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Abstract Objective: The aim of this commentary was to evaluate the current evidence regarding the use of synthetic insulin analogues in the 'real-world' clinic setting for the treatment of type 2 diabetes mellitus (T2DM). Methods: Relevant publications were searched on PubMed MEDLINE, EMBASE, Cochrane Register of Controlled Trials Google Scholar, NLM Gateway, Science Direct, Web of Science and OVID for the period of January 2007 to June 2010. Articles were included if they (a) provided specific study results on the use of insulin analogues in T2DM and (b) gave sufficiently clear methodology details to establish treatment strategies, diagnosis and diagnostic criteria using an observational study (OS) design. Results: Twenty one articles specifically addressing both type 2 diabetes management and the use of synthetic insulin analogues were identified. Results from recently published OS in patients with T2DM have shown, in the patient populations tested, the effective initiation, optimization and switch to use of insulin analogues in routine clinical settings (day-to-day common practice), with a good safety profile. Conclusions: OS can provide clinicians with additional insights into the management of T2DM patients in their practices. However, the selection and initiation of insulin analogue regimens should be tailored to the individual patient and be one that the physician is comfortable using. [ABSTRACT FROM AUTHOR]

BACKGROUND: In this era of evidence-based medicine, clinicians require a comprehensive range of well-designed studies to support prescribing decisions and patient management. In recent years, data from observational studies have become an increasingly important source of evidence because of improvements in observational-study methods and advances in statistical analysis. OBJECTIVE: This article reviews the current literature and reports some of the key studies indicating that observational studies can both complement and build on the evidence base established by randomized controlled trials (RCTs). METHODS: A literature search using the MEDLINE/ PubMed database (years: 1966-present) was carried out using the search terms observational or observational study(ies), historical control, nonrandomized, and postmarketing surveillance. All references comparing observational studies with randomized controlled trials were obtained and reviewed and were also hand-checked for studies not identified in the database searches. RESULTS: Observational studies play an important role in investigating treatment outcomes. Data from large observational studies can clarify the tolerability profile of marketed medicines. In particular, observational studies can be of benefit in the study of large, heterogeneous patient populations with complex, chronic diseases such as diabetes mellitus. Observational studies have played a key role in supporting the results of Phase III studies of insulin analogues for the treatment of patients with type 1 and type 2 diabetes. Future observational studies in the field of diabetes such as PREDICTIVE (Predictable Results and Experience in Diabetes through Intensification and Control to Target: an International Variability Evaluation) and IMPROVE will further our understanding of this global pandemic. CONCLUSIONS: Well-designed observational studies can play a key role in supporting the evidence base for drugs and therapies. Current evidence suggests that observational studies can be conducted using the same exacting and rigorous standards as are used for RCTs. The observational study design should be considered as a complementary rather than a rival analytic technique. [ABSTRACT FROM AUTHOR]

Aims: Evaluate the safety and efficacy of once-daily insulin detemir initiated in routine clinical practice in patients with type 2 diabetes mellitus inadequately controlled with oral hypoglycaemic agents (OHAs)., Methods: This large observational study was conducted in 10 countries. Adverse event data (including hypoglycaemia) and glycaemic control were recorded before and 24 weeks following insulin initiation while patients continued routine clinical management., Results: In this study, 17 374 patients (53% male) were included. Mean pre-insulin values (±s.d.) were: age 62 ± 12 years; body mass index (BMI) 29.3 ± 5.4 kg/m(2); diabetes duration 10 ± 7 years; haemoglobin A1c (HbA1c) 8.9 ± 1.6%. During the study, 27 patients experienced serious adverse drug reaction, severe hypoglycaemic events or both; and there were 31 episodes of severe hypoglycaemia in 21 patients. After 24 weeks, HbA1c was 7.5 ± 1.2% (change of -1.3%; p < 0.001) and mean weight change was -0.6 kg (confidence interval -0.7, -0.5 kg, p < 0.001). Daily insulin dose increased from 13 ± 6 U (0.16 ± 0.09 U/kg) to 22 ± 16 U (0.27 ± 0.17U/kg) by 24 weeks. Multivariate regression analysis identified several independent demographic and treatment predictors of end of study HbA1c., Conclusions: Addition of once-daily insulin detemir to patients with type 2 diabetes mellitus on OHA therapy resulted in few adverse events, significant improvements in glycaemic control, small reductions in weight and low rates of hypoglycaemia. On the basis of this study, concerns about hypoglycaemia or weight gain should not preclude initiation of basal insulin analogues in patients with poor glycaemic control on OHAs., (© 2012 Blackwell Publishing Ltd.)

