The lipodystrophies are a group of disorders characterized by the absence or reduction of subcutaneous adipose tissue. Partial lipodystrophy (PLD; MIM 151660) is an inherited condition in which a ...regional (trunk and limbs) loss of fat occurs during the peri-pubertal phase. Additionally, variable degrees of resistance to insulin action, together with a hyperlipidaemic state, may occur and simulate the metabolic features commonly associated with predisposition to atherosclerotic disease. The PLD locus has been mapped to chromosome 1q with no evidence of genetic heterogeneity. We, and others, have refined the location to a 5.3-cM interval between markers D1S305 and D1S1600 (refs 5, 6). Through a positional cloning approach we have identified five different missense mutations in LMNA among ten kindreds and three individuals with PLD. The protein product of LMNA is lamin A/C, which is a component of the nuclear envelope. Heterozygous mutations in LMNA have recently been identified in kindreds with the variant form of muscular dystrophy (MD) known as autosomal dominant Emery-Dreifuss MD (EDMD-AD; ref. 7) and dilated cardiomyopathy and conduction-system disease (CMD1A). As LMNA is ubiquitously expressed, the finding of site-specific amino acid substitutions in PLD, EDMD-AD and CMD1A reveals distinct functional domains of the lamin A/C protein required for the maintenance and integrity of different cell types.
Routine immunisation of infants in The Gambia with a
Haemophilus influenzae type b (Hib) polysaccharide-tetanus toxoid conjugate vaccine began in May, 1997. We investigated the effectiveness of the ...vaccine when delivered through the expanded programme on immunisation and the effect of national immunisation on incidence of Hib disease.
Surveillance for Hib disease was maintained in the western half of The Gambia using standard methods with an emphasis on meningitis. We estimated vaccine efficacy using the case control method, and vaccine coverage and population denominators for incidence rates using a cluster sample survey. Prevalence of Hib carriage in a sample of 1–2-year old children attending health centres for vaccination was ascertained with oropharyngeal swabs plated onto antiserum agar.
Between May, 1997, and April, 2002, a total of 5984 children were examined for possible Hib infections. 49 children had Hib disease, 36 of whom had meningitis. The annual incidence rates of Hib meningitis before any use of the vaccine (1990–93) dropped from over 200 per 100 000 children aged younger than 1 year to none per 100 000 in 2002, and from 60 to no cases per 100 000 in children younger than 5 years. The prevalence of Hib carriage decreased from 12% to 0·25% (p<0·0001). Two doses of vaccine were needed for direct protection from Hib disease (vaccine efficacy 94%, 95% CI 62–99). Since most children received a protective dose after the age of greatest disease risk, indirect effects were important in reducing disease incidence.
The Gambian Hib immunisation programme reduced the occurrence of Hib disease despite irregular vaccine supply. The effect of the programme in The Gambia has important implications for the introduction of the vaccine into routine immunisation programmes of other developing countries.
Therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC) can be accompanied by treatment-emergent small-cell neuroendocrine carcinoma (t-SCNC), a morphologically distinct ...subtype. We performed integrative whole-genome and -transcriptome analysis of mCRPC tumor biopsies including paired biopsies after progression, and multiple samples from the same individual. t-SCNC was significantly less likely to have amplification of
or an intergenic
enhancer locus, and demonstrated lower expression of
and its downstream transcriptional targets. Genomic and transcriptional hallmarks of t-SCNC included biallelic loss of
, elevated expression levels of
and
1, and loss of expression of the
and
-responsive genes including
and
. We identified three tumors that converted from adenocarcinoma to t-SCNC and demonstrate spatial and temporal intrapatient heterogeneity of metastatic tumors harboring adenocarcinoma, t-SCNC, or mixed expression phenotypes, with implications for treatment strategies in which dual targeting of adenocarcinoma and t-SCNC phenotypes may be necessary. IMPLICATIONS: The t-SCNC phenotype is characterized by lack of
enhancer gain and loss of
function, and demonstrates both interindividual and intraindividual heterogeneity.
http://mcr.aacrjournals.org/content/molcanres/17/6/1235/F1.large.jpg.
