Mechanism For Copper(II)-Mediated Disaggregation Of A Porphyrin J-Aggregate

J-aggregates of anionic meso-tetrakis(4-sulfonatophenyl)porphyrin form at intermediate pH (2.3–3.1) in the presence of NiSO₄ or ZnSO₄ (ionic strength, I.S. = 3.2 M). These aggregates convert to monomeric porphyrin units via metallation with copper(II) ions. The kinetics for the disassembly process, as monitored by UV/vis spectroscopy, exhibits zeroth-order behavior. The observed zeroth-order rate constants show a two-term dependence on copper(II) ion concentrations: linear and second order. Also observed is an inverse dependence on hydrogen ion concentration. Activation parameters have been determined for the disassembly process leading to ΔH^≠ = (+163 ± 15) kJ·mol⁻¹ and ΔS^≠ = (+136 ± 11) J·K⁻¹. A mechanism is proposed in which copper(II) cation is in pre-equilibrium with a reactive site at the rim of the J-aggregate. An intermediate copper species is thus formed that eventually leads to the final metallated porphyrin either through an assisted attack of a second metal ion or through a direct insertion of the metal cation into the macrocycle core

Lumbar spine bone mineral density and trabecular bone score-adjusted FRAX, but not FRAX without bone mineral density, identify subclinical carotid atherosclerosis

Purpose: Osteoporosis and atherosclerosis share common risk factors. Aim of this study was to test if FRAX (which is an algorithm that can identify subjects at risk of fracture), without or with BMD values, also adjusted for trabecular bone score (TBS) was able to identify subclinical atherosclerosis, evaluated by measurement of carotid intima media thickness (cIMT ≥ 0.9 mm) as compared to DXA values. Methods: Ninety postmenopausal women underwent DXA measurement and cIMT evaluation. For each patient, the FRAX algorithm for major osteoporotic fracture (M) and for hip fracture (H) without BMD was computed, together with FRAX with BMD and TBS-adjusted FRAX. Serum levels of osteoprotegerin, sRANKL, and interleukin-6 were also measured. Results: There were no differences in anthropometric parameters and cardiovascular risk factors between subjects with cIMT ≥ 0.9 mm (35% of subjects, group A) compared to those with cIMT < 0.9 mm (group B). The prevalence of osteoporosis and FRAX BMD, TBS-adjusted FRAX both for M and H were higher in group A compared to group B. The best ROC curves to identify subjects with a cIMT ≥ 0.9 mm were: lumbar spine T-score, with a threshold of − 2.5 SD (area under the curve, AUC 0.64; p = 0.02) with a sensibility of 50% and a specificity of 76%; TBS-adjusted FRAX H with a sensibility of 50% and a specificity of 72% (AUC 0.64; p = 0.01 with a threshold of 3%). Interleukin-6 positively correlated with FRAX BMD H and M. Conclusions: FRAX without BMD does not identify subclinical carotid atherosclerosis, while lumbar spine T-score and TBS-adjusted FRAX H similarly detected it with higher specificity for T-score

Update on the safety and efficacy of teriparatide in the treatment of osteoporosis

Following the completion of the Fracture Prevention Trial, teriparatide was approved by the United States Food and Drug Administration and the European Medicine Agency as the first therapeutic anabolic agent for the treatment of postmenopausal women with severe osteoporosis. It subsequently received additional approval for the treatment of osteoporosis in men, and for the treatment of osteoporosis associated with glucocorticoid therapy in men and women at risk of fracture. In this review, we summarize the most important data concerning PTH 1-34 therapy before 2016 in the treatment of osteoporosis, and report some outstanding results published in the last 2 years. New data on safety will also discussed, together with the state of art of nonclassical utilization. Finally, in view of the recent approval of biosimilars, possible future landscapes are discussed

