The neglected role of relative humidity in the interannual variability of urban malaria in Indian cities.

The rapid pace of urbanization makes it imperative that we better understand the influence of climate forcing on urban malaria transmission. Despite extensive study of temperature effects in vector-borne infections in general, consideration of relative humidity remains limited. With process-based dynamical models informed by almost two decades of monthly surveillance data, we address the role of relative humidity in the interannual variability of epidemic malaria in two semi-arid cities of India. We show a strong and significant effect of humidity during the pre-transmission season on malaria burden in coastal Surat and more arid inland Ahmedabad. Simulations of the climate-driven transmission model with the MLE (Maximum Likelihood Estimates) of the parameters retrospectively capture the observed variability of disease incidence, and also prospectively predict that of 'out-of-fit' cases in more recent years, with high accuracy. Our findings indicate that relative humidity is a critical factor in the spread of urban malaria and potentially other vector-borne epidemics, and that climate change and lack of hydrological planning in cities might jeopardize malaria elimination efforts.

[NHG 'Traumatic wounds and bite wounds' treatment guideline]. / NHG-behandelrichtlijn 'Traumatische wonden en bijtwonden'.

- The 'Traumatic wounds and bite wounds' treatment guideline by the NHG (Dutch College of General Practitioners) has recommendations for treating traumatic wounds, bite wounds and wound infection.- It is important to distinguish between traumatic wounds and bite wounds because treatment of lacerations and cuts differs from treatment of bites.- Clean a wound under a lukewarm water tap; avoid using disinfectants.- Preferably close traumatic wounds within 12 hours, provided that the wounds have been carefully cleaned and that there are no referral indications. The strict limit of 6 hours has been abandoned because the age of the wound does not seem to be related to increased infection risk.- Do not close bite wounds unless there is a low estimated risk of infection, it is considered cosmetically important, closure is possible within 8 hours, provided that the wounds have been carefully cleaned, and there are no referral indications.

El Niño-based malaria epidemic warning for Oromia, Ethiopia, from August 2016 to July 2017.

OBJECTIVE: Tropical highland malaria intensifies and shifts to higher altitudes during exceptionally warm years. Above-normal temperatures associated with El Niño during boreal winter months (December-March) may intensify malaria in East African highlands. We assessed the malaria risk for Oromia, the largest region of Ethiopia with around 30 million inhabitants. METHODS: Simple linear regression and spatial analyses were used to associate sea surface temperatures (SST) in the Pacific and surface temperatures in Ethiopia with annual malaria risk in Oromia, based on confirmed cases of malaria between 1982 and 2005. RESULTS: A strong association (R2 = 0.6, P < 0.001) was identified between malaria and sea surface temperatures in the Pacific, anticipating a 70% increase in malaria risk for the period from August 2016 to July 2017. This forecast was quantitatively supported by elevated land surface temperatures (+1.6 °C) in December 2015. When more station data become available and mean March 2016 temperatures from meteorological stations can be taken into account, a more robust prediction can be issued. CONCLUSION: An epidemic warning is issued for Oromia, Ethiopia, between August 2016 and July 2017 and may include the pre-July short malaria season. Similar relationships reported for Madagascar point to an epidemic risk for all East African highlands with around 150 million people. Preparedness for this high risk period would include pre-emptive intradomestic spraying with insecticides, adequate stocking of antimalarials, and spatial extension of diagnostic capacity and more frequent reporting to enable a rapid public health response when and where required.

Altitudinal changes in malaria incidence in highlands of Ethiopia and Colombia.

The impact of global warming on insect-borne diseases and on highland malaria in particular remains controversial. Temperature is known to influence transmission intensity through its effects on the population growth of the mosquito vector and on pathogen development within the vector. Spatiotemporal data at a regional scale in highlands of Colombia and Ethiopia supplied an opportunity to examine how the spatial distribution of the disease changes with the interannual variability of temperature. We provide evidence for an increase in the altitude of malaria distribution in warmer years, which implies that climate change will, without mitigation, result in an increase of the malaria burden in the densely populated highlands of Africa and South America.

