Acute effects of L-tryptophan on brain extracellular 5-HT and 5-HIAA levels in chronic experimental portal-systemic encephalopathy

Portal-systemic encephalopathy (PSE) is associated with increased brain turnover of serotonin (5-hydroxytryptamine; 5-HT). Despite this metabolic increase, neuronal release of 5-HT is unaltered in neocortex of portacaval shunted (PCS) rats. In the present study, frontal neocortical extracellular 5-HT and 5-hydroxyindole-3-acetic acid (5-HIAA) levels were determined in PCS rats and sham-operated controls prior to, as well as, after acute challenge with L-tryptophan (L-TRP; a bolus dose of 280 mg/kg i.p. followed by 5 consecutive hourly doses of 50 mg/kg). Neither basal 5-HT nor 5-HIAA extracellular levels were significantly altered in PCS rats compared to controls. L-TRP administration resulted in unaltered extracellular 5-HT but elevated 5-HIAA levels in PCS and sham rats. These findings do not suggest that changes in brain neuronal 5-HT release play any major functional role in the pathogenesis of chronic PSE. The present data also emphasize the importance of distinguishing between brain 5-HT metabolism and brain 5-HT release.     

In vivo response of Plasmodium falciparum to different doses of chloroquine in semi-immune children in Liberia, West Africa

The efficacy of different doses of chloroquine in suppressing patent parasitaemia was investigated in 326 children two to 12 years old, living in six villages with holoendemic malaria. The children were given single doses (2, 3, 5-7 or 9-12 mg base kg-1) or a standard treatment over three days (25 mg base kg-1). Parasite prevalences were recorded after one, two, three, four, six and eight weeks. Complete clearance of Plasmodium falciparum trophozoites (TC) by day 7 was achieved by a dosage of 9-12 mg kg-1. By probit analysis of log dose response, 50% clearance (TC50) was established at about 1.5 mg kg-1, whereas a TC95 required 5.5 mg kg-1. The reappearance of patent parasitaemia was dependent on the dose of chloroquine given and on malaria transmission. After the standard dose treatment, only one re-infection in 56 children appeared within 21 days despite high sporozoite inoculation rates in the area. The dosage of 9-12 mg kg-1 yielded a hundredfold reduction of mean parasite density in the children if calculated over a four-week period. It may represent a suitable monthly regimen in a malaria control scheme in a holoendemic area with high P. falciparum sensitivity to chloroquine.     

Enhancing Syndromic Surveillance With Online Respondent-Driven Detection

Objectives. We investigated the feasibility of combining an online chain recruitment method (respondent-driven detection) and participatory surveillance panels to collect previously undetected information on infectious diseases via social networks of participants.Methods. In 2014, volunteers from 2 large panels in the Netherlands were invited to complete a survey focusing on symptoms of upper respiratory tract infections and to invite 4 individuals they had met in the preceding 2 weeks to take part in the study. We compared sociodemographic characteristics among panel participants, individuals who volunteered for our survey, and individuals recruited via respondent-driven detection.Results. Starting from 1015 panel members, the survey spread through all provinces of the Netherlands and all age groups in 83 days. A total of 433 individuals completed the survey via peer recruitment. Participants who reported symptoms were 6.1% (95% confidence interval = 5.4, 6.9) more likely to invite contact persons than were participants who did not report symptoms. Participants with symptoms invited more symptomatic recruits to take part than did participants without symptoms.Conclusions. Our findings suggest that online respondent-driven detection can enhance identification of symptomatic patients by making use of individuals’ local social networks.Syndromic surveillance provides information necessary to monitor trends in disease incidence and implement and evaluate response plans.1,2 To date, most efforts have focused on developing systems based on data from inpatient and ambulatory care health records.3 In a majority of high-income countries, including the Netherlands, influenza surveillance is based on a combination of reports of influenza-like illness (ILI) collected by sentinel surveillance clinics and additional microbiological testing of subgroups of symptomatic patients.4 This type of system excludes symptomatic patients who do not visit a general practitioner, and such patients are likely to account for the majority of cases in most influenza outbreaks.5Many communicable diseases (e.g., influenza, severe acute respiratory syndrome, measles) spread largely between socially connected individuals, such as household members and schoolchildren, and they often occur in clusters.6,7 Therefore, cases of infection are expected to cluster in social networks (i.e., contacts of an infected individual are infected at a level of probability higher than that expected if the distribution was random), and clusters can be detected via local social networks of individuals reporting symptoms.Increased Internet use facilitated the emergence of participatory surveillance (PS) systems, which enable real-time monitoring of diseases through regular submission of syndromic information by volunteers.8,9 These systems provide information that is not collected in regular surveillance, such as the proportion of symptomatic individuals who actually visit a general practitioner and the proportion who are hospitalized.To test the feasibility of eliciting information about infections in local networks of symptomatic individuals, we combined a chain recruitment method with existing online PS platforms. Under certain conditions, such a recruitment method permits stepwise and controlled sampling of contacts of contacts, and so forth, in social networks in the general population.10 We asked PS volunteers to complete a questionnaire and to invite their contacts into the study. In this way, we collected data on chains of contacts to analyze whether other symptomatic individuals could be detected via the local social network of symptomatic respondents. Our aims were to determine whether respondents can be recruited via respondent-driven detection, to report on which individuals are reached, and to assess whether there is clustering of symptomatic patients.     

