Use of the Trendelenburg position as the resuscitation position: to T or not to T?

OBJECTIVE: To review the literature on use of the Trendelenburg position as a position for resuscitation of patients who are hypotensive. METHODS: PubMed online, cited bibliographies, critical care textbooks, and Advanced Cardiac Life Support guidelines were searched for information on the position used for resuscitation. Because of the heterogeneity of the data, only pertinent articles and chapters were summarized. RESULTS: Eight peer-reviewed publications on the position used for resuscitation were found. Pertinent information from 2 critical care textbooks and from the Advanced Cardiac Life Support guidelines was included in the review. Literature on the position was scarce, lacked strength, and seemed to be guided by "expert opinion." CONCLUSION: The general "slant" of the available data seems to indicate that the Trendelenburg position is probably not a good position for resuscitation of patients who are hypotensive. Further clinical studies are needed to determine the optimal position for resuscitation.     

Clinically important venous thromboembolism in pediatric critical care: a Canadian survey

PURPOSE: Pediatric venous thromboembolism (VTE) is becoming an increasingly recognized morbidity associated with critical illness. The objective of this survey is to identify the patient factors and radiological features that pediatric intensivists consider more or less likely to make a venous thrombosis (VTE) clinically important in their patients. MATERIALS AND METHODS: Our definition of clinically important VTE was a VTE likely to result in short- or long-term morbidity or mortality if left untreated. We asked respondents to rate the likelihood that patient factors and radiological features make a venous thrombosis clinically important using a 5-point scale (1 = much less likely to 5 = much more likely). RESULTS: The 38 (58.5%) of 65 pediatric intensivists responding rated 4 patient factors as most likely to make a VTE clinically important: clinical suspicion of pulmonary embolism (mean score, 4.8), symptoms (mean, 4.5), detection by physical exam (mean, 4.4), and the presence of an acute or chronic cardiopulmonary comorbidity that might limit a patient's ability to tolerate pulmonary embolism (mean, 4.3). Of the radiological features, the 2 considered most important were VTE involving the vena cava extending into the right atrium (mean, 5) and central veins (mean, 4.5). CONCLUSIONS: When labeling a VTE as clinically important, pediatric intensivists rely on several specific patient factors and thrombus characteristics.     

A peer-based substance abuse intervention for HIV+ rural women: a pilot study

Alcohol and other drug (AOD) use plays a major role in the acquisition and spread of HIV, and the majority of women living with HIV are either active or recovering drug users. Forty-six percent of women's cases of HIV infection have been attributed to injection-drug use and 18% to women's heterosexual contacts with injection-drug users. Substance abuse often contributes to noncompliance with HIV treatment. Individuals with multiple diagnoses, such as those with HIV and substance abuse, may not be able to withstand the burden of integrating the different clinical approaches used to treat their substance abuse and other comorbid disorders such as HIV. This article reports the results of an intervention pilot study testing a peer counseling intervention for substance abuse in rural women with HIV. Thirteen women completed the intervention. Although limited by sample size, results suggest that this intervention was effective in helping women to acknowledge problems with their alcohol and drug abuse and to begin taking steps to achieve sobriety.     

Enhancement of brain distribution of anticancer agents using DeltaG, the 12 kDa active fragment of ZOT

OBJECTIVE: The objective of this study was to evaluate the ability of DeltaG, the 12 kDa active fragment of ZOT, to increase the brain distribution of MTX and paclitaxel, two commonly used anticancer agents with poor distribution into the brain. METHODS: As part of dose estimation of DeltaG, [14C]-sucrose (40 microCi/kg), a hydrophilic paracellular marker, was co-administered with DeltaG (0, 400 and 800 microg/kg) with and without protease inhibitors to male Sprague-Dawley rats (n=3 per group) via an intracarotid cannula. MTX (50 mg/kg) and [3H]-paclitaxel (120 microCi/kg) were co-administered with the effective doses of DeltaG determined from the above study via the intracarotid cannula. Animals were euthanized by carbon dioxide asphyxiation at the specified time periods and brain and plasma samples were analyzed for the respective drug. RESULTS: The brain distribution of [14C]-sucrose was significantly enhanced at both doses of DeltaG. A fold enhancement in the B/P ratios of 1.88 and 2.68 was observed at the 400 and 800 microg/kg doses respectively, when the protein was protected from metabolic degradation with PIs. DeltaG significantly increased the brain distribution of MTX at each of the doses administered, with over a seven-fold increase at the 600 microg/kg dose. [3H]-paclitaxel brain AUC(0-60 min) was significantly higher in the presence of DeltaG (800 microg/kg with PIs) with a 2.5-fold enhancement in brain exposure. CONCLUSIONS: DeltaG significantly enhances the brain distribution of MTX (hydrophilic) and paclitaxel (lipophilic) and has the potential to be further developed as adjunct therapy to increase delivery of poorly permeable chemotherapeutic and other CNS targeted compounds.     

