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Background and Aims: Hyperlipidemia leads to the accumulation of oxidized low-density lipoprotein (oxLDL) within the vessel wall where it causes chronic inflammation in endothelial cells (ECs) and drives atherosclerotic lesions. Although focal adhesion kinase (FAK) is critical in proinflammatory NF-κB activation in ECs, it is unknown if hyperlipidemia alters FAK-mediated NF-κB activity in vivo to affect atherosclerosis progression., Methods: We investigated changes in EC FAK and NF-κB activation using Apoe -/- mice fed a western diet (WD). Both pharmacological FAK inhibition and EC-specific FAK inhibited mouse models were utilized. FAK and NF-κB localization and activity were also analyzed in human atherosclerotic samples., Results: ECs of hyperlipidemic mice clearly showed much higher levels of FAK activation in the cytoplasm, which was associated with increased NF-κB activation compared to normal diet (ND) group. On the contrary, FAK is mostly localized in the nucleus and inactive in ECs under healthy conditions with a low NF-κB activity. Both pharmacological and EC-specific genetic FAK inhibition in WD fed Apoe -/- mice exhibited a significant decrease in FAK activity and cytoplasmic localization, NF-κB activation, macrophage recruitment, and atherosclerotic lesions compared to the vehicle or FAK wild-type groups. Analyses of human atherosclerotic specimens revealed a positive correlation between increased active cytoplasmic FAK within ECs and NF-κB activation in the lesions., Conclusions: Hyperlipidemic conditions activate NF-κB pathway by increasing EC FAK activity and cytoplasmic localization in mice and human atherosclerotic samples. As FAK inhibition can efficiently reduce vascular inflammation and atherosclerotic lesions in mice by reversing EC FAK localization and NF-κB activation, these findings support a potential use for FAK inhibitors in treating atherosclerosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Rationale: Vascular smooth muscle cells (SMCs) exhibit remarkable plasticity and can undergo dedifferentiation upon pathological stimuli associated with disease and interventions., Objective: Although epigenetic changes are critical in SMC phenotype switching, a fundamental regulator that governs the epigenetic machineries regulating the fate of SMC phenotype has not been elucidated., Methods and Results: Using SMCs, mouse models, and human atherosclerosis specimens, we found that FAK (focal adhesion kinase) activation elicits SMC dedifferentiation by stabilizing DNMT3A (DNA methyltransferase 3A). FAK in SMCs is activated in the cytoplasm upon serum stimulation in vitro or vessel injury and active FAK prevents DNMT3A from nuclear FAK-mediated degradation. However, pharmacological or genetic FAK catalytic inhibition forced FAK nuclear localization, which reduced DNMT3A protein via enhanced ubiquitination and proteasomal degradation. Reduced DNMT3A protein led to DNA hypomethylation in contractile gene promoters, which increased SMC contractile protein expression. RNA-sequencing identified SMC contractile genes as a foremost upregulated group by FAK inhibition from injured femoral artery samples compared with vehicle group. DNMT3A knockdown in injured arteries reduced DNA methylation and enhanced contractile gene expression supports the notion that nuclear FAK-mediated DNMT3A degradation via E3 ligase TRAF6 (TNF [tumor necrosis factor] receptor-associated factor 6) drives differentiation of SMCs. Furthermore, we observed that SMCs of human atherosclerotic lesions exhibited decreased nuclear FAK, which was associated with increased DNMT3A levels and decreased contractile gene expression., Conclusions: This study reveals that nuclear FAK induced by FAK catalytic inhibition specifically suppresses DNMT3A expression in injured vessels resulting in maintaining SMC differentiation by promoting the contractile gene expression. Thus, FAK inhibitors may provide a new treatment option to block SMC phenotypic switching during vascular remodeling and atherosclerosis.

While sustained nuclear factor-κB (NF-κB) activation is critical for proinflammatory molecule expression, regulators of NF-κB activity during chronic inflammation are not known. We investigated the role of focal adhesion kinase (FAK) on sustained NF-κB activation in tumor necrosis factor-α (TNF-α)-stimulated endothelial cells (ECs) both in vitro and in vivo. We found that FAK inhibition abolished TNF-α-mediated sustained NF-κB activity in ECs by disrupting formation of TNF-α receptor complex-I (TNFRC-I). Additionally, FAK inhibition diminished recruitment of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and the inhibitor of NF-κB (IκB) kinase (IKK) complex to TNFRC-I, resulting in elevated stability of IκBα protein. In mice given TNF-α, pharmacological and genetic FAK inhibition blocked TNF-α-induced IKK-NF-κB activation in aortic ECs. Mechanistically, TNF-α activated and redistributed FAK from the nucleus to the cytoplasm, causing elevated IKK-NF-κB activation. On the other hand, FAK inhibition trapped FAK in the nucleus of ECs even upon TNF-α stimulation, leading to reduced IKK-NF-κB activity. Together, these findings support a potential use for FAK inhibitors in treating chronic inflammatory diseases.

Introduction: Variations in postnatal length of refrigerated, unfixed umbilical cords were studied over time to elucidate natural changes and times of stability., Methods: Length was measured in 132 cords following severance, repeated at varying timed intervals and studied by analysis of variance and regression analysis., Results: Data show immediate rapid initial phase shortening (mean 4.2+/-3.9 cm SD); an interval of lengthening; stable length at hours 3-4 following severance, a slower second phase shortening (mean 1.5+/-0.7 cm SD) beginning at 5 hours and peaking at 12 hours; and gradual lengthening to stable length after 23 hours. Overall, there was a significant net mean decrease of 3.49+/-2.29 cm SD. Shortening was greatest for intact long cord segments (p=0.0001), as much as 11 cm. Two highly significant models for predicting umbilical cord length at delivery (OL) were determined using the post-delivery lengths (Length) measured at different times following delivery (Hours), as follows:At ≤ 3 hours following delivery: OL=1.02xLength cm+1.11xHoursAt >3 hours following delivery: OL=1.07xLength+0.44xHours-0.01x(Hours)2., Conclusion: Cord lengths stabilized between hours 3-4 and after 23 hours following severance. Phase one shortening resembles vasoconstriction; phase two resembles rigor mortis. The models allow prediction of the original umbilical cord length at delivery, regardless of the time of measurement.

