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Because many episodes of ventricular fibrillation (VF) are believed to be triggered by ventricular tachycardia (VT), patients who present with VT or VF are usually grouped together in discussions of natural history and treatment. However, there are significant differences in the clinical profiles of these 2 patient groups, and some studies have suggested differences in their response to therapy. We examined arrhythmias occurring spontaneously in 449 patients assigned to implantable cardioverter-defibrillator (ICD) therapy in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial to determine whether patients who receive an ICD after VT have arrhythmias during follow-up that are different from patients who present with VF. ICD printouts were analyzed both by a committee blinded to the patients' original presenting arrhythmia and by the local investigator. During 31 +/- 14 months of follow-up, 2,673 therapies were reported. Patients who were enrolled in the AVID trial after an episode of VT were more likely to have an episode of VT (73.5% vs 30.1%, p <0.001), and were less likely to have an episode of VF (18.3% vs 28.0%, p = 0.013) than patients enrolled after an episode of VF. Adjustment for differences in ejection fraction, previous infarction, and beta-blocker and antiarrhythmic therapy did not appreciably change the results. Ventricular arrhythmia recurrence during follow-up is different in patients who originally present with VT than in those who originally present with VF. These findings suggest there are important differences in the electrophysiologic characteristics of these 2 patient populations. [ABSTRACT FROM AUTHOR]

Introduction: We observed a change in the atrial activation sequence during radiofrequency (RF) energy application in patients undergoing left accessory pathway (AP) ablation. This occurred without damage to the AP and in the absence of a second AP or alternative arrhythmia mechanism. We hypothesized that block in a left atrial 'isthmus' of tissue between the mitral annulus and a left inferior pulmonary vein was responsible for these findings. Methods and Results: Electrophysiologic studies of 159 patients who underwent RF ablation of a left free-wall AP from 1995 to 1999 were reviewed. All studies with intra-atrial conduction block resulting from RF energy delivery were identified. Fluoroscopic catheter positions were reviewed. Intra-atrial conduction block was observed following RF delivery in 11 cases (6.9%). This was evidenced by a sudden change in retrograde left atrial activation sequence despite persistent and unaffected pathway conduction. In six patients, reversal of eccentric atrial excitation during orthodromic reciprocating tachycardia falsely suggested the presence of a second (septal) AP. A multipolar coronary sinus catheter in two patients directly demonstrated conduction block along the mitral annulus during tachycardia. Conclusion: An isthmus of conductive tissue is present in the low lateral left atrium of some individuals. Awareness of this structure may avoid misinterpretation of the electrogram during left AP ablation and may be useful in future therapies of atypical atrial flutter and fibrillation. [ABSTRACT FROM AUTHOR]

Background: This guideline addressed VTE prevention in hospitalized medical patients, outpatients with cancer, the chronically immobilized, long-distance travelers, and those with asymptomatic thrombophilia.Methods: This guideline follows methods described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.Results: For acutely ill hospitalized medical patients at increased risk of thrombosis, we recommend anticoagulant thromboprophylaxis with low-molecular-weight heparin (LMWH), low-dose unfractionated heparin (LDUH) bid, LDUH tid, or fondaparinux (Grade 1B) and suggest against extending the duration of thromboprophylaxis beyond the period of patient immobilization or acute hospital stay (Grade 2B). For acutely ill hospitalized medical patients at low risk of thrombosis, we recommend against the use of pharmacologic prophylaxis or mechanical prophylaxis (Grade 1B). For acutely ill hospitalized medical patients at increased risk of thrombosis who are bleeding or are at high risk for major bleeding, we suggest mechanical thromboprophylaxis with graduated compression stockings (GCS) (Grade 2C) or intermittent pneumatic compression (IPC) (Grade 2C). For critically ill patients, we suggest using LMWH or LDUH thromboprophylaxis (Grade 2C). For critically ill patients who are bleeding or are at high risk for major bleeding, we suggest mechanical thromboprophylaxis with GCS and/or IPC at least until the bleeding risk decreases (Grade 2C). In outpatients with cancer who have no additional risk factors for VTE we suggest against routine prophylaxis with LMWH or LDUH (Grade 2B) and recommend against the prophylactic use of vitamin K antagonists (Grade 1B).Conclusions: Decisions regarding prophylaxis in nonsurgical patients should be made after consideration of risk factors for both thrombosis and bleeding, clinical context, and patients' values and preferences. [ABSTRACT FROM AUTHOR]

Background: Prostaglandin E 2 (PGE 2 ) and leukotriene B 4 (LTB 4 ) are eicosanoids involved in modulation of the antiviral immune response. Recent studies have identified increased levels of several eicosanoids in the plasma and bronchoalveolar lavage of patients with coronavirus disease (COVID-19). This study investigated correlations between plasma levels of PGE 2 and LTB 4 and clinical severity of COVID-19., Methods: This cross-sectional study involved non-infected (n = 10) individuals and COVID-19 patients classified as cured (n = 13), oligosymptomatic (n = 29), severe (n = 15) or deceased (n = 11). Levels of D-dimer a, known COVID-19 severity marker, PGE 2 and LTB 4 were measured by ELISAs and data were analysed with respect to viral load., Results: PGE 2 plasma levels were decreased in COVID-19 patients compared to the non-infected group. Changes in PGE 2 and LTB 4 levels did not correlate with any particular clinical presentations of COVID-19. However, LTB 4 was related to decreased SARS-CoV-2 burden in patients, suggesting that only LTB 4 is associated with control of viral load., Conclusions: Our data indicate that PGE 2 /LTB 4 plasma levels are not associated with COVID-19 clinical severity. Hospitalized patients with COVID-19 are treated with corticosteroids, which may influence the observed eicosanoid imbalance. Additional analyses are required to fully understand the participation of PGE 2 receptors in the pathophysiology of COVID-19., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Patients with severe coronavirus disease 2019 (COVID-19) often present with coagulopathies and have high titres of circulating antibodies against viral proteins., Objectives: Herein, we evaluated the association between D-dimer and circulating immunoglobulin levels against viral proteins in patients at different clinical stages of COVID-19., Methods: For this, we performed a cross-sectional study involving patients of the first wave of COVID-19 clinically classified as oligosymptomatic (n = 22), severe (n = 30), cured (n = 27) and non-infected (n = 9). Next, we measured in the plasma samples the total and fraction of immunoglobulins against the nucleoprotein (NP) and the receptor-binding domain (RBD) of the spike proteins by enzyme-linked immunosorbent assay (ELISA) assays., Findings: Patients with severe disease had a coagulation disorder with high levels of D-dimer as well as circulating IgG against the NP but not the RBD compared to other groups of patients. In addition, high levels of D-dimer and IgG against the NP and RBD were associated with disease severity among the patients in this study., Main Conclusions: Our data suggest that IgG against NP and RBD participates in the worsening of COVID-19. Although the humoral response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is partially understood, and more efforts are needed to clarify gaps in the knowledge of this process.

