Recent years have seen an increase in primary care workload, especially following the introduction of a new General Medical Services contract in 2004. Telephone triage and telephone consultation with patients seeking health care represent initiatives aimed at improving access to care. Some evidence suggests that such approaches may be feasible but conclusions regarding GP workload, cost, and patients’ experience of care, safety, and health status are equivocal. The ESTEEM trial aims to assess the clinical- and cost-effectiveness of nurse-led computer-supported telephone triage and GP-led telephone triage, compared to usual care, for patients requesting same-day consultations in general practice.
ESTEEM is a pragmatic, multi-centre cluster randomised clinical trial with patients randomised at practice level to usual care, computer decision-supported nurse triage, or GP-led triage. Following triage of 350–550 patients per practice we anticipate estimating and comparing total primary care workload (volume and time), the economic cost to the NHS, and patient experience of care, safety, and health status in the 4-week period following the index same-day consultation request across the three trial conditions.
We will recruit all patients seeking a non-emergency same-day appointment in primary care. Patients aged 12.0–15.9 years and temporary residents will be excluded from the study.
The primary outcome is the number of healthcare contacts taking place in the 4-week period following (and including) the index same-day consultation request. A range of secondary outcomes will be examined including patient flow, primary care NHS resource use, patients’ experience of care, safety, and health status.
The estimated sample size required is 3,751 patients (11,253 total) in each of the three trial conditions, to detect a mean difference of 0.36 consultations per patient in the four week follow-up period between either intervention group and usual care 90% power, 5% alpha, and an estimated intracluster correlation coefficient ICC of 0.05. The primary analysis will be based on the intention-to-treat principle and take the form of a random effects regression analysis taking account of the hierarchical nature of the study design. Statistical models will allow for adjustment for practice level minimisation variables and patient-level baseline covariates shown to differ at baseline.
Current Controlled Trials ISCRTN20687662
Primary care; Telephone triage; Decision support; General practitioner; Nurse; Workload; Satisfaction; Cost-effectiveness; Cluster randomised controlled trial
This dose-effect study extends previous observations showing that psilocybin can occasion mystical-type experiences having persisting positive effects on attitudes, mood, and behavior.
This double-blind study evaluated psilocybin (0, 5, 10, 20, 30 mg/70 kg, p.o.) administered under supportive conditions.
Participants were 18 adults (17 hallucinogen-naïve). Five 8-hour sessions were conducted individually for each participant at 1-month intervals. Participants were randomized to receive the four active doses in either ascending or descending order (9 participants each). Placebo was scheduled quasi-randomly. During sessions volunteers used eyeshades and were instructed to direct their attention inward. Volunteers completed questionnaires assessing effects immediately after and 1 month after each session, and at 14 months follow-up.
Psilocybin produced acute perceptual and subjective effects including, at 20 and/or 30 mg/70 kg, extreme anxiety/fear (39% of volunteers) and/or mystical-type experience (72% of volunteers). One month after sessions at the two highest doses, volunteers rated the psilocybin experience as having substantial personal and spiritual significance, and attributed to the experience sustained positive changes in attitudes, mood, and behavior, with the ascending dose sequence showing greater positive effects. At 14 months, ratings were undiminished and were consistent with changes rated by community observers. Both the acute and persisting effects of psilocybin were generally a monotonically increasing function of dose, with the lowest dose showing significant effects.
Under supportive conditions, 20 and 30 mg/70 kg psilocybin occasioned mystical-type experiences having persisting positive effects on attitudes, mood and behavior. Implications for therapeutic trials are discussed.
psilocybin; dose-effects; hallucinogen; entheogen; psychedelic; mystical experience; fear; spiritual; religion; positive psychology; humans
Elimination of onchocerciasis (river blindness) through mass administration of ivermectin in the six countries in Latin America where it is endemic is considered feasible due to the relatively small size and geographic isolation of endemic foci. We evaluated whether transmission of onchocerciasis has been interrupted in the endemic focus of Escuintla-Guatemala in Guatemala, based on World Health Organization criteria for the certification of elimination of onchocerciasis.