Black Lives Matter is a clarion call for racial equality and racial justice. With the arrival of Africans as slaves in 1619, a racial hierarchy was formed in the United States. However, slavery is commonly dismissed as that less than noble aspect of the United States' history without really confronting the legacies of racial inequality and racial injustice left in its wake. White supremacy, based on the myths of white superiority and Black inferiority, have obscured racial inequality and racial injustice, resulting in blaming the victims. Using Black Lives Matter as a platform, we focus on some key considerations for theory, research, education, training, and practice in clinical, community, and larger systems contexts. Broadly, we focus on Black Lives Matter, literally; Black dehumanization; historical oppression; healing; and implications for the field of family therapy. More specifically, we draw attention to health disparities, mass incarceration and aggressive policing, intergenerational racial trauma, restorative justice, and antiracist work., (© 2020 Family Process Institute.)

Background: This is the third update of a review that was originally published in the Cochrane Library in 2002, Issue 2. People with cancer, their families and carers have a high prevalence of psychological stress, which may be minimised by effective communication and support from their attending healthcare professionals (HCPs). Research suggests communication skills do not reliably improve with experience, therefore, considerable effort is dedicated to courses that may improve communication skills for HCPs involved in cancer care. A variety of communication skills training (CST) courses are in practice. We conducted this review to determine whether CST works and which types of CST, if any, are the most effective., Objectives: To assess whether communication skills training is effective in changing behaviour of HCPs working in cancer care and in improving HCP well-being, patient health status and satisfaction., Search Methods: For this update, we searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 4), MEDLINE via Ovid, Embase via Ovid, PsycInfo and CINAHL up to May 2018. In addition, we searched the US National Library of Medicine Clinical Trial Registry and handsearched the reference lists of relevant articles and conference proceedings for additional studies., Selection Criteria: The original review was a narrative review that included randomised controlled trials (RCTs) and controlled before-and-after studies. In updated versions, we limited our criteria to RCTs evaluating CST compared with no CST or other CST in HCPs working in cancer care. Primary outcomes were changes in HCP communication skills measured in interactions with real or simulated people with cancer or both, using objective scales. We excluded studies whose focus was communication skills in encounters related to informed consent for research., Data Collection and Analysis: Two review authors independently assessed trials and extracted data to a pre-designed data collection form. We pooled data using the random-effects method. For continuous data, we used standardised mean differences (SMDs)., Main Results: We included 17 RCTs conducted mainly in outpatient settings. Eleven trials compared CST with no CST intervention; three trials compared the effect of a follow-up CST intervention after initial CST training; two trials compared the effect of CST and patient coaching; and one trial compared two types of CST. The types of CST courses evaluated in these trials were diverse. Study participants included oncologists, residents, other doctors, nurses and a mixed team of HCPs. Overall, 1240 HCPs participated (612 doctors including 151 residents, 532 nurses, and 96 mixed HCPs).Ten trials contributed data to the meta-analyses. HCPs in the intervention groups were more likely to use open questions in the post-intervention interviews than the control group (SMD 0.25, 95% CI 0.02 to 0.48; P = 0.03, I² = 62%; 5 studies, 796 participant interviews; very low-certainty evidence); more likely to show empathy towards their patients (SMD 0.18, 95% CI 0.05 to 0.32; P = 0.008, I² = 0%; 6 studies, 844 participant interviews; moderate-certainty evidence), and less likely to give facts only (SMD -0.26, 95% CI -0.51 to -0.01; P = 0.05, I² = 68%; 5 studies, 780 participant interviews; low-certainty evidence). Evidence suggesting no difference between CST and no CST on eliciting patient concerns and providing appropriate information was of a moderate-certainty. There was no evidence of differences in the other HCP communication skills, including clarifying and/or summarising information, and negotiation. Doctors and nurses did not perform differently for any HCP outcomes.There were no differences between the groups with regard to HCP 'burnout' (low-certainty evidence) nor with regard to patient satisfaction or patient perception of the HCPs communication skills (very low-certainty evidence). Out of the 17 included RCTs 15 were considered to be at a low risk of overall bias., Authors' Conclusions: Various CST courses appear to be effective in improving HCP communication skills related to supportive skills and to help HCPs to be less likely to give facts only without individualising their responses to the patient's emotions or offering support. We were unable to determine whether the effects of CST are sustained over time, whether consolidation sessions are necessary, and which types of CST programs are most likely to work. We found no evidence to support a beneficial effect of CST on HCP 'burnout', the mental or physical health and satisfaction of people with cancer.

Background: Risk standardization for adverse events after congenital cardiac catheterization is needed to equitably compare patient outcomes among different hospitals as a foundation for quality improvement. The goal of this project was to develop a risk-standardization methodology to adjust for patient characteristics when comparing major adverse outcomes in the NCDR's (National Cardiovascular Data Registry) IMPACT Registry (Improving Pediatric and Adult Congenital Treatment)., Methods: Between January 2011 and March 2014, 39 725 consecutive patients within IMPACT undergoing cardiac catheterization were identified. Given the heterogeneity of interventional procedures for congenital heart disease, new procedure-type risk categories were derived with empirical data and expert opinion, as were markers of hemodynamic vulnerability. A multivariable hierarchical logistic regression model to identify patient and procedural characteristics predictive of a major adverse event or death after cardiac catheterization was derived in 70% of the cohort and validated in the remaining 30%., Results: The rate of major adverse event or death was 7.1% and 7.2% in the derivation and validation cohorts, respectively. Six procedure-type risk categories and 6 independent indicators of hemodynamic vulnerability were identified. The final risk adjustment model included procedure-type risk category, number of hemodynamic vulnerability indicators, renal insufficiency, single-ventricle physiology, and coagulation disorder. The model had good discrimination, with a C-statistic of 0.76 and 0.75 in the derivation and validation cohorts, respectively. Model calibration in the validation cohort was excellent, with a slope of 0.97 (standard error, 0.04; P value [for difference from 1] =0.53) and an intercept of 0.007 (standard error, 0.12; P value [for difference from 0] =0.95)., Conclusions: The creation of a validated risk-standardization model for adverse outcomes after congenital cardiac catheterization can support reporting of risk-adjusted outcomes in the IMPACT Registry as a foundation for quality improvement., (© 2017 American Heart Association, Inc.)

