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Invasive infection with the opportunistic fungus Aspergillus fumigatus predominantly affects people with impaired cell mediated immunity. The case of a 31 year old woman with no identified cause for immunosuppression who presented with severe refractory aspergillosis of the paranasal sinuses is reported. She subsequently developed clinical and molecular evidence of mitochondrial encephalomyopathy with lactic acidosis and stroke-like events (MELAS) syndrome. It is proposed that MELAS syndrome may represent an unusual risk factor for the development of invasive aspergillosis and mechanisms are supported by which mitochondrial dysfunction may predispose to this. [ABSTRACT FROM AUTHOR]

Background: Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify.Methods: SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748.Findings: For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1.57 [95% CI 1.19-2.08]), but there was no significant difference between valproate and lamotrigine (1.25 [0.94-1.68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1.55 [1.07-2.24] and topiramate (1.89 [1.32-2.70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0.76 [0.62-0.94]), and for the subgroup with an idiopathic generalised epilepsy 0.68 (0.53-0.89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy.Interpretation: Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered. [ABSTRACT FROM AUTHOR]

Background: Carbamazepine is widely accepted as a drug of first choice for patients with partial onset seizures. Several newer drugs possess efficacy against these seizure types but previous randomised controlled trials have failed to inform a choice between these drugs. We aimed to assess efficacy with regards to longer-term outcomes, quality of life, and health economic outcomes.Methods: SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm A recruited 1721 patients for whom carbamazepine was deemed to be standard treatment, and they were randomly assigned to receive carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate. Primary outcomes were time to treatment failure, and time to 12-months remission, and assessment was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748.Findings: For time to treatment failure, lamotrigine was significantly better than carbamazepine (hazard ratio [HR] 0.78 [95% CI 0.63-0.97]), gabapentin (0.65 [0.52-0.80]), and topiramate (0.64 [0.52-0.79]), and had a non-significant advantage compared with oxcarbazepine (1.15 [0.86-1.54]). For time to 12-month remission carbamazepine was significantly better than gabapentin (0.75 [0.63-0.90]), and estimates suggest a non-significant advantage for carbamazepine against lamotrigine (0.91 [0.77-1.09]), topiramate (0.86 [0.72-1.03]), and oxcarbazepine (0.92 [0.73-1.18]). In a per-protocol analysis, at 2 and 4 years the difference (95% CI) in the proportion achieving a 12-month remission (lamotrigine-carbamazepine) is 0 (-8 to 7) and 5 (-3 to 12), suggesting non-inferiority of lamotrigine compared with carbamazepine.Interpretation: Lamotrigine is clinically better than carbamazepine, the standard drug treatment, for time to treatment failure outcomes and is therefore a cost-effective alternative for patients diagnosed with partial onset seizures. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review discusses the epidemiology of food insecurity (FI) and its consequences in children with congenital heart disease. We aimed to highlight current interventions to screen and address food insecurity in the context of pediatric cardiology and to offer strategies for providers to engage in this meaningful work., Recent Findings: Food insecurity is consistently associated with poor health outcomes in children. In the United States, 17.3% of households with children experience FI. Nonwhite and single-parent families are disproportionately affected. Interestingly, because of a low-quality diet, FI is associated with childhood obesity, putting affected children at increased risk for cardiovascular morbidity and mortality over time. Children with congenital heart disease are susceptible to poor outcomes due to unique altered metabolic demands, increased risk for growth impairment, frequent need for specialized feeding regimens, and additional morbidity associated with heart surgery in underweight children., Summary: Today, the burden of screening for FI is most commonly placed on general pediatricians. Considering the importance of nutrition to cardiovascular health and general wellbeing, and the ease with which screening can be performed, pediatric cardiologists and other subspecialists should take a more active role in FI screening., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Tilt testing can help to diagnose unexplained syncope, by precipitating an episode during cardiac monitoring. The Italian protocol, now most widely used, involves giving sublingual nitroglycerine after 15 min, while monitoring beat-to-beat blood pressure (BP) and recording on video. Tilt testing is time-consuming but it is clinically useful and can guide therapy. Complications are rare. Syncope types include vasovagal syncope where BP falls after >3 min of tilt-up and later the heart rate falls; classic orthostatic hypotension where there is an immediate, progressive BP fall with minimal heart rate change; delayed orthostatic hypotension with a late BP fall after a stable phase but little or no heart rate rise; psychogenic pseudosyncope with apparent loss of consciousness, but no BP fall and a moderate heart rate rise; and postural orthostatic tachycardia syndrome where there is a significant heart rate rise but no BP fall., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Following hyperacute management after traumatic brain injury (TBI), most patients receive treatment which is inadequate or inappropriate, and delayed. This results in suboptimal rehabilitation outcome and avoidable detrimental chronic effects on patients' recovery. This worsens long-term disability, and magnifies costs to the individual and society. We believe that accurate diagnosis (at the level of pathology, impairment and function) of the causes of disability is a prerequisite for appropriate care and for accessing effective rehabilitation. An expert-led, integrated care pathway is needed to deliver accurate and timely diagnosis and optimal treatment at all stages during a TBI patient's care.We propose the introduction of a specialist interdisciplinary traumatic brain injury team, led by a neurosciences-trained brain injury consultant. This team would engage acutely and for a longer term after TBI to provide accurate diagnoses, which guides subsequent management and rehabilitation. This approach would also encourage more efficient collaboration between research and the clinic. We propose that the current major trauma network is leveraged to introduce and evaluate this proposal. Improvements to patient outcomes through this approach would lead to reduced personal, societal and economic impact of TBI., (© Royal College of Physicians 2021. All rights reserved.)

