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PURPOSE: The European Organisation for Research and Treatment of Cancer (EORTC) health-related quality of life questionnaire for anal cancer (QLQ-ANL27) supplements the EORTC cancer generic measure (QLQ-C30) to measure concerns specific to people with anal cancer treated with chemoradiotherapy. This study tested the psychometric properties and acceptability of the QLQ-ANL27.METHODS AND MATERIALS: People with anal cancer were recruited from 15 countries to complete the QLQ-C30 and QLQ-ANL27 and provide feedback on the QLQ-ANL27. Item responses, scale structure (multitrait scaling, factor analysis), reliability (internal consistency and reproducibility) and sensitivity (known group comparisons and responsiveness to change) of the QLQ-ANL27 were evaluated.RESULTS: Data from 382 people were included in the analyses. The EORTC QLQ-ANL27 was acceptable, comprehensive, and easy to complete, taking an average 8 minutes to complete. Psychometric analyses supported the EORTC QLQ-ANL27 items and reliability (Cronbach's α ranging from 0.71-0.93 and test-retest coefficients above 0.7) and validity of the scales (particularly nonstoma bowel symptoms and pain/discomfort). Most scales distinguished people according to treatment phase and performance status. Bowel (nonstoma), pain/discomfort, and vaginal symptoms were sensitive to deteriorations over time. The stoma-related scales remained untested because of low numbers of people with a stoma. Revisions to the scoring and question ordering of the sexual items were proposed.CONCLUSIONS: The QLQ-ANL27 has good psychometric properties and is available in 16 languages for people treated with chemoradiotherapy for anal cancer. It is used in clinical trials and has a potential role in clinical practice.

Purpose: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). Methods: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. Results: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to alpha helical transition. Conclusion: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.

Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. GPAA1 (glycosylphosphatidylinositol anchor attachment 1) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT, and PIGU (phosphatidylinositol-glycan biosynthesis classes K, S, T, and U, respectively). This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum. Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families. Using whole-exome sequencing, we identified two frameshift mutations (c.981_993del [p.Gln327Hisfs∗102] and c.920delG [p.Gly307Alafs∗11]), one intronic splicing mutation (c.1164+5C>T), and six missense mutations (c.152C>T [p.Ser51Leu], c.160_161delinsAA [p.Ala54Asn], c.527G>C [p.Trp176Ser], c.869T>C [p.Leu290Pro], c.872T>C [p.Leu291Pro], and c.1165G>C [p.Ala389Pro]). Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia. The splicing mutation was found to decrease GPAA1 mRNA. Moreover, flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system.

This work proposes a novel Situation-Aware FEar Learning (SAFEL) model for robots. SAFEL combines concepts of situation-aware expert systems with well-known neuroscientific findings on the brain fear-learning mechanism to allow companion robots to predict undesirable or threatening situations based on past experiences. One of the main objectives is to allow robots to learn complex temporal patterns of sensed environmental stimuli and create a representation of these patterns. This memory can be later associated with a negative or positive “emotion”, analogous to fear and confidence. Experiments with a real robot demonstrated SAFEL's success in generating contextual fear conditioning behavior with predictive capabilities based on situational information.

Resealing of tears in the sarcolemma of myofibers is a necessary step in the repair of muscle tissue. Recent work suggests a critical role for dysferlin in the membrane repair process and that mutations in dysferlin are responsible for limb girdle muscular dystrophy 2B and Miyoshi myopathy. Beyond membrane repair, dysferlin has been linked to SNARE-mediated exocytotic events including cytokine release and acid sphingomyelinase secretion. However, it is unclear whether dysferlin regulates SNARE-mediated membrane fusion. In this study we demonstrate a direct interaction between dysferlin and the SNARE proteins syntaxin 4 and SNAP-23. In addition, analysis of FRET and in vitro reconstituted lipid mixing assays indicate that dysferlin accelerates syntaxin 4/SNAP-23 heterodimer formation and SNARE-mediated lipid mixing in a calcium-sensitive manner. These results support a function for dysferlin as a calcium-sensing SNARE effector for membrane fusion events.

Mutations in pre-mRNA processing factors (PRPFs) cause 40% of autosomal dominant retinitis pigmentosa (RP), but it is unclear why mutations in ubiquitously expressed PRPFs cause retinal disease. To understand the molecular basis of this phenotype, we have generated RP type 11 (PRPF31-mutated) patient-specific retinal organoids and retinal pigment epithelium (RPE) from induced pluripotent stem cells (iPSC). Impaired alternative splicing of genes encoding pre-mRNA splicing proteins occurred in patient-specific retinal cells and Prpf31 /- mouse retinae, but not fibroblasts and iPSCs, providing mechanistic insights into retinal-specific phenotypes of PRPFs. RPE was the most affected, characterised by loss of apical-basal polarity, reduced trans-epithelial resistance, phagocytic capacity, microvilli, and cilia length and incidence. Disrupted cilia morphology was observed in patient-derived-photoreceptors that displayed progressive features associated with degeneration and cell stress. In situ gene-editing of a pathogenic mutation rescued key structural and functional phenotypes in RPE and photoreceptors, providing proof-of-concept for future therapeutic strategies.

