Distribution of tuberculosis in migrant children and young people in Europe: a retrospective database analysis of European data.

OBJECTIVE: The burden of tuberculosis (TB) in migrant children and young people (CYP) is commonly overlooked, despite the increasing incidence of TB in migrant populations in the European region. This study aimed to examine the distribution and disease characteristics of TB among migrant and native-born CYP through analysis of data from the European Centre for Disease Prevention and Control (ECDC) surveillance system (TESSy). STUDY DESIGN: Retrospective database analysis. METHODS: A retrospective database analysis was conducted on all CYP TB cases (0-17 years) reported to TESSy (1995-2017), exploring distribution, site of TB, and presence of MDR-TB using multivariate analysis in R statistical software. RESULTS: Of the 73,176 CYP TB cases reported in the EU/EFTA (1995-2017), 24.4% (n = 17,879) occurred in migrant CYP and 75.6% (n = 55,297) occurred in native-born CYP. Migrant CYP were more likely (P < 0.001) to have pulmonary TB (OR: 1.90; 95% CI: 1.74-2.09) and unsuccessful treatment outcomes (OR: 2.05; 95% CI: 1.74-2.40) compared to native-born CYP. The proportion of extrapulmonary TB, compared to pulmonary TB across total CYP cases was higher than the existing evidence base. CONCLUSIONS: Overall, there were significant differences in the site of TB and treatment outcomes between migrant and native-born CYP. To improve outcomes, TB screening and detection practices should focus on facilitating care in migrant CYP. However, to better understand the implications of these findings on broader TB control, TB among CYP should be addressed more frequently in reports and research.

Sustainable Development Goals' health-related indicators for Brazil and Ecuador: an analysis for the period of 1990-2019.

OBJECTIVE: This article aims to analyse the evolution of 40 Sustainable Development Goals' (SDGs) health-related indicators in Brazil and Ecuador from 1990 to 2019. STUDY DESIGN: Epidemiological study of long-term trends in 40 SDGs' health-related indicators for Brazil and Ecuador from 1990 to 2019, using estimates from the Global Burden of Disease Study. METHODS: Forty SDGs' health-related indicators and an index from 1990 to 2017 for Brazil and Ecuador, and their projections up to 2030 were extracted from the Institute for Health Metrics and Evaluation's Global Burden of Disease website and analysed. The percent annual change (PC) between 1990 and 2019 was calculated for both countries. RESULTS: Both countries have made progress on child stunting (Brazil: PC = -38%; Ecuador: PC = -43%) and child wasting prevalences (Brazil: PC = -42%; Ecuador: PC = -41%), percent of vaccine coverage (Brazil: PC = +215%; Ecuador: PC = +175%), under-5 (Brazil: PC = -75%; Ecuador: PC = -60%) and neonatal mortality rates (Brazil: PC = -69%; Ecuador: PC = -51%), health worker density per 1000 population (Brazil: PC = +153%; Ecuador: PC = +175%), reduction of neglected diseases prevalences (Brazil: PC = -40%; Ecuador: PC = -58%), tuberculosis (Brazil: PC = -27%; Ecuador: PC = -55%) and malaria incidences (Brazil: PC = -97%; Ecuador: PC = -100%), water, sanitation and hygiene mortality rates (Brazil and Ecuador: PC = -89%). However, both countries did not show sufficient improvement in maternal mortality ratio to meet SDGs targets (Brazil: PC = -37%; Ecuador: PC = -40%). Worsening of indicators were found for violence, such as non-intimate partner violence for both countries (Brazil: PC = +26%; Ecuador: PC = +18%) and suicide mortality rate for Ecuador (PC = +66%), child overweight indicator for Brazil (PC = -67%), disaster mortality rates (Brazil: PC = +100%; Ecuador: PC = +325%) and alcohol consumption (Brazil: PC = +46%; Ecuador: PC = +35%). CONCLUSIONS: Significant improvements are necessary in both countries requiring the strengthening of health and other policies, particularly concerning the prevention and management of violence and alcohol consumption, and preparedness for dealing with environmental disasters.