Background: Ketogenic diets (KDs) are high in fat and low in carbohydrates and have been suggested to reduce seizure frequency in people with epilepsy. Such diets may be beneficial for children with drug-resistant epilepsy. This is an update of a review first published in 2003, and last updated in 2018., Objectives: To assess the effects of ketogenic diets for people with drug-resistant epilepsy., Search Methods: For this update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 26 April 2019) on 29 April 2019. The Cochrane Register of Studies includes the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), and randomised controlled trials (RCTs) from Embase, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We imposed no language restrictions. We checked the reference lists of retrieved studies for additional relevant studies., Selection Criteria: RCTs or quasi-RCTs of KDs for people of any age with drug-resistant epilepsy., Data Collection and Analysis: Two review authors independently applied predefined criteria to extract data and evaluated study quality. We assessed the outcomes: seizure freedom, seizure reduction (50% or greater reduction in seizure frequency), adverse effects, cognition and behaviour, quality of life, and attrition rate. We incorporated a meta-analysis. We utilised an intention-to-treat (ITT) population for all primary analyses. We presented the results as risk ratios (RRs) with 95% confidence intervals (CIs)., Main Results: We identified 13 studies with 932 participants; 711 children (4 months to 18 years) and 221 adults (16 years and over). We assessed all 13 studies to be at high risk of performance and detection bias, due to lack of blinding. Assessments varied from low to high risk of bias for all other domains. We rated the evidence for all outcomes as low to very low certainty. Ketogenic diets versus usual care for children Seizure freedom (RR 3.16, 95% CI 1.20 to 8.35; P = 0.02; 4 studies, 385 participants; very low-certainty evidence) and seizure reduction (RR 5.80, 95% CI 3.48 to 9.65; P < 0.001; 4 studies, 385 participants; low-certainty evidence) favoured KDs (including: classic KD, medium-chain triglyceride (MCT) KD combined, MCT KD only, simplified modified Atkins diet (MAD) compared to usual care for children. We are not confident that these estimated effects are accurate. The most commonly reported adverse effects were vomiting, constipation and diarrhoea for both the intervention and usual care group, but the true effect could be substantially different (low-certainty evidence). Ketogenic diet versus usual care for adults In adults, no participants experienced seizure freedom. Seizure reduction favoured KDs (MAD only) over usual care but, again, we are not confident that the effect estimated is accurate (RR 5.03, 95% CI 0.26 to 97.68; P = 0.29; 2 studies, 141 participants; very low-certainty evidence). Adults receiving MAD most commonly reported vomiting, constipation and diarrhoea (very low-certainty evidence). One study reported a reduction in body mass index (BMI) plus increased cholesterol in the MAD group. The other reported weight loss. The true effect could be substantially different to that reported. Ketogenic diet versus ketogenic diet for children Up to 55% of children achieved seizure freedom with a classical 4:1 KD after three months whilst up to 85% of children achieved seizure reduction (very low-certainty evidence). One trial reported a greater incidence of seizure reduction with gradual-onset KD, as opposed to fasting-onset KD. Up to 25% of children were seizure free with MAD and up to 60% achieved seizure reduction. Up to 25% of children became seizure free with MAD and up to 60% experienced seizure reduction. One study used a simplified MAD (sMAD) and reported that 15% of children gained seizure freedom rates and 56% achieved seizure reduction. We judged all the evidence described as very low certainty, thus we are very unsure whether the results are accurate. The most commonly reported adverse effects were vomiting, constipation and diarrhoea (5 studies, very low-certainty evidence). Two studies reported weight loss. One stated that weight loss and gastrointestinal disturbances were more frequent, with 4:1 versus 3:1 KD, whilst one reported no difference in weight loss with 20 mg/d versus 10 mg/d carbohydrates. In one study, there was a higher incidence of hypercalcuria amongst children receiving classic KD compared to MAD. All effects described are unlikely to be accurate. Ketogenic diet versus ketogenic diet for adults One study randomised 80 adults (aged 18 years and over) to either MAD plus KetoCal during the first month with MAD alone for the second month, or MAD alone for the first month followed by MAD plus KetoCal for the second month. No adults achieved seizure freedom. More adults achieved seizure reduction at one month with MAD alone (42.5%) compared to MAD plus KetoCal (32.5%), however, by three months only 10% of adults in both groups maintained seizure reduction. The evidence for both outcomes was of very low certainty; we are very uncertain whether the effects are accurate. Constipation was more frequently reported in the MAD plus KetoCal group (17.5%) compared to the MAD only group (5%) (1 study, very low-certainty evidence). Diarrhoea and increase/change in seizure pattern/semiology were also commonly reported (17.5% to 20% of participants). The true effects of the diets could be substantially different to that reported., Authors' Conclusions: The evidence suggests that KDs could demonstrate effectiveness in children with drug-resistant epilepsy, however, the evidence for the use of KDs in adults remains uncertain. We identified a limited number of studies which all had small sample sizes. Due to the associated risk of bias and imprecision caused by small study populations, the evidence for the use of KDs was of low to very low certainty. More palatable but related diets, such as the MAD, may have a similar effect on seizure control as the classical KD, but could be associated with fewer adverse effects. This assumption requires more investigation. For people who have drug-resistant epilepsy or who are unsuitable for surgical intervention, KDs remain a valid option. Further research is required, particularly for adults with drug-resistant epilepsy., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Ketogenic diets (KDs), being high in fat and low in carbohydrates, have been suggested to reduce seizure frequency in people with epilepsy. At present, such diets are mainly recommended for children who continue to have seizures despite treatment with antiepileptic drugs (AEDs) (drug-resistant epilepsy). Recently, there has been interest in less restrictive KDs, including the modified Atkins diet (MAD), and the use of these diets has extended into adult practice. This is an update of a review first published in 2003 and last updated in 2016., Objectives: To assess the effects of KDs for drug-resistant epilepsy by reviewing the evidence from randomised controlled trials., Search Methods: For the latest update we searched the Cochrane Epilepsy Group's Specialized Register (11 April 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 11 April 2017), MEDLINE (Ovid, 11 April 2017), ClinicalTrials.gov (11 April 2017) and the WHO International Clinical Trials Registry Platform (ICTRP, 11 April 2017). We imposed no language restrictions. We checked the reference lists of retrieved studies for additional reports of relevant studies., Selection Criteria: Randomised controlled trials or quasi-randomised controlled trials of ketogenic diets for people with drug-resistant epilepsy., Data Collection and Analysis: Two review authors independently applied predefined criteria to extract data and assessed study quality., Main Results: We identified 11 randomised controlled trials (RCTs) that generated 15 publications.All trials applied an intention-to-treat analysis with varied randomisation methods. The 11 studies recruited 778 patients; 712 children and adolescents and 66 adults. We assessed all 11 studies to be at low to unclear risk of bias for the following domains: random sequence generation, allocation concealment and selective reporting. For the other domains (blinding, incomplete outcome data, other bias) assessments were varied (low, unclear and high risk of bias). We could not conduct a meta-analysis due to the heterogeneity of the studies and the quality of the evidence was low to very low (GRADE ratings).Reported rates of seizure freedom reached as high as 55% in a classical 4:1 KD group after three months and reported rates of seizure reduction reached as high as 85% in a classical 4:1 KD group after three months (GRADE rating low).One trial found no significant difference between the fasting-onset and gradual-onset KD for rates of seizure freedom, and reported a greater rate of seizure reduction in the gradual-onset KD group.Studies assessing the efficacy of the MAD reported seizure freedom rates of up to 25% and seizure reduction rates of up to 60% in children. One study used a simplified MAD (sMAD) and reported seizure freedom rates of 15% and seizure reduction rates of 56% in children. One study utilised a MAD in adults and reported seizure reduction rates of 35%, but no patients became seizure free (GRADE rating low).Adverse effects of the dietary interventions were experienced in all studies. The most commonly reported adverse effects were gastrointestinal syndromes. It was common that adverse effects were the reason for participants dropping out of trials (GRADE rating low). Other reasons for dropout included lack of efficacy and non-acceptance of the diet (GRADE rating low).Although there was some evidence for greater antiepileptic efficacy for a classical 4:1 KD over lower ratios, the classical 4:1 KD was consistently associated with more adverse effects.One study assessed the effect of dietary interventions on quality of life, cognition and behavioural functioning, reporting participants in the KD group to be more active, more productive and less anxious after four months, compared to the control group. However, no significant difference was found in quality-adjusted life years (QALYs) between the KD group and control group at four or 16 months (GRADE rating very low)., Authors' Conclusions: The RCTs discussed in this review show promising results for the use of KDs in epilepsy. However, the limited number of studies, small sample sizes and the limited studies in adults, resulted in a low to very low overall quality of evidence.There were adverse effects within all of the studies and for all KD variations, such as short-term gastrointestinal-related disturbances and increased cholesterol. However, study periods were short, therefore the long-term risks associated with these adverse effects is unknown. Attrition rates remained a problem with all KDs and across all studies; reasons for this being lack of observed efficacy and dietary tolerance.Only one study reported the use of KDs in adults with epilepsy; therefore further research would be of benefit.Other more palatable but related diets, such as the MAD, may have a similar effect on seizure control as the classical KD, but this assumption requires more investigation. For people who have medically intractable epilepsy or people who are not suitable for surgical intervention, KDs remain a valid option; however, further research is required.

