Inhibition of phosphoenolpyruvate carboxykinase by streptonigrin

Streptonigrin, an antibiotic with antineoplastic activity, inhibited rat liver phosphoenolpyruvate carboxykinase with an I₅₀ of 0.3 μM when excess FeCl₂ was present. No inhibition occurred in the absence of added metal ion. Inhibition was partial and noncompetitive versus ITP and oxalacetic acid. The enzyme was more susceptible to inhibition by Streptonigrin in the absence of substrates. Fe²⁺ supported inhibition by Streptonigrin to a greater extent than did Fe³⁺, while Mn²⁺ activated the enzyme in the presence of Streptonigrin. For maximum inhibition, at least a 3-fold molar excess of iron over Streptonigrin was required. The methyl ester of Streptonigrin was also an inhibitor (I₅₀ = 4 μM) while the fragment containing the C and D rings was not, indicating that inhibition did not depend solely on the presence of the picolinic acid moiety. When oxalacetate synthesis was measured, Streptonigrin plus iron had no more effect on enzymatic activity than iron alone, and Mn²⁺ was capable of stimulating the streptonigrin-Fe²⁺ inhibited enzyme.     

Ratio of triglycerides to HDL cholesterol is an indicator of LDL particle size in patients with type 2 diabetes and normal HDL cholesterol levels

OBJECTIVE: In patients with type 2 diabetes, a normal HDL cholesterol level does not rule out that LDL particles may be small. Although techniques for analyzing LDL subfractions are not likely to be used in clinical practice, a prediction of LDL size based on a regular lipid profile may be useful for assessment of cardiovascular risk. RESEARCH DESIGN AND METHODS: Sixty patients with type 2 diabetes with acceptable glycemic control and an HDL cholesterol level > or = 1 mmol/l were recruited after cessation of lipid-altering treatments. LDL size was determined by 2-20% PAGE; patients having small LDL (n = 30) were compared with those having intermediate or large LDL (n = 30). RESULTS: Clinical characteristics, pharmacological therapies, lifestyle, and prevalence of diabetes-related complications were similar in both patient groups. LDL size correlated negatively with plasma triglycerides (TGs) (R2 = 0.52) and positively with HDL cholesterol (R2 = 0.14). However, an inverse correlation between the TG-to-HDL cholesterol molar ratio and LDL size was even stronger (R2 = 0.59). The ratio was > 1.33 in 90% of the patients with small LDL particles (95% CI 79.3-100) and 16.5% of those with larger LDL particles. A cutoff point of 1.33 for the TG-to-HDL cholesterol ratio distinguishes between patients having small LDL values better than TG cutoff of 1.70 and 1.45 mmol/l. CONCLUSIONS: The TG-to-HDL cholesterol ratio may be related to the processes involved in LDL size pathophysiology and relevant with regard to the risk of clinical vascular disease. It may be suitable for the selection of patients needing an earlier and aggressive treatment of lipid abnormalities.     

C-Terminus of Botulinum A Protease Has Profound and Unanticipated Kinetic Consequences upon the Catalytic Cleft

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Allo-exposure status and leucocyte antibody positivity of blood donors show a similar relation with TRALI

Introduction: The fraction of transfusion‐related acute lung injury (TRALI) cases preventable by deferral of allo‐exposed donors has previously been estimated, under the assumption this indirectly estimated the contribution of leucocyte antibodies to the occurrence of TRALI. Our aim was to estimate the fraction preventable by deferral of leucocyte antibody positive donors and to investigate the validity of allo‐exposure as a marker for leucocyte antibodies. Methods: All donors involved in a series of previously published TRALI patients were tested for leucocyte antibodies. The observed number of antibody positive donors was compared to the expected number. From this comparison we estimated the contribution of leucocyte antibodies to the occurrence of TRALI and compared this to the previously reported estimate for allo‐exposed donors. Results: Sixty‐one TRALI patients were included. Of 288 involved donors 43 were expected and 67 were observed to be leucocyte antibody positive. The observed percentage of positive donors was 8·3% (95% confidence interval (CI): 5·1–11·5%) in excess of the expected. Overall 59% (95% CI: 34–85%) of TRALI cases was estimated to be preventable by the exclusion of all leucocyte antibody positive donors. For plasma‐poor products this was 16% (95% CI: ?5·0 to 36%). Conclusions: These estimates were similar to those previously published for allo‐exposed donors. This suggests allo‐exposure status can effectively be used in donor deferral strategies.     

Characterization of a new allele: HLA-A*03:134

The new A*03:134 differs from A*03:01:01:01 by one amino acid change at codon 264.     