We conducted evaluations of ocular morbidity and past exposure to Onchocerca volvulus in the human population, while potential vectors (Simulium ochraceum) were captured and tested for O. volvulus DNA; all of the evaluations were carried out in potentially endemic communities (PEC; those with a history of actual or suspected transmission or those currently under semiannual mass treatment with ivermectin) within the focus. The prevalence of microfilariae in the anterior segment of the eye in 329 individuals (≥7 years old, resident in the PEC for at least 5 years) was 0% (one-sided 95% confidence interval [CI] 0–0.9%). The prevalence of antibodies to a recombinant O. volvulus antigen (Ov-16) in 6,432 school children (aged 6 to 12 years old) was 0% (one-sided 95% IC 0–0.05%). Out of a total of 14,099 S. ochraceum tested for O. volvulus DNA, none was positive (95% CI 0–0.01%). The seasonal transmission potential was, therefore, 0 infective stage larvae per person per season.
Based on these evaluations, transmission of onchocerciasis in the Escuintla-Guatemala focus has been successfully interrupted. Although this is the second onchocerciasis focus in Latin America to have demonstrated interruption of transmission, it is the first focus with a well-documented history of intense transmission to have eliminated O. volvulus.
Brought to the Americas from Africa by the slave trade, onchocerciasis is present in six countries in Latin America. The disease is caused by a round worm and is transmitted to humans by the bite of an infected black fly. Once in a human, the adult worms produce larvae that circulate through the body, causing itching or even blindness. Ivermectin, a drug that kills the larvae, is delivered by public health authorities in countries where the disease is present. If the larvae are killed, then the disease cannot be transmitted to more people. People living in the Escuintla-Guatemala focus, a region in Guatemala where the disease was common, have been taking ivermectin for many years. The Ministry of Health of Guatemala believes that onchocerciasis is no longer being transmitted in the area. To prove that there is no more transmission of the disease, the authors examined the eyes of residents of the area to see if they could find any evidence of the worms. They also conducted analyses of blood in school children to see if they had ever been exposed to the worm, and they caught thousands of black flies and tested them to see if they were infected. These evaluations found no evidence of transmission of the disease in the Escuintla-Guatemala focus. As a result, local public health authorities can stop giving ivermectin and invest their human resources in other important diseases.
BACKGROUND: Common mental health problems account for up to 40% of all general practitioner (GP) consultations. Patients have limited access to evidence-based psychological therapies. Cognitive behavioural therapy self-help strategies offer one potential solution. AIM: To determine differences in clinical outcome, patient satisfaction and costs, between a cognitive behavioural-based self-help package facilitated by practice nurses compared to ordinary care by GPs for mild to moderate anxiety and depression. DESIGN OF STUDY: Randomised controlled trial. SETTING: Seventeen primary healthcare teams. METHOD: Patients presenting to their GP with mild to moderate anxiety and/or depression were recruited to the study and randomised to receive either a self-help intervention facilitated by practice nurses or ordinary care. The self-help intervention consisted of up to three appointments: two 1 week apart and a third 3 months later. There were no restrictions on ordinary care. RESULTS: Intention-to-treat analysis showed that patients treated with practice nurse-supported cognitive behavioural therapy self-help attained similar clinical outcomes for similar costs and were more satisfied than patients treated by GPs with ordinary care. On-treatment analysis showed patients receiving the facilitated cognitive behavioural therapy self-help were more likely to be below clinical threshold at 1 month compared to the ordinary care group (odds ratio [OR] = 3.65, 95% confidence interval [CI] = 1.87 to 4.37). This difference was less well marked at 3 months (OR = 1.36, 95% CI = 0.52 to 3.56). CONCLUSION: Facilitated cognitive behavioural self-help may provide a short-term cost-effective clinical benefit for patients with mild to moderate anxiety and depression. This has the potential to help primary care provide a choice of effective psychological as well as pharmacological treatments for mental health problems.