Hypoglycemia is a significant problem in elderly adults with diabetes mellitus. Elderly individuals with diabetes mellitus are at greater risk than younger adults for hypoglycemic events. Several factors contribute to this risk, including the high prevalence of comorbidities, polypharmacy, cognitive impairment, and concomitant use of agents that interfere with glucose metabolism. To minimize the risk of hypoglycemia and maximize the benefits of glycemic control, guidelines typically recommend individualizing glycosylated hemoglobin (HbA1c) targets based on life expectancy, functional status, and individual goals. Although many individuals with type 2 diabetes mellitus will ultimately require insulin therapy to achieve and maintain glycemic control, earlier insulin initiation in elderly individuals may be warranted, particularly in those with renal, cardiovascular, or hepatic concerns that could interfere with the use of oral agents. There are few data on the use of insulin-or other glucose-lowering agents-in elderly adults, but limited evidence suggests that the use of insulin, especially insulin analogs, may be appropriate in this population. Insulin analogs offer a better pharmacokinetic profile, greater convenience, and less variable glycemic control than human insulin. Because of the high prevalence of cognitive impairment and other geriatric syndromes in elderly adults, clinicians should perform a comprehensive assessment of patients' ability to administer and monitor insulin therapy and recognize and treat hypoglycemia., (© 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.)

Background: The majority of patients with type 2 diabetes mellitus (T2DM) are overweight or obese. Obesity is a significant risk factor for increased morbidity and mortality in people with T2DM, and increased weight has been shown to worsen glycemic control and increase the risk of diabetes progression., Methods: A search was conducted of the National Library of Medicine (PubMed) for articles published from 1990 to 2009 about the treatments of T2DM, relationship between T2DM and weight gain, obesity-related comorbidities of T2DM, and T2DM therapies associated with increased weight. Reference lists of retrieved articles were reviewed for additional publications., Findings: Results from large, prospective clinical trials have shown that weight reduction significantly improves glycemic control and blood pressure in T2DM patients and lowers the risk of progression of T2DM as well as CV disease and cancer. Treatment-related weight gain is a side effect of many oral antidiabetes agents and insulin. The thiazolidinediones (TZD), sulfonylureas, and glinides are associated with weight gain. Despite the weight gain, TZDs also redistribute fat from the central to peripheral compartments, which may lead to a beneficial effect on insulin resistance. Among insulin products, the basal insulin analog detemir is typically associated with a smaller weight increase than human insulin and insulin analog preparations, including glargine, biphasic, and prandial insulin regimens. Alpha-glucosidase inhibitors and dipeptidyl peptidase-4 inhibitors are weight neutral, whereas glucagon-like peptide1-R agonists and metformin are associated with weight loss., Discussion: An effective approach to management of the obese patient with diabetes is to communicate the significant benefits of a 1 kg reduction in body weight or prevention of weight gain on glycemic control and reduced morbidity and mortality., Limitation: This article is based on an extensive literature review rather than the prospective studies needed to define further the effect of weight gain on the management of T2DM., Conclusion: Weight management should be an integral part of a T2DM treatment strategy that includes selecting oral antidiabetes medications and insulin products that are weight beneficial.

In 2009, consensus guidelines were published on intensification of insulin therapy using the premix analog biphasic insulin aspart (BIAsp) 30 in the treatment of type 2 diabetes, based on the recommendations of an international, independent expert panel. The guidelines included recommendations and titration algorithms for intensification from basal insulin once (OD) or twice daily (BID) to BIAsp 30 BID, from OD BIAsp 30 to BID, and from BID BIAsp 30 to three times daily (TID). Building on these recommendations, the objective was to develop similar, simple and effective guidelines for intensification switch from a BIAsp 30 to a mid-/high-ratio premix regimen for the vast majority of patients with type 2 diabetes. A panel of independent experts with extensive clinical experience in premix analog therapy met in October 2009 to review the therapeutic role of mid- and high-ratio premixes (BIAsp 50 and 70, respectively). The panel outlined a series of algorithms for intensifying BIAsp 30 BID and TID with mid-/high-ratio premixes, along with practical suggestions relating to intensification for individual patients. A simple tool to aid dose adjustment was also developed. The guidelines suggested here should assist physicians in introducing mid-/high-ratio premixes to optimize the insulin therapy of patients with type 2 diabetes who are failing to achieve glycemic targets on a BIAsp 30 BID or TID regimen.

Objective: To compare efficacy and safety of biphasic insulin aspart 70/30 (BIAsp 30) with insulin (glargine) in type 2 diabetic patients who were not maintaining glycemic control on basal insulin and oral antidiabetic drugs., Methods: In a 24-week, open-label, parallel-group trial, type 2 diabetic patients who were not maintaining glycemic control on basal insulin (glargine or neutral protamine Hagedorn) + oral antidiabetic drugs were randomly assigned to twice-daily BIAsp 30 + metformin or once-daily glargine + metformin + secretagogues (secretagogues were discontinued in the BIAsp 30 arm)., Results: One hundred thirty-seven patients were randomly assigned to the BIAsp 30 group and 143 patients were randomly assigned to the glargine group. Of 280 patients randomized, 229 (81.8%) completed the study. End-of-trial hemoglobin A1c reductions were -1.3% (BIAsp 30) vs -1.2% (glargine) (treatment difference: 95% confidence interval, -0.06 [-0.32 to 0.20]; P = .657). Of patients taking BIAsp 30, 27.3% reached a hemoglobin A1c level <7.0% compared with 22.0% of patients taking glargine (treatment difference: P = .388). Glucose increment averaged over 3 meals was lower in the BIAsp 30 arm (treatment difference: -17.8 mg/dL, P = .001). Fasting plasma glucose reductions from baseline were -13.8 mg/dL (BIAsp 30) vs -42.5 mg/dL (glargine) (P = .0002). Final minor hypoglycemia rate, insulin dose, and weight change were higher in the BIAsp 30 arm (6.5 vs 3.4 events/patient per year, P<.05; 1.19 vs 0.63 U/kg; and 3.1 vs 1.4 kg, P = .0004, respectively)., Conclusions: Despite not receiving secretagogues, patients taking BIAsp 30 + metformin achieved similar hemoglobin A1c levels and lower postprandial plasma glucose compared with those receiving glargine + metformin + secretagogues. The large improvement in the glargine group suggests the patients were not true basal failures at randomization. While switching to BIAsp 30 improves glycemic control in this patient population, remaining on basal insulin and optimizing the dose may be equally effective in the short term.

Background: To describe the epidemiology and trends of imported malaria in the Netherlands from 2000 through 2007., Methods: Based on national surveillance data regarding all reported infections of imported malaria, diagnosed 2000 through 2007, incidence and trends of imported malaria in the Netherlands were estimated. Travellers statistics were used to estimate incidence, and data on malaria chemoprophylaxis prescriptions were used to estimate the number of unprotected travellers., Results: Importation of malaria to the Netherlands is declining even as more travellers visit malaria-endemic countries. On average, 82% were acquired in sub-Saharan Africa, and 75% were caused by Plasmodium falciparum. The overall incidence in imported falciparum malaria fell from 21.5 to 6.6/10,000 of unprotected travellers. The percentage of unprotected travellers rose from 47% to 52% of all travellers. The incidence of imported falciparum infections is greatest from Middle and West Africa, and decreased from 121.3 to 36.5/10,000 travellers. The import of malaria from this region by immigrants visiting friends and relatives (VFR) decreased from 138 infections in 2000, to 69 infections in 2007., Conclusion: The annual number of imported malaria shows a continuing declining trend, even with an increasing number of travellers visiting malaria endemic countries. VFR import less malaria than previously, and contribute largely to the declining incidence seen. The decline is not readily explained by increased use of chemoprophylaxis and may reflect a reduced risk of infection due to decreasing local malaria transmission as observed in some malaria endemic areas. Nevertheless, the increasing number of unprotected travellers remains worrisome.

Some patients with type 2 diabetes continue to have high postprandial blood glucose levels on twice-daily regimens of 'low-ratio' premix insulin formulations (up to 30% rapid-acting, with 70% protracted insulin). These patients require intensified insulin therapy, which can be provided by a twice- or thrice-daily regimen of mid-ratio (50% rapid-acting and 50% protaminated intermediate-acting insulin - human or analogue) or high-ratio (70% rapid-acting and 30% protaminated insulin - analogue only) premix insulin. Alternatively, a third daily injection of low-ratio premix insulin can be added to the regimen, with the option of incorporating one or more injections of mid- or high-ratio premix as required, and as an alternative to basal-bolus therapy. How these mid- and high-ratio formulations differ from the low-ratio premix insulins is reviewed here, with the aim of identifying the role of these formulations in diabetes management. Glucose clamp studies have shown that premix analogues give serum insulin levels proportional to their percentage of rapid-acting uncomplexed insulin: the higher the proportion, the greater the maximum level reached. Other pharmacokinetic parameters were not always significantly different between the mid- and high-ratio formulations. In clinical trials, postprandial plasma glucose and glycated haemoglobin A1c (HbA(1c)) levels were significantly reduced with thrice-daily mid- /high-ratio premix analogue when compared with twice-daily low-ratio biphasic human insulin (BHI) 30/70 or once-daily insulin glargine. Moreover, glycaemic control with mid-/high-ratio premix analogue was found to be similar to that with a basal-bolus therapy. Mid- and high-ratio premix regimens are generally well tolerated. The frequency of minor hypoglycaemia was reportedly higher with mid- /high-ratio premix analogues than with BHI 30, but nocturnal hypoglycaemia was less frequent. Although there is little evidence that clinical outcomes with mid-ratio premix analogues are different from those with high-ratio, they are useful additions to the low-ratio formulations for the management of diabetes, and addressing postprandial hyperglycaemia in particular.

Background: Insulin is recommended as a second-line treatment after diet and metformin fail to reach and/or maintain glycemic targets considered to minimize the risk for long-term diabetic complications. Hypoglycemia and the fear of developing hypoglyce-mia, however, remain substantial barriers to the initiation and optimal use of insulin., Objective: The aim of this study was to compare biphasic insulin aspart 30 (BIAsp 30) with biphasic human insulin 30 (BHI 30) with respect to glycemic control and the risk for hypoglycemia using a meta-analysis of clinical trials comparing these insulins in patients with type 2 diabetes mellitus (T2DM)., Methods: We included all published and unpublished, randomized, controlled trials in adult patients with T2DM (treatment duration > or = 12 weeks) for which individual patient data were available. All clinical databases and local trial registries of Novo Nordisk A/S (Soeborg, Denmark) were searched to identify clinical trials comparing the 2 products. The predefined primary end point of the study was the overall rate of nocturnal hypoglyce-mia (major, minor, and symptoms-only hypoglycemia occurring from 12:00-6:00 AM). Hypoglycemia was analyzed using a negative binomial distribution model, accounting for exposure time. Glycemic end points were analyzed at 12 to 16 weeks of treatment using ANCOVA, adjusting for baseline. Secondary safety end points were the rates of major hypoglycemia (hypoglycemia requiring third-party assistance), minor hypoglycemia (symptoms confirmed by plasma glucose [PG] <3.1 mmol/L), daytime hypoglycemia (major, minor, and symptoms-only hypoglycemia occurring from 6:01 AM-11:59 PM), overall hypoglycemia (the sum of all major, minor, and symptoms-only episodes), and change in weight from baseline to 12 to 16 weeks of treatment. Secondary efficacy end points were changes in glycosylated hemoglobin (HbA(1c)), fasting PG (FPG), postprandial PG increment (averaged over breakfast, lunch, and dinner), and insulin dose., Results: Nine randomized, parallel or crossover trials were included (N = 1674; male sex, 57%; mean [SD] age, 61.0 [10.6] years; body mass index, 26.7 [4.6] kg/m(2); HbA(1c), 8.1% [1.4%]; duration of diabetes, 10.9 [7.9] years). Rates of overall hypoglycemia were not significantly different (rate ratio [RR] = 1.08; 95% CI, 0.94-1.24; P = NS) between treatments. BIAsp 30 had a 50% lower rate of nocturnal hypoglycemia than BHI 30 (RR = 0.50; 95% CI, 0.38-0.67; P < 0.01), whereas the rate of daytime hypoglycemia was 24% lower for BHI 30 (RR = 1.24; 95% CI, 1.08-1.43; P < 0.01). The likelihood of major hypo-glycemia was significantly lower with BIAsp 30 compared with BHI 30 (odds ratio = 0.45; 95% CI, 0.22-0.93; P < 0.05). BIAsp 30 was associated with reduced PPG increment (averaged over breakfast, lunch and dinner) compared with BHI 30 (treatment difference, -0.31; 95% CI, -0.49 to -0.07; P < 0.01). There was a significantly larger reduction in FPG associated with BHI 30 (treatment difference, 0.63; 95% CI, 0.31-0.95; P < 0.01). However, no significant treatment difference was found for HbA(1c) (treatment difference, 0.04; 95% CI, -0.02 to 0.10; P = NS)., Conclusion: This meta-analysis found BIAsp 30 to be associated with a significantly lower rate of nocturnal and major hypoglycemia, but a significantly increased risk for daytime hypoglycemia, compared with BHI 30 at a similar level of HbA(1c) in patients with T2DM.

Aims: This 18-month study assessed the improvement in glycaemic control and proportion of patients reaching glycated haemoglobin (HbA(1c)) targets with biphasic insulin aspart 30/70 (BIAsp 30) in clinical practice., Methods: Type-2 diabetes patients failing on oral antidiabetic drugs (n=90) or existing insulin regimens (n=59) started or switched to BIAsp 30. Thiazolidinediones were stopped, metformin was continued. BIAsp 30 was given once daily (n=41), twice daily (n=96), or three times daily (n=12). Patients were taught self-monitoring and self-titration using an algorithm, adding daily doses of BIAsp 30 when necessary., Results: Mean baseline HbA(1c) was 8.4%, weight 85.4 kg, and age 57.9 years. All patients experienced significant reductions in HbA(1c) (mean 1.9%+/-0.1), fasting plasma glucose (mean 2.8 mmol/l), and post-prandial glycaemia (mean 2.9 mmol/l); 91% of patients achieved HbA(1c)<7% and 52% achieved HbA(1c) < or=6.5%. No major or nocturnal hypoglycaemia were reported; 15% of patients reported minor hypoglycaemia. Insulin-naïve patients gained mean 2.7 kg; patients who switched from another insulin lost weight (mean -0.6kg)., Conclusion: The results from this study from routine care suggest that BIAsp 30 may allow a large proportion of type-2 diabetes patients (90%) to improve glycaemic control and reach target HbA(1c)<7%, using self-titration.

