What influences postgraduate psychiatric trainees' attitudes to clinical audit?

INTRODUCTION: Clinical audit is an important component of safe and ethical practice but many clinicians cite barriers to engagement in audit. METHODOLOGY: A total of 81 basic specialist trainees in psychiatry were surveyed in terms of their basic demographic details and their knowledge, direct experience and attitudes in relation to clinical audit. RESULTS: Among the 49 (60.5%) who responded, 57.1% had received formal training in audit, but only 20.4% had received more than four hours of training in their whole career. The median positivity score was 30 out of a possible 54 (range 12-40), suggesting that participating trainees were barely more than 'undecided' overall when it comes to positive attitudes to clinical audit. Age, nationality and specific training did not predict attitudes to clinical audit. Gender, years of clinical experience and direct experience of clinical audit did not significantly predict attitudes to clinical audit, but these findings are at odds with some previous research. DISCUSSION: Much work is needed in improving postgraduate trainees' attitudes to clinical audit, given that clinical audit is essential for good medical practice. Ours is an initial study of this area of training limited by sample size and the narrowness of the group tested. Further study of other specialities, higher trainees and consultant trainers would further enhance our understanding.

Management of self-inflicted gunshot wounds to the face: retrospective review from a single tertiary care trauma centre.

There are limited published data about the surgical management of self-inflicted facial gunshot wounds. The aim of this retrospective study was to review our management of subjects who initially survive such a wound and were admitted to a tertiary care trauma centre between 2002 and 2012. Only subjects with definitive evidence of a self-inflicted facial gunshot wound and who were admitted alive were included. Data collected included personal and clinical details, characteristics of the gunshot wound, and medical and surgical management. Types of operations and their duration were recorded, and primary reconstruction was divided into early (within the first 48hours after presentation) or delayed (longer than 48hours). Determinants of infection were assessed with univariate analysis. Seventy-six subjects (65 male and 11 female, mean (range) age 44 (18-83) years) were included in the study. Twenty-five patients needed an early surgical airway and five needed emergency intervention to control haemorrhage. Forty-five patients had primary reconstructions (28 early and 17 delayed) and 12 who were treated by delayed repair had a submental entry site to the wound. There were no significant differences in infection rates between those who had early, compared with those who had late, reconstructions. Early primary reconstruction can be successful for patients with self-inflicted facial gunshot wounds, particularly when the entry point of the bullet is in the upper and midface area. Delayed primary reconstruction was more common when the bullet entered the lower face.

The Prevalence of Malformations of Cortical Development in a Pediatric Hereditary Hemorrhagic Telangiectasia Population.

BACKGROUND AND PURPOSE: Brain AVM, cerebral abscess, and ischemic stroke are among the well known neurologic manifestations of hereditary hemorrhagic telangiectasia. However, recently reported data suggest an additional association with malformations of cortical development. The purpose of this study was to determine the prevalence of malformations of cortical development in a population of pediatric patients with hereditary hemorrhagic telangiectasia. MATERIALS AND METHODS: A retrospective review of brain MRIs from 116 pediatric patients was performed. Each patient was referred from our institution's Hereditary Hemorrhagic Telangiectasia Clinic. Each MRI included a 3D sequence, most frequently MPRAGE. The 3D sequence was evaluated by a neuroradiology fellow, with specific attention to the presence or absence of malformations of cortical development. Positive studies were subsequently reviewed by 2 attending neuroradiologists, who rendered a final diagnosis. RESULTS: Fourteen of 116 (12.1%) patients were found to have a malformation of cortical development. Among these 14, there were 12 cases of polymicrogyria and 2 cases of bifrontal periventricular nodular heterotopia. CONCLUSIONS: Pediatric patients with hereditary hemorrhagic telangiectasia have a relatively high prevalence of malformations of cortical development, typically perisylvian polymicrogyria.

Systematic review of high-intensity focused ultrasound ablation in the treatment of breast cancer.