AIMS: To study the expression of cell adhesion molecules in the renal biopsy specimens of patients with systemic vasculitis and Henoch-Schönlein purpura (HSP); to correlate this with the severity of glomerular inflammation. METHODS: Renal biopsy specimens obtained from eight patients with untreated systemic vasculitis (four with Wegener's granulomatosis and four with microscopic polyarteritis), eight with HSP and nine controls (four with normal histopathology and five with thin glomerular basement membrane disease) were stained using the alkaline phosphatase anti-alkaline phosphatase method with monoclonal antibodies directed against intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. RESULTS: Biopsy specimens of normal kidneys expressed ICAM-1 in glomerular endocapillary cells, Bowman's capsule epithelium, interstitial cells and interstitial vascular endothelium, and VCAM-1 in Bowman's capsule epithelium, proximal tubular epithelium and interstitial vascular endothelium. No staining with antibody directed against E-selectin was seen in any of the biopsy specimens. Biopsy specimens of patients with a vasculitic glomerulonephritis (segmental necrotising glomerulonephritis) expressed VCAM-1 in glomerular endocapillary cells (four of eight patients with systemic vasculitis; two of eight patients with HSP). In patients with a systemic vasculitis glomerular VCAM-1 expression was associated with a more severe renal lesoin (44, 50, 60, and 65% of glomeruli involved) than in those not showing glomerular VCAM-1 expression (3, 3, 11, and 39% of glomeruli involved). CONCLUSION: Expression of VCAM-1 by glomerular endocapillary cells in renal biopsy specimens raises the possibility that recruitment of VLA-4 bearing leucocytes may contribute to glomerular injury in Wegener's granulomatosis and microscopic polyarteritis.
OBJECTIVE--To examine the possible effects of discrimination by sex and race on the career patterns of doctors up to six years after qualifying. DESIGN--Postal questionnaire follow up survey. PARTICIPANTS--1572 Doctors who graduated from five British medical schools in 1981, 1983, and 1985, including 587 women and 131 doctors from ethnic minorities. MAIN OUTCOME MEASURES--Reported success rates of applications for training posts. RESULTS--Comparison of the career patterns of women and men yielded no evidence of discrimination against women in competition for posts. In contrast, there were striking differences in career patterns between graduates of native European origin and those of ethnic minority origin. Graduates from ethnic minorities reported lower success rates and more difficulty in obtaining house officer posts, registrar posts, and places in vocational training schemes in general practice. Most of this discrimination seemed to occur at the stage of shortlisting for interview. Graduates from ethnic minorities were more likely than graduates of native European origin to have experienced spells of unemployment while seeking work. They were also more likely to have changed their original choice of career because of difficulty in obtaining suitable training posts or unfavourable career prospects. CONCLUSIONS--Discrimination against ethnic minorities occurs in the competition for training posts among graduates from British medical schools. There was no evidence of discrimination against women graduates. Shortlisting procedures based on objective scoring systems may help to ensure equality of opportunity in future.
Idiopathic clubfoot is a common orthopedic birth defect that affects approximately 135,000 newborns worldwide. It is characterized by equinus, varus and adductus deformities of the ankle and foot. While numerous studies suggest a multifactorial etiology, the specific genetic and environmental components have yet to be delineated. Maternal smoking during pregnancy is the only common environmental factor consistently shown to increase the risk for clubfoot. Moreover, a positive family history of clubfoot, in conjunction with maternal smoking, increases the risk twenty-fold. These findings suggest that genetic variation in smoking metabolism (xenobiotic) genes may increase susceptibility to clubfoot. Based on this reasoning, we interrogated eight candidate genes (CYP1A1, CYP1A2, CYP1B1, CYP2A6, EPHX1, NAT2, GSTM1 and GSTT1), chosen based on their involvement in xenobiotic metabolism. Twenty-two SNPs and two null alleles in these genes were genotyped in a dataset composed of nonHispanic white and Hispanic multiplex and simplex families. Only rs1048943/CYP1A1 had significantly altered transmission in the aggregate and multiplex NHW datasets (p=0.003 and p=0.009, respectively). Perturbation of CYP1A1 can cause an increase in harmful, adduct forming metabolic intermediates. A significant interaction between EPHX1 and NAT2 was also found (p=0.007). Importantly, for CYP1A2, significant maternal (p=0.03; RR=1.24; 95% CI: 1.04–1.44) and fetal (p=0.01; RR=1.33; 95% CI: 1.13–1.54) genotypic effects were identified, suggesting that both maternal and fetal genotypes can negatively impact limb development. No association was found between maternal smoking status and variation in xenobiotic metabolism genes. Together, these results suggest that xenobiotic metabolism genes are unlikely to play a major role in clubfoot, however, perturbation of this pathway may still play a contributory role.
