Nutritional Supplementation Reduces Lesion Size and Neuroinflammation in a Sex-Dependent Manner in a Mouse Model of Perinatal Hypoxic-Ischemic Brain Injury

Perinatal hypoxia-ischemia (HI) is a major cause of neonatal brain injury, leading to long-term neurological impairments. Medical nutrition can be rapidly implemented in the clinic, making it a viable intervention to improve neurodevelopment after injury. The omega-3 (n-3) fatty acids docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3), uridine monophosphate (UMP) and choline have previously been shown in rodents to synergistically enhance brain phospholipids, synaptic components and cognitive performance. The objective of this study was to test the efficacy of an experimental diet containing DHA, EPA, UMP, choline, iodide, zinc, and vitamin B12 in a mouse model of perinatal HI. Male and female C57Bl/6 mice received the experimental diet or an isocaloric control diet from birth. Hypoxic ischemic encephalopathy was induced on postnatal day 9 by ligation of the right common carotid artery and systemic hypoxia. To assess the effects of the experimental diet on long-term motor and cognitive outcome, mice were subjected to a behavioral test battery. Lesion size, neuroinflammation, brain fatty acids and phospholipids were analyzed at 15 weeks after HI. The experimental diet reduced lesion size and neuroinflammation specifically in males. In both sexes, brain n-3 fatty acids were increased after receiving the experimental diet. The experimental diet also improved novel object recognition, but no significant effects on motor performance were observed. Current data indicates that early life nutritional supplementation with a combination of DHA, EPA, UMP, choline, iodide, zinc, and vitamin B12 may provide neuroprotection after perinatal HI.     

The role of dermal irritation in the skin tumor promoting activity of petroleum middle distillates.

Petroleum middle distillates (PMDs), a class of hydrocarbons which boil between 350-700 degrees F, are tumor promoters in mouse skin. The promotional activity is produced under conditions that also result in local changes, including chronic irritation and epidermal hyperplasia. The present study was conducted by comparing equal weekly doses of irritating and minimally or nonirritating test materials, to assess whether tumor promotion was a secondary response to these effects. Four PMDs, C10-C14 normal paraffins (NP), lightly refined paraffinic oil (LRPO), Jet Fuel A (JF), and steam-cracked gas oil (SCGO), were evaluated. Test materials were applied undiluted (2x/week) or as 28.6% (7x/week) or 50% (4x/week) concentrations in mineral oil for 52 weeks following initiation with dimethylbenzanthracene (DMBA). When applied undiluted, all materials produced moderate irritation and significant increase in tumor incidence. When NP, LRPO, or JF were applied in mineral oil diluent, skin irritation was generally ameliorated and few, if any, tumors were produced. SCGO was irritating and produced a significant increase in tumor frequency when administered in mineral-oil diluent. These data indicate that the promotional activity of straight-run PMDs is likely related to chronic irritation at the application site and not to dose. Thus, when used appropriately in the absence of prolonged irritation, these materials should not present a tumorigenic hazard to humans.     

Incidence and prevalence of abnormal liver associated enzymes in patients with atrial fibrillation in a routine clinical care population

The prevalence of elevated liver enzymes has not been described in patients with atrial fibrillation (AF) who may be more likely to develop these abnormalities due to comorbidities and medications. As signals of liver injury lead to termination of drug development programs, an attempt to better define the background prevalence would aid in interpreting these elevations in the setting of exposure to a new drug. The aim of this study was to estimate the prevalence and incidence of alanine aminotransferase (ALT) elevations in a cohort with AF. METHODS: Retrospective cohort of patients with AF using the outpatient medical record of the University of Pennsylvania Health System (UPHS). Primary outcomes were prevalence and incidence of ALT elevations (>40 U/L). We also examined the prevalence of risk factors for ALT elevations. RESULTS: Liver enzymes were measured at least once in 1630 of 2151 patients (76%). The prevalence of ALT >40 U/L was 27.6% (95%CI 25.7-29.5%). The incidence of new ALT elevations was 14.5/100 person-years (95%CI 13.0-16.1) for ALT > 40 U/L and 2.1/100 person-years (95%CI 1.6-2.8) for ALT elevations above twice the upper limit of normal (ULN). New persistent ALT elevations above twice the ULN were identified in 0.2% of patients. CONCLUSION: Elevated ALT is common among patients with AF, although new and persistent elevation greater than twice the ULN is uncommon. In the setting of a new drug, these factors make it difficult to delineate drug-induced liver injury from incident elevations due to comorbidities.     

