Postmarketing surveillance of adverse drug reactions: problems and solutions.

The surveillance of adverse drug reactions (ADRs) is an unqualified must. However, the optimal means of surveillance is still unclear. Although anecdotal reports are the backbone of an ADR surveillance system, they are not enough. The pharmaceutical industry, academics and regulatory agencies need to expand their efforts in monitoring ADRs. The author discusses the various techniques for counting and evaluating adverse reactions and suggests ways in which the system could be improved.     

Predictors of mortality in insulin dependent diabetes: 10 year observational follow up study.

OBJECTIVE: To evaluate the prognostic significance of microalbuminuria and overt diabetic nephropathy and other putative risk factors for cardiovascular and all cause mortality in insulin dependent diabetes. DESIGN: Ten year observational follow up study. SETTING: Outpatient diabetic clinic in a tertiary referral centre. SUBJECTS: All 939 adults with insulin dependent diabetes (duration of diabetes five years or more) attending the clinic in 1984; 593 had normal urinary albumin excretion (< or = 30 mg/24 h), 181 persistent microalbuminuria (31-299 mg/24 h), and 165 overt nephropathy (> or = 300 mg/24 h). MAIN OUTCOME MEASURE: All cause and cardiovascular mortality. RESULTS: Fifteen per cent of patients (90/593) with normoalbuminuria, 25% (45/181) with microalbuminuria, and 44% (72/165) with overt nephropathy at baseline died during follow up. Cox multiple regression analysis identified the following significant predictors of all cause mortality: male sex (relative risk 2.03; 95% confidence interval 1.37 to 3.02), age (1.07; 1.06 to 1.08), height (0.96; 0.94 to 0.98), smoking (1.51; 1.09 to 2.08), social class V versus social class IV (1.70; 1.25 to 2.31), log10 urinary albumin excretion (1.45; 1.18 to 1.77), hypertension (1.63; 1.18 to 2.25), log10 serum creatinine concentration (8.96; 3.34 to 24.08), and haemoglobin A1c concentration (1.11; 1.03 to 1.20). Age, smoking, microalbuminuria, overt nephropathy, and hypertension were significant predictors of cardiovascular mortality. Mortality in patients with microalbuminuria was only slightly increased compared with that in patients with normoalbuminuria. Median survival time after the onset of overt diabetic nephropathy was 13.9 years (95% confidence interval 11.8 to 17.2 years). CONCLUSIONS: Abnormally increased urinary albumin excretion and other potentially modifiable risk factors such as hypertension, smoking, poor glycaemic control, and social class predict increased mortality in insulin dependent diabetes. Microalbuminuria by itself confers only a small increase in mortality. The prognosis of patients with overt diabetic nephropathy has improved, probably owing to effective antihypertensive treatment.     

Stomatal responses of Douglas-fir seedlings to elevated carbon dioxide and temperature during the third and fourth years of exposure

Two major components of climate change, increasing atmospheric [CO₂] and increasing temperature, may substantially alter the effects of water availability to plants through effects on the rate of water loss from leaves. We examined the interactive effects of elevated [CO₂] and temperature on seasonal patterns of stomatal conductance (g_s), transpiration (E) and instantaneous transpiration efficiency (ITE) in Douglas‐fir (Pseudotsuga menziesii (Mirb.) Franco) seedlings. Seedlings were grown in sunlit chambers at either ambient CO₂ (AC) or ambient + 180 µmol mol^?1 CO₂ (EC), and at ambient temperature (AT) or ambient + 3·5 °C (ET) in a full‐factorial design. Needle gas exchange at the target growth conditions was measured approximately monthly over 21 months. Across the study period and across temperature treatments, growth in elevated [CO₂] decreased E by an average of 12% and increased ITE by an average of 46%. The absolute reduction of E associated with elevated [CO₂] significantly increased with seasonal increases in the needle‐to‐air vapour pressure deficit (D). Across CO₂ treatments, growth in elevated temperature increased E an average of 37%, and did not affect ITE. Combined, growth in elevated [CO₂] and elevated temperature increased E an average of 19% compared with the ACAT treatment. The CO₂ supply and growth temperature did not significantly affect stomatal sensitivity to D or the relationship between g_s and net photosynthetic rates. This study suggests that elevated [CO₂] may not completely ameliorate the effect of elevated temperature on E, and that climate change may substantially alter needle‐level water loss and water use efficiency of Douglas‐fir seedlings.     

Diagnosis of abnormalities of the human fetus during the first, second, and third trimesters.

Clinical teratologists will have new challenges during the 1990s as birth defects are diagnosed more frequently than in previous decades. Malformations and genetic disorders will be diagnosed in utero during all three trimesters of pregnancy. The teratologist may participate in or lead a multispecialty group to give the involved family optimal interpretation of test results, counseling, and recommendations regarding subsequent clinical management.     

Socioeconomic differences in mortality among diabetic people in Finland: five year follow up.

