Broad anti-pathogen potential of DEAD box RNA helicase eIF4A-targeting rocaglates.

Inhibition of eukaryotic initiation factor 4A has been proposed as a strategy to fight pathogens. Rocaglates exhibit the highest specificities among eIF4A inhibitors, but their anti-pathogenic potential has not been comprehensively assessed across eukaryotes. In silico analysis of the substitution patterns of six eIF4A1 aa residues critical to rocaglate binding, uncovered 35 variants. Molecular docking of eIF4A:RNA:rocaglate complexes, and in vitro thermal shift assays with select recombinantly expressed eIF4A variants, revealed that sensitivity correlated with low inferred binding energies and high melting temperature shifts. In vitro testing with silvestrol validated predicted resistance in Caenorhabditis elegans and Leishmania amazonensis and predicted sensitivity in Aedes sp., Schistosoma mansoni, Trypanosoma brucei, Plasmodium falciparum, and Toxoplasma gondii. Our analysis further revealed the possibility of targeting important insect, plant, animal, and human pathogens with rocaglates. Finally, our findings might help design novel synthetic rocaglate derivatives or alternative eIF4A inhibitors to fight pathogens.

Strong Relationship Between Rapid Auditory Processing and Affective Prosody Recognition Among Adults with High Autistic Traits.

This study investigated whether individuals with high autistic traits rely on psychoacoustic abilities in affective prosody recognition (APR). In 94 college students, Autism Spectrum Quotient (AQ) and psychoacoustic abilities were measured. Results indicated that higher AQ, higher rapid auditory processing (RAP), and maleness were associated with a lower APR accuracy for low-intensity prosodies. There was a strong positive association between RAP and APR for participants with high AQ, whereas low-AQ participants showed no such pattern. The findings suggest a reliance on psychoacoustic abilities as compensatory mechanism for deficits in higher-order processing of emotional signals in social interactions, and imply potential benefits of auditory interventions in improving APR among individuals with high autistic traits.

Multimodal Evidence of Atypical Processing of Eye Gaze and Facial Emotion in Children With Autistic Traits.

According to the shared signal hypothesis (SSH) the impact of facial expressions on emotion processing partially depends on whether the gaze is directed toward or away from the observer. In autism spectrum disorder (ASD) several aspects of face processing have been found to be atypical, including attention to eye gaze and the identification of emotional expressions. However, there is little research on how gaze direction affects emotional expression processing in typically developing (TD) individuals and in those with ASD. This question is investigated here in two multimodal experiments. Experiment 1 required processing eye gaze direction while faces differed in emotional expression. Forty-seven children (aged 9-12 years) participated. Their Autism Diagnostic Observation Schedule (ADOS) scores ranged from 0 to 6 in the experiment. Event-related potentials (ERPs) were sensitive to gaze direction and emotion, but emotion processing did not depend on gaze direction. However, for angry faces the gaze direction effect on the N170 amplitude, as typically observed in TD individuals, diminished with increasing ADOS score. For neutral expressions this correlation was not significant. Experiment 2 required explicit emotion classifications in a facial emotion composite task while eye gaze was manipulated incidentally. A group of 22 children with ASD was compared to a propensity score-matched group of TD children (mean age = 13 years). The same comparison was carried out for a subgroup of nine children with ASD who were less trained in social cognition, according to clinician's report. The ASD group performed overall worse in emotion recognition than the TD group, independently of emotion or gaze direction. However, for disgust expressions, eye tracking data revealed that TD children fixated relatively longer on the eyes of the stimulus face with a direct gaze as compared with averted gaze. In children with ASD we observed no such modulation of fixation behavior as a function of gaze direction. Overall, the present findings from ERPs and eye tracking confirm the hypothesis of an impaired sensitivity to gaze direction in children with ASD or elevated autistic traits, at least for specific emotions. Therefore, we conclude that multimodal investigations of the interaction between emotional processing and stimulus gaze direction are promising to understand the characteristics of individuals differing along the autism trait dimension.

Sex differences in behavioral and brain responses to incongruity in emotional speech controlling for autistic traits.

Accurate interpretation of speech requires the integration of verbal and nonverbal signals. This study investigated sex differences in behavior and neural activities associated with the integration of semantic content and emotional speech prosody, while the level of autistic traits was controlled for. Adults listened to Cantonese words spoken with happy and sad prosody, and made judgments on semantic valence while event-related potentials (ERP) were recorded. Behaviorally, men were slower than women in making semantic valence judgments. At the neural level, men had a greater congruity effect in the N400 component, whereas women had a greater congruity effect in the 1150-1300 ms time window for happy prosodies. There was no effect of sex in case of sad prosodies. Our study reveals novel findings on sex differences in the timing of the integration between verbal and non-verbal signals that cannot be explained by differences in autistic traits.

