189 Storrs Rd
Mansfield Center CT 06250
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Early experience with tedizolid: clinical efficacy, pharmacodynamics, and resistance. - Pharmacotherapy
Antimicrobial resistance among gram-positive organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) continues to limit therapeutic options. The oxazolidinones are a synthetic class of agents now commonly relied on for the treatment of serious MRSA and VRE infections. With increasing utilization of linezolid, resistant pathogens have once again begun to emerge. Tedizolid, a next-generation oxazolidinone, possesses a spectrum of activity including MRSA and VRE, with significantly enhanced potency also against linezolid-resistant strains. Preclinical and early clinical studies have reported positive results, demonstrating a favorable pharmacokinetic profile in combination with key potential safety advantages. In two phase III clinical trials, tedizolid was found noninferior to linezolid in the treatment of acute bacterial skin and skin structure infections. Investigations for treatment of ventilator-acquired and health care-associated pneumonia are currently underway. Tedizolid has been subjected to pharmacodynamics studies throughout its development that have highlighted properties unique to this agent. Considerable accumulations in epithelial lining fluid and antimicrobial activity greatly augmented by the presence of granulocytes suggest that slow but bactericidal activity may be possible in some clinical scenarios. Structural distinctions between tedizolid and linezolid suggest that tedizolid has decreased vulnerability to oxazolidinone resistance mechanisms. Tedizolid minimum inhibitory concentrations are essentially unchanged in organisms possessing the chloramphenicol-florfenicol resistance gene, a horizontally transferable linezolid resistance mechanism. Although the clinical experience with tedizolid remains limited, early data suggest a potential role in the treatment of serious infections due to multidrug-resistant gram-positive pathogens.Â© 2014 Pharmacotherapy Publications, Inc.
Effects of extended-release niacin with laropiprant in high-risk patients. - The New England journal of medicine
Patients with evidence of vascular disease are at increased risk for subsequent vascular events despite effective use of statins to lower the low-density lipoprotein (LDL) cholesterol level. Niacin lowers the LDL cholesterol level and raises the high-density lipoprotein (HDL) cholesterol level, but its clinical efficacy and safety are uncertain.After a prerandomization run-in phase to standardize the background statin-based LDL cholesterol-lowering therapy and to establish participants' ability to take extended-release niacin without clinically significant adverse effects, we randomly assigned 25,673 adults with vascular disease to receive 2 g of extended-release niacin and 40 mg of laropiprant or a matching placebo daily. The primary outcome was the first major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization).During a median follow-up period of 3.9 years, participants who were assigned to extended-release niacin-laropiprant had an LDL cholesterol level that was an average of 10 mg per deciliter (0.25 mmol per liter as measured in the central laboratory) lower and an HDL cholesterol level that was an average of 6 mg per deciliter (0.16 mmol per liter) higher than the levels in those assigned to placebo. Assignment to niacin-laropiprant, as compared with assignment to placebo, had no significant effect on the incidence of major vascular events (13.2% and 13.7% of participants with an event, respectively; rate ratio, 0.96; 95% confidence interval [CI], 0.90 to 1.03; P=0.29). Niacin-laropiprant was associated with an increased incidence of disturbances in diabetes control that were considered to be serious (absolute excess as compared with placebo, 3.7 percentage points; P<0.001) and with an increased incidence of diabetes diagnoses (absolute excess, 1.3 percentage points; P<0.001), as well as increases in serious adverse events associated with the gastrointestinal system (absolute excess, 1.0 percentage point; P<0.001), musculoskeletal system (absolute excess, 0.7 percentage points; P<0.001), skin (absolute excess, 0.3 percentage points; P=0.003), and unexpectedly, infection (absolute excess, 1.4 percentage points; P<0.001) and bleeding (absolute excess, 0.7 percentage points; P<0.001).Among participants with atherosclerotic vascular disease, the addition of extended-release niacin-laropiprant to statin-based LDL cholesterol-lowering therapy did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events. (Funded by Merck and others; HPS2-THRIVE ClinicalTrials.gov number, NCT00461630.).
Fulminant Invasive Pulmonary Aspergillosis After a Near-Drowning Accident in an Immunocompetent Patient. - The Annals of pharmacotherapy
To report on invasive aspergillosis infection in an immunocompetent adult after a near-drowning event, which allowed this pathogen to easily gain access to the human respiratory system and result in rapid, severe infection.A 51-year-old female developed severe pneumonia after a near-drowning accident. Two days after admission, a bronchial alveolar lavage (BAL) was performed and was positive for Aspergillus fumigatus. After a 30-day hospital course, multiple antifungals, and various routes of administration, the patient expired.Pneumonia is particularly common because of the aspiration of contaminated water. Whereas pneumococci, staphylococci, and Gram-negative bacteria are all common pathogens for this type of infection, fungi such as Aspergillus spp can also be involved and may be life threatening. Typically, these cases are reported in individuals with an immunodeficiency such as from receipt of myelosuppressive chemotherapy, bone marrow transplants, or lung transplants. Despite initiation of an appropriate empirical antifungal regimen, the rapid recovery of A fumigatus from pulmonary alveolar lavage and BAL samples as well as extremely elevated levels of galactomannan and (1â†’3)-Î²-D glucan may have indicated an invasive fungal infection (IFI).IFIs are uncommon in immunocompetent adults, but in the event of a near-drowning accident, environmental fungi can gain access to the human respiratory system and result in rapid, severe infection. Based on this case and the others described, it appears that near-drowning patients need an early initial evaluation for IFI.Â© The Author(s) 2014.