clubfoot; smoking; tobacco; genetics; xenobiotic genes; CYP
Abnormalities in structural and functional connectivity have been reported in autism spectrum disorders (ASD) across a wide age range. However, developmental changes in white matter microstructure are poorly understood. We used a cross-sectional design to determine whether white matter abnormalities measured using diffusion tensor imaging (DTI) were present in adolescents and adults with ASD and whether age-related changes in white matter microstructure differed between ASD and typically developing (TD) individuals. Participants included 28 individuals with ASD and 33 TD controls matched on age and IQ and assessed at one time point. Widespread decreased fractional anisotropy (FA), and increased radial diffusivity (RaD) and mean diffusivity (MD) were observed in the ASD group compared to the TD group. In addition, significant group-by-age interactions were also observed in FA, RaD, and MD in all major tracts except the brain stem, indicating that age-related changes in white matter microstructure differed between the groups. We propose that white matter microstructural changes in ASD may reflect myelination and/or other structural differences including differences in axonal density/arborization. In addition, we suggest that white matter microstuctural impairments may be normalizing during young adulthood in ASD. Future longitudinal studies that include a wider range of ages and more extensive clinical characterization will be critical for further uncovering the neurodevelopmental processes unfolding during this dynamic time in development.
autism; white matter; DTI; age; interaction
Cancer survival in England is lower than the European average, which has been at least partly attributed to later stage at diagnosis in English patients. There are substantial regional and demographic variations in cancer survival across England. The majority of patients are diagnosed following symptomatic or incidental presentation. This study defines a methodology by which the route the patient follows to the point of diagnosis can be categorised to examine demographic, organisational, service and personal reasons for delayed diagnosis.
Administrative Hospital Episode Statistics data are linked with Cancer Waiting Times data, data from the cancer screening programmes and cancer registration data. Using these data sets, every case of cancer registered in England, which was diagnosed in 2006–2008, is categorised into one of eight ‘Routes to Diagnosis'.
Different cancer types show substantial differences between the proportion of cases that present by each route, in reasonable agreement with previous clinical studies. Patients presenting via Emergency routes have substantially lower 1-year relative survival.
Linked cancer registration and administrative data can be used to robustly categorise the route to a cancer diagnosis for all patients. These categories can be used to enhance understanding of and explore possible reasons for delayed diagnosis.
diagnosis; pathways; referral; survival; emergency; route
Light onset can be both a sensory reinforcer (SR) with intrinsic reinforcing properties, and a conditioned reinforcer (CR) which predicts a biologically important reinforcer. Stimulant drugs, such as methamphetamine (METH), may increase the reinforcing effectiveness of CRs by enhancing the predictive properties of the CR. In contrast, METH-induced increases in the reinforcing effectiveness of SRs, are mediated by the immediate sensory consequences of the light.
The effects of novelty (on SRs) and METH (on both CRs and SRs) were tested. Experiment 1: Rats were pre-exposed to 5 s light and water pairings presented according to a variable-time (VT) 2 min schedule or unpaired water and light presented according to independent, concurrent VT 2 min schedules. Experiment 2: Rats were pre-exposed to 5 s light presented according to a VT 2 min schedule, or no stimuli. In both experiments, the pre-exposure phase was followed by a test phase in which 5 s light onset was made response-contingent on a variable-interval (VI) 2 min schedule and the effects of METH (0.5 mg/kg) were determined.
Novel light onset was a more effective reinforcer than familiar light onset. METH increased the absolute rate of responding without increasing the relative frequency of responding for both CRs and SRs.
Novelty plays a role in determining the reinforcing effectiveness of SRs. The results are consistent with the interpretation that METH-induced increases in reinforcer effectiveness of CRs and SRs may be mediated by immediate sensory consequences, rather than prediction.
