Guy's and St Thomas' NHS Foundation Trust

About: Guy's and St Thomas' NHS Foundation Trust is a healthcare organization based out in London, United Kingdom. It is known for research contribution in the topics: Population & Randomized controlled trial. The organization has 7686 authors who have published 9631 publications receiving 399353 citations. The organization is also known as: Guy's and St Thomas' National Health Service Foundation Trust & Guy's and St Thomas' National Health Service Trust.

Schwannomatosis: a genetic and epidemiological study

Abstract: Objectives Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2. Methods Schwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2 , LZTR1 and SMARCB1 on blood and tumour DNA samples when available. Results Regional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1 -associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%–2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004). Conclusions Within the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.

Mutations in the gamma-secretase genes NCSTN, PSENEN and PSEN1 underlie rare forms of hidradenitis suppurativa (acne inversa)

Abstract: TO THE EDITOR Hidradenitis suppurativa (HS; OMIM1 42690) is a chronic inflammatory skin disease that presents with nodules, cysts, and abscesses in apocrine gland–bearing sites. It affects 1% of Europeans and is primarily thought to be a disease of follicular occlusion (Alikhan et al., 2009). Associated factors include smoking (B90%), obesity (475%), and infection (Alikhan et al., 2009). HS may segregate as an autosomal dominant trait, and heterozygous mutations in the g-secretase genes NCSTN, PSENEN, and PSEN1 have recently been reported in a small number of kindreds (Wang et al., 2010; Li et al., 2011; Liu et al., 2011; Pink et al., 2011). We previously identified mutations in NCSTN and PSENEN in two of seven multiplex HS pedigrees. In contrast to previous studies, which have predominantly focussed on the identification of mutations in multiplex kindreds, the aim of this study was to determine the prevalence of mutations in each of these genes among a large cohort of subjects sequentially recruited from a tertiary referral HS clinic. We performed mutational analysis of NCSTN, PSENEN, and PSEN1 by direct sequencing of all coding regions and assessment of large-scale deletions and duplications by multiplex ligation phosphorylation assay (MLPA). In all, 48 individuals with HS (diagnostic criteria from Von der Werth et al., 2000) were sequentially consented and recruited from our tertiary referral clinic. The study was conducted in accordance with the Declaration of Helsinki Principles and approved by the East London REC2 (09/H0704/50). Population data are shown in Supplementary Table S1 online. The cohort was of mixed ethnicity, the average body mass index (BMI) was 31.1 (clinically obese), 69% reported a smoking history, and the average Sartorius score (Sartorius et al., 2003) was 49.9. A total of 20 (42%) patients reported a family history of HS, 19 consistent with autosomal dominant inheritance. The DNA was extracted from venous blood or saliva. All coding regions and associated splice sites of NCSTN, PSEN1, and PSENEN were amplified by PCR, using exon flanking intronic primers and Sanger sequenced in all 48 patients. In three subjects we identified heterozygous DNA changes in NCSTN (Supplementary Table S2 online), a missense substitution (NCSTN c.553G4A, p.Asp185Asn), and two single-base substitutions located within 10 bp of donor splice junctions (NCSTN c.996þ 7G4A and NCSTN c.1101þ 10A4G). To our knowledge these variants have not previously been reported and none were observed in dbSNP, 1,000 genomes, or in 400 European controls. All 48 patients were assessed for whole gene/exon deletions and duplications in NCSTN, PSENEN, and PSEN1 using MLPA (Supplementary Methods online; Hills et al., 2010). No genomic deletions or duplications were detected. The heterozygous missense variant in exon 5 of NCSTN (c.553G4A, p.Asp185Asn) was identified in a 45-yearold female (patient HS-01; Supplementary Table S2 online, Figure 1). The missense variant is predicted to lead to the substitution of an evolutionary conserved aspartic acid residue with an asparagine residue. A heterozygous substitution of the conserved seventh base of intron 8 of NCSTN (c.996þ 7G4A) was identified in a 38-year-old female (patient HS-02 Supplementary Table S2 online, Figure 1). Computational splice site analysis (https://splice. uwo.ca) predicts this substitution to have a detrimental effect on splicing. NCSTN mRNA expression levels were significantly lower than wild-type controls, suggesting that the mutant transcript is subject to nonsense-mediated decay (Supplementary Methods and Supplementary Figure S1 online). A third heterozygous variant was detected in the donor splice site of NCSTN exon 9 (c.1101þ 10A4G) in a 24-year-old male (patient HS-03; Supplementary Table S2 online, Figure 1). Computational splice site analysis suggests that this mutation is unlikely to have a significant effect on splicing. Indeed, no aberrant transcripts were detected (via reverse transcriptase–PCR and sequencing of the full-length NCSTN transcript, Supplementary Figures S2 and S3 online) and NCSTN mRNA expression level was within the range of wild-type controls (data not shown). The potential pathogenicity of this variant is therefore unclear and it may represent a rare variant unlinked to HS in this individual. The two individuals with likely pathogenic variants in NCSTN had chronic, severe disease (Sartorius scores of 56 and 160, respectively) comprising painful nodules, cysts, abscesses, sinus tracts, and scarring, involving at least the axillae, groin, and buttocks (see Supplementary Table S2 online). Their