OBJECTIVE: To compare socioeconomic differences in mortality (by cause of death) among diabetic people with those in the rest of the population. DESIGN: Five year follow up of mortality in the population of Finland, comparing people with diabetes and those without diabetes. SETTING: Finland. SUBJECTS: All residents of Finland aged 30 to 74 included in the 1980 census. Subjects were classified as diabetic (230,000 person years) or other (12,400,000 person years) according to whether they were exempted from charges for medication for diabetes. During 1981-5 there were 114,058 deaths, of which 11,215 were in people with diabetes. MAIN OUTCOME MEASURES: Age standardised mortality by sex, social class, and cause of death for the diabetic and non-diabetic populations. RESULTS: No significant social class differences in mortality were found among women with diabetes. Among diabetic men there was a slight increasing trend in mortality from the upper while collar group to the unskilled blue collar workers but it was much less steep than that of non-diabetic men. CONCLUSIONS: Among people with diabetes in Finland the quality of treatment and compliance with treatment probably do not vary by socioeconomic status. Health education for diabetic people seems to be effective in all socioeconomic strata; in people from the lower strata this leads to greater changes because their health behavior was originally less good.     

Biological activity of Pakistani isolate SpltNPV-Pak-BNG in second,third and fourth instar larvae of the leafworm Spodoptera litura

Recently, a novel isolate of the baculovirus Spodoptera litura nucleopolyhedrovirus (SpltNPV) has been isolated from Pakistan, which is distinct from the type species SpltNPV-G2 (ICTV). Here, we examined the biological activity of this isolate (SpltNPV-Pak-BNG) in second (L2), third (L3) and fourth instar (L4) larvae of the leafworm S. litura, more specifically to measure biological properties that are relevant for use of this virus for pest control under field conditions. The median lethal dose for L2 and L3 instar larvae was similar, but significantly lower than for L4 larvae. Likewise, the survival time was similar for L2 and L3 larvae (84?h), but was significantly longer for L4 instar larvae (108?h). Thus, in terms of efficacy, S. litura L2 and L3 instar larvae are the preferred targets for S. litura control with SpltNPV-Pak-BNG in field crops in Pakistan. On the basis of our data spray regimes can be designed to control the leafworm in cotton and vegetable crops targeting L2 and L3 larvae.     

Nutritional status and mortality of refugee and resident children in a non-camp setting during conflict: follow up study in Guinea-Bissau

ObjectiveTo study the effects on children of humanitarian aid agencies restricting help to refugee families (internally displaced people).DesignFollow up study of 3 months.SettingPrabis peninsular outside Bissau, the capital of Guinea-Bissau, which has functioned as a refugee area for internally displaced people in the ongoing war, and the study area of the Bandim health project in Bissau.Participants422 children aged 9-23 months in 30 clusters.ResultsDuring the refugee situation all children deteriorated nutritionally, and mortality was high (3.0% in a 6 week period). Rice consumption was higher in families resident in Prabis than in refugees from Bissau but there was no difference in food expenditure. Nutritional status, measured by mid- upper arm circumference, was not associated with rice consumption levels in the family, and the decline in circumference was significantly worse for resident than for refugee children; the mid-upper arm circumference of refugee children increased faster than that of resident children. For resident children, mortality was 4.5 times higher (95% confidence interval 1.1 to 30.0) than for refugee children. Mortality for both resident and refugee children was 7.2 times higher (1.3 to 133.9) during the refugee’s stay in Prabis compared with the period after the departure of the refugees.ConclusionIn a non-camp setting, residents may be more malnourished and have higher mortality than refugees. Major improvements in nutritional status and a reduction in mortality occurred in resident and refugee children as soon as refugees returned home despite the fact that there was no improvement in food availability.

Key messages

• During the war in Guinea-Bissau, most of the population fled from the capital and moved in with relatives, friends, or strangers
• International agencies insisted on only providing help to refugees (internally displaced people)
• During the first month of conflict, there were already profound effects on the nutritional status and mortality of young children
• Food consumption was higher in resident families, but resident children were more malnourished and had higher mortality than refugee children
• Nutritional status and survival improved for both refugee and resident children once the refugees returned to Bissau

     

Meningitis in infancy in England and Wales: follow up at age 5 years

ObjectiveTo describe important sequelae occurring among a cohort of children aged 5 years who had had meningitis during the first year of life and who had been identified by a prospective national study of meningitis in infancy in England and Wales between 1985 and 1987.DesignFollow up questionnaires asking about the children''s health and development were sent to general practitioners and parents of the children and to parents of matched controls. The organism that caused the infection and age at infection were also recorded.SettingEngland and Wales.ParticipantsGeneral practitioners and parents of children who had had meningitis before the age of 1 year and of matched controls.ResultsAltogether, 1584 of 1717 (92.2%) children who had had meningitis and 1391 of 1485 (93.6%) controls were successfully followed up. Among children who survived to age 5 years 247 of 1584 (15.6%) had a disability; there was a 10-fold increase in the risk of severe or moderate disability at 5 years of age among children who had had meningitis (relative risk 10.3, 95% confidence interval 6.7 to 16.0, P<0.001). There was considerable variation in the rates of severe or moderate disability in children infected with different organisms.ConclusionThe long term consequences of having meningitis during the first year of life are significant: 32 of 1717 (1.8%) children died within five years. Not only did almost a fifth of children with meningitis have a permanent, severe or moderately severe disability, but subtle deficits were also more prevalent.

