A prevalent polymorphism in the promoter of the UCP3 gene and its relationship to body mass index and long term body weight change in the Danish population

Variability of the uncoupling protein 3 (UCP3) promoter has been associated with increased body mass index (BMI) and altered lipid profiles. Here we tested the hypothesis that variation of the UCP3 promoter is associated with either juvenile or maturity-onset obesity or body weight change over a 26-yr follow-up among Danish subjects. Mutation screening of approximately 1 kb 5' upstream of the UCP3 gene revealed one previously described -55 C-->T variant. The frequency of the polymorphism was evaluated by restriction fragment length polymorphism analysis in four groups of subjects: 1) a group of 744 obese Danish men who at the draft board examinations had a body mass index (BMI) of at least 31 kg/m(2), 2) a randomly selected control group consisting of 857 draftees, 3) 258 middle-aged subjects, and 4) 409 60-yr-old subjects. The frequency of the T allele was 26.0% (95% confidence interval, 23.8-28.2%) among the obese draftees and 26.9% (24.8-29.0%) in the control group (P = 0.6). The variant was not associated with BMI at a young age or with weight gain after a 26-yr follow-up. The frequency of the T allele was 29.5% (25.6-33.4%) in the middle-aged group and 25.8% (22.8-28.8%) among the 60-yr-old subjects. The polymorphism was not associated with increased BMI or percent body fat in these 2 groups. It is concluded that this variant does not play a major role in the development of common obesity among Danish subjects.     

Interactions between physical activity and variants of the genes encoding uncoupling proteins -2 and -3 in relation to body weight changes during a 10-y follow-up

OBJECTIVE: To examine interactions between physical activity and possibly functional variants of the genes encoding uncoupling proteins -2 and -3 in relation to body weight change. We hypothesize that physical inactivity acts synergistically with a 45 bp insertion variant in the 3'untranslated region (3'UTR) of the UCP2-gene and with a t-allele of codon -55 in the promoter of the UCP3-gene in relation to subsequent weight change. DESIGN: Population-based longitudinal study of cohorts of juvenile obese and nonobese men, who were identified at the mandatory draft board examination in Copenhagen and adjacent regions at a median age of 19 y in 1943-77 and later examined at general health surveys in 1981-83 and 1991-93. The juvenile obese cohort included 568 men who at the draft board had a BMI > or =31 kg/m2 and the cohort of controls included 717 randomly selected draftees. MEASUREMENTS: Height and weight were measured, and information about physical activity was collected from a self-administered questionnaire. The genotyping of the polymorphisms was performed using RFLP techniques. The main outcome measure was change in BMI during the 10-y follow-up period. Additional outcome measures were obesity, waist circumference and body fat mass index measured at follow-up. RESULTS: Physical activity, the 3'UTR insertion polymorphism and the -55 c/t polymorphism were not consistently associated with changes in BMI, and there were no evidence for interactions between the UCP-variants and physical activity in relation to changes in BMI. No evidence for interaction between the UCP-variants and physical activity was found in relation to the additional obesity measures. CONCLUSION: This study does not support that interactions between physical activity and variants in the UCP2- or UCP3-gene are major determinants of subsequent weight changes in Danish Caucasian men.     

Alcohol consumption, TaqIB polymorphism of cholesteryl ester transfer protein, high-density lipoprotein cholesterol, and risk of coronary heart disease in men and women.

AIMS: To investigate whether a common polymorphism in the cholesteryl ester transfer protein (CETP) gene modifies the relationship of alcohol intake with high-density lipoprotein cholesterol (HDL-C) and risk of coronary heart disease (CHD). METHODS AND RESULTS: Parallel nested case-control studies among women [Nurses' Health Study (NHS)] and men [Health Professionals Follow-up Study (HPFS)] where 246 women and 259 men who developed incident CHD were matched to controls (1:2) on age and smoking. The TaqIB variant and alcohol consumption were associated with higher HDL-C, with the most pronounced effects of alcohol among B2 carriers. In the NHS we did not find an inverse association between alcohol and CHD in B2 non-carriers (P trend: 0.5), but did among B2 carriers (P trend <0.01). Among non-carriers the odds ratio (OR) for CHD among women with an intake of 5-14 g/day was 1.4 (95% CI: 0.6-3.7) compared with non-drinkers, whereas among B2 carriers the OR was 0.4 (0.2-0.8). Results in men were less suggestive of an interaction; corresponding OR's were 1.9 (0.8-4.5) and 0.9 (0.5-1.6), for B2 non-carriers and carriers, respectively. CONCLUSIONS: The association of alcohol with HDL-C levels was modified by CETP TaqIB2 carrier status, and there was also a suggestion of a gene-environment interaction on the risk of CHD.     

Fatal poisoning and other health hazards connected with industrial fishing

Dalgaard, J. B., Dencker, F., Fallentin, B., Hansen, P., Kaempe, B., Steensberg, J., and Wilhardt, P. (1972).Brit. J. industr. Med.,29, 307-316. Fatal poisoning and other health hazards connected with industrial fishing. The literature about death and health problems related to work with fish for industrial use is reviewed. Three fatal cases and several instances of unconsciousness or cases of fainting are reported. An investigation was carried out into the composition of the air in the holds and forecastles of Danish industrial-fishing cutters on their arrival at port. The laboratory procedures are described, and the results are reported. In several instances the low concentrations of oxygen and/or high concentrations of carbon dioxide and hydrogen sulphide found were considered to be hazardous to life. The fatalities and sudden loss of consciousness in the reported cases are ascribed to these changes, hypoxia and hypercapnia being the most important causes. The risk of poisoning seems to be greatest during the landing of trash-fish and in fish-meal plants. Persons under the influence of alcohol may, for one reason or another, be particularly susceptible.