Sarcoidosis is an idiopathic multisystem granulomatous disorder of unknown cause. Nervous system involvement (central and/or peripheral) is uncommon, developing in 5%-10%. The presenting symptoms are variable, reflecting the level of involvement, and frequently fluctuate and progress. Diagnosing neurosarcoidosis in people with previously confirmed systemic disease may be relatively straightforward, but diagnosing primary neurosarcoidosis is challenging. Managing neurosarcoidosis is primarily consensus based; corticosteroid is its mainstay, alongside corticosteroid-sparing agents and emerging novel therapies. We describe a 39-year-old woman who presented with cranial neuropathy. Serial imaging, cerebrospinal fluid sampling and tissue biopsy gave a diagnosis of probable neurosarcoidosis. Her clinical course was complicated by intracerebral haemorrhage following intravenous corticosteroids for neurological relapse. This is a very rare complication of neurosarcoidosis; we discuss its possible causes and suggest ways to reduce its risk., Competing Interests: Competing interests: PNC was an expert advisor and one of the authors of the National Institute of Health and Care Excellence evidence review of infliximab., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: The ketogenic diet (KD), being high in fat and low in carbohydrates, has been suggested to reduce seizure frequency. It is currently used mainly for children who continue to have seizures despite treatment with antiepileptic drugs. Recently, there has been interest in less restrictive KDs including the modified Atkins diet (MAD) and the use of these diets has extended into adult practice., Objectives: To review the evidence for efficacy and tolerability from randomised controlled trials regarding the effects of KD and similar diets., Search Methods: We searched the Cochrane Epilepsy Group's Specialized Register (30 March 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 30 March 2015), MEDLINE (Ovid, 30 March 2015), ClinicalTrials.gov (30 March 2015) and the WHO International Clinical Trials Registry Platform (ICTRP, 30 March 2015). We imposed no language restrictions. We checked the reference lists of retrieved studies for additional reports of relevant studies., Selection Criteria: Studies of KDs and similar diets for people with epilepsy., Data Collection and Analysis: Two review authors independently applied pre-defined criteria to extract data and assessed study quality., Main Results: We identified seven randomised controlled trials that generated eight publications.All trials applied an intention-to-treat analysis with varied randomisation methods. The seven studies recruited 427 children and adolescents and no adults. We could not conduct a meta-analysis due to the heterogeneity of the studies.Reported rates of seizure freedom reached as high as 55% in a 4 : 1 KD group after three months and reported rates of seizure reduction reached as high as 85% in a 4 : 1 KD group after three months.One trial found no significant difference between the fasting-onset and gradual-onset KD for rates of seizure freedom and reported a greater rate of seizure reduction in the gradual-onset KD group.Studies assessing the efficacy of the MAD reported seizure freedom rates of up to 10% and seizure reduction rates of up to 60%. One study compared the MAD to a 4 : 1 KD, but did not report rates of seizure freedom or seizure reduction.Adverse effects were fairly consistent across different dietary interventions. The most commonly reported adverse effects were gastrointestinal syndromes. It was common that adverse effects were the reason for participants dropping out of trials. Other reasons for drop-out included lack of efficacy and non-acceptance of the diet.Although there was some evidence for greater antiepileptic efficacy for a 4 : 1 KD over lower ratios, the 4 : 1 KD was consistently associated with more adverse effects.No studies assessed the effect of dietary interventions on quality of life, or cognitive or behavioural functioning., Authors' Conclusions: The randomised controlled trials discussed in this review show promising results for the use of KDs in epilepsy. However, the limited number of studies, small sample sizes and a sole paediatric population resulted in a poor overall quality of evidence.There were adverse effects within all of the studies and for all KD variations, such as short-term gastrointestinal-related disturbances, to longer-term cardiovascular complications. Attrition rates remained a problem with all KDs and across all studies, reasons for this being lack of observed efficacy and dietary tolerance.There was a lack of evidence to support the clinical use of KD in adults with epilepsy, therefore, further research would be of benefit.Other more palatable but related diets, such as the MAD ketogenic diet, may have a similar effect on seizure control as classical KD but this assumption requires more investigation. For people who have medically intractable epilepsy or people who are not suitable for surgical intervention, a KD remains a valid option; however, further research is required.

