Augmentation of 5-lipoxygenase activity and expression during dengue serotype-2 infection.

BACKGROUND: Leukotriene B4, a 5-lipoxygenase product of arachidonic acid with potent chemotactic effects on neutrophils, has not been assessed in dengue patients. In this study, plasma leukotriene B4 and serum high-sensitivity C-reactive protein levels were determined in adult patients during the febrile, convalescent and defervescent stages of dengue serotype-2 (DENV-2) infection, and compared with those of age-matched healthy and non-dengue febrile subjects. In vitro studies were performed to examine the effects of live and heat-inactivated DENV-2 on the activities and expression of 5-lipoxygenase in human neutrophils. RESULTS: Plasma leukotriene B4 was elevated during the febrile stages of dengue infection compared to levels during convalescence and in study controls. Plasma leukotriene B4 also correlated with serum high-sensitivity C-reactive protein in dengue patients (febrile, r = 0.91, p < 0.001; defervescence, r = 0.87, p < 0.001; convalescence, r = 0.87, p < 0.001). Exposure of human neutrophils to DENV-2 resulted in a significant rise in leukotriene B4; the extent of increase, however, did not differ between exposure to live and heat-inactivated DENV-2. Pre-incubation of either live or heat-inactivated DENV-2 resulted in reduced leukotriene B4 release by neutrophils, indicating that contact with dengue antigens (and not replication) triggers the neutrophil response. Production of leukotriene B4 was associated with an increase in 5-lipoxygenase expression in human neutrophils; addition of MK886 (a 5-lipoxygenase activating protein inhibitor) attenuated further increase in leukotriene B4 production. CONCLUSION: These findings provide important clinical and mechanistic data on the involvement of 5-lipoxygenase and its metabolites in dengue infection. Further studies are needed to elucidate the therapeutic implications of these findings.

Oxidative damage in ischemic stroke revealed using multiple biomarkers.

BACKGROUND AND PURPOSE: We investigated changes in oxidative damage after ischemic stroke using multiple biomarkers. METHODS: Serial blood and urine samples of ischemic stroke subjects and age-matched control subjects were assayed for F2-isoprostanes, hydroxyeicosatetraenoic acid products, F4-neuroprostanes, 24-hydroxycholesterol, allantoin, and urate. RESULTS: Sixty-six stroke subjects (mean age, 65 years; median National Institutes of Health Stroke Scale 17) and 132 control subjects were recruited. A bimodal pattern of change was observed in plasma and urinary F2-isoprostanes and plasma 24-hydroxycholesterol. The rise in plasma hydroxyeicosatetraenoic acid products, F4-neuroprostanes, and allantoin was highest 6 to 12 hours after stroke onset, whereas plasma urate was significantly lower than controls on Days 1 to 3. After adjusting for age and baseline National Institutes of Health Stroke Scale, baseline plasma esterified hydroxyeicosatetraenoic acid products (OR, 1.01; 95% CI, 1.01 to 1.02), plasma urate (1.01; 1.00 to 1.01), and plasma free F4-neuroprostanes (2.73; 1.76 to 3.93) were associated with 90-day good functional recovery (modified Rankin Scale ≤1). CONCLUSIONS: Multiple markers of oxidative damage are increased immediately after stroke and remain elevated for several days. Recognition of these temporal changes may help design better antioxidant treatment trials for acute ischemic stroke.

Can demographic and admission laboratory variables be useful to identify long-stay patients with acute ischemic stroke? A hospital-based cohort study in Singapore.

The demographic and laboratory predictors of long-stay patients with ischemic stroke were sought in this retrospective hospital-based study. In the univariate and multivariate analysis, advanced age, male gender, leukocytosis, elevated creatinine, low-serum albumin, elevated alkaline transaminases, and lactate dehydrogenase were identified as independent predictors of "long" stayers. At an optimal probability cut-offs, the receiver operating curve incorporating these variables was 0.70, sensitivity 68%, specificity 80%, positive-predictive value 39% and negative-predictive value 95%. Application of this information may assist physicians to triage patients at risk of severe stroke for early therapy and care.

Novel chloride channel mutations leading to mild myotonia among Chinese.

