Evaluator empathy in risk assessment interviews.

OBJECTIVE: Should forensic evaluators convey empathy during forensic assessments? Opponents contend that empathy causes harm by leading evaluees to disclose potentially incriminating information, but proponents hold that empathy is crucial for establishing rapport and conveying respect. This study provides a comprehensive examination of experienced forensic evaluators' use of empathy in forensic assessment. HYPOTHESES: The study was exploratory and not hypothesis-driven, but we expected to find identifiable subgroups of evaluators who differed in their use of empathy in the context of a risk assessment interview. We also expected that evaluator subgroups would differ in their attitudes and practices regarding empathy and that higher levels of empathy may be associated with more favorable views of evaluees. METHOD: Experienced forensic evaluators (N = 200) assumed the role of interviewer in a written parole risk assessment interview and chose questions (high or low empathy) they would ask the evaluee if they were conducting the interview. Evaluators also provided ratings of their perceptions of the evaluee and responded to questions regarding their attitudes toward, and use of, empathy in forensic assessment. RESULTS: Latent class analysis results indicated that most evaluators fell into low- (46.0%) or moderate- (43.0%) empathy subgroups, with few falling into a high-empathy subgroup (11.0%). Higher levels of empathy in the interview were associated with attitudes and practices supporting empathy use and higher self-reported understanding of the evaluee, but not with opinions of the evaluee's risk or suitability for parole. CONCLUSIONS: These findings of clear differences in evaluator empathy add to the growing body of research documenting the extent to which forensic evaluators differ in their evaluation styles and tendencies. Although there was support for both very low and very high levels of empathy, support for very high levels of empathy was uncommon. Most evaluators opted for low to moderate empathy. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Effectiveness of the Med Safety mobile application in improving adverse drug reaction reporting by healthcare professionals in Uganda: a protocol for a pragmatic cluster-randomised controlled trial.

INTRODUCTION: Combination antiretroviral therapy (cART) has massively reduced HIV mortality. However, long-term cART increases the risk of adverse drug reactions (ADRs), which can lead to higher morbidity, mortality and healthcare costs for people living with HIV (PLHIV).Pharmacovigilance-monitoring the effects of medicines-is essential for understanding real-world drug safety. In Uganda, pharmacovigilance systems have only recently been developed, and rates of ADR reporting for cART are very low. Thus, the safety profile of medicines currently used to treat HIV and tuberculosis in our population is poorly understood.The Med Safety mobile application has been developed through the European Union's Innovative Medicines Initiative WEB-Recognising Adverse Drug Reactions project to promote digital pharmacovigilance. This mobile application has been approved for ADR-reporting by Uganda's National Drug Authority. However, the barriers and facilitators to Med Safety uptake, and its effectiveness in improving pharmacovigilance, are as yet unknown. METHODS AND ANALYSIS: A pragmatic cluster-randomised controlled trial will be implemented over 30 months at 191 intervention and 191 comparison cART sites to evaluate Med Safety. Using a randomisation sequence generated by the sealed envelope software, we shall randomly assign the 382 prescreened cART sites to the intervention and comparison arms. Each cART site is a cluster that consists of healthcare professionals and PLHIV receiving dolutegravir-based cART and/or isoniazid preventive therapy. Healthcare professionals enrolled in the intervention arm will be trained in the use of mobile-based, paper-based and web-based reporting, while those in the comparison arm will be trained in paper-based and web-based reporting only. ETHICS AND DISSEMINATION: Ethical approval was given by the School of Biomedical Sciences Research and Ethics Committee at Makerere University (SBS-REC-720), and administrative clearance was obtained from Uganda National Council for Science and Technology (HS1366ES). Study results will be shared with healthcare professionals, policymakers, the public and academia. TRIAL REGISTRATION NUMBER: PACTR202009822379650.

Pharmacogenomics of Drug Hypersensitivity: Technology and Translation.