Retinal dystrophies are an overlapping group of genetically heterogeneous conditions resulting from mutations in more than 250 genes. Here we describe five families affected by an adult-onset retinal dystrophy with early macular involvement and associated central visual loss in the third or fourth decade of life. Affected individuals were found to harbor disease-causing variants in DRAM2 (DNA-damage regulated autophagy modulator protein 2). Homozygosity mapping and exome sequencing in a large, consanguineous British family of Pakistani origin revealed a homozygous frameshift variant (c.140delG [p.Gly47Valfs∗3]) in nine affected family members. Sanger sequencing of DRAM2 in 322 unrelated probands with retinal dystrophy revealed one European subject with compound heterozygous DRAM2 changes (c.494G>A [p.Trp165∗] and c.131G>A [p.Ser44Asn]). Inspection of previously generated exome sequencing data in unsolved retinal dystrophy cases identified a homozygous variant in an individual of Indian origin (c.64_66del [p.Ala22del]). Independently, a gene-based case-control association study was conducted via an exome sequencing dataset of 18 phenotypically similar case subjects and 1,917 control subjects. Using a recessive model and a binomial test for rare, presumed biallelic, variants, we found DRAM2 to be the most statistically enriched gene; one subject was a homozygote (c.362A>T [p.His121Leu]) and another a compound heterozygote (c.79T>C [p.Tyr27His] and c.217_225del [p.Val73_Tyr75del]). DRAM2 encodes a transmembrane lysosomal protein thought to play a role in the initiation of autophagy. Immunohistochemical analysis showed DRAM2 localization to photoreceptor inner segments and to the apical surface of retinal pigment epithelial cells where it might be involved in the process of photoreceptor renewal and recycling to preserve visual function.

SummaryVertebrate hedgehog signaling is coordinated by the differential localization of the receptors patched-1 and Smoothened in the primary cilium. Cilia assembly is mediated by intraflagellar transport (IFT), and cilia defects disrupt hedgehog signaling, causing many structural birth defects. We generated Ift25 and Ift27 knockout mice and show that they have structural birth defects indicative of hedgehog signaling dysfunction. Surprisingly, ciliary assembly is not affected, but abnormal hedgehog signaling is observed in conjunction with ciliary accumulation of patched-1 and Smoothened. Similarly, Smoothened accumulates in cilia on cells mutated for BBSome components or the BBS binding protein/regulator Lztfl1. Interestingly, the BBSome and Lztfl1 accumulate to high levels in Ift27 mutant cilia. Because Lztfl1 mutant cells accumulate BBSome but not IFT27, it is likely that Lztfl1 functions downstream of IFT27 to couple the BBSome to the IFT particle for coordinated removal of patched-1 and Smoothened from cilia during hedgehog signaling.

Meckel–Gruber syndrome (MKS) is an embryonic lethal ciliopathy resulting from mutations in genes encoding proteins localising to the primary cilium. Mutations in the basal body protein MKS1 account for 7% of cases of MKS. The condition affects the development of multiple organs, including brain, kidney and skeleton. Here we present a novel Mks1tm1a(EUCOMM)Wtsi knockout mouse which accurately recapitulates the human condition, consistently developing pre-axial polydactyly, complex posterior fossa defects (including the Dandy–Walker malformation), and renal cystic dysplasia. TOPFlash Wnt reporter assays in mouse embryonic fibroblasts (MEFs) showed general de-regulated high levels of canonical Wnt/β-catenin signalling in Mks1−/− cells. In addition to these signalling defects, we also observed ectopic high proliferation in the brain and kidney of mutant animals at mid- to late-gestation. The specific role of Mks1 in regulating cell proliferation was confirmed in Mks1 siRNA knockdown experiments which showed increased levels of proliferation after knockdown, an effect not seen after knockdown of other ciliopathy genes. We suggest that this is a result of the de-regulation of multiple signalling pathways (Wnt, mTOR and Hh) in the absence of functional Mks1. This novel model system offers insights into the role of MKS1 in Wnt signalling and proliferation, and the impact of deregulation of these processes on brain and kidney development in MKS, as well as expanding our understanding of the role of Mks1 in multiple signalling pathways.

Data on enhanced recovery programmes after pancreatoduodenectomy (ERP-PD) is limited. The aim of this pilot study was to evaluate the feasibility, safety and clinical outcomes of ERP-PD when implemented at a high-volume UK university referral centre.This was an observational single-surgeon case-control study (before-and-after pathway). A total of 20 consecutive patients were prospectively enrolled for the ERP-PD and compared with 24 consecutive patients previously treated during an equal time frame.Patients in the ERP-PD group had a significant shorter time to remove naso-gastric tube (median of 5 vs. 7 days, p = 0.0001), start liquid diet (median of 2 vs. 5 days, p0.0001), start solid food (median of 4 vs. 9 days, p0.0001), pass stools (median of 6 vs. 7 days, p = 0.002), and had shorter length of stay (median of 8.5 days vs. 13 days, p = 0.015) compared to the pre-pathway group. Postoperative complications were overall less frequent but not significantly different in the ERP-PD group (p = 0.077). No difference in mortality and readmission rates was found.Our findings support the feasibility and safety of ERP-PD. Improved patients' outcomes, significant bed day savings and increase National Health Service productivity are anticipated with implementation of ERP-PD on a larger scale.

