Antipsychotics and Identity: The Adverse Effect No One is Talking About.

People who take antipsychotics, and people who are prescribed antipsychotics without taking them, experience effects which are not frequently discussed: effects on their identity and sense of self. Qualitative research indicates the relationship between taking APs and identity is multilayered, and changeable. Taking APs can restore people to their earlier, pre-symptom sense of self. Being prescribed and taking APs can also, on the other hand, be experienced as damaging, erasing and dulling people's sense of who they are. This complexity deserves exploration in clinical practice, which we believe is currently not done routinely. More work is needed to understand whether, and how, the relationship between identity and APs is being addressed. We outline the importance of having discussions in a clinical space around identity, and a sense of agency, on the grounds that true recovery-oriented care, which enacts shared decision-making principles, demands it. Further, we argue that it will allow for better therapeutic alliance and trust to be forged between clinician and client, ultimately leading to better care.

Comparative value-based pricing of an Ebola vaccine in resource-constrained countries based on cost-effectiveness analysis.

OBJECTIVES: Pricing, affordability, and access are important deliberations around infectious disease interventions. Determining a fair price that not only incentivizes development but ensures value and access for patients is critical given the increasing global health crisis. Using Ebola virus disease (EVD) as an exemplar, we aim to elucidate the estimation of a jurisdiction-specific value-based price (VBP) for a vaccine package and to consider how prices compare across selected countries that have experienced EVD outbreaks. METHODS: Using a dynamic transmission model, we assessed the cost-effectiveness of a vaccine package - composed of the vaccine, storage, maintenance, and administration - for vaccination toward herd immunity in 4 countries affected with EVD (Democratic Republic of Congo, Liberia, Sierra Leone, Uganda). Based on the cost-effectiveness metrics and using willingness-to-pay thresholds equal to varying percentages of the Gross Domestic Product (GDP), we demonstrated how a VBP is calculated using a cost-effectiveness-based approach. RESULTS: The VBP for the vaccine is directly proportional to effectiveness (DALYs prevented), cost-effectiveness (ICER) and GDP per capita. Higher effectiveness, greater cost-effectiveness, and higher GDP per capita resulted in higher price ceilings compared to lower cost-effectiveness and lower GDP. CONCLUSION: Despite the concerns with the cost-effectiveness-based approach, we illustrated that it is an easily comprehensible method for determining the VBP of a vaccine using cost-effectiveness analysis. Choice of data, population characteristics, and disease dynamics are among the factors that need to be considered when comparisons are made across countries.

In infectious diseases, issues related to pricing, affordability and access to interventions are very important; particularly in low-income countries (LIC) because of the scarcity of resources coupled with several competing priorities. Pricing interventions fairly in LICs facilitates the prevention and management of infectious diseases, promotes innovation, and ensures patient access to valuable interventions. We were interested in determining a fair price of an intervention for an infectious disease (here, vaccination against Ebola virus disease) based on the cost-effectiveness (or value) of vaccination in four African countries.Using data from EVD outbreaks in Liberia, the Democratic Republic of Congo, Uganda, and Sierra Leone, we estimated the number of susceptible people who were exposed to the virus, became infected, recovered, or died. We did this for two scenarios: not vaccinating versus vaccinating to achieve herd immunity. We determined how many disability-adjusted life years (DALY; loss of the equivalent of a year of full health) would be prevented by vaccination; setting this as our value metric. Using this value metric and percentages of the gross domestic product (GDP) per capita as the willingness-to-pay (WTP) threshold (the price a payer might be prepared to pay for the intervention) we demonstrate how to calculate the maximum price for the vaccine package.The combination of greater effectiveness (DALYs averted), greater cost-effectiveness (value) and higher GDP per capita (WTP) resulted in different price ceilings in the four countries. The method proposed here is easy to understand and requires minimum data to determine a price for an intervention's price based on its value.

Cross-sectional associations between adipose tissue depots and areal bone mineral density in the UK Biobank imaging study.