Hypersensitivity reactions are caused by many structurally unrelated drugs used for many different diseases. These reactions vary in severity and can be fatal. Only a minority of patients are affected by drug hypersensitivity reactions. Predisposition seems to be mediated by genetic factors, particularly within the HLA system. Apart from HLA-B∗57:01 testing, which is routine to prevent abacavir hypersensitivity, uptake of HLA testing into clinical practice has been slow and challenging. As genomic medicine becomes mainstream, it will be important for genetic testing in this area to move from the current reactive strategy to a more pre-emptive approach.

COVID-19 associated phrenic nerve mononeuritis: a case series.

This study characterised the hemidiaphragm elevation on 3-month interval chest X-rays (CXRs) of patients post COVID-19 pneumonia. 467 CXRs were screened; 19 (4.1%) had an elevated hemidiaphragm. There were 15 (3.2%) patients of interest with new hemidiaphragm elevation, persisting on average 7 months post COVID-19 diagnosis. Symptomatic patients underwent diaphragm ultrasound (n=12), pulmonary function test (n=10), muscle function test (n=6) and neurophysiology (n=5), investigating phrenic nerve function. Ultrasound demonstrated reduced/paradoxical diaphragmatic movements in eight; four of eight had reduced thickening fraction. Neurophysiology peripheral limb studies did not support the differential diagnoses of critical illness neuropathy/myopathy. We propose that, in selected patients, COVID-19 may cause phrenic nerve mononeuritis.

Factors Affecting Patient and Physician Engagement in Remote Health Care for Heart Failure: Systematic Review.

BACKGROUND: Adult chronic heart failure mainly affects an elderly population with multiple comorbidities that often require frequent medical visits to prevent poor health outcomes. However, the heart failure disease process reduces their independence by reducing mobility, exercise tolerance, and cognitive decline. Remote care technologies can bridge the gap in care for these patients by allowing them to be followed up within the comfort of their home and encourage their self-care. However, patients, carers, and health care professionals need to engage with the technology for it to be useful. OBJECTIVE: This systematic review explores qualitative primary studies of remote care technologies used in heart failure, to determine the factors that affect user engagement with the technology. This is explored from the perspective of patients, carers, and health care professionals. METHODS: Relevant studies published between January 1, 1990, and September 19, 2020, were identified from EMBASE, Ovid MEDLINE, PubMed, Cochrane Library, and Scopus. These studies were then synthesized using thematic analysis. Relevant user experiences with remote care were extracted using line-by-line coding. These codes were summarized into secondary codes and core concepts, which were further merged into overarching themes that encapsulate user experience with remote care. RESULTS: The review included 47 studies, which led to the generation of 5 overarching themes that affect engagement: (1) "Convenience" relates to time saved by the intervention; (2) "Clinical Care" relates to perceived quality of care and health outcomes; (3) "Communication" involves feedback and interaction between patients, staff, and carers; (4) "Education" concerns the tailored information provided; and (5) "Ease of Use" relates to accessibility and technical barriers to engagement. Each theme was applied to each user base of patient, carer, and health care professional in a different manner. CONCLUSIONS: The 5 themes identified highlight aspects of remote care that facilitate engagement, and should be considered in both future design and trials evaluating these technologies.

Coordination of autonomic and endocrine stress responses to the Trier Social Stress Test in adolescence.

Dysregulations in autonomic and endocrine stress responses are linked to the emergence of psychopathology in adolescence. However, most studies fail to consider the interplay between these systems giving rise to conflicting findings and a gap in understanding adolescent stress response regulation. A multisystem framework-investigation of parasympathetic (PNS), sympathetic (SNS), and hypothalamic pituitary adrenal (HPA) axis components and their coordination-is necessary to understand individual differences in stress response coordination which contribute to stress vulnerabilities. As the first investigation to comprehensively evaluate these three systems in adolescence, the current study employed the Trier Social Stress Test in 72 typically developing adolescents (mean age = 13) to address how PNS, SNS, and HPA stress responses are coordinated in adolescence. Hypotheses tested key predictions of the Adaptive Calibration Model (ACM) of stress response coordination. PNS and SNS responses were assessed via heart rate variability (HRV) and salivary alpha amylase (sAA) respectively. HPA responses were indexed by salivary cortisol. Analyses utilized piecewise growth curve modeling to investigate these aims. Supporting the ACM theory, there was significant hierarchical coordination between the systems such that those with low HRV had higher sAA and cortisol reactivity and those with high HRV had low-to-moderate sAA and cortisol responsivity. Our novel results reveal the necessity of studying multisystem dynamics in an integrative fashion to uncover the true mechanisms of stress response and regulation during development. Additionally, our findings support the existence of characteristic stress response profiles as predicted by the ACM model.