Oligozoospermia with normal fertility in male mice lacking the androgen receptor in testis peritubular myoid cells

Androgens and the androgen receptor (AR) play important roles in the testes. Previously we have shown that male total AR knockout (T-AR-/y) mice revealed incomplete germ cell development and lowered serum testosterone levels, which resulted in azoospermia and infertility. However, the consequences of AR loss in particular types of testicular cells remain unclear. Using a Cre-loxP conditional knockout strategy, we generated a tissue-selective knockout mouse with the AR gene deleted in testis peritubular myoid cells (PM-AR-/y). Phenotype analyses showed that PM-AR-/y mice were indistinguishable from WT AR (AR+/y) mice with the exception of smaller testes size. PM-AR-/y mice have serum testosterone concentrations comparable with AR+/y mice. PM-AR-/y mice have oligozoospermia in the epididymis; however, fertility was normal. Although normal germ cell distribution ratio was found, total germ cell number decreased in PM-AR-/y mice. Further mechanistic studies demonstrated that PM-AR-/y mice have defects in the expression of Sertoli cells' functional marker genes such as tranferrin, epidermal fatty acid-binding protein, androgen-binding protein, and other junction genes including occludin, testin, nectin, zyxin, vinculin, laminingamma3, gelsolin, connection43, and N-cadherin. Furthermore, there were defects in peritubular myoid cell contractility-related genes such as endothelin-1, endothelin receptor A and B, adrenomedullin, adrenomedullin receptor, and vasopressin receptor 1a. Together, our PM-AR-/y mice provide in vivo evidence for the requirement of functional AR in peritubular myoid cells to maintain normal Sertoli cells function and peritubular myoid cell contractility, thus ensuring normal spermatogenesis and sperm output.     

Laparoscopic pyloromyotomy for hypertrophic pyloric stenosis: a survey of 407 children

Introduction

Pyloromyotomy is the standard care for hypertrophic pyloric stenosis. The traditional approach for this procedure is a right upper quadrant transverse incision, although other “open” approaches, such as circumumbilical or periumbilical incision have been described. The more recent approach used is laparoscopic pyloromyotomy (LP), but experience feedback is still debated and its benefits remain unproven. The aim of this study was to make a review of all our LP procedures with an objective evaluation according to the literature.

Methods

A retrospective analysis of all the LPs performed in one University Children’s Hospital between 1 January 1996, and 30 December 2015 was realized. Information regarding the patient’s status, intraoperative and postoperative data was analyzed.

Results

407 patients were included in this study. The mean operative time of the overall procedure was 24?±?13 min, which significantly increased with the length of the pyloric muscle (p?=?0.004) and significantly impacted the full feeding time (p?=?0.006). 3.4% required conversion to an open procedure during the LP. We observed a significant correlation between conversion for mucosal perforation and weight loss (p?=?0.04) and between conversion for mucosal perforation and preoperative weight (p?=?0.002). A redo procedure was indicated in 3.7%, for incomplete pyloromyotomy each time. The mean postoperative hospital length of stay for all procedures was 1.6?±?0.8 days. There were no inflammatory scars. None had incisional hernias or wound dehiscence.

Discussion

LP procedure appeared to be as quick as the open procedure. Our results were similar to others series for intraoperative complications. According to operative time, this technique does not have an impact on operative room utilization. Vomiting duration at presentation in HPS does not seem to have a significant impact on postoperative outcomes. LP procedure causes little pain during the postoperative period. No wound complications were registered.

     

Suppression of Δ5-androstenediol-induced androgen receptor transactivation by selective steroids in human prostate cancer cells

Our earlier report suggested that androst-5-ene-3beta,7beta-diol (Delta(5)-androstenediol or Adiol) is a natural hormone with androgenic activity and that two potent antiandrogens, hydroxyflutamide (Eulexin) and bicalutamide (Casodex), fail to block completely the Adiol-induced androgen receptor (AR) transactivation in prostate cancer cells. Here, we report the development of a reporter assay to screen several selective steroids with anti-Adiol activity. Among 22 derivatives/metabolites of dehydroepiandrosterone, we found 4 steroids [no. 4, 1,3,5(10)-estratriene-17alpha-ethynyl-3, 17beta-diol; no. 6, 17alpha-ethynyl-androstene-diol; no. 8, 3beta, 17beta-dihydroxy-androst-5-ene-16-one; and no. 10, 3beta-methylcarbonate-androst-5-ene-7,17-dione] that have no androgenic activity and could also block the Adiol-induced AR transactivation in prostate cancer PC-3 cells. Interestingly, these compounds, in combination with hydroxyflutamide, further suppressed the Adiol-induced AR transactivation. Reporter assays further showed that these four anti-Adiol steroids have relatively lower glucocorticoid, progesterone, and estrogenic activity. Together, these data suggest some selective steroids might have anti-Adiol activity, which may have potential clinical application in the battle against the androgen-dependent prostate cancer growth.