BACKGROUND: A systematic review was undertaken to assess the clinical efficacy of non-invasive high-intensity focused ultrasound (HIFU) ablation in the treatment of breast cancer. METHODS: MEDLINE/PubMed library databases were used to identify all studies published up to December 2013 that evaluated the role of HIFU ablation in the treatment of breast cancer. Studies were eligible if they were performed on patients with breast cancer and objectively recorded at least one clinical outcome measure of response (imaging, histopathological or cosmetic) to HIFU treatment. RESULTS: Nine studies fulfilled the inclusion criteria. The absence of tumour or residual tumour after treatment was reported for 95·8 per cent of patients (160 of 167). No residual tumour was found in 46·2 per cent (55 of 119; range 17-100 per cent), less than 10 per cent residual tumour in 29·4 per cent (35 of 119; range 0-53 per cent), and between 10 and 90 per cent residual tumour in 22·7 per cent (27 of 119; range 0-60 per cent). The most common complication associated with HIFU ablation was pain (40·1 per cent) and less frequently oedema (16·8 per cent), skin burn (4·2 per cent) and pectoralis major injury (3·6 per cent). MRI showed an absence of contrast enhancement after treatment in 82 per cent of patients (31 of 38; range 50-100 per cent), indicative of coagulative necrosis. Correlation of contrast enhancement on pretreatment and post-treatment MRI successfully predicted the presence of residual disease. CONCLUSION: HIFU treatment can induce coagulative necrosis in breast cancers. Complete ablation has not been reported consistently on histopathology and no imaging modality has been able confidently to predict the percentage of complete ablation. Consistent tumour and margin necrosis with reliable follow-up imaging are required before HIFU ablation can be evaluated within large, prospective clinical trials.

The ruptured PIP breast implant.

Public concern erupted about the safety of Poly Implant Prothèse (PIP) breast implants when it was revealed in 2011 that they contained an inferior, unlicensed industrial-grade silicone associated with a high rate of rupture. There followed national guidance for UK clinicians, which led to a considerable increase in referrals of asymptomatic women for breast implant assessment. In this review we discuss possible approaches to screening the PIP cohort and the salient characteristics of a ruptured implant.

Plain abdominal radiographs in patients with Crohn's disease: radiological findings and diagnostic value.

AIM: To determine the diagnostic yield and clinical value of plain film of the abdomen (PFA) in Crohn's disease (CD) patients and to determine whether performance of PFA yields definitive diagnostic information or whether additional imaging examinations are required. MATERIALS AND METHODS: One hundred and seventy-seven CD patients underwent 643 PFAs during the period September 1992 to August 2008. Two radiologists blinded to the clinical details independently evaluated individual PFAs and/or their reports for abnormal findings using the following criteria: normal, small bowel (SB) findings; colonic findings, acute CD complications, extra-colonic findings; global assessment/impression. The results of additional imaging studies performed within 5 days of PFA were recorded and findings were analysed. RESULTS: A mean of 3.6 (range 1-22) PFAs was performed per patient during the study period. Almost 70% of films were normal (n = 449). SB abnormalities were detected in 21.8% (n = 140) PFAs; most commonly dilated loops (18.8%, n = 121) and mucosal oedema (5%, n = 32). Colonic abnormalities were present in 11.4% (n = 73); most commonly mucosal oedema (7.5%, n = 48) and dilated loops (5%, n = 32). Four cases of pneumoperitoneum were detected. There was no case of toxic megacolon. There was one case in which intra-abdominal abscess/collection was suspected and two cases of obstruction/ileus. Extracolonic findings (renal calculi, sacro-iliitis, etc.) were identified in 7.5% (n = 48). PFAs were followed by additional abdominal imaging within 5 days of PFA in 273/643 (42.5%) of cases. CONCLUSION: Despite the high rates of utilization of PFA in CD patients, there is a low incidence of abnormal findings (32.5%). Many of the findings are non-specific and clinically irrelevant and PFA is frequently followed by additional abdominal imaging examinations.

