Updating the epidemiological transition model.

The main feature of the epidemiological transition is a shift in the recorded causes of death from infectious diseases to other morbid conditions. This paper outlines modifications made to Omran's original model and stages of transition, and suggests that without a focus on aetiology and morbidity, these have been basically descriptive rather than explanatory, and potentially misleading because infections have been confirmed as causes of various chronic diseases. Common infections and related immune responses or inflammatory processes contribute to the multifactorial aetiology of morbid conditions that together make a substantial contribution to overall mortality, and infectious causation is suspected for many others because of strong evidence of association. Investigation into possible infectious causes of conditions frequently recorded as the underlying cause of death can be integrated into a framework for comparative research on patterns of disease and mortality in support of public health and prevention. A theory of epidemiological transition aimed at understanding changes in disease patterns can encompass the role in different conditions and chronic diseases of infections contracted over the life course, and their contribution to disability, morbidity and mortality relative to other causes and determinants.

Long-term trends in cardiovascular disease mortality and association with respiratory disease.

The recent decline in cardiovascular disease mortality in Western countries has been linked with changes in life style and treatment. This study considers periods of decline before effective medical interventions or knowledge about risk factors. Trends in annual age-standardized death rates from cerebrovascular disease, heart disease and circulatory disease, and all cardiovascular disease are reviewed for three phases, 1881-1916, 1920-1939, and 1940-2000. There was a consistent decline in the cerebrovascular disease death rate between 1891 and 2000, apart from brief increases after the two world wars. The heart disease and circulatory disease death rate was declining between 1891 and 1910 before cigarette smoking became prevalent. The early peak in cardiovascular mortality in 1891 coincided with an influenza pandemic and a peak in the death rate from bronchitis, pneumonia and influenza. There is also correspondence between short-term fluctuations in the death rates from these respiratory diseases and cardiovascular disease. This evidence of ecological association is consistent with the findings of many studies that seasonal influenza can trigger acute myocardial infarction and episodes of respiratory infection are followed by increased risk of cardiovascular events. Vaccination studies could provide more definitive evidence of the role in cardiovascular disease and mortality of influenza, other viruses, and common bacterial agents of respiratory infection.

Infrared lidar observations of stratospheric aerosols.

We observed the stratospheric aerosol layer at 34° north latitude with a photon-counting 1574 nm lidar on three occasions in 2011. During all of the observations, we also operated a nearby 523.5 nm micropulse lidar and acquired National Weather Service upper air data. We analyzed the lidar data to find scattering ratio profiles and the integrated aerosol backscatter at both wavelengths and then calculated the color ratio and wavelength exponent for lidar backscattering from the stratospheric aerosols. The visible-light integrated backscatter values of the layer were in the range 2.8-3.5×10⁻4 sr⁻¹ and the infrared integrated backscatter values ranged from 2.4 to 3.7×10⁻5 sr⁻¹. The wavelength exponent was determined to be 1.9±0.2.

Location of release sites and calcium-activated chloride channels relative to calcium channels at the photoreceptor ribbon synapse.

Vesicle release from photoreceptor ribbon synapses is regulated by L-type Ca(2+) channels, which are in turn regulated by Cl(-) moving through calcium-activated chloride [Cl(Ca)] channels. We assessed the proximity of Ca(2+) channels to release sites and Cl(Ca) channels in synaptic terminals of salamander photoreceptors by comparing fast (BAPTA) and slow (EGTA) intracellular Ca(2+) buffers. BAPTA did not fully block synaptic release, indicating some release sites are <100 nm from Ca(2+) channels. Comparing Cl(Ca) currents with predicted Ca(2+) diffusion profiles suggested that Cl(Ca) and Ca(2+) channels average a few hundred nanometers apart, but the inability of BAPTA to block Cl(Ca) currents completely suggested some channels are much closer together. Diffuse immunolabeling of terminals with an antibody to the putative Cl(Ca) channel TMEM16A supports the idea that Cl(Ca) channels are dispersed throughout the presynaptic terminal, in contrast with clustering of Ca(2+) channels near ribbons. Cl(Ca) currents evoked by intracellular calcium ion concentration ([Ca(2+)](i)) elevation through flash photolysis of DM-nitrophen exhibited EC(50) values of 556 and 377 nM with Hill slopes of 1.8 and 2.4 in rods and cones, respectively. These relationships were used to estimate average submembrane [Ca(2+)](i) in photoreceptor terminals. Consistent with control of exocytosis by [Ca(2+)] nanodomains near Ca(2+) channels, average submembrane [Ca(2+)](i) remained below the vesicle release threshold (∼ 400 nM) over much of the physiological voltage range for cones. Positioning Ca(2+) channels near release sites may improve fidelity in converting voltage changes to synaptic release. A diffuse distribution of Cl(Ca) channels may allow Ca(2+) influx at one site to influence relatively distant Ca(2+) channels.