Bromodomains (BRDs) are epigenetic interaction domains currently recognized as emerging drug targets for development of anticancer or anti-inflammatory agents. In this study, development of a selective ligand of the fifth BRD of polybromo protein-1 (PB1(5)) related to switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes is presented. A compound collection was evaluated by consensus virtual screening and a hit was identified. The biophysical study of protein-ligand interactions was performed using X-ray crystallography and isothermal titration calorimetry. Collective data supported the hypothesis that affinity improvement could be achieved by enhancing interactions of the complex with the solvent. The derived SAR along with free energy calculations and a consensus hydration analysis using WaterMap and SZmap algorithms guided rational design of a set of novel analogues. The most potent analogue demonstrated high affinity of 3.3 μM and an excellent selectivity profile, thus comprising a promising lead for the development of chemical probes targeting PB1(5)., Competing Interests: The authors declare no competing financial interest.

Objectives: We sought to develop a scoring system that predicts the risk of serious adverse events (SAE's) for individual pediatric patients undergoing cardiac catheterization procedures., Background: Systematic assessment of risk of SAE in pediatric catheterization can be challenging in view of a wide variation in procedure and patient complexity as well as rapidly evolving technology., Methods: A 10 component scoring system was originally developed based on expert consensus and review of the existing literature. Data from an international multi-institutional catheterization registry (CCISC) between 2008 and 2013 were used to validate this scoring system. In addition we used multivariate methods to further refine the original risk score to improve its predictive power of SAE's., Results: Univariate analysis confirmed the strong correlation of each of the 10 components of the original risk score with SAE attributed to a pediatric cardiac catheterization (P < 0.001 for all variables). Multivariate analysis resulted in a modified risk score (CRISP) that corresponds to an increase in value of area under a receiver operating characteristic curve (AUC) from 0.715 to 0.741., Conclusion: The CRISP score predicts risk of occurrence of an SAE for individual patients undergoing pediatric cardiac catheterization procedures., (© 2015 Wiley Periodicals, Inc.)

Background: Gastric banding surgery can fail if the patient develops frequent vomiting, intolerance of common food types or reflux. These patients can be divided into those with a well-defined anatomical problem such as slippage and those without. Intermittent gastric prolapse (IGP) is a possible explanation for some patients who do not achieve adequate early satiety without excessive food intolerance but have normal imaging., Methods: A series of eight patients was identified over a 2-year period with findings consistent with IGP. Cases were identified in the process of normal clinical practice and details reviewed retrospectively. Specific diagnostic methods included measures to increase pouch pressure above the band by either stress barium or endoscopy with pressure challenge., Results: The median time until diagnosis of IGP was 48.0 months (16-124), and weight loss over that time was 26.4 kg, or 69.6 % excess weight loss (EWL) (5.8-101.8). This fell to 43.7 % EWL after IGP was diagnosed and managed. The mean fill volume when the patients experienced IGP was 6.8 ml (4.5-9.0). Most patients were diagnosed by radiological investigation. Four patients underwent revisional surgery with the remainder treated conservatively., Conclusions: Intermittent gastric prolapse may explain excessive food and fluid intolerance in gastric band patients who have normal initial imaging. These patients typically experience gross food intolerance with a relatively small increment in fluid volume with relief when the increment is removed. The diagnosis is best made with either modified stress barium or endoscopy with pressure challenge. Management entails establishment of a safe fill volume, modification of weight loss expectations and earlier discussion of revisional surgery.

Background: Melody Transcatheter Pulmonary Valve (TPV) replacement therapy represents an important advance in congenital cardiovascular interventions. The off-label extension of the Melody TPV to patients with nonconduit outflow tracts (right ventricular outflow tract [RVOT]) has the potential to vastly expand the population of patients eligible to benefit from nonsurgical restoration of RVOT function. However, knowledge on the performance of the Melody TPV in this setting is limited., Methods and Results: This is a multicenter, retrospective review of the Melody TPV when placed in nonconduit RVOTs, in which at least a portion of the circumference was composed of native tissue. Five centers contributed data on 31 patients. The median age at implantation was 24 years (range, 7-66). At a median follow-up of 15 months, all patients were alive. No patient had greater than mild TPV insufficiency, and the median maximum instantaneous gradients across the RVOT was 23 mm Hg. Stent fracture occurred in 32%. Eight patients developed more than mild TPV obstruction, of whom 6 were associated with identified stent fracture. Three patients developed blood stream infections. There were 5 reinterventions in 3 patients, including 3 repeat TPV implantations and 2 TPV explantations., Conclusions: Melody TPV implantation is feasible in selected patients with RVOTs comprised solely or predominantly native tissue and has the potential to expand the population of patients eligible to benefit from nonsurgical restoration of RVOT function. In early follow-up, valve competency seems preserved. The dominant mechanism of valve dysfunction seems to be related to stent fracture with recurrent obstruction. Additional data are necessary to better understand how to safely expand TPV therapy to this population., (© 2014 American Heart Association, Inc.)