Bone mineral density in primary care patients related to serum calcium concentrations: a longitudinal cohort study from Sweden

Objective: Elevated calcium concentration is a commonly used measure in screening analyses for primary hyperparathyroidism (pHPT) and cancer. Low bone mineral density (BMD) and osteoporosis are common features of pHPT and strengthen the indication for parathyroidectomy. It is not known whether an elevated calcium concentration could be a marker of low BMD in suspected pHPT patients with a normal parathyroid hormone concentration.

Purpose: To study if low BMD and osteoporosis are more common after ten years in patients with elevated compared with normal calcium concentrations at baseline.

Design: Prospective case control study.

Setting: Primary care, southern Sweden.

Subjects: One hundred twenty-seven patients (28 men) with baseline elevated, and 254 patients (56 men) with baseline normal calcium concentrations, mean age 61 years, were recruited. After ten years, 77% of those still alive (74 with elevated and 154 with normal calcium concentrations at baseline) participated in a dual energy x-ray absorptiometry measurement for BMD assessment and analysis of calcium and parathyroid hormone concentrations.

Main outcome measures: Association between elevated and normal calcium concentration at base-line and BMD at follow-up. Correlation between calcium and parathyroid hormone concentrations and BMD at follow-up.

Results: A larger proportion of the patients with elevated baseline calcium concentrations who participated in the follow-up had osteoporosis (p value?=?0.036), compared with the patients with normal concentrations. In contrast, no correlation was found between calcium or parathyroid hormone concentrations and BMD at follow-up.

Conclusions: In this study, patients with elevated calcium concentrations at baseline had osteoporosis ten years later more often than controls (45% vs. 29%), which highlights the importance of examining these patients further using absorptiometry, even when their parathyroid hormone level is normal.

• Key Points

• Osteoporosis is common, difficult to detect and usually untreated. It is not known whether elevated calcium concentrations, irrespective of the PTH level, could be a marker of low bone mineral density.

• No correlation was found between calcium or parathyroid hormone concentrations and bone mineral density at follow-up.

• In this study, patients with elevated calcium concentrations at baseline had osteoporosis ten years later more often than controls (45% vs. 29%).

     

Socioeconomic factors and physical activity in relation to cardiovascular disease and death. A 12 year follow up of participants in a population study of women in Gothenburg, Sweden

In a prospective population study of middle aged women socioeconomic factors and physical activity as initially reported were related to the 12 year incidence of ischaemic heart disease and to total mortality. There was a significant age specific correlation between low socioeconomic status according to the husband's occupation and myocardial infarction. No such association was seen between the socioeconomic status of the women themselves and myocardial infarction. Women with a low educational level had a significantly increased age specific incidence of angina pectoris. There was no significant correlation between marital status or number of children and incidence of ischaemic heart disease or overall mortality. Women who initially reported low physical activity at work during the last year had a significantly increased age specific 12 year incidence of stroke and death, as did those who reported low physical activity during leisure hours in whom the incidence of myocardial infarction and electrocardiographic changes indicating ischaemic heart disease were also increased. Multivariate analyses showed that the association between low educational level and incidence of angina pectoris was independent of socioeconomic group, smoking habits, systolic blood pressure, indices of obesity, serum triglycerides, and serum cholesterol. Similarly, low physical activity during leisure hours seemed to be an independent risk factor for stroke, and low physical activity at work was an independent risk factor for overall mortality.     

Long-term prognosis in relation to ECG findings in acute myocardial infarction

In 680 patients with acute myocardial infarction the prognosis during the following 5 years was related to observations made in a standard electrocardiogram (ECG) and 24 precordial chest leads. Patients with a Q-wave infarction (based on a 12-lead standard ECG) had a mortality rate during hospitalization of 10.2% which was much higher than that in patients with a non-Q-wave infarction (1.9%, p less than 0.001). At 5 years' follow-up 33.6% of those with a Q-wave infarction had died versus 28.4% of those with a non-Q-wave infarction (p greater than 0.2). Corresponding mortality rate among patients with no previous infarction (n = 587) was 32.1% and 25.2%, respectively (p = 0.17). In patients with anterior infarction and no previous infarction there was no correlation between Q- and R-wave changes in the 24 chest leads 4 days after admission to hospital and 5-year mortality rate. We thus conclude that patients with a Q-wave infarction had a higher in-hospital mortality compared with non-Q-wave infarction as judged from standard ECG, whereas 5-year mortality was similar. Similarly, there was no correlation between Q- and R-wave changes in an increased number of chest leads and 5-year mortality rate.     