Pharmacokinetics of novel erythropoiesis stimulating protein (NESP) in cancer patients: preliminary report.

Anaemia is a common occurrence in patients with cancer, and currently can be treated in several ways. Novel erythropoiesis stimulating protein (NESP, darbepoetin alfa) was created using site-directed mutagenesis to have 8 more sialic acid side chains than recombinant human erythropoietin (rHuEPO). The additional sialic acid content has resulted in an approximately 3-fold greater half-life relative to rHuEPO in patients with chronic renal failure. This study evaluates the pharmacokinetic profile of NESP in patients receiving multiple cycles of chemotherapy. Anaemic patients (haemoglobin < or = 11.0 g dl(-1)) who had non-myeloid malignancies received NESP weekly (2.25 mcg kg(-1) wk(-1)) under the supervision of a physician, starting on day 1 of chemotherapy for 3 chemotherapy cycles given at 3-week intervals. Blood samples were collected during chemotherapy cycles 1 and 3 for pharmacokinetic analysis. All patients were followed for 4 weeks after treatment. NESP was well tolerated by all patients. After a single dose during chemotherapy cycle 1, pharmacokinetic parameters (mean (SD), n) for the first 15 patients were: T(max)86.1 (22.8) h (n = 14); C(max)9.0 (5.1) ng ml(-1)(n = 14); t(1/2,z)32.6 (11.8) h (n = 7); CL/F 3.7 (1.0) ml h(-1) kg(-1)(n = 7). The subjects for whom all parameters could be calculated may represent a sub-group of the entire population. Similar results were obtained in cycle 3. In addition, haemoglobin response data suggests that, in this patient population, dosing less frequently than the 3 times weekly doses used for rHuEPO may be possible while improving anaemia.

Lack of an effect of zolmitriptan (Zomig, 311C90) on psychometric task performance: results of a placebo-controlled study in healthy volunteers.

The novel selective 5-hydroxytryptamine (5-HT)1B/1D agonist, zolmitriptan (Zomig, formerly known as 311C90), has shown good efficacy in the acute oral treatment of migraine. Zolmitriptan acts both centrally and peripherally, therefore it is important to assess central nervous system effects. At single doses of 25-50 mg (up to 8 times the likely therapeutic dose), zolmitriptan can cause sedation; therefore, a study was designed to examine the dose-response. A double-blind, randomized, placebo-controlled, six-limb crossover study in 13 healthy volunteers compared the effects of single oral doses of zolmitriptan (5, 10, 15 or 20 mg) and lorazepam (2 mg) on various psychometric tests. Zolmitriptan doses less than 20 mg had no statistically significant effects on choice reaction time, the Stroop test, visual analog scale (VAS) assessments of physical sedation, tranquilization and other types of feelings, the logical reasoning test or the adaptive tracking test. There was a mild transient increase in the subjective assessment on VAS of mental sedation which was dose related and occurred mainly with the highest zolmitriptan dose and were not reflected in objective measures of drug effects. In contrast, lorazepam (used as a positive control) was associated with statistically significant impairment in all tests (except tranquilization) for up to 10 h after dosing. The results demonstrate that therapeutic doses of zolmitriptan are unlikely to cause clinically significant impairment in psychometric performance.

Disposition of atovaquone in humans.