The relationship between obesity and osteoporosis is poorly understood. In this study, we assessed the association between adiposity and bone. The fat-bone relationship was dependent on sex, body mass index classification, and menopausal status. Results highlight the importance of accounting for direct measures of adiposity (beyond BMI) and menopause status. INTRODUCTION: Assess the relationship between direct measures of adiposity (total body fat mass, visceral adipose tissue, and abdominal subcutaneous adipose tissue) with the whole body and clinically relevant bone sites of the lumbar spine, and femoral neck areal bone mineral density (aBMD) in men and women. METHODS: This cross-sectional analysis was conducted utilizing de-identified data from the UK Biobank on participants (n = 3674) with available dual-energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) data. Sex-stratified multiple linear regression was used to assess the relationship between adiposity measures and aBMD outcomes, controlling for age, race, total body lean mass (DXA), height, BMI class, physical activity, smoking, menopausal status (women), and hormone use (women). RESULTS: In men, significant interactions were observed between measures of adiposity and BMI on aBMD for the whole body and lumbar spine. Interactions indicated a positive relationship between adiposity and aBMD in men classified as normal weight, but an inverse relationship in men with elevated BMI. In women, significant interactions between adiposity measures and menopausal status were observed primarily for the whole body and femoral neck aBMD bone outcomes which indicated a negative relationship between adiposity and aBMD in premenopausal women, but a positive relationship in postmenopausal women. CONCLUSION: Total body adiposity, abdominal subcutaneous adipose tissue, and visceral adipose tissue were all significantly associated with aBMD in both men and women. The strength and direction of association were dependent on sex, BMI classification, and menopausal status (women).

Longitudinal assessment of nonavalent vaccine HPV types in a sample of sexually active African American women from ten U.S. Cities.

BACKGROUND: Chronic infection with high-risk human papillomavirus is a necessary cause for cervical carcinogenesis. This study examined prevalence of nonavalent vaccine preventable HPV types over four months among sexually active women in the United States. METHODS: This sub-study obtained meta-data for 80 of the 1,365 women (18-25 years), enrolled in the BRAVO study, a randomized, open-label trial of home screening and treatment of asymptomatic bacterial vaginosis at high-risk for sexually transmitted infections conducted between 2008 and 2013. Participants were randomized to treatment or standard-of-care, and followed every 2-months for 12 months. Stored vaginal swabs from the first three visits were tested for the nine vaccine preventable HPV types using quantitative PCR. Prevalence and associated 95% confidence intervals for the HPV types were assessed using R (version 3.6.1). RESULTS: The average age of the participants was 21.5 (SD ± 2.11) years, with 60% having ever been pregnant and all were African-American. Majority (71%) reported ≥ two sex partners in the prior year with 89% having unprotected vaginal sex and 45% having a new sex partner in the prior year. About 30% had ≥ one of the nine nonavalent vaccine HPV types at all three time points over a period of four months, 15% at two of any three visits, 19% at one of the three visits and 36% were negative for all nine vaccine HPV types at all time points. The most frequently detected HPV vaccine types were 52, 58, 16, and 18. The prevalence of any vaccine HPV types, and high-risk HPV types was 63.8% and 58.8%, respectively. CONCLUSIONS: Our findings suggest that HPV vaccination which is currently recommended for all unvaccinated persons through age 26 years, is likely to be more beneficial than previously thought as nonavalent HPV vaccine was not available during the time these data were collected.

The Sleep Side of Aging and Alzheimer's Disease.

As we age, sleep patterns undergo significant modifications in micro and macrostructure, worsening cognition and quality of life. These are associated with remarkable brain changes, like deterioration in synaptic plasticity, gray and white matter, and significant modifications in hormone levels. Sleep alterations are also a core component of mild cognitive impairment (MCI) and Alzheimer's Disease (AD). AD night time is characterized by a gradual decrease in slow-wave activity and a substantial reduction of REM sleep. Sleep abnormalities can accelerate AD pathophysiology, promoting the accumulation of amyloid-ß (Aß) and phosphorylated tau. Thus, interventions that target sleep disturbances in elderly people and MCI patients have been suggested as a possible strategy to prevent or decelerate conversion to dementia. Although cognitive-behavioral therapy and pharmacological medications are still first-line treatments, despite being scarcely effective, new interventions have been proposed, such as sensory stimulation and Noninvasive Brain Stimulation (NiBS). The present review outlines the current state of the art of the relationship between sleep modifications in healthy aging and the neurobiological mechanisms underlying age-related changes. Furthermore, we provide a critical analysis showing how sleep abnormalities influence the prognosis of AD pathology by intensifying Aß and tau protein accumulation. We discuss potential therapeutic strategies to target sleep disruptions and conclude that there is an urgent need for testing new therapeutic sleep interventions.