A nucleotide signature for identification of Aglaia stellatopilosa Pannell.

Members of the genus Aglaia have been reported to contain bioactive phytochemicals. The genus, belonging to the Meliaceae family, is represented by at least 120 known species of woody trees or shrubs in the tropical rain forest. As some of these species are very similar in their morphology, taxonomic identification can be difficult. A reliable and definitive molecular method which can identify Aglaia to the level of the species will hence be useful in comparing the content of specific bioactive compounds between the species of this genus. Here, we report the analysis of DNA sequences in the internal transcribed spacer (ITS) of the nuclear ribosomal DNA and the observation of a unique nucleotide signature in the ITS that can be used for the identification of Aglaia stellatopilosa. The nucleotide signature consists of nine bases over the length of the ITS sequence (654 bp). This uniqueness was validated in 37 samples identified as Aglaia stellatopilosa by an expert taxonomist, whereas the nucleotide signature was lacking in a selection of other Aglaia species and non-Aglaia genera. This finding suggests that molecular typing could be utilized in the identification of Aglaia stellatopilosa.

When is a peri-procedural death iatrogenic in nature?

In almost any instance of suspected iatrogenic fatality, the attending forensic pathologist faces the challenging and often daunting task in ascertaining the cause of death, determining if an iatrogenic injury had indeed occurred and if so, its contribution to the causation of death. The Forensic Medicine Division of the Health Sciences Authority in Singapore embarked on a 6 year study of such deaths to identify pertinent factors that may facilitate the assessment of iatrogenic injuries and their contribution to mortality. A total of 106 iatrogenic deaths, arising from 613 coroner's peri-procedural autopsies conducted during the period of 2005-2010 were reviewed with particular reference to the following parameters: (1) clinico-pathological correlation; (2) the length of survival; (3) the number of interventional procedures. A comprehensive analysis of these cases indicated that they could be classified into the following 3 categories, in relation to the role of clinico-pathological correlation in the ascertainment of the causes of death: (A) advantageous but not essential; (B) essential; (C) critical. A large proportion of the cases (76.5%) were assigned categories B and C. Only the minority of cases (23.6%) were assigned category A. Also, as the number of days of survival between injury and death, and the number of interventional procedures after injury increases, the greater the need for detailed clinical documentation to ascertain the cause of death.

A review of fatal road traffic accidents in Singapore from 2000 to 2004.

INTRODUCTION: This retrospective study aims to assess the epidemiology of road traffic accident (RTA) fatalities in Singapore, other causes of death besides trauma in a RTA, and identify the groups at risk. MATERIALS AND METHODS: Data of 1038 RTA fatalities were reported between 2000 and 2004. Analyses using the Fisher's exact test for discrete variables and multivariate Cox regression analysis were performed to identify groups at risk. The risk of fatality was measured using the prevalence rate ratio (PRR). RESULTS: The median age of victims in the sample was 36 years (interquartile range 24 to 55). Eight hundred and thirty six cases (78%) were in the economically productive age range of 15 to 65 years. Over the 5-year period, there was a preponderance of males. Majority of fatalities involved multiple injuries. There were also 64 (6.2%) and 25 (2.4%) cases of RTA fatalities from infective and cardiovascular (CVS) causes, respectively. Multivariate analyses showed that those > or = 60 years were 4 (95% CI of PRR, 3.04 to 5.43) times as likely to be pedestrian fatalities. Conversely, the risk of fatalities involving pedestrians and cyclists was reduced for males (PRR = 0.58; 95% CI, 0.46 to 0.73). However, males were at increased risk of fatalities involving motorcyclists, scooter and pillion riders (PRR = 1.96; 95% CI, 1.43 to 2.70), whereas such risk was reduced for those aged 30 to 59 (PRR = 0.70; 95% CI, 0.58 to 0.85) or > or = 60 years (PRR = 0.30; 95% CI, 0.21 to 0.42), respectively. CONCLUSION: As such, it appears that the groups at-risk had varying demographic characteristics. Public education could be modified to target these different groups to reduce the number of fatalities.

Fatal cerebral infarction complicating therapeutic embolisation of a facial cavernous haemangioma: a case report.

