Effects of sirolimus on plasma lipids,lipoprotein levels,and fatty acid metabolism in renal transplant patients

Sirolimus (Rapammune, rapamycin, RAPA) is a potent immunosuppressive drug that reduces renal transplant rejection. Hyperlipidemia is a significant side effect of sirolimus treatment, and frequently leads to cardiovascular disease. This study was undertaken to determine the repeatability, reversibility, and dose dependence of the plasma lipid and apolipoprotein altering effects of sirolimus, and to elucidate the mechanism by which sirolimus induces hypertriglyceridemia in some renal transplant patients. Six patients with renal allografts maintained on cyclosporine A and prednisone were selected on the basis of their previous hyperlipidemic response to short term (14 days) sirolimus administration. For longer-term treatment, each patient was started on 10 mg/day sirolimus and continued as tolerated for 42 days to reinduce hyperlipidemia. Timed blood samples were analyzed for lipid, apolipoprotein, and sirolimus levels. During sirolimus administration, mean total plasma cholesterol increased from 214 mg/dl to 322 mg/dl (+50%; range 25-92%); LDL-cholesterol levels followed a similar pattern. Mean triglyceride level rose from 227 to 432 mg/dl (+95%; range 9-254%). ApoB-100 concentration rose from 124 to 160 mg/dl (+28%; P < 0.05). ApoC-III level increased from 28.9 to 55.5 mg/dl, +92%; (P < 0.013). These lipid and apolipoprotein changes were found to be repeatable, reversible, and dose dependent. [(13)C(4)]palmitate metabolic studies in four patients with hypertriglyceridemia indicated that the free fatty acid pool was expanded by sirolimus treatment (mean = 42.3%). Incorporation of [(13)C(4)]palmitate into triglycerides of VLDL, IDL, and LDL was decreased 38.3%, 42,1%, and 38.4%, respectively, by sirolimus treatment of these patients. These results suggest that sirolimus alters the insulin signaling pathway so as to increase adipose tissue lipase activity and/or decrease lipoprotein lipase activity, resulting in increased hepatic synthesis of triglyceride, increased secretion of VLDL, and increased hypertriglyceridemia.     

Designing Alginate/Chitosan Nanoparticles Containing Echinacea angustifolia: A Novel Candidate for Combating Multidrug-Resistant Staphylococcus aureus

Nanoparticles (NPs) may help treat multidrug-resistant Staphylococcus aureus (MDR). This study prepared and evaluated chitosan/alginate-encapsulated Echinacea angustifolia extract against MDR strains. Evaluating synthesized NPs with SEM, DLS, and FT-IR. Congo red agar and colorimetric plate techniques examined isolate biofilm formation. NP antibacterial power was assessed using well diffusion. Real-time PCR assessed biofilm-forming genes. MTT assessed the synthesized NPs′ toxicity. According to DLS measurements, spherical E. angustifolia NPs had a diameter of 335.3±1.43 nm. The PDI was 0.681, and the entrapment effectiveness (EE%) of the E. angustifolia extract reached 83.45 %. Synthesized NPs were most antimicrobial. S. aureus resistant to several treatments was 80 percent of 100 clinical samples. Biofilm production was linked to MDR in all strains. The ALG/CS-encapsulated extract had a 4 to 32-fold lower MIC than the free extract, which had no bactericidal action. They also significantly decreased the expression of genes involved in biofilm formation. E. angustifolia-encapsulated ALG/CS decreased IcaD, IcaA, and IcaC gene expression in all MDR strains (***p<0.001). Free extract, free NPs, and E. angustifolia-NPs had 57.5 %, 85.5 %, and 90.0 % cell viability at 256 μg/ml. These discoveries could assist generate stable plant extracts by releasing natural-derived substances under controlled conditions.     

High Urinary Tungsten Concentration Is Associated with Stroke in the National Health and Nutrition Examination Survey 1999–2010

Background

In recent years there has been an exponential increase in tungsten demand, potentially increasing human exposure to the metal. Currently, the toxicology of tungsten is poorly understood, but mounting evidence suggests that both the elemental metal and its alloys have cytotoxic effects. Here, we investigate the association between tungsten and cardiovascular disease (CVD) or stroke using six waves of the National Health and Nutrition Examination Survey (NHANES).

Methods

We investigated associations using crude and adjusted logistic regression models in a cohort of 8614 adults (18–74 years) with 193 reported stroke diagnoses and 428 reported diagnoses of CVD. We also stratified our data to characterize associations in a subset of younger individuals (18–50 years).

Results

Elevated tungsten concentrations were strongly associated with an increase in the prevalence of stroke, independent of typical risk factors (Odds Ratio (OR): 1.66, 95% Confidence Interval (95% CI): 1.17, 2.34). The association between tungsten and stroke in the young age category was still evident (OR: 2.17, 95% CI: 1.33, 3.53).

Conclusion

This study represents the most comprehensive analysis of the human health effects of tungsten to date. Individuals with higher urinary tungsten concentrations have double the odds of reported stroke. We hypothesize that the pathological pathway resulting from tungsten exposure may involve oxidative stress.     

Dosimetry of small photon fields in the presence of bone heterogeneity using MAGIC polymer gel,Gafchromic film,and Monte Carlo simulation

BackgroundThe presence of heterogeneity within the radiation field increases the challenges of small field dosimetry. In this study, the performance of MAGIC polymer gel was evaluated in the dosimetry of small fields beyond bone heterogeneity.Materials and methodsCircular field sizes of 5, 10, 20 and 30 mm were used and Polytetrafluoroethylene with density of 2.2 g/cm³ was used as the bone equivalent material. The PDD curves, beam profiles, and penumbra widths were measured using MAGIC polymer gel, EBT2 film, and Monte Carlo simulation.ResultsThe maximum differences between MAGIC and EBT2 are 6.1, 4.7, 2.4, and 2.2 for PDD curves at 5, 10, 20, and 30 mm circular fields, respectively. The dose differences and distance to agreement between MAGIC and MC were within 1.89%/0.46 mm, 1.66%/0.43 mm, 1.28%/0.77 mm, and 1.31%/0.81 mm for beam profile values behind bone heterogeneity at 5, 10, 20, and 30 mm field sizes, respectively.ConclusionThe results presented that the MAGIC polymer gel dosimeter is a proper instrument for dosimetry beyond high density heterogeneity.     