Background: This is an updated version of a review that was originally published in the Cochrane Database of Systematic Reviews in 2004, Issue 2. People with cancer, their families and carers have a high prevalence of psychological stress which may be minimised by effective communication and support from their attending healthcare professionals (HCPs). Research suggests communication skills do not reliably improve with experience, therefore, considerable effort is dedicated to courses that may improve communication skills for HCPs involved in cancer care. A variety of communication skills training (CST) courses have been proposed and are in practice. We conducted this review to determine whether CST works and which types of CST, if any, are the most effective., Objectives: To assess whether CST is effective in improving the communication skills of HCPs involved in cancer care, and in improving patient health status and satisfaction., Search Methods: We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2012, MEDLINE, EMBASE, PsycInfo and CINAHL to February 2012. The original search was conducted in November 2001. In addition, we handsearched the reference lists of relevant articles and relevant conference proceedings for additional studies., Selection Criteria: The original review was a narrative review that included randomised controlled trials (RCTs) and controlled before-and-after studies. In this updated version, we limited our criteria to RCTs evaluating 'CST' compared with 'no CST' or other CST in HCPs working in cancer care. Primary outcomes were changes in HCP communication skills measured in interactions with real and/or simulated patients with cancer, using objective scales. We excluded studies whose focus was communication skills in encounters related to informed consent for research., Data Collection and Analysis: Two review authors independently assessed trials and extracted data to a pre-designed data collection form. We pooled data using the random-effects model and, for continuous data, we used standardised mean differences (SMDs)., Main Results: We included 15 RCTs (42 records), conducted mainly in outpatient settings. Eleven studies compared CST with no CST intervention, three studies compared the effect of a follow-up CST intervention after initial CST training, and one study compared two types of CST. The types of CST courses evaluated in these trials were diverse. Study participants included oncologists (six studies), residents (one study) other doctors (one study), nurses (six studies) and a mixed team of HCPs (one study). Overall, 1147 HCPs participated (536 doctors, 522 nurses and 80 mixed HCPs).Ten studies contributed data to the meta-analyses. HCPs in the CST group were statistically significantly more likely to use open questions in the post-intervention interviews than the control group (five studies, 679 participant interviews; P = 0.04, I² = 65%) and more likely to show empathy towards patients (six studies, 727 participant interviews; P = 0.004, I² = 0%); we considered this evidence to be of moderate and high quality, respectively. Doctors and nurses did not perform statistically significantly differently for any HCP outcomes.There were no statistically significant differences in the other HCP communication skills except for the subgroup of participant interviews with simulated patients, where the intervention group was significantly less likely to present 'facts only' compared with the control group (four studies, 344 participant interviews; P = 0.01, I² = 70%).There were no significant differences between the groups with regard to outcomes assessing HCP 'burnout', patient satisfaction or patient perception of the HCPs communication skills. Patients in the control group experienced a greater reduction in mean anxiety scores in a meta-analyses of two studies (169 participant interviews; P = 0.02; I² = 8%); we considered this evidence to be of a very low quality., Authors' Conclusions: Various CST courses appear to be effective in improving some types of HCP communication skills related to information gathering and supportive skills. We were unable to determine whether the effects of CST are sustained over time, whether consolidation sessions are necessary, and which types of CST programs are most likely to work. We found no evidence to support a beneficial effect of CST on HCP 'burnout', patients' mental or physical health, and patient satisfaction.

The Alabama Coalition for a Healthier Black was a demonstration of concept project. This paper is a descriptive and qualitative overview of this 2.5 year project. Limited key project results are reported here. Located in the rural Black Belt region of Alabama this coalition had several key aims: to develop a collaboration between primary care and mental health care through co-location of services; use of video-conferencing capability to provide mental health services more efficiently; enhanced training in rural healthcare; and development of stigma reduction campaigns along with other coalition partner specific initiatives. Co-location and telepsychiatry implementation produced the major challenges and resulting adaptations to original aims. Despite many challenges these new service patterns were put into place and appear to be sustainable.

The goal of this study was to examine the linguistic correlates of social anxiety disorder (SAD). Twenty-four individuals with SAD (8 of them with a generalised subtype) and 21 non-anxious controls were asked to give speeches in front of an audience. The transcribed speeches were examined for the frequency of negations, I-statements, we-statements, negative emotion words, and positive emotion words. During their speech, individuals with either SAD subtype used positive emotion words more often than controls. No significant differences were observed in the other linguistic categories. These results are discussed in the context of evolutionary and cognitive perspectives of SAD.

Developmental thresholds, degree-days for development, larval weights, and head capsule widths for each larval instar and the pupal stage of Anoplophora glabripennis (Motschulsky) (Coleoptera: Cerambycidae) were studied at eight constant temperatures (5, 10, 15, 20, 25, 30, 35, and 40°C) for two source populations (Ravenswood, Chicago, IL [IL], and Bayside, Queens, NY [NY]). The estimated lower threshold temperature for development of instars 1-5 and the pupal stage was near 10°C and was near 12°C for the higher instars. Developmental rate was less temperature sensitive for instars 5-9 compared with instars 1-4. Development for all but the first instar was inhibited at constant temperatures >30°C, and all instars failed to develop at 40°C. Although the two source populations had similar responses to temperature, IL larvae were heavier than those from NY. Temperature and its influence on larval weight had profound impacts on whether a larva proceeded to pupation. Based on the temperature effects detailed here, larval development and pupation should be possible in most of the continental United States where suitable hosts are available. These data can be used to develop a degree-day model to estimate beetle phenology; however, at least 2°C should be added to air temperatures to adjust for the mediation of temperature by the wood. These data provide a basis for predicting the potential geographical range of this species and for developing phenological models to predict the timing of immature stages, both of which are important for management programs.

Recent studies demonstrated that the excitotoxic amino acid homocysteine induces apoptotic death of retinal ganglion cells in vivo. In the present study, an in vitro rat retinal ganglion cell (RGC-5), culture system was used to analyze the toxicity of acute exposure to high levels of homocysteine, the mechanism of homocysteine-induced toxicity, and the usefulness of type 1 sigma receptor (sigmaR1) ligands as neuroprotectants. When cultured RGC-5 cells were subjected to treatment with 1 mM D,L-homocysteine, a significant increase in cell death was detected by terminal dUTP nick end labeling (TUNEL) analysis and analysis of activated caspase. When cells were treated with homocysteine- or glutamate in the presence of MK-801, an antagonist of the N-methyl-D-aspartate (NMDA) receptor, the cell death was inhibited significantly. In contrast, NBQX, an antagonist of the AMPA/Kainate receptor, and nifedipine, a calcium channel blocker, did not prevent the homocysteine- or glutamate-induced cell death. Semiquantitative RT-PCR and immunocytochemical analysis demonstrated that RGC-5 cells were exposed to homocysteine or glutamate express type 1 sigma receptor at levels similar to control cells. Treatment of RGC-5 cells with 3 or 10 microM concentrations of the sigmaR1-specific ligand (+)-pentazocine inhibited significantly the apoptotic cell death induced by homocysteine or glutamate. The results suggest that homocysteine is toxic to ganglion cells in vitro, that the toxicity is mediated via NMDA receptor activation, and that the sigmaR1-specific ligand (+)-pentazocine can block the RGC-5 cell death induced by homocysteine and glutamate.