There is mounting recognition that, to aid surgical decision making, treatment efficacy needs to be measured in a variety of ways, with health-related quality of life now widely regarded as an important outcome in pulmonary surgical populations. The aim of this review is to provide a comprehensive overview of the key issues to consider if an investigator wishes to incorporate health-related quality of life assessment into trials and studies of pulmonary surgery, drawing on recent studies of lung cancer surgery as an example.

Decision trees have been widely used in data mining and machine learning as a comprehensible knowledge representation. While ant colony optimization (ACO) algorithms have been successfully applied to extract classification rules, decision tree induction with ACO algorithms remains an almost unexplored research area. In this paper we propose a novel ACO algorithm to induce decision trees, combining commonly used strategies from both traditional decision tree induction algorithms and ACO. The proposed algorithm is compared against three decision tree induction algorithms, namely C4.5, CART and cACDT, in 22 publicly available data sets. The results show that the predictive accuracy of the proposed algorithm is statistically significantly higher than the accuracy of both C4.5 and CART, which are well-known conventional algorithms for decision tree induction, and the accuracy of the ACO-based cACDT decision tree algorithm.

Autozygosity mapping and clonal sequencing of an Omani family identified mutations in the uncharacterized gene, C4orf26, as a cause of recessive hypomineralized amelogenesis imperfecta (AI), a disease in which the formation of tooth enamel fails. Screening of a panel of 57 autosomal-recessive AI-affected families identified eight further families with loss-of-function mutations in C4orf26. C4orf26 encodes a putative extracellular matrix acidic phosphoprotein expressed in the enamel organ. A mineral nucleation assay showed that the protein's phosphorylated C terminus has the capacity to promote nucleation of hydroxyapatite, suggesting a possible function in enamel mineralization during amelogenesis.

Orofaciodigital syndromes (OFDSs) consist of a group of heterogeneous disorders characterized by abnormalities in the oral cavity, face, and digits and associated phenotypic abnormalities that lead to the delineation of 13 OFDS subtypes. Here, by a combined approach of homozygozity mapping and exome ciliary sequencing, we identified truncating TCTN3 mutations as the cause of an extreme form of OFD associated with bone dysplasia, tibial defect, cystic kidneys, and brain anomalies (OFD IV, Mohr-Majewski syndrome). Analysis of 184 individuals with various ciliopathies (OFD, Meckel, Joubert, and short rib polydactyly syndromes) led us to identify four additional truncating TCTN3 mutations in unrelated fetal cases with overlapping Meckel and OFD IV syndromes and one homozygous missense mutation in a family with Joubert syndrome. By exploring roles of TCTN3 in human ciliary related functions, we found that TCTN3 is necessary for transduction of the sonic hedgehog (SHH) signaling pathway, as revealed by abnormal processing of GLI3 in patient cells. These results are consistent with the suggested role of its murine ortholog, which forms a complex at the ciliary transition zone with TCTN1 and TCTN2, both of which are also implicated in the transduction of SHH signaling. Overall, our data show the involvement of the transition zone protein TCTN3 in the regulation of the key SHH signaling pathway and that its disruption causes a severe form of ciliopathy, combining features of Meckel and OFD IV syndromes.

Nephronophthisis-related ciliopathies (NPHP-RC) are degenerative recessive diseases that affect kidney, retina and brain. Genetic defects in NPHP gene products that localize to cilia and centrosomes defined them as ‘ciliopathies’. However, disease mechanisms remain poorly understood. Here we identify by whole exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway, hitherto not implicated in ciliopathies. We demonstrate that, upon induced DNA damage, the NPHP-RC proteins ZNF423, CEP164 and NPHP10 colocalize to nuclear foci positive for TIP60, known to activate ATM at sites of DNA damage. We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents, and that cep164 knockdown in zebrafish results in dysregulated DDR and an NPHP-RC phenotype. We identify TTBK2, CCDC92, NPHP3 and DVL3 as novel CEP164 interaction partners. Our findings link degenerative diseases of kidney and retina, disorders of increasing prevalence, to mechanisms of DDR.

The impact of cancer on patients' lives can be measured using self-reported questionnaires, known as Health-Related Quality of Life (HRQOL) measures. HRQOL is defined as a multi-dimensional construct covering disease and treatment-related symptoms, physical, psychological, and social functioning.The EORTC Quality of Life Group (QLG) was created in 1984 with the mission to develop measures of HRQOL and to promote and coordinate clinical studies concerning the quality of life of cancer patients. The EORTC Quality of Life Department (QL Department) was founded in 1993 with the support of an EU grant to provide administrative, practical and scientific support to co-operative groups conducting clinical trials with HRQOL outcomes.We are proud to report significant scientific achievements that have made us international leaders in HRQOL research and have led to real changes to cancer patient treatments.We developed a modular system for HRQOL measurement consisting of the EORTC QLQ-C30, a core cancer quality of life questionnaire and supplementary questionnaire modules. The EORTC-QLQ-C30 has been one of the most widely used cancer questionnaires in randomized trials in oncology as demonstrated by systematic reviews. To date, the EORTC QLQ-C30 has been translated and linguistically validated into more than 60 languages.HRQOL outcome measures have been an integral part of EORTC clinical trials for the last 30 years. We present examples of significant, practice-changing clinical trials evaluating HRQOL in several cancer sites, such as brain tumors, breast and ovarian cancers, and malignant melanoma. In a series of systematic reviews, we examined the quality of reporting HRQOL in international cancer clinical trials, and the impact of the results on oncology practice that led to a recommendation to improve CONSORT (Consolidated Standards of Reporting Trials) with regard to reporting of HRQOL.The QLG is an international leader in methodological research in the measurement of HRQOL in oncology and pursues research in several key areas, such as cross-cultural differences between populations in HRQOL assessment, Computer-Adaptive Testing, electronic administration of EORTC QLQ-C30, and summary scores for EORTC QLQ-C30.In summary, the QLG and QL Department have been international leaders in the field. Our questionnaires have brought HRQOL assessment to the fore in many international trials that have changed oncology practice and brought the patient's perspective into cancer research.