Mutations responsible for high light sensitivity in an atrazine-resistant mutant of Synechcystis 6714

The primary target of photoinhibition is the photosystem II reaction center. The process involves a reversible damage, followed by an irreversible inhibition of photosystem II activity. During cell exposition to high light intensity, the D₁ protein is specially degraded. An atrazine-resistant mutant of Synechocystis 6714, AzV, reaches the irreversible step of photoinhibition faster than wild-type cells. Two point mutations present in the psbA gene of AzV (coding for D₁) lead to the modification of Phe 211 to Ser and Ala 251 to Val in D₁. Transformation of wild-type cells with the AzV psbA gene shows that these two mutations are sufficient to induce a faster photodamage of PSII. Other DCMU-and/or atrazine-resistant mutants do not differ from the wild type when photoinhibited. We conclude that the Q_B pocket is involved in PSII photodamage and we propose that the mutation of Ala 251 might be related to a lower rate of proteolysis of the D₁ protein than in the wild type.Abbreviations DCMU 3-(3,4-dichlorophenyl)-1,1-dimethylurea - PSII photosystem II - RCII reaction center II     

Substituted thiazoles VII. Synthesis and antitumor activity of certain 2-(substituted amino)-4-phenyl-1,3-thiazole analogs

A novel series of 2-acetamido- or 2-propanamido-4-(4-substituted phenyl)-1,3-thiazoles (11–34) was designed and synthesized. Compounds were subjected to National Cancer Institute (NCI) in vitro assessment for their antitumor activity, at a single dose of 10 μM. Most of the investigated compounds exhibited broad-spectrum antitumor activity. Compounds 19 and 28 believed to be the most active members in this study, with MG-MID GI₅₀, TGI, and LC₅₀ values of 2.8, 11.4, 44.7; and 3.3, 13.1, 46.8, respectively. Compounds 19 and 28 proved to be nine and sevenfold more active than the standard antitumor drug 5-FU, respectively.     

Optimization of phytase production by Penicillium purpurogenum GE1 under solid state fermentation by using Box–Behnken design

Phytase production by Penicillium purpurogenum GE1 isolated from soil around bean root nodules was investigated by solid state fermentation (SSF) using mixed substrates consisted of corn cob and corn bran. The SSF conditions were optimized by using one-variable–at-a-time strategy. The optimum conditions for phytase production were at 27 °C, pH 8 and 66% moisture content. The study of different carbon and nitrogen sources revealed that glucose and peptone registered the highest enzyme productivity (92 ± 5.6 U/g ds, 125 ± 4.9 U/g ds). Among different surfactants, maximum phytase productivity was observed with Tween 80 at 0.001 concentrations (170 ± 4.2 U/g ds). A Box–Behnken design was employed to investigate the optimization of the most significant variables affecting the enzyme production. Maximal phytase production was detected after the addition of (g/5 g ds): 0.75 glucose, 0.375 peptone and 0, 01 tween 80. This result represented an improvement in phytase production of 2.6 folds when compared to that previously obtained using the basal medium under the same cultivation conditions. The generated model was found to be very adequate for phytase production (90% accuracy) as the experimental value was 444 ± 3.5 U/g ds compared to 401 U/g ds for the predicted value. In brief, the production of phytase using corn cob and corn bran is a novel and cheap way for the production of this important enzyme and opens a new way for researchers to discover and explore this arena.     

A Systematic Review of Recent Clinical Practice Guidelines on the Diagnosis,Assessment and Management of Hypertension

Background

Despite the availability of clinical practice guidelines (CPGs), optimal hypertension control is not achieved in many parts of the world; one of the challenges is the volume of guidelines on this topic and their variable quality. To systematically review the quality, methodology, and consistency of recommendations of recently-developed national CPGs on the diagnosis, assessment and the management of hypertension.

Methodology/Principal Findings

MEDLINE, EMBASE, guidelines'' websites and Google were searched for CPGs written in English on the general management of hypertension in any clinical setting published between January 2006 and September 2011. Four raters independently appraised each CPG using the AGREE-II instrument and 2 reviewers independently extracted the data. Conflicts were resolved by discussion or the involvement of an additional reviewer. Eleven CPGs were identified. The overall quality ranged from 2.5 to 6 out of 7 on the AGREE-II tool. The highest scores were for “clarity of presentation” (44.4% −88.9%) and the lowest were for “rigour of development” (8.3%–30% for 9 CGPs). None of them clearly reported being newly developed or adapted. Only one reported having a patient representative in its development team. Systematic reviews were not consistently used and only 2 up-to-date Cochrane reviews were cited. Two CPGs graded some recommendations and related that to levels (but not quality) of evidence. The CPGs'' recommendations on assessment and non-pharmacological management were fairly consistent. Guidelines varied in the selection of first-line treatment, adjustment of therapy and drug combinations. Important specific aspects of care (e.g. resistant hypertension) were ignored by 6/11 CPGs. The CPGs varied in methodological quality, suggesting that their implementation might not result in less variation of care or in better health-related outcomes.

Conclusions/Significance

More efforts are needed to promote the realistic approach of localization or local adaptation of existing high-quality CPGs to the national context.