Hypophosphatemic Rickets and Short Stature.

An 18-month old male presented with gross motor delay and poor growth (weight z-score -2.21, length z-score -4.26). Radiographs showed metaphyseal irregularities suggesting metaphyseal dysplasia and sagittal craniosynostosis. Biochemical evaluation revealed evidence of hypophosphatemic rickets [serum phosphorus 2.3 mg/dL (reference range (RR) 4.3-6.8), alkaline phosphatase 754 unit/L (RR 156-369)] due to renal phosphate wasting (TmP/GFR 4.3 mg/dL, normal for age 4.3-6.8), with C-terminal FGF23 125 RU/mL (>90 during hypophosphatemia suggests FGF23-mediated hypophosphatemia). Treatment was initiated with calcitriol and phosphate. Genetic analysis showed a pathogenic variant of FGF23: c.527G > A (p.Arg176Gln) indicative of autosomal dominant hypophosphatemic rickets (ADHR). Consistent with reports linking iron deficiency with the ADHR phenotype, low ferritin was detected, 18 ng/mL (RR 24-336). Oral ferrous sulfate replacement was initiated. Following normalization of ferritin level (41 ng/mL) biochemical improvement was demonstrated (FGF23 69 RU/mL, phosphorus 5.0 mg/dL and alkaline phosphatase 228 unit/L). Calcitriol and phosphate were discontinued. Three years later, the patient demonstrated improved developmental milestones, linear growth (length Z-score -2.01), radiographic normalization of metaphyses, and stabilization of craniosynostosis. While the most common cause of hypophosphatemic rickets is X-linked hypophosphatemia, other etiologies should be considered as treatment differs. In ADHR, normalization of iron leads to biochemical and clinical improvement.

In utero ultrasound diagnosis of bilateral cataract and hydrops in a mule pregnancy: Case report.

Once diagnosed pregnant with ultrasound at an early stage of gestation, mares are usually not examined before foaling. The objective of this case report was to highlight the importance of transrectal ultrasound screening examination and to report a unique case of fetal congenital cataracts associated with other feto-placental abnormalities in a mule pregnancy, its in utero ultrasound diagnosis and outcome. A 17-year-old Thoroughbred research mare carrying a mule fetus was examined by transrectal ultrasonography at 186 days of gestation for a routine pregnancy examination. Ultrasonography allowed in utero diagnosis of fetal congenital cataracts, hyperechogenic bowels, intrauterine growth restriction (IUGR), hydramnios and placental abnormalities. The mare was monitored bi-monthly to observe the progress of the pregnancy. At 258 days of gestation, the abnormal chorioallantois detached at the cervical star and at 272 days, fetal asystole was diagnosed. Abortion was induced and the fetus was delivered uneventfully. Post-mortem gross and histologic findings confirmed the prenatal ultrasonographic diagnosis. This case highlights the diagnostic value of a complete fetal ultrasound examination to detect equine fetal abnormalities.

Transfer of MicroRNAs From Epididymal Epithelium to Equine Spermatozoa.

All epididymal regions are lined with multiple epithelial cell types, each with different functions to provide the luminal environment for spermatozoal maturation. Epithelial cells also create apical blebs, which are released from the apical surface via apocrine secretion and disintegrate in the lumen, thereby releasing epididymosomes. Epididymosomes transport proteins to spermatozoa and contain microRNAs. We hypothesized that epididymosomes also transfer miRNA from epididymal epithelium to spermatozoa. Quantitative real-time polymerase chain reaction was used to determine miRNA profiles of epididymal tissue from caput and cauda, epididymal spermatozoa from caput and cauda, and epididymosomes and from caput, proximal corpus, distal corpus, and cauda. Pathway analysis was performed using DIANA tools on the miRNA unique to caudal spermatozoa. We found 66 newly acquired miRNAs in spermatozoa located in the caudal epididymis. Predicted pathways targeted by these miRNAs suggest a role in cell motility and viability and factors in oocyte and embryo maturation and development. These findings suggest that miRNAs are transported to spermatozoa from epididymal epithelium via epididymosomes.

Effects of immunization against bone morphogenetic protein-15 and growth differentiation factor-9 on ovarian function in mares.

