Selective deficiency of HIF-1alpha in myeloid cells influences secondary intention wound healing in mouse skin.

BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) influences myeloid cell function. In this study we examined the role of myeloid cell HIF-1alpha on wound healing in vivo using a cell-specific knockout (KO) mouse model. MATERIALS AND METHODS: HIF-1alpha KO mice and wild-type (WT) controls received 8 mm full thickness dorsal dermal wounds. Wound dimensions were measured until full closure. Tissue was obtained from 3-day-old wounds for (immuno-)histochemical analysis. Production of interleukin-1beta (IL-1beta) and nitric oxide (NO) in response to lipopolysaccharide (LPS) and/or desferrioxamine (DFX) was examined in vitro. RESULTS: Early wound closure occurred significantly faster in HIF-1alpha KO mice than in WT mice. Wounds of KO mice contained similar numbers of neutrophils and macrophages, but more activated keratinocytes, consistent with accelerated re-epithelialization. Interestingly, while LPS and LPS+DFX elicited a similar IL-1beta response in macrophages from the 2 mouse types, NO production was blunted in HIF-1alpha KO macrophages. CONCLUSION: Absence of HIF-1alpha in myeloid cells accelerates the early phase of secondary intention wound healing in vivo. This may be associated with a deficient ability of myeloid cells to initiate an appropriate NO production response. Pharmacologic modulators of HIF-1alpha should be explored in situations with abnormal wound healing.

Endometrial intraepithelial neoplasia.

CONTEXT: Developed in conjunction with molecular and progression data, the sequence classification schema for endometrial intraepithelial neoplasia (EIN)/benign hyperplasia (BH) provides an easy to adopt and reproducible method for classification of endometrial biopsies. OBJECTIVE: To review current data supporting the use of BH/EIN to classify endometrial biopsies, and to discuss the hormone-driven endometrial sequence from anovulation/disordered proliferative endometrium through BH and EIN and their diagnostic difficulty. DATA SOURCES: A comprehensive review of EIN literature based on literature indexed by PubMed (National Library of Medicine) and Google Scholar. CONCLUSIONS: The BH/EIN schema is gaining wider acceptance among pathologist and clinicians. The research leading to the EIN criteria is based on molecular and progression data. The BH/EIN schema has better reproducibility among pathologists, is intuitively easy to use, and requires understanding of endometrial physiology and neoplasia.

Heterogeneity of publicly accessible online critical values for therapeutic drugs.

INTRODUCTION: Critical values are reported to clinicians when laboratory values are life threatening and require immediate attention. To date no definitive critical value limit recommendations have been produced regarding therapeutic drug monitoring. Some laboratories choose to publish critical value lists online. These publicly available values may be accessed and potentially utilized by laboratory staff, patient care providers, and patients. MATERIALS AND METHODS: A web-based search of laboratories associated with the Accreditation Council for Graduate Medical Education pathology residency programs was initiated to determine which therapeutic drugs had critical values and to examine the degree of variation in published critical values for these institutions. RESULTS: Of the 107 institutions with university-based pathology training programs, 36 had published critical values online for review. Thirteen therapeutic drugs were investigated and the number of institutions reporting critical value limits for the drug, as well as the median, range, standard deviation, and the coefficient of variation of critical value concentration limits for each drug were determined. A number of the online critical value limits were deemed to be erroneous, most likely due to incorrectly listed units of measurement. CONCLUSIONS: There was a large degree of heterogeneity with regard to the chosen critical value limits for therapeutic drugs. This wide variance in critical values appears to be greater than that observed in interassay proficiency testing. Institutions should reexamine the rationale for their current critical value parameters and ensure that critical value limits and associated units are accurately published online.

Acute dilatory and negative inotropic effects of homocysteine are inhibited by an adenosine blocker.

1. Previous studies have shown that homocysteine elicits acute negative inotropic and coronary vasodilatory effects in rat hearts. In addition, this earlier work suggested that the inotropic action is mediated via an endothelium-derived agent that is neither nitric oxide (NO) nor a cyclooxygenase product, while the coronary actions were found to be antagonized by the NOS inhibitor l-NNA. Current experiments, which utilized coronary-perfused rat hearts, were designed to determine if muscarinic or adenosine receptors are involved in these acute actions of homocysteine. 2. Left ventricular developed pressure was used as a measure of systolic function in electrically paced, Langendorff-perfused heart with coronary pressure being used to monitor coronary vascular tone. Acute effects of homocysteine (10-300 micromol/L) were examined in the presence and absence of 1 yen 10(-6) mol atropine or 7 yen 10(-5) mol 8-(p-sulfophenyl) theophylline (SPT), a non-selective adenosine receptor antagonist. 3. Atropine had no effect on either the inotropic or vascular actions of homocysteine. In contrast, SPT partially antagonized both actions of the amino acid with the antagonism of the vasodilation being much greater than its inhibition of the negative inotropic effect. Experiments with adenosine demonstrated that the selected dose of SPT elicited marked rightward shifts in the dose-response curves for both the inotropic and vascular actions. 4. Current results suggest that adenosine plays a role in both the negative inotropic and vasodilatory actions of homocysteine. However, the relatively minor antagonistic action of SPT on the inotropic effect of homocysteine suggests that additional endothelium-derived mediators underlie its effects on contractility.

Acute negative inotropic effects of homocysteine are mediated via the endothelium.

Previous studies have shown that chronic hyperhomocysteinemia is associated with an adverse cardiac remodeling and heart failure. This study, which utilized coronary-perfused hearts and superfused papillary muscle, was designed to determine whether homocysteine acts acutely to alter cardiac contractile function. Left ventricular developed pressure was used as a measure of systolic function in the Langendorff-perfused heart, whereas isometric developed tension was used in papillary muscle. All preparations were bathed in physiological buffer and paced electrically. Initial results showed that homocysteine elicits a relatively rapid onset (maximum effect observed within 5 min), concentration-dependent (10-300 microM), and moderate negative inotropic action (maximum decrease in tension was approximately 15% of control values) in Langendorff-perfused hearts but not in papillary muscle. In contrast, effluent from homocysteine-treated hearts decreased contractility in papillary muscle, and all inotropic actions were largely eliminated when brief Triton X-100 treatment was utilized to inactivate the coronary endothelium in the intact heart. The homocysteine-induced decrease in contractile function was not antagonized by N(omega)-nitro-l-arginine, a nitric oxide synthase inhibitor, or the cyclooxygenase inhibitor indomethacin. Thus data suggest that pathophysiological concentrations of homocysteine elicit an acute negative inotropic effect on ventricular myocardium that is mediated by a coronary endothelium-derived agent other than nitric oxide or products of cyclooxygenase. Future studies are required to elucidate the mechanism by which homocysteine acts to elicit the release of the proposed endothelial mediator, the identity of the proposed paracrine agent, and the mechanism of its negative inotropic action.