We describe two Chinese families with a mild form of the myotonia congenita due to novel chloride channel (ClCN1) mutations. In one case, heterozygous I553F and H555N mutations were found. The patient shared the I553F mutation with his healthy father, and his mother had a history of mild myotonia when she was younger. In another family, autosomal dominant myotonia congenita was due to a L844F change. The physiological effects of the mutations were examined by using the two-electrode voltage-clamp technique after expression of the channels in Xenopus oocytes. All mutations drastically shifted the voltage required for half-maximal activation, more under conditions mimicking the homozygous situation, than under conditions mimicking the heterozygous situation. The larger effect was seen in the compound heterozygous situation combining the I553F and the H555N mutations. Our data suggest that myotonia congenita caused by CLCN1 mutations in Chinese have similar variable features to those found in the West.

Evaluating a bedside tool for neuroanatomical localization with extended-matching questions.

Neuroanatomical localization (NL) is a key skill in neurology, but learners often have difficulty with it. This study aims to evaluate a concise NL tool (NLT) developed to help teach and learn NL. To evaluate the NLT, an extended-matching questions (EMQ) test to assess NL was designed and validated. The EMQ was validated with fourth-year medical students and internal medicine and neurology residents. The NLT's usability was evaluated with third- and fourth-year students, and the effectiveness was evaluated with an experimental study of second-year students, using the EMQ as the outcome measure. Students were taught how to use both the NLT and textbook algorithms (control) to perform NL, then randomized into either group, and only allowed to use their assigned tool to complete the EMQ. Primary outcome was the difference in mean EMQ scores expressed as a percentage of total score. For EMQ validation, students (n = 56) scored lower than residents (n = 50) (76.7% ± 1.7 vs. 83.0% ± 1.6; mean ± standard error of mean, P < 0.009). The EMQ demonstrated good reliability (Cronbach's α 0.85) and generalizability (G-coefficient 0.85). Third- (n = 77) and fourth-year (n = 42) students found the NLT user-friendly and helpful in their learning of NL. In the experimental study, scores were significantly higher for NLT group (n = 94) than for controls (n = 101) (42.5 vs. 37.0%, P = 0.014); the effect size (Cohen's d) was 0.36. The EMQ is validated to reliably assess NL and is generalizable, feasible, practical, and of low cost. The concise and user-friendly NLT for NL was effective in aiding medical student performance of NL. Anat Sci Educ 11: 262-269. © 2017 American Association of Anatomists.

Post-infectious fatigue syndrome in dengue infection.

BACKGROUND: Although the acute manifestations of dengue are well known, few studies have assessed the long-term consequences of dengue infection. We prospectively studied the incidence and factors associated with fatigue in a cohort of patients following dengue infection. METHODS: We included patients with serologically confirmed dengue infection admitted to the National University Hospital, Singapore, during a dengue outbreak from October-November 2005. The severity of dengue was graded as dengue fever, dengue haemorrhagic fever and dengue shock syndrome. A follow-up telephone interview was performed two months following hospital discharge, where a Fatigue Questionnaire was administered. The presence of significant fatigue was considered as the main outcome measure. Significance was assessed at P<0.05. RESULTS: One hundred twenty-seven patients, 71 (55.9%) males and 56 (44.1%) females, of mean age 36.06 years (range, 16-70; S.D., 13.722), participated in this study. Twenty-five (19.7%) patients had dengue haemorrhagic fever and the remaining 102 (80.3%) had dengue fever. In multivariate analysis, increased age, female sex, the presence of chills, and the absence of rashes were significantly associated with the development of fatigue post-dengue infection. There was no significant association between fatigue and dengue severity. CONCLUSIONS: This observation represents the first systematic evidence that dengue can result in clinical disease beyond the acute phases of infection. Host factors, such as age and sex may be important in the pathogenesis of this clinical entity.

Symptoms and risk factors of ocular complications following dengue infection.

