Shave biopsy technique and hemostasis pearl.

ABSTRACT: Nurse practitioners (NPs) are frequently called on to assess and diagnose patients presenting with suspicious or aggravated skin lesions. Performing shave biopsies and removing small neoplasms can be within the scope of a general NP. We offer a thorough review of shave biopsy methods, including required materials, photographic documentation, blade preparation and orientation, and hemostasis techniques. Diagnostic considerations when choosing a shave versus other biopsy techniques are reviewed as is the removal of lesions in cosmetically sensitive areas. Finally, a unique tip to diminish intraprocedure bleeding using aluminum chloride before procedure initiation is presented.

Dietary Supplementation of Yeast Culture Into Pelleted Total Mixed Rations Improves the Growth Performance of Fattening Lambs.

There is a growing interest in the use of yeast (Saccharomyces cerevisiae) culture (YC) for the enhancement of growth performance and general animal health. Grain-based pelleted total mixed rations (TMR) are emerging in intensive sheep farming systems, but it is uncertain if the process of pelleting results in YC becoming ineffective. This study aimed to examine the effects of YC supplemented to pelleted TMR at two proportions of corn in the diet on animal performance, feed digestion, blood parameters, rumen fermentation, and microbial community in fattening lambs. A 2 × 2 factorial design was adopted with two experimental factors and two levels in each factor, resulting in four treatments: (1) low proportion of corn in the diet (LC; 350 g corn/kg diet) without YC, (2) LC with YC (5 g/kg diet), (3) high proportion of corn in the diet (HC; 600 g corn/kg diet) without YC, and (4) HC with YC. Fifty-six 3-month-old male F2 hybrids of thin-tailed sheep and Northeast fine-wool sheep with a liveweight of 19.9 ± 2.7 kg were randomly assigned to the four treatment groups with an equal number of animals in each group. The results showed that live yeast cells could not survive during pelleting, and thus, any biological effects of the YC were the result of feeding dead yeast and the metabolites of yeast fermentation rather than live yeast cells. The supplementation of YC resulted in 31.1 g/day more average daily gain regardless of the proportion of corn in the diet with unchanged feed intake during the 56-day growth measurement period. The digestibility of neutral detergent fibre and acid detergent fibre was increased, but the digestibility of dry matter, organic matter, and crude protein was not affected by YC. The supplementation of YC altered the rumen bacterial population and species, but the most abundant phyla Bacteroidetes, Firmicutes, and Proteobacteria remained unchanged. This study indicates that YC products can be supplemented to pelleted TMR for improved lamb growth performance, although live yeast cells are inactive after pelleting. The improved performance could be attributed to improved fibre digestibility.

Designing effective capstone experiences and projects for entry-level doctoral students in occupational therapy: One program's approaches and lessons learned.

Entry-level doctoral occupational therapy programs require students to complete a capstone experience and project that supports advanced skills through an in-depth learning experience with a student-selected mentor. Strong curriculum design and mentorship are vital aspects of successful capstone experiences and projects. Through the application of these key components, students are supported, in collaboration with mentors, to achieve mutually beneficial projects allowing advancement of the profession through dissemination of capstone work.

The role of high resolution oesophageal manometry in occult respiratory symptoms.

PURPOSE: Cough Hypersensitivity Syndrome is the urge to cough following minimal stimulation, but its mechanism and method of provocation remain unexplained. 121 patients (44 males, 77 females; age range 18-81 years) were evaluated. PROCEDURES: High resolution manometry was performed on consecutive patients presenting with unexplained respiratory symptoms (Respiratory Group 61). Data were compared with matched controls, i.e. dyspepsia without respiratory symptoms (Dyspepsia Group 60). MAIN FINDINGS: Results showed increased inspiratory gastro-oesophageal pressure gradient due to significantly lower intra-oesophageal pressure on inspiration (p = 0.001), and reduced oesophageal motility in the Respiratory Group. CONCLUSIONS: Further research in respiratory conditions characterised by decreased intrathoracic pressure during inspiration is needed.

Dihydrobenzisoxazole-4-one compounds are novel selective inhibitors of aldosterone synthase (CYP11B2) with in vivo activity.

6,7-Dihydro-5H-2,1-benzisoxazol-4-one analogs are potent inhibitors of aldosterone synthase (CYP11B2) with selectivity over the highly homologous enzyme cortisol synthase (CYP11B1). These compounds are unique among inhibitors of CYP11B2 in their lack of a strong-heme binding group such as a pyridine or imidazole. Poor metabolic stability in hepatocyte incubations was found to proceed via a reduction of the isoxazole ring. While the enzyme responsible for the reductive metabolism remains unknown, the rate of metabolism could be attenuated by the addition of polar functionality. The in vitro CYP11B2 potency and selectivity were confirmed in vivo in a cynomolgus monkey model by the inhibition of ACTH stimulated aldosterone production without impacting plasma cortisol concentrations.