IRF6 Screening of Syndromic and a priori Non-Syndromic Cleft Lip and Palate Patients: Identification of a New Type of Minor VWS Sign.

Van der Woude syndrome (VWS), caused by dominant IRF6 mutation, is the most common cleft syndrome. In 15% of the patients, lip pits are absent and the phenotype mimics isolated clefts. Therefore, we hypothesized that some of the families classified as having non-syndromic inherited cleft lip and palate could have an IRF6 mutation. We screened in total 170 patients with cleft lip with or without cleft palate (CL/P): 75 were syndromic and 95 were a priori part of multiplex non-syndromic families. A mutation was identified in 62.7 and 3.3% of the patients, respectively. In one of the 95 a priori non-syndromic families with an autosomal dominant inheritance (family B), new insights into the family history revealed the presence, at birth, of lower lip pits in two members and the diagnosis was revised as VWS. A novel lower lip sign was observed in one individual in this family. Interestingly, a similar lower lip sign was also observed in one individual from a 2nd family (family A). This consists of 2 nodules below the lower lip on the external side. In a 3rd multiplex family (family C), a de novo mutation was identified in an a priori non-syndromic CL/P patient. Re-examination after mutation screening revealed the presence of a tiny pit-looking lesion on the inner side of the lower lip leading to a revised diagnosis of VWS. On the basis of this data, we conclude that IRF6 should be screened when any doubt rises about the normality of the lower lip and also if a non-syndromic cleft lip patient (with or without cleft palate) has a family history suggestive of autosomal dominant inheritance.

Prescribing quality indicators of type 2 diabetes mellitus ambulatory care.

BACKGROUND: Existing performance indicators for assessing quality of care in type 2 diabetes mellitus (T2DM) focus mostly on registration of measurements and clinical outcomes, and not on quality of prescribing. OBJECTIVE: To develop a set of valid prescribing quality indicators (PQI) for internal use in T2DM, and assess the operational validity of the PQI using electronic medical records. METHODS: Potential PQI for hypertension, hyperglycaemia, dyslipidaemia and antiplatelet treatment in T2DM were based on clinical guidelines, and assessed on face and content validity in an expert panel followed by a panel of GPs and diabetologists. Analysis of ratings was performed using the RAND/UCLA Appropriateness Method. The operational validity of selected indicators was assessed in a dataset of 3214 T2DM patients registered with 70 GPs. RESULTS: Out of 31 potential prescribing indicators, the expert panel considered 18 indicators as sufficiently valid, of which 14 indicators remained valid after assessment by the panel of GPs and diabetologists. Of these 14 indicators, one could not be calculated because of an absence of eligible patients. For the remaining indicators, outcomes varied from 10% for timely prescribing of insulin to 96% for prescribing of any antihyperglycemic medication in patients with elevated HbA1c levels. CONCLUSIONS: This study provides a set of face- and content-valid PQI for pharmacological management of patients with T2DM. While outcomes of some PQI were limited to patients with registration of clinical values, the selected PQI had good operational validity to be used in practice for assessment of prescribing quality.

Anderson's disease (chylomicron retention disease): a new mutation in the SARA2 gene associated with muscular and cardiac abnormalities.

Anderson's disease (AD) or chylomicron retention disease (CMRD) is a rare hereditary lipid malabsorption syndrome linked to SARA2 gene mutations. We report in this study a novel mutation in two sisters for which the Sar1b protein is predicted to be truncated by 32 amino acids at its carboxyl-terminus. Because the SARA2 gene is also expressed in the muscle, heart, liver and placenta, extraintestinal clinical manifestations may exist. For the first time, we describe in this study in the two sisters muscular as well as cardiac abnormalities that could be related to the reported expression of SARA2 in these tissues. We also evaluated six other patients for potential manifestations of the SARA2 mutation. The creatine phosphokinase levels were increased in all patients [1.5-9.4 x normal (N)] and transaminases were moderately elevated in five of the eight patients (1.2-2.6 x N), probably related to muscle disease rather than to liver dysfunction. A decreased ejection fraction occurred in one patient (40%, N: 60%). The muscle, liver and placental tissues that were examined had no specific abnormalities and, in particular, no lipid accumulation. These results suggest that myolysis and other extraintestinal abnormalities can occur in AD/CMRD and that the clinical evaluation of patients should reflect this.