Physical activity, sedentary time, and longitudinal bone strength in adolescent girls.

The association between baseline physical activity and sedentary time with 2-year longitudinal bone strength was evaluated. The effect of physical activity on bone depended on maturity status. Sedentary time did not negatively impact bone outcomes, regardless of maturity. Maturity should be considered when developing exercise interventions to improve bone outcomes. INTRODUCTION: Physical activity during adolescence is important to obtain peak bone mass; however, adolescents are increasingly sedentary, potentially increasing risk for osteoporosis later in life. The aim of this study was to assess the association of physical activity and sedentary time with 2-year longitudinal bone outcomes in adolescent females (69% Hispanic/31% non-Hispanic). METHODS: Bone strength was assessed at the 66% tibia, 20% femur, and 66% radius of 9- to 12-year-old girls (n = 131) using peripheral quantitative computed tomography at baseline and 2-year follow-up. Physical activity and sedentary time were assessed via accelerometry. Linear regression analyses were used to assess whether baseline vigorous physical activity (VPA), moderate physical activity (MPA), light physical activity (LPA), or sedentary time predict longitudinal bone outcomes, adjusting for relevant confounders. RESULTS: Significant interactions were found between maturity offset and physical activity. In weight-bearing bones, significant interactions were primarily identified between VPA and maturity offset. Interactions indicated that VPA was associated with favorable bone outcomes at the tibia and femur in girls further past the age of PHV. However, this favorable effect was not observed in girls closer to the age of PHV. At the radius, interactions were primarily observed between LPA and maturity offset. Again, LPA was more beneficial for girls further past the age of PHV. Sedentary time did not significantly influence bone outcomes. CONCLUSION: The effects of physical activity on bone may be dependent on maturity. Therefore, physical activity interventions, with attention to maturity status, may be required to optimize bone strength in girls.

Revealing complete complex KIR haplotypes phased by long-read sequencing technology.

The killer cell immunoglobulin-like receptor (KIR) region of human chromosome 19 contains up to 16 genes for natural killer (NK) cell receptors that recognize human leukocyte antigen (HLA)/peptide complexes and other ligands. The KIR proteins fulfill functional roles in infections, pregnancy, autoimmune diseases and transplantation. However, their characterization remains a constant challenge. Not only are the genes highly homologous due to their recent evolution by tandem duplications, but the region is structurally dynamic due to frequent transposon-mediated recombination. A sequencing approach that precisely captures the complexity of KIR haplotypes for functional annotation is desirable. We present a unique approach to haplotype the KIR loci using single-molecule, real-time (SMRT) sequencing. Using this method, we have-for the first time-comprehensively sequenced and phased sixteen KIR haplotypes from eight individuals without imputation. The information revealed four novel haplotype structures, a novel gene-fusion allele, novel and confirmed insertion/deletion events, a homozygous individual, and overall diversity for the structural haplotypes and their alleles. These KIR haplotypes augment our existing knowledge by providing high-quality references, evolutionary informers, and source material for imputation. The haplotype sequences and gene annotations provide alternative loci for the KIR region in the human genome reference GrCh38.p8.

Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP in Post-Lung Transplant Primary Graft Dysfunction Risk.