Schizophrenia: a five-year follow-up of patient outcome following psycho-education for caregivers.

INTRODUCTION: There is evidence that psycho-education courses for caregivers of individuals with schizophrenia improve the short-term outcome of the condition. However, most of the outcome studies are limited to two-year follow-up. MATERIALS AND METHODS: This study is a five-year retrospective case-control follow-up of an original cohort of 63 patients and their 101 caregivers who completed a six-week Caregiver Psycho-education Programme (CPP) for schizophrenia and psychosis between 2002 and 2005, and 60 controls, matched for age, gender and severity of their psychotic illness. RESULTS: Patients whose caregivers learned more from the six-week psycho-education course had a significantly longer time to relapse (P = 0.04) and a significantly shorter length of stay during their first relapse (P < 0.05). Patients whose caregivers attended the six-week psycho-education course (regardless of how much the caregivers learned) had a significantly better outcome than controls. This included a significantly smaller number of relapses (P < 0.01), longer time to relapse (P < 0.01), shorter length of stay during their first relapse (P < 0.01) and smaller number of bed days over five years (P < 0.01). The odds ratio of controls relapsing, although insignificant at one year, was 4.13 (1.85-9.21) at five years. Outcome was not affected by either the numbers of caregivers attending for each patient, or caregiver gender. DISCUSSION AND CONCLUSIONS: This study, which is among the first to examine outcome over five years, supports the efficacy of psycho-education for caregivers in improving outcome for patients. Caregivers should be encouraged to take up psycho-education where it is available.

The spectrum of functional gastrointestinal disorders in a tertiary referral clinic in Ireland.

BACKGROUND: The functional gastrointestinal disorders (FGIDs) are a heterogenous group of chronic conditions which cause troubling gastrointestinal symptoms. Though common and sometimes disabling, causing considerable social and economic burden, there is little recent literature on presentation or impact of FGIDs in Ireland. AIM: To describe the characteristics of patients with FGIDs at a tertiary referral clinic in Ireland. METHODS: A retrospective review of those attending a university hospital gastroenterology clinic with a special interest in FGIDs between January 1999 and July 2008 was performed. Data were mined from electronic outpatient records and clinic letters. RESULTS: A total of 1,909 patients were included. Of these patients, 41.2% (787 of 1,909) received a diagnosis of FGID. FGID patients were predominantly (70.14%) female and the average age at first presentation was 38.3 years. Of these, 76% (598 of 787) were referred from general practice; 35.8% (282 of 787) received onward referrals to other specialties. Nine hundred FGIDs were diagnosed. The most common FGID was irritable bowel syndrome (633 of 900, 70.3%). In the FGID group, 13.1% of patients (103 of 787) had more than one FGID diagnosis. Females received a definitive diagnosis of FGID faster than males; mean diagnostic latency: 5.3 versus 6.4 months (p < 0.05). Sixty-six percent (523 of 787) of FGID patients had non-gastrointestinal co-morbidities, with 315 (60.2%) of these having more than one co-morbidity. The burden of non-GI co-morbidity was significantly higher in patients with overlapping functional syndromes than in patients with single FGID (p < 0.05). CONCLUSIONS: In Ireland, FGIDs are common, represent a significant burden for the health-care system and deserve greater recognition and further research attention.

The imaging features of MACROLANE™ in breast augmentation.

Macrolane™ is an injectable, biocompatible, soft-tissue filler that has been available in the UK since 2008 and is promoted for use in breast augmentation. There are few data available on the long-term effects of this relatively new product and concerns have been raised about the implications for breast imaging, in particular breast screening. In this context we present a spectrum of imaging appearances and complications encountered to date.

Minimization of radiation exposure due to computed tomography in inflammatory bowel disease.