Familial biparental hydatidiform mole (FBHM) is the only known pure maternal-effect recessive inherited disorder in humans. Affected women, although developmentally normal themselves, suffer repeated pregnancy loss because of the development of the conceptus into a complete hydatidiform mole in which extraembryonic trophoblastic tissue develops but the embryo itself suffers early demise. This developmental phenotype results from a genome-wide failure to correctly specify or maintain a maternal epigenotype at imprinted loci. Most cases of FBHM result from mutations of NLRP7, but genetic heterogeneity has been demonstrated. Here, we report biallelic mutations of C6orf221 in three families with FBHM. The previously described biological properties of their respective gene families suggest that NLRP7 and C6orf221 may interact as components of an oocyte complex that is directly or indirectly required for determination of epigenetic status on the oocyte genome.

Anterior segment dysgenesis describes a group of heterogeneous developmental disorders that affect the anterior chamber of the eye and are associated with an increased risk of glaucoma. Here, we report homozygous mutations in peroxidasin (PXDN) in two consanguineous Pakistani families with congenital cataract-microcornea with mild to moderate corneal opacity and in a consanguineous Cambodian family with developmental glaucoma and severe corneal opacification. These results highlight the diverse ocular phenotypes caused by PXDN mutations, which are likely due to differences in genetic background and environmental factors. Peroxidasin is an extracellular matrix-associated protein with peroxidase catalytic activity, and we confirmed localization of the protein to the cornea and lens epithelial layers. Our findings imply that peroxidasin is essential for normal development of the anterior chamber of the eye, where it may have a structural role in supporting cornea and lens architecture as well as an enzymatic role as an antioxidant enzyme in protecting the lens, trabecular meshwork, and cornea against oxidative damage.

Possible effects of climate change on air quality are studied for two urban sites in the UK, London and Glasgow. Hourly meteorological data were obtained from climate simulations for two periods representing the current climate and a plausible late 21st century climate. Of the meteorological quantities relevant to air quality, significant changes were found in temperature, specific humidity, wind speed, wind direction, cloud cover, solar radiation, surface sensible heat flux and precipitation. Using these data, dispersion estimates were made for a variety of single sources and some significant changes in environmental impact were found in the future climate. In addition, estimates for future background concentrations of NOx, NO2, ozone and PM10 upwind of London and Glasgow were made using the meteorological data in a statistical model. These showed falls in NOx and increases in ozone for London, while a fall in NO2 was the largest percentage change for Glasgow. Other changes were small. With these background estimates, annual-average concentrations of NOx, NO2, ozone and PM10 were estimated within the two urban areas. For London, results averaged over a number of sites showed a fall in NOx and a rise in ozone, but only small changes in NO2 and PM10. For Glasgow, the changes in all four chemical species were small. Large-scale background ozone values from a global chemical transport model are also presented. These show a decrease in background ozone due to climate change. To assess the net impact of both large scale and local processes will require models which treat all relevant scales.

In chronic pancreatitis (CP), a debilitating, progressive and incurable disease, patients' wellbeing is considerably impaired, but the different factors affecting quality of life (QoL), have not been identified yet.69 patients with CP were evaluated (M/F 55/14; mean age 46.6 +/- 10.05 years). Different degrees of pancreatic damage were defined using the Cambridge classification; pain intensity and frequency were assessed using pain index. QoL was measured using EORTC QLQ-C30 and the PAN26 questionnaire. Although developed for pancreatic cancer, the C30/PAN26 has been validated for chronic pancreatitis.Digestive symptoms, financial difficulties, fear of future health and general pain scales showed considerable effects of CP on QoL. We observed significant negative correlation between mean QoL scores and pain index in almost all domains (p0.001, p0.05). Pain intensity affects QoL scales more often than pain frequency. BMI correlated positively with QoL in global health status, altered bowel habits, body image and satisfaction with health care domains (p0.01, p0.05).Pain index, BMI, Cambridge classification and disease duration are the most important factors adversely affecting QoL in CP. Measurement of QoL is essential in the disease management and improves the knowledge of psychosocial functioning of these patients. and IAP.