Insights into the mechanism of initial transcription in Escherichia coli RNA polymerase. - The Journal of biological chemistry
It has long been known that during initial transcription of the first 8-10 bases of RNA, complexes are relatively unstable, leading to the release of short abortive RNA transcripts. An early "stressed intermediate" model led to a more specific mechanistic model proposing "scrunching" stress as the basis for the instability. Recent studies in the single subunit T7 RNA polymerase have argued against scrunching as the energetic driving force and instead argue for a model in which pushing of the RNA-DNA hybrid against a protein element associated with promoter binding, while likely driving promoter release, reciprocally leads to instability of the hybrid. In this study, we test these models in the structurally unrelated multisubunit bacterial RNA polymerase. Via the targeted introduction of mismatches and nicks in the DNA, we demonstrate that neither downstream bubble collapse nor compaction/scrunching of either the single-stranded template or nontemplate strands is a major force driving abortive instability (although collapse from the downstream end of the bubble does contribute significantly to the instability of artificially halted complexes). In contrast, pushing of the hybrid against a mobile protein element (Ïƒ3.2 in the bacterial enzyme) results in substantially increased abortive instability and is likely the primary energetic contributor to abortive cycling. The results suggest that abortive instability is a by-product of the mechanistic need to couple the energy of nucleotide addition (RNA chain growth) to driving the timed release of promoter contacts during initial transcription.
Clopidogrel treatment and the incidence and severity of community acquired pneumonia in a cohort study and meta-analysis of antiplatelet therapy in pneumonia and critical illness. - Journal of thrombosis and thrombolysis
Platelet activation results in the release and upregulation of mediators responsible for immune cell activation and recruitment, suggesting that platelets play an active role in immunity. Animal models and retrospective data have demonstrated benefit of antiplatelet therapy on inflammatory mediator expression and clinical outcomes. This study sought to characterize effects of clopidogrel on the incidence and severity of community-acquired pneumonia (CAP). A retrospective cohort study was conducted of Kentucky Medicaid patients (2001-2005). The exposed cohort consisted of patients receiving at least six consecutive clopidogrel prescriptions; the non-exposed cohort was comprised of patients not prescribed clopidogrel. Primary endpoints included incidence of CAP and inpatient treatment. Secondary severity endpoints included mortality, intensive care unit admission, mechanical ventilation, sepsis, and acute respiratory distress syndrome/acute lung injury. CAP incidence was significantly greater in the exposed cohort (OR 3.39, 95% CI 3.27-3.51, p < 0.0001) that remained after adjustment (OR 1.48, 95% CI 1.41-1.55, p < 0.0001). Inpatient treatment was more common in the exposed cohort (OR 1.96, 95% CI 1.85-2.07, p < 0.0001), but no significant difference remained after adjustment. Trends favoring the exposed cohort were found for the secondary severity endpoints of mechanical ventilation (p = 0.07) and mortality (p = 0.10). Pooled analysis of published studies supports these findings. While clopidogrel use may be associated with increased CAP incidence, clopidogrel does not appear to increase--and may reduce--its severity among inpatients. Because this study was retrospective and could not quantify all variables (e.g., aspirin use), these findings should be explored prospectively.
Getting under the skin of adverse drug reactions. - Orthopedics
Cutaneous drug reactions are among the most commonly reported adverse drug reactions. Drugs prescribed by orthopedic surgeons, such as antibiotics, opiates, and nonsteroidal anti-inflammatory drugs, are common offenders. Cutaneous drug reactions can range from those that are common, mild nuisances to those that are rare, severe, and life-threatening. Medications should be considered part of a differential diagnosis for any dermatologic condition. It is important to recognize the different clinical features and common drugs that are related to each type of reaction. This review characterizes the different forms of cutaneous drug reactions and the clinical features, proposed mechanisms, and drugs frequently associated with each.Copyright 2012, SLACK Incorporated.
