Assessment of aquo-ethanolic extract of Camellia sinensis against Carbapenem Resistant Escherichia coli: In Vivo Trials in a Murine Model

The prevalence of Carbapenem Resistant Escherichia coli (CRE) has increased considerably during the last decade, which can be ascribed to relative scarcity of effective non toxic antimicrobial agents. The present study was conducted to evaluate the antimicrobial activity of aquo-ethanolic (1:1) extract of leaves of Camellia sinensis (PTRC-31911-A) against Carbapenem Resistant Escherichia coli at preclinical level using peritonitis infection model in Sprague Dawley rats. Efficacy analysis of PTRC-31911-A involved enumeration of CRE colonies in blood and urine samples of test animals for a period of 5 days from infection. A reduction in microbial count of biological fluids was considered as the primary endpoint of the selected murine model. Physical, biochemical, hematological and histological indices of toxicity were employed as secondary relative indicators of the induced disease. Physical manifestations of infected rats included significantly high body temperature (Temp_Infected = 103.18 °F, ∼5% increase) and noteworthy reduction in weight (Weight_Infected = 126.83 g, ∼15% decrease) as compared to control. Significant (P < 0.05) increase in total white blood cells, eosinophil and monocyte counts as well as a significant decrease (P < 0.05) in erythrocytes count, hematocrit volume, red blood cell distribution width and hemoglobin concentration were observed in the infected group as compared to the control group. Furthermore, noteworthy increase in liver and kidney function test parameters were observed in case of infected groups. All the hematological and biochemical parameters were found to be within optimum range in case of treatment group, indicating restoration of homeostasis. Histopathological studies also presented symptoms of hemorrhage and glomerular damage with structural distortion in glomerular capillary loops of infected groups, which were later recovered in treated groups, indicating the nephro-protective potential of PTRC-31911-A. The study clearly points out that Camellia sinensis extract (PTRC-31911-A; single dose of 5 mg/Kg bwt; oral, + 24 h) is highly effective against Carbapenem Resistant Escherichia coli owing mainly to the presence of flavonoids and polyphenolic compounds, identified by LCMS. Ongoing studies are expected to further unravel the mechanism of action and bioactivity determinants of this broad spectrum plant extract.     

Improved cisplatin delivery in cervical cancer cells by utilizing folate-grafted non-aggregated gelatin nanoparticles

PurposeCisplatin is highly effective in the treatment of cervical cancer. However, in therapeutic doses, cisplatin induces several adverse effects due to undesirable tissue distribution. Therefore, it is worth targeting cisplatin in cervical cancer cells by implicating non-aggregated ligand-modified nanotherapeutics.Methods and resultsHere, we report the preparation of non-aggregated folic acid-conjugated gelatin nanoparticles of cisplatin (Cis-GNs-FA) by two-step desolvation method with mean particle size of 210.6 ± 9.6 nm and 140.5 ± 10.9 nm for Cis-GNs to improve the drug delivery in cervical cancer, HeLa cells. FTIR and DSC spectra confirmed the presence and stability of cisplatin in gelatin matrix. Furthermore, amorphization of cisplatin in nanoparticles was ascertained by PXRD. Drug release followed a first-order release kinetic at both pH ∼ 5.6 (cervical cancer pH) and pH ∼ 7.4. In addition, a significant (P < 0.05) decrease in IC₅₀ value (8.3 μM) and enhanced apoptosis were observed in HeLa cells treated with Cis-GNs-FA as compared to Cis-GNs (15.1 μM) and cisplatin solution (40.2 μM). In contrast, A549 lung cancer cells did not discriminate between Cis-GNs-FA and Cis-GNs due to the absence of folate receptors-α (FR-α). Consistently, higher cellular uptake, 80.54 ± 7.60% was promoted by Cis-GNs-FA significantly (two-way ANOVA, P < 0.05) greater than 51.68 ± 9.78%, by Cis-GNs. This was also illustrated by CLSM images, which indicated that Cis-GNs-FA preferably accumulated in the cytoplasm of HeLa cells nearby nucleus by following receptor-mediated endocytosis pathway as compared to Cis-GNs.ConclusionTherefore, Cis-GNs-FA warrants further in-depth in vitro and in vivo investigations to scale up the technology for clinical translation.     