The authors previously identified plasma plasminogen activator inhibitor-1 (PAI-1) level as a quantitative lung injury biomarker in primary graft dysfunction (PGD). They hypothesized that plasma levels of PAI-1 used as a quantitative trait could facilitate discovery of genetic loci important in PGD pathogenesis. A two-stage cohort study was performed. In stage 1, they tested associations of loci with PAI-1 plasma level using linear modeling. Genotyping was performed using the Illumina CVD Bead Chip v2. Loci meeting a p < 5 × 10(-4) cutoff were carried forward and tested in stage 2 for association with PGD. Two hundred ninety-seven enrollees were evaluated in stage 1. Six loci, associated with PAI-1, were carried forward to stage 2 and evaluated in 728 patients. rs3168046 (Toll interacting protein [TOLLIP]) was significantly associated with PGD (p = 0.006). The increased risk of PGD for carrying at least one copy of this variant was 11.7% (95% confidence interval 4.9-18.5%). The false-positive rate for individuals with this genotype who did not have PGD was 6.1%. Variants in the TOLLIP gene are associated with higher circulating PAI-1 plasma levels and validate for association with clinical PGD. A protein quantitative trait analysis for PGD risk prioritizes genetic variations in TOLLIP and supports a role for Toll-like receptors in PGD pathogenesis.

Development of an informatics infrastructure for data exchange of biomolecular simulations: Architecture, data models and ontology.

Biomolecular simulations aim to simulate structure, dynamics, interactions, and energetics of complex biomolecular systems. With the recent advances in hardware, it is now possible to use more complex and accurate models, but also reach time scales that are biologically significant. Molecular simulations have become a standard tool for toxicology and pharmacology research, but organizing and sharing data - both within the same organization and among different ones - remains a substantial challenge. In this paper we review our recent work leading to the development of a comprehensive informatics infrastructure to facilitate the organization and exchange of biomolecular simulations data. Our efforts include the design of data models and dictionary tools that allow the standardization of the metadata used to describe the biomedical simulations, the development of a thesaurus and ontology for computational reasoning when searching for biomolecular simulations in distributed environments, and the development of systems based on these models to manage and share the data at a large scale (iBIOMES), and within smaller groups of researchers at laboratory scale (iBIOMES Lite), that take advantage of the standardization of the meta data used to describe biomolecular simulations.

Objective Estimates Improve Risk Stratification for Primary Graft Dysfunction after Lung Transplantation.

Primary graft dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in the Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002 to 2010; with separate validation in 382 subjects accrued from 2011 to 2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 h, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed three prediction models, where low-risk recipients had a normal BMI (18.5-25 kg/m(2) ), chronic obstructive pulmonary disease/cystic fibrosis, and absent or mild pulmonary hypertension (mPAP<40 mmHg). All others were considered higher-risk. Low-risk recipients had a predicted PGD risk of 4-7%, and high-risk a predicted PGD risk of 15-18%. Adding a donor-smoking lung to a higher-risk recipient significantly increased PGD risk, although risk did not change in low-risk recipients. Validation demonstrated that probability estimates were generally accurate and that models worked best at baseline PGD incidences between 5% and 25%. We conclude that valid estimates of PGD risk can be produced using readily available clinical variables.

Age of onset group characteristics in forensic patients with schizophrenia.

This study aims to empirically identify age of onset groups and their clinical and background characteristics in forensic patients with schizophrenia. Hospital charts were reviewed of all 138 forensic patients with schizophrenia admitted to Geha Psychiatric Hospital that serves a catchment area of approximately 500,000 people, from 2000 to 2009 inclusive. Admixture analysis empirically identified early- (M=19.99, SD=3.31) and late-onset groups (M=36.13, SD=9.25). Early-onset was associated with more suicide attempts, violence before the age of 15, and early conduct problems, whereas late-onset was associated with a greater likelihood of violence after the age of 18 and marriage (P<0.01). The current findings provide clinicians with a unique direction for risk assessment and indicate differences in violence between early- and late-onset schizophrenia, particularly co-occurrence of harmful behavioral phenotypes.

Fluxionality of [(Ph3P)3M(X)] (M = Rh, Ir). The red and orange forms of [(Ph3P)3Ir(Cl)]. Which phosphine dissociates faster from Wilkinson's catalyst?

