Treatment of behavioral problems in intellectually disabled adult patients with epilepsy.

Behavioral disorders are common in people with epilepsy and intellectual disability. Although in some genetic disorders behavioral problems are part of the established phenotype, they may also be a manifestation of underlying physical or mental illness, or may be unrecognized seizure activity. In light of this, assessment of behavioral disorders should take into account person factors such as the physical health and mental state of the person and environmental factors such as the quality of their interactions with carers and their living conditions. Video-electroencephalography ( EEG) is recommended where possible. We review potential pharmacologic and behavioral management strategies for behavioral disorders in people with intellectual disability.

Assessment of the role of the Edinburgh dysphagia score in referral triage in a national service evaluation of the urgent suspected upper gastrointestinal cancer pathway.

BACKGROUND: The British Society of Gastroenterology has recommended the Edinburgh Dysphagia Score (EDS) to risk-stratify dysphagia referrals during the endoscopy COVID recovery phase. AIMS: External validation of the diagnostic accuracy of EDS and exploration of potential changes to improve its diagnostic performance. METHODS: A prospective multicentre study of consecutive patients referred with dysphagia on an urgent suspected upper gastrointestinal (UGI) cancer pathway between May 2020 and February 2021. The sensitivity and negative predictive value (NPV) of EDS were calculated. Variables associated with UGI cancer were identified by forward stepwise logistic regression and a modified Cancer Dysphagia Score (CDS) developed. RESULTS: 1301 patients were included from 19 endoscopy providers; 43% male; median age 62 (IQR 51-73) years. 91 (7%) UGI cancers were diagnosed, including 80 oesophageal, 10 gastric and one duodenal cancer. An EDS ≥3.5 had a sensitivity of 96.7 (95% CI 90.7-99.3)% and an NPV of 99.3 (97.8-99.8)%. Age, male sex, progressive dysphagia and unintentional weight loss >3 kg were positively associated and acid reflux and localisation to the neck were negatively associated with UGI cancer. Dysphagia duration <6 months utilised in EDS was replaced with progressive dysphagia in CDS. CDS ≥5.5 had a sensitivity of 97.8 (92.3-99.7)% and NPV of 99.5 (98.1-99.9)%. Area under receiver operating curve was 0.83 for CDS, compared to 0.81 for EDS. CONCLUSIONS: In a national cohort, the EDS has high sensitivity and NPV as a triage tool for UGI cancer. The CDS offers even higher diagnostic accuracy. The EDS or CDS should be incorporated into the urgent suspected UGI cancer pathway.

The life of Roger Williams.

In this brief obituary, we celebrate the life and achievements of Professor Roger Williams, who set up the UK's first liver transplant programme and championed excellence in hepatology for six decades.

Stably transfected common fragile site sequences exhibit instability at ectopic sites.

Common fragile sites (CFSs) are loci that are especially prone to forming gaps and breaks on metaphase chromosomes under conditions of replication stress. Although much has been learned about the cellular responses to gaps and breaks at CFSs, less is known about what makes these sites inherently unstable. CFS sequences are highly conserved in mammalian evolution and contain a number of sequence motifs that are hypothesized to contribute to their instability. To examine the role of CFS sequences in chromosome breakage, we stably transfected two BACs containing FRA3B sequences and two nonCFS control BACs containing similar sequence content into HCT116 cells and isolated cell clones with BACs integrated at ectopic sites. Integrated BACs were present at just a few to several hundred contiguous copies. Cell clones containing integrated FRA3B BACs showed a significant, three to sevenfold increase in aphidicolin-induced gaps and breaks at the integration site as compared to control BACs. Furthermore, many FRA3B integration sites displayed additional chromosome rearrangements associated with CFS instability. Clones were examined for replication timing and it was found that the integrated FRA3B sequences were not dependent on late replication for their fragility. This is the first direct evidence in human cells that introduction of CFS sequences into ectopic nonfragile loci is sufficient to recapitulate the instability found at CFSs. These data support the hypothesis that sequences at CFSs are inherently unstable, and are a major factor in the formation of replication stress induced gaps and breaks at CFSs.

Provision of out-of-hours services for acute upper gastrointestinal bleeding in England: results of the 2014-2015 BSG/NHS England national survey.