The objective of this study was to examine the agreement between health care professionals' (HCPs) and patients' evaluation of health-related quality of life (HRQOL) issues for cancer patients with bone metastases. A total of 413 patients and 152 HCPs were interviewed across five centres worldwide. Mean scores were almost always higher for HCPs than for patients. Patients and HCPs agreed that four issues affect HRQOL of bone metastases patients profoundly: 'long-term (chronic) pain', 'difficulty in carrying out usual daily tasks', 'able to perform self-care' and 'able to perform role functioning'. A substantial difference was found with respect to the perceived importance of psychosocial and somatic issues. Patients emphasised psychosocial issues with a particular focus on 'worry' about loss of mobility, dependence on others and disease progression, HCPs however rated 'symptom' issues as more important, specifically those related to 'pain'. In conclusion, patients and HCPs agreed that pain and physical/role functioning are important to the HRQOL of cancer patients with bone metastases, but patients also emphasized the importance of psychosocial issues to HRQOL. This information has been an important component in the development of a health-related quality of life questionnaire for patients with bone metastases (EORTC QLQ-BM 22).

Aim The aim of this study was to develop a bone metastases module to supplement the European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) or the EORTC QLQ-C15-PAL for patients with bone metastases. Methods Phases 1–2 of module development were conducted in Canada, Australia and Germany according to EORTC QOL group guidelines. Phase 3 was conducted in nine countries in seven languages. Results Sixty-one health-related quality of life (HRQOL) issues were generated from health care professionals (n = 152) and patients (n = 413). This resulted in a 22-item provisional module. Further testing in 170 patients from nine countries resulted in the EORTC QLQ-BM22 module, containing 22 items, conceptualised into both symptom scales, with five painful sites and three pain characteristics, and also functional scales, with eight functional interference and six psychosocial aspects. Conclusion This study provides a provisional comprehensive HRQOL measurement tool for future trials, which will continue to undergo further validation.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous inherited disorder arising from dysmotility of motile cilia and sperm. This is associated with a variety of ultrastructural defects of the cilia and sperm axoneme that affect movement, leading to clinical consequences on respiratory-tract mucociliary clearance and lung function, fertility, and left-right body-axis determination. We performed whole-genome SNP-based linkage analysis in seven consanguineous families with PCD and central-microtubular-pair abnormalities. This identified two loci, in two families with intermittent absence of the central-pair structure (chromosome 6p21.1, Zmax 6.7) and in five families with complete absence of the central pair (chromosome 6q22.1, Zmax 7.0). Mutations were subsequently identified in two positional candidate genes, RSPH9 on chromosome 6p21.1 and RSPH4A on chromosome 6q22.1. Haplotype analysis identified a common ancestral founder effect RSPH4A mutation present in UK-Pakistani pedigrees. Both RSPH9 and RSPH4A encode protein components of the axonemal radial spoke head. In situ hybridization of murine Rsph9 shows gene expression restricted to regions containing motile cilia. Investigation of the effect of knockdown or mutations of RSPH9 orthologs in zebrafish and Chlamydomonas indicate that radial spoke head proteins are important in maintaining normal movement in motile, “9+2”-structure cilia and flagella. This effect is rescued by reintroduction of gene expression for restoration of a normal beat pattern in zebrafish. Disturbance in function of these genes was not associated with defects in left-right axis determination in humans or zebrafish.

Aim The aim of this paper is to systematically review the use and validation of HRQOL instruments in older cancer patients. Method A systematic review of 5 databases and 3 research registers identified studies reporting the use and validation of HRQOL instruments in cancer patients aged over 65 years from 1995 to mid 2007. Results Thirty-one studies reported the use of HRQOL measures in older people, using a range of generic and disease-specific instruments. Little work was reported in patients aged over 80 years. All studies exhibited methodological limitations. Fourteen studies were identified with variable evidence on the psychometric properties and clinical usefulness of identified instruments. Conclusion Our review identified that the development, validation and use of HRQOL instruments often ignore the specific needs of older people. This review highlights the need for a HRQOL instrument specifically designed to capture the issues and concerns most relevant to older cancer patients.

Objective To quantify the influence of soccer-specific fatigue on functional stability. Participants and design Ten male semi-professional soccer players completed a 90min treadmill protocol replicating the activity profile of match-play with a passive 15min half-time interval. Main outcome measures At 15min intervals players completed a 30s single-legged balance task on an unstable platform. Balance performance was quantified as a stability index and the mean deflection of the platform. Results There was no significant ( P >0.05) main effect for exercise duration in the stability index, suggesting that balance performance was maintained throughout the simulated match. However, the mean deflection of the platform was significantly ( P Conclusion A change in balance strategy was evident during the latter stages of match-play, which may increase injury risk. It is recommended that soccer players perform proprioception training in the rested and exercised state to further develop neuromuscular control.