Discovery of a potent, orally available, and isoform-selective retinoic acid beta2 receptor agonist

4'-Octyl-4-biphenylcarboxylic acid (1g, AC-55649) was identified as a highly isoform-selective agonist at the human RARbeta2 receptor in a functional intact cell-based screening assay. The subsequent hit to lead optimization transformed the lipophilic, poorly soluble hit into a more potent and orally available compound (2, AC-261066) with retained beta2 selectivity and greatly improved physiochemical properties. Being an isoform-selective RARbeta2 receptor agonist that discriminates between nuclear receptor isoforms having identical ligand binding domains, 2 will be useful as a pharmacological research tool but also a valuable starting point for drug development.     

CEP-11004, an inhibitor of the SAPK/JNK pathway, reduces TNF-alpha release from lipopolysaccharide-treated cells and mice

Oxidative stress and low-grade inflammation are hallmarks of diabetes mellitus. We explored protective, blood pressure-independent effects of the angiotensin II type 1 (AT₁) receptor antagonist candesartan and the selective β₁-adrenoceptor antagonist metoprolol. Diabetes mellitus was induced in 8-week-old Sprague–Dawley rats after injection of streptozotocin. Diabetic rats were randomized to treatment with candesartan or metoprolol in sub-antihypertensive doses or to placebo treatment. In the quadriceps, musculature markers of oxidative stress and inflammation were determined. Function of the inherent vascular bed was measured in vivo in the autoperfused hindlimb. Increases in NAD(P)H activity, expression of its cytosolic subunit p22^phox and of endothelial NO synthase e(NOS) displayed enhanced oxidative stress. Upregulated intercellular (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 and of inducible NOS (iNOS) revealed inflammatory processes. Diabetes was associated with severe impairment of endothelium-dependent and -independent vasodilatation. Candesartan, but not metoprolol, reduced NAD(P)H activity, attenuated diabetes-induced over-expression of p22^phox and eNOS mRNA as well as ICAM-1, VCAM-1, iNOS and eNOS immunoreactivity and led to a substantial improvement of endothelium-dependent vasodilatation (+ 46.3% vs. placebo treatment; P < 0.05). Angiotensin AT₁ receptor antagonism, but not β₁-adrenoceptor antagonism, ameliorates diabetes-generated oxidative stress, indicating a pivotal role of the renin–angiotensin system in the development of diabetic complications.     

Prion protein gene (PRNP) variants and evidence for strong purifying selection in functionally important regions of bovine exon 3

Amino acid replacements encoded by the prion protein gene (PRNP) have been associated with transmissible and hereditary spongiform encephalopathies in mammalian species. However, an association between bovine spongiform encephalopathy (BSE) and bovine PRNP exon 3 has not been detected. Moreover, little is currently known regarding the mechanisms of evolution influencing the bovine PRNP gene. Therefore, in this study we evaluated the patterns of nucleotide variation associated with PRNP exon 3 for 36 breeds of domestic cattle and representative samples for 10 additional species of Bovinae. The results of our study indicate that strong purifying selection has intensely constrained PRNP over the long-term evolutionary history of the subfamily Bovinae, especially in regions considered to be of functional, structural, and pathogenic importance in humans as well as other mammals. The driving force behind this intense level of purifying selection remains to be explained.