Full‐thickness splinted skin wound healing models in db/db and heterozygous mice: Implications for wound healing impairment

The excisional dorsal full‐thickness skin wound model with or without splinting is widely utilized in wound healing studies using diabetic or normal mice. However, the effects of splinting on dermal wound healing have not been fully characterized, and there are limited data on the direct comparison of wound parameters in the splinted model between diabetic and normal mice. We compared full‐thickness excisional dermal wound healing in db/db and heterozygous mice by investigating the effects of splinting, semi‐occlusive dressing, and poly(ethylene glycol) treatment. Two 8‐mm full‐thickness wounds were made with or without splinting in db/db and heterozygous mice. Body weights, splint maintenance, wound contraction, wound closure, and histopathological parameters including reepithelialization, wound bed collagen deposition, and inflammation were compared between groups. Our results show that silicone splint application effectively reduced wound contraction in heterozygous and db/db mice. Splinted wounds, as opposed to nonsplinted wounds, exhibited no significant differences in wound closure between heterozygous and db/db mice. Finally, polyethylene glycol and the noncontact dressing had no significant effect on wound healing in heterozygous or db/db mice. We believe these findings will help investigators in selection of the appropriate wound model and data interpretation with fully defined parameters.     

Diagnosis and management of hereditary haemochromatosis

Hereditary haemochromatosis, one of the most common genetic disorders in the United States, can produce systemic iron deposition leading to end-organ failure and death if untreated. The diagnosis of this condition can be challenging as elevated serum ferritin may be seen in a variety of conditions, including acute and chronic liver disease, a range of systemic inflammatory states, and both primary and secondary iron overload syndromes. Appropriate and timely diagnosis of haemochromatosis is paramount as simple interventions, such as phlebotomy, can prevent or reverse organ damage from iron overload. The recognition of other aetiologies of elevated ferritin is also vital to ensure that appropriate intervention is provided and phlebotomy only utilized in patients who require it. In this review, we summarize the existing data on the work up and management of hereditary haemochromatosis and present a practical algorithm for the diagnosis and management of this disease.     

The linker of des-Glu84-calmodulin is bent.

The crystal structure of a mutant calmodulin (CaM) lacking Glu-84 has been refined to R = 0.23 using data measured to 2.9-A resolution. In native CaM the central helix is fully extended, and the molecule is dumbbell shaped. In contrast, the deletion of Glu-84 causes a bend of 95 degrees in the linker region of the central helix at Ile-85. However, EF-hand domains 1 and 2 (lobe 1,2) do not touch lobe 3,4. The length, by alpha-carbon separation, of des-Glu84-CaM is 56 A; that of native CaM is 64 A. The shape of des-Glu84-CaM is similar to that of native CaM, as it is bound to the target peptide of myosin light-chain kinase. This result supports the proposal that the linker region of the central helix of CaM functions as a flexible tether.     

Control of the mutagenicity of arylamines by protein kinases and phosphatases: II. Lack of response of rat liver N-acetyl transferases to phosphorylation modulators

Treatment of rat hepatocytes with the phosphatase inhibitors okadaic acid or ortho-vanadate had led to an 80% decrease in the bacterial mutagenicity of several aromatic amines metabolically activated by these hepatocytes. This is the most dramatic change yet demonstrated in mutagenicity by phosphorylation modulation. However, incorporation of phosphate into and catalytic activity of cytochromes P450 (CYP) 1A1 and 1A2, the major catalysts for the first step in the toxication of aromatic amines, were unchanged. We therefore investigated whether changes in the phosphorylation status would influence the activities of the N-acetyltransferases NAT1 and/or NAT2, being responsible for one of the two major pathways leading to the ultimate mutagens, the reactive esters which are derived from the N-hydroxylated metabolites of aromatic amines. Hepatocytes were derived from the livers of rats pretreated with CYP1A1/1A2 inducers and from untreated rats using conditions under which the phosphorylation-dependent drastic decrease of the arylamine mutagenicity was observed. Treatments were exposure to 1 mM dibutyryl-cAMP (protein kinase A stimulator), 100 nM okadaic acid or 20 nM calyculin A (preferential inhibitors of serine/threonine phosphatases PP2A and PP1, respectively), 2 mM ortho-vanadate (inhibitor of tyrosine phosphatases), and 50 mM NaF (stimulator of adenylate cyclase and non-specific inhibitor of protein phosphatases). None of the phosphorylation modulators led to a significant change in NAT1 or NAT2 activities. This was true for hepatocytes from rats which had been pretreated with inducers for CYP1A1 and CYP1A2 as well as from untreated rats. The inducers led to the expected increases in CYP1A1 and CYP1A2 but the NAT1 and NAT2 activities remained unchanged. Our study shows that the N-acetyl transferases NAT1 or NAT2, the catalysts responsible for the formation of the highly reactive N-acetoxy derivatives of N-hydroxylated aromatic amines, are not responsible for the drastic decrease in arylamine genotoxicity after treatment of the metabolizing system with protein phosphatase inhibitors. The data also shown that NAT1 and NAT2 are not regulated by the classical xenobiotic metabolizing enzyme inducers nor by any of the phosphorylation modulators used.     