High rate of autonomic neuropathy in Cornelia de Lange Syndrome.

BACKGROUND: Cornelia de Lange Syndrome (CdLS) is a rare congenital disorder characterized by typical facial features, growth failure, limb abnormalities, and gastroesophageal dysfunction that may be caused by mutations in several genes that disrupt gene regulation early in development. Symptoms in individuals with CdLS suggest that the peripheral nervous system (PNS) is involved, yet there is little direct evidence. METHOD: Somatic nervous system was evaluated by conventional motor and sensory nerve conduction studies and autonomic nervous system by heart rate variability, sympathetic skin response and sudomotor testing. CdLS Clinical Score and genetic studies were also obtained. RESULTS: Sympathetic skin response and sudomotor test were pathological in 35% and 34% of the individuals with CdLS, respectively. Nevertheless, normal values in large fiber nerve function studies. CONCLUSIONS: Autonomic nervous system (ANS) dysfunction is found in many individuals with Cornelia de Lange Syndrome, and could be related to premature aging.

Direct evidence of sex and a hypothesis about meiosis in Symbiodiniaceae.

Dinoflagellates in the family Symbiodiniaceae are obligate endosymbionts of diverse marine invertebrates, including corals, and impact the capacity of their hosts to respond to climate change-driven ocean warming. Understanding the conditions under which increased genetic variation in Symbiodiniaceae arises via sexual recombination can support efforts to evolve thermal tolerance in these symbionts and ultimately mitigate coral bleaching, the breakdown of the coral-Symbiodiniaceae partnership under stress. However, direct observations of meiosis in Symbiodiniaceae have not been reported, despite various lines of indirect evidence that it occurs. We present the first cytological evidence of sex in Symbiodiniaceae based on nuclear DNA content and morphology using Image Flow Cytometry, Cell Sorting and Confocal Microscopy. We show the Symbiodiniaceae species, Cladocopium latusorum, undergoes gamete conjugation, zygote formation, and meiosis within a dominant reef-building coral in situ. On average, sex was detected in 1.5% of the cells analyzed (N = 10,000-40,000 cells observed per sample in a total of 20 samples obtained from 3 Pocillopora colonies). We hypothesize that meiosis follows a two-step process described in other dinoflagellates, in which diploid zygotes form dyads during meiosis I, and triads and tetrads as final products of meiosis II. This study sets the stage for investigating environmental triggers of Symbiodiniaceae sexuality and can accelerate the assisted evolution of a key coral symbiont in order to combat reef degradation.

Adaptive genetic variation underlies biocomplexity of Atlantic Cod in the Gulf of Maine and on Georges Bank.

Atlantic cod (Gadus morhua) populations in the Gulf of Maine (GoM) are at a fraction of their historical abundance, creating economic hardships for fishermen and putting at risk the genetic diversity of the remaining populations. An understanding of the biocomplexity among GoM populations will allow for adaptive genetic diversity to be conserved to maximize the evolutionary potential and resilience of the fishery in a rapidly changing environment. We used restriction-site-associated DNA sequencing (RADseq) to characterize the population structure and adaptive genetic diversity of five spawning aggregations from the western GoM and Georges Bank. We also analyzed cod caught in the eastern GoM, an under-sampled area where spawning aggregations have been extirpated. Using 3,128 single nucleotide polymorphisms (SNPs), we confirmed the existence of three genetically separable spawning groups: (1) winter spawning cod from the western GoM, (2) spring spawning cod, also from the western GoM, and (3) Georges Bank cod. Non-spawning cod from the eastern GoM could not be decisively linked to either of the three spawning groups and may represent a unique component of the resource, a mixed sample, or cod from other unsampled source populations. The genetic differentiation among the three major spawning groups was primarily driven by loci putatively under selection, particularly loci in regions known to contain genomic inversions on linkage groups (LG) 7 and 12. These LGs have been found to be linked to thermal regime in cod across the Atlantic, and so it is possible that variation in timing of spawning in western GoM cod has resulted in temperature-driven adaptive divergence. This complex population structure and adaptive genetic differentiation could be crucial to ensuring the long-term productivity and resilience of the cod fishery, and so it should be considered in future management plans.