Exposure to ionising radiation as a result of diagnostic imaging is increasing among patients with inflammatory bowel disease (IBD), primarily due to the more widespread use of computed tomography (CT). The potentially harmful effects of ionising radiation are a major cause for concern and radiologists, technologists and referring physicians who have a responsibility to the patient to ensure judicious use of those imaging modalities which result in exposure to ionising radiation and, when imaging is necessary, to ensure that a diagnostic quality imaging examination is acquired with lowest possible radiation exposure. This can be achieved by limiting the use of those imaging studies which involve ionising radiation to clinical situations where they are likely to change management, by implementing advances in low-dose CT technology, and, where feasible, by using alternative imaging modalities, such as ultrasonography or magnetic resonance imaging, which avoid radiation exposure.

Reversible blunting of arousal from sleep in response to intermittent hypoxia in the developing rat.

Arousal is an important survival mechanism when infants are confronted with hypoxia during sleep. Many sudden infant death syndrome (SIDS) infants are exposed to repeated episodes of hypoxia before death and have impaired arousal mechanisms. We hypothesized that repeated exposures to hypoxia would cause a progressive blunting of arousal, and that a reversal of this process would occur if the hypoxia was terminated at the time of arousal. P5 (postnatal age of 5 days), P15, and P25 rat pups were exposed to either eight trials of hypoxia (3 min 5% O(2) alternating with room air) (group A), or three hypoxia trials as in group A, followed by five trials in which hypoxia was terminated at arousal (group B). In both groups A and B, latency increased over the first four trials of hypoxia, but reversed in group B animals during trials 5-8. Progressive arousal blunting was more pronounced in the older pups. The effects of intermittent hypoxia on heart rate also depended on age. In the older pups, heart rate increased with each hypoxia exposure. In the P5 pups, however, heart rate decreased during hypoxia and did not return to baseline between exposures, resulting in a progressive fall of baseline values over successive hypoxia exposures. In the group B animals, heart rate changes during trials 1-4 also reversed during trials 5-8. We conclude that exposure to repeated episodes of hypoxia can cause progressive blunting of arousal, which is reversible by altering the exposure times to hypoxia and the period of recovery between hypoxia exposures.

Tracking the oxidative kinetics of carbohydrates, amino acids and fatty acids in the house sparrow using exhaled 13CO2.

Clinicians commonly measure the (13)CO(2) in exhaled breath samples following administration of a metabolic tracer (breath testing) to diagnose certain infections and metabolic disorders. We believe that breath testing can become a powerful tool to investigate novel questions about the influence of ecological and physiological factors on the oxidative fates of exogenous nutrients. Here we examined several predictions regarding the oxidative kinetics of specific carbohydrates, amino acids and fatty acids in a dietary generalist, the house sparrow (Passer domesticus). After administering postprandial birds with 20 mg of one of seven (13)C-labeled tracers, we measured rates of (13)CO(2) production every 15 min over 2 h. We found that sparrows oxidized exogenous amino acids far more rapidly than carbohydrates or fatty acids, and that different tracers belonging to the same class of physiological fuels had unique oxidative kinetics. Glycine had a mean maximum rate of oxidation (2021 nmol min(-1)) that was significantly higher than that of leucine (351 nmol min(-1)), supporting our prediction that nonessential amino acids are oxidized more rapidly than essential amino acids. Exogenous glucose and fructose were oxidized to a similar extent (5.9% of dose), but the time required to reach maximum rates of oxidation was longer for fructose. The maximum rates of oxidation were significantly higher when exogenous glucose was administered as an aqueous solution (122 nmol min(-1)), rather than as an oil suspension (93 nmol min(-1)), supporting our prediction that exogenous lipids negatively influence rates of exogenous glucose oxidation. Dietary fatty acids had the lowest maximum rates of oxidation (2-6 nmol min(-1)), and differed significantly in the extent to which each was oxidized, with 0.73%, 0.63% and 0.21% of palmitic, oleic and stearic acid tracers oxidized, respectively.