Background: The European Organisation for Research and Treatment of Cancer quality of life (EORTC QL) questionnaires are used in international trials and therefore standardised translation procedures are required. This report summarises the EORTC translation procedure, recent accomplishments and challenges. Methods: Translations follow a forward-backward procedure, independently carried out by two native-speakers of the target language. Discrepancies are arbitrated by a third consultant, and solutions are reached by consensus. Translated questionnaires undergo a pilot-testing. Suggestions are incorporated into the final questionnaire. Requests for translations originate from the module developers, physicians or pharmaceutical industry, and most translations are performed by professional translators. The translation procedure is managed and supervised by a Translation Coordinator within the EORTC QL Unit in Brussels. Results: To date, the EORTC QLQ-C30 has been translated and validated into more than 60 languages, with further translations in progress. Translations include all major Western, and many African and Asian languages. The following translation problems were encountered: lack of expressions for specific symptoms in various languages, the use of old-fashioned language, recent spelling reforms in several European countries and different priorities of social issues between Western and Eastern cultures. The EORTC measurement system is now registered for use in over 9000 clinical trials worldwide. Conclusions: The EORTC provides strong infrastructure and quality control to produce robust translated questionnaires. Nevertheless, translation problems have been identified. The key to improvements may lie in the particular features and strengths of the group, consisting of researchers from 21 countries representing 25 languages and include the development of simple source versions, the use of advanced computerised tools, rigorous pilot-testing, certification procedures and insights from a unique cross-cultural database of nearly 40,000 questionnaire responses.

Meckel syndrome (MKS) is a rare autosomal recessive lethal condition characterized by central nervous system malformations, polydactyly, multicystic kidney dysplasia, and ductal changes of the liver. Three loci have been mapped (MKS1–MKS3), and two genes have been identified (MKS1/FLJ20345 and MKS3/TMEM67), whereas the gene at the MKS2 locus remains unknown. To identify new MKS loci, a genomewide linkage scan was performed using 10-cM–resolution microsatellite markers in eight families. The highest heterogeneity LOD score was obtained for chromosome 12, in an interval containing CEP290, a gene recently identified as causative of Joubert syndrome (JS) and isolated Leber congenital amaurosis. In view of our recent findings of allelism, at the MKS3 locus, between these two disorders, CEP290 was considered a candidate, and homozygous or compound heterozygous truncating mutations were identified in four families. Sequencing of additional cases identified CEP290 mutations in two fetuses with MKS and in four families presenting a cerebro-reno-digital syndrome, with a phenotype overlapping MKS and JS, further demonstrating that MKS and JS can be variable expressions of the same ciliopathy. These data identify a fourth locus for MKS (MKS4) and the CEP290 gene as responsible for MKS.

After pancreaticoduodenectomy (PD) patients may be deficient in essential micronutrients. This study was designed to determine if this is a consequence of surgery.Long-term survivors (6 months) of PD for peri-ampullary neoplasia and healthy controls (patients' spouse/partner) were enrolled in the study. Specific clinical parameters were recorded, serum micronutrient levels were measured and subjects completed 7-day food diaries.Thirty-seven patients were studied, 25 with paired controls. All were well nourished, as defined by body mass index and food diary analysis. Patients with paired controls were representative of all patients studied. Patients had raised transferrin (median 2.60 vs. 2.16 g/l, p = 0.001) and low ferritin levels (34.9 vs. 119.0 g/l, p0.001) indicating relative iron deficiency. Patients also demonstrated lower levels of the anti-oxidants selenium (0.77 vs. 0.93 micromol/l, p0.001) and vitamin E (23.2 vs. 35.7 micromol/l, p0.001) with 57% of patients having frank selenium deficiencies. Patients had lower levels of vitamin D than controls (15.7 vs. 19.6 micromol/l, p = 0.001) and 30% of patients had a raised parathyroid hormone level, suggesting compensatory mechanisms operate to maintain normocalcaemia.Long-term survivors of PD are relatively deficient in several micronutrients compared to non-operated controls taking the same diet. We recommend that micronutrient status should be regularly checked in these patients and treated where necessary.

Obesity is considered a risk factor in patients with acute pancreatitis. However, the relationship between obesity and mortality in this disease has not been confirmed definitively even in a previous meta-analysis. Since the publication of our previous meta-analysis, one study has been reported about the prognostic value of obesity in acute pancreatitis. We have performed a new meta-analysis to confirm the relationship between obesity and the outcome of acute pancreatitis.A MEDLINE search using 'pancreatitis', 'obesity' and 'body mass index' as search terms.Clinical studies which investigated the prognostic value of obesity in acute pancreatitis with the following criteria: (a) inclusion of mild and severe acute pancreatitis; (b) use of body mass index (BMI) as the measure of obesity; (c) definition of obesity as BMIor=30 kg/m(2); (d) definition of severity of acute pancreatitis according to the criteria established in the Atlanta Symposium. Five studies including patients with mild and severe acute pancreatitis and obesity measured by BMI were analyzed. The end points of the meta-analysis were the severity of acute pancreatitis, local complications, systemic complications and mortality. Pooled odds ratio (OR) and confidence intervals (CI) were calculated according to the Mantel-Haenszel method, and heterogeneity was assessed by the multiplicative inverse variance method.Seven hundred and thirty-nine patients were included. There was no heterogeneity for the variables severity, systemic complications, local complications and mortality among the included studies. Severe acute pancreatitis was significantly more frequent in obese patients (OR 2.9, 95% CI 1.8-4.6). Furthermore, those patients developed significantly more systemic (OR 2.3, 95% CI 1.4-3.8) and especially local complications (OR 3.8, 95% CI 2.4-6.6). In this new analysis, mortality was also higher in obese patients (OR 2.1, 95% CI 1.0-4.8).Obesity is not only a risk factor for the development of local and systemic complications in acute pancreatitis: it also increases the mortality of this disease.