Purpose: To determine whether taurine transporter (TauT) activity and expression are regulated by hyperosmolarity in RPE, ganglion, and Müller cells., Methods: Uptake of taurine was measured in ARPE-19 cells cultured in DMEM-F12 medium without or with the addition of 50 mM NaCl or 100 mM mannitol. The kinetics of the transport were analyzed. RT-PCR and Northern and Western blot analyses were used to assess TauT mRNA and protein levels. The influence of hyperosmolarity on the uptake of taurine, myo-inositol, and gamma-aminobutyric acid GABA was studied in RPE, RGC-5, and rMC1 cells., Results: TauT activity was abundant in RPE and was stimulated (3.5-fold) when the cells were exposed to hyperosmolar conditions (DMEM-F12 culture medium plus 50 mM NaCl or 100 mM mannitol). Peak stimulation of taurine uptake occurred after 17 hours of exposure to hyperosmolar medium. Kinetic analysis revealed that the hyperosmolarity-induced stimulation was associated with an increase in V(max) of TauT with no change in K(m). TauT mRNA and protein levels increased in RPE cells exposed to hyperosmolar conditions. Hyperosmolarity also stimulated the uptake of myo-inositol ( approximately 15-fold); GABA uptake was influenced less markedly. Immunofluorescence and functional studies showed that TauT is present in cultured RGC-5 and rMC1 cells. TauT activity was robust in these cells in normal osmolar conditions and increased by approximately twofold in hyperosmolar conditions., Conclusions: These studies provide the first evidence that hyperosmolarity regulates TauT activity and expression in RPE and that TauT is present in ganglion and Müller cells and is regulated by hypertonicity. The data are relevant to diseases such as diabetes, macular degeneration, and neurodegeneration, in which retinal cell volumes may fluctuate dramatically.

Purpose: To investigate and document the neuropsychological and emotional effects of epilepsy in people with intractable temporal lobe epilepsy (TLE)., Methods: 273 patients with a diagnosis of TLE underwent a complete neuropsychological and psychological examination as a routine part of their investigation for epilepsy surgery. Neuropsychological assessment included measures of intellect, memory, language functioning, higher executive functioning, emotional well-being and the psychosocial impact of epilepsy and its treatment., Results: The sample comprised 135 females and 138 males with a clearly lateralised epileptogenic focus. Patients were mildly anxious but not depressed, although many reported that epilepsy and its treatment had a marked effect on their daily lives. Current reading ability was in the average range; the mean obtained full scale IQ was 88 (low average range). Verbal memory functioning was within the borderline impaired range with visual memory functioning within the average range. Mean language performance was between the 5-10th percentile. Higher executive functioning results were in the normal range. Multiple univariate analyses were performed according to onset laterality. There were no significant differences between the groups on measures of psychological or emotional functioning. Participants with left TLE scored significantly lower than those in the right temporal group on measures of verbal intelligence, general intelligence, attention span and expressive language functioning., Conclusions: Patients with intractable epilepsy suffer significant neuropsychological difficulties in terms of their intellect, memory and language. Higher executive functioning appears unaffected. In addition, there is also evidence of emotional distress. These all impact upon their day-to-day functioning, which can be improved by the application of various psychological therapies and interventions., (Copyright 2002 Published by Elsevier Science Ltd on behalf of BEA Trading Ltd.)

Background: Patients taking warfarin and at high risk for thromboembolic complications have traditionally been hospitalized for two to three days to receive standard treatment with intravenous heparin both prior to and following procedures while their international normalized ratio (INR) is subtherapeutic., Objective: To assess the feasibility of protocol implementation for outpatient anticoagulation with low-molecular-weight heparin to eliminate or reduce the length of hospital admission needed solely for anticoagulation., Methods: Patients included were receiving warfarin for a prosthetic heart valve, mitral valve disease with atrial fibrillation, or recent episode of venous thromboembolism. Warfarin was discontinued four days prior to the procedure. Subcutaneous dalteparin 200 units/kg was given on the two mornings prior to the procedure and restarted 12-24 hours after the procedure until the INR was in the therapeutic range. Warfarin was reinitiated on the evening of surgery., Results: Twenty-four patients underwent 26 procedures. There were two minor bleeding complications, and one patient experienced a transient ischemic attack. Patients received a median of five days of dalteparin. The INR returned to the therapeutic range on the median postoperative day 4. All patients avoided two days of hospitalization prior to the procedure (i.e., no patients needed to be admitted preoperatively for anticoagulation). A median of four days would have been required for the sole purpose of postoperative anticoagulation., Conclusions: Outpatient perioperative anticoagulation with dalteparin for high-risk patients requiring long-term oral anticoagulation appears feasible and warrants further study.

Central nervous system (CNS) vasculitis occurs in a variety of clinical settings. Some exhibit a distinct age preference; others a tissue tropism. Most frequently encountered are giant cell arteritis (temporal arteritis) and vasculitis secondary to infections. The CNS may be involved in the systemic vasculitides, and neurologic abnormalities occasionally appear as a presenting manifestation of disease. Isolated angiitis of the CNS, a rare form of vasculitis restricted to the CNS, must be distinguished from other causes of CNS inflammation and from noninflammatory vascular disease. We are learning a great deal about the cellular mechanisms of vascular inflammation in the brain. Some manifestations of the clinical disease result from histologic features of the infiltrate and the size of affected vessel. However, the local consequences of inflammation such as increased coagulation and altered vasomotor tone, as well as the systemic consequences such as activation of the central noradrenergic systems, trigeminovascular system, and hypothalamic pituitary adrenal axis contribute to both pathogenesis of disease and recovery. Two central issues that confront us now are improving the accuracy of the diagnosis (including identifying any underlying infectious causes) and limiting the long-term damage both from disease and its therapies.

The vasculitides are a collection of diseases sharing the central feature of tissue injury due to inflammation of blood vessels. Although some occur frequently, many are encountered uncommonly or rarely. Nonetheless, because peripheral or central nervous system abnormalities may be a prominent part of these disorders, neurologists should know or be able to refer to studies on the classification, pathophysiology, treatments, and long-term complications of vasculitis. Two central issues that confront us now are 1) improving the accuracy of diagnosis, including identifying any underlying infectious causes, and 2) limiting the long-term damage from both the disease and its therapies.

