A lifestyle intervention programme for the prevention of Type 2 diabetes mellitus among South Asian women with gestational diabetes mellitus [LIVING study]: protocol for a randomized trial.

AIM: This study aims to determine whether a resource- and culturally appropriate lifestyle intervention programme in South Asian countries, provided to women with gestational diabetes (GDM) after childbirth, will reduce the incidence of worsening of glycaemic status in a manner that is affordable, acceptable and scalable. METHODS: Women with GDM (diagnosed by oral glucose tolerance test using the International Association of the Diabetes and Pregnancy Study Groups criteria) will be recruited from 16 hospitals in India, Sri Lanka and Bangladesh. Participants will undergo a repeat oral glucose tolerance test at 6 ± 3 months postpartum and those without Type 2 diabetes, a total sample size of 1414, will be randomly allocated to the intervention or usual care. The intervention will consist of four group sessions, 84 SMS or voice messages and review phone calls over the first year. Participants requiring intensification of the intervention will receive two additional individual sessions over the latter half of the first year. Median follow-up will be 2 years. The primary outcome is the proportion of women with a change in glycaemic category, using the American Diabetes Association criteria: (i) normal glucose tolerance to impaired fasting glucose, or impaired glucose tolerance, or Type 2 diabetes; or (ii) impaired fasting glucose or impaired glucose tolerance to Type 2 diabetes. Process evaluation will explore barriers and facilitators of implementation of the intervention in each local context, while trial-based and modelled economic evaluations will assess cost-effectiveness. DISCUSSION: The study will generate important new evidence about a potential strategy to address the long-term sequelae of GDM, a major and growing problem among women in South Asia. (Clinical Trials Registry of India No: CTRI/2017/06/008744; Sri Lanka Clinical Trials Registry No: SLCTR/2017/001; and ClinicalTrials.gov Identifier No: NCT03305939).

Alzheimer's disease with cerebrovascular disease: current status in the Asia-Pacific region.

BACKGROUND: There is growing awareness of the coexistence of Alzheimer's disease and cerebrovascular disease (AD+CVD), however, due to lack of well-defined criteria and treatment guidelines AD+CVD may be underdiagnosed in Asia. METHODS: Sixteen dementia specialists from nine Asia Pacific countries completed a survey in September 2014 and met in November 2014 to review the epidemiology, diagnosis and treatment of AD+CVD in Asia. A consensus was reached by discussion, with evidence provided by published studies when available. RESULTS: AD accounts for up to 60% and AD+CVD accounts for 10-20% of all dementia cases in Asia. The reasons for underdiagnosis of AD+CVD include lack of awareness as a result of a lack of diagnostic criteria, misdiagnosis as vascular dementia or AD, lack of diagnostic facilities, resource constraints and cost of investigations. There is variability in the tools used to diagnose AD+CVD in clinical practice. Diagnosis of AD+CVD should be performed in a stepwise manner of clinical evaluation followed by neuroimaging. Dementia patients should be assessed for cognition, behavioural and psychological symptoms, functional staging and instrumental activities of daily living. Neuroimaging should be performed using computed tomography or magnetic resonance imaging. The treatment goals are to stabilize or slow progression as well as to reduce behavioural and psychological symptoms, improve quality of life and reduce disease burden. First-line therapy is usually an acetylcholinesterase inhibitor such as donepezil. CONCLUSION: AD+CVD is likely to be under-recognised in Asia. Further research is needed to establish the true prevalence of this treatable and potentially preventable disease.

Neurophysiological findings in patients 1 year after snake bite induced neurotoxicity in Sri Lanka.

Snake bite causes significant morbidity and mortality in Sri Lanka. Snake venoms contain neurotoxins that block neuromuscular junction transmission. Presynaptic neurotoxicity most commonly causes destruction of nerve terminals with recovery by regrowth, whilst postsynaptic neurotoxicity usually involves competition at the acetylcholine receptor. The aim of this study was to investigate whether there were long-term clinical or neurophysiological changes in snake bite survivors 1 year after their envenoming. Detailed neurophysiological tests and clinical examinations were performed on 26 snake bite victims who had presented with neurotoxicity 12 months previously, and their results were compared with controls recruited from the same communities. Significant differences were observed in some nerve conduction parameters in some snake bite victims compared with controls, predominantly in those thought to have elapid bites, including prolongation of sensory, motor and F-wave latencies and reduction of conduction velocities. There was no evidence of any residual deficits in neuromuscular junction transmission. These results suggest a possible demyelinating type polyneuropathy. None of the cases or controls had abnormalities on clinical examination. This is one of the few studies to report possible long-term neurological damage following systemic neurotoxicity after snake bite. The clinical significance of these neurophysiological abnormalities is uncertain and further studies are required to investigate whether the abnormalities persist and to see whether clinical consequences develop.

Efficacy of rivastigmine on activities of daily living in Sri Lankan patients with Alzheimer disease and on improving caregiver burden: a prospective study.

OBJECTIVE: This open label, parallel group, prospective cohort study investigated the efficacy of rivastigmine treatment on activities of daily living (ADL) in patients with mild to moderate Alzheimer's disease (AD) and the possible benefits of this therapy on caregiver stress levels. METHODS: Thirty eight consecutive patients with mild to moderate AD were recruited; 22 received rivastigmine 3-6 mg twice daily (treatment group) for 20 weeks. Sixteen patients who did not receive rivastigmine served as the control group. The 17-item ADL Index was used to assess ADL and to determine the presence of functional deterioration. Caregivers were evaluated with the Caregiver Stress Scale (CSS). Each patient was required to have a committed caregiver and all caregivers were interviewed and administered the ADL Index and the Caregiver Stress Scale (CSS) at the start of treatment (week 0) and at the end of 20 weeks of treatment (week 20). RESULTS: Patients in the control group showed a significant decline in ADL Index score at 20 weeks compared to rivastigmine-treated patients (difference in mean ADL Index score = 8.5; p < 0.001). At week 20, mean change from baseline scores for CSS total and individual domain scores were better for caregivers in the treatment group than those in the control group (CSS total mean difference = 19.2). CONCLUSION: We conclude that treatment of AD patients with rivastigmine for 20 weeks produces a significant improvement in patient ADL functioning, and lower levels of caregiver stress.

Comparison of one week and two weeks of triple therapy for the eradication of Helicobacter pylori in a Sri Lankan population: a randomised, controlled study.

INTRODUCTION: Resistance of Helicobacter pylori to antibiotics may be particularly high in parts of the tropics. Infection may prove difficult to eradicate in such situations, and there is some evidence of benefit in increasing the duration of treatment (triple therapy) from 1 week to 2 or 3 weeks. AIM: To assess the efficacy and tolerability of 1 week versus 2 weeks of triple therapy for eradication of H. pylori in a Sri Lankan population. METHODS: Eighty two patients aged 18-70 years with gastritis or peptic ulcer and testing positive for H. pylori infection were randomly allocated to two treatment groups. Both groups received omeprazole 20 mg, clarithromycin 250 mg, and tinidazole 500 mg. Group A (n = 42) received the trial medication twice daily for 1 week and the Group B (n = 40) twice daily for 2 weeks. H. pylori eradication was defined as a negative 14C labelled urea breath test at 2 weeks after completion of the therapy. RESULTS: H. pylori infection was eradicated in 36 (85.7%) patients in Group A and 36 (90%) patients in Group B (p = 0.9). Twenty three (55%) patients in Group A and 17 (43%) in Group B reported adverse effects attributable to trial medication (p = 0.387); none were serious. Three (7.5%) patients in Group B discontinued treatment due to adverse events that developed on days 7, 9 and 10. CONCLUSION: Twice daily treatment with clarithromycin, tinidazole, and omeprazole for 1 week is well tolerated and provides as good a rate of H. pylori eradication as 2-week therapy in Sri Lankan patients.

Prevalence of dementia in a semi-urban population in Sri Lanka: report from a regional survey.

BACKGROUND: The prevalence of dementia in Sri Lanka, which has a rapidly ageing population, is unknown. OBJECTIVE: This study aimed to determine the prevalence of Alzheimer's disease (AD) and other dementias in a semi-urban elderly Sinhala-speaking population in Ragama, Sri Lanka. METHODS: The study was conducted in two phases. Phase I: After informed consent 703 subjects aged > or =65 years from the study area (population 15 828) were screened for cognitive impairment using the Sinhalese Mini Mental State Examination. Subjects scoring < or =17 were regarded as suspected dementia cases. Phase II: All subjects who screened positive in phase I were included in phase II for detailed evaluation for dementia according DSM IV and NINCDS-ADRDA criteria which included structured neuropsychiatric assessment, laboratory investigations, an axial CT scan of the brain and an informant interview. RESULTS: In the study sample, 61% were female and 86% were between 65-75 years. 42 subjects screened positive in phase I. Of these, 28 subjects were diagnosed as having dementia, giving an overall prevalence rate of 3.98% (95% Confidence Intervals (CI) =2.6-5.7%). Of these, 20 (71.4%) had probable AD, four had vascular dementia (14.3%), two had mixed (vascular and AD) dementia (7.1%), one had Lewy body dementia, and one had dementia due to syphilis. Greater age, illiteracy and female gender were associated with higher prevalence of dementia. CONCLUSION: Comparison with other community studies performed in North India suggests that dementia prevalence is higher in Sri Lanka. This may be due to regional differences in disease incidence.