Exposure to cold but not exercise increases carbon turnover rates in specific tissues of a passerine.

Carbon turnover differs between tissues within an animal, but the extent to which ecologically relevant increases in metabolism affect carbon turnover rates is largely unknown. We tested the energy expenditure and protein turnover hypotheses that predict increased carbon turnover, either in association with increased daily energy expenditure, or in concert with tissue-specific increased protein metabolism. We used stable-isotope-labeled diets to quantify the rate of carbon turnover in 12 different tissues for three groups of zebra finches (Taeniopygia guttata): cold-exposed birds kept at ambient temperatures below their thermoneutral zone, exercised birds that were flown for 2 h per day in a flight arena, and control birds that were kept at ambient temperatures within their thermoneutral zone and that were not exercised. We found that increases in metabolism associated with cold-exposure but not exercise produced measurable increases in carbon turnover rate of, on average, 2.4+/-0.3 days for pectoral muscle, gizzard, pancreas and heart, even though daily energy intake was similar for exercised and cold-exposed birds. This evidence does not support the energy expenditure hypothesis, and we invoke two physiological processes related to protein metabolism that can explain these treatment effects: organ mass increase and tissue-specific increase in activity. Such changes in carbon turnover rate associated with cold temperatures translate into substantial variation in the estimated time window for which resource use is estimated and this has important ecological relevance.

Experience with concomitant ultrasound-guided foam sclerotherapy and endovenous laser treatment in chronic venous disorder and its influence on Health Related Quality of Life: interim analysis of more than 1000 consecutive procedures.

AIM: The aim of this paper was to evaluate the efficacy of the concomitant use of endovenous laser treatment (ELT) and ultrasound-guided foam sclerotherapy (USGFS) in the management of chronic venous disorder and to objectively analyze the influence of the combination therapy on the Health Related Quality of Life (HRQL) of the treated patients. METHODS: In this prospective series, 1 114 varicose veins in 924 consecutive subjects were treated either with a 980 nm (7-15W) or a 1320 nm (3-10W) endovenous laser. INCLUSION CRITERIA: informed consent, clinical, etiologic, anatomical, and pathophysiological (CEAP) clinical class >or=2, and an accessible vein. EXCLUSION CRITERIA: coagulation disorder, pregnancy, lactation, current thrombosis, systemic disease, poor general health, or allergy to sodium tetradecyl sulfate (STS). ELT was performed on refluxing saphenous truncal and non-saphenous veins, including incompetent perforators. USGFS was utilized to treat selective refluxing, symptomatic varicose tributaries that were not amenable to ELT alone. The Venous Dysfunction Score (VDS) and Health Related Quality of Life (HRQL) were assessed. All of the patients were strictly monitored and had Duplex ultrasound scanning to evaluate for deep vein thrombosis (DVT) at 24-72 hours. Thorough Duplex scanning was done at 1 week, 1 month, 3 months, 6 months, 12 months, and 24 months. RESULTS: At 1 month, there was continued reflux (> 0.5 seconds) in 26 SFJs (3.0%, N=824) and 4 SPJ s (2.5%, N=155) and at 3 months in 15 SFJs (1.8%), 5 SPJ s (3.7%). At 6 months, reflux was present in 10 SFJs (1.2%) and 4 SPJs (2.5%). At a mean of 12+/-10 months of post-treatment follow-up, 4 SFJ (1.9%, N=207) and 1 SPJ (1.9%, N=52) had reflux. Overall, there was elimination of reflux in 98% of junctions. The posterior accessory saphenous veins (PAV: N=117) had 100 % elimination of reflux at 1 month, a result that remained unchanged for more than a year (P<0.001). Similarly, anterior accessory saphenous veins (AAV: N=56), cranial, caudal, or thigh, extensions of the small saphenous vein (CESSV: N=31), and non-saphenous veins and incompetent perforators (NSV, IP: N=31) all had sustained and statistically significant response (P<0.001). Sequentially assessed VDS showed significant improvement (P<0.001). The Aberdeen Varicose Vein Questionnaire (AVVQ) revealed significant improvement in HRQL at 1-2 year (P<0.001). Failed ELT attempts occurred in six cases due to vein spasm (N=4, 0.36%) or fiber/laser machine malfunction (N=2, 0.18%). These veins were successfully treated with ultrasound-guided foam sclerotherapy. Thirty-two patients (2.9%) complained of a small area of numbness at one month. There was complete resolution in 6 (18.8%) of the patients by 6 months. There were four cases of a localized cellulitis at laser venous access sites. These resolved uneventfully with oral antibiotics. There were also two skin reactions, with localized urticaria, due to dressing tape. These required no additional treatment. There were two cases of superficial phlebitis that resolved with continued compression and NSAIDs. There was one asymptomatic popliteal DVT and one uncomplicated superficial skin burn that both resolved uneventfully with no treatment other than observation. No pulmonary embolism (PE), thrombophlebitis, or visual disturbance occurred. CONCLUSIONS: Ultrasound-guided foam sclerotherapy given concomitantly with ELT is safe and highly efficacious in the management of GSV, SSV reflux and in their tributaries or in non-saphenous veins. CVD patients treated with combination therapy given in this manner demonstrated significant improvement in their HRQL.