Atovaquone is an antiprotozoal compound with good in vitro stability against metabolic inactivation. Previous human studies which did not involve radiolabelling had not accounted for a substantial proportion of the dose. The possible metabolism of atovaquone in men was examined in a radiolabelling study involving four healthy male volunteers. Radioactivity was eliminated almost exclusively via the feces. All radioactivity in plasma, urine, and feces was accounted for by atovaquone, with no evidence of metabolites. Radiolabelled atovaquone was administered to a patient with an indwelling biliary tube after surgery. Biliary radioactivity was approximately 10- to 40-fold higher than that in plasma and was accounted for by atovaquone. Atovaquone is not significantly metabolized in humans but is excreted into bile against a high concentration gradient.

The epidemic of visceral leishmaniasis in western Upper Nile, southern Sudan: course and impact from 1984 to 1994.

BACKGROUND: Although endemic in parts of southern Sudan, visceral leishmaniasis (VL) had not been reported in Western Upper Nile (WUN) until an epidemic was confirmed in 1989. A combination of circumstances created conditions for transmission among a population of mainly Nuer and Dinka people who had no immunity. The civil war which restarted in 1983 has been a major contributing cause and continues to hinder provision of treatment, data collection and control measures. METHODS: Since the first of three clinics to treat VL was established in WUN in 1989, data on the epidemic and mortality have been collected in seven retrospective surveys of villages and among patients. Adults were interviewed about surviving family members and those who had died since the epidemic came. Survey death rates are used here to estimate mortality from VL and 'excess mortality' above expected levels. RESULTS: The surveys found high mortality at all ages and suggest an overall death rate of 38-57% since the epidemic started in 1984, and up to 70% in the most affected areas. Both methods of estimation suggest that around 100,000 deaths, among about 280,000 people in the epidemic area, might be attributable to VL. CONCLUSIONS: This continuing epidemic has shown that VL can cause high mortality in an outbreak with astonishingly high infection rates. Population movement has been a major factor in transmission and poor nutritional status has probably contributed to the risk of clinical infection. Although over 17,000 people have been successfully treated for VL at the clinics in WUN, the disease is likely to become endemic there.

PIP: The syndrome of fever, wasting, and enlarged spleen or lymph glands resulting from visceral leishmaniasis (VL) is usually fatal unless treated. While VL is endemic in parts of southern Sudan, it was first reported in Western Upper Nile (WUN) during a confirmed epidemic in 1989 among a population of mainly Nuer and Dinka people who had no immunity. Civil war has been a major contributing factor to the continuation and spread of the epidemic, and continues to impede the provision of treatment, data collection, and control measures. The first of three clinics to treat VL was established in WUN in 1989. Data have since been collected in seven retrospective surveys in villages and among patients. Survey death rates were used to estimate mortality from VL and excess mortality above expected levels. Mortality was high at all ages. The overall death rate is estimated at 38-57% since the epidemic started in 1984, and up to 70% in the most affected areas. Approximately 100,000 deaths, among approximately 280,000 people in the epidemic area, may be attributable to VL.

Epidemic visceral leishmaniasis in southern Sudan: treatment of severely debilitated patients under wartime conditions and with limited resources.