NMR studies of intramolecular exchange in [(Ph(3)P)(3)Rh(X)] (X = CF(3), CH(3), H, Ph, Cl) have produced full sets of activation parameters for X = CH(3) (E(a) = 16.4 +/- 0.6 kcal mol(-1), DeltaH(double dagger) = 16.0 +/- 0.6 kcal mol(-1), and DeltaS(double dagger) = 12.7 +/- 2.5 eu), H (E(a) = 10.7 +/- 0.2 kcal mol(-1), DeltaH(double dagger) = 10.3 +/- 0.2 kcal mol(-1), and DeltaS(double dagger) = -7.2 +/- 0.8 eu), and Cl (E(a) = 16.3 +/- 0.2 kcal mol(-1), DeltaH(double dagger) = 15.7 +/- 0.2 kcal mol(-1), and DeltaS(double dagger) = -0.8 +/- 0.8 eu). Computational studies have shown that for strong trans influence ligands (X = H, Me, Ph, CF(3)), the rearrangement occurs via a near-trigonal transition state that is made more accessible by bulkier ligands and strongly donating X. The exceedingly fast exchange in novel [(Ph(3)P)(3)Rh(CF(3))] (12.1 s(-1) at -100 degrees C) is due to strong electron donation from the CF(3) ligand to Rh, as demonstrated by computed charge distributions. For weaker donors X, this transition state is insufficiently stabilized, and hence intramolecular exchange in [(Ph(3)P)(3)Rh(Cl)] proceeds via a different, spin-crossover mechanism involving triplet, distorted-tetrahedral [(Ph(3)P)(3)Rh(Cl)] as an intermediate. Simultaneous intermolecular exchange of [(Ph(3)P)(3)Rh(Cl)] with free PPh(3) (THF) via a dissociative mechanism occurs exclusively from the sites cis to Cl (E(a) = 19.0 +/- 0.3 kcal mol(-1), DeltaH(double dagger) = 18.5 +/- 0.3 kcal mol(-1), and DeltaS(double dagger) = 4.4 +/- 0.9 eu). Similar exchange processes are much slower for [(Ph(3)P)(3)Ir(Cl)] which has been found to exist in orange and red crystallographic forms isostructural with those of [(Ph(3)P)(3)Rh(Cl)].

Clinical diagnosis of acute coronary syndrome in patients with chest pain and a normal or non-diagnostic electrocardiogram.

BACKGROUND: Clinical features may be used to determine which patients with suspected acute coronary syndrome (ACS), but a normal or non-diagnostic ECG, should be selected for further investigation or inpatient care. We aimed to measure the diagnostic value of clinical features for ACS. METHODS: Standardised data relating to presenting characteristics, associated features and risk factors were collected at seven chest pain units established for the ESCAPE trial. All patients received troponin measurement at least 6 h after last significant symptoms, creatine kinase MB(mass) gradient over 2 h and, if appropriate, treadmill exercise testing. The reference standard of ACS was defined as troponin >0.03 ng/ml, creatine kinase MB(mass) gradient >3.0 ng/ml or early positive treadmill exercise test. RESULTS: 1576 patients were analysed, including 132 (8.4%) with ACS. Patients with ACS were older, had longer symptom duration, were more likely to be a man, hypertensive and an ex-smoker or have pain radiating to their right arm. On multivariate analysis, only age, duration, sex and radiation of pain to the right arm were independently associated with ACS. Likelihood ratios (95% CI) were radiation of pain to the right arm, 2.9 (95% CI 1.4 to 6.3), male sex 1.2 (95% CI 1.0 to 1.3) and female sex 0.79 (95% CI 0.62 to 1.0). The area under the receiver operator characteristic curve for age was 0.629 (95% CI 0.573 to 0.686) and for duration was 0.546 (95% CI 0.481 to 0.610). CONCLUSION: Clinical features have very limited value for diagnosing ACS in patients with a normal or non-diagnostic ECG. Radiation of pain to the right arm increases the likelihood of ACS.

Immunosuppressant therapy adherence and graft failure among pediatric renal transplant recipients.

The study objective was to determine the association between immunosuppressant therapy (IST) adherence and graft failure among pediatric renal transplant recipients (RTRs) using data reported in the United States Renal Data System (USRDS), which contains Medicare prescription claims. RTRs (

Fluxionality of [(Ph3P)3Rh(X)]: the extreme case of X = CF3.

