Leukocyte apoptosis and its significance in sepsis and shock

Sepsis and multiple organ failure continue to be significant problems among trauma, burn, and the critically ill patient population. Thus, a number of laboratories have focused on understanding the role of altered apoptotic cell death in contributing to immune and organ dysfunction seen in sepsis and shock. Immune cells that undergo altered apoptotic changes include neutrophils, macrophages, dendritic cells, as well as various lymphocyte populations. Evidence of epithelial as well as endothelial cell apoptotic changes has also been reported. Although mediators such as steroids, tumor necrosis factor, nitric oxide, C5a, and Fas ligand (FasL) appear to contribute to the apoptotic changes, their effects are tissue- and cell population-selective. As inhibiting Fas-FasL signaling (e.g., gene deficiency, Fas fusion protein, or Fas short interfering RNA administration), caspase inhibition (caspase mimetic peptides), and/or the overexpression of downstream antiapoptotic molecules (e.g., Bcl-2, Akt) improve survival of septic mice, it not only demonstrates the pathological significance of this process but points to novel targets for the treatment of sepsis.     

RENAL MEDULLARY CARCINOMA: A Potential Sickle Cell Nephropathy of Children and Adolescents

An extremely aggressive malignant epithelial neoplasm of the kidney has recently been described and named renal medullary carcinoma. The finding of this tumor is highly predictive of drepanocytes (sickle cells) in tissue sections and thus the presence of sickle hemoglobin, specifically sickle cell trait, in the patient. We present a case report of this rare tumor in a 10-year-old male. The tumor displayed a variable histologic architecture including gland-like areas with intra- and extracytoplasmic material resembling mucin with hematoxylin and eosin stain. This material was negative with periodic acid-Schiff and mucicarmine stains, stained only weakly with Alcian Blue, and was positive using antibodies against peanut agglutinin. Tumor cells stained positively with antibodies to epithelial membrane antigen, cytokeratin, vimentin, and Ulex europaeus lectin. The luminal face of tumor cells stained with peanut agglutinin. Stains using antibodies against carcinoembryonic antigen and alpha-fetoprotein were negative. Ultrastructurally, the tumor cells were characterized by short microvilli lining the luminal surface and lateral complex infoldings of adjacent plasma membranes. We discuss the relationship of this neoplasm to another renal pelvic neoplasm, collecting duct carcinoma, which may rarely occur in children. Renal medullary carcinoma should be included in the differential diagnosis of gross hematuria, which is most commonly benign self-limited hematuria, in young patients with sickle cell trait.     

MicroRNA signatures characterize diffuse large B-cell lymphomas and follicular lymphomas

MicroRNAs (miRNA, miR) are negative regulators of gene expression that play an important role in diverse biological processes such as development, cell growth, apoptosis and haematopoiesis, suggesting their association with cancer. Here we analysed the expression signatures of 157 miRNAs in 58 diffuse large B-cell lymphoma (DLBCL), 46 follicular lymphoma (FL) and seven non-neoplastic lymph nodes (LN). Comparison of the possible combinations of DLBCL-, FL- and LN resulted in specific DLBCL- and FL-signatures, which include miRNAs with previously published function in haematopoiesis ( MIRN150 and MIRN155 ) or tumour development ( MIRN210 , MIRN10A , MIRN17-5P and MIRN145 ). As compared to LN, some miRNAs are differentially regulated in both lymphoma types ( MIRN155 , MIRN210 , MIRN106A , MIRN149 and MIRN139 ). Conversely, some miRNAs show lymphoma-specific aberrant expression, such as MIRN9/9* , MIRN301 , MIRN338 and MIRN213 in FL and MIRN150 , MIRN17-5P , MIRN145 , MIRN328 and others in DLBCL. A classification tree was computed using four miRNAs ( MIRN330 , MIRN17-5P , MIRN106a and MIRN210 ) to correctly identify 98% of all 111 cases that were analysed in this study. Finally, eight miRNAs were found to correlate with event-free and overall survival in DLBCL including known tumour suppressors ( MIRN21 , MIRN127 and MIRN34a ) and oncogenes ( MIRN195 and MIRNLET7G ).     

Vigabatrin pediatric dosing information for refractory complex partial seizures: Results from a population dose–response analysis

We predicted vigabatrin dosages for adjunctive therapy for pediatric patients with refractory complex partial seizures (rCPS) that would produce efficacy comparable to that observed for approved adult dosages. A dose–response model related seizure‐count data to vigabatrin dosage to identify dosages for pediatric rCPS patients. Seizure‐count data were obtained from three pediatric and two adult rCPS clinical trials. Dosages were predicted for oral solution and tablet formulations. Predicted oral solution dosages to achieve efficacy comparable to that of a 1 g/day adult dosage were 350 and 450 mg/day for patients with body weight ranges 10–15 and >15–20 kg, respectively. Predicted oral solution dosages for efficacy comparable to a 3 g/day adult dosage were 1,050 and 1,300 mg/day for weight ranges 10–15 and >15–20 kg, respectively. Predicted tablet dosage for efficacy comparable to a 1 g/day adult dosage was 500 mg/day for weight ranges 25–60 kg. Predicted tablet dosage for efficacy comparable to a 3 g/day adult dosage was 2,000 mg for weight ranges 25–60 kg. Vigabatrin dosages were identified for pediatric rCPS patients with body weights ≥10 kg.     

Trajectories of the cortisol awakening responses during weight gain in anorexia nervosa patients with severe and less severe symptoms

The aim of this study was to examine the features and changes of the cortisol awakening response (CAR) in patients with anorexia nervosa (AN) with severe and less severe symptoms over the course of inpatient treatment.     