Crohn's disease: factors associated with exposure to high levels of diagnostic radiation.

AIMS: Exposure to diagnostic radiation may be associated with increased risk of malignancy. The aims of this study were to (1) examine patterns of use of imaging in Crohn's disease; (2) quantify the cumulative effective dose (CED) of diagnostic radiation received by patients; and (3) identify patients at greatest risk of exposure to high levels of diagnostic radiation. METHODS: 409 patients with Crohn's disease were identified at a tertiary centre. CED was calculated retrospectively from imaging performed between July 1992 and June 2007. High exposure was defined as CED>75 mSv, an exposure level which has been reported to increase cancer mortality by 7.3%. Complete data were available for 399 patients. 45 were excluded (20 attended outside the study period, 25 were primarily managed at other centres). RESULTS: Use of computed tomography increased significantly and accounted for 77.2% of diagnostic radiation. Mean CED was 36.1 mSv and exceeded 75 mSv in 15.5% of patients. Factors associated with high cumulative exposure were: age <17 years at diagnosis (hazard ratio 2.1, confidence interval (CI) 1.1 to 4.1), upper gastrointestinal tract disease (odds ratio (OR) 2.4, CI 1.2 to 4.9), penetrating disease (OR 2.0, CI 1.0 to 3.9) and requirement for intravenous steroids (OR 3.7, CI 2.0 to 6.6); infliximab (OR 2.3, CI 1.2 to 4.4); or multiple (>1) surgeries (OR 2.7, CI 1.4 to 5.4). CONCLUSIONS: Identifiable subsets of patients with Crohn's disease are at risk of exposure to significant amounts of diagnostic radiation. Given the background risk of neoplasia and exposure to potentially synergistic agents such as purine analogues and other immune modulators, specialist centres should develop low-radiation imaging protocols.

Novel skeletal muscle ryanodine receptor mutation in a large Brazilian family with malignant hyperthermia.

Malignant hyperthermia (MH) is an autosomal dominant disorder that predisposes susceptible individuals to a potentially life-threatening crisis when exposed to commonly used anesthetics. Mutations in the skeletal muscle calcium release channel, ryanodine receptor (RYR1) are associated with MH in over 50% of affected families. Linkage analysis of the RYR1 gene region at 19q13 was performed in a large Brazilian family and a distinct disease co-segregating haplotype was revealed in the majority of members with diagnosis of MH. Subsequent sequencing of RYR1 mutational hot spots revealed a nucleotide substitution of C to T at position 7062, causing a novel amino acid change from Arg2355 to Cys associated with MH in the family. Haplotype analysis of the RYR1 gene area at 19q13 in the family with multiple MH members is an important tool in identification of genetic cause underlying this disease.