Epidemiologic studies clearly document the public health burden of sudden unexpected death in epilepsy (SUDEP). Clinical and experimental studies have uncovered dynamic cardiorespiratory dysfunction, both interictally and at the time of sudden death due to epilepsy. Genetic analyses in humans and in model systems have facilitated our current molecular understanding of SUDEP. Many discoveries have been informed by progress in the field of sudden cardiac death and sudden infant death syndrome. It is becoming apparent that SUDEP genomic complexity parallels that of sudden cardiac death, and that there is a pauci1ty of analytically useful postmortem material. Because many challenges remain, future progress in SUDEP research, molecular diagnostics, and prevention rests in international, collaborative, and transdisciplinary dialogue in human and experimental translational research of sudden death., Competing Interests: of Conflicts of Interest None of the remaining authors has any conflicts of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Background: The ketogenic diet, being high in fat and low in carbohydrates, has been suggested to reduce seizure frequency. It is currently used mainly for children who continue to have seizures despite treatment with antiepileptic drugs. Recently there has been interest in less restrictive ketogenic diets including the Atkins diet and the use of these diets has extended into adult practice., Objectives: To review the evidence from randomised controlled trials regarding the effects of ketogenic and similar diets., Search Methods: We searched the Cochrane Epilepsy Group's Specialised Register (June 2011), the Cochrane Central Register of Controlled Trials (CENTRAL 2011, Issue 2 of 4), MEDLINE (1948 to May week 4, 2011) and EMBASE (1980 to March 2003). No language restrictions were imposed. We checked the reference lists of retrieved studies for additional reports of relevant studies., Selection Criteria: Studies of ketogenic diets and similar diets for people with epilepsy., Data Collection and Analysis: Three review authors independently applied pre-defined criteria to extract data and also assessed study quality., Main Results: We identified four randomised controlled trials which generated five publications.These included Kossoff 2007, Bergqvist 2005, Seo 2007, Neal 2008 and Neal 2009. All trials applied the intention-to-treat analysis with varied randomisation method. The four studies recruited a total of 289 children and adolescents and no adults. Meta-analysis could not be conducted due to heterogeneity of the studies. Seven prospective studies and four retrospective studies were also identified., Authors' Conclusions: Our review update included data from four new randomised studies of the ketogenic diet. Although none were blinded, some were of good quality. These studies suggest that in children, the ketogenic diet results in short to medium term benefits in seizure control, the effects of which are comparable to modern antiepileptic drugs. However, one study of long term outcome reports a high attrition rate for the diet. This would suggest that many children find the diet difficult to tolerate. The main reasons for drop-outs in the included studies included gastrointestinal side effects and dislike for the diet.We found just three studies on the use of the diet in adults and none of these were randomised. There has been less research involving other diets. We found one randomised study of reasonable quality of the Atkins diet. This study showed similar benefits in seizure control with a less restrictive diet.For those with medically intractable epilepsy or those in whom surgery is unsuitable, a ketogenic diet could improve seizure control, but tolerability is poor. One observational study suggested that the Atkins diet may have a similar effect on seizure control, but this requires more investigation.

Description: Transient loss of consciousness (TLoC) is common and often leads to incorrect diagnosis, unnecessary investigation, or inappropriate choice of specialist referral. In August 2010, the National Institute for Health and Clinical Excellence published a guideline that addressed the initial assessment of and most appropriate specialist referral for persons who have experienced TLoC. The guideline focused on correct diagnosis and relevant specialist referral and did not make treatment recommendations. This synopsis describes the principal recommendations concerning assessment and referral of a patient with TLoC., Methods: The National Clinical Guideline Centre developed the guidelines by using the standard methodology of the National Institute for Health and Clinical Excellence. A multidisciplinary guideline panel generated review questions, discussed evidence, and formulated recommendations. The panel included a technical team from the National Clinical Guideline Centre, who reviewed and graded all relevant evidence identified from literature searches published in English up to November 2009 and performed health-economic modeling. Both guideline development and final modifications were informed by comments from stakeholders and the public., Recommendations: The panel made clear recommendations regarding the assessment of a person after TLoC, which emphasized the importance of clinical reasoning in diagnosis. Persons with uncomplicated faint, situational syncope, or orthostatic hypotension should receive electrocardiography but do not otherwise require immediate further investigation or specialist referral. Persons with features that suggest epilepsy should be referred for specialist neurologic assessment; brief seizure-like activity was recognized as a common occurrence during syncope that should not be regarded as indicating epilepsy. Persons with a suspected cardiac cause for TLoC or in whom TLoC is unexplained after initial assessment should receive specialist cardiovascular assessment. Guidance was provided on the appropriate choices of cardiovascular investigation, according to the presenting clinical circumstances.

Scalp lacerations are frequently seen in both living trauma victims and at post-mortem examination. In clinical circles, it is well known that even "trivial" lacerations of blood-rich areas such as the scalp may bleed profusely and persistently.It is less well known, however, that hemorrhage even from simple scalp lacerations may be fatal. We present seven cases in which hemorrhage from simple scalp lacerations was considered to be the principle cause of death.Chronic alcohol misuse, alcoholic liver disease, and the co-existence of other pathologies such as ischemic heart disease were frequently contributory factors.

A previously healthy 11 year old boy died unexpectedly after a rapid course of progressive pneumonia. Postmortem microbiology and histopathology suggested an underlying diagnosis of chronic granulomatous disease. This was confirmed by neutrophil oxidative burst and gene mutation analysis of other family members, one of whom benefited from early bone marrow transplantation.

Commotio cordis is a recognised cause of sudden death in which an apparently minor blow to the chest causes ventricular fibrillation and cardiac arrest. It is best known for causing death during games of youth baseball in the United States, but individual cases have been recorded as a result of a wide range of activities, principally sporting. The underlying biochemical and mechano-electric causes have been well documented. However, there are few reported cases where commotio cordis is implicated as the cause of death in homicide cases. We present three cases from the north-east of England where an assault caused death by this mechanism.

The management of acute optic neuritis by neurologists and ophthalmologists in the north west of England was assessed in the light of the Optic Neuritis Treatment Trial (ONTT) recommendations. A questionnaire on a fictitious case of typical unilateral optic neuritis was mailed to all consultant ophthalmologists and neurologists working in the North West and Merseyside Health Authorities. They were then asked to comment on management of the case. Fifty two out of 86 ophthalmologists and 20 out of 28 neurologists replied. The overall response rate was 63%. Sixty five per cent of neurologists and 46% of ophthalmologists would investigate a typical case of acute optic neuritis further. Forty six per cent of neurologists and 36% of ophthalmologists were likely to arrange MRI of the brain or orbit. Significantly more neurologists (55%) than ophthalmologists (9%) chose to treat with intravenous methylprednisolone (p<0.005). Significantly more ophthalmologists (64%) than neurologists (32%) chose not to give steroids (p<0.025). Oral prednisolone alone was rarely selected for treatment. Respondents were more likely to discuss multiple sclerosis with the referring doctor than with the patient. Only 32% of ophthalmologists and 20% of neurologists would clearly mention the possibility of improvement to the patient. Clear differences in practice between ophthalmologists and neurologists remain. A consensus on practice guidelines on the issues raised might be useful.

Both in vitro and in vivo studies of scavenger receptor class B type I (SR-BI) have implicated it as a likely participant in the metabolism of HDL cholesterol. To investigate the effect of SR-BI on atherogenesis, we examined two lines of SR-BI transgenic mice with high (10-fold increases) and low (2-fold increases) SR-BI expression in an inbred mouse background hemizygous for a human apolipoprotein (apo) B transgene. Unlike non-HDL cholesterol levels that minimally differed in the various groups of animals, HDL cholesterol levels were inversely related to SR-BI expression. Mice with the low expression SR-BI transgene had a 50% reduction in HDL cholesterol, whereas the high expression SR-BI transgene was associated with 2-fold decreases in HDL cholesterol as well as dramatic alterations in HDL composition and size including the near absence of alpha-migrating particles as determined by two-dimensional electrophoresis. The low expression SR-BI/apo B transgenics had more than a 2-fold decrease in the development of diet-induced fatty streak lesions compared with the apo B transgenics (4448 +/- 1908 micrometer(2)/aorta to 10133 +/- 4035 micrometer (2)/aorta; p < 0.001), whereas the high expression SR-BI/apo B transgenics had an atherogenic response similar to that of the apo B transgenics (14692 +/- 7238 micrometer(2)/aorta) but 3-fold greater than the low SR-BI/apo B mice (p < 0.001). The prominent anti-atherogenic effect of moderate SR-BI expression provides in vivo support for the hypothesis that HDL functions to inhibit atherogenesis through its interactions with SR-BI in facilitating reverse cholesterol transport. The failure of the high SR-BI/apo B transgenics to have similar or even greater reductions in atherogenesis suggests that the changes resulting from extremely high SR-BI expression including dramatic changes in lipoproteins may have both pro- and anti-atherogenic consequences, illustrating the complexity of the relationship between SR-BI and atherogenesis.

Recent studies have indicated that the scavenger receptor class B type I (SR-BI) may play an important role in the uptake of high density lipoprotein (HDL) cholesteryl ester in liver and steroidogenic tissues. To investigate the in vivo effects of liver-specific SR-BI overexpression on lipid metabolism, we created several lines of SR-BI transgenic mice with an SR-BI genomic construct where the SR-BI promoter region had been replaced by the apolipoprotein (apo)A-I promoter. The effect of constitutively increased SR-BI expression on plasma HDL and non-HDL lipoproteins and apolipoproteins was characterized. There was an inverse correlation between SR-BI expression and apoA-I and HDL cholesterol levels in transgenic mice fed either mouse chow or a diet high in fat and cholesterol. An unexpected finding in the SR-BI transgenic mice was the dramatic impact of the SR-BI transgene on non-HDL cholesterol and apoB whose levels were also inversely correlated with SR-BI expression. Consistent with the decrease in plasma HDL and non-HDL cholesterol was an accelerated clearance of HDL, non-HDL, and their major associated apolipoproteins in the transgenics compared with control animals. These in vivo studies of the effect of SR-BI overexpression on plasma lipoproteins support the previously proposed hypothesis that SR-BI accelerates the metabolism of HDL and also highlight the capacity of this receptor to participate in the metabolism of non-HDL lipoproteins.

We have previously shown that the neurovascular anatomy and length of the long head of biceps femoris (LHBF) is suitable for its possible use in the creation of a dynamic perianal myoplasty to restore faecal continence. If intramuscular arterioarterial anastomoses exist between a muscle's vascular pedicles then the delay procedure, i.e. ligating the vascular pedicles to the transposed section of the muscle, 4-6 wk before transposition, can be used to improve blood flow to the distal part of the transposed muscle. The intramuscular arterial anatomy of 20 biceps femoris muscles was shown by dissection (14) or radiographically (6). The mean entry point of the upper major vascular pedicle to the LHBF was 12 cm (S.D. 3.3) and the mean length of the LHBF was 36.8 cm (S.D. 1.8). Therefore the ratio between upper major vascular pedicle entry point and muscle length in 95% of specimens was 0.33 (0.2). In the present study intramuscular arterioarterial anastomoses were found between the arterial pedicles to the nontransposed and transposed sections of the LHBF and between the long and short heads of this muscle. Using the delay procedure would therefore theoretically allow the intramuscular arterioarterial anastomoses between the arterial pedicle to the nontransposed and transposed sections of the LHBF to open up enhancing blood flow to the distal part of the myoplasty.

Two cases of Coxsackie B viral meningo-encephalitis in pregnant women are described. Both patients recovered well and delivered healthy babies, but because of delay in establishing the aetiology of their infections both mothers, and one child, received acyclovir therapy. The differential diagnosis of non-pyogenic meningo-encephalitis in late pregnancy can present particular problems: clinicians caring for such women should remain aware of the potential for enteroviral infection in their patients, and take appropriate action to prevent cross-infection in neonatal units., (1996 Lippincott Williams & Wilkins.)

Using PCR and restriction digest analysis, the frequencies of the variant cytochrome P450 debrisoquine hydroxylase CYP2D6 alleles CYP2D6(A) and CYP2D6(B) were investigated in 50 patients with amyotrophic lateral sclerosis (ALS) and 13 patients with ALS and frontotemporal dementia (FTD) and compared to those frequencies in patients with FTD alone and Alzheimer's disease (AD). The CYP2D6(T) allelic frequency was also assessed in ALS and ALS + FTD. Although the frequency of a poor metabolizer genotype was not increased in any disease group, there was a significant increase in the frequency of the CYP2D6(B) allele in the ALS patient group. This suggests that possession of a CYP2D6(B) allele may be a risk factor for the development of ALS, possibly conferring a 'gain of function' imposed by the mutation or reflecting linkage disequilibrium to a nearby susceptibility gene.

Fronto-temporal dementia is a clinical syndrome with a number of pathological substrates, including frontal lobe degeneration, Pick's disease, and motor neuron disease with dementia; it also includes patients with a primary progressive language disorder. Twenty-four brains were examined, using immunohistochemistry for glial fibrillary acidic protein (GFAP) and ferritin. Five cases of fronto-temporal dementia with a Pick's disease type of histology showed marked cortical gliosis with striking microglial activity in both grey and white matter. In seven cases of frontal lobe degeneration, there was little gliosis and microglial activity was confined largely to the white matter; two of the seven cases of progressive language disorder showed similar changes to frontal lobe degeneration. Five cases of motor neuron disease with dementia showed both astrocytic and microglial activity within the white matter. We suggest that cases of fronto-temporal dementia due to Pick type histology may result from a process which primarily involves grey matter, whereas cases of frontal lobe degeneration might represent a disorder of white matter.

Objective: We investigated the use of immunostaining with antibodies to tau, ubiquitin, and alpha B-crystallin in defining a protocol for the staged neuropathologic examination of brains from patients with a progressive frontotemporal dementia., Design: Brains obtained from 50 patients dying with the clinical diagnosis of frontotemporal dementia were examined histopathologically to define pathologic distinctions., Setting: Two university hospital neuropathology departments., Results: Anti-tau immunostaining defined corticobasal degeneration, Alzheimer's disease, and Pick's disease; antiubiquitin defined motor neuron disease with dementia. The remaining brains have frontal lobe degeneration: the use of alpha B-crystallin immunostaining, on these, to detect ballooned neurons may help to define two groups of patients, one of which we believe may represent a variant of Pick's disease., Conclusion: These findings indicate that immunostaining with these antibodies is essential for the evaluation of frontal dementia.

This study investigates the under-reporting of suicide with particular reference to differences between sex and age groups and the various modes of suicide. The study was performed retrospectively using the files of H M Coroner for South Yorkshire (West) over the years 1985 to 1991. There were 536 deaths judged on the balance of probability to be suicidal in nature. Only 60 per cent of these deaths received a suicide verdict and would therefore register in official suicide statistics. A significantly smaller proportion of females (51.7 per cent) received a suicide verdict than males (64.5 per cent). Of the young females (< 45) 61.7 per cent were given a suicide verdict compared to 46.6 per cent of older females (45+). These differences are explained by different preferences for mode of suicide, in particular for poisoning using solids or liquids. Only 40 per cent of cases within this category received a suicide verdict. Drowning showed an even smaller percentage (24 per cent). Self-immolation (42 per cent) and jumping from a height (51 per cent) were also under-represented. Of these, self-poisoning, drowning and jumping from a height were relatively popular among females. In contrast, common causes of death favoured predominantly by males--hanging and carbon monoxide poisoning--received a high percentage of suicide verdicts (81 per cent and 90 per cent). Thus official suicide statistics produce a distorted view of the suicide population with relative under-reporting of females, particularly older females, and marked under-reporting of some causes of death, notably poisoning using solids or liquids, drowning, self-immolation and jumping from a height.

Prion gene sequence is thought to affect the phenotypic expression of prion disease and the E2 variant of apolipoprotein E (Apo E) can be neuroprotective in dementia. We determined codon 129 of the prion gene and the Apo E variants in Creutzfeldt-Jakob disease (CJD) using PCR and restriction digest. We found a significant correlation between valine at codon 129 of the prion protein gene and the presence of plaque in CJD and a later age of onset in CJD cases possessing the Apo E2 allele. This study provides further evidence that sequence variations in the prion gene can modify disease pathology and the neuroprotection afforded by Apo E2 is not confined to Alzheimer's disease.

The skin affords an excellent model of human carcinogenesis because a variety of lesions from benign tumours to invasive malignancy, with or without metastatic potential, are commonly found, and are accessible to biopsy. To date, few genetic alterations have been observed in skin neoplasia. In this study we have used a recently developed monoclonal antibody (DO7) to examine p53 protein expression in a wide variety of benign and malignant skin lesions. Benign skin lesions were negative, but a significant number of malignant epithelial lesions showed detectable p53; 56% of squamous carcinomas and 42% of basal cell carcinomas were positive. A smaller proportion of dysplastic epithelial lesions were positive (27%), and only 3.6% of malignant melanomas were positive. Thus, although detectable p53 protein is a common occurrence in malignant epithelial lesions, it does not correlate with the malignant phenotype or with metastatic potential. The finding of a lower proportion of positivity in dysplastic lesions, and absence of staining in benign tumours, suggests that p53 mutation may be involved in the progression towards invasive malignancy in human squamous skin lesions.

A case of rhabdomyolysis associated acute renal failure (RM-ARF) occurring as a result of strenuous exercise is presented. Diagnostic renal biopsy was performed. The histological appearances, combined with immunoperoxidase staining for myoglobin, allowed a positive diagnosis of RM-ARF to be made and excluded the possibility of glomerulonephritis. The patient recovered completely after a stormy clinical course.

Histological sections of 102 stromal neoplasms of the gastrointestinal tract occurring in 100 patients have been assessed for 23 clinical and histological parameters and the corresponding paraffin embedded (archival) material processed for flow cytometry. Where possible, information as to clinical presentation and survival was obtained. The only absolute criterion for malignancy was the presence of spread of tumour beyond the organ of origin at the time of diagnosis. Of the remaining tumours (i.e., tumours locally confined at diagnosis), those found incidentally at operation and those of a small size (less than 60 mm diameter) behaved in a generally benign fashion. Of the histological parameters, six correlated with malignant behaviour: high mitotic count, high cellularity, marked nuclear pleomorphism, rounded as opposed to spindle cell shape, bizarre mitoses, and vascular invasion. The presence of DNA aneuploidy as shown by flow cytometry correlated strongly with a poor prognosis (p less than 0.0005). Tumours with a high mitotic count [greater than 9 per 10 high-power fields (hpf) (1.59 mm2)] behaved in an almost uniformly malignant fashion. Those with a low mitotic count [less than 3/10hpf (1.59 mm2)], behaved in a benign fashion apart from one case where no mitoses were discernible yet the tumour metastasised and killed the patient. The intermediate group of tumours (3-9 mitoses per 10 hpf inclusive) were difficult to predict, although the majority behaved in a malignant fashion. Within this group the presence of DNA aneuploidy appeared most useful in predicting prognosis.