Multiple-dose activated charcoal for treatment of yellow oleander poisoning: a single-blind, randomised, placebo-controlled trial.

BACKGROUND: Deliberate self-poisoning with yellow oleander seeds is common in Sri Lanka and is associated with severe cardiac toxicity and a mortality rate of about 10%. Specialised treatment with antidigoxin Fab fragments and temporary cardiac pacing is expensive and not widely available. Multiple-dose activated charcoal binds cardiac glycosides in the gut lumen and promotes their elimination. We aimed to assess the efficacy of multiple-dose activated charcoal in the treatment of patients with yellow-oleander poisoning. METHODS: On admission, participants received one dose of activated charcoal and were then randomly assigned either 50 g of activated charcoal every 6 h for 3 days or sterile water as placebo. A standard treatment protocol was used in all patients. We monitored cardiac rhythm and did 12-lead electocardiographs as needed. Death was the primary endpoint, and secondary endpoints were life-threatening cardiac arrhythmias, dose of atropine used, need for cardiac pacing, admission to intensive care, and number of days in hospital. Analysis was by intention to treat. FINDINGS: 201 patients received multiple-dose activated charcoal and 200 placebo. There were fewer deaths in the treatment group (five [2.5%] vs 16 [8%]; percentage difference 5.5%; 95% CI 0.6-10.3; p=0.025), and we noted difference in favour of the treatment group for all secondary endpoints, apart from number of days in hospital. The drug was safe and well tolerated. INTERPRETATION: Multiple-dose activated charcoal is effective in reducing deaths and life-threatening cardiac arrhythmias after yellow oleander poisoning and should be considered in all patients. Use of activated charcoal could reduce the cost of treatment.

Liv.52 in alcoholic liver disease: a prospective, controlled trial.

Liv.52, a hepatoprotective agent of herbal origin, is used empirically for the treatment of alcoholic liver disease in Sri Lanka. We conducted a controlled trial to assess the efficacy of Liv.52 in patients with alcoholic liver disease. Patients with evidence of alcoholic liver disease attending outpatient clinics were included in a prospective, double blind, randomized, placebo controlled trial. During the trial period, 80 patients who fulfilled inclusion criteria were randomly assigned Liv.52 (cases; n = 40) or placebo (controls) the recommended dose of three capsules twice daily for 6 months. All patients underwent clinical examination (for which a clinical score was computed), and laboratory investigations for routine blood chemistry and liver function before commencement of therapy (baseline). Thereafter, clinical assessments were done monthly for 6 months, while laboratory investigations were done after 1 and 6 months of therapy. There was no significant difference in the age composition, alcohol intake and baseline liver function between the two groups. The two-sample t-test was used to analyze data obtained after 1 and 6 months of therapy against baseline values. There was no significant difference in clinical outcome and liver chemistry between the two groups at any time point. There were no reports of adverse effects attributable to the drug. Our results suggest that Liv.52 may not be useful in the management of patients with alcohol induced liver disease.

Mini Mental State Examination in Sinhalese: a sensitive test to screen for dementia in Sri Lanka.

BACKGROUND: Although the Sri Lankan population is ageing rapidly, dementia has not been systematically investigated here. The Mini Mental State Examination (MMSE) is a brief global instrument used to assess cognitive abilities in the elderly. OBJECTIVE: This study aimed to develop and validate a Sinhalese translation of the MMSE, which could be used as a screening instrument to detect impaired cognition in an epidemiological investigation of dementia in Sri Lanka. METHODS: Due to the high literacy rate in the country, the MMSE was translated and modified slightly without having to make major changes to the original version. 380 randomly selected subjects over 65 years in a semi-urban area were screened with the translated version of the MMSE. The cut-off score for cognitive impairment was taken as 17. Of the 380 subjects screened, 33 scored < or = 17, and were thus considered cases of suspected dementia. All 33 who scored < or = 17 and 24 randomly selected subjects who scored>17 on the MMSE, thus considered cognitively normal, underwent a brief clinical examination and neuropsychological assessment with the more comprehensive neuropsychiatric test battery, Cambridge Cognitive Score (CAMCOG), to determine the presence of dementia. RESULTS: Evaluated against the performance at the CAMCOG, the sensitivity and specificity of the translated MMSE were 93.5% and 84.6% respectively. CONCLUSION: Therefore, the Sinhalese translation of the MMSE described here is a sensitive instrument to screen for dementia in Sri Lanka.