Robotic Assisted Caval Replacement for Recurrent Renal Cell Carcinoma Invading the Wall of the Inferior Vena Cava.

OBJECTIVE: To describe a case of robotic inferior vena cava (IVC) resection for an advanced case of renal cell carcinoma with accompanying robotic caval replacement using a synthetic graft. METHODS: In this report and accompanying video we describe a case of complete caval reconstruction with 3 year follow up. A 49-year-old male who at the age of 40 (9 years ago) had undergone right open partial nephrectomy for a pT1b 4.6 cm Fuhrman Grade 2 clear cell RCC with negative margins was found to have a recurrent mass at 6 years of follow up with suspicion of invasion into duodenum and IVC. For his recurrence, he underwent robotic assisted laparoscopic right radical nephrectomy and IVC resection followed by a placement of a 18 mm GORE-TEX graft anastomosed to the caudal and cephalad edges of the resected cava. RESULTS: The surgery was successfully completed using robotic assistance with a total operative time of 6 hours and 40 minutes and 900 cc blood loss. The patient experienced no intraoperative or perioperative complications and was discharged home on postoperative day #2. At 3 year of follow up there is no evidence of local recurrence. The radiology reports repeatedly commented on vascular structures "within normal limits." The patient had experienced no graft issues at a present follow up. CONCLUSION: This case provides a description of the surgery with video demonstration of technique as well as provides a few technical suggestions that may be useful for those who attempt similar surgery in the future.

Patterns of balance loss with systematic perturbations in Parkinson's disease and multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) and Parkinson's disease (PD) may affect balance differently. However, no studies have compared loss of balance (LOB) patterns following multi-directional perturbations. OBJECTIVE: 1) determine reliability of LOB ratings following standardized manual perturbations; 2) compare LOB ratings in MS, PD, and healthy control (HC) groups following perturbations at upper/lower torso, in anterior/posterior, right/left, and rotational directions. METHODS: 1) reviewers rated videotaped LOB following perturbations applied by 4 clinicians in 6-10 HCs. 2) three groups (64 MS, 42 PD and 32 HC) received perturbations. LOB ratings following perturbations were analyzed using two-factor mixed ANOVAs for magnitude and prevalence. RESULTS: 1) LOB ratings showed moderate to good ICC and good to excellent agreement. 2) MS group showed greater magnitude and prevalence of LOB than PD or HC groups (p < .001). All groups showed greater LOB from right/left versus anterior/posterior perturbations (p < .01). PD showed greater LOB from perturbations at upper versus lower torso; MS and HC showed greater LOB from posterior versus anterior perturbations. CONCLUSIONS: Our reliable rating scale showed differences in patterns of LOB following manual perturbations in MS, PD, and HC. Clinically accessible and reliable assessment of LOB could facilitate targeted perturbation-based interventions and reduce falls in vulnerable populations.

Dimethyl fumarate induced lymphopenia in multiple sclerosis: A review of the literature.

