Mechanisms of Successful Amoxicillin Prophylaxis of Experimental Endocarditis Due to Streptococcus intermedius

Prophylaxis with amoxicillin (40 mg/kg) was studied in rats with aortic valve vegetations. Bacteria on the valves were quantitated early (10 min to 6 hr) and late (three days) after intravenous challenge with tolerant Streptococcus intermedius. Amoxicillin reduced by 40% the number of bacteria per valve 10 min after intravenous challenge with 105 S. intermedius (P < .05) and by 74% the incidence of endocarditis three days thereafter (P < .0001). Bacterial multiplication started 2 hr after challenge in control rats, whereas bacteria disappeared in 6 hr in amoxicillin-treated rats. Intravenous penicillinase 30 min after challenge abolished successful amoxicillin prophylaxis, a result demonstrating the necessity of prolonged growth inhibition for protection. Growth inhibition for 18 hr (two subsequent amoxicillin doses) was necessary for protection after intravenous challenge with 105 S. intermedius. Thus, in the absence of bacterial killing, inhibition of valvular colonization by amoxicillin was not as important a mechanism of endocarditis prophylaxis as was prolonged inhibition of bacterial growth, which allowed adherent bacteria to be cleared from the valve

Predictors of Endocarditis in Isolates from Cultures of Blood Following Dental Extractions in Rats with Periodontal Disease

Rats with periodontitis and catheter-induced aortic valve vegetations underwent dental extractions. Cultures of blood obtained 1 min later showed polymicrobial bacteremia in 19 of 19 rats, mostly due to viridans streptococci (18 of 19), Morganella (15 of 19), group G streptococci (13 of 19), and Staphylococcus aureus (10 of 19). Viridans streptococci circulated in higher numbers than did group G streptococci and S. aureus (P < .01). Three days after dental extractions, 18 of 20 rats had endocarditis. Fifteen (83%) of 18 infections were due to group G streptococci, 9 (50%) of 18 were due to S. aureus, and 2 (11%) of 18 were due to viridans streptococci (P < .05). In vitro, adherence to platelet-fibrin matrices of endocarditis strain 8 of group G streptococcus was two times greater than that of endocarditis strain S. aureus 23 and three to four times greater than that of Streptococcus sanguis 44 and Morganella morganii 93 (P < 10−5). The inoculum size that produced endocarditis in 90% of rats after iv challenge was 105 cfu for group G streptococcus strain 8 and 107 for S. sanguis 4

Allyship for the Rural Health Care Workforce

The COVID-19 pandemic revealed a lot about the American impressive yet fragile and overtaxed health care system. Our support systems – both institutional and human- were taxed. Building our network through a variety of methods can help to strengthen our support system while also helping to dismantle the structural inequities that have negative consequences for our workforce and for patient care. Seeking allies in medicine has become an integral component of building one’s network and becoming an ally for those communities that are isolated or under resourced and for those who are underrepresented in medicine has become an important way to help promote structural change at the institutional level

Efavirenz inhibits the human ether-a-go-go related current (hERG) and induces QT interval prolongation in CYP2B6*6*6 allele carriers

Background Efavirenz (EFV) has been associated with torsade de pointes despite marginal QT interval lengthening. Since EFV is metabolized by the cytochrome P450 (CYP) 2B6 enzyme, we hypothesized that EFV would lengthen the rate-corrected QT (QTcF) interval in carriers of the CYP2B6*6 decreased functional allele. Objective The primary objective of this study was to evaluate EFV-associated QT interval changes with regard to CYP2B6 genotype and to explore mechanisms of QT interval lengthening. Methods EFV was administered to healthy volunteers (n=57) as a single 600 mg dose followed by multiple doses to steady-state. Subjects were genotyped for known CYP2B6 alleles and ECGs and EFV plasma concentrations were obtained serially. Whole-cell, voltage-clamp experiments were performed on cells stably expressing hERG and exposed to EFV in the presence and absence of CYP2B6 expression. Results EFV demonstrated a gene-dose effect and exceeded the FDA criteria for QTcF interval prolongation in CYP2B6*6/*6 carriers. The largest mean time-matched differences ΔΔQTcF were observed at 6 hrs (14 ms; 95% CI [1; 27]), 12 hrs (18 ms; 95% CI [−4; 40] and 18 hrs (6 ms; 95% CI [−1; 14]) in the CYP2B6*6/*6 genotype. EFV concentrations exceeding 0.4 µg/mL significantly inhibited outward hERG tail currents (P<0.05). Conclusions This study demonstrates that homozygous carriers of CYP2B6*6 allele may be at increased risk for EFV-induced QTcF interval prolongation via inhibition of hERG

Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression

Background: This report provides histopathological evidence to support prior neuroimaging findings of decreased volume and altered metabolism in the frontal cortex in major depressive disorder. Methods: Computer-assisted three-dimensional cell counting was used to reveal abnormal cytoarchitecture in left rostral and caudal orbitofrontal and dorsolateral prefrontal cortical regions in subjects with major depression as compared to psychiatrically normal controls. Results: Depressed subjects had decreases in cortical thickness, neuronal sizes, and neuronal and glial densities in the upper (II–IV) cortical layers of the rostral orbitofrontal region. In the caudal orbitofrontal cortex in depressed subjects, there were prominent reductions in glial densities in the lower (V–VI) cortical layers that were accompanied by small but significant decreases in neuronal sizes. In the dorsolateral prefrontal cortex of depressed subjects marked reductions in the density and size of neurons and glial cells were found in both supra- and infragranular layers. Conclusions: These results reveal that major depression can be distinguished by specific histopathology of both neurons and glial cells in the prefrontal cortex. Our data will contribute to the interpretation of neuroimaging findings and identification of dysfunctional neuronal circuits in major depression

Epidermal growth factor mediates detachment from and invasion through collagen I and Matrigel in Capan-1 pancreatic cancer cells

BACKGROUND: Pancreatic adenocarcinoma is a highly invasive neoplasm. Epidermal growth factor (EGF) and its receptor are over expressed in pancreatic cancer, and expression correlates with invasion and metastasis. We hypothesized that EGF receptor and integrin signalling pathways interact in mediating cellular adhesion and invasion in pancreatic cancer, and that invasiveness correlates temporally with detachment from extracellular matrix. METHODS: We tested this hypothesis by investigating the role of EGF in mediating adhesion to and invasion through collagen I and Matrigel in the metastatic pancreatic adenocarcinoma cell line Capan-1. Adhesion and invasion were measured using in vitro assays of fluorescently-labeled cells. Adhesion and invasion assays were also performed in the primary pancreatic adenocarcinoma cell line MIA PaCa-2. RESULTS: EGF inhibited adhesion to collagen I and Matrigel in Capan-1 cells. The loss of adhesion was reversed by AG825, an inhibitor of erbB2 receptor signalling and by wortmannin, a PI3K inhibitor, but not by the protein synthesis inhibitor cycloheximide. EGF stimulated invasion through collagen I and Matrigel at concentrations and time courses similar to those mediating detachment from these extracellular matrix components. Adhesion to collagen I was different in MIA PaCa-2 cells, with no significant change elicited following EGF treatment, whereas treatment with the EGF family member heregulin-alpha elicited a marked increase in adhesion. Invasion through Matrigel in response to EGF, however, was similar to that observed in Capan-1 cells. CONCLUSION: An inverse relationship exists between adhesion and invasion capabilities in Capan-1 cells but not in MIA PaCa-2 cells. EGF receptor signalling involving the erbB2 and PI3K pathways plays a role in mediating these events in Capan-1 cells

Enhanced Response to Drug-Induced QT Interval Lengthening in Patients with Heart Failure with Preserved Ejection Fraction