Lower limb muscle volumes in bilateral spastic cerebral palsy

Abstract: Aim: Muscle weakness is a feature of individuals with spastic cerebral palsy (SCP) but there are few reports in the literature of muscle volume in this group. This study compares muscle volumes in adolescents and young adults with SCP with those of their typically developing (TD) peers. Design: Measurements of the volumes of nine major lower limb muscles in 19 independently ambulant subjects with SCP (mean age 14.2 years (sd 2.7), 11 male, GMFCS I ( n = 5); GMFCS II ( n = 14)), 19 TD subjects (mean age 16.5 years (sd 3.0), 11 male) were made using magnetic resonance imaging. Results: Lower limb muscles were smaller in the SCP group ( p ⩽ 0.023 in all muscles) than the TD group with the exception of the vastii (lateralis + intermedius; p = 0.868) and gluteus maximus ( p = 0.056). Average muscle volume deficit was 27.9%. Muscle volume deficits were significantly greater for distal muscles than proximal muscles ( p Conclusions: Reduced muscle size in adolescence and the natural history of sarcopenia in adulthood may contribute to the early loss of mobility of adults with SCP.

EuroGuiDerm Guideline on the systemic treatment of Psoriasis vulgaris - Part 1: treatment and monitoring recommendations.

Abstract: This evidence- and consensus-based guideline on the treatment of psoriasis vulgaris was developed following the EuroGuiDerm Guideline and Consensus Statement Development Manual. The first part of the guideline includes general information on the scope and purpose, health questions covered, target users and strength/limitations of the guideline. Suggestions for disease severity grading and treatment goals are provided. It presents the general treatment recommendations as well as detailed management and monitoring recommendations for the individual drugs. The treatment options discussed in this guideline are as follows: acitretin, ciclosporin, fumarates, methotrexate, adalimumab, apremilast, brodalumab, certolizumab pegol, etanercept, guselkumab, infliximab, ixekizumab, risankizumab, secukinumab, tildrakizumab and ustekinumab.

Bench-to-bedside review: Immunoglobulin therapy for sepsis - biological plausibility from a critical care perspective

Abstract: Sepsis represents a dysregulated host response to infection, the extent of which determines the severity of organ dysfunction and subsequent outcome. All trialled immunomodulatory strategies to date have resulted in either outright failure or inconsistent degrees of success. Intravenous immunoglobulin (IVIg) therapy falls into the latter category with opinion still divided as to its utility. This article provides a narrative review of the biological rationale for using IVIg in sepsis. A literature search was conducted using the PubMed database (1966 to February 2011). The strategy included the following text terms and combinations of these: IVIg, intravenous immune globulin, intravenous immunoglobulin, immunoglobulin, immunoglobulin therapy, pentaglobin, sepsis, inflammation, immune modulation, apoptosis. Preclinical and extrapolated clinical data of IVIg therapy in sepsis suggests improved bacterial clearance, inhibitory effects upon upstream mediators of the host response (for example, the nuclear factor kappa B (NF-κB) transcription factor), scavenging of downstream inflammatory mediators (for example, cytokines), direct anti-inflammatory effects mediated via Fcγ receptors, and a potential ability to attenuate lymphocyte apoptosis and thus sepsis-related immunosuppression. Characterizing the trajectory of change in immunoglobulin levels during sepsis, understanding mechanisms contributing to these changes, and undertaking IVIg dose-finding studies should be performed prior to further large-scale interventional trials to enhance the likelihood of a successful outcome.