Nonclinical Safety Profile of BMS-986001, a Nucleoside Transcriptase Inhibitor for Combination Retroviral Therapy.

Nucleoside reverse transcriptase inhibitors (NRTIs)/nucleotide reverse transcriptase inhibitors are key components of combination antiretroviral therapy for HIV infection. First-generation NRTIs are associated with mitochondrial toxicity in patients, mainly due to inhibition of human DNA polymerase γ (hDNA polγ) that manifests as adverse events such as lipodystrophy, lactic acidosis, myopathy, cardiomyopathy, or nephropathy in patients. In chronic nonclinical studies in rodents and nonrodents, eukaryotic (host) mitochondrial toxicity manifests as some drug-specific toxicities similar to human toxicity. BMS-986001, a novel thymidine analog with minimal hDNA polγ inhibition, has demonstrated antiretroviral activity in early clinical studies. The primary toxicity of BMS-986001 in rats and monkeys is bone marrow dyserythropoiesis with associated decreases in red blood cell mass. Additionally, at high doses, severe platelet reductions accompanied by cutaneous petechiae began during weeks 8 and 11 in 3 of 60 monkeys in chronic toxicity studies. In a 6-month study, platelet reductions required euthanasia of the 2 affected monkeys (300 mg/kg/d) at week 14, but with dose reduction (200 mg/kg/d) remaining monkeys had no platelet changes. One affected monkey (200 mg/kg/d) in a 9-month study completed dosing and its platelet counts recovered during a 1-month recovery. Formation of platelet-bound immunoglobulin in the presence of BMS-986001, together with rapid and complete platelet recovery in the absence of BMS-986001, suggested that platelet decreases in monkeys may be immune mediated. No findings indicative of mitochondrial toxicity were observed in rats or monkeys given BMS-986001, suggesting an improved safety profile compared to marketed NRTI or tenofovir disoproxil fumarate.

Utility of immediate evaluation of endoscopic ultrasound-guided transesophageal fine needle aspiration of mediastinal lymph nodes.

OBJECTIVE: To assess the value of immediate cytologic evaluation (ICE) in mediastinal endoscopic ultrasound-guided transesophageal fine needle aspiration (EUS-FNA). STUDY DESIGN: Fifty eight patients with mediastinal lymphadenopathy underwent transesophageal EUS-FNA. Cellularity, number of needle passes and number of slides prepared were reviewed retrospectively. RESULTS: Of moderate to highly cellular passes, 75% were diagnostic. ICE had a 100% positive predictive value and 97% negative predictive value. ICE allowed a diagnosis in all cases. Calculated diagnostic accuracy was 70% if the procedure ended after a single specimen of at least moderate cellularity or after completion of 4 needle passes. CONCLUSION: Immediate cytologic evaluation of EUS-FNA specimens allowed a diagnosis in all cases and contributed to the utility of EUS-FNA as a diagnostic procedure for mediastinal adenopathy.

Evidence of oxidative stress in the brains of fetuses with CNS anomalies and islet cell hyperplasia.

Infants of diabetic mothers have an increased frequency of congenital anomalies, including CNS malformations. Fetal hyperglycemia may promote such damage via oxidative stress. Postmortem studies have shown that fetal hyperglycemia associated with maternal diabetes results in islet cell hyperplasia. Islet cell hyperplasia may correlate with the presence of oxidative stress injury in the CNS because of hyperglycemia and related metabolic derangement. This study examines 3-nitrotyrosine immunoreactivity as a marker of oxidative stress in the brains of fetuses stratified by the presence or absence of islet cell hyperplasia and CNS developmental anomalies. Fetuses with both islet cell hyperplasia and CNS developmental anomalies showed a 1.8-fold increase in semiquantitatively scored 3-nitrotyrosine immunostaining compared to negative controls. Fetuses with islet cell hyperplasia but no CNS anomalies demonstrated a 1.6-fold increase. Comparison between fetuses with islet cell hyperplasia which were stratified by presence or absence of CNS anomalies were not statistically different but did show more intense staining in those with CNS malformations. These results support the contention that hyperglycemia may contribute to CNS malformation via oxidative stress.

Acardiac twin with externalized intestine adherent to placenta: unusual manifestation of omphalocele.

TRAP (twin reversed arterial perfusion) syndrome produces an acardiac twin (acardiac monster, acardius, acardiacus, chorioangiopagus parasiticus, etc.). Acardiacs result from monozygotic multiple births in which three anatomic anomalies occur: (1) a fetus' cardiac development is disturbed; (2) artery-artery anastomosis carries blood from a normal ("pump") twin to the acardiac; (3) vein-vein anastomosis carries blood from the acardiac back to the normal twin. Whether reversal of blood flow in the acardiac results from or causes cardiac dysmorphogenesis has not been resolved. Acardiac twins demonstrate a complex constellation of malformations usually thought to result from reversed blood flow; omphalocele is particularly common. We report monochorionic monoamnionic male twins in which an acardiac twin demonstrated externalized intestines adherent to the placenta. The twins were delivered from a 30-year-old primigravida mother by cesarean section without maternal complications at 33 w. The mother has no significant past medical history. The macerated acardius had a 4-cm long attenuated umbilical cord with indeterminate number of vessels. Structures rostral to the thorax were absent save for one poorly developed hand and arm. The abdomen contained loose mesenchyme and no organs. The entire intestine (21 cm) along with two testes was located in a sac on the surface of the placenta. No histopathologic anomalies of formed structures were identified aside from spatial relationships and incomplete development. The normal twin required no intensive care and is doing well. To our knowledge, this is the first report of externalized intestine, which may represent an unusual consequence of omphalocele.

Aberrant Pax1 and Pax9 expression in Jarcho-Levin syndrome: report of two Caucasian siblings and literature review.

We report two consecutive Caucasian male siblings of nonconsanguineous parents autopsied at 22 and 13 weeks gestational age both with prenatal diagnosis of Jarcho-Levin syndrome (JLS). Segmentation anomalies of the vertebrae and ribs encompass a spectrum of syndromes with or without associated anomalies of other developmental fields, and include spondylothoracic dysostosis (STD), JLS, Casamassima-Morton-Nance (CMN) syndrome, and spondylocostal dysostosis (SCD), among others. In both these new JLS cases the autopsies confirmed that there were severe developmental alterations in the thoracic and vertebral skeleton (including "crab-like" thorax), accompanied in the older fetus by renal defects. Because vertebral development is controlled by a limited number of master genes including Pax1 and Pax9, we analyzed protein expression from these genes in these two cases compared to age-matched controls. Immunochemical analysis showed a significant reduction in levels of Pax1 and Pax9 protein expression in chondrocytes of the vertebral column. Implications for the etiology and pathogenesis of JLS and related disorders are discussed.