Context.—: The gold standard test to identify the presence of SARS-CoV-2 in COVID-19 patients is the real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR), but inconclusive data and false-positive diagnosis remain the major problem of this approach., Objective.—: To compare the fitness of 2 primer sets to the SARS-CoV-2 nucleocapsid phosphoprotein gene (NP) in the molecular diagnosis of COVID-19, we verified the inconclusive data and confidence of high cycle threshold (Ct) values in SARS-CoV-2 detection., Design.—: The 970 patient samples were tested by using United States Centers for Disease Control and Prevention protocol. We compared the fitness of 2 primer sets to 2 different regions of the NP gene. In addition, we checked the consistency of positive samples with high Ct values by retesting extracted SARS-CoV-2 RNA or by second testing of patients., Results.—: N1 and N2 displayed similar fitness during testing, with no differences between Ct values. Then, we verified security range Ct values related to positive diagnostics, with Ct values above 34 failing in 21 of 32 cases (65.6%) after retesting of samples. The patient samples with Ct values above 34.89 that were doubly positive revealed a low sensitivity (52.4%) and specificity (63.6%) of the test in samples with Ct values above 34., Conclusions.—: It is safe to use 1 primer set for the NP gene to identify SARS-CoV-2 in samples. However, samples with high Ct values may be considered inconclusive and retested to avoid false-positive diagnosis., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article.

Background: Few studies have examined the association between APOE genotype and alcohol use. Although some of these studies have reported outcomes associated with a history of drinking, none have examined alcohol-seeking behavior. In addition, no preclinical studies have examined alcohol use as a function of APOE genotype with or without traumatic brain injury., Methods: Male and female human APOE3- and APOE4-targeted replacement (TR) mice were used to assess voluntary alcohol seeking longitudinally using a 2-bottle choice paradigm conducted within the automated IntelliCage system prior to and following repeated mild TBI (rmTBI). Following an acquisition phase in which the concentration of ethanol (EtOH) was increased to 12%, a variety of drinking paradigms that included extended alcohol access (EAA1 and EAA2), alcohol deprivation effect (ADE), limited access drinking in the dark (DID), and progressive ratio (PR) were used to assess alcohol-seeking behavior. Additional behavioral tasks were performed to measure cognitive function and anxiety-like behavior., Results: All groups readily consumed increasing concentrations of EtOH (4-12%) during the acquisition phase. During the EAA1 period (12% EtOH), there was a significant genotype effect in both males and females for EtOH preference. Following a 3-week abstinence period, mice received sham or rmTBI resulting in a genotype- and sex-independent main effect of rmTBI on the recovery of righting reflex and a main effect of rmTBI on spontaneous home-cage activity in females only. Reintroduction of 12% EtOH (EAA2) resulted in a significant effect genotype for alcohol preference in males with APOE4 mice displaying increased preference and motivation for alcohol compared with APOE3 mice independent of TBI while in females, there was a significant genotype × TBI interaction under the ADE and DID paradigms. Finally, there was a main effect of rmTBI on increased risk-seeking behavior in both sexes, but no effect on spatial learning or cognitive flexibility., Conclusion: These results suggest that sex and APOE genotype play a significant role in alcohol consumption and may subsequently influence long-term recovery following traumatic brain insults., (© 2021 by the Research Society on Alcoholism.)

It is not clear if COVID-19 can be indirectly transmitted. It is not possible to conclude the role of the environment in transmission of SARS-CoV-2 without studying areas in which people transit in great numbers. In this work we aimed to better understand the role of environment in the spread of COVID-19. We investigated the presence of SARS-CoV-2 in fomites as well as in the air and in the sewage using RT-qPCR. We studied both, a reference market area and a COVID-19 reference hospital at Barreiras city, Brazil. We collected and analyzed a total of 418 samples from mask fronts, cell phones, paper money, card machines, sewage, air and bedding during the ascendant phase of the epidemiological curve of COVID-19 in Barreiras. As a result, we detected the human RNAse P gene in most of samples, which indicates the presence of human cells or their fragments in specimens. However, we did not detect any trace of SARS-CoV-2 in all samples analyzed. We conclude that, so far, the environment and inanimate materials did not have an important role in COVID-19 transmission in Barreiras city. Therefore, similar results can probably be found in other cities, mainly those with COVID-19 epidemiological scenarios similar to that of Barreiras city. Our study is a small piece indicating the possibility that fomites and the environment do not have an important role in COVID-19 transmission. However, further studies are necessary to better understand the world scenario., (© 2021. The Author(s).)

Serotonin (5-HT) receptors are found throughout central and peripheral nervous systems, mainly in brain regions involved in the neurobiology of anxiety and depression. 5-HT receptors are currently promising targets for discovering new drugs for treating disorders ranging from migraine to neuropsychiatric upsets, such as anxiety and depression. It is well described in the current literature that the brain expresses seven types of 5-HT receptors comprising eighteen distinct subtypes. In this article, we comprehensively reviewed 5-HT1-7 receptors. Of the eighteen 5-HT receptors known today, thirteen are G protein-coupled receptors (GPCRs) and represent targets for approximately 40% of drugs used in humans. Signaling pathways related to these receptors play a crucial role in neurodevelopment and can be modulated to develop effective therapies to treat anxiety and depression. This review presents the experimental evidence of the modulation of the "serotonergic receptosome" in the treatment of anxiety and depression, as well as demonstrating state-of-the-art research related to phytochemicals and these disorders. In addition, detailed aspects of the pharmacological mechanism of action of all currently known 5-HT receptor families were reviewed. From this review, it will be possible to direct the rational design of drugs towards new therapies that involve signaling via 5-HT receptors.

Rationale: Ethanol can enhance GABA release in various brain regions via presynaptic mechanisms. However, the presynaptic action of ethanol on inhibitory GABA release is still not well understood., Objectives: Since calcium is required for neurotransmitter release from presynaptic terminals, the purpose of this study was to investigate the role of both internal and external calcium signaling in ethanol-induced enhancement of GABA release within the central amygdala nucleus (CeA) in acute brain slice preparations., Methods: Whole-cell patch clamp electrophysiology was used to record miniature GABA A receptor-mediated inhibitory postsynaptic currents (mIPSCs) from CeA neurons. Ethanol-enhanced mIPSCs were recorded in the presence of antagonists that regulate internal and external calcium-mediated processes., Results: Bath-applied ethanol dose-dependently increased the mean frequency of mIPSCs without altering mIPSC amplitude. Ethanol-induced increases in mIPSC frequency were antagonized by dantrolene, 2-APB, and the endoplasmic reticulum calcium pump (SERCA) antagonists thapsigargin and cyclopiazonic acid (CPA). Blocking calcium release from mitochondria or via exocytosis with ruthenium red also attenuated mIPSCs while frequency was not altered in the presence of a non-selective calcium channel blocker cadmium. The L-type calcium blocker nifedipine, but not its analogue nimodipine, blocked ethanol-induced enhancement in CeA neurons., Conclusions: These results demonstrate ethanol-induced presynaptic release of GABA is mediated by internal calcium stores and by disrupting neurotransmitter exocytosis within the CeA, a critical brain area involved in drugs of abuse and alcohol addiction.

