Obesity‐related hypertension: Pathogenesis,cardiovascular risk,and treatment—A position paper of the The Obesity Society and the American Society of Hypertension

In light of the worldwide epidemic of obesity, and in recognition of hypertension as a major factor in the cardiovascular morbidity and mortality associated with obesity, The Obesity Society and The American Society of Hypertension agreed to jointly sponsor a position paper on obesity‐related hypertension to be published jointly in the journals of each society. The purpose is to inform the members of both societies, as well as practicing clinicians, with a timely review of the association between obesity and high blood pressure, the risk that this association entails, and the options for rational, evidenced‐based treatment. The position paper is divided into six sections plus a summary as follows: pathophysiology, epidemiology and cardiovascular risk, the metabolic syndrome, lifestyle management in prevention and treatment, pharmacologic treatment of hypertension in the obese, and the medical and surgical treatment of obesity in obese hypertensive patients. Obesity (2012)     

Comparison of renal effects of ibuprofen versus indomethacin during treatment of patent ductus arteriosus in contiguous historical cohorts

Background

The study aimed to investigate the pharmacokinetics of intravenous ciprofloxacin and the adequacy of 400 mg every 12 hours in critically ill Intensive Care Unit (ICU) patients on continuous veno-venous haemodiafiltration (CVVHDF) with particular reference to the effect of achieved flow rates on drug clearance.

Methods

This was an open prospective study conducted in the intensive care unit and research unit of a university teaching hospital. The study population was seven critically ill patients with sepsis requiring CVVHDF. Blood and ultrafiltrate samples were collected and assayed for ciprofloxacin by High Performance Liquid Chromatography (HPLC) to calculate the model independent pharmacokinetic parameters; total body clearance (TBC), half-life (t_1/2) and volume of distribution (Vd). CVVHDF was performed at prescribed dialysate rates of 1 or 2 L/hr and ultrafiltration rate of 2 L/hr. The blood flow rate was 200 ml/min, achieved using a Gambro blood pump and Hospal AN69HF haemofilter.

Results

Seventeen profiles were obtained. CVVHDF resulted in a median ciprofloxacin t_1/2 of 13.8 (range 5.15-39.4) hr, median TBC of 9.90 (range 3.10-13.2) L/hr, a median V_dss of 125 (range 79.5-554) L, a CVVHDF clearance of 2.47+/-0.29 L/hr and a clearance of creatinine (Cl_cr) of 2.66+/-0.25 L/hr. Thus CVVHDF, at an average flow rate of ~3.5 L/hr, was responsible for removing 26% of ciprofloxacin cleared. At the dose rate of 400 mg every 12 hr, the median estimated C_pmax/MIC and AUC_0-24/MIC ratios were 10.3 and 161 respectively (for a MIC of 0.5 mg/L) and exceed the proposed criteria of >10 for C_pmax/MIC and > 100 for AUC_0-24/MIC. There was a suggestion towards increased ciprofloxacin clearance by CVVHDF with increasing effluent flow rate.

Conclusions

Given the growing microbial resistance to ciprofloxacin our results suggest that a dose rate of 400 mg every 12 hr, may be necessary to achieve the desired pharmacokinetic - pharmacodynamic (PK-PD) goals in patients on CVVHDF, however an extended interval may be required if there is concomitant hepatic impairment. A correlation between ciprofloxacin clearance due to CVVHDF and creatinine clearance by the filter was observed (r² = 0.76), providing a useful clinical surrogate marker for ciprofloxacin clearance within the range studied.

Trial Registration

Current Controlled Trials ISRCTN52722850     

Charge effect on the photoinactivation of Gram-negative and Gram-positive bacteria by cationic meso-substituted porphyrins

Background  

In recent times photodynamic antimicrobial therapy has been used to efficiently destroy Gram (+) and Gram (-) bacteria using cationic porphyrins as photosensitizers. There is an increasing interest in this approach, namely in the search of photosensitizers with adequate structural features for an efficient photoinactivation process. In this study we propose to compare the efficiency of seven cationic porphyrins differing in meso-substituent groups, charge number and charge distribution, on the photodynamic inactivation of a Gram (+) bacterium (Enterococcus faecalis) and of a Gram (-) bacterium (Escherichia coli). The present study complements our previous work on the search for photosensitizers that might be considered good candidates for the photoinactivation of a large spectrum of environmental microorganisms.     

Comparison of PCR and clinical laboratory tests for diagnosing <Emphasis Type="Italic">H. pylori</Emphasis> infection in pediatric patients

Background

Histology and/or culture are generally considered the gold standard for the detection of H. pylori infection. Especially in children, these tests may result in a false negative outcome because of patchy distribution of the organism in the stomach mucosa. We have developed a PCR assay utilizing nested primer pairs directed against a subunit of the H. pylori urease gene (ureA). As part of a prospective evaluation of diagnostic tests to aid in detecting H. pylori infection in children, the aim of this study was to compare our PCR and Western blot assays with results obtained from histologic examination of biopsy specimens, rapid urease tests, and an FDA approved serologic assay and published PCR results to determine if we could validate the assays for diagnostic use on our patient population.