OBJECTIVES: 1) To determine the proportions of patients with visceral leishmaniasis who had various treatment outcomes when cared for under wartime conditions and with limited resources and 2) to identify patient characteristics associated with the outcomes. DESIGN: Cohort study. SETTING: Médecins sans Frontières-Holland's treatment center in Duar, Western Upper Nile Province, an area in southern Sudan that has been severely affected by Sudan's civil war and a massive epidemic of visceral leishmaniasis. PATIENTS: 3076 consecutive patients who had visceral leishmaniasis, were admitted to the treatment center the first year the center was operational (August 1990 to July 1991), and were treated with the pentavalent antimonial compound sodium stibogluconate. MEASUREMENTS: Patient characteristics on admission and four mutually exclusive treatment outcomes (default during first admission, death during first admission, discharge and readmission for retreatment [relapse], and discharge and no readmission for retreatment [successful treatment]). RESULTS: The patients had a median age of 15 years and were notably anemic (median hemoglobin level, 77g/L) and malnourished (median body mass index of adults [> or = 18 years of age], 15.2 kg/m2); most (91.0%) had been sick less than 5 months. Although patients could not be monitored after treatment to document cure, most (2562 [83.3%]) were successfully treated; 336 (10.9%) died during their first admission, and 79 are known to have relapsed (3.0% of those discharged alive [that is, those whose final treatment outcome was successful treatment or relapse]). In univariable analysis, young and older age (<5 or > or = 45 years of age), long duration of illness (> or = 5 months), markedly low hemoglobin level or body mass index, large spleen, high parasite density, and vomiting at least once during the treatment course were associated with death. In multiple logistic regression analysis of data for a subgroup of 1207 adults (those who did not default or relapse and for whom data were recorded on age, sex, duration of illness, hemoglobin level, body mass index, and spleen size), the approximate risk ratios for death were 2.2 (95% Cl, 1.4 to 3.6) for those with a long duration of illness, 3.6 (Cl, 2.1 to 5.9) for those 45 years of age or older, 4.6 (Cl, 2.2 to 9.4) for those with a hemoglobin level less than 60 g/L, and 12.2 (Cl, 3.2 to 47.2) for those with a body mass index less than 12.2 kg/m2. CONCLUSION; Despite the severe debility of the patients and the exceptionally difficult circumstances under which they were treated, most fared remarkably well.

Guinea worm disease in Ayod, Upper Nile Province, southern Sudan: a cross-sectional study.

Upper Nile Province is one of the four main endemic areas for Guinea worm disease in the Sudan. In December 1994, a survey was conducted in the village of Ayod where the disease is endemic, to investigate morbidity and local knowledge of transmission and prevention. Interviews were conducted in households selected by standard cluster sampling procedures and of the 759 people examined, 156 (20.6%) had Guinea worm lesions. Adjusted odds ratios were used to estimate the relative risk for people with different personal or household characteristics in a multivariate analysis. After controlling for the possible confounding effects of other study variables, having a filter in the household, gender, and lack of knowledge about transmission and about prevention, were not associated with lesions. Only two variables were significantly associated with Guinea worm disease: getting water from a source other than a well increased the risk by a factor of 2.3, and being aged 5 years or more increased the risk by a factor of 31.1. This study demonstrates the clear association between the source of water for drinking and Guinea worm disease found elsewhere. We suggest the provision of reliable sources of pure drinking water and health education are the most suitable long-term preventive measures. The Sudan now represents the greatest challenge to the goal of global eradication of Guinea worm disease, following the reduction in cases in Nigeria. The continuing civil war and insecurity in southern Sudan hinder the implementation of an effective water programme and other control measures, but the potential benefits through reduced incapacity and improved agricultural productivity are considerable.

Pharmacokinetics and pharmacodynamics of tucaresol, an antisickling agent, in healthy volunteers.

1. Tucaresol is an orally administered antisickling agent which increases the oxygen affinity of haemoglobin. 2. The pharmacokinetics, effects on moderate graded exercise and psychometric performance of tucaresol were examined in a double-blind, placebo-controlled, parallel groups study in 12 healthy men. 3. Three doses of tucaresol were given at 48 h intervals intended to modify 15, 25 and 32.5% of a subject's haemoglobin to a high affinity form (%MOD). 4. Mean peak %MOD was 34%. Mean Cmax values in plasma and erythrocytes were 81.4 and 1459 micrograms ml-1, respectively. 5. Heart rate, compared with baseline, increased in the tucaresol group with the greatest changes at the highest %MOD and workload. There were no differences between groups in psychometric test performance. 6. Three volunteers on active drug developed fever, rash and tender cervical lymphadenopathy with onset 7-10 days from the start of dosing, suggesting an immune mechanism. 7. The acute increase in oxygen affinity with tucaresol is physiologically well-tolerated, but the utility of tucaresol in the management of sickle cell disease will depend on the identification of a dosing regimen with a lower incidence of drug allergy.

Examination of some factors responsible for a food-induced increase in absorption of atovaquone.