[(Ph(3)P)(3)Rh(F)] reacts with CF(3)SiMe(3) to produce trans-[(Ph(3)P)(2)Rh(CF(2))(F)] (1; X-ray), which is equilibrated with a number of species in solution. Addition of excess Ph(3)P shifts all of the equilibria to [(Ph(3)P)(3)Rh(CF(3))] (2; X-ray) as the only NMR-observable and isolable (84%) species. Complex 2 is uniquely highly fluxional in solution, maintaining ligand exchange even at -100 degrees C (12.1 s(-1)). Activation parameters have been determined (variable-temperature (31)P NMR) for the similar but slower exchange in the Me analogue of 2, [(Ph(3)P)(3)Rh(CH(3))]: E(a) = 16.5 +/- 0.6 kcal mol(-1), DeltaG(double dagger) = 12.9 kcal mol(-1) (calculated at -30 degrees C), DeltaH(double dagger) = 16.0 +/- 0.6 kcal mol(-1), and DeltaS(double dagger) = 12.8 +/- 2.3 e.u. Intramolecular exchange in [(R(3)P)(3)Rh(X)] occurs (DFT, MP2//BP86) via a distorted trigonal transition state (TS) with X in an axial position trans to a vacant site. The rearrangement is governed by a combination of steric and electronic factors and is facilitated by bulkier ligands on Rh as well as by strongly donating X that stabilize the TS. The Rh atom in [(H(3)P)(3)Rh(X)] has been shown to be more negatively charged (NPA) for X = CF(3) than for X = CH(3), despite the strongly oppositely charged carbon atoms of the CF(3) (+0.79e) and CH(3) (-0.96e) ligands. Clarification of stereochemical rigidity (X = halide, CN, OR, NR(2)) versus fluxionality (X = H, Alk, Ar, CF(3)) is provided, along with a resolution of the long-standing contradiction between the electron-withdrawing effect of CF(3) in organic compounds and its strong trans influence (electron donation) in metal complexes.

Age-related reduction in microcolumnar structure correlates with cognitive decline in ventral but not dorsal area 46 of the rhesus monkey.

The age-related decline in cognitive function that is observed in normal aging monkeys and humans occurs without significant loss of cortical neurons. This suggests that cognitive impairment results from subtle, sub-lethal changes in the cortex. Recently, changes in the structural coherence in mini- or microcolumns without loss of neurons have been linked to loss of function. Here we use a density map method to quantify microcolumnar structure in both banks of the sulcus principalis (prefrontal cortical area 46) of 16 (ventral) and 19 (dorsal) behaviorally tested female rhesus monkeys from 6 to 33 years of age. While total neuronal density does not change with age in either of these banks, there is a significant age-related reduction in the strength of microcolumns in both regions on the order of 40%. This likely reflects a subtle but definite loss of organization in the structure of the cortical microcolumn. The reduction in strength in ventral area 46 correlates with cognitive impairments in learning and memory while the reduction in dorsal area 46 does not. This result is congruent with published data attributing cognitive functions to ventral area 46 that are similar to our particular cognitive battery which does not optimally tap cognitive functions attributed to dorsal area 46. While the exact mechanisms underlying this loss of microcolumnar organization remain to be determined, it is plausible that they reflect age-related alterations in dendritic and/or axonal organization which alter connectivity and may contribute to age-related declines in cognitive performance.

Carnitine palmitoyltransferase II deficiency: successful anaplerotic diet therapy.

BACKGROUND: Carnitine palmitoyltransferase II (CPT II) deficiency is an important cause of recurrent rhabdomyolysis in children and adults. Current treatment includes dietary fat restriction, with increased carbohydrate intake and exercise restriction to avoid muscle pain and rhabdomyolysis. METHODS: CPT II enzyme assay, DNA mutation analysis, quantitative analysis of acylcarnitines in blood and cultured fibroblasts, urinary organic acids, the standardized 36-item Short-Form Health Status survey (SF-36) version 2, and bioelectric impedance for body fat composition. Diet treatment with triheptanoin at 30% to 35% of total daily caloric intake was used for all patients. RESULTS: Seven patients with CPT II deficiency were studied from 7 to 61 months on the triheptanoin (anaplerotic) diet. Five had previous episodes of rhabdomyolysis requiring hospitalizations and muscle pain on exertion prior to the diet (two younger patients had not had rhabdomyolysis). While on the diet, only two patients experienced mild muscle pain with exercise. During short periods of noncompliance, two patients experienced rhabdomyolysis with exercise. None experienced rhabdomyolysis or hospitalizations while on the diet. All patients returned to normal physical activities including strenuous sports. Exercise restriction was eliminated. Previously abnormal SF-36 physical composite scores returned to normal levels that persisted for the duration of the therapy in all five symptomatic patients. CONCLUSIONS: The triheptanoin diet seems to be an effective therapy for adult-onset carnitine palmitoyltransferase II deficiency.