The growing field of regenerative rehabilitation has great potential to improve clinical outcomes for individuals with disabilities. However, the science to elucidate the specific biological ...underpinnings of regenerative rehabilitation-based approaches is still in its infancy and critical questions regarding clinical translation and implementation still exist. In a recent roundtable discussion from International Consortium for Regenerative Rehabilitation stakeholders, key challenges to progress in the field were identified. The goal of this article is to summarize those discussions and to initiate a broader discussion among clinicians and scientists across the fields of regenerative medicine and rehabilitation science to ultimately progress regenerative rehabilitation from an emerging field to an established interdisciplinary one. Strategies and case studies from consortium institutions-including interdisciplinary research centers, formalized courses, degree programs, international symposia, and collaborative grants-are presented. We propose that these strategic directions have the potential to engage and train clinical practitioners and basic scientists, transform clinical practice, and, ultimately, optimize patient outcomes.
Measurements of nitryl chloride (ClNO2) and its precursors (O3, NO2, particulate chloride) were made in 2014–2016 at three contrasting locations in the United Kingdom: Leicester, Penlee Point and ...Weybourne. ClNO2 was observed at all sites and in every season, with the highest concentrations between 00:00 and 04:00 GMT. The median nocturnal concentration of ClNO2 ranged between the detection limit (4.2 ppt) and 139 ppt. A clear seasonal cycle, with maxima in spring and winter, and significant differences between locations in the same season were observed. The main source of particulate chloride was sea salt aerosol (including at Leicester, ∼200 km from the coast). In general, ClNO2 levels were controlled by the concentrations of O3 and NO2, rather than by the uptake and reaction of N2O5 with particulate chloride. Under these conditions, the seasonality and geographical distribution of ClNO2 can be explained in terms of O3‐limited and NO2‐limited regimes affecting the formation of the N2O5 precursor. A global version of the GEOS‐Chem model at medium resolution (2° × 2.5°) was not able to fully capture the observed seasonality of ClNO2, mostly because the model overestimated the concentrations of the precursors, particularly of nocturnal O3. A higher‐resolution (0.25° × 0.3125°) version of GEOS‐Chem showed better agreement with the observations, although it still overestimated ClNO2 concentrations during summer.
Measurements of nitryl chloride (ClNO2) in the United Kingdom show a distinct seasonal cycle and wide geographical distribution. Under conditions where particulate chloride is not a limiting factor, the observed variability of ClNO2 can be explained in terms of O3‐limited and NO2‐limited chemical regimes. These conditions are typical of large areas of Northern Europe and are particularly relevant for coastal urbanized regions.
There is some evidence of differences in psychosis care provision by ethnicity. We investigated variations in the receipt of Cognitive Behavioural Therapy for psychosis (CBTp) and family intervention ...across ethnic groups in Early Intervention in Psychosis (EIP) teams throughout England, where national policy mandates offering these interventions to all. We included data on 29,610 service users from the National Clinical Audit of Psychosis (NCAP), collected between 2018 and 2021. We conducted mixed effects logistic regression analyses to examine odds ratios of receiving an intervention (CBTp, family intervention, either intervention) across 17 ethnic groups while accounting for the effect of years and variance between teams and adjusting for individual- (age, gender, occupational status) and team-level covariates (care-coordinator caseload, inequalities strategies). Compared with White British people, every minoritized ethnic group, except those of mixed Asian-White and mixed Black African-White ethnicities, had significantly lower adjusted odds of receiving CBTp. People of Black African, Black Caribbean, non-African/Caribbean Black, non-British/Irish White, and of "any other" ethnicity also experienced significantly lower adjusted odds of receiving family intervention. Pervasive inequalities in receiving CBTp for first episode psychosis exist for almost all minoritized ethnic groups, and family intervention for many groups. Investigating how these inequalities arise should be a research priority.