Breast examination of older women in a teaching hospital.

INTRODUCTION: Breast examination during routine physical examination may help detect breast cancer and effect early treatment. OBJECTIVE: To determine whether doctors routinely perform breast examination in older women, and to assess attitudes of patients and doctors to this examination. METHODS: A questionnaire based survey of 150 women over 65 years attending a teaching hospital, and 51 doctors working in this hospital. RESULTS: Very few women had a breast examination performed by a doctor. All thought breast examination was important, and would give consent for this examination. Although the great majority of doctors thought breast examination should be done routinely only very few do so. CONCLUSION: Older women have a positive attitude towards breast examination, but this is not reflected by the practice of doctors. There is a need for change in attitudes and training among doctors so that breast examination would be performed routinely.

Multiple system atrophy/progressive supranuclear palsy: alpha-Synuclein, synphilin, tau, and APOE.

Article abstract-Alpha synuclein, tau, synphilin, and APOE genotypes were analyzed in patients with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) and controls. The predisposing effect of the tau insertion polymorphism to the development of PSP is confirmed. However, no effect of alpha-synuclein, synphilin, or APOE variability on the development of PSP, or of tau, alpha-synuclein, APOE, or synphilin gene variability on the development of MSA, are demonstrated.

Abnormal function of potassium channels in platelets of patients with Alzheimer's disease.

BACKGROUND: Reports of abnormalities of potassium-channel function in various cultured cells of Alzheimer's disease patients led us to attempt to characterise the pharmacological characteristics of the abnormal channel. METHODS: We studied platelets from 14 patients with Alzheimer-type dementia and 14 non-demented controls matched for age and sex. The effects of specific inhibitors of K+ channels on the efflux of rubidium-86 ions, a radioactive analogue of K+, from the platelets were measured. FINDINGS: Normal platelets contain three types of K+ channel, sensitive to the inhibitory actions of apamin (small-conductance calcium-dependent potassium channels), charybdotoxin (of less specificity, but probably intermediate-conductance calcium-dependent K+ channels), and alpha-dendrotoxin (voltage-sensitive K+ channels). However, 8Rb+ efflux from the platelets of patients with Alzheimer-type dementia was not inhibited by either apamin or charybdotoxin. By contrast, inhibition by alpha-dendrotoxin did occur. INTERPRETATION: Our results suggest that calcium-dependent K+ channels in platelets are selectively impaired in Alzheimer's disease. A similar abnormality in neurons could contribute to the pathophysiology of the disorder.

Evidence for an R(+)-[(dihydroindenyl)oxy]alkanoic acid-sensitive K+/Cl- co-transporter in human platelets and its interaction with the Na+/K+/2Cl- co-transporter.

1. The K+/Cl- co-transport system is activated by a number of interventions, such as cell swelling and stimulation with N-ethylmaleimide. It is specifically inhibited by R(+)-[(dihydroindenyl)oxy]alkanoic acid and requires the presence of K+ and Cl- on the same side of the cell membrane. This co-transporter has been studied extensively, mainly in erythrocytes of many species, in which it plays a key role in cell volume regulation. Here we present evidence that human platelets contain K+/Cl- co-transporters. 2. We have studied the efflux of 86Rb+ (a marker for K+) from 86Rb(+)-loaded human platelets, and have defined their response to stimulation by N-ethylmaleimide. 3. N-Ethylmaleimide (0.5 and 1 mmol/l) stimulated an increase in cumulative 86Rb+ efflux in a concentration-dependent manner. This efflux was inhibited by R(+)-[(dihydroindenyl)oxy]alkanoic acid (10 mumol/l) but was insensitive to bumetanide. It also required the presence of external Cl-. 4. These observations suggest that 86Rb+ efflux from the platelets stimulated by N-ethylmaleimide occurs via K+/Cl- co-transport. 5. When the K+/Cl- co-transporter was stimulated by N-ethylmaleimide we were unable to stimulate the Na+/K+/2Cl- co-transporter with a high external concentration of KCl or inhibit 86Rb+ efflux with bumetanide. Together with other evidence, this suggests that when the K+/Cl- co-transporter is stimulated with N-ethylmaleimide, the Na+/K+/2Cl- co-transporter is inhibited.

Pharmacological evidence of calcium-activated and voltage-gated potassium channels in human platelets.