Automated identification of neurons and their locations.

Individual locations of many neuronal cell bodies (>10(4)) are needed to enable statistically significant measurements of spatial organization within the brain such as nearest-neighbour and microcolumnarity measurements. In this paper, we introduce an Automated Neuron Recognition Algorithm (ANRA) which obtains the (x, y) location of individual neurons within digitized images of Nissl-stained, 30 microm thick, frozen sections of the cerebral cortex of the Rhesus monkey. Identification of neurons within such Nissl-stained sections is inherently difficult due to the variability in neuron staining, the overlap of neurons, the presence of partial or damaged neurons at tissue surfaces, and the presence of non-neuron objects, such as glial cells, blood vessels, and random artefacts. To overcome these challenges and identify neurons, ANRA applies a combination of image segmentation and machine learning. The steps involve active contour segmentation to find outlines of potential neuron cell bodies followed by artificial neural network training using the segmentation properties (size, optical density, gyration, etc.) to distinguish between neuron and non-neuron segmentations. ANRA positively identifies 86 +/- 5% neurons with 15 +/- 8% error (mean +/- SD) on a wide range of Nissl-stained images, whereas semi-automatic methods obtain 80 +/- 7%/17 +/- 12%. A further advantage of ANRA is that it affords an unlimited increase in speed from semi-automatic methods, and is computationally efficient, with the ability to recognize approximately 100 neurons per minute using a standard personal computer. ANRA is amenable to analysis of huge photo-montages of Nissl-stained tissue, thereby opening the door to fast, efficient and quantitative analysis of vast stores of archival material that exist in laboratories and research collections around the world.

Mechanisms of catalyst poisoning in palladium-catalyzed cyanation of haloarenes. remarkably facile C-N bond activation in the [(Ph3P)4Pd]/[Bu4N]+ CN- system.

Reaction paths leading to palladium catalyst deactivation during cyanation of haloarenes (eq 1) have been identified and studied. Each key step of the catalytic loop (Scheme 1) can be disrupted by excess cyanide, including ArX oxidative addition, X/CN exchange, and ArCN reductive elimination. The catalytic reaction is terminated via the facile formation of inactive [(CN)4Pd]2-, [(CN)3PdH]2-, and [(CN)3PdAr]2-. Moisture is particularly harmful to the catalysis because of facile CN- hydrolysis to HCN that is highly reactive toward Pd(0). Depending on conditions, the reaction of [(Ph3P)4Pd] with HCN in the presence of extra CN- can give rise to [(CN)4Pd]2- and/or the remarkably stable new hydride [(CN)3PdH]2- (NMR, X-ray). The X/CN exchange and reductive elimination steps are vulnerable to excess CN- because of facile phosphine displacement leading to stable [(CN)3PdAr]2- that can undergo ArCN reductive elimination only in the absence of extra CN-. When a quaternary ammonium cation such as [Bu4N]+ is used as a phase-transfer agent for the cyanation reaction, C-N bond cleavage in the cation can occur via two different processes. In the presence of trace water, CN- hydrolysis yields HCN that reacts with Pd(0) to give [(CN)3PdH]2-. This also releases highly active OH- that causes Hofmann elimination of [Bu4N]+ to give Bu3N, 1-butene, and water. This decomposition mode is therefore catalytic in H2O. Under anhydrous conditions, the formation of a new species, [(CN)3PdBu]2-, is observed, and experimental studies suggest that electron-rich mixed cyano phosphine Pd(0) species are responsible for this unusual reaction. A combination of experimental (kinetics, labeling) and computational studies demonstrate that in this case C-N activation occurs via an S(N)2-type displacement of amine and rule out alternative 3-center C-N oxidative addition or Hofmann elimination processes.