Responses of epidermal cell turgor pressure and photosynthetic activity of leaves of the atmospheric epiphyte Tillandsia usneoides (Bromeliaceae) after exposure to high humidity. - Journal of plant physiology
It has been well-established that many epiphytic bromeliads of the atmospheric-type morphology, i.e., with leaf surfaces completely covered by large, overlapping, multicellular trichomes, are capable of absorbing water vapor from the atmosphere when air humidity increases. It is much less clear, however, whether this absorption of water vapor can hydrate the living cells of the leaves and, as a consequence, enhance physiological processes in such cells. The goal of this research was to determine if the absorption of atmospheric water vapor by the atmospheric epiphyte Tillandsia usneoides results in an increase in turgor pressure in leaf epidermal cells that subtend the large trichomes, and, by using chlorophyll fluorescence techniques, to determine if the absorption of atmospheric water vapor by leaves of this epiphyte results in increased photosynthetic activity. Results of measurements on living cells of attached leaves of this epiphytic bromeliad, using a pressure probe and of whole-shoot fluorescence imaging analyses clearly illustrated that the turgor pressure of leaf epidermal cells did not increase, and the photosynthetic activity of leaves did not increase, following exposure of the leaves to high humidity air. These results experimentally demonstrate, for the first time, that the absorption of water vapor following increases in atmospheric humidity in atmospheric epiphytic bromeliads is mostly likely a physical phenomenon resulting from hydration of non-living leaf structures, e.g., trichomes, and has no physiological significance for the plant's living tissues.Copyright Â© 2012 Elsevier GmbH. All rights reserved.
New insights into the mechanism of initial transcription: the T7 RNA polymerase mutant P266L transitions to elongation at longer RNA lengths than wild type. - The Journal of biological chemistry
RNA polymerases undergo substantial structural and functional changes in transitioning from sequence-specific initial transcription to stable and relatively sequence-independent elongation. Initially, transcribing complexes are characteristically unstable, yielding short abortive products on the path to elongation. However, protein mutations have been isolated in RNA polymerases that dramatically reduce abortive instability. Understanding these mutations is essential to understanding the energetics of initial transcription and promoter clearance. We demonstrate here that the P266L point mutation in T7 RNA polymerase, which shows dramatically reduced abortive cycling, also transitions to elongation later, i.e. at longer lengths of RNA. These two properties of the mutant are not necessarily coupled, but rather we propose that they both derive from a weakening of the barrier to RNA-DNA hybrid-driven rotation of the promoter binding N-terminal platform, a motion necessary to achieve programmatically timed release of promoter contacts in the transition to elongation. Parallels in the multisubunit RNA polymerases are discussed.
A positive Tinel sign as predictor of pain relief or sensory recovery after decompression of chronic tibial nerve compression in patients with diabetic neuropathy. - Journal of reconstructive microsurgery
Predictive ability of a positive Tinel sign over the tibial nerve in the tarsal was evaluated as a prognostic sign in determining sensory outcomes after distal tibial neurolysis in diabetics with chronic nerve compression at this location. Outcomes were evaluated with a visual analog score (VAS) for pain and measurements of the cutaneous pressure threshold/two-point discrimination. A multicenter prospective study enrolled 628 patients who had a positive Tinel sign. Of these patients, 465 (74%) had VAS >5. Each patient had a release of the tarsal tunnel and a neurolysis of the medial and lateral plantar and calcaneal tunnels. Subsequent, contralateral, identical surgery was done in 211 of the patients (152 of which had a VAS >5). Mean VAS score decreased from 8.5 to 2.0 (p <0.001) at 6 months, and remained at this level for 3.5 years. Sensibility improved from a loss of protective sensation to recovery of some two-point discrimination during this same time period. It is concluded that a positive Tinel sign over the tibial nerve at the tarsal tunnel in a diabetic patient with chronic nerve compression at this location predicts significant relief of pain and improvement in plantar sensibility.Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
Prevention of ulceration, amputation, and reduction of hospitalization: outcomes of a prospective multicenter trial of tibial neurolysis in patients with diabetic neuropathy. - Journal of reconstructive microsurgery
This is the first multicenter prospective study of outcomes of tibial neurolysis in diabetics with neuropathy and chronic compression of the tibial nerve in the tarsal tunnels. A total of 38 surgeons enrolled 628 patients using the same technique for diagnosis of compression, neurolysis of four medial ankle tunnels, and objective outcomes: ulceration, amputation, and hospitalization for foot infection. Contralateral limb tibial neurolysis occurred in 211 patients for a total of 839 operated limbs. Kaplan-Meier proportional hazards were used for analysis. New ulcerations occurred in 2 (0.2%) of 782 patients with no previous ulceration history, recurrent ulcerations in 2 (3.8%) of 57 patients with a previous ulcer history, and amputations in 1 (0.2%) of 839 at risk limbs. Admission to the hospital for foot infections was 0.6%. In patients with diabetic neuropathy and chronic tibial nerve compression, neurolysis can result in prevention of ulceration and amputation, and decrease in hospitalization for foot infection.Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
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189 Storrs Rd Mansfield Center, CT 06250
189 Storrs Rd Natchaug Hospital
189 Storrs Rd Natchaug Hospital
6 Ledgebrook Dr Ste A