1. Atovaquone is a potent antiprotozoal slowly and irregularly absorbed after administration as tablets to fasting volunteers. A series of studies was performed to investigate the effects of food, bile and formulation on atovaquone absorption. 2. In 18 healthy male volunteers, a high-fat breakfast administered 45 min before 500 mg atovaquone as tablets increased AUC by 3.3-fold (95% CI 2.8-4.0) and Cmax 5.3-fold (4.3-6.6) compared with fasting. 3. The absorption of atovaquone from tablets was examined in 12 healthy male volunteers after an overnight fast, following toast alone, toast with 28 g butter (LOFAT), or toast with 56 g butter (HIFAT). Compared with absorption when fasted, toast had no significant effect but LOFAT increased AUC 3.0-fold (2.1-4.2) and Cmax 3.9-fold (2.6-5.8). HIFAT increased AUC 3.9-fold (2.7-5.5) and Cmax 5.6-fold (3.8-8.4). 4. The absorption of atovaquone was examined in nine healthy fasting male volunteers from tablets, an aqueous suspension, and an oily solution/suspension in miglyol (fractionated coconut oil). Compared with tablets, AUC following the aqueous suspension was increased 1.7-fold (1.0-2.7) and Cmax 2.4-fold (1.7-3.5). Following miglyol, AUC was increased to the same extent but Cmax was only increased 1.8-fold (1.2-2.6). 5. Atovaquone absorption was examined in eight healthy fasting male volunteers following an i.v. infusion of cholecystokinin octapeptide (CCK-OP) which decreased gallbladder volume by 82% (73%-90%) on occasion 1 or saline on occasion 2. AUC(0,12) was increased following CCK-OP by 1.6-fold (1.1-2.4) and Cmax by 1.5-fold (0.98-2.4).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of zolpidem on saccadic eye movements and psychomotor performance: a double-blind, placebo controlled study in healthy volunteers.

1. Peak saccade velocity provides a valuable means of assessing the sedative effect of drugs in humans. The present study investigated the effects of zolpidem, an imidazopyridine hypnotic, on saccade velocity in healthy volunteers after single and repeated administration. 2. Zolpidem 5 mg, 10 mg and 20 mg significantly and dose dependently depressed peak saccade velocity during the 1.5 h after a single administration. On the morning after zolpidem administration, peak saccade velocity had returned towards pretreatment levels. Nitrazepam 10 mg also significantly depressed peak saccade velocity but the effect was maintained the following morning. The saccade response to zolpidem (5 and 10 mg) was undiminished after the seven nightly doses. 3. Nightly administration of zolpidem improved subjective sleep quality and there was no evidence of rebound insomnia following cessation of drug treatment.

Migration from plasticized films into foods. 5. Identification of individual species in a polymeric plasticizer and their migration into foods.

To assess the significance of migration of polymeric plasticizers into foods, chemical characterization and quantification of individual oligomeric species is required. This paper reports the identification of seven individual oligomers isolated from a poly(butylene adipate) plasticizer. Based on mass spectrometry, NMR and chemical degradation, the oligomers were identified as a series of diol-terminated units ranging from a trimer up to an 11-monomer unit, along with a cyclic tetramer, all in the molecular weight range of 300-1100. A study of the migration of polymeric plasticizer from PVC film into olive oil indicated preferential migration of low molecular weight species. These oligomers which comprised 24% of the parent plasticizer contributed more than 90% of the plasticizer migration with the smallest oligomers migrating 90-fold more readily than the bulk of the plasticizer. From a knowledge of total polymeric plasticizer migration from PVC films under actual conditions of food-use, the abundance of individual oligomers in the foods has been estimated.

Gas chromatographic-mass spectrometric determination of adipate-based polymeric plasticizers in foods.

A method for the quantitative determination of adipate-based polymeric plasticizers in foods is described. The procedure involves extraction from the food and transmethylation of the polymeric plasticizer to form dimethyladipate (DMA). The derivative is cleaned up by size-exclusion chromatography and determined by capillary gas chromatography-mass spectrometry with selected ion monitoring. The use of a deuterated internal standard at the extraction stage enables quantitation by stable isotope dilution. A detection limit of 0.1 mg/kg of the polymeric plasticizer in foods and a relative standard deviation of 4% have been achieved routinely. The method has been applied successfully to the analysis of cheese, sandwiches, meat, biscuits, and cake that have been in contact with polymeric plasticized poly(vinyl chloride) films.