Early targeted brain COOLing in the cardiac CATHeterisation laboratory following cardiac arrest (COOLCATH)

IntroductionTrials demonstrate significant clinical benefit in patients receiving therapeutic hypothermia (TH) after cardiac arrest. However, incidence of mortality and morbidity remains high in this patient group. Rapid targeted brain hypothermia induction, together with prompt correction of the underlying cause may improve outcomes in these patients. This study investigates the efficacy of Rhinochill^®, an intranasal cooling device over Blanketrol^®, a surface cooling device in inducing TH in cardiac arrest patients within the cardiac catheter laboratory.Methods70 patients were randomized to TH induction with either Rhinochill^® or Blanketrol^®. Primary outcome measures were time to reach tympanic ≤34 °C from randomisation as a surrogate for brain temperature and oesophageal ≤34 °C from randomisation as a measurement of core body temperature. Secondary outcomes included first hour temperature drop, length of stay in intensive care unit, hospital stay, neurological recovery and all-cause mortality at hospital discharge.ResultsThere was no difference in time to reach ≤34 °C between Rhinochill^® and Blanketrol^® (Tympanic ≤34 °C, 75 vs. 107 mins; p = 0.101; Oesophageal ≤34 °C, 85 vs. 115 mins; p = 0.151). Tympanic temperature dropped significantly with Rhinochill^® in the first hour (1.75 vs. 0.94 °C; p < 0.001). No difference was detected in any other secondary outcome measures. Catheter laboratory-based TH induction resulted in a survival to hospital discharge of 67.1%.ConclusionIn this study, Rhinochill^® was not found to be more efficient than Blanketrol^® for TH induction, although there was a non-significant trend in favour of Rhinochill^® that potentially warrants further investigation with a larger trial.     

Changes in treatments and outcomes among elderly patients with out-of-hospital cardiac arrest between 2002 and 2012: A post hoc analysis of the SOS-KANTO 2002 and 2012

BackgroundLittle is known about recent changes in pre- and in-hospital treatments and outcomes for elderly patients with out-of-hospital cardiac arrest (OHCA).MethodsWe compared data collected for the SOS-KANTO study in 2002 and 2012. We included patients aged ≥65 years who experienced OHCA of cardiac aetiology. The primary endpoint was favourable neurological outcomes 1 month after cardiac arrest.ResultsA total of 8,964 (2002 vs. 2012: 3,544 vs. 5,420) patients were eligible for the current analysis. The proportion of pre-hospital return of spontaneous circulation (ROSC) increased significantly (3.8 vs. 5.6%, p < 0.001). Among patients achieving ROSC, the proportion of advanced in-hospital treatments (i.e. extracorporeal membrane oxygenation, therapeutic hypothermia, and/or percutaneous coronary angiogram/intervention) provided increased significantly in 2012 (1.2 vs. 5.5%, p < 0.001; 2.6 vs. 15.1%, p < 0.001; 4.9 vs. 16.5%, p < 0.001; respectively). The proportion of favourable neurological outcomes at 1 month increased significantly in 2012 (1.6 vs. 2.7%, p = 0.001). A logistic regression analysis that did not consider advanced in-hospital treatments showed a significantly higher rate of favourable neurological outcomes in the 2012 group than that in the 2002 group (OR, 2.2; 95% CI, 1.4–3.5). However, this difference was no longer observed in the second regression model that accounted for advanced in-hospital treatments (OR, 1.6; 95% CI, 0.9–2.9).ConclusionThere was an increased proportion of aggressive treatment, both pre- and in-hospital, for elderly patients with cardiogenic OHCA in the Kanto area, Japan. Favourable neurological outcomes improved significantly over 10 years.     