Dimethyl fumarate (DMF) is a first line medication for multiple sclerosis. It has a favourable safety profile, however, there is concern regarding the occurrence of moderate-severe and sustained lymphopenia and the associated risk of progressive multifocal leukoencephalopathy. We carried out an extensive literature review to understand the molecular mechanisms underlying this adverse reaction. Dynamic changes in certain components of the immune system are likely to be important for the therapeutic effects of DMF, including depletion of memory T cells and decrease in activated T cells together with expansion of naïve T cells. Similar modifications were reported for the B cell components. CD8+ T cells are particularly susceptible to DMF-induced cell death, with marked reductions observed in lymphopenic subjects. The reasons underlying such increased sensitivity are not known, nor it is known how expansion of other lymphocyte subsets occurs. Understanding the molecular mechanisms underlying DMF action is challenging: in vivo DMF is rapidly metabolized to monomethyl fumarate (MMF), a less potent immunomodulator in vitro. Pharmacokinetics indicate that MMF is the main active species in vivo. However, the relative importance of DMF and MMF in toxicity remains unclear, with evidence presented in favour of either of the compounds as toxic species. Pharmacogenetic studies to identify genetic predictors of DMF-induced lymphopenia are limited, with inconclusive results. A role of the gut microbiome in the pharmacological effects of DMF is emerging. It is clear that further investigations are necessary to understand the mechanisms of DMF-induced lymphopenia and devise preventive strategies. Periodic monitoring of absolute lymphocyte counts, currently performed in clinical practise, allows for the early detection of lymphopenia as a risk-minimization strategy.

Liquid buccal mucosa graft endoscopic urethroplasty: a validation animal study.

PURPOSE: To validate a novel method of urethral stricture treatment using liquid buccal mucosal grafts (LBMG) to augment direct vision internal urethrotomy (DVIU) in an animal model. MATERIALS AND METHODS: A rabbit stricture model was used to test this method. Strictures were induced in 26 rabbits using electroresection of urethral epithelium. The animals were randomized into two groups: Group-1, treated with DVIU and LBMG in fibrin glue, and Group-2, DVIU with fibrin glue only. LBMG was prepared by suspension of mechanically minced buccal mucosa micrografts in fibrin glue. This LBMG-fibrin glue mixture was later injected into the urethrotomies of Group-1 animals. All animals were killed at 24 weeks after repeat retrograde urethrogram (RUG) and urethroscopy by surgeon blinded to the treatment arm. Radiographic images and histological specimens were reviewed by a radiologist and a pathologist, respectively, blinded to the treatment arm. Stricture treatment was considered a success if a diameter measured on RUG increased by ≥ 50% compared to pre-treatment RUG diameter. Histological specimens were assessed for the presence of BMG engraftment. RESULTS: In Group-1, 8/12(67%) animals demonstrated engraftment of LBMG, compared to none in Group-2 (p = 0.0005). 7/12(58%) in Group-1 showed radiographic resolution/improvement of strictures compared to 5/13 Group-2 rabbits (38%, p = 0.145). The median percent change for the Group-1 was 59%, compared to 41.6% for Group-2 (p = 0.29). CONCLUSION: This proof-of-concept study demonstrates feasibility of LBMG for endoscopic urethral stricture repairs. Further studies are needed to establish the role of this novel concept in treatment of urethral strictures.

Development and validation of diagnostic triage criteria for liver disease from a minimum data set enabling the 'intelligent LFT' pathway for the automated assessment of deranged liver enzymes.

BACKGROUND: Liver function tests (LFTs) are commonly abnormal; most patients with 'incidental' abnormal LFTs are not investigated appropriately and for those who are, current care pathways are geared to find an explanation for the abnormality by a lengthy process of investigation and exclusion, with costs to the patient and to the health service. OBJECTIVE: To validate an intelligent automatable analysis tool (iLFT) for abnormal liver enzymes, which diagnoses common liver conditions, provides fibrosis stage and recommends management. DESIGN: A retrospective case note review from three tertiary referral liver centres, with application of the iLFT algorithm and comparison with the clinician's final opinion as gold standard. RESULTS: The iLFT algorithm in 91.3% of cases would have correctly recommended referral or management in primary care. In the majority of the rest of the cases, iLFT failed safe and recommended referral even when the final clinical diagnosis could have been managed in primary care. Diagnostic accuracy was achieved in 82.4% of cases, consistent with the fail-safe design of the algorithm. Two cases would have remained in primary care as per the algorithm outcome, however on clinical review had features of advanced fibrosis. CONCLUSION: iLFT analysis of abnormal liver enzymes offers a safe and robust method of risk stratifying patients to the most appropriate care pathway as well as providing reliable diagnostic information based on a single blood draw, without repeated contacts with health services. Offers the possibility of high quality investigation and diagnosis to all patients rather than a tiny minority.