The Growth Factor Midkine Antagonizes VEGF Signaling In Vitro and In Vivo

Midkine (MDK) is a heparin-binding growth factor involved in growth, survival, migration, and differentiation of various target cells and dysregulation of MDK signaling is implicated in a variety of inflammatory diseases and cancers. Although MDK has been reported to act on endothelial cells and to have proangiogenic effects, the exact role of MDK in angiogenesis is poorly defined. Here, we report that MDK is actually a modulator of angiogenesis and that it can abrogate the vascular endothelial growth factor A (VEGF-A)-induced proliferation of human microvascular endothelial cells in vitro through the downregulation of proangiogenic cytokines and through the upregulation of the antiangiogenic factor, tissue inhibitor of metalloproteinase 2. Phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR-2) and of downstream signaling molecules, such as phosphatidylinositol-3-kinase and mitogen-activated protein kinases, is also impaired. Moreover, MDK downregulates VEGF-A-induced neovascularization and vascular permeability in vivo. We propose a model in which MDK is a new modulator of the VEGF-A-VEGFR-2 axis.     

Mechanism of cardiotoxicity of halofantrine

OBJECTIVES AND METHODS: To further evaluate the scope and mechanism of potential cardiotoxicity associated with the antimalarial drug halofantrine, case reports submitted to the US Food and Drug Administration Spontaneous Reporting System were examined. Because halofantrine was associated with electrocardiographic prolongation of the QT interval and ventricular arrhythmias, in vitro cardiac electrophysiologic studies (isolated perfused cardiac model and isolated ventricular myocytes) were conducted to test the hypothesis that halofantrine or its metabolite is responsible for cardiotoxicity. RESULTS: Although it is difficult to ascertain causality and to estimate overall incidence, a significant number of adverse events related to the cardiovascular system were reported, including QT interval prolongation, life-threatening arrhythmias, and sudden death. The effect of halofantrine and its active metabolite (N-desbutylhalofantrine) on repolarization were examined in an isolated perfused heart model. Results indicate that halofantrine was able to prolong the QT interval, whereas N-desbutylhalofantrine had minimal effect on the QT interval relative to baseline. In an attempt to further elucidate the mechanism of QT interval prolongation, the effects of racemic halofantrine, its stereoisomers, and N-desbutylhalofantrine on repolarizing currents in isolated ventricular myocytes were studied with use of patch-clamp techniques. Halofantrine produced a stereoselective block of the delayed rectifier potassium channel in isolated feline myocytes. CONCLUSIONS: These results indicate that halofantrine is similar to quinidine and class III antiarrhythmics in its ability to prolong repolarization. We conclude that high plasma concentrations of halofantrine should be avoided, especially in women, and that N-desbutylhalofantrine may have potential as a safer antimalarial drug.     

The clinical importance of routine measurement of liver enzymes, total protein and albumin in a general medicine outpatient clinic: a prospective study.

The objective was to study the usefulness of routine measurement of liver enzymes (ASAT, ALAT, alkaline phosphatase, gamma-GT), and total protein (TP) and albumin (Alb) in a general medicine outpatient clinic. A prospective study was made of consecutive patients who were classified according to whether or not an indication for the tests was present. All six tests were measured in all patients. Physicians were kept unaware of the results of tests in patients with no indication for ordering the test. The setting was a general internal medicine outpatient clinic in a 850-bed teaching hospital which serves as a referral clinic for general practitioners. There were 615 consecutive patients who were all new referrals to the outpatient clinic. The results of all patients with no indication for the test but who had abnormal results were presented to a panel of three experienced internists who decided whether the results had any clinical importance. Repeat measurements of the tests or follow-up results were obtained in all these patients. Seventy-eight of 320 patients in whom no indication for the test for liver enzymes existed had abnormal results. In only six of these (1.9%) were the abnormalities of clinical significance. In 56 of 449 patients in whom no indications were present for TP and Alb measurement the results were abnormal. In only 2 (0.4%) was this clinically important. Conclusion: the routine measurement of these six tests in general medicine outpatient clinics should be abandoned because of the low yield.     

Restrictive dermopathy: report of a case and review of the literature

BACKGROUND: Restrictive dermopathy is a rare autosomal recessive skin disorder that is fatal in the neonatal period. Clinical and pathologic findings are distinctive and allow for a specific diagnosis in most cases. METHODS: We present a case of an affected infant and a review of the previously reported cases in the literature. RESULTS: The infant had thick shiny skin with reduced compliance and multiple spontaneous linear splits. Additional findings included an abnormal facies with a distinctive small, round and open mouth, low set ears, small nose, widely spaced sutures, flexion contractures of the extremities, and poorly expanded lungs. The infant expired 65 h after birth. Histologic findings of the skin at autopsy included a relatively unremarkable epidermis, a flat dermal-epidermal junction (absent rete ridges), an overall thinned dermis with hypoplastic appendage structures, a dense fibrotic reticular dermis with collagen parallel to the epidermis, a sharp subcutaneous margin, and an abnormally thick layer of subcutaneous adipose tissue. Electron microscopic findings included dense dermal patches of collagen and fibroblasts with abundant endoplasmic reticulum and unusually small tonofilaments. Review of previously reported cases reveals strikingly consistent findings. CONCLUSIONS: This rare condition illustrates that abnormal cutaneous development may produce fetal hypokinesia, leading to profound effects on intrauterine growth and development. The autosomal recessive pattern of inheritance and morphologic changes of the skin and skeletal system in this disorder suggest that a structural protein or enzyme defect, perhaps of collagen metabolism, may underlie the pathogenesis.