The antivirulence approach to fighting biofilm-based infections caused by Staphylococcus aureus is a promising therapy that has been studied extensively. Here, we compare the antibiofilm activity of a purified lectin from Bothrops jararacussu venom (BJcuL) and commercial lectins obtained from Triticum vulgaris (Wheat Germ Agglutinin, WGA), Bandeiraea simplicifolia BS-II, and Maclura pomifera. Only WGA had antibiofilm activity, although no effect was seen on pre-formed biofilms. The pre-incubation of WGA and BJcuL with their preferential sugars inhibited the biological activity of WGA, but not that of BJcuL, suggesting that biofilm disruption does not involve carbohydrate-recognition domains (CRDs). Quantitative real-time PCR showed that BJcuL promotes modulation of expression of S. aureus genes involved in biofilm formation. Light microscopy revealed cocci and small cell clusters after biofilm formation in the presence of BJcuL, showing that the lectin treatment was unable to completely disrupt biofilm structure. Exposing the free cells to 50 times the minimum inhibitory concentration of gentamicin or ciprofloxacin did not prevent biofilm reestablishment, although inhibition was stronger than in the control (no lectin). This disruption of the biofilm architecture can expose the bacterial cell and may facilitate clearance by the immune system., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Significance: Historically, honey has been regarded as a potent agent in bacterial inhibition and wound healing. An increased prevalence of antibiotic resistant pathogens spurred an initial resurgence in honey's clinical popularity, with it quickly finding a place in wound care and regenerative medicine. However, this renewed usage demanded a need for improved delivery and overall research of its bioactive properties. This review provides an overview of the antibacterial properties and clinical use of honey. Recent Advances: The past and present clinical use of honey is noted, focusing specifically on burns and ulcers, as these are the most common applications of the natural agent. While honey is often used without modification clinically, there are also commercially available products ranging from dressings to gels, which are discussed. Critical Issues: Despite these products growing in popularity, the need for improved delivery and a structure to support wound healing could improve the treatment method. Future Directions: Tissue engineering scaffolds can provide an alternative method of honey delivery with research focusing primarily on electrospun scaffolds, hydrogels, and cryogels. Current studies on these scaffolds are discussed with respect to their advantages and potential for future clinical work. Overall, this review provides a comprehensive overview of the properties of honey, its current use in wound healing, and the potential for future incorporation into tissue-engineered scaffolds to provide an innovative wound healing agent., Competing Interests: No competing financial interests exist. The content of this article was expressly written by the authors listed. No ghostwriters were used to write this article., (Copyright 2019, Mary Ann Liebert, Inc., publishers.)

The molecular biology era, together with morphology, molecular phylogenetics, bioinformatics, and high-throughput sequencing technologies, improved the taxonomic identification of Argasidae family members, especially when considering specimens at different development stages, which remains a great difficulty for acarologists. These tools could provide important data and insights on the history and evolutionary relationships of argasids. To better understand these relationships, we sequenced and assembled the first complete mitochondrial genome of Nothoaspis amazoniensis . We used phylogenomics to identify the evolutionary history of this species of tick, comparing the data obtained with 26 complete mitochondrial sequences available in biological databases. The results demonstrated the absence of genetic rearrangements, high similarity and identity, and a close organizational link between the mitogenomes of N . amazoniensis and other argasids analyzed. In addition, the mitogenome had a monophyletic cladistic taxonomic arrangement, encompassed by representatives of the Afrotropical and Neotropical regions, with specific parasitism in bats, which may be indicative of an evolutionary process of cospeciation between vectors and the host., Competing Interests: The authors declare that they have no conflict of interest.

The mitogenome of Amblyomma sculptum was sequenced, providing important information for understanding the evolutionary relationships among species of the A. cajennense complex. The mitochondrial genome has a circular structure with 37 genes, including 13 coding DNA sequences, two ribosomal RNA genes (12S rRNA and 16S rRNA) and 22 tRNA genes. Comparative analysis with the mitogenomes of six reference species of the genus Amblyomma revealed that the ND5 gene, which is related to energy metabolism, and control regions 1 and 2 of the mitogenomes have polymorphisms that can be exploited as molecular markers to differentiate A. sculptum from other tick species in the Amblyomma cajennense complex as well as other Amblyomma species., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Traumatic brain injury (TBI) is a leading cause of death and disability among young adults and is highly prevalent among recently deployed military personnel. Survivors of TBI often experience cognitive and emotional deficits, suggesting that long-term effects of injury may disrupt neuronal function in critical brain regions, including the amygdala, which is involved in emotion and fear memory. Amygdala hyperexcitability has been reported in both TBI and posttraumatic stress disorder patients, yet little is known regarding the effects of combined stress and TBI on amygdala structure and function at the neuronal level. The present study seeks to determine how the long-term effects of preinjury foot-shock stress and TBI interact to influence synaptic plasticity in the lateral amygdala (LA) of adult male C57BL/6J mice by using whole-cell patch clamp electrophysiology 2-3 months postinjury. In the absence of stress, TBI resulted in a significant increase in membrane excitability and spontaneous excitatory postsynaptic currents (sEPSCs) in LA pyramidal-like neurons. Foot-shock stress in the absence of TBI also resulted in increased sEPSC activity. In contrast, when preinjury stress and TBI occurred in combination, sEPSC activity was significantly decreased compared with either condition alone. There were no significant differences in inhibitory activity or total dendritic length among any of the treatment groups. These results demonstrate that stress and TBI may be contributing to amygdala hyperexcitability via different mechanisms and that these pathways may counterbalance each other with respect to long-term pathophysiology in the LA., (© 2015 Wiley Periodicals, Inc.)

Here, we present the draft genome sequences of four Staphylococcus aureus strains isolated from mastitic milk collected from animals with subclinical manifestations. Three of them were typed as sequence type 126 (ST126), a genotype with no genome sequence available. ST126 is found in several herds of southern Brazil and is described as a bovine pathogen strongly associated with milk around the world., (Copyright © 2016 Silva et al.)

Background: Despite the clinical benefit of whole brain radiotherapy (WBRT), patients and physicians are concerned by the long-term impact on cognitive functioning. Many studies investigating the molecular and cellular impact of WBRT have used rodent models. However, there has not been a rodent protocol comparable to the recently reported Radiation Therapy Oncology Group (RTOG) protocol for WBRT with hippocampal avoidance (HA) which is intended to spare cognitive function. The aim of this study was to develop a hippocampal-sparing WBRT protocol in Wistar rats., Methods: The technical and clinical challenges encountered in hippocampal sparing during rat WBRT are substantial. Three key challenges were identified: hippocampal localization, treatment planning, and treatment localization. Hippocampal localization was achieved with sophisticated imaging techniques requiring deformable registration of a rat MRI atlas with a high resolution MRI followed by fusion via rigid registration to a CBCT. Treatment planning employed a Monte Carlo dose calculation in SmART-Plan and creation of 0.5 cm thick lead blocks custom-shaped to match DRR projections. Treatment localization necessitated the on-board image-guidance capability of the XRAD C225Cx micro-CT/micro-irradiator (Precision X-Ray). Treatment was accomplished with opposed lateral fields with 225 KVp X-rays at a current of 13 mA filtered through 0.3 mm of copper using a 40x40 mm square collimator and the lead blocks. A single fraction of 4 Gy was delivered (2 Gy per lateral field) with a 41 second beam on time per field at a dose rate of 304.5 cGy/min. Dosimetric verification of hippocampal sparing was performed using radiochromic film. In vivo verification of HA was performed after delivery of a single 4 Gy fraction either with or without HA using γ-H2Ax staining of tissue sections from the brain to quantify the amount of DNA damage in rats treated with HA, WBRT, or sham-irradiated (negative controls)., Results: The mean dose delivered to radiochromic film beneath the hippocampal block was 0.52 Gy compared to 3.93 Gy without the block, indicating an 87% reduction in the dose delivered to the hippocampus. This difference was consistent with doses predicted by Monte Carlo dose calculation. The Dose Volume Histogram (DVH) generated via Monte Carlo simulation showed an underdose of the target volume (brain minus hippocampus) with 50% of the target volume receiving 100% of the prescription isodose as a result of the lateral blocking techniques sparing some midline thalamic and subcortical tissue. Staining of brain sections with anti-phospho-Histone H2A.X (reflecting double-strand DNA breaks) demonstrated that this treatment protocol limited radiation dose to the hippocampus in vivo. The mean signal intensity from γ-H2Ax staining in the cortex was not significantly different from the signal intensity in the cortex of rats treated with WBRT (5.40 v. 5.75, P = 0.32). In contrast, the signal intensity in the hippocampus of rats treated with HA was significantly lower than rats treated with WBRT (4.55 v. 6.93, P = 0.012)., Conclusion: Despite the challenges of planning conformal treatments for small volumes in rodents, our dosimetric and in vivo data show that WBRT with HA is feasible in rats. This study provides a useful platform for further application and refinement of the technique.