1. Previous electrophysiological studies have suggested the presence of KCa and Kv channels in human platelets. However, the pharmacology of these channels has not been defined. 2. We have studied potassium channels in human platelets by measuring the efflux of 86Rb+ (a marker for K+) from 86Rb(+)-loaded cells, and have defined their responses to stimulation by the platelet agonist thrombin and the calcium ionophore ionomycin. 3. Thrombin (0.1-0.6 i.u./ml) stimulated an increase in 86Rb+ efflux from the platelets in a concentration-dependent manner. This efflux was significantly inhibited by apamin (100 nmol/l), charybdotoxin (300 nmol/l) and alpha-dendrotoxin (100-200 nmol/l), blockers of SKCa channels, KCh channels and Kv channels respectively. Iberiotoxin (300 nmol/l), a specific inhibitor of BKCa channels, had no effect on the thrombin-stimulated 86Rb+ efflux. Although glibenclamide, an inhibitor of KATP channels, inhibited the thrombin-stimulated efflux, it did so only in a high concentration (20 mumol/l). 4. Ionomycin (1-5 mumol/l) stimulated an increase in 86Rb+ efflux from the platelets in a concentration-dependent manner. This efflux was significantly inhibited by apamin (100 nmol/l) and charybdotoxin (300 nmol/l). However, iberiotoxin (300 nmol/l) had no effect on the ionomycin-stimulated 86Rb+ efflux. 5. These findings suggest that 86Rb+ efflux from platelets stimulated by thrombin and ionomycin occurs via two types of KCa channel: SKCa and KCh channels. Thrombin also stimulated efflux via Kv channels.

Cell-specific expression of beta-amyloid precursor protein isoform mRNAs and proteins in neurons and astrocytes.

The abnormal accumulation of beta-amyloid (A beta) in senile plaques appears to be a central pathological process in Alzheimer's disease. A beta is formed by proteolysis of beta-amyloid precursor protein (APP) with several isoforms generated by alternative splicing of exons 7, 8 and 15. A semi-quantitative reverse transcription (RT)-polymerase chain reaction (PCR) analysis showed that APP695 mRNA lacking exon 7 and 8 was most abundant in primary cultures of rat neurons, while APP770 and APP751 representing, respectively, the full length and exon 8 lacking isoforms predominated in cultured astroglial cells. Antisera AP-2 and AP-4 were produced by immunizing rabbits with keyhole limpet haemocyanin coupled with synthetic peptides representing KPI region APP301-316 and A beta region APP670-686 of APP770, respectively. These polyclonal antisera were purified against the corresponding peptide using affinity chromatography. Western blot analysis of homogenates of relatively enriched neuronal and astroglial cultures showed that these antibodies discretely stained bands of proteins in a cell-specific manner. Dot-blot analysis using AP-2, AP-4 and 22C11 antibodies indicated that, in comparison with neurons, cultured astrocytes contained 3-fold greater KPI-containing APP isoform proteins. The amount of total APP proteins, which include both KPI-containing and KPI-lacking APP isoforms, was approximately 90% higher in astrocytes than in neurons. Consistent with these in vitro findings in cultured astrocytes, in fimbria-fornix lesioned rat hippocampus, labelling with AP-2 antibody, which specifically reacts with KPI-containing APP proteins, was mainly observed in glial fibrillary acidic protein-positive reactive astrocytes in vivo. The results showed that APP isoforms are expressed in a cell type-specific manner in the brain and, since deposition of A beta is closely associated with the expression of KPI-containing APP isoforms, provide further evidence for the involvement of astrocytes in plaque biogenesis.

Presenilins and early-onset familial Alzheimer's disease.

Thirty-seven missense mutations and a splice-site mutation in the presenilin gene PS1 on chromosome 14 and two missense mutations PS2 on chromosome 1 co-segregate with early-onset familial Alzheimer's disease (AD). The presenilins belong to a family of conserved integral membrane proteins which include Caenorhabditis elegans SPE4 and SEL12 and the rat apoptosis-linked gene, ALG3. This review summarizes the genetics of presenilins in AD and indicators of putative function based on cellular localization and the functions of non-human homologues. Findings to date suggest an important role of presenilins in beta-amyloid (A beta) production: in vitro and in vivo studies have shown that presenilin mutations are associated with relatively increased production of the longer, and highly fibrillogenic A beta 42(43) peptide, and a marked elevation in the number of A beta 42-immunoreactive plaques in the brains of individuals with familial AD who carry PS1 and PS2 mutations. There is growing evidence that the deposition of A beta 42(43) could in some cases be an early and key event in the AD pathogenic cascade. The genetic and molecular biological data discussed in this review describe mechanisms by which presenilin mutations could lead to the development of AD. Also, mutant presenilins may be more proapoptotic. It is argued that the understanding of the processes by which presenilin mutations lead to the development of AD will help in devising a coherent framework for therapeutic strategies.