We identified a homozygous missense mutation in the noncatalytic subunit (RAB3GAP2) of RAB3GAP that results in abnormal splicing in a family with congenital cataracts, hypogonadism, and mild mental retardation (Martsolf syndrome). Recently, mutations in the catalytic subunit of RAB3GAP (RAB3GAP1), a key regulator of calcium-mediated hormone and neurotransmitter exocytosis, were reported in Warburg micro syndrome, a severe neurodevelopmental condition with overlapping clinical features. RAB3GAP is a heterodimeric protein that consists of a catalytic subunit and a noncatalytic subunit encoded by RAB3GAP1 and RAB3GAP2, respectively. We performed messenger RNA–expression studies of RAB3GAP1 and RAB3GAP2 orthologues in Danio rerio embryos and demonstrated that, whereas developmental expression of rab3gap1 was generalized (similar to that reported elsewhere in mice), rab3gap2 expression was restricted to the central nervous system. These findings are consistent with RAB3GAP2 having a key role in neurodevelopment and may indicate that Warburg micro and Martsolf syndromes represent a spectrum of disorders. However, we did not detect RAB3GAP2 mutations in patients with Warburg micro syndrome. These findings suggest that RAB3GAP dysregulation may result in a spectrum of phenotypes that range from Warburg micro syndrome to Martsolf syndrome.

A global chemistry-transport model has been used to study the deposition of acidic nitrogen and sulphur species in the present day (1990s) and future (2090s). For the oxidised nitrogen species, climate change increases the amount of nitric acid produced and deposited to soils. However, for reduced nitrogen species, both climate change and pollutant emission increases act to convert more ammonia to ammonium sulphate which in turn may result in further acidification of soils. This change occurs via increased aqueous phase oxidation of sulphur dioxide, indicating that the sulphur and reduced nitrogen cycles are closely linked. The modelled acid deposition fluxes have been used with estimates of base cation deposition fluxes to identify areas with excess deposition above the critical loads. These data show an increasing risk of acidification in parts of the USA and South-East Asia. Certain areas, especially in Asia, remain at risk even when higher values of critical loads and base cation deposition fluxes are used.

A global 3-D chemistry-transport model STOCHEM has been employed to study trends in the mole fractions of methane, carbon monoxide and ozone in baseline air masses entering Europe from the Atlantic Ocean over the period from 1990 to 2030. With a range of emission scenarios for man-made ozone precursor emission sources available, a wide range of model trends were predicted for the period up to 2030. In the scenario based on current planned air pollution controls, IIASA CLE, methane shows a strong upward trend, ozone shows a weaker upward trend, and carbon monoxide is approximately flat in baseline air masses. In one of the more pessimistic IPCC SRES scenarios, A2, all three gases show future increases. However, in the scenario based on maximum feasible emission reductions, IIASA MFR all three trace gases decline. By 2030, projected climate change reduces the growth in CH4, but has insignificant effects on baseline CO and O3 in these simulations. Global or hemispheric ozone precursor emissions and their controls exert a potentially large external influence on Europe’s air quality. This influence is currently not taken into account in future European air quality policy formulation. r 2005 Elsevier Ltd. All rights reserved.

Hermansky-Pudlak syndrome (HPS) is genetically heterogeneous, and mutations in seven genes have been reported to cause HPS. Autozygosity mapping studies were undertaken in a large consanguineous family with HPS. Affected individuals displayed features of incomplete oculocutaneous albinism and platelet dysfunction. Skin biopsy demonstrated abnormal aggregates of melanosomes within basal epidermal keratinocytes. A homozygous germline frameshift mutation in BLOC1S3 (p.Gln150ArgfsX75) was identified in all affected individuals. BLOC1S3 mutations have not been previously described in patients with HPS, but BLOC1S3 encodes a subunit of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Mutations in other BLOC-1 subunits have been associated with an HPS phenotype in humans and/or mouse, and a nonsense mutation in the murine orthologue of BLOC1S3 causes the reduced pigmentation (rp) model of HPS. Interestingly, eye pigment formation is reported to be normal in rp, but we found visual defects (nystagmus, iris transilluminancy, foveal hypoplasia, reduced visual acuity, and evidence of optic pathway misrouting) in affected individuals. These findings define a novel form of human HPS (HPS8) and extend genotype-phenotype correlations in HPS.

Molecular force measurements quantified the impact of polysialylation on the adhesive properties both of membrane-bound neural cell adhesion molecule (NCAM) and of other proteins on the same membrane. These results show quantitatively that NCAM polysialylation increases the range and magnitude of intermembrane repulsion. The repulsion is sufficient to overwhelm both homophilic NCAM and cadherin attraction at physiological ionic strength, and it abrogates the protein-mediated intermembrane adhesion. The steric repulsion is ionic strength dependent and decreases substantially at high monovalent salt concentrations with a concomitant increase in the intermembrane attraction. The magnitude of the repulsion also depends on the amount of polysialic acid (PSA) on the membranes, and the PSA-dependent attenuation of cadherin adhesion increases with increasing PSA-NCAM:cadherin ratios. These findings agree qualitatively with independent reports based on cell adhesion studies and reveal the likely molecular mechanism by which NCAM polysialylation regulates cell adhesion and intermembrane space.