Determination of the full-length thyroid-stimulating hormone receptor (TSHR) structure by cryo-electron microscopy (cryo-EM) is described. The TSHR complexed with human monoclonal TSHR autoantibody ...K1-70™ (a powerful inhibitor of TSH action) was detergent solubilised, purified to homogeneity and analysed by cryo-EM. The structure (global resolution 3.3 Å) is a monomer with all three domains visible: leucine-rich domain (LRD), hinge region (HR) and transmembrane domain (TMD). The TSHR extracellular domain (ECD, composed of the LRD and HR) is positioned on top of the TMD extracellular surface. Extensive interactions between the TMD and ECD are observed in the structure, and their analysis provides an explanation of the effects of various TSHR mutations on TSHR constitutive activity and on ligand-induced activation. K1-70™ is seen to be well clear of the lipid bilayer. However, superimposition of M22™ (a human monoclonal TSHR autoantibody which is a powerful stimulator of the TSHR) on the cryo-EM structure shows that it would clash with the bilayer unless the TSHR HR rotates upwards as part of the M22™ binding process. This rotation could have an important role in TSHR stimulation by M22™ and as such provides an explanation as to why K1-70™ blocks the binding of TSH and M22™ without activating the receptor itself.
Plasma kallikrein is a serine protease and circulating component of inflammation, which exerts clinically significant effects on vasogenic edema. This study examines the role of plasma kallikrein in ...VEGF-induced retinal edema.
Intravitreal injections of VEGF and saline vehicle were performed in plasma prekallikrein-deficient (KLKB1-/-) and wild-type (WT) mice, and in both rats and mice receiving a selective plasma kallikrein inhibitor, VA999272. Retinal vascular permeability (RVP) and retinal thickness were measured by Evans blue permeation and optical coherence tomography, respectively. The retinal kallikrein kinin system was examined by Western blotting and immunohistochemistry. Retinal neovascularization was investigated in KLKB1-/- and WT mice subjected to oxygen-induced retinopathy.
Vascular endothelial growth factor-induced RVP and retinal thickening were reduced in KLKB1-/- mice by 68% and 47%, respectively, compared to VEGF responses in WT mice. Plasma kallikrein also contributes to TNFα-induced retinal thickening, which was reduced by 52% in KLKB1-/- mice. Systemic administration of VA999272 reduced VEGF-induced retinal thickening by 57% (P < 0.001) in mice and 53% (P < 0.001) in rats, compared to vehicle-treated controls. Intravitreal injection of VEGF in WT mice increased plasma prekallikrein in the retina, which was diffusely distributed throughout the inner and outer retinal layers. Avascular and neovascular areas induced by oxygen-induced retinopathy were similar in WT and KLKB1-/- mice.
Vascular endothelial growth factor increases extravasation of plasma kallikrein into the retina, and plasma kallikrein is required for the full effects of VEGF on RVP and retinal thickening in rodents. Systemic plasma kallikrein inhibition may provide a therapeutic opportunity to treat VEGF-induced retina edema.
Neurofibromatosis 2 (NF2) is an autosomal-dominant tumour predisposition syndrome characterised by bilateral vestibular schwannomas, considerable morbidity and reduced life expectancy. Although ...genotype-phenotype correlations are well established in NF2, little is known about effects of mutation type or location within the gene on mortality. Improvements in NF2 diagnosis and management have occurred, but their effect on patient survival is unknown.
We evaluated clinical and molecular predictors of mortality in 1192 patients (771 with known causal mutations) identified through the UK National NF2 Registry. Kaplan-Meier survival and Cox regression analyses were used to evaluate predictors of mortality, with jackknife adjustment of parameter SEs to account for the strong intrafamilial phenotypic correlations that occur in NF2.
The study included 241 deaths during 10 995 patient-years of follow-up since diagnosis. Early age at diagnosis and the presence of intracranial meningiomas were associated with increased mortality, and having a mosaic, rather than non-mosaic, NF2 mutation was associated with reduced mortality. Patients with splice-site or missense mutations had lower mortality than patients with truncating mutations (OR 0.459, 95% CI 0.213 to 0.990, and OR 0.196, 95% CI 0.213 to 0.990, respectively). Patients with splice-site mutations in exons 6-15 had lower mortality than patients with splice-site mutations in exons 1-5 (OR 0.333, 95% CI 0.129 to 0.858). The mortality of patients with NF2 diagnosed in more recent decades was lower than that of patients diagnosed earlier.
Continuing advances in molecular diagnosis, imaging and treatment of NF2-associated tumours offer hope for even better survival in the future.
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