Rats; Drug Abuse; Psychomotor Stimulant; Operant Conditioning; Pavlovian Conditioning; Dopamine
The efficacy of ablative surgery for head and neck squamous cell carcinoma (HNSCC) depends critically on obtaining negative margins. While intraoperative "frozen section" analysis of margins is a valuable adjunct, it is expensive, time-consuming, and highly dependent on pathologist expertise. Optical imaging has potential to improve the accuracy of margins by identifying cancerous tissue in real time. Our aim was to determine the accuracy and inter-rater reliability of head and neck cancer specialists using high-resolution microendoscopic (HRME) images to discriminate between cancerous and benign mucosa.
Thirty-eight patients diagnosed with HNSCC were enrolled in this single-center study. HRME was used to image each specimen after application of proflavine, with concurrent standard histopathologic analysis. Images were evaluated for quality control, and a training set containing representative images of benign and neoplastic tissue was assembled. After viewing training images, seven head and neck cancer specialists with no prior HRME experience reviewed 37 test images and were asked to classify each.
The mean accuracy of all reviewers in correctly diagnosing neoplastic mucosa was 97 percent (95% Cl = 94–99%). The mean sensitivity and specificity were 98 percent (97–100%) and 92 percent (87–98%), respectively. The Fleiss kappa statistic for inter-rater reliability was 0.84 (0.77–0.91).
Medical professionals can be quickly trained to use HRME to discriminate between benign and neoplastic mucosa in the head and neck. With further development, the HRME shows promise as a method of real-time margin determination at the point of care.
Blue copper proteins (BCPs) comprise classic cases of Nature's profound control over the electronic structures and chemical reactivity of transition metal ions. Early studies of BCPs focused on their inner coordination spheres, that is, residues that directly coordinate Cu. Equally important are the electronic and geometric perturbations to these ligands provided by the outer coordination sphere. In this tribute to Hans Freeman, we review investigations that have advanced the understanding of how inner-sphere and outer-sphere coordination affects biological Cu properties.
blue copper; electron transfer; reorganization energy
The term “sensory reinforcer” has been used to refer to sensory stimuli (e.g. light onset) that are primary reinforcers in order to differentiate them from other more biologically important primary reinforcers (e.g. food and water). Acquisition of snout poke responding for a visual stimulus (5 s light onset) with fixed ratio 1 (FR 1), variable-interval 1 minute (VI 1 min), or variable-interval 6 minute (VI 6 min) schedules of reinforcement was tested in three groups of rats (n = 8/group). The VI 6 min schedule of reinforcement produced a higher response rate than the FR 1 or VI 1 min schedules of visual stimulus reinforcement. One explanation for greater responding on the VI 6 min schedule relative to the FR 1 and VI 1 min schedules is that the reinforcing effectiveness of light onset habituated more rapidly in the FR 1 and VI 1 min groups as compared to the VI 6 min group. The inverse relationship between response rate and the rate of visual stimulus reinforcement is opposite to results from studies with biologically important reinforcers which indicate a positive relationship between response and reinforcement rate. Rapid habituation of reinforcing effectiveness may be a fundamental characteristic of sensory reinforcers that differentiates them from biologically important reinforcers, which are required to maintain homeostatic balance.
Learning; Novelty; Operant Conditioning; Rat; Sensory Reinforcement
Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed eQTL analysis and bioinformatics network analysis.
We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS-) and femoral neck (FN-) BMD, in 25,353 individuals from eight cohorts. In a second stage, we followed up the 12 top SNPs (P<1×10−5) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs.
We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 & p-value = 3.0×10−5; female effect = −0.007 & p-value=3.3×10−2) and eleven suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (P<5×10−8) gene-by-sex interaction in the joint analysis of discovery and replication cohorts.
Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found influencing BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP.
gene-by-sex; interaction; BMD; association; aging
To determine whether 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) affect the risk of developing open-angle glaucoma (OAG) in persons with hyperlipidemia.
Retrospective longitudinal cohort analysis.
Individuals age ≥60 with hyperlipidemia enrolled in a national United States managed care network between 2001 and 2009.
Multivariable Cox regression analyses were performed to assess the relationship between statin use and the development of OAG (from no prior OAG diagnosis), progression from a prior diagnosis of suspected glaucoma to a diagnosis of OAG, and need for medical or surgical interventions for OAG. Regression models were adjusted for sociodemographic factors, medical and ocular comorbidities.
Main Outcome Measures
Hazard ratios (HR) with 95% confidence intervals (CI).