Association between a variant in the 11 beta-hydroxysteroid dehydrogenase type 2 gene and primary hypertension

The enzyme 11 beta-hydroxysteroid dehydrogenase type 2 (11BHSD2) converts cortisol to cortisone in the kidney, thereby protecting the mineralocorticoid receptor from the mineralocorticoid actions of cortisol. The syndrome of Apparent Mineralocorticoid Excess (AME), a rare monogenic form of early onset hypertension with autosomal recessive inheritance, is caused by homozygous or compound heterozygous loss of function mutations in the 11BHSD2 gene. Association has been reported between a microsatellite marker flanking the 11BHSD2 gene (D16S496) and primary hypertension. The aim of this study was to identify variants in the 11BHSD2 gene and to test if such variants or the D16S496 are associated with primary hypertension, in Swedes. To address this, the coding sequences of the 11BHSD2 gene was screened for mutations in 20 patients with primary hypertension with single strand conformation polymorphism and direct DNA sequencing techniques. A polymorphism was identified in exon 3; G534A (Glu178Glu). This polymorphism and the D16S496 microsatellite were tested for association with primary hypertension in a population consisting of 292 patients with primary hypertension and 263 normotensive control subjects. The frequency of G534G homozygotes was higher in patients with primary hypertension than in normotensive control subjects (92.8% vs 87.8%; P < 0.05). The allele frequencies of the D16S496 microsatellite did not differ between the two groups (chi(2) = 11.0, df = 10; P = 0.36). In conclusion, over-representation of individuals homozygous for the G534 allele in hypertensive patients compared with control subjects suggests that a mutation in linkage disequilibrium with the G534A polymorphism could increase susceptibility to primary hypertension. Journal of Human Hypertension (2000) 14, 819-823     

Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial.

The aim of the study was to compare the safety and effectiveness of as-needed formoterol with salbutamol in a large international real-life asthma study. Children and adults (n=18,124) were randomised to 6 months as-needed treatment with open-label formoterol 4.5 microg Turbuhaler or salbutamol 200 microg pressurised metered dose inhaler or equivalent. Primary safety variables were asthma-related and nonasthma-related serious adverse events (SAE)s and adverse events (AE)s resulting in discontinuation (DAE)s. The primary efficacy variable was time to first asthma exacerbation. The incidences of AEs, SAEs and DAEs arising from SAEs were not significantly different between treatments. DAEs for nonserious AEs were higher with formoterol. Asthma-related AEs decreased with formoterol (1,098 (12.3%) versus 1,206 (13.5%)), asthma-related SAEs were similar (108 (1.2%) versus 121 (1.4%)) but more asthma-related DAEs occurred in the formoterol group (89 (1.0%) versus 48 (0.5%)). Time to first exacerbation was prolonged (hazard ratio 0.86) and less as-needed and maintenance medication was used with formoterol. Reductions of exacerbations with as-needed formoterol versus salbutamol increased with increasing age and asthma medication level. This real-life study demonstrates that formoterol as-needed has a similar safety profile to salbutamol, and its use as a reliever therapy is associated with fewer asthma symptoms and exacerbations.     

Morbidity, mortality, and quality of life for patients treated with levothyroxine

In a population study of 1462 middle-aged women initiated in 1968 and 1969 we identified 29 women treated with levothyroxine from 1 to 28 years. In a 12-year follow-up in 1980 and 1981 we investigated the subjects for end-point myocardial infarction, diabetes mellitus, stroke, cancer, and death (the status of 99.7% of the initial participants was established). The women treated with levothyroxine showed no increase in morbidity or mortality. Of the 24 women still receiving levothyroxine in 1980 and 1981, 22 had serum thyrotropin and triiodothyronine concentrations with-in reference limits. These individuals were compared with the 968 women from the population study having no history of thyroid disease, and appeared identical as to laboratory and clinical data, with the exception of a slightly higher body mass, taller stature, and lower serum cholesterol concentration. The treated group did not differ in a life quality estimate based on 19 questions regarding life satisfaction and sensory function. We conclude that the levothyroxine-treated woman suffers no side effects from her life-long therapy.