Uncovering BRCA1-regulated signalling pathways by microarray-based expression profiling.

The introduction of microarray technology to the scientific and medical communities has dramatically changed the way in which we now address basic biomedical questions. Expression profiling using microarrays facilitates an experimental approach where alterations in the transcript level of entire transcriptomes can be simultaneously assayed in response to defined stimuli. We have used microarray analysis to identify downstream transcriptional targets of the BRCA1 (Breast Cancer 1) tumour-suppressor gene as a means of defining its function. BRCA1 has been implicated in the predisposition to early onset breast and ovarian cancer and while its exact function remains to be defined, roles in DNA repair, cell-cycle control and transcriptional regulation have been implied. In the current study we have generated cell lines with tetracycline-regulated, inducible expression of BRCA1 as a tool to identify genes, which might represent important effectors of BRCA1 function. Oligonucleotide array-based expression profiling identified a number of genes that were upregulated at various times following inducible expression of BRCA1 including the DNA damage-responsive gene GADD45 (Growth Arrest after DNA Damage). Identified targets were confirmed by Northern blot analysis and their functional significance as BRCA1 targets examined.

BRCA1 and GADD45 mediated G2/M cell cycle arrest in response to antimicrotubule agents.

BRCA1 is a tumour suppressor gene implicated in the predisposition to early onset breast and ovarian cancer. We have generated cell lines with inducible expression of BRCA1 to evaluate its role in mediating the cellular response to various chemotherapeutic drugs commonly used in the treatment of breast and ovarian cancer. Induction of BRCA1 in the presence of Taxol and Vincristine resulted in a dramatic increase in cell death; an effect that was preceded by an acute arrest at the G2/M phase of the cell cycle and which correlated with BRCA1 mediated induction of GADD45. A proportion of the arrested cells were blocked in mitosis suggesting activation of both a G2 and a mitotic spindle checkpoint. In contrast, no specific interaction was observed between BRCA1 induction and treatment of cells with a range of DNA damaging agents including Cisplatin and Adriamycin. Inducible expression of GADD45 in the presence of Taxol induced both G2 and mitotic arrest in these cells consistent with a role for GADD45 in contributing to these effects. Our results support a role for both BRCA1 and GADD45 in selectively regulating a G2/M checkpoint in response to antimicrotubule agents and raise the possibility that their expression levels in cells may contribute to the toxicity observed with these compounds.

Single-amino-acid deletion in the RYR1 gene, associated with malignant hyperthermia susceptibility and unusual contraction phenotype.

Malignant hyperthermia (MH) is an anesthetic-drug-induced, life-threatening hypermetabolic syndrome caused by abnormal calcium regulation in skeletal muscle. Often inherited as an autosomal dominant trait, MH has linkage to 30 different mutations in the RYR1 gene, which encodes a calcium-release-channel protein found in the sarcoplasmic reticulum membrane in skeletal muscle. All published RYR1 mutations exclusively represent single-nucleotide changes. The present report documents, in exon 44 of RYR1 in two unrelated, MH-susceptible families, a 3-bp deletion that results in deletion of a conserved glutamic acid at position 2347. This is the first deletion, in RYR1, found to be associated with MH susceptibility. MH susceptibility was confirmed among some family members by in vitro diagnostic pharmacological contracture testing of biopsied skeletal muscle. Although a single-amino-acid deletion appears to be a subtle change in the protein, the deletion of Glu2347 from RYR1 produces an unusually large electrically evoked contraction tension in MH-positive individuals, suggesting that this deletion produces an alteration in skeletal-muscle calcium regulation, even in the absence of pharmacological agents.