The most important preventive measure is improvement of the quality of the raw material which would also reduce the nuisance from smell. Two safety belts with ropes should be provided in the vessels and close to the pits in the fish-meal plants. Fishermen should leave the vessel after arrival in port and not return until after unloading has been completed. During unloading and in the factories, effective mechanical ventilation is essential. Apparatus to monitor the concentrations of oxygen, carbon dioxide, hydrogen sulphide, and ammonia should be available in the fishing ports, and cases of accident, including mere `faintings', should be subjected to prompt medical and technical investigation.

From the occupational medical aspect, fishermen are in a less satisfactory situation than workers on shore. An occupational health service, including pre-employment and periodic examinations of personnel and working conditions, is recommended.

     

Prochloraz: an imidazole fungicide with multiple mechanisms of action

Prochloraz is an imidazole fungicide that is widely used in Europe, Australia, Asia and South America within gardening and agriculture. Screening studies have shown that prochloraz elicits multiple mechanisms of action in vitro, as it antagonizes the androgen and the oestrogen receptor, agonizes the Ah receptor and inhibits aromatase activity. In vivo prochloraz acts as an antiandrogen in the Hershberger assay by reducing weights of reproductive organs, affecting androgen-regulated gene expressions in the prostate and increasing luteinizing hormone levels. In order to investigate the developmental effects of prochloraz, pregnant Wistar dams were dosed perinatally with 30 mg/kg prochloraz. Results showed that prochloraz significantly reduced plasma and testicular testosterone levels in gestational day 21 male foetuses, whereas testicular progesterone was increased. Gestational length was increased by prochloraz. In male pups a significant increase in nipple retention was found, and the weight of the bulbourethral glands was decreased. Behavioural studies showed that the activity level and sweet preference of adult males were significantly increased, indicating that exposure during gestation and lactation causes permanent effects in adulthood. Overall, these results indicate that prochloraz feminizes the male offspring after perinatal exposure, and that these effects are due, at least in part, to diminished fetal steroidogenesis. Thus, a novel endocrine disruptor has been identified that is mechanistically interesting as it elicits dual mechanisms of action and acts as an antiandrogen both by blocking the androgen receptor and by inhibiting fetal steroidogenesis. That a fungicide with such effects is so widely used is a cause for concern, and its use should be reduced, thereby minimizing the risk of human exposure.     

Cerebral blood flow increases evoked by electrical stimulation of rat cerebellar cortex: relation to excitatory synaptic activity and nitric oxide synthesis

The purpose of this study was to examine mechanisms involved in the coupling of neuronal activity to cerebral blood flow (CBF). CBF was measured in rat cerebellum using laser-Doppler flowmetry during stimulus-evoked neuronal activity and related to the distribution of the extracellular field potential. Local electrical stimulation of the cerebellar cortex activated a narrow beam of parallel fibers (PFs) 100 μm across and evoked increases of CBF along (On-B) and perpendicular (Off-B) to the beam. Increases of CBF and field potentials were recorded for a distance of up to 1500 μm along the activated beam, and perpendicular to the beam, in a zone approximately 1000 μm wide, i.e. about 10 times wider than the zone in which synaptic excitation took place. CBF increased as a function of stimulus frequency up to 75 Hz, the response being larger On-B than Off-B. TTX abolished both the field potentials and the CBF responses at all frequencies, suggesting that action potentials were mechanistically related to the evoked CBF increases. CBF changes were unchanged by picrotoxin, a blocker of GABA_A receptors, consistent with the idea that inhibitory synaptic activity does not contribute to CBF increases. The latency to the CBF rise was much shorter On-B than Off-B for the same distance from the stimulating electrode. This may suggest that the CBF response Off-B is dependent on diffusion of vasoactive substances from neuronal structures activated by the parallel fibers On-B. Nitric oxide (NO) synthase inhibition withN^G-nitro-l-Arginine increased the time latency to onset of CBF rise by 2–4 times and attenuated the evoked CBF increase by approximately 50%. Sodium nitroprusside, a NO donor, increased baseline CBF, but did not reverse the effects ofl-NNA. Thus the initial part of the evoked CBF rise is probably mediated by NO, which also contributes to the later part of the response. This study provides insight into the distribution and mechanism of neurally evoked increases of CBF, of putative importance for the interpretation of activation studies in animals and humans.     

A model for determining the effect of mammography service screening

In an overview, Swedish mammography screening trials demonstrated a 29% reduction in breast cancer mortality in women aged 50-69 and no effect on total mortality. Three Danish regions introduced mammography screening in the 1990s. The authors developed a method to evaluate the effect of mammography service screening on breast cancer mortality and validated it applying it to total mortality, where no effect was expected. Study groups and historical and national control groups were analysed using Poisson regression. Total mortality in the screening regions and periods was close to that expected in the absence of screening. A small (3%) excess risk, also seen in a non-screening area, probably results from regional differences changing over time. The effect of this is inseparable from the screening effect. The design is adequate for analysing the effect of mammography service screening on breast cancer mortality.