Of the 524,109 individuals with hyperlipidemia, 316,182 (60%) had at least 1 outpatient prescription for statins. The hazard of developing OAG decreased 0.3% (adjusted HR = 0.997, CI (0.994–0.999)) for every additional month of statin consumption. Individuals with hyperlipidemia who took statins continuously for 2 years had an 8% (adjusted HR = 0.922, CI (0.870–0.976) decreased OAG risk relative to those who received no statin therapy. The hazard of progressing from a diagnosis of suspected glaucoma to OAG decreased 0.4% (adjusted HR = 0.996, CI (0.993–0.999)) for every additional month of statin exposure. Individuals who took statins continuously for 2 years had a 9% (adjusted HR = 0.907, CI (0.846–0.973) decreased risk of progressing from suspected glaucoma to OAG relative to those who received no statin therapy. The hazard of requiring medical treatment for OAG decreased 0.4% (adjusted HR = 0.996, CI (0.993–0.998)) for every additional month of statin exposure. No significant differences in need for glaucoma surgery were noted among those with OAG who were and were not taking statins (adjusted HR = 1.002, CI (0.994–1.010)).
Statin use was associated with a significant reduction in the risk of OAG in persons with hyperlipidemia. Given the mounting evidence of statin protection against OAG including both basic science and observational clinical studies, an interventional prospective study might provide additional insights into the role of statins in the prevention of early OAG.
Dengue virus (DENV) is transmitted to humans through the bite of mosquitoes. In November 2010, a dengue outbreak was reported in Monroe County in southern Florida (FL), including greater than 20 confirmed human cases. The virus collected from the human cases was verified as DENV serotype 1 (DENV-1) and one isolate was provided for sequence analysis. RNA was extracted from the DENV-1 isolate and was used in reverse transcription polymerase chain reaction (RT-PCR) to amplify PCR fragments to sequence. Nucleic acid primers were designed to generate overlapping PCR fragments that covered the entire genome. The DENV-1 isolate found in Key West (KW), FL was sequenced for whole genome characterization. Sequence assembly, Genbank searches, and recombination analyses were performed to verify the identity of the genome sequences and to determine percent similarity to known DENV-1 sequences. We show that the KW DENV-1 strain is 99% identical to Nicaraguan and Mexican DENV-1 strains. Phylogenetic and recombination analyses suggest that the DENV-1 isolated in KW originated from Nicaragua (NI) and the KW strain may circulate in KW. Also, recombination analysis results detected recombination events in the KW strain compared to DENV-1 strains from Puerto Rico. We evaluate the relative growth of KW strain of DENV-1 compared to other dengue viruses to determine whether the underlying genetics of the strain is associated with a replicative advantage, an important consideration since local transmission of DENV may result because domestic tourism can spread DENVs.
Non-Hodgkin lymphomas (NHL) are a heterogeneous group of solid tumours of lymphoid cell origin. Three important aspects of lymphocyte development include immunity and inflammation, DNA repair, and programmed cell death. We have used a previously established case-control study of NHL to ask whether genetic variation in genes involved in these three important processes influences risk of this cancer. 118 genes in these three categories were tagged with single nucleotide polymorphisms (SNPs), which were tested for association with NHL and its subtypes. The main analysis used logistic regression (additive model) to estimate odds ratios in European-ancestry cases and controls. 599 SNPs and 1116 samples (569 cases and 547 controls) passed quality control measures and were included in analyses. Following multiple-testing correction, one SNP in MSH3, a mismatch repair gene, showed an association with diffuse large B-cell lymphoma (OR: 1.91; 95% CI: 1.41–2.59; uncorrected p = 0.00003; corrected p = 0.010). This association was not replicated in an independent European-ancestry sample set of 251 diffuse large B-cell lymphoma cases and 737 controls, indicating this result was likely a false positive. It is likely that moderate sample size, inter-subtype and other genetic heterogeneity, and small true effect sizes account for the lack of replicable findings.