Systemic lupus erythematosus (SLE) is a spontaneously occurring, chronic autoimmune disease that can manifest neuropsychiatric abnormalities. The pathways mediating these central changes are not known; however, neuroendocrine alterations associated with inflammation may play a role. Predisposition to and progression of autoimmune disease has been associated with altered hypothalamic-pituitary-adrenal (HPA) function and inflammation has been reported to alter hypothalamic regulation of HPA responses. We investigated whether disease progression in a murine model of systemic lupus erythematosus (MRL +/+. MRL lpr/lpr) resulted in altered expression of HPA regulatory peptides at the level of the hypothalamus and how these alterations related to circulating levels of corticosterone, corticosterone binding globulin, and autoantibody titers. We report that as MRL +/+ and MRL lpr/lpr mice age and circulating levels of autoantibodies increase, there is a decrease in hypothalamic CRH mRNA expression and finally an increase in AVP mRNA expression. We also report that associated with increased autoantibody levels, disease progression, and altered hypothalamic peptide expression there is an increase in circulating levels of corticosterone and a trend for levels of corticosterone binding globulin to decrease. Our data complement previous observations of altered peptidergic regulation of the HPA axis and increased HPA activity during chronic inflammation in exogenously induced rodent models of chronic inflammation and indicate that similar processes may occur in spontaneous murine models of SLE., (Copyright 1999 Academic Press.)

Twenty carefully selected snake phobics were exposed to a caged snake for eight trials via a conveyor apparatus. During the first and eighth trials the subjects brought the snake toward themselves as closely as tolerable; records were kept of the end-of-trial distances remaining between the subject and the snake. For the six intervening trials the experimenter placed the snake a standard distance away; records were kept of the subjects' heart rates and skin-conductance levels before and during the exposures, and of their self-reported fear intensities after the exposures. Half of the subjects had received six sessions of progressive relaxation training before the exposures occurred. The results for subjects who had received relaxation training versus subjects who had not received relaxation training showed clearly that the training served to attenuate arousal and fear in the context of in vivo exposure. The results showed also that relaxation worked by lowering arousal throughout the course of exposure, not by hastening or facilitating arousal decrement during exposure. Some implications of the results are discussed.

Vascular inflammation stands at the center of innumerable physiological and pathological processes. Dissecting the mechanisms of successful vascular injury and repair, investigators provide information for scientists and clinicians. The neurologist benefits from studies across several disciplines. Details of the cellular functions in the infiltrates of temporal arteries impart a basis for rational therapy. The interactions of herpes virus with vessels wall remind us of the affinity of numerous infectious agents for the vasculature. Several animal models are enabling us to explore the genetic links in autoimmunity. Although clinical studies may not yet provide us with answers for accurate diagnosis and treatment of many of our patients, data from this year will keep our interest high.

Central nervous system vasculitis occurs in a variety of clinical settings. Some exhibit a distinct age preference; others a tissue tropism. Most frequently encountered are giant cell arteritis (temporal arteritis) and vasculitis secondary to infections. The central nervous system may be involved in the antineutrophil cytoplasmic antibody-associated systemic vasculitides and occasionally neurologic abnormalities appear as a presenting manifestation of disease. Isolated angiitis of the central nervous system, a rare form of vasculitis that is restricted to the central nervous system, must be distinguished from other causes of central nervous system inflammation and from noninflammatory vascular disease. We are learning a great deal about the cellular mechanisms of vascular inflammation in general. Some manifestations of the clinical disease result from histologic features of the infiltrate and the size of affected vessel. However, the local consequences of inflammation, such as increased coagulation and altered vasomotor tone, as well as the systemic consequences, such as activation of the central noradrenergic systems, trigeminovascular system, and hypothalamic pituitary adrenal axis, contribute both to pathogenesis of disease and to recovery.

It is now established that communication between the CNS and the immune system is bidirectional, that endocrine factors can alter immune function and that immune responses can alter both endocrine and CNS responses. In many respects CNS and endocrine responses to acute inflammation are similar to the changes associated with acute stress exposure. In contrast, during chronic inflammation associated with adjuvant induced arthritis (AA), although circulating levels of corticosterone are increased, the peptidergic regulation of the hypothalamus is different from that seen during acute stress. As the disease progresses, a paradoxical reduction occurs in CRH mRNA in the paraventricular nucleus (PVN), whereas PVN AVP mRNA increases. These data suggest that there is increased expression of AVP mRNA within the CRH cells of the PVN with an increased emphasis on AVP regulation of HPA output. Additionally, HPA function is altered during chronic inflammation such that responses to psychological stress (i.e. restraint) are significantly dampened, while responses to further inflammatory challenges are maintained. These data suggest that alterations in PVN peptide colocalization may be important in regulating the progression of peripheral inflammatory responses and that the effects of inflammation on the hypothalamus alter stress-responsive systems. In addition to the AA model, we have similarly observed alterations in PVN peptide mRNA expression with disease onset in the murine MRL lpr/lpr and MRL +/+ model of SLE. Disease onset in murine SLE is spontaneous and does not rely on exogenous application of adjuvant; however, decreased levels of CRH in the PVN were observed from early disease onset in this animal model. It is suggested that alterations in CRH regulation in response to either acute or chronic inflammation may contribute as etiological factors to both psychiatric (i.e. neuropsychiatric SLE) and stress-related disease.

In murine models of SLE, particular patterns of abnormalities of social interaction and memory collectively known as neurobehavioral dysfunction (NBD) correlate with the occurrence of brain reactive autoantibodies. Study of the immunopathogenic effects of these antibodies has been limited by the absence of isolated autoantibodies and antigens. In order to identify the molecular targets, we isolated autoantibodies highly specific for brain plasma membranes from MRL/lpr mice. After immunoscreening a brain expression library with these brain specific autoantibodies, we identified a single cDNA clone of unique sequence and relevant anatomic distribution. Transcript for this cDNA is wide spread among mammalian species but appears to be present only in the brain. Addition features, suggesting this cDNA is pertinent for further study include (1) the expressed protein, called lupus brain antigen 1, reacts with the screening immunoglobulins as well as immunoglobulins from other strains of murine neuro-SLE not used to screen the library, but not with immunoglobulins from normal mice, (2) the transcript distribution within the brain is similar to immunochemical localization of binding of the spontaneous autoantibodies and (3) the localization of transcript within the brain, in the hippocampus, hypothalamus an cingulate gyrus, corresponds to anticipated anatomical regions of clinical dysfunction. Further, the transcript is a large, potentially structural molecule of unique sequence. Antibodies to this molecule may mediate changes in behavior either by direct interactions with the cognate antigen or by indirect influences through neuro-endocrine axes.