[Summary of the practice guideline 'Viral hepatitis and other liver diseases' (second revision) from the Dutch College of General Practitioners]. / Samenvatting van de standaard 'Virushepatitis en andere leveraandoeningen' (tweede herziening) van het Nederlands Huisartsen Genootschap.

The revised Dutch College of General Practitioners' practice guideline 'Viral hepatitis and other liver diseases' offers advice in the diagnosis and management of viral hepatitis A, B and C and other liver diseases. The guideline is important for general practitioners as well as specialists in internal medicine and gastroenterology. The emphasis is on the management of chronic hepatitis B en C, because the prevalence of these diseases has increased in the Netherlands and, in addition, the treatment options for chronic hepatitis have improved. Consequently, timely recognition and adequate referral of patients with chronic hepatitis B or hepatitis C have become more important. However, many patients with a chronic liver disease have no symptoms. Therefore, the general practitioner should be aware that a patient visiting the practice with fatigue and malaise could have a liver disease if he or she belongs to a high-risk group or has had high-risk contacts. If the general practitioner repeatedly finds increased liver transaminase values during routine examination of asymptomatic patients, additional diagnostic tests should be performed. Further tests should focus on viral hepatitis as well as on non-alcoholic fatty liver disease and non-alcoholic steatohepatitis or, depending on the history-taking, liver damage due to excessive alcohol, medication or drug use.

Shifting patterns: malaria dynamics and rainfall variability in an African highland.

The long-term patterns of malaria in the East African highlands typically involve not only a general upward trend in cases but also a dramatic increase in the size of epidemic outbreaks. The role of climate variability in driving epidemic cycles at interannual time scales remains controversial, in part because it has been seen as conflicting with the alternative explanation of purely endogenous cycles exclusively generated by the nonlinear dynamics of the disease. We analyse a long temporal record of monthly cases from 1970 to 2003 in a highland of western Kenya with both a time-series epidemiological model (time-series susceptible-infected-recovered) and a statistical approach specifically developed for non-stationary patterns. Results show that multiyear cycles of malaria outbreaks appear in the 1980s, concomitant with the timing of a regime shift in the dynamics of cases; the cycles become more pronounced in the 1990s, when the coupling between disease and rainfall is also stronger as the variance of rainfall increased at the frequencies of coupling. Disease dynamics and climate forcing play complementary and interacting roles at different temporal scales. Thus, these mechanisms should not be viewed as alternative and their interaction needs to be integrated in the development of future predictive models.

Decreased expression of Intestinal I- and L-FABP levels in rare human genetic lipid malabsorption syndromes.

We investigated, for the first time, the expression of I- and L-FABP in two very rare hereditary lipid malabsorption syndromes as compared with normal subjects. Abetalipoproteinemia (ABL) and Anderson's disease (AD) are characterized by an inability to export alimentary lipids as chylomicrons that result in fat loading of enterocytes. Duodeno-jejunal biopsies were obtained from 14 fasted normal subjects, and from four patients with ABL and from six with AD. Intestinal FABP expression was investigated by immuno-histochemistry, western blot, ELISA and Northern blot analysis. In contrast to normal subjects, the cellular immunostaining for both FABPs was clearly decreased in patients, as the enterocytes became fat-laden. In patients with ABL, the intestinal contents of I- (60.7 +/- 13.38 ng/mg protein) and L-FABP (750.3 +/- 121.3 ng/mg protein) are significantly reduced (50 and 35%, P < 0.05, respectively) as compared to normal subjects (I-135.3 +/- 11.1 ng, L-1211 +/- 110 ng/mg protein). In AD, the patients also exhibited decreased expression (50%, P < 0.05; I-59 +/- 11.88 ng, L-618.2 +/- 104.6 ng/mg protein). Decreased FABP expression was not associated with decreased mRNA levels. The results suggest that enterocytes might regulate intracellular FABP content in response to intracellular fatty acids, which we speculate may act as lipid sensors to prevent their intracellular transport.