Although suramin (Sur) is suggested as a potential drug candidate in the management of Chagas disease, this issue has not been objectively tested. In this study, we examined the applicability of concomitant treatment with benznidazole (Bz) and suramin in mice infected with a virulent strain of Trypanosoma cruzi. Eighty 12-week-old male C57BL/6 mice were equally randomized in eight groups: (i) noninfected mice (negative control) and mice infected with T. cruzi Y strain receiving (ii) no treatment (positive control), (iii) Bz, 100 mg/kg of body weight per day, (iv) Sur, 20 mg/kg/day, and (v to viii) Sur, 20 mg/kg/day, combined with Bz, 100, 50, 25, or 5 mg/kg/day. Bz was administered by gavage, and Sur was administered intraperitoneally. Sur dramatically increased the parasitemia, cardiac content of parasite DNA, inflammation, oxidative tissue damage, and mortality. In response to high parasitic load in cardiac tissue, Sur stimulated the immune system in a manner typical of the acute phase of Chagas disease, increasing tissue levels of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) and inducing a preferential IgG2a anti-T. cruzi serum pattern. When Sur and Bz were combined, the infection severity was attenuated, showing a dose-dependent Bz response. Sur therapy had a more harmful effect on the host than on the parasite and reduced the efficacy of Bz against T. cruzi infection. Considering that Sur drastically reinforced the infection evolution, potentiating the inflammatory process and the severity of cardiac lesions, the in vivo findings contradicted the in vitro anti-T. cruzi potential described for this drug., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: Human adolescence is a crucial stage of neurological development during which ethanol (EtOH) consumption is often at its highest. Alcohol abuse during adolescence may render individuals at heightened risk for subsequent alcohol abuse disorders, cognitive dysfunction, or other neurological impairments by irreversibly altering long-term brain function. To test this possibility, we modeled adolescent alcohol abuse (i.e., intermittent EtOH exposure during adolescence [AIE]) in rats to determine whether adolescent exposure to alcohol leads to long-term structural and functional changes that are manifested in adult neuronal circuitry., Methods: We specifically focused on hippocampal area CA1, a brain region associated with learning and memory. Using electrophysiological, immunohistochemical, and neuroanatomical approaches, we measured post-AIE changes in synaptic plasticity, dendritic spine morphology, and synaptic structure in adulthood., Results: We found that AIE-pretreated adult rats manifest robust long-term potentiation, induced at stimulus intensities lower than those required in controls, suggesting a state of enhanced synaptic plasticity. Moreover, AIE resulted in an increased number of dendritic spines with characteristics typical of immaturity. Immunohistochemistry-based analysis of synaptic structures indicated a significant decrease in the number of co-localized pre- and postsynaptic puncta. This decrease is driven by an overall decrease in 2 postsynaptic density proteins, PSD-95 and SAP102., Conclusions: Taken together, these findings reveal that repeated alcohol exposure during adolescence results in enduring structural and functional abnormalities in the hippocampus. These synaptic changes in the hippocampal circuits may help to explain learning-related behavioral changes in adult animals preexposed to AIE., (Copyright © 2015 by the Research Society on Alcoholism.)

Background: The apolipoprotein E (APOE) ε4 allele has been implicated in a range of neuropsychiatric conditions. The present research examined if the ε4 allele of the APOE gene moderated the effect of combat exposure on posttraumatic stress disorder (PTSD) among Iraq/Afghanistan-era veterans., Method: Participants included 765 non-Hispanic White (NHW) and 859 non-Hispanic Black (NHB) Iraq/Afghanistan-era veterans. A structured interview established psychiatric diagnoses. Combat exposure and PTSD symptom severity were assessed via self-report., Results: The most common lifetime diagnoses were depression (39.2%), PTSD (38.4%), and alcohol dependence (24.38%). After correcting for multiple comparisons, no significant effects were observed on any of the outcomes among the NHW sample; however, within the NHB sample, significant gene × environment (G × E) interactions were observed for lifetime PTSD (P = .0029) and PTSD symptom severity (P = .0009). In each case, the APOE ε4 allele had no effect on the outcomes when combat exposure was low; however, when combat exposure was high, an additive effect was observed such that ε4 homozygotes exposed to high levels of combat reported the highest rates of PTSD (92%) and the worst symptom severity scores on the Davidson Trauma Scale (M = 79.5)., Conclusions: Although preliminary, these findings suggest that the APOE ε4 allele, in conjunction with exposure to high levels of combat exposure, may increase veterans' risk for developing PTSD., (© 2015 Wiley Periodicals, Inc.)

Bovine mastitis is a major threat to animal health and the dairy industry. Staphylococcus aureus is a contagious pathogen that is usually associated with persistent intramammary infections, and biofilm formation is a relevant aspect of the outcome of these infections. Several biological activities have been described for snake venoms, which led us to screen secretions of Bothrops jararacussu for antibiofilm activity against S. aureus NRS155. Crude venom was fractionated by size-exclusion chromatography, and the fractions were tested against S. aureus. Biofilm growth, but not bacterial growth, was affected by several fractions. Two fractions (15 and 16) showed the best activities and were also assayed against S. epidermidis NRS101. Fraction 15 was identified by TripleTOF mass spectrometry as a galactose-binding C-type lectin with a molecular weight of 15 kDa. The lectin was purified from the crude venom by D-galactose affinity chromatography, and only one peak was observed. This pure lectin was able to inhibit 75% and 80% of S. aureus and S. epidermidis biofilms, respectively, without affecting bacterial cell viability. The lectin also exhibited a dose-dependent inhibitory effect on both bacterial biofilms. The antibiofilm activity was confirmed using scanning electron microscopy. A pre-formed S. epidermidis biofilm was significantly disrupted by the C-type lectin in a time-dependent manner. Additionally, the lectin demonstrated the ability to inhibit biofilm formation by several mastitis pathogens, including different field strains of S. aureus, S. hyicus, S. chromogenes, Streptococcus agalactiae, and Escherichia coli. These findings reveal a new activity for C-type lectins. Studies are underway to evaluate the biological activity of these lectins in a mouse mastitis model.

Staphylococcus aureus is a significant pathogen frequently causing persistent intramammary infections (IMI) in dairy cows. We compared some genotypic and phenotypic characteristics of 285 strains collected from quarter milk samples from cows with persistent and nonpersistent subclinical IMI across Canada. Variable number of tandem repeats typing was used to infer the persistence of the same S. aureus strain in 3 consecutive quarter milk samples collected at intervals of 3 wk during lactation or before and after dry-off. All first isolates of the series were used as the representative strains from persistent IMI and were compared with nonpersistent strains for the presence of genes seg, sen, sec, and tst as well as by spa typing. Biofilm production in vitro and hld-RNAIII expression levels were also quantified. The gene seg was associated with a reduction in the likelihood of the bacteria to cause a persistent IMI during lactation. Strains persisting through the dry period produced significantly more biofilm in vitro than strains that do not persist after calving. Also, we showed that strains expressing more hld were more likely to be nonpersistent during either lactation or through the dry period. Three spa types were predominant (t529, t267, and a novel type: t13401). In the strains studied, the spa type tbl 2645 was the most frequent, and 97.0% of the strains of this spa type carried both sen and seg. Strains from the spa type tbl 2645 were less likely to cause a persistent IMI in the dry period. Most (86.7%) of the strains of the novel spa type (t13401) were negative for seg, sen, or both and produced significantly more biofilm in vitro than tbl 2645 and t267. The present study expanded our current knowledge on the genotypic and phenotypic traits of S. aureus strains recovered from persistent and nonpersistent IMI in Canada., (Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

The human APOE4 allele is associated with an early age of onset and increased risk of Alzheimer's disease (AD). Apolipoprotein E is secreted as part of a high-density lipoprotein-like particle by glial cells in the brain for the primary purpose of transport of lipophilic compounds involved in the maintenance of synapses. Previous studies examining synaptic integrity in the amygdala of human apoE targeted replacement (TR) mice showed a decrease in spontaneous excitatory synaptic activity, dendritic arbor, and spine density associated with apoE4 compared with apoE3 and apoE2 in adult male mice. In the present study, we assessed how APOE genotype affects synaptic integrity of amygdala neurons by comparing electrophysiological and morphometric properties in human apoE3, E4, and E2/4 TR mice at the age of 18-20 months. In contrast to adult mice, we found that aged apoE4 TR mice exhibited the highest level of excitatory synaptic activity compared with other cohorts. Additionally, apoE4 mice had significantly greater spontaneous inhibitory activity than all other cohorts. Taken together, there was a significant interaction between genotypes when comparing inhibition relative to excitation; there was a simple main effect of frequency type with an imbalance toward inhibition in apoE4 mice but not in apoE3 or apoE2/4 mice. These results suggest that apoE isoforms differentially influence synaptic transmission throughout the life span, where aging coupled with apoE4 expression, results in an imbalance in maintaining integrity of synaptic transmission., (Published by Elsevier Inc.)

The human apolipoprotein ε4 allele (APOE4) has been implicated as one of the strongest genetic risk factors associated with Alzheimer's disease (AD) and in influencing normal cognitive functioning. Previous studies have demonstrated that mice expressing human apoE4 display deficits in behavioral and neurophysiological outcomes compared to those with apoE3. Ovarian hormones have also been shown to be important in modulating synaptic processes underlying cognitive function, yet little is known about how their effects are influenced by apoE. In the current study, female adult human APOE targeted replacement (TR) mice were utilized to examine the effects of human APOE genotype and long-term ovarian hormone loss on synaptic plasticity in limbic regions by measuring dendritic spine density and electrophysiological function. No significant genotype differences were observed on any outcomes within intact mice. However, there was a significant main effect of genotype on total spine density in apical dendrites in the hippocampus, with post-hoc t-tests revealing a significant reduction in spine density in apoE3 ovariectomized (OVX) mice compared to sham operated mice. There was also a significant main effect of OVX on the magnitude of LTP, with post-hoc t-tests revealing a decrease in apoE3 OVX mice relative to sham. In contrast, apoE4 OVX mice showed increased synaptic activity relative to sham. In the lateral amygdala, there was a significant increase in total spine density in apoE4 OVX mice relative to sham. This increase in spine density was consistent with a significant increase in spontaneous excitatory activity in apoE4 OVX mice. These findings suggest that ovarian hormones differentially modulate synaptic integrity in an apoE-dependent manner within brain regions that are susceptible to neurophysiological dysfunction associated with AD.

This report describes efforts over a more than a 15-year period to improve air quality and reduce exposures to formaldehyde during anatomical dissections at the Yale University School of Medicine, including first-year medical student gross anatomy classes. During this time, a number of steps were taken to improve general ventilation system efficiency and work practices in the original facility. Subsequently, during the design phase for a new research and teaching building, a new anatomical laboratory was planned to incorporate 42 individually ventilated dissection tables. The tables were customized from a commercially available design to operate at lower volumetric airflow rates while still providing a high degree of formaldehyde containment. Air monitoring performed throughout this time period showed progressive reductions in formaldehyde exposure as ventilation modifications were made. However, significant reductions only occurred after the installation of the ventilated tables. Personal and area exposure monitoring during thoracic and abdominal dissections now show a five- to tenfold reduction in formaldehyde exposure compared to previous operations, with exposures consistently below 0.1 ppm.

Staphylococcus aureus is a leading cause of bovine mastitis, a condition in which the udder of the cow is inflamed, reducing the quality and quantity of milk produced. Staphylococcal mastitis is a common infection that can develop into a chronic form. The segregation of infected animals is an important preventive practice but relies on an effective diagnostic method. For this purpose, we constructed a genomic library of S. aureus, and a screening step was conducted with antiserum produced using the total protein extract of the pathogen. The nucleotide sequences of the immunoselected clones were aligned with the genome of bovine S. aureus RF122, which enabled the identification of 65 different loci, including proteins related to metabolism, adhesion and cell wall production, toxins, regulatory proteins, and hypothetical proteins. The subcellular location of the immunoreactive polypeptides was also determined. Fifty-two percent were cytoplasmic, 34 % were located in areas exposed to the host's immune system, and for 14 %, the location could not be determined. In silico analysis of the presence of these proteins in mastitis pathogens showed that Fib, ClfA, and the hypothetical protein SAB0166 were the only proteins specific for S. aureus. Therefore, these proteins are promising candidates for the serodiagnosis of staphylococcal mastitis.

Staphylococcus aureus is a well-armed pathogen that is a leading cause of bovine mastitis. Attempts to define a set of bacterial proteins that are crucial for infection have failed. The identification of these proteins is important to define biomarkers that can be used for diagnostic purposes and to identify potential vaccine targets. In this study, seven genes that encode virulence factors were analyzed in 85 bacterial isolates that were derived from animals with bovine mastitis. The clfB, spa, sdrCDE and fnBP genes were detected in 91.8%, 85.9%, 85.9% and 63.5% of the isolates, respectively. At least one gene was present in all of the strains, while the most prevalent combination was clfB and sdrCDE (82.4%). The genetic diversity of the isolates was high and allowed for clustering into more than 40 groups, with each group containing bacteria collected from different locations. The gene expression of the four most prevalent adhesins was examined in nine genetically distinct strains. No common pattern of expression was observed for the genes, suggesting that the capacity of S. aureus to cause infection may rely on differential expression of the virulence factors in different isolates. Our results conclude that using only one antigen is unlikely to provide effective protection against bovine mastitis and suggest that a combination of at least three adhesins may be more suitable for developing preventive therapies. We also conclude that the characterization of isolates distributed worldwide is necessary to improve our understanding of pathogenesis in the natural populations of S. aureus., (Copyright © 2012 Elsevier B.V. All rights reserved.)

In this work, we have used classical genetics techniques to find improved starter strains to produce cachaça with superior sensorial quality. Our strategy included the selection of yeast strains resistant to 5,5',5″-trifluor-D: ,L: -leucine (TLF) and cerulenin, since these strains produce higher levels of higher alcohols and esters than parental strains. However, no clear relationship was observed when levels of flavoring compounds were compared with the levels expression of the genes (BAT1, BAT2, ATF2, EEB1 genes) involved with the biosynthesis of flavoring compounds. Furthermore, we determined the stability of phenotypes considered as the best indicators of the quality of the cachaça for a parental strain and its segregants. By applying the principal component analysis, a cluster of segregants, showing a high number of characteristics similar to the parental strain, was recognized. One segregant, that was resistant to TLF and cerulenin, also showed growth stability after six consecutive replications on plates containing high concentrations of sugar and ethanol. "Cachaça" produced at laboratory scale using a parental strain and this segregant showed a higher level of flavoring compounds. Both strains predominated in an open fermentative process through seven cycles, as was shown by mitochondrial restriction fragment length polymorphisms analysis. Based on the physical chemical composition of the obtained products, the results demonstrate the usefulness of the developed strategies for the selection of yeast strains to be used as starters in "cachaça" production.

Inheritance of the APOE4 allele is a well established genetic risk factor linked to the development of late onset Alzheimer's disease. As the major lipid transport protein in the central nervous system, apolipoprotein (apo) E plays an important role in the assembly and maintenance of synaptic connections. Our previous work showed that 7 month old human apoE4 targeted replacement (TR) mice displayed significant synaptic deficits in the principal neurons of the lateral amygdala, a region that is critical for memory formation and also one of the primary regions affected in Alzheimer's disease, compared to apoE3 TR mice. In the current study, we determined how age and varying APOE genotype affect synaptic integrity of amygdala neurons by comparing electrophysiological and morphometric properties in C57BL6, apoE knockout, and human apoE3, E4 and E2/4 TR mice at 1 month and 7 months. The apoE4 TR mice exhibited the lowest level of excitatory synaptic activity and dendritic arbor compared to other cohorts at both ages, and became progressively worse by 7 months. In contrast, the apoE3 TR mice exhibited the highest synaptic activity and dendritic arbor of all cohorts at both ages. C57BL6 mice displayed virtually identical synaptic activity to apoE3 TR mice at 1 month; however this activity decreased by 7 months. ApoE knockout mice exhibited a similar synaptic activity profile with apoE4 TR mice at 7 months. Consistent with previous reports that APOE2 confers protection, the apoE4-dependent deficits in excitatory activity were significantly attenuated in apoE2/4 TR mice at both ages. These findings demonstrate that expression of human apoE4 contributes to functional deficits in the amygdala very early in development and may be responsible for altering neuronal circuitry that eventually leads to cognitive and affective disorders later in life., (Copyright © 2010 Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

The inheritance of the varepsilon4 allele of apolipoprotein E (ApoE4) and cholinergic system dysfunction have long been associated with the pathology of Alzheimer's disease (AD). Recently, in vitro studies have established a direct link between ApoE and cholinergic function in that synthetic peptides containing segments of the ApoE protein (ApoE(133-149) and ApoE(141-148)) interact with alpha7 nicotinic acetylcholine receptors (nAChRs) in the hippocampus. This raises the possibility that ApoE peptides may contribute to cognitive impairment in AD in that the hippocampus plays a key role in cognitive functioning. To test this, we acutely infused ApoE peptides into the ventral hippocampus of female Sprague-Dawley rats and assessed the resultant effects on radial-arm maze choice accuracy over a period of weeks after the infusion. Local ventral hippocampal infusion of ApoE peptides caused significant cognitive impairment in radial-arm maze learning that persisted several weeks after the acute infusion. This persisting deficit may be an important model for understanding the relationship between ApoE protein-induced neurotoxicity and cognitive impairment as well as serve as a platform for the development of new therapies to avoid neurotoxicity and cognitive decline.

A variety of peptide ligands are known to inhibit the function of neuronal nicotinic acetylcholine receptors (nAChRs), including small toxins and brain-derived peptides such as beta-amyloid(1-42) and synthetic apolipoproteinE peptides. The myristoylated alanine-rich C kinase substrate (MARCKS) protein is a major substrate of protein kinase C and is highly expressed in the developing and adult brain. The ability of a 25-amino acid synthetic MARCKS peptide, derived from the effector domain (ED), to modulate nAChR activity was tested. To determine the effects of the MARCKS ED peptide on nAChR function, receptors were expressed in Xenopus laevis oocytes, and two-electrode voltage-clamp experiments were performed. The MARCKS ED peptide completely inhibited acetylcholine (ACh)-evoked responses from alpha7 nAChRs in a dose-dependent manner, yielding an IC(50) value of 16 nM. Inhibition of ACh-induced responses was both activity- and voltage-independent. The MARCKS ED peptide was unable to block alpha-bungarotoxin binding. A MARCKS ED peptide in which four serine residues were replaced with aspartate residues was unable to inhibit alpha7 nAChR-mediated currents. The MARCKS ED peptide inhibited ACh-induced alpha4beta2 and alpha2beta2 responses, although with decreased potency. The effects of the MARCKS ED peptide on native nAChRs were tested using acutely isolated rat hippocampal slices. In hippocampal interneurons, the MARCKS ED peptide was able to block native alpha7 nAChRs in a dose-dependent manner. The MARCKS ED peptide represents a novel antagonist of neuronal nAChRs that has considerable utility as a research tool.

A researcher at the author's facility was carrying out a routine surgical procedure in a mouse that was anesthetized with vaporized isoflurane. When the researcher brought an active cauterizer close to the mouse, a flame erupted from the anesthesia nosecone. An investigation concluded that the fire was ignited when the cauterizer came into contact with the oxygen-enriched atmosphere that was streaming from the anesthetic equipment. The author presents recommendations for preventing similar incidents in the future.

Background: Heart rate turbulence (HRT) has been shown to be vagally mediated with a strong correlation to baroreflex indices. However, the relationship between HRT and peripheral sympathetic nerve activity (SNA) after a premature ventricular contraction (PVC) remains unclear., Objective: We sought to evaluate the relationship between HRT and the changes in peripheral SNA after PVCs., Methods: We recorded postganglionic muscle SNA during electrocardiogram monitoring in eight patients with spontaneous PVCs. Fifty-two PVCs were observed and analyzed for turbulence onset (TO) and slope (TS). SNA was quantified during (1) the dominant burst after the PVC (dominant burst area) and (2) the 10 seconds after the dominant burst (postburst SNA)., Results: The mean TO was 0.1% +/- 4.6%, and the mean TS was 6.1 +/- 6.6. The dominant burst area negatively correlated with TO (r = -0.50, P = .0002). The postburst SNA showed a significant positive correlation with TO (r = 0.44, P = .001) and a negative correlation with TS (r = -0.42, P = .002). These correlations remained significant after controlling for either the PVC coupling interval or the left ventricular ejection fraction., Conclusions: Our findings highlight the relationship between perturbations in HRT and pathology in the sympathetic limb of the autonomic nervous system. Future studies are needed to evaluate the prognostic role of baroreflex control of sympathetic activity in patients with structural heart disease.

Background: We have recently shown that atrial fibrillation is associated with an increase in sympathetic nerve activity (SNA) compared with sinus rhythm. It remains unclear, however, whether these findings are true at various rates and whether the magnitude of sympathoexcitation is related to the degree of irregularity., Objective: To determine the role of irregularity in mediating the SNA changes at various pacing rates. Univariate analysis showed that as the irregularity increased, SBP increased (r = 0.44, P < .001) but that MAP and DBP did not change significantly., Methods: Using custom-made software, atrioventricular sequential pacing with predetermined rates (100, 120, and 140 bpm) and irregularities (standard deviation = 0%, 5%, 15%, and 25% of mean cycle length) was performed in 23 patients referred for electrophysiologic evaluation. Pacing at each rate/irregularity was performed for 2 minutes, with 2 minutes of recovery in between. Systolic, diastolic, and mean arterial blood pressure (SBP, DBP, and MAP), central venous pressure (CVP), and SNA were measured at baseline and during pacing., Results: Univariate analysis showed that as the irregularity increased, SBP increased (r = 0.44, P < .001 but that MAP and DBP did not change significantly. A significant correlation was found between the pacing irregularity and SNA, with greater sympathoexcitation noted at greater degrees of irregularity (r = 0.2, P = .04). A five-variable linear model using DBP, MAP, CVP, and degree of pacing irregularity to predict SNA was highly statistically significant (r = 0.46, P < .001). After controlling for hemodynamic changes, for every 1% increase in irregularity, there was a 6.1% increase in SNA., Conclusion: We have shown that greater degrees of irregularity cause greater sympathoexcitation and that the effects of irregular pacing on SNA are independent of the hemodynamic changes.

Multiple subtypes of nicotinic acetylcholine receptors (nAChRs) are expressed in the CNS. The amygdala complex, the limbic structure important for emotional memory formation, receives cholinergic innervation from the basal forebrain. Although cholinergic drugs have been shown to regulate passive avoidance performance via the amygdala, the neuronal subtypes and circuits involved in this regulation are unknown. In the present study, whole-cell patch-clamp electrophysiological techniques were used to identify and characterize the presence of functional somato-dendritic nAChRs within the basolateral complex of the amygdala. Pressure-application of acetylcholine (ACh; 2 mm) evoked inward current responses in a subset of neurons from both the lateral (49%) and basolateral nuclei (72%). All responses displayed rapid activation kinetics, and were blocked by the alpha7-selective antagonist methyllycaconitine. In addition, the alpha7-selective agonist choline induced inward current responses that were similar to ACh-evoked responses. Spiking patterns were consistent with pyramidal class I neurons (the major neuronal type in the basolateral complex); however, there was no correlation between firing frequency and the response to ACh. The local photolysis of caged carbachol demonstrated that the functional expression of nAChRs is located both on the soma and dendrites. This is the first report demonstrating the presence of functional nAChR-mediated current responses from rat amygdala slices, where they may be playing a significant role in fear and aversively motivated memory.

Background: Despite the wide use of antitachycardia pacing (ATP) in patients with implantable cardioverter defibrillators (ICDs), predictors of ATP success remain poorly understood. We hypothesize that the degree of sympathoexcitation, as measured by the sinus cycle length (SCL) shortening during ventricular tachycardia (VT), is a predictor of ATP success., Methods and Results: The charts of 462 patients with dual-chamber ICDs were reviewed. A total of 88 events in 26 patients met the inclusion criteria and were analyzed. The mean SCL during the 4 seconds preceding the VT onset (SCL-baseline), and during the 4 seconds prior to ATP delivery (SCL-VT) was measured. The percent shortening in SCL was calculated as ((SCL-baseline) - (SCL-VT))/(SCL-baseline) x 100. Patients were classified into the ATP-success and ATP-failure groups depending on the VT(s) response to ATP. Using a t-test analogue for clustered data, patients in the ATP-success group exhibited a greater shortening in SCL when compared with the ATP-Failure group (5.8% compared to 4.7%, P = 0.007). The successful ATP events displayed an average SCL shortening of 6.0% compared to 1.8% in the unsuccessful ATP events (P = 0.029). When the events were analyzed, the sensitivity and specificity of a shortening in SCL of >10% in predicting ATP success were 0.29 and 1., Conclusion: We have shown that the SCL change during VT, a marker of the autonomic changes that accompany a tachycardia, is useful in predicting ATP success. Our findings suggest that analysis of the SCL during VT might play a role in future programming of ATP in patients with ICDs.

For decades, the pathology of Alzheimer's disease has been associated with dysfunction of cholinergic signaling; however, the cellular mechanisms by which nicotinic acetylcholine receptor (nAChR) function is impaired in Alzheimer's disease are as yet unknown. The most significant genetic risk factor for the development of Alzheimer's disease is inheritance of the epsilon4 allele of apolipoprotein E (apoE). Recent data have demonstrated the ability of apoE-derived peptides to inhibit nAChRs in rat hippocampus. In the current study, the functional interaction between nAChRs and apoE-derived peptides was investigated in Xenopus oocytes expressing selected nAChRs. Both a 17-amino acid peptide fragment, apoE(133-149), and an eight-amino acid peptide, apoE(141-148), were able to maximally block acetylcholine (ACh)-mediated peak current responses for homomeric alpha7 nAChRs. ApoE peptide inhibition was dose-dependent and voltage- and activity-independent. The current findings suggest that apoE peptides are noncompetitive for acetylcholine and do not block functional alpha-bungarotoxin binding. ApoE peptides had a significantly decreased ability to inhibit ACh-mediated peak current responses for alpha4beta2 and alpha2beta2 nAChRs. Amino acid substitutions in the apoE peptide sequence suggest that the arginines are critical for peptide blockade of the alpha7 nAChR. The current data suggest that apoE fragments can disrupt nAChR signaling through a direct blockade of alpha7 nAChRs. These results may be useful in elucidating the mechanisms underlying memory loss and cognitive decline seen in Alzheimer's disease as well as aid in the development of novel therapeutics using apoE-derived peptides.

Diverse subtypes of nicotinic acetylcholine receptors (nAChRs), including fast-desensitizing alpha7-containing receptors, are expressed in the CNS. While nAChRs appear to regulate cognitive processing and synaptic plasticity, little is known to date about how this regulation occurs, particularly in brain regions known to be important for cognition. By combining patch-clamp electrophysiology with local photolysis of caged carbachol to rapidly activate the alpha7-containing nAChRs in rat hippocampal CA1 stratum radiatum interneurones in slices, we describe a novel transient up-regulation of channel function. The nAChRs were activated using a paired-pulse uncaging protocol, where the duration of the UV laser pulses (5-25 ms) and the interval between pulses (200 ms to 30 s) were varied. At relatively long interpulse intervals, we observed a strong (> 75%) decrease in the amplitude of the second response due to desensitization. However, when two pulses were applied at a 200 ms interval, a > 3-fold increase in the amplitude of the second response was observed, a phenomenon referred to here as paired-pulse potentiation. Interestingly, this potentiation appeared to be regulated by [Ca2+]i, and/or Ca2+-dependent processes, as it was significantly enhanced by dialysing cells with either the Ca2+ chelator BAPTA, or with peptide inhibitors of either calcineurin or PKC, and was attenuated by dialysing cells with the CaMKII inhibitor KN-93. No potentiation was observed using caged GABA or glutamate, indicating some specificity for nAChRs. Thus, rat hippocampal alpha7-containing nAChRs possess a newly described phenomenon of paired-pulse potentiation that may be involved in regulating synaptic plasticity in the hippocampus.

