Effect of l-Arginine on Human Coronary Endothelium-Dependent and Physiologic Vasodilation

AbstractObjectives. We hypothesized that l-arginine would improve abnormal coronary vasodilation in response to physiologic stress in patients with atherosclerosis and its risk factors by reversing coronary endothelial dysfunction.Background. Studies have demonstrated that physiologic coronary vasodilation correlates with endothelial function and that l-arginine, the substrate for nitric oxide synthesis, improves the response to acetylcholine (Ach).Methods. Changes in coronary blood flow and epicardial diameter response to Ach, adenosine and cardiac pacing were measured in 32 patients with coronary atherosclerosis or its risk factors and in 7 patients without risk factors and normal coronary angiograms.Results. Intracoronary l-arginine did not alter baseline coronary vascular tone, but the epicardial and microvascular responses to Ach were enhanced (both p < 0.001). The improvement after l-arginine was greater in epicardial segments that initially constricted with Ach; similarly, l-arginine abolished microvascular constriction produced by higher doses of Ach. Thus, there was a negative correlation between the initial epicardial and vascular resistance responses to Ach and the magnitude of improvement with l-arginine (r = −0.55 and r = −0.50, respectively, p < 0.001). d-Arginine did not affect the responses to Ach, and adenosine responses were unchanged with l-arginine. Cardiac pacing-induced epicardial constriction was abolished by l-arginine, but microvascular dilation remained unaffected.Conclusions. Thus, l-arginine improved endothelium-dependent coronary epicardial and microvascular function in patients with endothelial dysfunction. Prevention of epicardial constriction during physiologic stress by l-arginine in patients with endothelial dysfunction may be of therapeutic value in the treatment of myocardial ischemia

Antigenic and structural differences among six proteins II expressed by a single strain of Neisseria gonorrhoeae.

Gonococci express a family of related outer membrane proteins designated protein II (P.II), which undergo both phase and antigenic variation. Six P.II proteins have been identified in strain FA1090. We developed monoclonal antibodies specific for each P.II protein. Using these antibodies as probes, we purified the six different P.II proteins of this strain. Despite the relatedness of the proteins, we could not purify all of them by a single purification scheme. Four P.II proteins were purified by chromatofocusing, and the remaining two proteins were purified by hydrophobic interaction chromatography on phenyl-Sepharose. The N-terminal amino acid sequence of the proteins showed a high degree of sequence conservation. However, there was variability at specific amino acid residues, giving each P.II protein a unique N-terminal amino acid sequence. Thus P.II proteins of one strain differ among themselves not only in antigenic determinants and primary structure, but also in other characteristics affecting their properties in different chromatographic systems

Multimodal x-ray and electron microscopy of the Allende meteorite.

Multimodal microscopy that combines complementary nanoscale imaging techniques is critical for extracting comprehensive chemical, structural, and functional information, particularly for heterogeneous samples. X-ray microscopy can achieve high-resolution imaging of bulk materials with chemical, magnetic, electronic, and bond orientation contrast, while electron microscopy provides atomic-scale spatial resolution with quantitative elemental composition. Here, we combine x-ray ptychography and scanning transmission x-ray spectromicroscopy with three-dimensional energy-dispersive spectroscopy and electron tomography to perform structural and chemical mapping of an Allende meteorite particle with 15-nm spatial resolution. We use textural and quantitative elemental information to infer the mineral composition and discuss potential processes that occurred before or after accretion. We anticipate that correlative x-ray and electron microscopy overcome the limitations of individual imaging modalities and open up a route to future multiscale nondestructive microscopies of complex functional materials and biological systems

CLUE: a randomized comparative effectiveness trial of IV nicardipine versus labetalol use in the emergency department

Abstract Introduction Our purpose was to compare the safety and efficacy of food and drug administration (FDA) recommended dosing of IV nicardipine versus IV labetalol for the management of acute hypertension. Methods Multicenter randomized clinical trial. Eligible patients had 2 systolic blood pressure (SBP) measures ≥180 mmHg and no contraindications to nicardipine or labetalol. Before randomization, the physician specified a target SBP ± 20 mmHg (the target range: TR). The primary endpoint was the percent of subjects meeting TR during the initial 30 minutes of treatment. Results Of 226 randomized patients, 110 received nicardipine and 116 labetalol. End organ damage preceded treatment in 143 (63.3%); 71 nicardipine and 72 labetalol patients. Median initial SBP was 212.5 (IQR 197, 230) and 212 mmHg (IQR 200,225) for nicardipine and labetalol patients (P = 0.68), respectively. Within 30 minutes, nicardipine patients more often reached TR than labetalol (91.7 vs. 82.5%, P = 0.039). Of 6 BP measures (taken every 5 minutes) during the study period, nicardipine patients had higher rates of five and six instances within TR than labetalol (47.3% vs. 32.8%, P = 0.026). Rescue medication need did not differ between nicardipine and labetalol (15.5 vs. 22.4%, P = 0.183). Labetalol patients had slower heart rates at all time points (P \u3c 0.01). Multivariable modeling showed nicardipine patients were more likely in TR than labetalol patients at 30 minutes (OR 2.73, P = 0.028; C stat for model = 0.72) Conclusions Patients treated with nicardipine are more likely to reach the physician-specified SBP target range within 30 minutes than those treated with labetalol. Trial registration ClinicalTrials.gov: NCT0076564

Effects of Canagliflozin in Patients with Baseline eGFR:Subgroup Analysis of the Randomized CREDENCE Trial

BACKGROUND AND OBJECTIVES: The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin reduced the risk of kidney failure and cardiovascular events in participants with type 2 diabetes mellitus and CKD. Little is known about the use of SGLT2 inhibitors in patients with eGFR 300-5000 mg/g, and an eGFR of 30 to 0.20). The estimate for kidney failure in participants with eGFR 0.12). CONCLUSIONS: This post hoc analysis suggests canagliflozin slowed progression of kidney disease, without increasing AKI, even in participants with eGFR <30 ml/min per 1.73 m2

Kidney, Cardiovascular, and Safety Outcomes of Canagliflozin according to Baseline Albuminuria:A CREDENCE Secondary Analysis

BACKGROUND AND OBJECTIVES: The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study enrolled 4401 participants with type 2 diabetes, an eGFR of 30 to 300 to 5000 mg/g. Using Cox proportional hazards regression, we examined the relative and absolute effects of canagliflozin on kidney, cardiovascular, and safety outcomes according to a baseline UACR of ≤1000 mg/g (n=2348), >1000 to 1000 to <3000 mg/g, and 37% (HR, 0.63; 95% CI, 0.47 to 0.84) in the highest subgroup (Pheterogeneity=0.55). Absolute risk reductions for kidney outcomes were greater in participants with higher baseline albuminuria; the number of primary composite events prevented across ascending UACR categories were 17 (95% CI, 3 to 38), 45 (95% CI, 9 to 81), and 119 (95% CI, 35 to 202) per 1000 treated participants over 2.6 years (Pheterogeneity=0.02). Rates of kidney-related adverse events were lower with canagliflozin, with a greater relative reduction in higher UACR categories. CONCLUSIONS: Canagliflozin safely reduces kidney and cardiovascular events in people with type 2 diabetes and severely increased albuminuria. In this population, the relative kidney benefits were consistent over a range of albuminuria levels, with greatest absolute kidney benefit in those with an UACR ≥3000 mg/g. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov: CREDENCE, NCT02065791. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_22_CJN15260920_final.mp3

Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease