Search

Polymicrogyria is a heterogeneous malformation of cortical development microscopically defined by an excessive folding of the cortical mantle resulting in small gyri with a fused surface. Polymicrogyria is responsible for a wide range of neurological symptoms (e.g. epilepsy, intellectual disability, motor dysfunction). Most cases have a supposed environmental clastic vascular or infectious origin but progress in genomics has revealed new monogenic entities. We report four cases from two independent families sharing a common recognizable lethal syndromic polymicrogyria of autosomal recessive inheritance. Beyond diffuse polymicrogyria detected prenatally, pathological examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. In all affected cases, exome sequencing showed a pathogenic homozygous nonsense ATP1A2 variant. This resulted in absence of immunodetectable ATP1A2 protein in two brains analysed. ATP1A2 encodes the alpha-2 isoform of the Na+/K+-ATPase, which is highly expressed in brain tissues and has previously been related to familial hemiplegic migraine (MIM#602481) and alternating hemiplegia of childhood (MIM#104290). Through the description of this genetic entity, we emphasize the possibility of dual mode of transmission for disease-causing genes and provide the key neuropathological features that should prompt geneticists to test for mutations in the ATP1A2 gene.

Summary Background Germline pathogenic variants in the E-cadherin gene ( CDH1 ) are strongly associated with the development of hereditary diffuse gastric cancer. There is a paucity of data to guide risk assessment and management of families with hereditary diffuse gastric cancer that do not carry a CDH1 pathogenic variant, making it difficult to make informed decisions about surveillance and risk-reducing surgery. We aimed to identify new candidate genes associated with predisposition to hereditary diffuse gastric cancer in affected families without pathogenic CDH1 variants. Methods We did whole-exome sequencing on DNA extracted from the blood of 39 individuals (28 individuals diagnosed with hereditary diffuse gastric cancer and 11 unaffected first-degree relatives) in 22 families without pathogenic CDH1 variants. Genes with loss-of-function variants were prioritised using gene-interaction analysis to identify clusters of genes that could be involved in predisposition to hereditary diffuse gastric cancer. Findings Protein-affecting germline variants were identified in probands from six families with hereditary diffuse gastric cancer; variants were found in genes known to predispose to cancer and in lesser-studied DNA repair genes. A frameshift deletion in PALB2 was found in one member of a family with a history of gastric and breast cancer. Two different MSH2 variants were identified in two unrelated affected individuals, including one frameshift insertion and one previously described start-codon loss. One family had a unique combination of variants in the DNA repair genes ATR and NBN . Two variants in the DNA repair gene RECQL5 were identified in two unrelated families: one missense variant and a splice-acceptor variant. Interpretation The results of this study suggest a role for the known cancer predisposition gene PALB2 in families with hereditary diffuse gastric cancer and no detected pathogenic CDH1 variants. We also identified new candidate genes associated with disease risk in these families. Funding UK Medical Research Council (Sackler programme), European Research Council under the European Union's Seventh Framework Programme (2007–13), National Institute for Health Research Cambridge Biomedical Research Centre, Experimental Cancer Medicine Centres, and Cancer Research UK.

There are no national recommendations for routine screening for sickle cell trait, nor is there guidance on whether or how to notify donors that they might be tested or identified as having sickle cell trait. As a result, the organizations that collect blood have implemented variable policies about whether and how to inform prospective donors of the possible screening and discovery of this noncommunicable condition. The question of what they should do is related to the broader question of how to handle incidental and secondary findings. In a recent report, the Presidential Commission for the Study of Bioethical Issues outline a framework for handling such findings in the clinical, research, and direct-to-consumer contexts. While the commission's report did not directly address incidental and secondary findings in the public health context of blood donation, it made several overarching recommendations that apply in all contexts where such findings might arise. This essay outlines the special issues raised by discovering sickle cell trait in blood donation and considers the implications of the commission's framework for that problem.

