli cells of mouse testes disrupted the blood-testis barrier that is essential for spermatogenesis. Furthermore, an inhibitor of nonclassical testosterone signaling blocked meiosis in pubertal mice and caused the loss of meiotic and postmeiotic germ cells in adult mouse testes. An inhibitor of the classical pathway caused the premature release of immature germ cells. Collectively, these observations indicate that classical and nonclassical testosterone signaling regulate overlapping and distinct functions that are required for the maintenance of spermatogenesis and male fertility.

Upstream stimulatory factor induces Nr5a1 and Shbg gene expression during the onset of rat Sertoli cell differentiation.

Within the testis, each Sertoli cell can support a finite number of developing germ cells. During development, the cessation of Sertoli cell proliferation and the onset of differentiation establish the final number of Sertoli cells and, thus, the total number of sperm that can be produced. The upstream stimulatory factors 1 and 2 (USF1 and USF2, respectively) differentially regulate numerous Sertoli cell genes during differentiation. To identify genes that are activated by USF proteins during differentiation, studies were conducted in Sertoli cells isolated from 5- and 11-day-old rats, representing proliferating and differentiating cells, respectively. Usf1 mRNA and USF1 protein levels were increased between 5 and 11 days after birth. In vitro studies revealed that USF1 and USF2 DNA-binding activity also increased at 11 days for the promoters of four potential target genes, Fshr, Gata4, Nr5a1, and Shbg. Chromatin immunoprecipitation assays confirmed that USF recruitment increased in vivo between 5 and 11 days after birth at the Fshr, Gata4, and Nr5a1 promoters. Expression of Nr5a1 and Shbg, but not of Fshr or Gata4, mRNAs was elevated in 11-day-old Sertoli cells compared with 5-day-old Sertoli cells. Transient transfection of USF1 and USF2 expression vectors up-regulated Nr5a1 and Shbg promoter activity. RNA interference assays demonstrated that USF1 and USF2 contribute to Nr5a1 and Shbg expression in differentiating cells. Together, these data indicate that increased USF levels induce the expression of Nr5a1 and Shbg during the differentiation of Sertoli cells, whereas Fshr and Gata4 expression is not altered by USF proteins during differentiation.

Treatment of relapsed multiple myeloma complicated by cardiac extramedullary plasmacytoma with D-PACE chemotherapy.

Cardiac extramedullary plasmacytomas (EMPs) are rare and may be a seen as a complication of multiple myeloma (MM) or in isolation. Here, we describe a case of cardiac EMP that presented clinically as a congestive heart failure exacerbation in a patient with relapsed and refractory IgG lambda MM. We highlight radiographic imaging in conjunction with laboratory biomarkers at presentation and in response to D-PACE (dexamethasone, cisplatin (Platinol), doxorubicin (Adriamycin), cyclophosphamide and etoposide) systemic chemotherapy.

Tragedy of transition: hypertensive crisis in a young adult secondary to unilateral ureteropelvic junction obstruction following pyeloplasty as an adolescent.

A 25-year-old man with a history of left ureteropelvic junction (UPJ) obstruction that was corrected surgically at the age of 16 presented with a chief complaint of syncope. He was found to have severe hypertension with evidence of end organ damage on laboratory evaluation. His blood pressure was controlled with intravenous and oral antihypertensives with improvement in end organ dysfunction. Workup for secondary causes of hypertension implicated failed left-sided pyeloplasty with resultant hydronephrosis as the aetiology. The patient was transitioned to an oral antihypertensive regimen and discharged with urological surgery follow-up. Blood pressure control was maintained with oral antihypertensives and a low-salt diet; however, evidence of chronic kidney disease persisted. This case highlights the importance of close follow-up and adequate transition of care in patients with UPJ obstruction who transitioned to adulthood.

Restoration of spermatogenesis and male fertility using an androgen receptor transgene.

Androgens signal through the androgen receptor (AR) to regulate male secondary sexual characteristics, reproductive tract development, prostate function, sperm production, bone and muscle mass as well as body hair growth among other functions. We developed a transgenic mouse model in which endogenous AR expression was replaced by a functionally modified AR transgene. A bacterial artificial chromosome (BAC) was constructed containing all AR exons and introns plus 40 kb each of 5' and 3' regulatory sequence. Insertion of an internal ribosome entry site and the EGFP gene 3' to AR allowed co-expression of AR and EGFP. Pronuclear injection of the BAC resulted in six founder mice that displayed EGFP production in appropriate AR expressing tissues. The six founder mice were mated into a Sertoli cell specific AR knockout (SCARKO) background in which spermatogenesis is blocked at the meiosis stage of germ cell development. The AR-EGFP transgene was expressed in a cyclical manner similar to that of endogenous AR in Sertoli cells and fertility was restored as offspring were produced in the absence of Sertoli cell AR. Thus, the AR-EGFP transgene under the control of AR regulatory elements is capable of rescuing AR function in a cell selective, AR-null background. These initial studies provide proof of principle that a strategy employing the AR-EGFP transgene can be used to understand AR functions. Transgenic mice expressing selective modifications of the AR-EGFP transgene may provide crucial information needed to elicit the molecular mechanisms by which AR acts in the testis and other androgen responsive tissues.