BACKGROUND: Dengue infection can result in severe ocular complications. We prospectively studied the range of ocular symptoms in a cohort of patients with dengue infection. METHODS: We included adult patients with serologically confirmed dengue infection who received clinical care at the National University Hospital, Singapore. They were assessed for demographic characteristics, ocular symptoms, laboratory parameters and dengue severity. Patients with two or more ocular symptoms were referred to an ophthalmologist and underwent full ophthalmologic examination that included visual acuity, slit-lamp examination and indirect fundoscopic examination. Descriptive and logistic regression analyses were performed and statistical significance was set at p<0.05. RESULTS: One hundred and fifty-six patients, aged (S.D.) 33.94 (12.7) years, consisting of 89 (57.1%) males and 67 (42.9%) females, participated in this study. They reported ocular symptoms, such as eye strain (30%), retro-ocular pain (20%), blurring of vision (10%), double vision (3%), foreign body sensation (3%), eye flashes (2%) and floaters (1%). Multivariate analysis identified white cell count (odds ratio, OR 0.531; 95% CI 0.292, 0.963) and serum albumin (OR 0.758; 95% confidence intervals, CI 0.618, 0.928) as significant predictors of clinically significant ocular symptoms. The triad of symptoms (eye flashes, floaters and blurring of vision) was highly predictive for the development of retinal hemorrhages (positive predictive value 100%). CONCLUSIONS: Dengue virus results in a spectrum of ocular manifestations, ranging from non-specific symptoms to severe retinal hemorrhages. Further studies are needed to validate the triad of ocular symptoms as a screening tool for severe ocular complications following dengue infection.

Botulinum toxin, Quo Vadis?

Botulinum toxin (BTX), derived from the exotoxin of Clostridium botulinum, cleaves Soluble N-ethylmaleimide-sensitive factor-Attachment protein REceptor (SNARE) proteins, causing chemodenervation of cholinergic neurons. BTX also inhibits exocytosis of vesicles containing norepinephrine, glutamate, substance P and calcitonin gene-related peptide (CGRP) and inhibits expression of the vanilloid receptor. Clinical applications of BTX, which include the treatment of overactive skeletal and smooth muscles, hypersecretory and painful disorders, have increased exponentially since it was first used clinically to treat strabismus more than two decades ago. In this editorial, we discuss reports of new therapeutic indications of BTX, and propose new areas for research.

Can botulinum toxin put the restless legs syndrome to rest?

The restless legs syndrome (RLS), affecting between 3% and 15% of the population, is characterised by an urge to move the legs during wakefulness, associated with a range of unpleasant sensory symptoms, especially when sitting or lying down at night. The symptoms can even be painful, and lead to sleep disturbances and depression. RLS is treated with dopaminergic agents, anticonvulsants, opioids, clonidine and benzodiazepines. In a small percentage of cases, RLS is refractory to treatment, requiring combination therapy. Botulinum toxin (BTX), derived from the exotoxin of Clostridium botulinum, cleaves soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, causing chemodenervation of cholinergic neurons. BTX has been demonstrated to ameliorate pain syndromes, possibly by reducing peripheral and central sensitization to pain. We postulate that BTX can be injected subcutaneously to the lower limbs to effect amelioration of the symptoms of RLS.

Is there a place for placebo in management of psychogenic movement disorders?

INTRODUCTION: The management of psychogenic movement disorders is fraught with difficulties. Empathy and a non-judgmental manner are essential in dealing with patients, and a neurobiological explanation of the symptoms may help to foster trust, acceptance, understanding and recovery. CLINICAL PICTURE: We report a 17-year-old Chinese girl with psychogenic blepharospasm. Her parents refused psychotherapy and pharmacotherapy. TREATMENT AND OUTCOME: Placebo therapy (with parental consent) was prescribed with favourable results. CONCLUSION: We examine the ethical considerations for and against placebo therapy, and explore the role of placebo therapy in the management of psychogenic movement disorders.

Take a bao if you are not superstitious.

INTRODUCTION: Singaporeans are superstitious, and medical staff are no exception to the rule. We conducted a survey to determine the prevalence of superstitious beliefs and practices amongst doctors, nurses and medical students in Singapore. METHODS: Internet and face-to-face surveys of 68 respondents, all of whom completed the survey after being threatened with curses and hexes. RESULTS: Sixty-eight doctors, nurses and medical students responded to our survey. Only 11 admitted to being superstitious, yet 31 believed in the ill-fortune associated with eating bao or meat dumplings, 6 in the nefarious powers of black (5) or red (1) outfits on call, and 14 believed that bathing (6 insisting on the powers of the seven-flower bath) prior to the onset of a call portended good fortune, in terms of busy-ness of a call. Twenty-four believed in "black clouds", i.e. people who attracted bad luck whilst on call, and 32 refused to mouth the words "having a good call" until the day after the event. We discovered 2 hitherto undescribed and undiscovered superstitions, namely the benefits of eating bread and the need to avoid beef, for the good and ill fortune associated with their ingestion. DISCUSSION: Superstitious practices are alive and well in modern-day Singapore, the practice not necessarily being restricted to the poorly-educated or foolish.