CK2 is a pivotal pro-survival protein kinase in multiple myeloma that may likely impinge on bortezomib-regulated cellular pathways. In the present study, we investigated CK2 expression in multiple myeloma and mantle cell lymphoma, two bortezomib-responsive B cell tumors, as well as its involvement in bortezomib-induced cytotoxicity and signaling cascades potentially mediating bortezomib resistance. In both tumors, CK2 expression correlated with that of its activated targets NF-κB and STAT3 transcription factors. Bortezomib-induced proliferation arrest and apoptosis were significantly amplified by the simultaneous inhibition of CK2 with two inhibitors (CX-4945 and K27) in multiple myeloma and mantle cell lymphoma cell lines, in a model of multiple myeloma bone marrow microenvironment and in cells isolated from patients. CK2 inhibition empowered bortezomib-triggered mitochondrial-dependent cell death. Phosphorylation of NF-κB p65 on Ser529 (a CK2 target site) and rise of the levels of the endoplasmic reticulum stress kinase/endoribonuclease Ire1α were markedly reduced upon CK2 inhibition, as were STAT3 phospho Ser727 levels. On the contrary, CK2 inhibition increased phospho Ser51 eIF2α levels and enhanced the bortezomib-dependent accumulation of poly-ubiquitylated proteins and of the proteotoxic stress-associated chaperone Hsp70. Our data suggest that CK2 over expression in multiple myeloma and mantle cell lymphoma cells might sustain survival signaling cascades and can antagonize bortezomib-induced apoptosis at different levels. CK2 inhibitors could be useful in bortezomib-based combination therapies.
To examine the association between early HIV viremia and mortality after HIV-associated lymphoma.
Multicenter observational cohort study.
Center for AIDS Research Network of Integrated Clinical Systems cohort.
HIV-infected patients with lymphoma diagnosed between 1996 and 2011, who were alive 6 months after lymphoma diagnosis and with ≥2 HIV RNA values during the 6 months after lymphoma diagnosis.
Cumulative HIV viremia during the 6 months after lymphoma diagnosis, expressed as viremia copy-6-months.
Main outcome measure
All-cause mortality between 6 months and 5 years after lymphoma diagnosis.
Of 224 included patients, 183 (82%) had non-Hodgkin lymphoma (NHL) and 41 (18%) had Hodgkin lymphoma (HL). At lymphoma diagnosis, 105 (47%) patients were on antiretroviral therapy (ART), median CD4 count was 148 cells/µlL (IQR 54– 322), and 33% had suppressed HIV RNA (<400 copies/mL). In adjusted analyses, mortality was associated with older age [adjusted hazard ratio (AHR) 1.37 per decade increase, 95% CI 1.03–1.83], lymphoma occurrence on ART (AHR 1.63, 95% CI 1.02– 2.63), lower CD4 count (AHR 0.75 per 100 cell/µL increase, 95% CI 0.64–0.89), and higher early cumulative viremia (AHR 1.35 per log10copies × 6-months/mL, 95% CI 1.11–1.65). The detrimental effect of early cumulative viremia was consistent across patient groups defined by ART status, CD4 count, and histology.
Exposure to each additional 1-unit log10 in HIV RNA throughout the 6 months after lymphoma diagnosis, was associated with a 35% increase in subsequent mortality. These results suggest that early and effective ART during chemotherapy may improve survival.
AIDS; Burkitt lymphoma; diffuse large B-cell lymphoma; HIV; Hodgkin lymphoma; lymphoma; non-Hodgkin lymphoma
An in vitro study using explanted porcine hearts was conducted to evaluate a novel annuloplasty band, reinforced with a two-phase, shape memory alloy, designed specifically for minimally invasive mitral valve repair.
In its rigid (austenitic) phase, this band provides the same mechanical properties as the commercial semi-rigid bands. In its compliant (martensitic) phase, this band is flexible enough to be introduced through an 8-mm trocar and is easily manipulated within the heart.
In its rigid phase, the prototype band displayed similar mechanical properties to commercially available semi-rigid rings. Dynamic flow testing demonstrated no statistical differences in the reduction of mitral valve regurgitation. In its flexible phase, the band was easily deployed through an 8-mm trocar, robotically manipulated and sutured into place.
Experimental results suggest that the shape memory alloy reinforced band could be a viable alternative to flexible and semi-rigid bands in minimally invasive mitral valve repair.