Changes in growth and sleep across school nights, weekends and a winter holiday period in two Australian schools.

Studies suggest that there may be an association between sleep and growth; however, the relationship is not well understood. Changes in biology and external factors such as school schedule heavily impact the sleep of adolescents, during a critical phase for growth. This study assessed the changes in sleep across school days, weekends and school holidays, while also measuring height and weight changes, and self-reported alterations in food intake and physical activity. The impact of morningness-eveningness (M-E) on height change and weight gain was also investigated. In a sample of 63 adolescents (mean age = 13.13, SD = 0.33, 31 males) from two independent schools in South Australia, height and weight were measured weekly for 4 weeks prior to the school holidays and 4 weeks after the school holidays. Participants also completed a Morningness/Eveningness Scale and 7-day sleep, diet and physical activity diaries prior to, during and after the school holidays. Participants at one school had earlier wake times during the weekends than participants attending the other school, leading to a significantly shorter sleep duration on weekends for those participants. Regardless of school, sleep was significantly later and longer during the holidays (p < 0.001) and those with a stronger morning preference fell asleep (F18,36 = 3.4, p = 0.001) and woke (F18,44 = 2.0, p = 0.027) earlier than evening types. Growth rate was lower during the holiday weeks. For those attending the school with limited sleep in opportunities, growth after the holidays was lower for those with greater evening preference, whereas for those at the other school, growth was greater for those with greater evening preference. The increase in average weight from pre- to post-holidays was greater for those attending the school with limited opportunities to sleep longer. Participants reported greater food intake during the holidays compared to school days and greater physical activity levels on weekends compared to school days, and school days compared to holidays. Results suggest that time of day preference may impact growth, with evening types who cannot sleep in growing at a slower rate than evening types who can or morning types. This may be related to sleep restriction. Despite sleep being both later and longer during the school holidays, participants' growth slowed during the holiday period. It is possible that this may be a reflection of other behavioural changes in the holidays (increased food intake and reduced physical activity), as sleep timing during the school period was related to growth.

A study protocol for a non-randomised comparison trial evaluating the feasibility and effectiveness of a mobile cognitive-behavioural programme with integrated coaching for anxious adults in primary care.

INTRODUCTION: Generalised anxiety disorder (GAD) and subclinical GAD are highly prevalent in primary care. Unmanaged anxiety worsens quality of life in patients seen in primary care practices and leads to increased medical utilisation and costs. Programmes that teach patients cognitive-behavioural therapy (CBT) techniques have been shown to improve anxiety and to prevent the evolution of anxiety symptoms to disorders, but access and engagement have hampered integration of CBT into medical settings. METHODS AND ANALYSIS: This pragmatic study takes place in University of Pittsburgh Medical Center primary care practices to evaluate a coach-supported mobile cognitive- behavioural programme (Lantern) on anxiety symptoms and quality of life. Clinics were non-randomly assigned to either enhanced treatment as usual or Lantern. All clinics provide electronic screening for anxiety and, within clinics assigned to Lantern, patients meeting a threshold level of mild anxiety (ie, >5 on Generalised Anxiety Disorder 7-Item Questionnaire (GAD-7)) are referred to Lantern. The first study phase is aimed at establishing feasibility, acceptability and effectiveness. The second phase focuses on long-term impact on psychosocial outcomes, healthcare utilisation and clinic/provider adoption/sustainable implementation using a propensity score matched parallel group study design. Primary outcomes are changes in anxiety symptoms (GAD-7) and quality of life (Short-Form Health Survey) between baseline and 6-month follow-ups, comparing control and intervention. Secondary outcomes include provider and patient satisfaction, patient engagement, durability of changes in anxiety symptoms and quality of life over 12 months and the impact of Lantern on healthcare utilisation over 12 months. Patients from control sites will be matched to the patients who use the mobile app. ETHICS AND DISSEMINATION: Ethics and human subject research approval were obtained. A data safety monitoring board is overseeing trial data and ethics. Results will be communicated to participating primary care practices, published and presented at clinical and scientific conferences. TRIAL REGISTRATION NUMBER: NCT03035019.