Efficacy of ixekizumab compared to etanercept and placebo in patients with moderate-to-severe plaque psoriasis and non-pustular palmoplantar involvement: results from three phase 3 trials (UNCOVER-1, UNCOVER-2 and UNCOVER-3).

BACKGROUND: Palmoplantar psoriasis has significant physical and emotional impact on patients and can be difficult to treat. OBJECTIVE: To evaluate the efficacy of ixekizumab in the treatment of patients with moderate-to-severe plaque psoriasis and moderate-to-severe non-pustular palmoplantar involvement. METHODS: In three phase 3, double-blind, placebo-controlled trials, patients with moderate-to-severe non-pustular plaque psoriasis [UNCOVER-1 (N = 1296), UNCOVER-2 (N = 1224), UNCOVER-3 (N = 1346)] were randomized to subcutaneous 80 mg ixekizumab every 2 or 4 weeks (Q2W, Q4W), after a 160-mg starting dose, or placebo through week 12. Additional UNCOVER-2 and UNCOVER-3 cohorts were randomized to 50 mg etanercept biweekly. Patients entering the open-label long-term extension (UNCOVER-3) received ixekizumab Q4W weeks 12-60. Moderate-to-severe palmoplantar involvement was defined as Palmoplantar Psoriasis Area and Severity Index (PPASI) ≥8. RESULTS: Twenty-eight percent of UNCOVER-1, UNCOVER-2 and UNCOVER-3 patients had baseline palmoplantar involvement (PPASI ≥0, n = 1092) and 9.1% (n = 350) had moderate-to-severe involvement, with mean baseline PPASI ~20, PASI ~24, and most (>60%) had static Physician's Global Assessment ≥4. Higher percentages of patients treated with ixekizumab vs. placebo or etanercept achieved PPASI 50 (approximately 80% vs. 32.9%, 67.8%; ixekizumab, placebo, etanercept, respectively) and PPASI 75 (approximately 70% vs. 18.8%, 44.1%; ixekizumab, placebo, etanercept, respectively) at week 12 (all P < 0.05). PPASI 100 was achieved by higher percentages of ixekizumab-treated patients vs. placebo (approximately 50% vs. 8.2%, P < 0.001) and ixekizumab Q2W-treated patients vs. etanercept (51.8% vs. 32.2%, P < 0.05). Outcomes were maintained or improved in patients continuing on ixekizumab Q4W through week 60. Differences between ixekizumab and placebo or etanercept were statistically significant as early as week 1. CONCLUSION: In a subpopulation analysis of patients from phase 3 trials with moderate-to-severe non-pustular palmoplantar involvement and moderate-to-severe plaque psoriasis, ixekizumab treatment resulted in greater and more rapid improvements than placebo and etanercept at week 12; improvements were sustained with continued treatment.

Risk factors associated with resistance to HIV testing among transwomen in Brazil.

Transwomen are a high-risk population for HIV/AIDS worldwide. However, many transwomen do not test for HIV. This study aimed to identify factors associated with resistance to HIV testing among transwomen in Fortaleza/CE. A cross-sectional study was conducted between August and December 2008 with a sample of 304 transwomen recruited through respondent-driven sampling. Data analysis utilized Respondent-Driven Sampling Analysis Tool and SPSS 11.0. Univariate, bivariate, and multivariate analyses examined risk factors associated with resistance to HIV testing. Less than 18 years of age (OR = 4.221; CI = 2.419-7.364), sexual debut before 10 years of age (OR = 6.760; CI = 2.996-15.256), using illegal drugs during sex (OR = 2.384; CI = 1.310-4.339), experience of discrimination (OR = 3.962; CI = 1.540-10.195) and a belief that the test results were not confidential (OR = 3.763; CI = 2.118-6.688) are independently associated with resistance to testing. Intersectoral and targeted strategies aimed at encouraging the adoption of safer sexual behaviors and testing for HIV among transwomen are required.