BACKGROUND: There has been a drive to raise the standard of management of acute upper gastrointestinal bleeding (AUGIB) in the UK, including three previous audits, sponsored by the British Society of Gastroenterology (BSG). OBJECTIVE: To review the results of the latest BSG/National Health Service (NHS) England national survey of endoscopy services in England between 2014 and 2015. METHOD: All NHS hospitals accepting acute admissions in England (168) were invited to respond to the survey. RESULTS: Overall, 142 hospitals (84%) returned data. 85% of hospitals used a validated risk assessment score at the time of patient's admission. While 80% of hospitals provided a 24/7 endoscopy service for unstable patients, and another 10% were in network to provide an acute service, only 60% performed an endoscopy within 24 hours for stable acute admissions or inpatients with AUGIB. 11% of hospitals operated an out-of-hours ad hoc rota. 43% felt that pressure from routine work affected their ability to offer a next-day oesophagogastroduodenoscopy service, while 20% of hospitals struggled to recruit endoscopists. 28% of units reported that the previous national audit performed in 2013 had a positive influence on service development. CONCLUSIONS: This survey has revealed significant deficiencies in provision of services for patients with AUGIB in England, without a significant increase in number of hospitals providing an emergency AUGIB service since the last national audit in 2013.

Mutation of the FOXC2 gene in familial distichiasis.

OBJECTIVE: To examine the FOXC2 gene in a family with hereditary distichiasis. BACKGROUND: Distichiasis, ie, a second row of eyelashes arising from the meibomian glands of the eyelids, can be inherited either alone (Online Mendelian Inheritance in Man [OMIM] no. 126300) or, more commonly, as part of the lymphedema-distichiasis (LD) syndrome (OMIM no. 153400). More than 45 families with mutations in the FOXC2 gene and LD have been described. Both lymphedema and distichiasis are highly penetrant. Distichiasis without lymphedema is not commonly seen. METHODS: We examined three generations of a family (N = nine members) with hereditary distichiasis but without lymphedema or other features of LD syndrome. The FOXC2 gene was polymerase chain reaction--amplified from genomic DNA from all family members and examined for mutations. RESULTS: Clinical examination showed distichiasis of all four lids in two affected family members across two generations. There were no other consistent ophthalmologic abnormalities in the family. A cytosine-to-adenine transversion was identified in DNA from affected study participants at nucleotide position 1076, which would be predicted to cause truncation of the protein at codon 359. This change was not observed in any of the nine unaffected family members participating. CONCLUSIONS: This finding suggests that hereditary distichiasis and LD may not be separate genetic disorders but different phenotypic expressions of the same underlying disorder. Ophthalmologists should be aware that LD may present as distichiasis alone and counsel and refer their patients appropriately.

Interprofessional care co-ordinators: the benefits and tensions associated with a new role in UK acute health care.

While more flexible models of service delivery are being introduced in UK health and social care, little is known about the impact of new roles, particularly support worker roles, on the work of existing practitioners. This action research study aimed to explore the impact of one such new role, that of interprofessional care co-ordinators (IPCCs). The general (internal) medical service of a UK hospital uses IPCCs to provide support to the interprofessional team and, in doing so, promote efficiency of acute bed use. Using a range of methods, mainly qualitative, this action research study sought to explore the characteristics and impact of the role on interprofessional team working. While the role's flexibility, autonomy and informality contributed to success in meeting its intended objectives, these characteristics also caused some tensions with interprofessional colleagues. These benefits and tensions mirror wider issues associated with the current modernisation agenda in UK health care.

Establishing a regional enterocutaneous fistula service: the Royal London hospital experience.

BACKGROUND: The development of enterocutaneous fistula (ECF) is one of the most challenging complications encountered in colorectal surgery. Currently, only two supra-regional centres are nationally designated in the United Kingdom to treat ECF patients. The aim of this study was to assess clinical outcome measures following the implementation of an ECF service at The Royal London Hospital. METHODS: All patients diagnosed with enterocutaneous fistula between December 2005 and November 2011 were recruited to the study. Clinical outcomes analysed included successful ECF closure, number of surgical procedures required for successful ECF closure, re-fistulation rates and morbidity/mortality data. RESULTS: 41 patients (20 M:21 F) of median age 54 years (range, 16-81) were studied. Patients had undergone a median of 4 (range, 1-18) operations prior to referral. Eleven fistulas (27%) healed spontaneously. Of the remaining 30 patients, 5 (17%) died before surgery due to uncontrollable sepsis and 6 (20%) refused surgical intervention and were managed conservatively. Nineteen patients (63%) underwent definitive surgical repair requiring a median of 1 (range, 1-2) operations, with recurrent fistulation reported in 4 patients (21%). No intra-operative mortality was encountered. Two (11%) patients died postoperatively due to cardio-respiratory complications. CONCLUSIONS: These data compare favourably with outcome measures reported by designated national centres, suggesting ECF patients can be safely managed closer to home in regional units that have the appropriate expertise. Nevertheless, management of this condition remains critically dependent upon a dedicated multidisciplinary team approach.

Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition.

Hutchinson-Gilford progeria syndrome (HGPS) is typically caused by mutations in codon 608 (G608G) of the LMNA gene, which activates a cryptic splice site resulting in the in-frame loss of 150 nucleotides from the lamin A message. The deleted region includes a protein cleavage site that normally removes 15 amino acids, including a CAAX box farnesylation site, from the lamin A protein. We investigated the processing of the C-terminus of the mutant protein, 'progerin', and found that it does not undergo cleavage and, indeed, remains farnesylated. The retention of the farnesyl group may have numerous consequences, as farnesyl groups increase lipophilicity and are involved in membrane association and in protein interactions, and is likely to be an important factor in the HGPS phenotype. To further investigate this, we studied the effects of farnesylation inhibition on nuclear phenotypes in cells expressing normal and mutant lamin A. Expression of a GFP-progerin fusion protein in normal fibroblasts caused a high incidence of nuclear abnormalities, as was also seen in HGPS fibroblasts, and resulted in abnormal nuclear localization of GFP-progerin in comparison with the localization pattern of GFP-lamin A. Expression of a GFP-lamin A fusion containing a mutation preventing the final cleavage step, causing the protein to remain farnesylated, displayed identical localization patterns and nuclear abnormalities as in HGPS cells and in cells expressing GFP-progerin. Exposure to a farnesyltransferase inhibitor (FTI), PD169541, caused a significant improvement in the nuclear morphology of cells expressing GFP-progerin and in HGPS cells. These results implicate the abnormal farnesylation of progerin in the cellular phenotype in HGPS cells and suggest that FTIs may represent a therapeutic option for patients with HGPS.

Prevalence of hepatitis C-related cirrhosis in elderly Asian patients infected in childhood.

BACKGROUND & AIMS: Approximately 20% of hepatitis C virus (HCV) patients develop cirrhosis from infection after about 20 years. The proportion of patients developing cirrhosis for longer than 30 years after infection is unknown. Our objectives were to determine the prevalence of HCV-related cirrhosis in a population of Asian patients who were infected in childhood 20 to 80 years ago and compare this with the prevalence of cirrhosis in Caucasian patients referred to the same hospitals. METHODS: Retrospective analyses were performed of all patients who had detectable HCV-RNA levels and who attended local hospitals in northeast London between 1992 and 2003. Factors implicated in the development of cirrhosis were examined by multivariable analysis. RESULTS: A total of 143 adult Asian patients who had been infected with HCV for many decades were compared with 239 Caucasian patients. The prevalence of cirrhosis increased with age. Of Asian patients aged 61-80 years (n = 55) 78% had cirrhosis, whereas 25% of Caucasian patients aged 61-80 years (n = 55) had cirrhosis. Multivariable linear analysis revealed that fibrosis progression and age were similar in both groups and the difference in the prevalence of cirrhosis was not explained by any unique Asian characteristic other than prolonged infection. CONCLUSIONS: The prevalence of cirrhosis in patients with chronic HCV increases with increasing duration of infection. In Asian patients infected at birth, infection for over 60 years causes cirrhosis in 71% of infected individuals. Because relationship between the severity of fibrosis and age in Asian patients is similar to that seen in Caucasian patients it is likely that similar rates of cirrhosis will be seen in other patients who are infected for more than 60 years.

Polyalanine expansion in HOXA13: three new affected families and the molecular consequences in a mouse model.

Polyalanine expansions in two of three large imperfect trinucleotide repeats encoded by the first exon of HOXA13 have been reported in hand-foot-genital syndrome (HFGS). Here we report additional families with expansions in the third repeat of 11 and 12 alanine residues, the latter being the largest expansion reported. We also report a patient with a novel, de novo 8-alanine expansion in the first large repeat. Thus, expansions in all three large HOXA13 polyalanine repeats can cause HFGS. To determine the molecular basis for impaired HOXA13 function, we performed homologous recombination in ES cells in mice to expand the size of the third largest polyalanine tract by 10 residues (HOXA13(ALA28)). Mutant mice were indistinguishable from Hoxa13 null mice. Mutant limb buds had normal steady-state Hoxa13 RNA expression, normal mRNA splicing and reduced levels of steady-state protein. In vitro translation efficiency of the HOXA13(ALA28) protein was normal. Thus, loss of function is secondary to a reduction in the in vivo abundance of the expanded protein likely due to degradation.

Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing. Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q-the inheritance of both copies of this material from one parent-and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders, revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo (that is, newly arisen and not inherited) single-base substitution, G608G(GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.