Aim: This trial evaluated the potential for improving glycaemic control by intensifying a conventional twice-daily therapy with premixed human insulin (HI) to a thrice-daily regimen using premixed formulations of biphasic insulin aspart (BIAsp) in patients with type 1 or type 2 diabetes., Methods: This was a multicentre, open-label, parallel group trial. After a 4-week run-in period, patients were randomized 1 : 1 to 16 weeks of treatment. A total of 748 patients were screened, 664 were exposed to trial drug and 604 completed the trial., Results: Haemoglobin A(1c), the primary efficacy endpoint, was shown to be significantly lower for the BIAsp treatment group compared with the biphasic HI (BHI) 30 group [estimated mean difference: -0.32, 95% confidence interval (CI) (-0.48; -0.16), p = 0.0001]. The average blood glucose level was significantly lower in the BIAsp group [estimated mean difference: -0.79, 95% CI (-1.17; -0.40), p = 0.0001]. There were few major hypoglycaemic episodes, 11 in the BIAsp group and 7 in the BHI 30 group. Although intensification of insulin therapy with BIAsp three times a day was associated with a higher risk of minor hypoglycaemia (relative risk = 1.58, p = 0.0038), the overall rate of minor hypoglycaemia remained low with both the BIAsp and the BHI treatments (13.1 vs. 8.3 episodes/patient year respectively). Overall safety and patient satisfaction were similar with the two insulin therapies., Conclusions: This trial confirmed that a thrice-daily BIAsp regimen can safely be used to intensify treatment for patients inadequately controlled on twice-daily BHI. A treat-to-target trial is required to explore the full potential of the BIAsp regimens and evaluate their use as a viable alternative to intensification with a basal-bolus regimen.

Objective: To determine for what reasons West African immigrants, who contribute the largest single group of malaria cases in the Netherlands, visit pre-travel preventive health services and whether use of such services is likely to improve use of preventive measures., Methods: Semi-structured interviews with eligible participants recruited through West African churches and societies and at a large festival., Results: A total of 70% of the total non-random sample of 292 participants said that they always use pre-travel preventive health services before travelling. Being from Ghana (OR = 2.5), having legal residency status (OR = 2.5), visiting friends and relatives rather than going for business or funeral (OR = 6.7), and living in Amsterdam (OR = 5.1) were all independently associated with using pre-travel preventive health services, as were taking general preventive measures (OR = 3.0), and self-reported use of malaria prophylaxis. Higher use of pre-travel preventive health services was not associated with better knowledge of malaria as such., Conclusions: West Africans, in particular non-Ghanaians, illegal immigrants and West African immigrants leaving at short notice should be encouraged to use pre-travel preventive health services. Adequate methods to reach these groups need to be developed, including health education on the importance of prevention in general.

Aims: To show that a thrice daily meal-time biphasic insulin aspart (BIAsp) treatment regimen is as efficacious as a 4 times daily basal-bolus regimen with human isophane insulin (NPH) and insulin aspart (IAsp)., Methods: A multinational, randomised, open-label parallel-group trial in 394 patients with type 2 diabetes on a once or twice daily insulin regimen. Patients were randomised 1:1 to BIAsp or IAsp+NPH for 16 weeks. The BIAsp group was treated according to individual needs using BMI as a surrogate index of insulin resistance. Subjects administered BIAsp 70 (BMI< or =30 kg/m (2)) or BIAsp 50 (BMI>30 kg/m (2)) with breakfast and lunch and BIAsp 30 with dinner. The IAsp+NPH group injected IAsp at meals and NPH at bedtime as basal insulin. HbAlc levels after 16 weeks were compared between treatments using a predefined non-inferiority criterion of 0.4%. The incidence of hypoglycaemic episodes and adverse events was evaluated., Results: Mean HbAlc (+/-SD) decreased from 9.1+/-0.7% to 7.8+/-1.0% with both treatments. Glycaemic control provided by BIAsp was non-inferior to that obtained by the IAsp+NPH (intention to treat ITT) population: diff, HbAlc -0.05%; 95% CI (-0.24; 0.14); per protocol (PP) population: diff, HbAlc -0.03%; 95% CI (-0.23; 0.16). Similar improvements in glycaemic control in both groups were confirmed by self-measured 8-point plasma glucose (PG) profiles, average and fasting PG concentrations, and average prandial PG increments. The incidence of adverse events and hypoglycaemic episodes was similar in the two treatment groups., Conclusions: A thrice daily meal-time BIAsp regimen is a suitable alternative to an intensified insulin regimen in people with inadequately controlled type 2 diabetes mellitus, and requires fewer daily injections than a basal-bolus therapy without compromising efficacy and safety.