The influence of post-rewarming temperature management on post-rewarming fever development after cardiac arrest

Aim of the studyWe evaluated the influence of post-rewarming temperature management (PRTM) on post-rewarming fever development and determined the association between the temperature in the immediate post-targeted temperature management (TTM) period and outcomes.MethodsThis retrospective observational study included consecutive adult cardiac arrest survivors treated with TTM from January 2008 to December 2013. Beginning in August 2010, our institution implemented a PRTM protocol involving continued use of temperature management device to maintain normothermia during the first 24 h after rewarming. The outcomes were in-hospital mortality and neurologic outcome at discharge. We evaluated the effect on clinical outcomes of post-rewarming fever defined at a temperature over 38 °C within 48 h after rewarming.ResultsOf 277 included patients, 55.2% underwent PRTM. The incidence of post-rewarming fever did not differ between the PRTM and no-PRTM groups (odds ratio [OR] 0.963, confidence interval [CI] 0.519, 1.787). Post-rewarming fever was associated with decreased in-hospital mortality (OR 0.243, CI 0.110, 0.534) and decreased rate of unfavorable neurologic outcome (OR 0.312, CI 0.182, 0.534). During 48 h following rewarming, mean temperature was 36.5 °C (36.2–36.8 °C), and peak temperature was 37.5 °C (36.8–38.1 °C). On multivariate analyses, lower mean temperature was associated with increased in-hospital mortality (OR 0.099, CI 0.037, 0.262) and unfavorable neurologic outcome (OR 0.071, CI 0.026, 0.193).ConclusionIt appeared that PRTM did not prevent post-rewarming fever development. Post-rewarming fever was associated with favorable outcomes while lower body temperature after rewarming was associated with unfavorable outcomes. Our results require further confirmation by larger prospective studies.     

Qi deficiency is associated with depression in chronic hemodialysis patients

ObjectiveDepression is a common bio-psycho-social problem in hemodialysis (HD) patients. Traditional Chinese medicine has been used for symptom management in patients with depression. Identification of the specific constitution in traditional Chinese medicine is critical for personalized care. However, the association between depression and specific constitution in HD patients is unknown.MethodsWe conducted a cross-sectional study in all chronic HD patients (HD for more than 3 months) at China Medical University Hospital in Taiwan. The depression symptom severity was determined using the Beck Depression Inventory II (BDI-II). Clinical patterns in Chinese medicine were determined using the Constitution in Chinese Medicine Questionnaire. The association between constitution and depression was analyzed using logistic regression.ResultsWe recruited 467 chronic hemodialysis patients, including 219 females and 248 males, with a mean age of 63 ± 12 years. The mean duration of HD was 5.8 years. The mean score for the BDI-II was 11 (interquartile range 8–14). The major constitution was Yang-deficiency (43.7%) among these chronic HD patients. Qi-deficiency was correlated with a duration of HD of more than 5.8 years (p = 0.04). Qi-deficiency [odds ratio (OR): 4.05, 95% confidence interval (CI): 1.69–9.72, p < 0.01] was also associated with depression in logistic regression with adjustments for confounders, including calcium, phosphorus and hemoglobin levels.ConclusionQi-deficiency constitution in Chinese medicine is associated with depression in chronic HD patients. Further studies are needed to determine whether treating Qi-deficiency integrating Chinese medicine treatment can improve patients’ depression symptoms.     

Stealth lipid coated aquasomes bearing recombinant human interferon-α-2b offered prolonged release and enhanced cytotoxicity in ovarian cancer cells