An eight-year-old female developed cerebral infarction, with eventual brain death, as a consequence of therapeutic embolisation of a large facial haemangioma. Post-mortem histological examination revealed the presence of identical foreign body emboli, consistent with at least one of the embolic agents used in the procedure, within the haemangioma and both cerebral hemispheres. It is possible that some of these particles might have entered the cerebral circulation through anastomoses between the right external and internal carotid arteries, and subsequently crossed over from the ipsilateral to the contralateral cerebral vasculature via the Arterial Circle of Willis.

Epidemiology of completed suicides in Singapore for 2001 and 2002.

This study provides an analysis of 640 completed suicide cases in Singapore for the years 2001 and 2002, compared to previous years and in relation to demographic and socioeconomic factors, as well as to the characteristics of a subgroup of suicide victims with prior psychiatric illness. There was little change in the suicide pattern over the 2 years studied compared to previous years. The sex ratio was constant at 1.5. Population-adjusted ratios were 1 for Chinese, 0.5 for Malays, and >1 for both Indians and other ethnic groups. Falling from heights ranked first in terms of method adopted for both years. A disproportionately higher number of suicides were recorded for the 25-34 and the > or =75-year-old age groups. A total of 47 (17.2%) in 2001 and 74 (20.2%) in 2002 of the cases had a history of prior psychiatric illness, with psychotic disorders being the most common diagnostic category. There was also a statistically significant correlation between unemployment and incidence rates. Although the overall rate of elderly suicides had gone down since the 1990s, prevention strategy should focus on the elderly as this rate is still about 3-4 times the national average.

Post-anaesthetic maternal death in a patient with mediastinal large B-cell lymphoma: a case report.

A 32-year-old female underwent laparoscopic salpingectomy of an ectopic (third) pregnancy under general anaesthesia, at approximately six weeks' amenorrhoea. She developed severe respiratory distress after extubation and died on the second postoperative day. It appears that she had a history of a mild, persistent productive cough for a period of about a month prior to the operation that was attributed to an upper respiratory tract infection. Autopsy demonstrated the presence of a large mediastinal tumour, whose existence was apparently unsuspected preoperatively, encasing the ascending thoracic aorta, aortic arch and the proximal segments of the brachiocephalic and subclavian arteries, and causing extrinsic airway compression. Subsequent microscopic examination showed histological and immunohistochemical features of a mediastinal large B-cell lymphoma. It is thought that the mechanical effects exerted by the advanced mediastinal tumour upon the airways and the thoracic cage, coupled with the pathophysiological effects of general anaesthesia on respiratory movement and airway patency, had led to the patient's unfortunate demise in early pregnancy.

Out-of-hospital cardiac arrests occurring in primary health care facilities in Singapore.

OBJECTIVES: To study out-of-hospital cardiac arrests (OHCA) occurring in primary healthcare facilities (HCF) in Singapore and to compare these with arrests occurring in the community. METHODS: This prospective observational study was part of the Cardiac Arrest and Resuscitation Epidemiology (CARE) project. Included were all patients with OHCA occurring in HCF. Patient characteristics, cardiac arrest circumstances, EMS response and outcomes were recorded according to the Utstein style. RESULTS: From 1 October 2001 to 14 October 2004, the data from 2428 subjects were received of which 138 patients were OHCA occurring in HCF. This is an incidence of 1.12/100,000 population per year and constituted 6.0% of all OHCA. Arrest occurring in HCF were more likely to be witnessed (p<0.01), or have bystander CPR (p<0.01). The HCF group was also more likely to receive CPR with both compression and ventilation (p<0.01) and have a non-trauma cause of arrest (p=0.03). HCF arrests also had a shorter collapse to call (EMS number) than the non-HCF group (HCF 1.54min versus non-HCF 5.36min, p=0.01). However, no HCF patient received defibrillation prior to EMS arrival. HCF patients were more likely to have return of spontaneous circulation at any time (p=0.05), survival to hospital admission (p<0.01) and survival to discharge (p<0.01) compared to non-HCF patients. CONCLUSION: This study suggests that primary health care providers do have an important role locally in managing out-of-hospital cardiac arrest. We propose an initiative to encourage early defibrillation by primary health care providers.

Victims of falls from a height surviving to hospital admission in two Singapore hospitals.

Falls from a height are a common problem in Singapore. However, there has been no analysis of the injury patterns and outcomes of patients who survived initial resuscitation after falls from a height in Singapore. One hundred and thirty-nine patients admitted over a two-and-a-half year period after falls of greater than one storey were studied. The higher the fall, the greater the likelihood of hypotension and neurological injury. The length of stay in hospital, the number of operative procedures and mortality also correlated with the height of the fall. The overall mortality rate was 11% but rose to 47% among patients who were hypotensive on admission. About half of the deaths were due to head injury with haemorrhage being the second most common cause. The majority of patients who fell from five or more storeys did so intentionally, and had more severe torso and extremity injuries compared with those who fell accidentally. These findings suggest that efforts in injury prevention and aggressive evaluation and treatment of fall victims arriving alive at the hospital continue to be important.