Background: Patients with heart failure (HF) with reduced ejection fraction demonstrate enhanced response to drug-induced QT interval lengthening and are at increased risk for torsades de pointes. The influence of HF with preserved ejection fraction (HFpEF) on response to drug-induced QT lengthening is unknown. Methods and results: We administered intravenous ibutilide 0.003 mg/kg to 10 patients with HFpEF and 10 age- and sex-matched control subjects without HF. Serial 12-lead electrocardiograms were obtained for determination of QT intervals. Demographics, maximum serum ibutilide concentrations, area under the serum ibutilide concentration vs time curves, and baseline Fridericia-corrected QT (QTF) (417 ± 14 vs 413 ± 15 ms, P = .54) were similar in the HFpEF and control groups. Area under the effect (QTFvs time) curve (AUEC) from 0 to 1.17 hours during and following the ibutilide infusion was greater in the HFpEF group (519 ± 19 vs 497 ± 18 ms·h, P= .04), as was AUEC from 0 to 8.17 hours (3576 ± 125 vs 3428 ± 161 ms·h, P = .03) indicating greater QTF interval exposure. Maximum QTF (454 ± 15 vs 443 ± 22 ms, P = .18) and maximum percent increase in QTF from baseline (8.2 ± 2.1 vs 6.7 ± 1.9%, P = .10) in the 2 groups were not significantly different. Conclusions: HFpEF is associated with enhanced response to drug-induced QT interval lengthening

Efficacy of essential oil mouthwash with and without alcohol: a 3-Day plaque accumulation model

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to evaluate the antiplaque effect of a new alcohol free essential oil mouthwash with respect to a control of an essential oil with alcohol mouthwash, using an <it>in vivo </it>plaque regrowth model of 3-days.</p> <p>Methods</p> <p>The study was designed as a double-masked, randomized, crossover clinical trial, involving 30 volunteers to compare two different essential oil containing mouthwashes, during a 3-day plaque accumulation model. After receiving a thorough professional prophylaxis at the baseline, over the next 3-days each volunteer refrained from all oral hygiene measures and had two daily rinses with 20 ml of the test mouthwash (alcohol free essential oil) or the control mouthwash (essential oil with alcohol). At the end of the each experimental period, plaque was assessed and the panelists filled out a questionnaire. Each subject underwent a 14 days washout period and there was a second allocation.</p> <p>Results</p> <p>The essential oil mouthwash with ethanol shows a better inhibitory effect of plaque regrowth in 3-days than the mouthwash test with only essential oil in the whole mouth (plaque index = 2.18 against 2.46, respectively, p < 0.05); for the lower jaw (plaque index = 2.28 against 2.57, respectively, p < 0.05); for the upper jaw (plaque index = 2.08 against 2.35, respectively, p < 0.05); for the incisors (plaque index = 1.93 against 2.27, respectively, p < 0.05); and the canines (plaque index = 1.99 against 2.47, respectively, p < 0.05).</p> <p>Conclusion</p> <p>The essential oil containing mouthwash without alcohol seems to have a less inhibiting effect on the plaque regrowth than the traditional alcoholic solution.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01411618">NCT01411618</a></p

Neuropathology of wild-type and nef-attenuated T cell tropic simian immunodeficiency virus (SIVmac32H) and macrophage tropic neurovirulent SIVmac17E-Fr in cynomolgus macaques

The neuropathology of simian immunodeficiency (SIV) infection in cynomolgus macaques (Macaca fascicularis) was investigated following infection with either T cell tropic SIVmacJ5, SIVmacC8 or macrophage tropic SIVmac17E-Fr. Formalin fixed, paraffin embedded brain tissue sections were analysed using a combination of in situ techniques. Macaques infected with either wild-type SIVmacJ5 or neurovirulent SIVmac17E-Fr showed evidence of neuronal dephosphorylation, loss of oligodendrocyte and CCR5 staining, lack of microglial MHC II expression, infiltration by CD4+ and CD8+ T cells and mild astrocytosis. SIVmacJ5-infected animals exhibited activation of microglia whilst those infected with SIVmac17E-Fr demonstrated a loss of microglia staining. These results are suggestive of impaired central nervous system (CNS) physiology. Furthermore, infiltration by T cells into the brain parenchyma indicated disruption of the blood brain barrier (BBB). Animals infected with the Δnef-attenuated SIVmacC8 showed microglial activation and astrogliosis indicative of an inflammatory response, lack of MHC II and CCR5 staining and infiltration by CD8+ T cells. These results demonstrate that the SIV infection of cynomolgus macaque can be used as a model to replicate the range of CNS pathologies observed following HIV infection of humans and to investigate the pathogenesis of HIV associated neuropathology