Identification of a potent sodium hydrogen exchanger isoform 1 (NHE1) inhibitor with a suitable profile for chronic dosing and demonstrated cardioprotective effects in a preclinical model of myocardial infarction in the rat.

Sodium-hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for intracellular pH regulation. During myocardial ischemia, low pH activates NHE1 and causes increased intracellular calcium levels and aberrant cellular processes, leading to myocardial stunning, arrhythmias, and ultimately cell damage and death. The role of NHE1 in cardiac injury has prompted interest in the development of NHE1 inhibitors for the treatment of heart failure. This report outlines our efforts to identify a compound suitable for once daily, oral administration with low drug-drug interaction potential starting from NHE1 inhibitor sabiporide. Substitution of a piperidine for the piperazine of sabiporide followed by replacement of the pyrrole moiety and subsequent optimization to improve potency and eliminate off-target activities resulted in the identification of N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (60). Pharmacological evaluation of 60 revealed a remarkable ability to prevent ischemic damage in an ex vivo model of ischemia reperfusion injury in isolated rat hearts.

Indole RSK inhibitors. Part 1: discovery and initial SAR.

A series of inhibitors for the 90 kDa ribosomal S6 kinase (RSK) based on an 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide scaffold were identified through high throughput screening. An RSK crystal structure and exploratory SAR were used to define the series pharmacophore. Compounds with good cell potency, such as compounds 43, 44, and 55 were identified, and form the basis for subsequent kinase selectivity optimization.

Mitigation of off-target adrenergic binding and effects on cardiovascular function in the discovery of novel ribosomal S6 kinase 2 inhibitors.

We previously reported the discovery of a novel ribosomal S6 kinase 2 (RSK2) inhibitor, (R)-5-Methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a] indole-8-carboxylic acid [1-(3-dimethylamino-propyl)-1H-benzoimidazol-2-yl]-amide (BIX 02565), with high potency (IC(50) = 1.1 nM) targeted for the treatment of heart failure. In the present study, we report that despite nanomolar potency at the target, BIX 02565 elicits off-target binding at multiple adrenergic receptor subtypes that are important in the control of vascular tone and cardiac function. To elucidate in vivo the functional consequence of receptor binding, we characterized the cardiovascular (CV) profile of the compound in an anesthetized rat CV screen and telemetry-instrumented conscious rats. Infusion of BIX 02565 (1, 3, and 10 mg/kg) in the rat CV screen resulted in a precipitous decrease in both mean arterial pressure (MAP; to -65 ± 6 mm Hg below baseline) and heart rate (-93 ± 13 beats/min). In telemetry-instrumented rats, BIX 02565 (30, 100, and 300 mg/kg p.o. QD for 4 days) elicited concentration-dependent decreases in MAP after each dose (to -39 ± 4 mm Hg on day 4 at T(max)); analysis by Demming regression demonstrated strong correlation independent of route of administration and influence of anesthesia. Because of pronounced off-target effects of BIX 02565 on cardiovascular function, a high-throughput selectivity screen at adrenergic α(1A) and α(2A) was performed for 30 additional RSK2 inhibitors in a novel chemical series; a wide range of adrenergic binding was achieved (0-92% inhibition), allowing for differentiation within the series. Eleven lead compounds with differential binding were advanced to the rat CV screen for in vivo profiling. This led to the identification of potent RSK2 inhibitors (cellular IC(50) <0.14 nM) without relevant α(1A) and α(2A) inhibition and no adverse cardiovascular effects in vivo.

Indole RSK inhibitors. Part 2: optimization of cell potency and kinase selectivity.

A series of inhibitors for the 90 kDa ribosomal S6 kinase (RSK) based on an 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide scaffold were optimized for cellular potency and kinase selectivity. This led to the identification of compound 24, BIX 02565, an attractive candidate for use in vitro and in vivo to explore the role of RSK as a target for the treatment heart failure.

Neisseria meningitidis PorB, a TLR2 ligand, induces an antigen-specific eosinophil recall response: potential adjuvant for helminth vaccines?

Efficacious adjuvants are important components of new vaccines. The neisserial outer membrane protein, PorB, is a TLR2 ligand with unique adjuvant activity. We demonstrate that PorB promotes Th2-skewed cellular immune response to the model Ag, OVA, in mice, including Ag-specific recall eosinophil recruitment to the peritoneum. PorB induces chemokine secretion by myeloid cells using both TLR2-dependent and -independent mechanisms, suggesting that anatomical distribution of TLR2(+) cells may not be a limiting factor for potential vaccine strategies. The results from this study suggest that PorB, and other TLR2 ligands, may be ideal for use against pathogens where eosinophilia may be protective, such as parasitic helminths.

