Distinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failure

Intrahepatic neutrophil infiltration has been implicated in severe alcoholic hepatitis (SAH) pathogenesis; however, the mechanism underlying neutrophil-induced injury in SAH remains obscure. This translational study aims to describe the patterns of intrahepatic neutrophil infiltration and its involvement in SAH pathogenesis. Immunohistochemistry analyses of explanted livers identified two SAH phenotypes despite a similar clinical presentation, one with high intrahepatic neutrophils (Neu^hi), but low levels of CD8⁺ T cells, and vice versa. RNA-Seq analyses demonstrated that neutrophil cytosolic factor 1 (NCF1), a key factor in controlling neutrophilic ROS production, was upregulated and correlated with hepatic inflammation and disease progression. To study specifically the mechanisms related to Neu^hi in AH patients and liver injury, we used the mouse model of chronic-plus-binge ethanol feeding and found that myeloid-specific deletion of the Ncf1 gene abolished ethanol-induced hepatic inflammation and steatosis. RNA-Seq analysis and the data from experimental models revealed that neutrophilic NCF1-dependent ROS promoted alcoholic hepatitis (AH) by inhibiting AMP-activated protein kinase (a key regulator of lipid metabolism) and microRNA-223 (a key antiinflammatory and antifibrotic microRNA). In conclusion, two distinct histopathological phenotypes based on liver immune phenotyping are observed in SAH patients, suggesting a separate mechanism driving liver injury and/or failure in these patients.     

Feto-maternal safety of intracervical sodium nitroprusside application in sheep

The feto-maternal safety of sodium nitroprusside (SNP) administration in the cervix of pregnant sheep is evaluated. Chronically catheterized pregnant sheep at approximately 0.9 gestation were divided into 2 groups that received 0.1 mg/kg maternal body weight of SNP gel (2%) or placebo into the internal cervical os. SNP or placebo gel was administered at 9 AM with both maternal and fetal blood gas/pH, and cardiovascular parameters were monitored for 6 hours. Except for a slight transient decrease of maternal oxygen and meta-hemoglobin content, and fetal oxygen content in the SNP group, no other significant changes were observed. However, such changes are minimal and unlikely to be of any clinical significance. Moreover, nitric oxide metabolites were unchanged in both maternal and fetal circulations.These data demonstrate few, if any, effects of intrauterine SNP administration on both cellular oxygenation and cardiovascular indexes. Thus, SNP treatment, once applied into the cervix, could be considered a safe procedure.     

Induced hyper and hypo amino acidemia in the ovine fetus near term: effects on electrocortical activity

Amino acid infusate (Primene) and insulin euglycemic (insulin + 10% dextrose) clamp techniques were used in the ovine fetus near term and the impact on the incidence of low-voltage and high-voltage electrocortical (ECOG) activities was determined. Fetal sheep were studied over a 2-hour control period and a subsequent 6-hour experimental period.With the Primene infusion, the basic and neutral amino acids were increased by 43% and 25%, respectively, whereas the acidic amino acids showed little change. With the insulin/dextrose infusion, the basic and neutral amino acids decreased by 48% and 30%, respectively, whereas the acidic amino acids were again little changed. A small fall in arterial oxygen saturation and an increase in fetal heart rate for both groups can be attributed to an insulin-mediated increase in fetal metabolic rate. Despite the moderate increases and decreases in circulating amino acid levels, there was no significant change in the mean percent time or duration of fetal ECOG activities for either study group.     

Review of cytotoxic cephalostatins and ritterazines: isolation and synthesis

The cephalostatins and ritterazines comprise a family of structurally related natural products reported by Professors G. R. Pettit and N. Fusetani from 1988 -1998. Isolated from the invertebrate marine chordates Cephalodiscus gilchristi and Ritterella tokioka, the cephalostatins and ritterazines exhibit potent cytotoxicity toward the murine P388 lymphocytic leukemia cell line. In fact, cephalostatin 1 ( 1, ED 50 0.1-0.001 pM) proved to be one of the most powerful cancer cell growth inhibitors ever tested by the U.S. National Cancer Institute. The ritterazines and cephalostatins share many common structural features in which two highly oxygenated steroidal units with side chains forming either 5/5 or 5/6 spiroketals are fused via a pyrazine core. Professor P. L. Fuchs and colleagues reported the total syntheses of 1, cephalostatins 7 ( 7), and 12 ( 12), ritterazines K ( 30) and M ( 32), and cytotoxic analogues. The synthesis of 1, described in 1998, required 65 synthetic operations to complete.     

Herbal and other complementary medicine use by Texas midwives

This cross-sectional survey sought to document complementary and alternative medicine (CAM) use by Texas midwives, as well as to determine whether licensed direct-entry midwives (LMs) and certified nurse-midwives (CNMs) differed significantly in their patterns of use. All respondents (n = 69) indicated that they used, recommended, or referred their clients for at least one CAM therapy during the preceding year. Ninety percent (90%) of respondents used, recommended, or referred their clients for an herbal remedy (not including homeopathic tinctures). Herbal therapies were among the top three modalities recommended for 7 of 12 (58%) clinical indications. Herbs were the most salient CAM therapy used for cervical ripening (83%), followed closely by use for nausea, vomiting, and hyperemesis (80%), and labor induction (77%). Herbal therapies also constituted 50% or more of the CAM therapies used for the following indications: anemia/iron supplementation (70%), perineal healing (66%), and anxiety/stress/fatigue (50%). LM respondents used, recommended, or referred their clients for a greater number of herbal therapies compared to CNMs. While several of the CAM modalities used or recommended by Texas midwives show potential for clinical benefit, few have been studied sufficiently to determine their efficacy or safety during pregnancy.     

Effects of Tick-Control Interventions on Tick Abundance,Human Encounters with Ticks,and Incidence of Tickborne Diseases in Residential Neighborhoods,New York,USA

Tickborne diseases (TBDs) such as Lyme disease result in ≈500,000 diagnoses annually in the United States. Various methods can reduce the abundance of ticks at small spatial scales, but whether these methods lower incidence of TBDs is poorly understood. We conducted a randomized, replicated, fully crossed, placebo-controlled, masked experiment to test whether 2 environmentally safe interventions, the Tick Control System (TCS) and Met52 fungal spray, used separately or together, affected risk for and incidence of TBDs in humans and pets in 24 residential neighborhoods. All participating properties in a neighborhood received the same treatment. TCS was associated with fewer questing ticks and fewer ticks feeding on rodents. The interventions did not result in a significant difference in incidence of human TBDs but did significantly reduce incidence in pets. Our study is consistent with previous evidence suggesting that reducing tick abundance in residential areas might not reduce incidence of TBDs in humans.