A fatal case of hepatic failure possibly induced by nitrosofenfluramine: a case report.

A 42-year-old female developed fulminant hepatic failure after having ingested an undetermined quantity of a herbal product over a period of approximately four months prior to the onset of her illness. Clinically, the cause of liver failure was assessed to be drug-induced and she eventually underwent total hepatectomy, with porto-caval shunting, in anticipation of a living-unrelated liver transplant. Unfortunately, her condition deteriorated and she died less than 48 hours post-operatively, approximately three weeks post-admission. An autopsy showed that the subject was deeply jaundiced and severely obese (BMI: 47.1 kg m(-2)), with evidence of diffuse haemorrhage, including the presence of 1.35 l of blood in the peritoneal cavity. The liver had been removed and was later recovered as a formalin-fixed specimen which was markedly contracted, comprising multiple micronodules interspersed with extensive areas of dense fibrotic tissue. Histologically, there was massive necrosis of the hepatic parenchyma, such that the residual hepatocytes were disposed as nodules displaying variable cellular regeneration and ballooning degeneration, attended by florid ductal proliferation and mixed inflammatory infiltrates. Infective, autoimmune, metabolic, vascular, neoplastic and most other natural causes of massive hepatocellular necrosis were effectively excluded. Analysis of the post-mortem blood samples yielded fluconazole, metronidazole, frusemide, lignocaine and tramadol, (therapeutic agents administered to the patient during her last illness). Subsequent analysis of the residual capsules revealed that they were adulterated by fenfluramine, N-nitrosofenfluramine (1.3-1.6 mg per capsule), nicotinamide (13.3-15.6 mg per capsule) and thyroid extract. None of the herbal ingredients is currently known to be hepatotoxic and much the same applies to fenfluramine, nicotinamide (except when taken in mega-doses) and thyroid extract. However, as nitrosamines are known to be variably hepatotoxic, it would be reasonable to surmise that, in the absence of a more plausible cause of liver damage, N-nitrosofenfluramine was the likely cause of massive hepatocellular necrosis in this instance.

Cholecystokinin-B receptor gene expression in cerebellum, pre-frontal cortex and cingulate gyrus and its association with suicide.

Suicide is a complex behaviour. Genetic and environmental factors are implicated in suicide. Both factors require genes to exert their effects. One gene hypothesized to be involved in the pathophysiology of suicide is cholecystokinin. Alterations in cholecystokinin receptor binding have been reported to be significant in young suicide victims as compared to matched controls in the frontal and cingulate cortex. In this study we report the Cholecystokinin-B gene expression using RT-PCR, between suicide completers [(N = 10); mean age 37.2+/-12 years] and control subjects [(N = 10); mean age 37.6+/-11.9 years]. Cholecystokinin-B gene expression was significantly higher in the cerebellum (P = 0.006), cingulate gyrus (P = 0.024) and pre-frontal cortex (P = 0.017) of suicide completers when compared to their age and sex-matched controls.

Fatal pulmonary thromboembolism in Singapore: has anything changed?

A previous study of fatal pulmonary thromboembolism (PE) during a five-year period (1989-1993) in Singapore found a low post-mortem prevalence of fatal PE (1.05%). The present study investigated cases of fatal PE among 10,097 coroner's post-mortems conducted between 1994 and 1998 at the Centre for Forensic Medicine, Health Sciences Authority, Singapore, and compared the results with the previous study. There were 130 cases of fatal PE, representing a post-mortem prevalence of 1.29%. This is comparable to the previous study but is lower than most other published series from other countries. There was a shift towards younger subjects, with the modal age group being 40 to 49 years, compared with 70 to 79 years previously. A large proportion of subjects had risk factors for PE, with 42.3%, 23.8% and 11.5% having had a history of surgery, trauma or malignancy respectively. After the onset of immobility or trauma, 50% of subjects developed PE in the first seven days and 76.8% in the first two weeks. PE was not suspected as the cause of death in 74.6% of cases under medical care. The incidence of fatal PE in Singapore remains low. However, a large proportion of cases continue to be unsuspected as the cause of death. It would appear that, on the whole, a correct clinical diagnosis of fatal pulmonary thromboembolism remains largely elusive.

A case of sudden death from primary intracranial germinoma complicated by microvascular disease of the heart.