PurposeIn present investigation, recombinant human interferon-α-2b (rhINF-α-2b) loaded aquasomes were prepared, optimized and overlaid with PEGylated phospholipid to offer prolong release and high therapeutic index against ovarian cancer, SKOV3 cells.Methods and resultsCentral Composite Design (CCD) and Response Surface Methodology (RSM) were employed to calculate the optimized conditions, 1:3 core to coat ratio, sonication power of 12.5 W and time of about 55 min for preparation of aquasomes. Consequently, rhINF-α-2b-Py-5-P-Aq.somes exhibited higher protein loading capacity and retained structural conformations of rhINF-α-2b, as compared to rhINF-α-2b-Cellob-Aq.somes, rhINF-α-2b-Tre-Aq.somes and rhINF-α-2b-Core (CaHPO₄). Further, optimized rhINF-α-2b-Py-5-P-Aq.somes was superimposed with phospholipid-PEG₂₀₀₀ to prolong the release pattern of rhINF-α-2b from aquasomes. The rhINF-α-2b-core (CaHPO₄) released 97.3% of protein in 1 h, while 95.3% of rhINF-α-2b was released by rhINF-α-2b-Tre-Aq.somes in 4 h. Concurrently, rhINF-α-2b-Cellob-Aq.somes and rhINF-α-2b-Py-5-P-Aq.somes released 96.2% and 97.8% of rhINF-α-2b respectively in 6 and 8 h. Ultimately, rhINF-α-2b-Py-5-P-Aq.somes-P-PEG₂₀₀₀ displayed evidence of its prolonged release pattern and released 98.1% of rhINF-α-2b in 336 h. FT–IR and XRD substantiated the involvement of vigorous intermolecular hydrogen bonding and amorphous geometry in rhINF-α-2b-Py-5-P-Aq.somes. In last, rhINF-α-2b-Py-5-P-Aq.somes-P-PEG₂₀₀₀ exhibited the ∼ 4.55, 1.92, 2.3, 2.8, and 3.84 fold reductions in IC₅₀ as compared to free rhINF-α-2b, rhINF-α-2b-Py-5-P-Aq.somes, rhINF-α-2b-Cellob-Aq.somes, rhINF-α-2b-Tre-Aq.somes and rhINF-α-2b-Core (CaHPO₄), respectively.ConclusionTherefore, rhINF-α-2b-Py-5-P-Aq.somes-P-PEG₂₀₀₀ warrant further in depth in vitro and in vivo antitumor study to scale up the technology for clinical intervention.     

Outcome and risk factors in children after traumatic cardiac arrest and successful resuscitation

IntroductionProspective collected data of the TraumaRegister DGU^® were analyzed to derive survival rates and predictors for non-survival in the children who had suffered traumatic cardiorespiratory arrest. Different time points of resuscitation efforts (only preclinical, in the emergency room (ER) or preclinical + ER) were analyzed in terms of mortality and neurological outcome.MethodsThe database of the TraumaRegister DGU^® comprising 122,742 patients from 1993 to 2013 was analyzed. The main focus of this survey was on the paediatric group defined by an age ≤14 years who could be compared to adults. Different statistical analysis (univariate and multivariate analysis, logistic regression) were performed with mortality as the target variable. Differences between the paedatric group and adults were analysed by Fisher's exact test.ResultsData after preclinical and/or ER resuscitation from 152 children and 1690 adults were analyzed. A good or moderate outcome (GOS 5 + 4) was found in 19.4% of the children's group compared to 12.4% of the adults (p = 0.02).Analysis of the GOS 5 + 4 subgroups after preclinical resuscitation only revealed that these outcomes were achieved by 19.4% of the paediatric group and 13.2% of the adults (p = 0.24), after ER-only resuscitation by 37.0% of the children and 19.6% of the adults (p = 0.046), and after preclinical and ER resuscitation by only 10.9% of the children compared to 2.5% of the adults (p = 0.006). Taking only survivors into account, 84.8% of the children and 62% of the adults had a GOS 4 + 5.The highest risk for mortality in the logistic regression model was associated with preclinical intubation, followed by GCS 3, blood transfusion and severe head injury with AIS ≥3 and ISS.ConclusionsCPR in children after severe trauma seems to yield a better outcome than in adults, and appears to be more justified than the current guidelines would imply. Resuscitation in the ER is associated with better neurological outcomes compared with resuscitation in a preclinical context or in both the preclinical phase and the ER. Our children's outcomes seem to be better than those in most of the earlier studies, and the data presented might support algorithms in the future especially for paediatric resuscitation.     