The differentiation between progressive supranuclear palsy (PSP) and Parkinson's disease (PD) may be difficult, especially in the early stages of disease. Positron emission tomography potentially provides a tool for making such a distinction. To identify key features in the spatial distributions of cerebral glucose metabolism, 18F-fluorodeoxyglucose (FDG) measurements of 10 patients with probable or possible PSP were directly compared with those of 9 PD patients. This analysis was done with statistic parametric mapping. After normalization of global brain uptake, in PSP, relative uptake of FDG was reduced in the caudal (motor) part of the anterior cingulate gyrus (Brodmann's area BA 24; P < 0.05, corrected for multiple comparisons). At a lower threshold, an additional decrease was present in the dorsal mesencephalon. In PD, relative hypometabolism was seen in extrastriate visual, ventrolateral temporal, posterior parietal, and orbitofrontal regions. Only reduction in the right fusiform gyrus and the lateral extrastriate visual cortex reached statistical significance. We concluded that particularly the reduction of medial frontal metabolism may be a valuable diagnostic imaging parameter in distinguishing PSP from PD. For PD, a possible association between occipitotemporal FDG decrease and vulnerability to hallucinations is suggested., (Copyright 2005 Movement Disorder Society)

We compared 2 studies of implantable cardiac defibrillators (ICDs) to determine the effects of device mode on outcomes. The Antiarrhythmics Versus Implantable Defibrillators (AVID) trial (1993 to 1997) demonstrated improved survival with the ICD compared with antiarrhythmic drug therapy. The Dual-chamber And VVI Implantable Defibrillator (DAVID) trial (2000 to 2002) showed that VVI pacing at 40 beats/min in patients with ICDs reduced the combined end point of death and hospitalization for congestive heart failure compared with DDDR pacing at 70 beats/min. Patients in the AVID trial (631 of 1,016) and the DAVID trial (221 of 506) meeting common inclusion and all exclusion criteria were studied. The major end points were the time to death, and the composite end point of time to death or hospitalization for congestive heart failure. Patients in the AVID and DAVID trials were similar, but more AVID patients had coronary artery disease (p = 0.04), history of myocardial infarction (p = 0.005), and previous ventricular arrhythmias (p = 0.03). DAVID patients underwent more previous revascularization procedures (coronary artery bypass surgery, p = 0.03; percutaneous coronary intervention, p = 0.001), and were more often taking beta-blocking drugs at hospital discharge (p <0.001). The backup VVI ICD groups in both studies had similar outcomes (p = 0.4), even when corrected for the previous demographic differences. The time-to- composite end point was similar in AVID patients treated with antiarrhythmic drugs and DAVID patients treated with DDDR ICDs (p = 0.6). Despite improved pharmacologic therapy and revascularization, outcomes have not improved with backup VVI pacing ICDs. If DDDR ICDs had been used in the AVID trial, benefit from ICDs for patients with serious ventricular arrhythmias could have been missed.

Background: The AFFIRM Study showed that treatment of patients with atrial fibrillation and a high risk for stroke or death with a rhythm-control strategy offered no survival advantage over a rate-control strategy in an intention-to-treat analysis. This article reports an "on-treatment" analysis of the relationship of survival to cardiac rhythm and treatment as they changed over time., Methods and Results: Modeling techniques were used to determine the relationships among survival, baseline clinical variables, and time-dependent variables. The following baseline variables were significantly associated with an increased risk of death: increasing age, coronary artery disease, congestive heart failure, diabetes, stroke or transient ischemic attack, smoking, left ventricular dysfunction, and mitral regurgitation. Among the time-dependent variables, the presence of sinus rhythm (SR) was associated with a lower risk of death, as was warfarin use. Antiarrhythmic drugs (AADs) were associated with increased mortality only after adjustment for the presence of SR. Consistent with the original intention-to-treat analysis, AADs were no longer associated with mortality when SR was removed from the model., Conclusions: Warfarin use improves survival. SR is either an important determinant of survival or a marker for other factors associated with survival that were not recorded, determined, or included in the survival model. Currently available AADs are not associated with improved survival, which suggests that any beneficial antiarrhythmic effects of AADs are offset by their adverse effects. If an effective method for maintaining SR with fewer adverse effects were available, it might be beneficial.

Apolipoprotein E (ApoE) is a well-known genetic risk factor for Alzheimer's disease (AD). Dysfunctions in cholinergic signaling, and in particular in the function of neuronal nicotinic acetylcholine receptors (nAChRs), have also been linked with AD and cognition. To address whether there is a link between ApoE and nAChR function, we used electrophysiological techniques to test the effects of synthetic ApoE-mimetic peptides derived from the low-density lipoprotein receptor (LDLR) binding domain for the ability to modulate nAChR activity in hippocampal interneurons. ApoE(133-149) completely inhibited ACh-evoked responses in a dose-dependent manner, yielding an IC(50) value of 720+/-70 nM. A shorter peptide spanning residues 141-148 mimicked this effect while a second peptide spanning residues 133-140 was without effect, indicating that the arginine-rich domain is responsible for nAChR interaction. Inhibition of ACh-evoked responses was voltage-independent, and displayed partial receptor specificity as no effect on glycine- or GABA-evoked responses occurred. These results demonstrate that peptides derived from the LDLR binding domain of ApoE block the function of nAChRs in hippocampal slices, an interaction that may have implications for AD.

Because of a significant survival benefit in the defibrillator arm of the Antiarrhythmics versus Implantable Defibrillator (AVID) Trial, patients in the antiarrhythmic drug (AAD) arm were advised to undergo ICD implantation. Despite this recommendation, ICD implantation in AAD patients was variable, with a large number of patients not undergoing ICD implantation. Patients were grouped by those who had been on AAD < 1 year (n = 111) and those on AAD > 1 year (n = 223). Multiple clinical and socioeconomic factors were evaluated to identify those who might be associated with a decision to implant an ICD. The primary reason for patients not undergoing ICD implantation was collected, as well as reasons for a delayed implantation, occurring later than 3 months from study termination. Of 111 patients on AAD for less than 1 year, 53 received an ICD within 3 months compared to 40/223 patients on AAD for more than 1 year (P < 0.001). Patient refusal was the most common reason to not implant an ICD in patients on drug < 1 year; physician recommendation against implantation was the most common in patients on drug > 1 year. Multivariate analysis showed ICD recipients on AAD < 1 year were more likely to be working and have a history of myocardial infarction (MI), while those on AAD > 1 year were more likely to be working, have a history of MI and ventricular fibrillation, and less likely to have experienced syncope, as compared to those who did not get an ICD. Having private insurance may have played a role in younger patients receiving an ICD.