Results

Gastric biopsy specimens obtained from 101 pediatric patients were evaluated for the presence of H. pylori using histologic techniques, rapid urease (CLOtest) test and the PCR assay. Serum samples from each patient were assayed using both ELISA and Western Blot for antibodies to H. pylori. A total of 32 patients tested were positive by at least one of the methods evaluated. Thirteen patients had positive histology, 13 had a positive CLOtest, and 17 patients had positive H. pylori PCR. Out of the 13 CLO positive patients, 12 were positive by histologic analysis and all 13 were positive by PCR. Results of serologic tests on the same population did not correlate well with other assays. Twenty-eight patients showed serologic evidence of H. pylori infection, of which 9 were both CLO and histology positive and 12 were positive by PCR. Of the seropositive patients, 26 were ELISA positive, 13 were positive by Western blot, and 11 by both serologic methods.

Conclusions

The results obtained suggest that our nested PCR assay has the specificity and sensitivity necessary for clinical application when compared to standard histologic examination and rapid urease test. In addition, we found the current commercially available approved ELISA method appears unable to accurately detect H. pylori in this population. The Western blot assay yielded better concordance with CLOtest and histology, but not as good as the nested PCR assay.

     

The major apoptotic pathway activated and suppressed by poliovirus

Cells respond to poliovirus infection by switching on the apoptotic program, implementation of which is usually suppressed by viral antiapoptotic functions. We show here that poliovirus infection of HeLa cells or derivatives of MCF-7 cells was accompanied by the efflux of cytochrome c from mitochondria. This efflux occurred during both abortive infection (e.g., interrupted by guanidine-HCl and ending with apoptosis) and productive infection (leading to cytopathic effect). The former type of infection, but not the latter, was accompanied by truncation of the proapoptotic protein Bid. The virus-triggered cytochrome c efflux was suppressed by overexpression of Bcl-2. Both abortive and productive infections also resulted in a decreased level of procaspase-9, as revealed by Western blotting. In the former case, this decrease was accompanied by the accumulation of a protein with the electrophoretic mobility of active caspase-9. In contrast, in the productively infected cells, the latter protein was absent but caspase-9-related polypeptides with altered mobility could be detected. Both caspase-9 and caspase-3 were shown to be essential for the development of such hallmarks of virus-induced apoptosis as chromatin condensation, DNA degradation, and nuclear fragmentation. These and some other results suggest the following scenario. Poliovirus infection activates the apoptotic pathway, involving mitochondrial damage, cytochrome c efflux, and consecutive activation of caspase-9 and caspase-3. The apoptotic signal appears to be amplified by a loop which includes secondary processing of Bid. The implementation of the apoptotic program in productively infected cells may be suppressed, however, by the viral antiapoptotic functions, which act at a step(s) downstream of the cytochrome c efflux. The suppression appears to be caused, at least in part, by aberrant processing and degradation of procaspase-9.     

Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction

To identify human proteins that bind to the Smac and caspase-9 binding pocket on the baculoviral inhibitor of apoptosis protein (IAP) repeat 3 (BIR3) domain of human XIAP, we used BIR3 as an affinity reagent, followed by elution with the BIR3 binding peptide AVPIA, microsequencing, and mass spectrometry. The mature serine protease Omi (also known as HtrA2) was identified as a mitochondrial direct BIR3-binding protein and a caspase activator. Like mature Smac (also known as Diablo), mature Omi contains a conserved IAP-binding motif (AVPS) at its N terminus, which is exposed after processing of its N-terminal mitochondrial targeting sequence upon import into the mitochondria. Mature Omi is released together with mature Smac from the mitochondria into the cytosol upon disruption of the outer mitochondrial membrane during apoptosis. Finally, mature Omi can induce apoptosis in human cells in a caspase-independent manner through its protease activity and in a caspase-dependent manner via its ability to disrupt caspase-IAP interaction. Our results provide clear evidence for the involvement of a mitochondrial serine protease in the apoptotic pathway, emphasizing the critical role of the mitochondria in cell death.     

Deficiency in caspase-9 or caspase-3 induces compensatory caspase activation

Dysregulation of apoptosis contributes to the pathogenesis of many human diseases. As effectors of the apoptotic machinery, caspases are considered potential therapeutic targets. Using an established in vivo model of Fas-mediated apoptosis, we demonstrate here that elimination of certain caspases was compensated in vivo by the activation of other caspases. Hepatocyte apoptosis and mouse death induced by the Fas agonistic antibody Jo2 required proapoptotic Bcl-2 family member Bid and used a Bid-mediated mitochondrial pathway of caspase activation; deficiency in caspases essential for this pathway, caspase-9 or caspase-3, unexpectedly resulted in rapid activation of alternate caspases after injection of Jo2, and therefore failed to protect mice against Jo2 toxicity. Moreover, both ultraviolet and gamma irradiation, two established inducers of the mitochondrial caspase-activation pathway, also elicited compensatory activation of caspases in cultured caspase-3(-/-) hepatocytes, indicating that the compensatory caspase activation was mediated through the mitochondria. Our findings provide direct experimental evidence for compensatory pathways of caspase activation. This issue should therefore be considered in developing caspase inhibitors for therapeutic applications.