The Wechsler Memory Scale-Revised (WMS-R) is used routinely as a presurgical assessment of memory for clients considering elective resection of the temporal lobe and/or hippocampus for the relief of intractable temporal lobe epilepsy. This research investigated the psychometric properties of the WMS-R in a population of people with epilepsy. The sample consisted of 181 patients with a diagnosis of epilepsy who underwent a complete neuropsychological examination as a routine part of their investigation. The results confirm that the WMS-R has acceptable levels of reliability as measured by internal consistency. A factor analysis revealed a consistent three-factor structure: Visual Memory, Verbal Memory, and Attention/ Concentration factors. Multiple regression analysis, however, indicated that the Visual Memory index was susceptible to a number of influences, throwing into question whether it is a pure measure of nonverbal memory functioning.

States attorneys general recently have intervened in transactions involving not-for-profit organizations that wish to convert to or transfer assets to for-profit status. These interventions are significant for two reasons: first, they reflect a tendency amount state attorneys general to involve states in the governance of not-for-profit healthcare organizations, and second, they demonstrate that attorneys general are paying renewed attention to the legal obligation of such organizations to provide a community health benefit, which imposes a charitable trust on not-for-profit healthcare organizations and the fiduciary duties of care and loyalty to that charitable trust on the organizations' officers and directors. To avoid state intervention in such transactions, officers and directors of not-for-profit organizations need to understand the circumstances under which attorneys general justify such intervention, which include the undervaluation of the organization's charitable assets; lack of a private letter ruling from the IRS; failure to adequately consider alternatives to the transaction; conflicts with the best interest of the organization; and inadequate responses to the attorney general's requests for information.

Due to the serious medical consequences in failing to recognize non-epileptic attack disorder (NEAD), and the frequency with which neurologists come into contact with such patients, clearly NEAD constitutes a major concern for clinicians in the field of epilepsy. This article presents the psychological characteristics of 185 patients with NEAD. Psychological factors that were identified as being important in the understanding of the development and maintenance of NEAD included: anxiety or stress; physical abuse; significant bereavement; family dysfunctioning; relationship problems; depression; sexual abuse. An absence of relevant psychological factors was found in only 5% of patients. From patients' descriptions of their attacks, it appears that many symptoms are related to anxiety. Our findings are largely supported by previous studies and their relevance to effective management and treatment of NEAD patients is discussed.

Objectives: We report the clinical course and unique hemodynamic findings after placement of a supraannular mitral valve prosthesis., Background: Children with symptomatic mitral valve disease whose annulus is too small for the smallest prosthesis are difficult to manage. One option is valve replacement with a prosthesis positioned entirely within the left atrium (LA)., Methods: We reviewed 17 patients (median age 10 months) with symptomatic mitral valve disease who underwent placement of a supraannular valve prosthesis between 1980 and 1994., Results: The actuarial survival rates were 88% at 1 month and 71%, 62% and 53% at 1, 2 and 10 years, respectively. Preoperative hemodynamic data (mean +/- SD)) compared with those after placement of the supraannular mitral prosthesis were as follows: "a" wave to left ventricular end-diastolic pressure gradient 17 +/- 5 versus 4 +/- 4 mm Hg (p = 0.003), mean LA pressure 25 +/- 6 versus 20 +/- 6 mm Hg (p = 0.07), "a" wave 30 +/- 6 versus 19 +/- 5 mm Hg (p = 0.006), "v" wave 28 +/- 5 versus 30 +/- 9 mm Hg (p = 0.31), mean pulmonary artery pressure 54 +/- 19 versus 42 +/- 15 mm Hg (p = 0.07) and left ventricular end-diastolic pressure 14 +/- 5 versus 16 +/- 4 mm Hg (p = 0.12)., Conclusions: Supraannular mitral valve replacement provides relief of mitral stenosis or mitral regurgitation. However, LA to left ventricular early diastolic gradients with large atrial "v" waves contribute to elevated mean LA pressures in the absence of prosthetic valve obstruction or regurgitation. As a result of this unexpected finding, associated left heart obstructive lesions and pulmonary and left ventricular end-diastolic hypertension, the outlook remains poor.

Purpose: The Wechsler Memory Scale-Revised (WMS-R) is used routinely for presurgical assessment of memory for patients considering elective resection of the temporal lobe and/or hippocampus for the relief of intractable temporal lobe epilepsy (TLE). We investigated the validity of the WMS-R in a population of people with TLE., Methods: The sample consisted of 138 patients with a diagnosis of TLE in which the epileptogenic focus was clearly and exclusively lateralized to either the right or left hemisphere. They underwent a complete neuropsychological examination as a routine part of their investigation for epilepsy surgery. Psychometric scores included in this study were: Wechsler Adult Intelligence Scale-Revised (WAIS-R) I.Q. scores, National Adult Reading Test Revised (NART-R) predicted-I.Q. scores, and WMS-R Memory Index and subtest scores., Results: Multiple univariate analyses were performed. The group with left temporal focus had significantly lower Verbal Memory Index, Logical memory (both immediate and delayed), and Digit Span scores. Visual/Verbal discrepancy scores incorrectly identified most patients with right temporal focus. Analyses of a total group of people with epilepsy (i.e., mixed temporal, frontal, occipital and unknown foci) as compared with the normative sample indicated that the patient group scored significantly lower across all memory index scores and most memory subtests., Conclusions: Our results confirm that the WMS-R is capable of lateralizing to left hemispheric impairment but is more problematic in the assessment of right hemispheric impairment. The Visual/Verbal Memory Index discrepancy has questionable validity. People with epilepsy performed less well on the WMS-R than did the normative sample. The need for reliable and valid nonverbal tests of memory is therefore warranted.