Patellofemoral pain (PFP) can cause significant pain leading to limitations in societal participation and physical activity. An international expert group has highlighted the need for a classification system to allow targeted intervention for patients with PFP; we have developed a work programme systematically investigating this. We have proposed six potential subgroups: hip abductor weakness, quadriceps weakness, patellar hypermobility, patellar hypomobility, pronated foot posture and lower limb biarticular muscle tightness. We could not uncover any evidence of the relative frequency with which patients with PFP fell into these subgroups or whether these subgroups were mutually exclusive. The aim of this study is to provide information on the clinical utility of our classification system.
Methods and analysis
150 participants will be recruited over 18 months in four National Health Services (NHS) physiotherapy departments in England. Inclusion criteria: adults 18–40 years with PFP for longer than 3 months, PFP in at least two predesignated functional activities and PFP elicited by clinical examination. Exclusion criteria: prior or forthcoming lower limb surgery; comorbid illness or health condition; and lower limb training or pregnancy. We will record medical history, demographic details, pain, quality of life, psychomotor movement awareness and knee temperature. We will assess hip abductor and quadriceps weakness, patellar hypermobility and hypomobility, foot posture and lower limb biarticular muscle tightness.
The primary analytic approach will be descriptive. We shall present numbers and percentages of participants who meet the criteria for membership of (1) each of the subgroups, (2) none of the subgroups and (3) multiple subgroups. Exact (binomial) 95% CIs for these percentages will also be presented.
Ethics and dissemination
This study has been approved by National Research Ethics Service (NRES) Committee North West—Greater Manchester North (11/NW/0814) and University of Central Lancashire (UCLan) Built, Sport, Health (BuSH) Ethics Committee (BuSH 025). An abstract has been accepted for the third International Patellofemoral Pain Research Retreat, Vancouver, September 2013.
The dentate gyrus is hypothesized to function as a “gate”, limiting the flow of excitation through the hippocampus. During epileptogenesis, adult-generated granule cells (DGC) form aberrant neuronal connections with neighboring DGC, disrupting the dentate gate. Hyperactivation of the mTOR signaling pathway is implicated in driving this aberrant circuit formation. While the presence of abnormal DGC in epilepsy has been known for decades, direct evidence linking abnormal DGC to seizures has been lacking. Here, we isolate the effects of abnormal DGC using a transgenic mouse model to selectively delete PTEN from postnatally-generated DGC. PTEN deletion led to hyperactivation of the mTOR pathway, producing abnormal DGC morphologically similar to those in epilepsy. Strikingly, animals in which PTEN was deleted from ≥9% of the DGC population developed spontaneous seizures in about four weeks, confirming that abnormal DGC – which are present in both animals and humans with epilepsy – are capable of causing the disease.
phosphatase and tensin homologue; PTEN; mammalian target of rapamycin; mTOR; epileptogenesis; dentate gate; hilar basal dendrite; ectopic dentate granule cell; mossy fiber sprouting; epilepsy
Renal function and blood pressure (BP) exhibit a circadian pattern of variation, but the molecular mechanism underlying this circadian regulation is not fully understood. We have previously shown that the circadian clock protein Per1 positively regulates the basal and aldosterone-mediated expression of the alpha subunit of the renal epithelial sodium channel (αENaC). The mechanism of this regulation has not been determined however. To further elucidate the mechanism of mineralocorticoid receptor (MR) and Per1 action, site-directed mutagenesis, DNA pull-down assays and chromatin immunoprecipitation (ChIP) methods were used to investigate the coordinate regulation of αENaC by Per1 and MR. Mutation of two circadian response E-boxes in the human αENaC promoter abolished both basal and aldosterone-mediated promoter activity. DNA pull down assays demonstrated the interaction of both MR and Per1 with the E-boxes from the αENaC promoter. These observations were corroborated by ChIP experiments showing increased occupancy of MR and Per1 on an E-box of the αENaC promoter in the presence of aldosterone. This is the first report of an aldosterone-mediated increase in Per1 on a target gene promoter. Taken together, these results demonstrate the novel finding that Per1 and MR mediate the aldosterone response of αENaC through DNA/protein interaction in renal collecting duct cells.
kidney; ENaC; E-box; MR; circadian clock