Smoothened activates breast cancer stem-like cell and promotes tumorigenesis and metastasis of breast cancer

Smoothened (Smo) is a G protein-coupled receptor protein encoded by the Smo gene of the hedgehog signalling pathway, which is thought to play an important role in maintaining organ patterning, cell differentiation and self-renewal. The possible role of Smo in the process of tumorigenesis and metastasis of breast cancer still remains unclear. The present experiments were to investigate the effect of Smo on activating breast cancer stem-like CD44⁺CD24⁻ cells and the tumorigenesis and metastasis of breast cancer. By injected CD44⁺CD24⁻ cells (1 × 10⁴) into the cleared fat pad of NOD/SCID mice, it was observed that CD44⁺CD24⁻ cells possess higher tumor-initiating capacity and metastasis properties than equal numbers of non-CD44⁺CD24⁻ cells. The mRNA and protein expressions of Smo in CD44⁺CD24⁻ cells were higher than those in non-CD44⁺CD24⁻ cells, indicating that Smo may play a role in maintaining breast cancer stem cell features. qRT–PCR results revealed that expressions of STAT3, Bcl-2 and cyclinD1 mRNA in MCF-7 cells were decreased after transfected by Smo siRNA. In addition, the expressions of MMP-2 and MMP-9 were downregulated in MCF-7 cells after Smo expression was inhibited. Smo inhibition may be a possible therapeutic target that potentially suppresses breast tumor formation and development.     

Prognostic values of gray matter to white matter ratios on early brain computed tomography in adult comatose patients after out-of-hospital cardiac arrest of cardiac etiology

Aim of the studyPrevious studies found that the gray matter to white matter ratio (GWR) on brain computed tomography (CT) could be used to predict poor outcomes in cardiac arrest survivors. However, these studies have included cardiac arrests of both cardiac and non-cardiac etiologies. We sought to evaluate if the GWR on brain CT can help to predict poor outcomes after out-of-hospital cardiac arrest (OHCA) of cardiac etiology.MethodsUsing a multicenter retrospective registry of adult cardiac arrest survivors treated with therapeutic hypothermia, we identified survivors of OHCA of cardiac etiology who underwent brain CT within 24 h after successful resuscitation. Gray and white matter attenuations were measured, and the GWRs were calculated as in previous studies. The prognostic values of the GWRs were analyzed, and a logistic regression analysis was performed to determine the contribution of the GWR in predicting poor outcomes (Cerebral Performance Category 3–5).Resultsof 283 included patients, 140 had good outcomes and 143 had poor outcomes. Although the GWRs could predict poor outcomes with statistical significance, the sensitivities were remarkably low (3.5% to 5.6%) at cutoff values with 100% specificity. No significant difference in predictive performance was found between the primary predictive model, containing independent poor outcome predictors, and the primary predictive model combined with the GWR.ConclusionIn a cohort of comatose adults after OHCA of cardiac etiology, the GWR demonstrated poor predictive performance and was not helpful in predicting poor outcomes.     

Clinical and Histologic Findings in Patients With Uveal Melanomas After Taking Tumor Necrosis Factor-α Inhibitors

ObjectiveTo describe the progression of uveal melanocytic lesions to melanomas after initiation of tumor necrosis factor-α (TNF-α) inhibitors.Patients and MethodsWe report 3 cases of uveal melanoma occurring after treatment with TNF-α inhibitors, 2 from Mayo Clinic and 1 from Yale University. The study took place from February 27, 2009, through July 15, 2013.ResultsTwo women and one man with inflammatory disease who received TNF-α inhibitors had subsequent development of uveal melanomas. The 2 women had inflammatory bowel disease and had been followed up for melanocytic tumors that grew markedly within 1 year after beginning treatment with TNF-α inhibitors to the point of requiring treatment. One had histologic confirmation of the melanoma. The male patient had rheumatoid arthritis that was being treated with TNF-α inhibitors. Serial ultrasonography was performed to monitor bilateral diffuse scleritis, and within 16 months of initiation of TNF-α inhibitor therapy, a choroidal mass was detected that continued to grow over the next 3 months. The patient elected to have enucleation, which revealed uveal melanoma and thinning of the sclera from the previous scleritis.ConclusionOur 3 cases of uveal melanocytic tumors occurring after the use of TNF-α inhibitors add to the growing literature suggesting a correlation between TNF-α inhibitors and the development of malignant neoplasms. Considering the association between cutaneous melanoma and TNF-α inhibitors, we recommend that patients have an eye examination before initiation of TNF-α inhibitors, and those with preexisting nevi should be followed up at regular intervals.     