Reduction in gastric cancer surgical mortality over 10 years: An adverse events analysis.

BACKGROUND: The reduction in gastric cancer mortality is due to a reduction in incidence and of surgical mortality. This study was to examine adverse events in patients with gastric cancer dying under surgical care. METHODS: Adverse events in surgical care were prospectively audited in patients who died of gastric cancer in Scottish hospitals. A cohort retrospective study examining deaths and contributing adverse events was compared for the periods 1996-2000 and 2001-2005. RESULTS: Between 1996 and 2005, 1083 patients with gastric cancer died on surgical wards in Scottish hospitals. The annual number of deaths under surgical care fell significantly from an average of 128 deaths per annum in years 1996-2000 to 88 deaths per annum in 2001-2005 (p < 0.001). This occurred in parallel with the decline in gastric cancer incidence over the same period. There was an increase in the proportion of gastric cancer resections carried out in 7 major hospitals in Scotland in the second period of the study (p < 0.001). The mean number of deaths in the group of patients, who had gastric cancer resection and palliative surgery, were significantly lower in the second period of the study In addition, when all patients were considered as a group, the mean number of anaesthetic, critical care, medical management and technical surgery adverse events were significantly lower in the second study period. CONCLUSION: There has been a reduction in deaths and adverse events for patients with gastric cancer under surgical care and this has been associated with surgical subspecialisation in oesophago-gastric cancer surgery.

Acute kidney injury: outcomes and quality of care.

BACKGROUND: Deficiencies in management have been highlighted as contributory factors in the death of many patients with acute kidney injury (AKI). However, there is little evidence addressing the quality of care provided to patients with milder AKI. AIM: The aim of this study is to evaluate the quality of care provided to a non-select cohort of patients with AKI and evaluate discrepancies in causation, recognition and management. DESIGN: Retrospective inception cohort study. METHODS: Demographic data were collected for all 1577 patients admitted to a University Teaching Hospital during a 1-month period. Baseline, admission and peak creatinine were correlated with mortality and length of hospital admission. AKI was classified according to Kidney Disease Improving Global Outcomes criteria. A retrospective case note review of all patients with AKI was carried out to evaluate quality of documentation and clinical management of AKI. Multivariate analysis was undertaken to determine risk factors for AKI. RESULTS: Incidence of AKI on admission was 4.6%. A further 10.3% developed AKI while in hospital. All cause mortality was 4-fold higher among patients with AKI compared with those without (19 vs. 3.8%; P < 0.001). Mortality was significantly higher in those patients who developed AKI while an in-patient compared with those with AKI on admission (27.3 vs. 11.8%; P < 0.001). Diabetes, clinician perception of frailty, age and treatment with angiotensin-converting enzyme inhibitor prior to admission were found to be independent risk factors for AKI. AKI was unrecognized in 23.5% of patients, two-thirds of whom were discharged without resolution of renal function. Significant weaknesses in management were poorly kept fluid balance charts (48.2%), failure to withhold nephrotoxic drugs (38.8%) and failure to act upon abnormal biochemistry (41%) in a timely fashion. CONCLUSION: AKI is common in hospitalized patients and associated with a significant increase in hospital stay and mortality. AKI is often found in conjunction with other organ failure and in many cases is not preventable. Nevertheless clinicians need to be more vigilant of small creatinine rises to permit early intervention particularly among elderly and frail patients.

Quantificação de Mycobacterium leprae em amostras de secreção nasal de casos paucibacilares e multibacilares por PCR quantitativo

A quantificação do bacilo realizada pelo exame baciloscópico e histopatológico apresenta sensibilidade limitada. Portanto, o emprego de uso de técnicas moleculares permite o diagnóstico direto do material clínico com elevada especificidade e sensibilidade. A PCR em tempo real (qPCR) é um ensaio sensível e específico que permite a quantificação do número de bacilos a partir de diversas amostras, além de poder ser utilizada no diagnóstico diferencial de muitos patógenos. Pacientes multibacilares hansenianos liberam o bacilo Mycobacterium leprae através da secreção nasal, sendo a coleta deste realizada por procedimento não invasivo. Até o momento, nenhum estudo avaliou a sensibilidade e especificidade da qPCR para o diagnóstico da hanseníase utilizando amostras de secreção nasal.

Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT.

BACKGROUND: Mutations in KIT are more frequent in specific melanoma subtypes, and response to KIT inhibition is likely to depend on the identified mutation. METHODS: A total of 32 patients with metastatic acral or mucosal melanoma were screened for mutations in KIT exons 11, 13 and 17. RESULTS: KIT mutations were found in 38% of mucosal and in 6% of acral melanomas. Three patients were treated with imatinib and one with sorafenib. All four patients responded to treatment, but three have since progressed within the brain. CONCLUSION: The observed clinical responses support further investigation of KIT inhibitors in metastatic melanoma, selected according to KIT mutation status.

The role of spatial dynamics in the stability, resilience, and productivity of an estuarine fish population.

Understanding mechanisms that support long-term persistence of populations and sustainability of productive fisheries is a priority in fisheries management. Complex spatial structure within populations is increasingly viewed as a result of a plastic behavioral response that can have consequences for the dynamics of a population. We incorporated spatial structure and environmental forcing into a population model to examine the consequences for population stability (coefficient of variation of spawning-stock biomass), resilience (time to recover from disturbance), and productivity (spawning-stock biomass). White perch (Morone americana) served as a model species that exhibits simultaneous occurrence of migratory and resident groups within a population. We evaluated the role that contingents (behavioral groups within populations that exhibit divergent life histories) play in mitigating population responses to unfavorable environmental conditions. We used age-structured models that incorporated contingent-specific vital rates to simulate population dynamics of white perch in a sub-estuary of Chesapeake Bay, USA. The dynamics of the population were most sensitive to the proportion of individuals within each contingent and to a lesser degree to the level of correlation in recruitment between contingents in their responses to the environment. Increased representation of the dispersive contingent within populations resulted in increased productivity and resilience, but decreased stability. Empirical evidence from the Patuxent River white perch population was consistent with these findings. A high negative correlation in resident and dispersive contingent recruitment dynamics resulted in increased productivity and stability, with little effect on resilience. With high positive correlation between contingent recruitments, the model showed similar responses in population productivity and resilience, but decreased stability. Because contingent structure involves differing patterns of nursery habitat use, spatial management that conserves sets of habitats rather than the single most productive nursery habitat would be expected to contribute to long-term population stability.

Pregnancy with epilepsy: obstetric and neonatal outcome of a controlled study.

PURPOSE: To determine the influence of epilepsy and its treatment on pregnancy and its outcome. DESIGN: Controlled, observational study. SETTING: National Health Service maternity hospitals in Liverpool and Manchester regions. POPULATION: 277 women with epilepsy (WWE) and 315 control women. METHODS: WWE were recruited from antenatal clinics. Controls were matched for age and parity but not gestational age. Information was obtained by interview and from clinical records. MAIN OUTCOME MEASURES: Obstetric complications, mode of delivery, condition of newborn. RESULTS: Distribution of epilepsy syndromes was similar to previous surveys. Most WWE (67%) received monotherapy with carbamazepine, sodium valproate or lamotrigine. Half WWE had no seizures during pregnancy but 34% had tonic clonic seizures. Seizure-related injuries were infrequent. Pregnancies with obstetric complications were increased in women with treated epilepsy (WWTE 45%, controls 33%; p=0.01). Most had normal vaginal delivery (WWTE 63%, controls 61%; p=0.65). Low birth weight was not increased (WWTE 6.2%, controls 5.2%; p=0.69). There were more major congenital malformations (MCM) (WWTE 6.6%, controls 2.1%; p=0.02) and fetal/infant deaths (WWTE 2.2%, controls 0.3%; p=0.09). Amongst monotherapies MCM prevalence was highest with valproate (11.3%; p=0.005). Lamotrigine (5.4%; p=0.23) and carbamazepine (3.0%; p=0.65) were closer to controls (2.1%). There was no association between MCM and dose of folic acid pre-conception. CONCLUSION: MCM were more prevalent in the babies of WWTE particularly amongst those receiving sodium valproate.