It has become clear that the neuroendocrine and immune systems are closely linked and interdependent. The exact mechanisms of this interaction are only beginning to be unravelled. The complexity of these connections may partly explain why the aetiopathogenesis of autoimmune diseases remains obscure and why genetic, hormonal, microbial, environmental, as well as a host of other factors, have all been put forward as explanations. What has become clear is that a number of neuroendocrine and hormonal factors have important immunomodulatory roles in health and disease.

Study of the vasculitides illustrates a spectrum of interactions from physiological to pathological between the immune system and the blood-vessel wall. Endothelial cells demonstrably recruit leukocytes by both antigen-specific and antigen-nonspecific mechanisms in the systemic vasculitides. A cascade of cytokine and factors can initiate, perpetuate, and regulate the close interactions of leukocytes and the endothelium. Specific types of leukocytes (neutrophils, T lymphocytes, eosinophils) predominate in the vascular infiltrates of specific diseases. Other mural cells potentially initiate the inflammatory process; this may be particularly important in the central nervous system where regulatory systems may diminish a primary role of the endothelium in vascular inflammation. Neurological abnormalities are a prominent feature of some vasculitides and rare in others. In polyarteritis nodosa, Wegener's granulomatosis, and lymphomatoid granulomatosis neurological features may be prominent and early. The cutaneous vasculitides, hypersensitivity vasculitis, are seldom associated with neurological abnormalities. Isolated angiitis of the central nervous system is notable because it invariably targets the central nervous system and because it must be distinguished from other causes of central nervous system vasculitis, including infections and toxins. In this article we review some of the recent information adding to our knowledge of the immunopathogenic and clinical features in the vasculitides affecting the nervous system.

Eight pairs of DSM-III-R snake phobic subjects (Ss) were exposed to a caged snake while seated in front of a package-conveyor apparatus during eight 4-minute trials. Heart rates and skin-conductance levels were recorded before and during each of the eight trials. Self-reports of fear were obtained after each trial. One S in each pair controlled the conveyor on alternating trials. One subject (S) in each pair had received a representative regimen of relaxation training beforehand. Heart-rate decreased more in Ss controlling the conveyor than in their yoked partners. Ss who had received relaxation training showed lower heart-rate change, lower skin-conductance change, and lower self-reports of fear after the exposure trials. Relaxed Ss also moved the snake closer to themselves than did unrelaxed subjects on some trials.

Neurologic complications of systemic lupus erythematosus (neuro-SLE) are common. The most frequent manifestations of neuro-SLE are seizures, encephalopathy, and behavioral changes, but a wide variety of other neurologic abnormalities affecting the central and peripheral nervous system and muscle also occur. Although the prevalence of neuro-SLE is high, the diversity of clinical presentations, the multiple potential etiologies, and the absence of sensitive and specific diagnostic tests render diagnosis difficult. Recent advances in understanding mechanisms of neuronal dysfunction combined with advances in imaging techniques, including functional imaging, should help in diagnosis and management. The mechanisms of neurologic injury can be divided into three broad categories. First, neuronal dysfunction may result from direct effects of the immune system on brain cells such as autoantibody binding to cell surface, immune complex deposition with secondary inflammation, and effects of cytokines. Second, immune- mediated injury to supportive structures such as the vasculature may also affect the nervous system by producing ischemia. Finally, the neuraxis may be affected by any one of several immune and non- immune effects of infection, toxins, and metabolic disturbances.

Autoantibodies from the MRL/lpr mice react with numerous proteins on neuronal cell surfaces. The purpose of this study was to isolate and characterize a population of autoantibodies reactive preferentially or exclusively with nervous system tissue. Using a purified plasma membrane preparation from brain cortex of balb/c mice coupled to diaminopropylamine agarose gel, we affinity-isolated antineuronal antibodies from pooled MRL/lpr immunoglobulins. The isolated immunoglobulins reacted with brain cortex plasma membranes and neuroblastoma cells (but not liver, kidney, or fibroblasts) by Western blot and indirect immunofluorescence with confocal microscopy. By Western blot, the epitopes in the brain cortex were proteins of apparent molecular weights 101, 63, 53, 43, 39, and 33, kd; the epitopes in the neuroblastoma cells were 63, 57, and 53 kd. Lectin column isolation revealed that the 101 and 63 kd epitopes were glycosylated. Indirect immunofluorescence revealed that the antibodies bound to the cell soma more intensely than to the cell processes of viable cultured neuroblastoma cells. The cell surface localization of this binding was confirmed by confocal microscopy. Within the central nervous system the antibodies bound more intensely to primary cultures of isolated neurons from fetal cortex than to hippocampal or neostriatal cells. With these antibodies we can begin studies of their potential pathogenic effects.

A successful laparoendoscopic excision of a 3-cm leiomyoma of the stomach is reported. Review of related literature and suggested technique and methods for this procedure are described.

Isolated angiitis of the CNS is a disease of unknown etiology characterized by signs and symptoms of diffuse ischemia or recurrent strokes and histologic evidence of vascular inflammation. Angiography frequently suggests the diagnosis, but angiographic changes over time have not been delineated. This study investigates the evolution of radiographic findings in CNS vasculitis by serial angiography in 19 patients. Abnormal angiographic findings include segmental arterial narrowings and dilatations, vascular occlusions, collateral formation, and prolonged circulation time. Smooth narrowings of the affected vessels occurring in multiple vascular distributions are the most frequent abnormality. Single stenotic areas in multiple vessels are more frequent than multiple stenotic areas along a single vessel segment. Vascular occlusions, the least diagnostic feature, affect small arteries in some patients. Serial studies demonstrate progression of angiographic changes prior to therapy and improvement or stabilization in patients with a clinical response to therapy. Correlation of clinical and angiographic features is consistent with the hypothesis that segmental narrowing initially results from reversible inflammation and vasospasm. The later irreversible angiographic features appear secondary to scarring. A limitation of angiography is demonstrated in this study by the apparently normal angiograms in two patients with biopsy-confirmed small-vessel vasculitis. Four patients with abnormal angiograms and histologic evidence of disease had normal MRIs.