[Summary of the practice guideline 'Diabetes mellitus type 2' (second revision) from the Dutch College of General Practitioners]. / Samenvatting van de standaard 'Diabetes mellitus type 2' (tweede herziening) van het Nederlands Huisartsen Genootschap.

The practice guideline 'Diabetes mellitus type 2' (second revision) addresses the diagnosis, treatment and management of adults with diabetes mellitus type 2 in general practice. The aim of management is the prevention and treatment of diabetes-related symptoms and complications such as cardiovascular disease, nephro-, retino- and neuropathy. The general practitioner gives the patient education and lifestyle advice and repeats this regularly. In addition, the general practitioner and the patient strive to achieve good glycaemic control. The agent of first choice in the medicinal treatment of all type 2 diabetic patients is metformin. This is continued even after the addition of a sulphonylurea derivative or insulin. This represents a change compared to the previous version of the practice guideline. The indications for thiazolidinediones are limited. To reduce the cardiovascular risk, it is advised to aim at a systolic blood pressure below 140 mmHg. It is also recommended that each patient be prescribed a statin, unless the patient belongs to a subgroup in which the indication for cholesterol lowering therapy is weak or the patient refuses it. Compared to the former guideline, more emphasis is placed on the prevention of nephropathy. The general practitioner is advised to calculate the creatinine clearance yearly and to test for relevant albuminuria in each patient with a life expectancy of 10 years or more. If microalbuminuria is present, the patient is prescribed an angiotensin converting enzyme (ACE) inhibitor, even if the blood pressure is not elevated. The detection of patients with a high risk of diabetic ulcer is also given more emphasis.

Malaria resurgence in the East African highlands: temperature trends revisited.

The incidence of malaria in the East African highlands has increased since the end of the 1970s. The role of climate change in the exacerbation of the disease has been controversial, and the specific influence of rising temperature (warming) has been highly debated following a previous study reporting no evidence to support a trend in temperature. We revisit this result using the same temperature data, now updated to the present from 1950 to 2002 for four high-altitude sites in East Africa where malaria has become a serious public health problem. With both nonparametric and parametric statistical analyses, we find evidence for a significant warming trend at all sites. To assess the biological significance of this trend, we drive a dynamical model for the population dynamics of the mosquito vector with the temperature time series and the corresponding detrended versions. This approach suggests that the observed temperature changes would be significantly amplified by the mosquito population dynamics with a difference in the biological response at least 1 order of magnitude larger than that in the environmental variable. Our results emphasize the importance of considering not just the statistical significance of climate trends but also their biological implications with dynamical models.

[Summary of the practice guideline 'Stable angina pectoris' (second revision) from the Dutch College of General Practitioners]. / Samenvatting van de standaard 'Stabiele angina pectoris' (tweede herziening) van het Nederlands Huisartsen Genootschap.

Typical angina pectoris is characterised by retrosternal complaints that are provoked by exertion, cold, emotional stress or heavy meals and are relieved by rest within 15 minutes or within a few minutes of using sublingual nitroglycerin. If 2 or 3 of these symptoms are present then the term 'atypical angina pectoris' is used. The general practitioner can estimate the risk of significant coronary artery disease on the basis of the anamnesis. Additional diagnostics in the form of an exercise ECG is only worthwhile if the pretest probability of coronary artery disease lies between 30% and 70% (atypical angina pectoris) and not if the diagnosis is extremely likely or extremely unlikely. Patients with angina pectoris should be informed about the alarm symptoms which can be indicative of unstable angina pectoris or acute myocardial infarction. Sublingual nitrate therapy is used for the short-term control of angina. If more than 2 attacks per week occur, a maintenance treatment consisting of beta-blockers, nitrates, or calcium channel blockers should be started in this order of preference. For secondary prevention, acetylsalicylic acid and statins should be prescribed and lifestyle advice should be given, such as smoking cessation, sufficient physical exercise and a healthy diet.