A coroner's autopsy conducted on an 11.5-year-old girl, with a history of hypopituitarism, manifesting as growth hormone deficiency associated with short stature, demonstrated the presence of an undiagnosed hypothalamic intracranial germinoma, showing hypophyseal and mesencephalic invasion, together with histological evidence of microvascular (small coronary artery) disease of the heart. The substantive, or primary, cause of her sudden death was clearly the intracranial germinoma, which was acutely haemorrhagic and necrotic. However, it is postulated that there might be an, as yet, undescribed association between this malignancy and the pathogenesis of the coronary microvascular disease; the latter being deemed, in this instance, to be a contributory cause of death.

Suicide trends in Singapore: two decades down the road.

In this study, recent trends in the incidence and methods of suicide in Singapore, over the period 1991-2000, were compared with the results of a previous study covering the period 1975-1984 (Tan, 1986). The present study included a total of 3,834 suicidal deaths reported to the coroner and investigated by the Centre for Forensic Medicine of the Health Sciences Authority. The results showed that the crude suicide rate had stabilised over the last decade and that the rate was highest among elderly males. The three most common methods employed were falls from a height (69.3%), hanging (20.7%) and poisoning (5.5%). Comparison of the results of both studies showed that the crude suicide rate had stabilised over the last two decades. However, there was an increase in the suicide rates among males, as compared with the previous study, and a marginal decrease in suicide rates among females over this time. There was also an appreciable change in the methods of suicide employed, in that there was an increase in the proportion of deaths due to falls from a height and corresponding reductions in the proportions of deaths by hanging and poisoning.

Comparison of human and porcine aortic valves.

We compared the anatomy of human and porcine aortic valves. Porcine hearts were collected from the abattoir. Human hearts from patients who had died of non-cardiac causes were examined in the mortuary; only undamaged and anatomically normal hearts were used. Silicon casts were prepared by injecting engineering silicon at 80 mm Hg into the aortic arch. Various features of the aortic valve were measured: circumference, length between the commissural end point and central point of coaptation, surface diameter, and surface area. In total, 12 porcine and 12 human aortic valves were studied. The average circumferences of the human and porcine aortic valves were 8.00 +/- 0.2 (SD) cm and 7.90 +/- 1.0 cm, respectively. The central point of coaptation in human valves was skewed toward the left coronary cusp, whereas in porcine valves it was skewed toward the non-coronary cusp. In human aortic valves, the non-coronary cusp had the largest surface diameter and surface area with mean measurements of 3.6 +/- 0.2 cm and 1.230 +/- 0.228 cm(2), respectively; the left coronary cusp was smallest for the same variables with measurements of 3.1 +/- 0.3 cm and 0.898 +/- 0.357 cm(2). In porcine valves, the right coronary cusp had the largest surface diameter and surface area with mean measurements of 3.9 +/- 0.7 cm and 1.716 +/- 0.81 cm(2), respectively; the non-coronary cusp was the smallest for the same variables with measurements of 2.9 +/- 0.5 cm and 1.023 +/- 0.659 cm(2). These differences suggest that when using porcine valves as transplant material (e.g., stentless valves), geometric considerations, such as commissural length, may be important.

Epidemic hand, foot and mouth disease caused by human enterovirus 71, Singapore.

Singapore experienced a large epidemic of hand, foot and mouth disease (HFMD) in 2000. After reviewing HFMD notifications from doctors and child-care centers, we found that the incidence of HFMD rose in September and declined at the end of October. During this period, 3,790 cases were reported. We performed enteroviral cultures on 311 and 157 specimens from 175 HFMD patients and 107 non-HFMD patients, respectively; human enterovirus 71 (HEV71) was the most frequently isolated virus from both groups. Most of the HFMD patients were

Massive hepatocellular [correction of hepatocullular] necrosis: was it caused by Orlistat?

Orlistat (tetrahydrolipostatin) is a lipase inhibitor which is used, in conjunction with appropriate dietary control, for the treatment of obesity. It is generally deemed to be a safe drug, which mainly exerts a topical action on the stomach and small bowel, with negligible systemic absorption and oral bioavailability. Consequently, its adverse effects have largely been limited to relatively mild gastrointestinal disorders. However, there have been recent, published reports of non-fatal acute hepatitis and systemic hypertension associated with its use. The present case concerns a 62-year-old male who died from massive hepatocellular necrosis, consistent with drug-induced, fulminant hepatitis, associated with the use of oral orlistat, presumably administered at the recommended daily dose of 360 mg. It is postulated that this may represent a rare idiosyncratic reaction to the drug.