A case of severe exercise-induced rhabdomyolysis associated with a weight-loss dietary supplement.

In response to questions about the safety of ephedra-based dietary products, ephedra-free products are now available. Many contain synephrine, a sympathomimetic amine with structural similarities to ephedra. We present a 22-year-old, previously healthy, African American male with sickle cell trait who developed rhabdomyolysis after ingestion of a synephrine-containing dietary supplement. The patient developed fatigue, dehydration, and myalgias while exercising. He developed severe rhabdomyolysis, with a peak creatine phosphokinase level of 2.8 million U/L, complicated by pulmonary edema, acute renal failure, disseminated intravascular coagulation, and bilateral compartment syndromes in his lower extremities. He required prolonged hospitalization for hemodialysis, multiple wound debridements, hyperbaric oxygen therapy, and physical therapy. He has permanent sensory and motor neurological deficits in his distal lower extremities. Military physicians should routinely inquire about the use of dietary supplements, educate patients about the potential adverse reactions associated with these agents, and encourage healthy diets and exercise for weight loss.

Media use and information needs of the disabled during a natural disaster.

This study examined differences in evacuation, crisis preparation, information-seeking patterns, and media use among the communities of disabled and non-disabled evacuees in the aftermath of Hurricane Katrina. Surveys were collected from 554 Katrina evacuees temporarily relocated in different areas of the United States. Results indicate differences in crisis preparation and evacuation plans, with disabled subpopulations being more likely to prepare emergency supplies but less likely to have an evacuation plan. Differences between the disabled and non-disabled subpopulations also existed in information-seeking habits. Media use was similar between disabled and non-disabled respondents.

PDE-10A inhibitors as insulin secretagogues.

Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured.

Induction of cell signaling events by the cholera toxin B subunit in antigen-presenting cells.

Cholera toxin (CT) is one of the most effective and widely studied mucosal adjuvants. Although the ADP-ribosylating A subunit has been implicated in augmenting immune responses, the receptor-binding B subunit (CT-B) has greater immunogenicity and may be a repository of adjuvant activity without potential toxicity. In order to elucidate mechanisms of immune modulation by CT-B alone, primary B cells and macrophages were assessed for responses to CT-B in vitro, as measured by the expression of cell surface markers, cellular signaling events, and cytokine secretion. Increased phosphorylation of multiple signaling molecules, including Erk1/2 and p38, was detected. CT-B also induced transactivation of the transcription elements cyclic AMP-responsive element and NF-kappaB, the latter of which was inhibited by phosphotyrosine inhibition. While specific inhibition of MEK1/2 did not reduce CT-B induction of cell surface marker expression, it did attenuate CT-B-mediated interleukin-6 secretion. These data show that CT-B induces a set of signaling events related to cellular activation, surface molecule expression, and cytokine production that has potential implications for elucidating CT-B adjuvant activity in the absence of enzymatically active holotoxin.

Test-retest reliability of a questionnaire on physical activity and its correlates among women from diverse racial and ethnic groups.

BACKGROUND: A better understanding of physical activity and its correlates is needed, especially among diverse populations of women. The objective of this study was to examine the test-retest reliability of a survey designed to measure physical activity and its correlates among women from diverse racial and ethnic groups. METHODS: Test and retest surveys were conducted in person or over the telephone with 344 white, Latina, African-American, and Native American women aged 20 to 50 years living in rural and urban areas of the United States. Reliability of self-reported physical activity and its correlates were determined using intraclass correlation coefficients (ICC) overall and separately by site and race/ethnicity. RESULTS: Of the women responding, 45% of the participants met recommendations for physical activity, 40% were insufficiently active, and 15% were inactive. Reliability for the physical activity measure was 0.69 (95% confidence interval [CI], 0.62-0.74), with an ICC of 0.30 to 0.95 across sites. Overall, the seven items on the physical environment had substantial reliability (ICC=0.64-0.91). The sense of community scale (0.79; 95% CI, 0.74-0.83), social issues (0.68; 95% CI, 0.61-0.74), social roles (0.64; 95% CI, 0.56-0.71), and self-efficacy for exercise (0.72; 95% CI, 0.66-0.77) all had acceptable reliability overall and across most sites. CONCLUSIONS: This study provides psychometric evidence that the questionnaire on physical activity and its correlates is reliable among diverse women aged 20 to 50 years from various racial and ethnic groups. These results suggest that test-retest reliability is not an obstacle to comparison of associations between physical activity and several hypothesized correlates of activity.