Isometric Exercise Training for Blood Pressure Management: A Systematic Review and Meta-analysis

ObjectiveTo conduct a systematic review and meta-analysis quantifying the effects of isometric resistance training on the change in systolic blood pressure(SBP), diastolic blood pressure (DBP), and mean arterial pressure in subclinical populations and to examine whether the magnitude of change in SBP and DBP was different with respect to blood pressure classification.Patients and MethodsWe conducted a systematic review and meta-analysis of randomized controlled trials lasting 4 or more weeks that investigated the effects of isometric exercise on blood pressure in healthy adults (aged ≥18 years) and were published in a peer-reviewed journal. PubMed, CINAHL, and the Cochrane Central Register of Controlled Trials were searched for trials reported between January 1, 1966, and July 31, 2013. We included 9 randomized trials, 6 of which studied normotensive participants and 3 that studied hypertensive patients, that included a total of 223 participants (127 who underwent exercise training and 96 controls).ResultsThe following reductions were observed after isometric exercise training: SBP—mean difference (MD), −6.77 mm Hg (95% CI, −7.93 to −5.62 mm Hg; P<.001); DBP—MD, −3.96 mm Hg (95% CI, −4.80 to −3.12 mm Hg; P<.001); and mean arterial pressure—MD, −3.94 mm Hg (95% CI, −4.73 to −3.16 mm Hg; P<.001). A slight reduction in resting heart rate was also observed (MD, −0.79 beats/min; 95% CI, −1.23 to −0.36 beats/min; P=.003).ConclusionIsometric resistance training lowers SBP, DBP, and mean arterial pressure. The magnitude of effect is larger than that previously reported in dynamic aerobic or resistance training. Our data suggest that this form of training has the potential to produce significant and clinically meaningful blood pressure reductions and could serve as an adjunctive exercise modality.     

A new choice of stent for transjugular intrahepatic portosystemic shunt creation: Viabahn ePTFE covered stent/bare metal stent combination

ObjectivesTo compare the clinical outcomes in terms of structure and function between the insertion of a transjugular intrahepatic portosystemic shunt (TIPS) created with the Viabahn ePTFE covered stent/bare metal stent (BMS) combination and the Fluency ePTFE covered stent/BMS combination.MethodsA total of 101 consecutive patients who received a TIPS from February 2016 to August 2018 in our center were retrospectively analyzed. Sixty-four subjects were enrolled in the Viabahn group and 37 were enrolled in the Fluency group. The geometry characteristics of the TIPS were calculated, and the associated occurrence of shunt dysfunction, survival, overt hepatic encephalopathy, and variceal rebleeding were evaluated.ResultsThe technical success rate was 100%. After the insertion of the TIPS, the rate of shunt dysfunction during the first 3 months was significantly different between the Viabahn and Fluency groups (1.6% and 13.5%, respectively; p ​= ​0.024). Multivariate analysis indicated that the angle of portal venous inflow (α) was the only independent risk factor for shunt dysfunction (hazard ratio ​= ​1.060, 95% confidence interval ​= ​1.009–1.112, p ​= ​0.020). In addition, 3 months after the TIPS insertion, the α angle distinctly increased from 20.9° ​± ​14.3°–26.9° ​± ​20.1° (p ​= ​0.005) in the Fluency group but did not change significantly in the Viabahn group (from 21.9° ​± ​15.1°–22.9° ​± ​17.6°, p ​= ​0.798).ConclusionsShunt dysfunction was related to the α angle owing to the slight effect on the α angle after the implantation of the TIPS. The Viabahn ePTFE covered stent/BMS combination was more stable in structure and promised higher short-term stent patency compared with the Fluency ePTFE covered stent/BMS combination.     