Genomic imbalances in mental retardation.

INTRODUCTION: It has been estimated that cytogenetically visible rearrangements are present in approximately 1% of newborns. These chromosomal changes can cause a wide range of deleterious developmental effects, including mental retardation (MR). It is assumed that many other cases exist where the cause is a submicroscopic deletion or duplication. To facilitate the detection of such cases, different techniques have been developed, which have differing efficiency as to the number of loci and patients that can be tested. METHODS: We implemented multiplex amplifiable probe hybridisation (MAPH) to test areas known to be rearranged in MR patients (for example, subtelomeric/pericentromeric regions and those affected in microdeletion syndromes) and to look for new regions that might be related to MR. RESULTS: In this study, over 30 000 screens for duplications and deletions were carried out; 162 different loci tested in each of 188 developmentally delayed patients. The analysis resulted in the detection of 19 rearrangements, of which approximately 65% would not have been detected by conventional cytogenetic analysis. A significant fraction (46%) of the rearrangements found were interstitial, despite the fact that only a limited number of these loci have so far been tested. DISCUSSION: Our results strengthen the arguments for whole genome screening within this population, as it can be assumed that many more interstitial rearrangements would be detected. The strengths of MAPH for this analysis are the simplicity, the high throughput potential, and the high resolution of analysis. This combination should help in the future identification of the specific genes that are responsible for MR.

Pharmaceutical development of a parenteral lyophilized formulation of the investigational polymer-conjugated platinum anticancer agent AP 5280.

AP 5280 is a novel polymer-conjugated platinum anticancer agent showing promising in vitro and in vivo activity against solid tumors. The aim of this study was to develop a parenteral pharmaceutical dosage form for phase I clinical trials. AP 5280 drug substance was characterized by using a wide range of analytical techniques and showed excellent solubility in water. However, as aqueous solutions of AP 5280 proved to be labile upon sterilization by moist heat, it was decided to develop a lyophilized dosage form. Initially, glass vials were used as primary packaging, but this led to a high breakage rate, which could be completely prevented by the use of CZ resin vials. Stability studies to date show that the lyophilized product in glass vials is stable for at least 12 months when stored at 2-8 degrees C in the dark and the lyophilized product in CZ resin vials is stable for at least 6 months under these conditions. Photostability testing revealed photolability of AP 5280 drug substance and lyophilized product in both types of primary container, necessitating storage in the dark. The first clinical experiences indicate that the proposed formulation is fully applicable for use in the clinical setting.

Pharmaceutical development of a parenteral lyophilized formulation of the antimetastatic ruthenium complex NAMI-A.

This paper describes the development of a stable pharmaceutical dosage form for NAMI-A, a novel antimetastatic ruthenium complex, for Phase I testing. NAMI-A drug substance was characterized using several spectrometric and chromatographic techniques. In preformulation studies, it was found that NAMI-A in aqueous solution was not stable enough to allow sterilization by moist heat. The effect of several excipients on the stability of the formulation solution was investigated. None of them provided sufficient stability to allow long-term storage of an aqueous solution of NAMI-A. Therefore, a lyophilized product was developed. Five different formulations were prepared and subjected to thermogravimetric (TG) analysis and stability studies at various conditions for 1 year. Minimal degradation during the production process is achieved with a formulation solution of pH 3-4. Of the acids tested, only hydrochloric acid (HCl 0.1 mM) both stabilized the formulation solution and was compatible with the lyophilized product. This product was stable for at least 1 year when stored at -20 degrees C, 25 degrees C/60% relative humidity (RH) and 40 degrees C/75% RH, and was also photostable.