Essential chemistry for biochemists.

Within every living organism, countless reactions occur every second. These reactions typically occur more rapidly and with greater efficiency than would be possible under the same conditions in the chemical laboratory, and while using only the subset of elements that are readily available in nature. Despite these apparent differences between life and the laboratory, biological reactions are governed by the same rules as any other chemical reaction. Thus, a firm understanding of the fundamentals of chemistry is invaluable in biochemistry. There are entire textbooks devoted to the application of chemical principles in biological systems and so it is not possible to cover all of the relevant topics in depth in this short article. The aim is instead to provide a brief overview of those areas in chemistry that are most relevant to biochemistry. We summarize the basic principles, give examples of how these principles are applied in biological systems and suggest further reading on individual topics.

Iminosugar antivirals: the therapeutic sweet spot.

Many viruses require the host endoplasmic reticulum protein-folding machinery in order to correctly fold one or more of their glycoproteins. Iminosugars with glucose stereochemistry target the glucosidases which are key for entry into the glycoprotein folding cycle. Viral glycoproteins are thus prevented from interacting with the protein-folding machinery leading to misfolding and an antiviral effect against a wide range of different viral families. As iminosugars target host enzymes, they should be refractory to mutations in the virus. Iminosugars therefore have great potential for development as broad-spectrum antiviral therapeutics. We outline the mechanism giving rise to the antiviral activity of iminosugars, the current progress in the development of iminosugar antivirals and future prospects for this field.

Developmental dysplasia of the hip: linkage mapping and whole exome sequencing identify a shared variant in CX3CR1 in all affected members of a large multigeneration family.

Developmental dysplasia of the hip (DDH) is a debilitating condition characterized by incomplete formation of the acetabulum leading to dislocation of the femur, suboptimal joint function, and accelerated wear of the articular cartilage resulting in arthritis. DDH affects 1 in 1000 newborns in the United States; there are well-defined "pockets" of high prevalence in Japan, and in Italy and other Mediterranean countries. Although reasonably accurate for detecting gross forms of hip dysplasia, existing techniques fail to find milder forms of dysplasia. Undetected hip dysplasia is the leading cause of osteoarthritis of the hip in young individuals, causing over 40% of cases in this age group. A sensitive and specific test for DDH has remained a desirable yet elusive goal in orthopedics for a long time. A 72-member, four-generation affected family has been recruited, and DNA from its members retrieved. Genomewide linkage analysis revealed a 2.61-Mb candidate region (38.7-41.31 Mb from the p term of chromosome 3) co-inherited by all affected members with a maximum logarithm (base 10) of odds (LOD) score of 3.31. Whole exome sequencing and analysis of this candidate region in four severely affected family members revealed one shared variant, rs3732378, that causes a threonine (polar) to methionine (non-polar) alteration at position 280 in the transmembrane domain of CX3CR1. This mutation is predicted to have a deleterious effect on its encoded protein, which functions as a receptor for the ligand fractalkine. By Sanger sequencing this variant was found to be present in the DNA of all affected individuals and obligate heterozygotes. CX3CR1 mediates cellular adhesive and migratory functions and is known to be expressed in mesenchymal stem cells destined to become chondrocytes. A genetic risk factor that might be among the etiologic factors for the family in this study has been identified, along with other possible aggravating mutations shared by four severely affected family members. These findings might illuminate the molecular pathways affecting chondrocyte maturation and bone formation.

Predicting inter-species cross-talk in two-component signalling systems.

Phosphosignalling pathways are an attractive option for the synthetic biologist looking for a wide repertoire of modular components from which to build. We demonstrate that two-component systems can be used in synthetic biology. However, their potential is limited by the fact that host cells contain many of their own phosphosignalling pathways and these may interact with, and cross-talk to, the introduced synthetic components. In this paper we also demonstrate a simple bioinformatic tool that can help predict whether interspecies cross-talk between introduced and native two-component signalling pathways will occur and show both in vitro and in vivo that the predicted interactions do take place. The ability to predict potential cross-talk prior to designing and constructing novel pathways or choosing a host organism is essential for the promise that phosphosignalling components hold for synthetic biology to be realised.