Body Composition and Mortality in a Large Cohort With Preserved Ejection Fraction: Untangling the Obesity Paradox

ObjectiveTo evaluate the effects of body composition as a function of lean mass index (LMI) and body fat (BF) on the correlation between increasing body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared) and decreasing mortality, which is known as the obesity paradox.Patients and MethodsWe retrospectively assessed 47,866 patients with preserved left ventricular ejection fraction (≥50%). We calculated BF by using the Jackson-Pollock equation and LMI using (1 − BF) × BMI. The population was divided according to the sex-adjusted BMI classification, sex-adjusted LMI classification, and sex-adjusted BF tertiles. The population was analyzed by using multivariate analysis for total mortality over a mean follow-up duration of 3.1 years by using the National Death Index, adjusting for left ventricular ejection fraction, left ventricular mass index, age, sex, and relative wall thickness.ResultsIn the entire population, higher BMI was narrowly associated (hazard ratio [HR], 0.99; P<.001) with lower mortality. The higher LMI group was clearly protective (HR, 0.71; P<.001), whereas BF tertile was associated with lower mortality only if no adjustment was made for LMI (HR, 0.87; P<.001 without LMI; HR, 0.97; P=.23 with LMI). In the lean patients, low BMI was clearly associated with higher mortality (HR, 0.92; P<.001) and lower BF tertile was associated with lower mortality only if no adjustment was made for LMI (HR, 0.80; P<.001 without LMI; HR, 1.01; P=.83 with LMI). The underweight patients stratified by BF seemed to have an increased mortality (HR, 1.91; 95% CI, 1.56-2.34) that was independent of LMI. However, in obese patients, both BMI (HR, 1.03; P<.001) and BF (HR, 1.18; P=.003) were associated with higher mortality, even after adjusting for LMI, which remained protective (HR, 0.57; P<.001) independently of BF.ConclusionBody composition could explain the inverse J shape of the mortality curve noted with increasing BMI. Body fat seems to be protective in this cohort only if no adjustment was made for LMI, although being underweight stratified by BF seems to be an independent risk factor. Lean mass index seems to remain protective in obese patients even when BMI is not.     

Experimental study of the efficacy of linezolid alone and in combinations against experimental meningitis due to Staphylococcus aureus strains with decreased susceptibility to beta-lactams and glycopeptides

BackgroundTo evaluate in vitro and in vivo efficacies of linezolid, vancomycin, and the combination of linezolid and rifampicin against two Staphylococcus aureus strains with reduced susceptibility to beta-lactams and one of them also to glycopeptides.MethodsIn vitro killing curves and a rabbit model: Meningitis was induced by intracisternal inoculation of 10⁸ CFU/ml of each strain. Five hours later (0 h), rabbits were randomly assigned to control or to therapeutic groups. CSF bacterial counts, lactate and protein concentrations, and pharmacokinetic parameters were determined.ResultsIn vivo: linezolid and its combination with rifampicin reduced bacterial concentrations at 24 h, median cfu/mL 4.85 vs 3.87 (p < 0.05) for linezolid and 5.02 vs 4.21 (p < 0.05) for linezolid + rifampicin, against the glycopeptide intermediate S. aureus (GISA) strain and improved inflammatory parameters.ConclusionsDespite the need for more experimental data, our results suggest that linezolid and its combinations could be considered as a potential alternative in difficult-to-treat CNS infections and especially in those due to GISA strains and deserve more studies.     

Incidence of Leukocytoclastic Vasculitis, 1996 to 2010: A Population-Based Study in Olmsted County,Minnesota

ObjectiveTo determine the population-based incidence of leukocytoclastic vasculitis (LCV).Patients and MethodsThis is a retrospective population-based study of all Olmsted County, Minnesota, residents with a skin biopsy–proven diagnosis of LCV from January 1, 1996, through December 31, 2010.ResultsA total of 84 patients (mean age at diagnosis, 48.3 years) with newly diagnosed skin biopsy–proven LCV (43 women and 41 men) were identified. The incidence rate (age and sex adjusted to the 2000 US white population) was 4.5 per 100,000 person-years (95% CI, 3.5-5.4). The incidence of LCV increased significantly with age at diagnosis (P<.001) and did not differ between female and male patients. Subtypes of LCV were cutaneous small-vessel vasculitis (CSVV), 38 patients (45%); IgA vasculitis, 25 (30%); urticarial vasculitis, 10 (12%); cryoglobulinemic vasculitis, 3 (4%); and antineutrophil cytoplasmic antibody–associated vasculitis, 8 (10%). LCV was idiopathic in 29 of 38 patients with CSVV (76%) and 24 of 25 patients with IgA vasculitis (96%). Thirty-nine of 84 patients (46%) had systemic involvement, with the renal system most commonly involved (17 of 39 [44%]). Twenty-four of 80 patients (30%) with follow-up data available had recurrent disease. Compared with the Minnesota white population, observed survival in the incident LCV cohort was significantly poorer than expected (P<.001), including the subset of patients with idiopathic CSVV (P=.03).ConclusionThe incidence of LCV was higher than that reported in previously published studies. Idiopathic LCV was more common in our population-based cohort than that described previously. Overall survival was significantly poorer (P<.001) and should be explored further in future studies.     