Most definitions of nonalcoholic fatty liver disease (NAFLD) allow some intake of alcohol but little attention has been paid to the possible contribution of alcohol-derived calories in the overall daily intake. The aim of the present study was to determine whether, in a group of 144 patients referred to liver outpatients with NAFLD, a more structured questioning of dietary habits and alcohol consumption would provide better information on alcohol-derived and dietary-derived calorie intake and the relationship with the BMI.Both food intake and calories resulting from alcohol ingestion were frequently underestimated as was the percentage of patients who were drinking excessively (30 U a week), which was surprisingly high at 40%. The substantial calorie intake resulting from alcohol consumption in this group was associated with a reduction in dietary calorie intake, so that the total daily calorie intake remained similar to those with low-to-moderate or no alcohol consumption. The findings also showed that the BMI, although still elevated, was significantly reduced in those drinking heavily compared with low and nondrinkers.Patients with NAFLD can have substantially higher levels of alcohol consumption than usually recognized. The additional calorie intake resulting from this is to some extent balanced by a reduction in dietary calorie intake with less elevation in BMI, and a clear distinction from an alcohol-induced steatosis may be difficult.

Background Experience with miniaturized coronary artery bypass (CAB) systems in coronary artery bypass graft (CABG) surgery on the beating heart is limited. We used a relatively new miniaturized cardiopulmonary bypass (CPB) system, which we termed assisted CAB (ACAB), to perform CABG on the beating heart in 110 patients, and we analyzed clinical outcomes in this patient group. Methods Between January 2004 and September 2006, we used ACAB to perform CABG on the beating heart in 110 patients. The mean patient age was 73 +/- 8.1 years. The ACAB system uses a small prime volume of only 500 mL, and the circuit is shorter than that used in conventional CPB. In addition, the tubing and oxygenator systems were surface-coated with phosphorylcholine. The initial heparin dose was 150 IU/kg, with a target activated clotting time of >250 seconds. With this management, none of the patients experienced system thrombosis. We did not use cardioplegia or aortic crossclamping and did not routinely retransfuse cardiotomy blood. Observational data for the 110 patients were analyzed. Results The mean number of anastomoses performed was 2.67. The rate of perioperative infarction was 1.8% (2 patients). Perioperative mortality was 7% (8 patients). The mean EuroSCORE for all patients was 6.4 +/- 4, whereas it was 13.75 +/- 6.18 for the patients who died. Mean CPB time was 64.96 +/- 16.66 minutes. Conclusion In our experience, beating heart CABG supported by a miniaturized CPB is a safe procedure with acceptable perioperative results.

Aims: To test the hypothesis that regional variations in the prevalence of alcoholic liver disease are contributed to by regional variations in ‘softness’ of drinking water, i.e. its mineral content. Methods: Annual hospital admission rates for alcoholic liver disease per 100,000 population in the 28 Strategic Health Authorities (SHAs) existing in England over the period 2003–2006 were compared with regional measures of water hardness, alcohol consumption and social deprivation. As corroborative evidence, the same relations were examined for hospital admission rates for osteoporosis, a disorder with an already established link with calcium deficiency in drinking water (as well as with heavy drinking). Results: Hospital admissions rates for alcoholic liver disease were higher in predominant-soft-water SHAs than with hard water SHAs. These areas, with one exception, were also associated with high alcohol consumption, but not with greater social deprivation. Hospital admission rates for osteoporosis were found to vary in a way similar to that for alcoholic liver disease, with significant correlations with soft water and alcohol consumption. Conclusion: Given experimental evidence that magnesium deficiency can aggravate liver damage from alcohol, soft water with its low magnesium concentration may be a factor additional to alcohol consumption in the development of liver damage. The parallel findings with osteoporosis admissions, explainable by low calcium and magnesium levels present in soft water, along with the known effect of heavy drinking on bone metabolism, provide corollary support for the hypothesis linking soft water with the pathogenesis of these two diseases.