Currently there is no contraceptive vaccine that can cause permanent sterility in mares. This study investigates the effect of vaccination against oocyte-specific growth factors, Bone Morphogenetic Protein 15 (BMP-15) and Growth Differentiation Factor 9 (GDF-9), on ovarian function of mares. It was hypothesized that immunization against these growth factors would prevent ovulation and/or accelerate depletion of the oocyte reserve. For this study, 30 mares were randomly assigned to three groups (n = 10/group) and vaccinated with BMP-15 or GDF-9 peptides conjugated to KLH and adjuvant, or a control of phosphate buffered saline and adjuvant. Horses received vaccinations at weeks 0, 6, 12, and 18. Ovarian activity and estrous behavior were evaluated 3 days a week via ultrasonography and interaction with a stallion. The study was initiated on March1, 2016. Upon evaluation of ovulation rate, the GDF-9 group did not have a difference (P = 0.66) in ovulation rate when compared to controls (10.8 and 10.0 ovulations, respectively), but the number of ovulations in the BMP-15 group was less (P = 0.02; 4.9 ovulations). Average follicle size prior to ovulation was less (P < 0.0001) in both treatment groups compared to controls. Estrous behavior was altered in both the BMP-15 and GDF-9 groups compared to controls after the second vaccination (P = 0.05 and 0.03, respectively). Although further research is required to determine the continued effects of vaccination against GDF-9 on ovulation rates, these results indicate that vaccination against BMP-15 and GDF-9 could serve as a contraceptive in wild horse populations.

A difficult case to swallow: herpes esophagitis after epidural steroid injection.

Herpes esophagitis due to infection with herpes simplex virus typically occurs in immunocompromised patients such as those with human immunodeficiency virus, malignancy, and those undergoing immunosuppressive therapy. Albeit rare, herpes esophagitis can occur in immunocompetent patients as a primary infection. We present a case of herpes esophagitis after corticosteroid treatment for back pain including epidural steroid injections. Corticosteroids, especially local injections, are a common treatment for chronic back pain, but they are not without risk. Epidural steroid injections can have systemic effects, which may go unrecognized and underappreciated. Although local infections have been reported after administering these injections, systemic immune suppression may allow for unexpected infections such as herpes esophagitis. Given the widespread use of epidural steroid injections, physicians should reevaluate the potential for harm when considering this treatment.

Effect of a stepped-care intervention approach on weight loss in adults: a randomized clinical trial.

CONTEXT: Given the obesity epidemic, effective but resource-efficient weight loss treatments are needed. Stepped-treatment approaches customize interventions based on milestone completion and can be more effective while costing less to administer than conventional treatment approaches. OBJECTIVE: To determine whether a stepped-care weight loss intervention (STEP) compared with a standard behavioral weight loss intervention (SBWI) would result in greater weight loss. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial of 363 overweight and obese adults (body mass index: 25-<40; age: 18-55 years, 33% nonwhite, and 83% female) who were randomized to SBWI (n = 165) or STEP (n = 198) at 2 universities affiliated with academic medical centers in the United States (Step-Up Study). Participants were enrolled between May 2008 and February 2010 and data collection was completed by September 2011. INTERVENTIONS: All participants were placed on a low-calorie diet, prescribed increases in physical activity, and attended group counseling sessions ranging from weekly to monthly during an 18-month period. The SBWI group was assigned to a fixed program. Counseling frequency, type, and weight loss strategies could be modified every 3 months for the STEP group in response to observed weight loss as it related to weight loss goals. MAIN OUTCOME MEASURE: Mean change in weight over 18 months. Additional outcomes included resting heart rate and blood pressure, waist circumference, body composition, fitness, physical activity, dietary intake, and cost of the program. RESULTS: Of the 363 participants randomized, 260 (71.6%) provided a measure of mean change in weight over 18 months. The 18-month intervention resulted in weight decreasing from 93.1 kg (95% CI, 91.0 to 95.2 kg) to 85.6 kg (95% CI, 83.4 to 87.7 kg) (P < .001) in the SBWI group and from 92.7 kg (95% CI, 90.8 to 94.6 kg) to 86.4 kg (95% CI, 84.5 to 88.4 kg) in the STEP group (P < .001). The percentage change in weight from baseline to 18 months was -8.1% (95% CI, -9.4% to -6.9%) in the SBWI group (P < .001) compared with -6.9% (95% CI, -8.0% to -5.8%) in the STEP group (P < .001). Although the between-group difference in 18-month weight loss was not statistically different (-1.3 kg [95% CI, -2.8 to 0.2 kg]; P = .09), there was a significant group × time interaction effect (P = .03). The cost per participant was $1357 (95% CI, $1272 to $1442) for the SBWI group vs $785 (95% CI, $739 to $830) for the STEP group (P < .001). Both groups had significant and comparable improvements in resting heart rate, blood pressure level, and fitness. CONCLUSIONS: Among overweight and obese adults, the use of SBWI resulted in a greater mean weight loss than STEP over 18 months. Compared with SBWI, STEP resulted in clinically meaningful weight loss that cost less to implement. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00714168.