Efficacy and safety of rivaroxaban compared with warfarin in patients with carotid artery disease and nonvalvular atrial fibrillation: Insights from the ROCKET AF trial

Background

Atrial fibrillation (AF) increases risk of stroke 5‐fold. Carotid artery disease (CD) also augments the risk of stroke, yet there are limited data about the interplay of these 2 diseases and clinical outcomes in patients with comorbid AF and CD.

Hypothesis

Among patients with both AF and CD, use of rivaroxaban when compared with warfarin is associated with a lower risk of stroke.

Methods

This post hoc analysis from ROCKET AF aimed to determine absolute rates of stroke/systemic embolism (SE) and bleeding, and the efficacy and safety of rivaroxaban compared with warfarin in patients with AF and CD (defined as history of carotid occlusive disease or carotid revascularization [endarterectomy and/or stenting]).

Results

A total of 593 (4.2%) patients had CD at enrollment. Patients with and without CD had similar rates of stroke or SE (adjusted hazard ratio [HR]: 0.99, 95% confidence interval [CI]: 0.66‐1.48, P = 0.96), and there was no difference in major or nonmajor clinically relevant bleeding (adjusted HR: 1.04, 95% CI: 0.88‐1.24, P = 0.62). The efficacy of rivaroxaban compared with warfarin for the prevention of stroke/SE was not statistically significant in patients with vs those without CD (interaction P = 0.25). The safety of rivaroxaban vs warfarin for major or nonmajor clinically relevant bleeding was similar in patients with and without CD (interaction P = 0.64).

Conclusions

Patients with CD in ROCKET AF had similar risk of stroke/SE compared with patients without CD. Additionally, there was no interaction between CD and the treatment effect of rivaroxaban or warfarin for stroke prevention or safety endpoints.     

Recruitment of Hispanics into an observational study of chronic kidney disease: The Hispanic Chronic Renal Insufficiency Cohort Study experience

Despite the large burden of chronic kidney disease (CKD) in Hispanics, this population has been underrepresented in research studies. We describe the recruitment strategies employed by the Hispanic Chronic Renal Insufficiency Cohort Study, which led to the successful enrollment of a large population of Hispanic adults with CKD into a prospective observational cohort study. Recruitment efforts by bilingual staff focused on community clinics with Hispanic providers in high-density Hispanic neighborhoods in Chicago, academic medical centers, and private nephrology practices. Methods of publicizing the study included church meetings, local Hispanic print media, Spanish television and radio stations, and local health fairs. From October 2005 to July 2008, we recruited 327 Hispanics aged 21–74 years with mild-to-moderate CKD as determined by age-specific estimated glomerular filtration rate (eGFR). Of 716 individuals completing a screening visit, 49% did not meet eGFR inclusion criteria and 46% completed a baseline visit. The mean age at enrollment was 57.1 and 67.1% of participants were male. Approximately 75% of enrolled individuals were Mexican American, 15% Puerto Rican, and 10% had other Latin American ancestry. Eighty two percent of participants were Spanish-speakers. Community-based and academic primary care clinics yielded the highest percentage of participants screened (45.9% and 22.4%) and enrolled (38.2% and 24.5%). However, academic and community-based specialty clinics achieved the highest enrollment yield from individuals screened (61.9% to 71.4%). A strategy focused on primary care and nephrology clinics and the use of bilingual recruiters allowed us to overcome barriers to the recruitment of Hispanics with CKD.     

Regulation of hematopoiesis in rats exposed to antiorthostatic, hypokinetic/hypodynamia: I. Model description

This paper provides baseline information regarding the regulation of hematopoiesis in antiorthostatic, hypokinetic/hypodynamic ("suspended") laboratory rats. The object of the study was to compare the hematological effects of suspension with those seen following space flight in man and/or rats. Observed in man after exposure to microgravity and in the suspended rats was a reduced red blood cell mass, suppressed erythropoiesis, a transient increase in hematocrit due to a reduction in plasma volume, a post-exposure hematocrit decrease, a weight loss (or failure to thrive) and a reduction in food and water consumption. A rightward shift in the oxyhemoglobin dissociation curve, observed in the rat "model", has been predicted to occur during manned space flight but has not yet been measured. Suppression of hematopoiesis is a common feature of rats during both space flight and suspension. Platelet counts showed no significant change in rats after suspension or in man during space flight. Unlike man in space but similar to space flight-exposed rats, no significant change in leukocyte number or reactivity to PHA in vitro, or in red blood cell shape distribution were observed in the suspended rats. At least in a gross sense, the rat "model" seems to reproduce many of the known hematological effects of space flight and offers promise as a 1 X g analog for understanding hematopoietic effects similar to those found in space flight.