OBJECTIVE: One of the major and devastating complications of the coronary artery bypass grafting (CABG) is the stroke. Avoiding cardiopulmonary bypass (CPB) may reduce this neurological complication. In the past years there was an increased interest in the off-pump coronary artery grafting (OPCAB). The benefit of this method of revascularization in term of stroke and mortality is controversially discussed. METHODS: A retrospective analysis of collected data from 252 patients were operated without cardiopulmonary bypass out of 1516 CABG procedures from January 2004 through May 2006. The mean age of the patient population was 70±11years, within a range of 27-88 years. Forty-eight (19%) patients were older than 80 years and there were 172 (69%) males. Mean graft per patient was 1.78±0.79. The internal mammary artery (IMA) graft was used in 95% of the patients. For eight (3.17%) patients this was the second procedure. RESULTS: Hospital mortality was 3.17%; Mean EuroSCORE in these patients was 10.36±6.67. No neurological complications occurred, six (2.38%) patients had temporary psycho syndrome. Postoperative myocardial infarction occurred in three (1.19%) patients. Two patients required rethoracotomy as a result of bleeding. Thirty-eight (15%) patients needed postoperative therapy for atrial fibrillation. CONCLUSION: CABG with OPCAB technique has the benefit of low mortality and morbidity in terms of stroke. The advantages of this technique depends on the patient's general condition at the time of the operation, the sufficiency of pump function and coronary morphology, as well as on the surgeon's experience. OBJETIVO: Uma das principais e devastadoras complicações da revascularização do miocárdio é o acidente cerebrovascular. Evitar a circulação extracorpórea (CEC) pode reduzir essa complicação neurológica. No passado, houve um interesse crescente na cirurgia de revascularização do miocárdio sem circulação extracorpórea. O benefício deste método de revascularização com relação ao acidente cerebrovascular e à mortalidade ainda é discutido de forma controversa. MÉTODOS: Uma análise retrospectiva dos dados coletados de 1.516 pacientes submetidos à cirurgia de revascularização do miocárdio, de janeiro de 2004 a maio de 2006, dos quais 252 pacientes que foram operados sem circulação extracorpórea. A média de idade da população da amostra foi de 70±11 anos, variando de 27 a 88 anos. Quarenta e oito pacientes (19%) tinham mais de 80 anos e 172 pacientes (69%) eram homens. O número médio de transplante por paciente foi de 1,78±0,79. A artéria torácica interna (ATI) foi usada em 95% dos pacientes, enquanto que para oito pacientes a ATI foi o segunda procedimento. RESULTADOS: A mortalidade hospitalar foi de 3,17%; o EuroScore médio nesses pacientes foi de 10,36±6,67. Não ocorreram complicações neurológicas, porém, seis pacientes (2,38%) tiveram psicossíndrome temporária. Infarto do miocárdio ocorreu em três pacientes (1,19%) após a cirurgia. Dois pacientes precisaram fazer uma nova toracotomia por motivo de sangramento e 38 (15%) de tratamento para fibrilação atrial após a cirurgia. CONCLUSÃO: A cirurgia de revascularização do miocárdio sem circulação extracorpórea apresenta o benefício da baixa mortalidade e morbidade com relação ao acidente cerebrovascular. As vantagens dessa técnica dependem da condição geral do paciente na época da cirurgia, da suficiência da função da bomba e da morfologia coronária, bem como da experiência do cirurgião.

Background Invasive meningococcal disease is a significant cause of mortality and morbidity in the UK. Administration of chemoprophylaxis to close contacts reduces the risk of a secondary case. However, unnecessary chemoprophylaxis may be associated with adverse reactions, increased antibiotic resistance and removal of organisms, such as Neisseria lactamica, which help to protect against meningococcal disease. Limited evidence exists to suggest that overuse of chemoprophylaxis may occur. This study aimed to evaluate prescribing of chemoprophylaxis for contacts of meningococcal disease by general practitioners and hospital staff. Methods Retrospective case note review of cases of meningococcal disease was conducted in one health district from 1st September 1997 to 31st August 1999. Routine hospital and general practitioner prescribing data was searched for chemoprophylactic prescriptions of rifampicin and ciprofloxacin. A questionnaire of general practitioners was undertaken to obtain more detailed information. Results Prescribing by hospital doctors was in line with recommendations by the Consultant for Communicable Disease Control. General practitioners prescribed 118% more chemoprophylaxis than was recommended. Size of practice and training status did not affect the level of additional prescribing, but there were significant differences by geographical area. The highest levels of prescribing occurred in areas with high disease rates and associated publicity. However, some true close contacts did not appear to receive prophylaxis. Conclusions Receipt of chemoprophylaxis is affected by a series of patient, doctor and community interactions. High publicity appears to increase demand for prophylaxis. Some true contacts do not receive appropriate chemoprophylaxis and are left at an unnecessarily increased risk.