Assessing the measurement properties of neighborhood scales: from psychometrics to ecometrics

Most studies examining the relation between residential environment and health have used census-derived measures of neighborhood socioeconomic position (SEP). There is a need to identify specific features of neighborhoods relevant to disease risk, but few measures of these features exist, and their measurement properties are understudied. In this paper, the authors 1) develop measures (scales) of neighborhood environment that are important in cardiovascular disease risk, 2) assess the psychometric and ecometric properties of these measures, and 3) examine individual- and neighborhood-level predictors of these measures. In 2004, data on neighborhood conditions were collected from a telephone survey of 5,988 residents at three US study sites (Baltimore, Maryland; Forsyth County, North Carolina; and New York, New York). Information collected covered seven dimensions of neighborhood environment (aesthetic quality, walking environment, availability of healthy foods, safety, violence, social cohesion, and activities with neighbors). Neighborhoods were defined as census tracts or census clusters. Cronbach's alpha coefficient ranged from 0.73 to 0.83, with test-retest reliabilities of 0.60-0.88. Intraneighborhood correlations were 0.28-0.51, and neighborhood reliabilities were 0.64-0.78 for census tracts for most scales. The neighborhood scales were strongly associated with neighborhood SEP but also provided information distinct from neighborhood SEP. These results illustrate a methodological approach for assessing the measurement properties of neighborhood-level constructs and show that these constructs can be measured reliably.     

Association between albumin administration and survival in cardiac surgery: a retrospective cohort study

Purpose

Albumin is widely used during and after on-pump cardiac surgery, although it is unclear whether this therapy improves clinical outcomes.

Methods

This observational study utilized the Cerner Health Facts® database (a large HIPAA-compliant clinical-administrative database maintained by Cerner Inc., USA) to identify a cohort of 6,188 adults that underwent on-pump cardiac surgery for valve and/or coronary artery procedures between January 2001 and March 2013. Of these, 1,095 patients who received 5% albumin with crystalloid solutions and 1,095 patients who received crystalloids alone on the day of or the day following cardiac surgery were selected by propensity-score matching. The primary outcome was all-cause in-hospital mortality. Three secondary outcomes analyzed include acute kidney injury severity, major morbidity composite, and all-cause 30-day readmissions.

Results

In the propensity-score matched cohort, receipt of perioperative 5% albumin was associated with decreased risk of in-hospital mortality (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.3 to 0.9; P = 0.02) and lower all-cause 30-day readmission rates (OR, 0.7; 98.3% CI, 0.5 to 0.9; P < 0.01). Albumin therapy was not associated with differences in overall major morbidity (OR, 0.9; 98.3% CI, 0.7 to 1.2; P = 0.39; composite) or acute kidney injury severity (OR, 0.9; 98.3% CI, 0.6 to 1.4; P = 0.53) compared with therapy with crystalloid solutions.

Conclusions

In this large retrospective study, use of 5% albumin solution was associated with significantly decreased odds of in-hospital mortality and all-cause 30-day readmission rate compared with administration of crystalloids alone in adult patients undergoing on-pump cardiac surgery. These results warrant further studies to examine fluid receipt, including 5% albumin, in surgical populations via randomized-controlled trials.

     

The role of genetics in stroke

Stroke is a leading cause of death and disability in developed countries. While both modifiable and non-modifiable risk factors are acknowledged, studies have shown that these may account for just 50% of stroke risk and that other factors, including genetic ones, may be important. Over recent years family history, twin and candidate gene studies have supported this and various mendelian stroke syndromes have now been identified in humans. This article provides an up-to-date summary of the common single gene disorders associated with stroke as a principle manifestation, including their genetic basis, pathogenesis, presentation and suggested management. Often these disorders present with stroke at a young age; this article provides a practical approach to the management and investigation of a young stroke patient.