Background: Mefloquine, a drug used for treatment and prophylaxis of malaria, is known for its neuropsychiatric adverse effects. We hypothesized that neuropsychiatric adverse effects of mefloquine are associated with polymorphisms in the MDR1/ABCB1 gene that encodes for the efflux pump P-glycoprotein., Methods: The association between MDR1 C1236T, G2677T, and C3435T single-nucleotide polymorphisms and the occurrence of neuropsychiatric adverse effects was examined in a prospective cohort study of 89 healthy white travelers taking mefloquine., Results: Of the subjects, 27 (28%) reported neuropsychiatric adverse effects, women significantly more frequently than men. Allele frequencies of the C1236T, G2677T, and C3435T polymorphisms were similar to those found in other white populations, and there was no significant association between any of the individual polymorphisms and neuropsychiatric adverse effects. However, women with the 1236TT, 2677TT, and 3435TT genotypes had a higher risk of neuropsychiatric adverse effects than the reference groups of women with heterozygous and homozygous CC or GG genotypes, with odds ratios of 6.3 (95% confidence interval [CI], 1.1-36.9), 10.5 (95% CI, 1.1-100.6), and 5.4 (95% CI, 1.1-30.0), respectively. The association for women homozygous for the 1236-2677-3435 TTT haplotype was even stronger (P = .004) than the effect of any of the individual polymorphisms. No associations with mefloquine blood levels were observed., Conclusion: In this study the MDR1 1236TT, 2677TT, and 3435TT genotypes, along with the 1236-2677-3435 TTT haplotype, were associated with neuropsychiatric adverse effects of mefloquine in women. MDR1 polymorphisms may play an important role in predicting the occurrence of neuropsychiatric adverse effects of mefloquine, particularly in female travelers.

The Irukandji syndrome is a jellyfish envenomation caused by Carukia barnesi or related jellyfish. In literature, the distribution of "Irukandji-like" syndromes is restricted to Australia. We report a case of probable Irukandji syndrome in Thailand. With this report, we hope to promote awareness to aid sting prevention and stimulate research.

Enterotoxigenic Escherichia coli (ETEC), which produces heat labile toxin (LT) and/or heat stable toxin (ST), is considered to be the most common known cause of travellers' diarrhoea (TD). Owing to the antigenic similarity between cholera toxin and LT, immunization with inactivated oral B-subunit/whole-cell cholera vaccine (BS-WC) offers short term (3 months) but significant (>67%) protection against TD caused by LT-related ETEC. Since it expresses the cholera toxin B (CTB) subunit, the live attenuated oral cholera vaccine strain CVD 103-HgR, may induce similar protection. A trial was performed to determine if CVD 103-HgR live oral cholera vaccine would provide a protective efficacy of at least 50% against TD. In addition, the protective efficacy of the vaccine against TD specifically due to LT-ETEC and LT/ST-ETEC was determined. Volunteers (n=134) travelling to Indonesia, India, Thailand or West-Africa were randomised to receive either a placebo (n=65) or the vaccine (n=69). In the placebo group, 46% reported an episode of diarrhoea, compared to 52% in the vaccine group. No significant group differences were found with regard to incidence, duration or severity of all caused TD or ETEC-associated TD. However, ETEC-associated TD occurred earlier in the placebo group (median 5 days), compared to the vaccine group (median 15 days). In conclusion, CVD 103-HgR live oral cholera vaccine failed to provide a 50% protection against TD. This study does not exclude that the vaccine may offer a short-lived protection against ETEC-associated TD. However, the power of the study was limited by the unexpected low incidence of LT-ETEC-associated diarrhoea (9% of all TD) compared to ST-associated TD (24% of all TD).

Aims: We performed a prospective cohort study to gain more insight into risk factors for neuropsychiatric effects of mefloquine among tourists travelling to tropical areas., Methods: We enrolled all patients who consulted the Travel Clinic of the Havenziekenhuis & Institute for Tropical Diseases Rotterdam for mefloquine prophylaxis during the period between 1 May 1999 and 7 March 2000. Each patient was followed from baseline (prior to starting mefloquine) up to 3 weeks after starting weekly intake of 250 mg mefloquine. We compared the intraindividual change in scores between baseline and follow-up visit on the Dutch shortened Profile of Mood States, and on the Continuous Performance Test (CPT) which measures sustained attention., Results: The final cohort consisted of 151 subjects with a mean age of 38 years. In this population, a significant impairment of mood state was observed in those with a body mass index (BMI) < or = 20 kg m(-2). Stratification for gender showed that the total mood disturbance in females in the lowest BMI category significantly increased by 8.42 points [95% confidence interval (CI) 3.33, 13.50], whereas BMI did not affect the risk in males. Stratification for history of use of mefloquine showed that the risks were highest in first-time users. Analyses of the CPT showed that reaction time in women with a BMI < or = 20 kg m(-2) increased significantly by 22.5 ms (95% CI 7.80, 37.20), whereas reaction time in men showed a slight and nonsignificant decrease., Conclusion: Risk factors for mefloquine-associated neuropsychiatric adverse events and concentration impairment are female gender, low BMI, and first-time use. The frequency of neuropsychiatric effects is highest in women with a BMI < or = 20 kg m(-2).