The Scottish Audit of Surgical Mortality: a review of areas of concern related to anaesthesia over 10 years.

The Scottish Audit of Surgical Mortality is a voluntary, peer reviewed, critical event analysis of patients who die under the care of consultant surgeons in acute hospitals in Scotland. The anaesthetic contribution to surgical mortality over a 10-year period from 1996 was reviewed. The total number of deaths was 44 230 or 1.5% of all admissions. Forty thousand, eight hundred and ninety-six deaths (92%) were audited. Deaths after elective surgery declined over 10 years. Over 80% of deaths followed emergency admission. The number of deaths where an anaesthetist was present was 16 981 or 0.6% of all admissions. Anaesthetic areas of concern were identified in 8% of deaths. Of these, 43% were related to pre-operative assessment. Anaesthesia also played a part in a further 18% of deaths where decision making was shared with the surgical team. Of these, 41% were related to access to critical care. A further 24% related to communication failures, principally when the operation should not have been done or was unnecessary.

Late dislocation after total hip arthroplasty.

OBJECTIVES: Instability after total hip arthroplasty is a troublesome complication. It commonly occurs in the first 3 postoperative months, but the risk continues over time. There are numerous treatment options, but they have relatively unpredictable outcomes. Numerous factors have been associated with dislocation, but research has mainly focused on the surgical ones. Epidemiological factors remain the subject of much debate. We aimed to establish the incidence of dislocation over time. METHODS: The Scottish National arthroplasty non-voluntary registry is based on SMR01 records (Scottish Morbidity Record) data. We analyzed the Scottish National Arthroplasty Project to find patients' dislocation rates. RESULTS: There were 62,175 total hip arthroplasties performed from April 1989 to March 2004 with an annual incidence of dislocation of 0.9%. We found no increase in the rate of dislocation after 2 years. CONCLUSIONS: It appears there is no late increase in dislocation rate. LEVEL OF EVIDENCE: Prognostic study, level II-1 (prospective study).

HIV-positive women in northeast Brazil: tubal sterilization, medical recommendation and reproductive rights.

Tubal sterilization is the most common contraceptive method used by Brazilian HIV-positive women. This cross sectional study describes the main reasons why HIV-positive women decide to be sterilized and identifies factors associated with choosing sterilization in HIV-positive women in Ceará, northeast Brazil. Data from 229 non-sterilized women, 80 women sterilized before HIV diagnosis and 48 women sterilized after diagnosis were analysed. Of the women sterilized after HIV diagnosis, 96% had the procedure done in the postpartum, during a caesarean section. No desire for more children was the most common appointed reason to be sterilized (39.6%), followed by medical recommendation because of HIV (31.3%). Seventy-nine women (28.5%) had a child after HIV diagnosis. Of those, 46 (58.2%) were sterilized in the postpartum. Factors associated with sterilization for HIV-positive women were: having a child after diagnosis (AOR: 120.9; 95%CI: 27.8-525.4) and having at least three children (AOR: 2.8; 95%CI: 1.1-7.1). It is recommended that non-coercive counselling should be provided so that HIV-positive women can make informed decisions on their reproductive options.

Proteomic analysis of gliomas.

Primary malignant brain tumours (anaplastic glioma and glioblastoma) display heterogenous histopathology and diverse genetic abnormalities. These tumours remain incurable with no significant improvement in median survival times in the last 20 years, despite significant technological advances in surgery and radiotherapy, and mechanistic insights into their aetiology. Recent clinical trials suggest molecular characterization of tumours is essential in guiding both therapy and predicting prognosis. Genetic insight into tumour biology and increasingly proteomic technology has opened new avenues for novel applied clinical research. Protein expression in human malignant glioma and matched normal brain tissues can now be reliably analysed using quantitative proteomic techniques, the most accessible of which is two-dimensional gel electrophoresis (2DGE) and matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry from which differentially expressed proteins can be identified and characterized. The potential of using differential proteomic profiling in gliomas to identify prognostic markers and to gain insight into tumour biology is currently being investigated. The current status of proteomic technology, its application to gliomas and the utility of such translational studies is reviewed.