Androgen control of cell proliferation and cytoskeletal reorganization in human fibrosarcoma cells: role of RhoB signaling.

We recently generated an HT-1080-derived cell line called HT-AR1 that responds to dihydrotestosterone (DHT) treatment by undergoing cell growth arrest in association with cytoskeletal reorganization and induction of neuroendocrine-like cell differentiation. In this report, we show that DHT induces a dose-dependent increase in G0/G1 growth-arrested cells using physiological levels of hormone. The arrested cells increase in cell size and contain a dramatic redistribution of desmoplakin, keratin 5, and chromogranin A proteins. DHT-induced cytoskeletal changes were also apparent from time lapse video microscopy that showed that androgen treatment resulted in the rapid appearance of neuronal-like membrane extensions. Expression profiling analysis using RNA isolated from DHT-treated HT-AR1 cells revealed that androgen receptor activation leads to the coordinate expression of numerous cell signaling genes including RhoB, PTGF-beta, caveolin-2, Egr-1, myosin 1B, and EHM2. Because RhoB has been shown to have a role in tumor suppression and neuronal differentiation in other cell types, we investigated RhoB signaling functions in the HT-AR1 steroid response. We found that steroid induction of RhoB was DHT-specific and that newly synthesized RhoB protein was post-translationally modified and localized to endocytic vesicles. Moreover, treatment with a farnesyl transferase inhibitor reduced DHT-dependent growth arrest, suggesting that prenylated RhoB might function to inhibit HT-AR1 cell proliferation. This was directly shown by transfecting HT-AR1 cells with RhoB coding sequences containing activating or dominant negative mutations.

The cardiovascular effects of eplerenone, a selective aldosterone-receptor antagonist.

BACKGROUND: The role of the renin-angiotensin-aldosterone system in the pathophysiology and treatment of hypertension and heart failure has been extensively studied. Angiotensin-converting enzyme inhibitors and angiotensin II-receptor blockers have been shown to effectively reduce blood pressure, protect the kidney, and reduce morbidity and mortality in patients with heart failure. Therefore, there is increased interest in the effects of aldosterone and the use of aldosterone-receptor antagonists in the treatment of cardiovascular disease. Eplerenone is the first selective aldosterone-receptor antagonist approved for the treatment of hypertension and left ventricular (LV) dysfunction after acute myocardial infarction (AMI). OBJECTIVE: The goal of this article was to review the pharmacologic properties, clinical efficacy, and tolerability of eplerenone in the treatment of hypertension, LV dysfunction, and proteinuria. METHODS: Relevant English-language articles were identified through searches of MEDLINE (1966-May 2003), Current Contents, and International Pharmaceutical Abstracts (1970-May 2003) using the terms hypertension, heart failure, eplerenone, aldosterone, and aldosterone antagonist. Other pertinent publications were identified from the reference lists of the identified articles. Information was also obtained from abstracts presented at national meetings and data on file with the manufacturer. RESULTS: In clinical trials, eplerenone alone and in combination with renin-angiotensin blockade significantly reduced both systolic and diastolic blood pressure compared with placebo (P < 0.05 to P < 0.001). In EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study), the addition eplerenone to optimal medical therapy reduced morbidity and mortality in patients with AMI and LV dysfunction, although the incidence of serious hyperkalemia was also significantly greater. In comparisons with spironolactone, eplerenone was associated with a lower incidence of gynecomastia and other sex hormone-related adverse effects. CONCLUSIONS: Either alone or in combination with other antihypertensive agents, eplerenone appears to be effective for the treatment of hypertension. Morbidity and mortality were reduced when eplerenone was added to standard therapy for LV dysfunction complicating AMI. The use of eplerenone for hypertension or heart failure may be limited in patients at risk for hyperkalemia.