Adult expatriates in countries where hepatitis B virus (HBV) is highly endemic have an increased risk of HBV infection, but little is known about risks to their children or about patterns of spread. The epidemiology of HBV infection was studied among 124 unvaccinated Dutch missionaries and family members who lived in a rural area of Nigeria. Antibodies to hepatitis B core antigen were found in 5 (9.8%) of 51 adults (incidence rate, 1.7 per 1000 person-months at risk [PMAR]) and 9 (12.3%) of 73 children (incidence rate, 2.8 per 1000 PMAR). Vertical transmission of HBV was a likely source of infection in 1 child and was a possible source of infection in 2 others. The prevalence of HBV infection showed strong family clustering (P<.0001), was associated with a history of temporary adoption of Nigerian children (P=.004), and increased with both the number of adoptive children (P=.009) and the total time that these children had stayed in the family (P=.036). Horizontal transmission from adoptive Nigerian children probably played an important role in the spread of HBV infection in this expatriate community.

Objectives: We performed a prospective, double-blind, randomized study to compare the occurrence of neuropsychiatric adverse events and concentration impairment during prophylactic use of either mefloquine or atovaquone plus chloroguanide (INN, proguanil)., Methods: Our potential study population consisted of all persons who were included in the MAL30010 trial at the Travel Clinic, Rotterdam, The Netherlands. All subjects were randomized to receive either active atovaquone (250 mg) plus chloroguanide (100 mg) daily plus a placebo for mefloquine weekly or active mefloquine (250 mg) weekly plus a placebo for atovaquone plus chloroguanide daily. Each subject was followed up from a baseline screening visit up to the index date, 7 days after he or she left the malaria-endemic area. We measured the interindividual and intraindividual changes in mood disturbance by means of the Dutch shortened Profile of Mood States and 3 domains of the Neurobehavioral Evaluation System, which included sustained attention, coding speed, and visuomotor accuracy between baseline and follow-up visit., Results: The cohort consisted of 119 subjects with a mean age of 35 years. A significant deterioration in depression, anger, fatigue, vigor, and total mood disturbance domains occurred during use of mefloquine but not during use of atovaquone plus chloroguanide. Stratification for sex showed between-treatment differences in female patients but not in male patients. In both treatment groups, sustained attention deteriorated after travel, especially with increased duration of stay., Conclusions: Prophylactic use of mefloquine was associated with significantly higher scores on scales for depression, anger, and fatigue and lower scores for vigor than prophylactic use of atovaquone plus chloroguanide.

Introduction: It has been suggested that neuropsychiatric events during use of mefloquine are more common in females than in males and are partly explained by the psychological stress of travelling. Therefore, we investigated neuropsychiatric events in females and males on mefloquine in the 3-week prophylactic period that precedes travelling. Furthermore, we investigated whether first-time users had a higher risk of neuropsychiatric adverse events than subjects with a history of mefloquine use., Methods: We enrolled all patients who visited a Travel Clinic for mefloquine prophylaxis during the period 1 May 1999 to 7 March 2000. Each patient was followed from baseline (prior to starting mefloquine) up to 3 weeks after the start of mefloquine but before travelling. We asked patients to register any adverse event in a diary and measured the intra-individual change in scores on the Dutch Shortened Profile Of Mood States (POMS) at baseline and at the end of follow-up., Results: The final cohort consisted of 179 subjects with a mean age of 3 years. Females reported adverse events more frequently than males ( P=0.005). Overall, we observed a small but significant increase in the score on the domain fatigue [0.74 points, 95% confidence interval (CI) 0.18, 1.30]. The effect was exclusively present in females and not in males. First-time users of mefloquine increased 2.81 points (95% CI 0.70, 4.92) on the total score of the POMS, and among those, women showed the largest increase of 4.58 points (95% CI 0.74, 8.43)., Conclusion: The use of mefloquine was associated with neuropsychiatric adverse effects. Females encountered neuropsychiatric effects more frequently than males, which could be confirmed by validated psychological tests. Neuropsychiatric effects were more common in first-time users than in individuals who had used mefloquine before.