Association of Dysglycemia and All-Cause Mortality Across the Spectrum of Coronary Artery Disease

ObjectiveTo assess the association between fasting plasma glucose (FPG) and all-cause mortality across the spectrum of coronary artery disease (CAD).Patients and MethodsThe study included 18,999 patients during a study period of April 1, 2004, through October 31, 2010. The primary end points were in-hospital and follow-up all-cause mortality. According to the quartiles of FPG levels, patients were categorized into 4 groups: quartile 1, less than 5.1 mmol/L; quartile 2, 5.1 to less than 5.9 mmol/L; quartile 3, 5.9 to less than 7.5 mmol/L; and quartile 4, 7.5 mmol/L or greater. The conversion factor for units of plasma glucose is 1.00 mmol/L equals 18 mg/dL. Presented as mg/dL, the 4 quartile ranges of plasma glucose concentrations used in our data analysis are ≤90.0 mg/dL, 90.1-106.0 mg/dL, 106.1 mg/dL-135.0 mg/dL and ≥135.1 mg/dL. Quartile 1 was recognized as the lower glycemic group, quartiles 2 and 3 as the normoglycemic groups, and quartile 4 as the higher glycemic group.ResultsIn patients with acute myocardial infarction, all-cause mortality for the dysglycemic groups was higher than for the normoglycemic groups: in-hospital mortality for quartiles 1, 2, 3, and 4 was 1.0%, 0.9%, 0.2%, and 1.5%, respectively (P=.001); follow-up mortality for quartiles 1, 2, 3, and 4 was 1.7%, 0.9%, 0.3%, and 1.8%, respectively (P<.001). In patients with stable CAD, no significant differences in mortality were found among groups. However, in patients with unstable angina pectoris, the normoglycemic groups had lower follow-up mortality and roughly equal in-hospital mortality compared with the dysglycemic groups. After adjusting for confounding factors, this observation persisted.ConclusionThe association between lower FPG level and mortality differed across the spectrum of CAD. In patients with acute myocardial infarction, there was a U-shaped relationship. In patients with stable CAD or unstable angina pectoris, mildly to moderately decreasing FPG level was associated with neither higher nor lower all-cause mortality.     

Quinoline: A promising antitubercular target

Tuberculosis (TB) remains a global public health problem in recent years. TB originated mainly from various strains of Mycobacterium tuberculosis, is a highly infectious and chronic disease with high infection rate since ancient times. Since the last 50 years, the same long-duration, multidrug treatment plan is being followed for the treatment of tuberculosis. Due to the development of resistance to conventional antibiotics there is a need for new therapeutic strategies to combat M. tuberculosis. Subsequently, there is an urgent need for the development of new drug molecules with newer targets and with an alternative mechanism of action. Among hetrocyclic compounds, quinoline compounds are important privileged structure in medicinal chemistry, are widely used as “parental” compounds to synthesize molecules with medical benefits, especially with anti-malarial and anti-microbial activities. Certain, quinoline-based compounds, also show effective anti-TB activity. This broad spectrum of biological and biochemical activities has been further facilitated by the synthetic versatility of quinoline, which allows the generation of a large number of structurally diverse derivatives. To pave the way for future research, there is a need to collect the latest information in this promising area. In the present review, we have collated published reports on this versatile core to provide an insight so that its full therapeutic potential can be utilized for the treatment tuberculosis. It is hoped that, this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic quinoline-based anti-TB drugs.