A functional variant in the core promoter of the CD95 cell death receptor gene predicts prognosis in acute promyelocytic leukemia.

Up to 15% of acute promyelocytic leukemia (APL) patients fail to achieve or maintain remission. We investigated a common G > A polymorphism at position -1377 (rs2234767) in the core promoter of the CD95 cell death receptor gene in 708 subjects with acute myeloid leukemia, including 231 patients with APL. Compared with the GG genotype, carrier status for the -1377A variant was associated with a significantly worse prognosis in APL patients. Carriers were more likely to fail remission induction (odds ratio = 4.22; 95% confidence interval, 1.41-12.6, P = .01), were more likely to die during the first 8 weeks of remission induction therapy (hazard ratio = 7.26; 95% confidence interval, 2.39-22.9, P = .0005), and had a significantly worse 5-year overall survival (odds ratio = 2.14; 95% confidence interval, 1.10-4.15, P = .03). The -1377A variant destroys a binding site for the SP1 transcriptional regulator and is associated with lower transcriptional activity of the CD95 promoter. Identifying patients at high risk of life-threatening events, such as remission induction failure, is a high priority in APL, especially because such events represent a major cause of death despite the introduction of differentiation therapy.

Variants in genes involved in functional pathways associated with hypertension in African Americans.

Essential hypertension (HBP) is a complex trait with a substantial heritable component. The purpose of this study was to determine if variants in the G-protein coupled receptor Kinase-4 (GRK4), nitric oxide synthase-3 (NOS3), or angiotensin converting enzyme (ACE) genes are associated singly or through complex interactions, with HBP in African Americans aged 18-49 years. TaqMan Assays were used for genotyping the GRK4 and NOS3 variants. The ACE I/D variant was obtained by polymerase chain reaction and electrophoresis. Allelic association tests were performed for the five markers using PLINK. Logistic regression models were fitted to investigate associations between HBP status and the genetic markers. Multilocus analyses were also conducted. The study included 173 hypertensives and 239 normotensives, with stratification into obese and nonobese groups. The GRK4 A486V variant was negatively associated with HBP in the nonobese group (p = 0.048). The TT/CT genotype of GRK4 A486V was associated with decreased risk for HBP relative to the CC genotype after adjusting for age, sex, and body mass index (p = 0.028). Individuals having at least one NOS3 A allele and GRK4 R65L genotype GG had odds of HBP of 2.97 relative to GG homozygotes for NOS3 and GRK4 R65L. These results show very modest effects and do not fully replicate previous studies.

Specificity of localization and phosphotransfer in the CheA proteins of Rhodobacter sphaeroides.

Specificity of protein-protein interactions plays a vital role in signal transduction. The chemosensory pathway of Rhodobacter sphaeroides comprises multiple homologues of chemotaxis proteins characterized in organisms such as Escherichia coli. Three CheA homologues are essential for chemotaxis in R. sphaeroides under laboratory conditions. These CheAs are differentially localized to two chemosensory clusters, one at the cell pole and one in the cytoplasm. The polar CheA, CheA(2), has the same domain structure as E. coli CheA and can phosphorylate all R. sphaeroides chemotaxis response regulators. CheA(3) and CheA(4) independently localize to the cytoplasmic cluster; each protein has a subset of the CheA domains, with CheA(3) phosphorylating CheA(4) together making a functional CheA protein. Interestingly, CheA(3)-P can only phosphorylate two response regulators, CheY(6) and CheB(2). R. sphaeroides CheAs exhibit two interesting differences in specificity: (i) the response regulators that they phosphorylate and (ii) the chemosensory cluster to which they localize. Using a domain-swapping approach we investigated the role of the P1 and P5 CheA domains in determining these specificities. We show that the P1 domain is sufficient to determine which response regulators will be phosphorylated in vitro while the P5 domain is sufficient to localize the CheAs to a specific chemosensory cluster.