A global three-dimensional Lagrangian chemistry-transport model is used to describe the formation, transport and destruction of tropospheric ozone using 1990s global emissions and 1998 meteorological archives. Using a labelling technique, the geographical origins of the ozone formed within the troposphere have been revealed, showing whether the ozone found at the surface in Europe has had its origins above the continents of North America, Europe or Asia or elsewhere in the world. In this way, contributions to the ozone found at 21 surface monitoring sites across Europe can be attributed to production over North America and Asia, demonstrating that intercontinental ozone transport is an efficient process. Sensitivity tests to the global man-made sources of NOx and carbon monoxide indicate that global ozone precursor emission controls may contribute towards reaching regional air quality policy goals for ozone in Europe. r 2004 Elsevier Ltd. All rights reserved.

Total enteral nutrition (TEN) within 48 h of admission has recently been shown to be safe and efficacious as part of the management of severe acute pancreatitis. Our aim was to ascertain the safety of immediate TEN in these patients and the effect of TEN on systemic inflammation, psychological state, oxidative stress, plasma glutamine levels and endotoxaemia.Patients admitted with predicted severe acute pancreatitis(APACHE II score5) were randomised to total enteral (TEN; n = 8) or total parenteral nutrition (TPN; n = 9). Measurements of systemic inflammation (C-reactive protein), fatigue (visual analogue scale), oxidative stress (plasma thiobarbituric acid-reactive substances), plasma glutamine and anti-endotoxin IgG and IgM antibody concentrations were made on admission and repeated on days 3 and 7 thereafter. Clinical progress was monitored using APACHE II score. Organ failure and complications were recorded.All patients tolerated the feeding regime well with few nutrition-related complications. Fatigue improved in both groups but more rapidly in the TEN group. Oxidative stress was high on admission and rose by similar amounts in both groups. Plasma glutamine concentrations did not change significantly in either group. In the TPN group, 3 patients developed respiratory failure and 3 developed non-respiratory single organ failure. There were no such complications in the TEN group. Hospital stay was shorter in the TEN group [7(4-14) vs. 10 (7-26) days; p = 0.05] as was time to passing flatus and time to opening bowels [1 (0-2) vs. 2 (1-5)days; p = 0.01]. The cost of TEN was considerably less than of TPN.Immediate institution of nutritional support in the form of TEN is safe in predicted severe acute pancreatitis. It is as safe and as efficacious as TPN and may be beneficial in the clinical course of this disease.

Multidomain proteins reside at the heart of cellular signaling, where they can act as multivalent scaffolds for the assembly of protein complexes and as ligand-dependent effectors of signal transduction. Despite their prevalence, it is unclear how multidomain proteins simultaneously interact with multiple clients, and how each domain contributes to the overall activity of the protein. Challenges, including the large size and low solubility have largely limited studies to smaller truncated forms of these proteins. Although more tractable, the relevance of studies on truncated proteins to our understanding of the full-length protein is questionable. Otoferlin, which consists of 6 consecutive C2 domains, serves an example. Expressed almost exclusively in vertebrate sensory hair cells, otoferlin is a 240 kDa transmembrane protein hypothesized to act as the calcium sensor for neurotransmitter release at hair cell ribbon synapses during the encoding of sound. While studies have suggested that some C2 domains of otoferlin may associate with SNARE proteins and the voltage gated calcium channel CaV1.3, no study has quantitatively characterized multivalent and concomitant binding properties of multi-domain or full-length otoferlin owing to its size and solubility. Thus, it remains unclear whether otoferlin can bind these proteins simultaneously and more generally. To address this limitation, we have developed a generally applicable real-time single-molecule colocalization binding titration assay which in combination with single-molecule photobleaching can resolve the binding multivalencies, stoichiometries, and binding affinities of large full-length multidomain proteins enriched from mammalian cell culture. Using this methodology, we conclude that one otoferlin molecule may bind both up to 4 Cav1.3 and 4 SNARE proteins simultaneously, and that physiologically relevant calcium concentrations alter the stoichiometry and affinity. Our results motivate a model in which otoferlin acts as a scaffolding/priming protein that localizes SNARE proteins and the calcium channel in close proximity to synchronize calcium influx and exocytosis.

Quality of life (QL) is an important outcome in clinical trials in oncology. There is currently no valid international QL measure for gastric cancer. This paper describes the development of a QL module for gastric cancer to supplement the European Organization for Research and Treatment of Cancer (EORTC) Quality of life (QLQ-C30) questionnaire. Phases I to III of module development were conducted in the United Kingdom, France, Germany and Spain according to EORTC QL Group guidelines. Twenty relevant QL issues were generated from the literature and interviews with health professionals (n=24) and patients (n=58). This produced a 24 item provisional module. Further testing in 115 patients resulted in the QLQ-STO22, containing 22 questions, conceptualised into five scales and four single items, related to disease symptoms, treatment side-effects and emotional issues specific to gastric cancer. The use of the QLQ-C30 supplemented by the QLQ-STO22 will provide a comprehensive QL measure for international trials in gastric cancer.