Acute transverse myelitis following dengue virus infection.

The spinal cord is infrequently affected following dengue virus infection. We report a case of transverse myelitis that developed 2 weeks after acute dengue infection and review the literature to elucidate the pathogenesis of spinal cord involvement in dengue infection. We postulate that temporal factors may play a role in the different clinical manifestations, i.e. that acute parainfectious dengue infection presents with flaccid paralysis, whereas late-stage (postinfectious) dengue infection, presents with spastic weakness. Further studies need to be performed to elucidate the mechanisms of spinal neurological damage in dengue.

Holiday review. Duty of care to the undiagnosed patient: ethical imperative, or just a load of Hogwarts?

With the restoration of You-Know-Who to full corporeal form, the practice of the dark arts may lead to multitudes being charmed, befuddled and confounded. At present, muggle ethics dictate that aid may be rendered in a life-or limb-threatening situation, but the margins are blurred when neither is at stake. Muggle and wizard healers, fearful of being labelled ambulance chasers, may shy away from approaching those who remain blissfully unaware of their illnesses. We describe 4 case studies in which we intervened as muggle healers, to salutary effect. The afflicted were healed or helped, without bringing the weight of the Ministries of Magic or Magical Healing upon us. We advocate a spirit of cooperation between muggle and magical folk, mindful of the strengths that the healing arts from each community have to offer. As long as the intent is beneficent, healers or even the wizard or muggle on the street may intervene and render aid to the afflicted.

Botulinum toxin-A injections for spastic toe clawing.

Spastic toe clawing describes extension at the metatarsophalangeal joints of the feet, flexion at the proximal interphalangeal joints and flexion at the distal interphalangeal joints that results from upper motor neuron lesions, such as stroke, intracranial hemorrhage, cervical myelopathy and brain tumors. Even though toe clawing is often asymptomatic, it can be painful. Previous studies have described the efficacy of injections of botulinum toxin type-A (BTX-A) to the long flexors of the toes, but this is often unsatisfactory as high dosages (up to 175 units) have been required, and patients often report significant residual toe clawing. We performed an open label, prospective study to assess the efficacy of BTX-A injections, targeting the long and short flexors of the toes, performed with electrical (motor point) stimulation under electromyographic guidance. Outcome measures, which included timed walking over 20m, objective assessment of toe clawing (modified Ashworth scale and a visual analog scale rating) and patient assessment of functional disability, were assessed before injections and at six-weeks' follow-up. Seven patients (five male and two female) of mean age 51 (range 38-70) were recruited. Four had spasticity from underlying intracranial hemorrhage, the remaining three from cerebral infarct, astrocytoma and post-traumatic cervical myelopathy. The total dose of BTX-A injected for toe clawing ranged from 40 to 90 units. Improvements were observed in all outcome measures except timed walking. Injecting BTX-A to the long and short flexors of the toes, with electrical stimulation under electromyographic guidance, is well tolerated and efficacious in the treatment of toe clawing from spasticity, allowing for lower dosages to be used.

Botulinum toxin: a novel therapeutic option for bronchial asthma?

Two components are essential for the development of an attack of bronchial asthma: inflammation and bronchoconstriction, the latter being mediated by smooth muscle contraction. Despite the efficacy of chronic therapy, many asthmatics relapse. Measures to inhibit contraction of the airway smooth muscle, such as vagotomy and thermoablation, may decrease the bronchoconstrictor component of the asthma attack and help to decrease morbidity and mortality from the disease. Botulinum toxin acts to weaken skeletal and smooth muscle by preventing the docking of the acetylcholine vesicle on the inner surface of the presynaptic membrane, thus causing chemical denervation and paresis of skeletal or smooth muscle. We explore the possibility that administration of botulinum toxin may achieve the same effect in bronchial asthma and examine the evidence to support this hypothesis.

Topical botulinum toxin to treat hyperhidrosis? No sweat!

Palmar, plantar and axillary hyperhidrosis, though benign, may be burdensome and occupationally restrictive, even hazardous. Treatment modalities range from topical antiperspirants, iontophoresis, systemic medications such as anticholinergics and benzodiazepines and injections of botulinum toxin, to thoracic sympathectomy. Intradermal injections of botulinum toxin (BTX), though effective, are painful especially when multiple injections are required. Iontophoretic administration of BTX has been described, the BTX entering the eccrine sweat glands via the sweat pores and through the sweat ducts. We postulate that BTX can be administered topically, either unassisted or assisted by application of an electrical gradient, low-frequency ultrasound or excipients such as dimethylsulfoxide. We examine the rationale and feasibility for such a treatment modality and route of administration.

Where has all the botox gone? (how) will we ever learn... using monoclonal antibodies to track botulinum toxin.

Botulinum toxin (BTX) is an important therapeutic tool in the treatment of overactive skeletal and smooth muscles, as well as hypersecretory and painful disorders. Despite advances in our understanding of how BTX works, much remains to be elucidated, such as how BTX ameliorates pain, how it produces weakness remote from the site of injection and the fate of the heavy and light chain components of the BTX molecule following endocytosis into the presynaptic membrane. BTX, conjugated to radionuclides, allows investigators to track the molecule both in vitro and in vivo. However, altering the BTX molecule may cause structural changes or pharmacokinetic and pharmacodynamic alterations, and disrupt its normal action. We propose instead to bind the biomarkers (appropriate dyes, radionuclides or MRI contrast agents) to monoclonal antibodies directed against either heavy or light chain components of BTX, thus allowing administration of native (i.e. unaltered) BTX.

Interesting in- and outpatient attendances at Hogwarts Infirmary and St Mungo's Hospital for magical maladies.

Ailments afflicting wizarding folk are underreported in the muggle world. The recent integration of muggles and magical folk with the return of You-Know-Who (aka He Who Must Not Be Named) may result in a similar affliction of inhabitants of both worlds. We describe interesting maladies afflicting muggles and wizarding folk alike, arising from the use and misuse of magic. We also provide a basic glossary of magical ailments, and describe their muggle corollaries. Further studies will hopefully result in the development of immunity against the unforgivable curses.

Computer-based versus pen-and-paper testing: students' perception.

BACKGROUND: Computer-based testing (CBT) has become increasingly popular as a testing modality in under- and postgraduate medical education. Since 2004, our medical school has utilised CBT to conduct 2 papers for the third- and final-year assessments - Paper 3, with 30 multiple choice questions featuring clinical vignettes, and the modified essay question (MEQ) paper. AIMS: To obtain feedback from final-year students on their preferred mode of testing for Paper 3 and MEQ components of the Medicine track examination, and the reasons underlying their preferences. METHODS: An online survey was carried out on 213 final-year undergraduates, in which they were asked to provide feedback on Paper 3 and MEQ papers. Students were asked if they thought that the CBT format was preferable to the pen-and-paper (PNP) format for Paper 3 and the MEQ, and why. RESULTS: One hundred and fourteen out of 213 (53.5%) students completed the online survey. For Paper 3, 91 (79.8%) felt that CBT was preferable to PNP, 11 (9.6%) preferred the PNP format and 12 (10.5%) were unsure. For the MEQ, 62 (54.4%) preferred CBT over PNP, 30 (26.3%) preferred the PNP format and 22 (19.3%) were unsure. Reasons given to explain preference for CBT over PNP for Paper 3 included independence from seating position, better image quality (as images were shown on personal computer screens instead of projected onto a common screen) and the fact that CBT allowed them to proceed at their own pace. For the MEQ, better image quality, neater answer scripts and better indication of answer length in CBT format were cited as reasons for their preference. CONCLUSIONS: Our survey indicated that whereas the majority of students preferred CBT over PNP for Paper 3, a smaller margin had the same preference for the MEQ.

Close temporal association of bronchial asthma and ischemic colitis--case report and review of the literature.

We report a case of ischemic colitis in an elderly male who had initially presented with acute asthma exacerbation. The clinical course of hospitalization, surgical and pathological findings were described. We review three previously reported cases of ischemic colitis and bronchial asthma and explore possible mechanisms to explain this association. The complex interaction of smooth muscle tone and autonomic nervous system in the etiopathogenesis of bronchial asthma and ischemic colitis is discussed. Further studies should be undertaken to clarify this association.