Nucleophosmin is a novel Bax chaperone that regulates apoptotic cell death.

The proapoptotic B-cell lymphoma-2 family protein Bax is a key regulatory point in the intrinsic apoptotic pathway. However, the factors controlling the process of Bax activation and translocation to mitochondria have yet to be fully identified and characterized. We performed affinity chromatography using peptides corresponding to the mitochondrial-targeting region of Bax, which is normally sequestered within the inactive structure. The molecular chaperone nucleophosmin was identified as a novel Bax-binding protein by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Reciprocal co-immunoprecipitation and proximity assays confirmed the Bax-nucleophosmin protein-protein interaction and verified that nucleophosmin only bound to activated conformationally altered Bax. Confocal microscopy in a cell-based apoptosis model, demonstrated that nucleophosmin translocation from nucleolus to cytosol preceded Bax movement. Specific knockdown of nucleophosmin expression using RNAi attenuated apoptosis as measured by mitochondrial cytochrome c release and activation of the caspase cascade. In a mouse model of ischaemic stroke, subcellular fractionation studies verified that nucleophosmin translocation occurred within 3 h, at a time before Bax translocation but after Bax conformational changes have occurred. Thus, we have elucidated a novel molecular mechanism whereby Bax becomes activated and translocates to the mitochondria to orchestrate mitochondrial dysfunction and apoptotic cell death, which opens new avenues for therapeutic intervention.

Epidemiology of dislocation after total hip arthroplasty.

Instability after total hip arthroplasty is an important complication. It usually occurs in the immediate postoperative period, but the risk also increases with time. There are numerous surgical treatment options, but they have relatively unpredictable outcomes. Numerous factors are associated with dislocation, but research has mainly focused on surgical factors. Epidemiological factors remain the subject of much debate. We aimed to establish the most significant epidemiological factors in Scotland and in particular the dislocation rate in neuromuscular conditions. The Scottish National arthroplasty nonvoluntary registry is based on SMR01 records (Scottish Morbidity Record) data. We analyzed the Scottish National Arthroplasty Project to find patients' dislocation rates up to 1 year postoperatively for surgeon volume, age, gender, previous surgery, diagnosis, and followup duration. There were 14,314 total hip arthroplasties performed from April 1996 to March 2004 with an annual incidence of dislocation of 1.9%. We found an association between rate of dislocation with age, surgical volume, and previous fracture. However, there was no increase in the rate of dislocation associated with gender or with diagnoses of stroke or Parkinson's disease. Our prognostic assessment of dislocation risk allows assessment for methods of reducing dislocation in high risk patients.

A GH receptor antisense oligonucleotide inhibits hepatic GH receptor expression, IGF-I production and body weight gain in normal mice.

Diabetic retinopathy and acromegaly are diseases associated with excess action of GH and its effector IGF-I, and there is a need for improved therapies. We have designed an optimised 2'-O-(2-methoxyethyl)-modified phosphorothioate oligodeoxynucleotide, ATL 227446, and demonstrated its ability to suppress GH receptor mRNA in vitro. Subcutaneous injections of ATL 227446 reduced GH receptor mRNA levels, GH binding activity and serum IGF-I levels in mice after seven days of dosing. The reduction in serum IGF-I could be sustained for over ten weeks of dosing at therapeutically relevant levels, during which there was also a significant decrease in body weight gain in antisense-treated mice relative to saline and mismatch control-treated mice. The findings indicate that administration of an antisense oligonucleotide to the GH receptor may be applicable to human diseases in which suppression of GH action provides therapeutic benefit.