Background: To assess whether there are clinically significant problems in patients with insulin-dependent diabetes mellitus (IDDM) traveling to tropical countries regarding metabolic dysregulations, infectious complications and general health problems., Methods: A retrospective, descriptive cohort study by telephone interview of all IDDM patients who had received pretravel health advice at our travel clinic during a 12 month period. Data were collected on IDDM related problems: hypo-/hyperglycemic dysregulation, infectious complications, practical difficulties, exploring risk factors, as well as on general health problems., Results: Of the 19 respondents, 13 (68%) reported any metabolic dysregulation, including all but one respondents with Type 1 diabetes. Fifty-five percent of Type 1 diabetics reported to have dysregulated more often than in the preceding period at home. Critical dysregulations occurred in 2 of the 19 study patients. Only 4 out of 11 (36%) type 1 IDDM patients increased frequency of blood glucose monitoring while traveling. Three travelers reported a febrile illness which resulted in hyperglycemic dysregulation. Five study patients experienced difficulties in the adjustment of their insulin dosage to the unfamiliar circumstances of traveling in the tropics., Conclusions: Metabolic dysregulation was a clinically significant problem, thus IDDM travelers to tropical destinations probably run extra health risks. Fever, easily acquired in the tropics, appeared to be an additional, serious health problem for this study population. As the number of diabetic travelers will increase, more research on the importance of risk factors possibly leading to dysregulation is necessary.

Objective: To assess the prevalence of HIV infection and related risk factors among Dutch expatriates returning from assignment in sub-Saharan Africa, Latin America, and South and South-east Asia., Methods: From July 1994 to January 1996, a questionnaire on the risks of sexual exposure was completed by 864 respondents, and blood samples were taken., Results: Of the 634 men, 41% reported having sex with casual or steady local partners and 11% with casual or steady expatriate partners, during an average stay of 26 months in the previous 3 years. Of the 230 women, these figures were 31 and 24%, respectively. Of the men with local casual partners (29%), 59% paid for sex at least once. For men as well as women, having sexual contacts abroad was associated with younger age, positive intention prior to departure to have sex abroad, being single at departure, and, only for the men, working for a commercial organization, and feelings of loneliness and boredom. Among men, consistent condom use with casual local partners was 69%, and with casual expatriate partners 63%. Among women, these figures were 64 and 48%, respectively. Consistent condom use with steady local or expatriate partners was much lower. Among men, non-consistent condom use with casual partners was more prevalent if they had been abroad for a longer time, condoms were not taken along from The Netherlands, the country where they were posted was Asian, and the estimated HIV prevalence among the local population was lower. Among the women, non-consistent condom use was more prevalent if condoms were not taken along, and if they did not have the intention before departure to have sex abroad. Of the persons from whom blood could be obtained, one man was HIV-positive. Another man who refused to participate in the study indicated that he was HIV-positive., Conclusions: Although 23% of the expatriates had unprotected sex with partners from endemic areas, very few HIV infections were found. In comparison with a previous study among this population carried out in 1987-1989, which found five out of 1968 expatriates to be HIV-infected, consistent condom use with casual local partners did increase considerably (from 21 to 67%). However, health education is needed to reduce the risk of HIV infection, which should emphasize the sociocultural differences in sexual practices.

Objective: To study the neuro-psychiatric adverse effects of antimalarial drugs., Setting: Persons who visited a Travel Clinic in Rotterdam over a period of 3 months., Design: Prospective cohort study on 394 persons taking mefloquine, 493 persons taking proguanil and 340 persons not taking antimalarial drugs who visited Africa, South America, Asia, or the Middle East., Methods: All persons received a structured questionnaire within 14 days of their return to the Netherlands. The questionnaire consisted of questions regarding use of alcohol, smoking, general health, medical history, tropical diseases during the trip, and other medicines, and contained an extensive list of general complaints regarding all body systems at four levels of severity. A modified and validated version of the Profile of Mood States was included., Results: In the study period, 2541 persons visited the Travel Clinic, of whom 1791 (70%) were both eligible and willing to co-operate. Of these 1791, data were obtained from 1501 (84%). Insomnia was most frequently encountered in users of mefloquine and mouth ulcers in proguanil users. After adjustment for gender, age, destination, and alcohol use, the relative risk for insomnia to mefloquine versus non-users of antimalarials was 1.6, and the excess risk was 6 per 100 users over an average period of 2 months. There were no significant differences between groups in depression, anxiety, agitation, and confusion. Stratification by gender demonstrated that insomnia was more common in women on mefloquine, but not in men. Also, women more frequently mentioned palpitations as an adverse event. After adjustment for age, destination, and alcohol use in women, the relative risks for insomnia and palpitations to mefloquine versus non-use of antimalarials were 2.4, and 22.5, respectively. When travellers were specifically asked for the adverse reactions they had experienced, anxiety, vertigo, agitation, and nightmares were significantly more frequently mentioned by mefloquine users., Conclusion: Insomnia was more commonly encountered during use of mefloquine than proguanil or during non-use of antimalarials.

A patient with Q fever is described who had been ill for a year before the diagnosis was made on the basis of serological data. In addition it was possible to isolate Coxiella burnetii, the causative agent by culture from the urine. This is very exceptional and is to our knowledge only the second case in which this has been achieved. The patient made a full recovery after lengthy treatment with tetracycline. Q fever should be considered in patients with pyrexia of unknown origin, particularly in travellers.