Mr Thakore and colleagues (March 2002 JRSM1) conclude that 55% of calls for emergency ambulances did not merit an immediate response. As they acknowledge, the design of the study was not ideal. The initial reason for the request was determined from ambulance crew and accident and emergency (A&E) data after the patient had been seen. This will almost inevitably introduce bias when applying the triage criteria, and the assessment should have been blinded. Also, it is much easier to make such determinations in hindsight, with additional time and clinical information, than when faced with a real call when one has to consider the consequences of the decision reached. It is surprising that this paper makes no reference to priority-based dispatch systems, such as the Advanced Medical Priority Dispatch System (AMPDS), as these are currently used by most ambulance services in the UK. These systems have been shown to have a low risk of serious under-prioritization of life-threatening episodes2. However, work that we have undertaken in Nottingham suggests that they may not be very effective in predicting low-priority 999 calls3. The NHS Executive has stressed the importance of developing telephone prioritization systems that will free ambulance services from having to respond to ‘patients who dialled 999 but who do not need emergency care’4. We believe this may be difficult to achieve. Appropriate and effective telephone triage on non-emergency 999 calls requires a greater understanding of the relationship between the initial telephone assessment by ambulance control and the subsequent outcome of the individual call. Without these data we will not be able to ensure that such a system could operate safely and we endorse the authors' views that prospective studies are essential to assess the feasibility of accurately identifying lower priority calls.

Granular cell myoblastoma is an uncommon tumor in the respiratory tract. It usually occurs in the tongue, skin, breast, or subcutaneous tissue. When it occurs in the respiratory tract, it is usually located in the bronchus or larynx. Primary tracheal location is rare with only nine such cases reported in the literature. This report describes a 26-year-old woman with granular cell myoblastoma of the trachea. She presented with a four-year history of bronchial asthma. The tumor was surgically excised by tracheal resection and reconstruction. The patient has remained well and free of obstructive airway symptoms, without recurrence of the tumor for more than one year.

Ten patients with acromegaly, six with active acromegaly and four with inactive acromegaly were studied with regard to the possible relationship between aldosterone metabolism and hypertension. It was noted that tetrahydroaldosterone-3-glucuronide levels were highest in those cases which exhibited the highest prolactin levels. It was in these cases that hypertension was present and they were active as judged by clinical and biochemical parameters. On administration of bromocryptine there was a reduction of tetrahydroaldosterone-3-glucuronide, prolactin and also a significant reduction of blood pressure. The significance of these results is discussed.

Ten patients with hypertension and obesity were studied during a program of weight loss on an unrestricted sodium diet. The study showed that weight loss during the ten month period was accompanied by a significant decrease in urinary aldosterone, tetrahydroaldosterone -3-glucuronide and plasma renin activity values. It was also demonstrated that successful reduction in body weight was associated with a reduction in blood pressure. It is postulated that blood pressure reduction in obese patients during weight reduction may depend on decreases in aldosterone and plasma renin activity. The reduction in levels of tetrahydroal-dosterone-3-glucuronide is due to an energy related depression of the glucuronidation process caused by carbohydrate deficiency. It is postulated that the lowered rate of metabolism of aldosterone as measured by the diminished formation of the metabolite tetrahydroaldosterone-3-glucuronide is an important determinant of blood pressure status during weight reduction.

Summary Two cases are described who developed epileptic seizures whilst taking maprotiline hydrochloride in therapeutic dosage. In both cases the electroencephalogram was normal and the fits stopped on withdrawal of the drug.

Summary Two cases of severe thyrotoxicosis are described. They both exhibited choreo-athetoid movements which were abolished by successful treatment of the thyrotoxicosis. It is suggested that the tremor of mild thyrotoxicosis is one end of a spectrum at which choreo-athetosis is at the most severe end. A tentative explanation of this hypothesis is given in the discussion.

Out of 102 patients with cardiac infarction admitted to the coronary care unit at this hospital and not treated with anticoagulants 30 (29%) developed isotopic evidence of deep vein thrombosis. Of the 65 smokers only 7 (11%) developed a deep vein thrombosis, whereas of the 37 non-smokers 23 (62%) developed a deep vein thrombosis. This difference is highly significant (P < 0·00001).

A case of aspiration pneumonia due to incoordination of swallowing is described. Its aetiology lies in the myopathy of thyrotoxicosis and a tentative hypothesis as to its causation is suggested.