Migration from plasticized films into foods. 3. Migration of phthalate, sebacate, citrate and phosphate esters from films used for retail food packaging.

A UK survey of plasticizer levels in retail foods (73 samples) wrapped in plasticized films or materials with plasticized coatings has been carried out. A wide range of different food-types packaged in vinylidene chloride copolymers (PVDC), nitrocellulose-coated regenerated cellulose film (RCF) and cellulose acetate were purchased from retail and 'take-away' outlets. Plasticizers found in these films were dibutyl sebacate (DBS) and acetyl tributyl citrate (ATBC) in PVDC, dibutyl phthalate (DBP), dicyclohexyl phthalate (DCHP), butylbenzyl phthalate (BBP), and diphenyl 2-ethylhexyl phosphate (DPOP) in RCF coatings, and diethyl phthlate (DEP) in cellulose acetate. Foodstuffs analysed included cheese, pate, chocolate and confectionery products, meat pies, cake, quiches and sandwiches. Analysis was by stable isotope dilution GC/MS for DBP, DCHP and DEP, GC/MS (selected ion monitoring) for BBP and DPOP, and GC with flame ionization detection for DBS and ATBC, but with mass spectrometric confirmation. Levels of plasticizers found in foods were in the following ranges: ATBC in cheese, 2-8 mg/kg; DBS in processed cheese and cooked meats, 76-137 mg/kg; 76-137 mg/kg; DBP, DCHP, BBP, and DPOP found individually or in combination in confectionery, meat pies, cake and sandwiches, total levels from 0.5 to 53 mg/kg; and DEP in quiches, 2-4 mg/kg.

Migration from plasticized films into foods. 2. Migration of di-(2-ethylhexyl)adipate from PVC films used for retail food packaging.

A UK survey of di-(2-ethylhexyl)adipate (DEHA) levels in retail foods (83 samples) wrapped in plasticized PVC film has been carried out, examining a wide range of different food types obtained from retail and take-away outlets. Foodstuffs analysed included fresh meat and poultry, ready-cooked poultry, cheese, fruit, vegetables and baked goods such as cakes, bread rolls and sandwiches. Analysis by stable isotope dilution GC/MS showed DEHA levels ranging from 1.0 to 72.8 mg/kg in uncooked meat and poultry, 9.4 to 48.6 mg/kg in cooked chicken portions, 27.8 to 135.0 mg/kg in cheese, less than 2.0 mg/kg in fruit and vegetables and 11 to 212 mg/kg in baked goods and sandwiches. The level of DEHA migration correlated with the extent of contact between the film and exposed fatty portions of the food, whether that was the mayonnaise filling of a sandwich or the surface fat from a joint of uncooked meat. The level of DEHA in meat exposed to plasticized film was not reduced significantly by volatilization or chemical transformation on subsequent cooking by grilling or frying.

Migration from plasticized films into foods. 1. Migration of di-(2-ethylhexyl)adipate from PVC films during home-use and microwave cooking.

Migration of di-(2-ethylhexyl)adipate (DEHA) into a diverse range of foods arising from the domestic use of plasticized PVC films has been determined using a stable isotope dilution GC/MS procedure. Aspects of home use reported in this study include the wrapping and covering of foods such as cheese, cooked meats, sandwiches, cakes, fresh fruit and vegetables; the use of films during food preparation such as marinading; covering during microwave reheating of previously prepared foods, and covering during microwave cooking. Contact between film and foods was for differing temperatures and times, representative of the range of conditions likely to be experienced in practice in the home. Migration increased with both the length of contact time and temperature of exposure, with the highest levels observed where there was a direct contact between the film and food, and where the latter had a high fat content on the contact surface. Highest levels of migration were observed for cheese, cooked meats, cakes and for microwave-cooked foods, whilst lower levels were observed for wrapping of unfilled sandwiches, fruit and vegetables (except avocado), and for food preparation including microwave reheating where there was covering of the food in a container but little or no direct contact.