Obesity Is A Modifier of Autonomic Cardiac Responses to Fine Metal Particulates

Background: Increasing evidence suggests that obesity may impart greater susceptibility to adverse effects of air pollution. Particulate matter, especially PM$_{2.5}$ (particulate matter with aero-dynamic diameter ≤2.5 μm), is associated with increased cardiac events and reduction of heart rate variability (HRV).Objectives Our goal was to investigate whether particle-mediated autonomic modulation is aggravated in obese individuals.Methods We examined PM$_{2.5}$-mediated acute effects on HRV and heart rate (HR) using 10 24-hr and 13 48-hr ambulatory electrocardiogram recordings collected from 18 boilermakers (39.5 ± 9.1 years of age) exposed to high levels of metal particulates. Average HR and 5-min HRV [SDNN: standard deviation of normal-to-normal intervals (NN); rMSSD: square-root of mean squared-differences of successive NN intervals; HF: high-frequency power 0.15–0.4 Hz] and personal PM$_{2.5}$ exposures were continuously monitored. Subjects with body mass index ≥ 30 kg/m$^2$ were classified as obese. Mixed-effect models were used for statistical analyses. Results: Half (50%) of the study subjects were obese. After adjustment for confounders, each 1-mg/m$^3$ increase in 4-hr moving average PM$_{2.5}$ was associated with HR increase of 5.9 bpm [95% confidence interval (CI), 4.2 to 7.7] and with 5-min HRV reduction by 6.5% (95% CI, 1.9 to 11.3%) for SDNN, 1.7% (95% CI, –4.9 to 8.4%) for rMSSD, and 8.8% (95% CI, –3.8 to 21.3%) for HF. Obese individuals had greater PM$_{2.5}$-mediated HRV reductions (2- to 3-fold differences) than nonobese individuals, and had more PM$_{2.5}$-mediated HR increases (9-bpm vs. 4-bpm increase in HR for each 1-mg/m$^3$ increase in PM$_{2.5}$; p < 0.001). Conclusions: Our study revealed greater autonomic cardiac responses to metal particulates in obese workers, supporting the hypothesis that obesity may impart greater susceptibility to acute cardiovascular effects of fine particles

Genetic aspects underlying the normocalcemic and hypercalcemic phenotypes of primary hyperparathyroidism

purpose: hypercalcemic primary hyperparathyroidism (PHPT) is a common endocrine disorder that has been very well characterized. In contrast, many aspects of normocalcemic primary hyperparathyroidism (NPHPT) such as natural history, organ damage, and management are still matter of debate. In addition, both the pathophysiology and molecular basis of NPHPT are unclear. we investigated whether PHPT and NPHPT patient cohorts share the same pattern of genetic variation in genes known to be involved in calcium and/or bone metabolism. Research design and methods: Genotyping for 9 single nucleotide polymorphisms (SNPs) was performed by Real-Time PCR (TaqMan assays) on 27 NPHPT and 31 PHPT patients evaluated in a tertiary referral center. the data of both groups were compared with 54 in house-controls and 503 subjects from the 1,000 genomes Project. All groups were compared for allele/haplotype frequencies, on a single locus, two loci and multi-locus basis. Results: The NPHPT group differed significantly at SNPs in OPG and ESR1. also, the NPHPT cohort was peculiar for pairwise associations of genotypes and for the overrepresentation of unusual multilocus genotypes. Conclusions: Our NPHPT patient set harboured a definitely larger quota of genetic diversity than the other samples. Specific genotypes may help in defining subgroups of NPHPT patients which deserve ad hoc clinical and follow-up studies

Straight aortic endograft in abdominal aortic disease

Background: We describe our 8-year experience with the use of endovascular techniques (ET) for the treatment of abdominal aortic aneurysms (AAA) through a straight endograft. Methods: We retrospectively reviewed data of all patients who were treated for AAA using ET in two centres from 1998 to 2012 and who received a single straight endograft (group A) or a double straight tube (group B). Outcomes were analyzed to assess survival, absence of endoleak and absence of reintervention for both groups. Log-rank and Chi-Square were used as appropriate to make comparison between the two groups. P values <.05 were considered statistically significant. Results: Fifty-three patients from 1998 to May 2012 were treated for AAA using a straight endograft. In 28 cases (52.8%) a single aortic straight tube was used (Group A), while in the remaining cases a "double trombone technique" was used (Group B). Primary success was obtained in 52 cases (98.1%). In one patient of group A immediately after the operation we observed a type Ia endoleak, which was correct with a proximal aortic cuff. Fluoroscopy time, operation time, amount of intraprocedural contrast medium and blood loss were slightly higher for group B, even if not significantly. Mortality at 30 days was nil for both groups. Mean follow-up was 49 months (range 2-153 months). Five patients died in group A, four of them for a neoplastic disease and the remaining for aortic rupture. No patients died in group B. Endoleaks occurred more frequently in patients of group A (5 type I endoleaks and 1 type II endoleak from a lumbar artery). Reintervention were more frequent for patients of group A, being type I endoleak the main cause. A stent fracture was observed in a patient who received EVAR by "trombone technique" 3 months later. Reintervention was then necessary and a third stent was successfully placed to cover the lesion. Conclusions: In our experience the endovascular repair of AAA using straight aortic endografts was a safe and effective technique. Reintervention and endoleaks were slightly more frequent in patients who had received a single endograft compared to patients who were treated using the "trombone technique"

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding: UK Medical Research Council and Health Technology Assessment Programme

Java SAM Typed Closures: A Sound and Complete Type Inference System for Nominal Types

The last proposal for Java closures, as emerged in JSR 000335, is mainly innovative in: (1)Use of nominal types, SAM types, for closures; (2) Introduction of target types and compatibility for a contextual typing of closures; (3) Need for a type inference that reconstructs the omitted type annotations of closures and closure arguments. The paper provides a sound and complete type system, with nominal types, for such a type inference and discusses role and formalization of targeting and of compatibility in the designed inference process