What is already known on this topic

Meningitis in infancy is associated with important long term consequencesThere is considerable variation in outcome depending on which organism caused the infection

What this study adds

This follow up study of 1717 children who had meningitis in infancy found that they had a 10-fold increase in risk of severe or moderate disabilities at age 5 years compared with children in the control groupThe outcome of having meningitis was associated with the age at infection, and children who had meningitis in the neonatal period were more likely to have health and development problems than those older than 1 monthSubtle deficits, such as middle ear disease and visual and behavioural problems, were more prevalent among children who had had meningitis in infancy     

Alcohol consumption and mortality from all causes,coronary heart disease,and stroke: results from a prospective cohort study of Scottish men with 21 years of follow up

ObjectivesTo relate alcohol consumption to mortality.DesignProspective cohort study.Setting27 workplaces in the west of Scotland.Participants5766 men aged 35-64 when screened in 1970-3 who answered questions on their usual weekly alcohol consumption.ResultsRisk for all cause mortality was similar for non-drinkers and men drinking up to 14 units a week. Mortality risk then showed a graded association with alcohol consumption (relative rate compared with non-drinkers 1.34 (95% confidence interval 1.14 to 1.58) for 15-21 units a week, 1.49 (1.27 to 1.75) for 22-34 units, 1.74 (1.47 to 2.06) for 35 or more units). Adjustment for risk factors attenuated the increased relative risks, but they remained significantly above 1 for men drinking 22 or more units a week. There was no strong relation between alcohol consumption and mortality from coronary heart disease after adjustment. A strong positive relation was seen between alcohol consumption and risk of mortality from stroke, with men drinking 35 or more units having double the risk of non-drinkers, even after adjustment.ConclusionsThe overall association between alcohol consumption and mortality is unfavourable for men drinking over 22 units a week, and there is no clear evidence of any protective effect for men drinking less than this.

Key messages

• Results from a large cohort study of employed Scottish men showed different relations between alcohol consumption and mortality than previous studies
• There was no relation between mortality from coronary heart disease and alcohol consumption once adjustments were made for potential confounding factors
• There was a strong relation with mortality from stroke; drinkers of over 35 units a week had double the risk of mortality compared with non-drinkers
• Some but not all of this could be accounted for by alcohol related increases in blood pressure
• Overall, risk of all cause mortality was higher in men drinking 22 or more units a week

     

Dietary habits and mortality in 11,000 vegetarians and health conscious people: results of a 17 year follow up.

OBJECTIVE: To investigate the association of dietary habits with mortality in a cohort of vegetarians and other health conscious people. DESIGN: Observational study. SETTING: United Kingdom. SUBJECTS: 4336 men and 6435 women recruited through health food shops, vegetarian societies, and magazines. MAIN OUTCOME MEASURES: Mortality ratios for vegetarianism and for daily versus less than daily consumption of wholemeal bread, bran cereals, nuts or dried fruit, fresh fruit, and raw salad in relation to all cause mortality and mortality from ischaemic heart disease, cerebrovascular disease, all malignant neoplasms, lung cancer, colorectal cancer, and breast cancer. RESULTS: 2064 (19%) subjects smoked, 4627 (43%) were vegetarian, 6699 (62%) ate wholemeal bread daily, 2948 (27%) ate bran cereals daily, 4091 (38%) ate nuts or dried fruit daily, 8304 (77%) ate fresh fruit daily, and 4105 (38%) ate raw salad daily. After a mean of 16.8 years follow up there were 1343 deaths before age 80. Overall the cohort had a mortality about half that of the general population. Within the cohort, daily consumption of fresh fruit was associated with significantly reduced mortality from ischaemic heart disease (rate ratio adjusted for smoking 0.76 (95% confidence interval 0.60 to 0.97)), cerebrovascular disease (0.68 (0.47 to 0.98)), and for all causes combined (0.79 (0.70 to 0.90)). CONCLUSIONS: In this cohort of health conscious individuals, daily consumption of fresh fruit is associated with a reduced mortality from ischaemic heart disease, cerebrovascular disease, and all causes combined.     

Contribution of deaths related to alcohol use of socioeconomic variation in mortality: register based follow up study.

OBJECTIVE: To estimate the contribution of excessive alcohol use to socioeconomic variation in mortality among men and women in Finland. DESIGN: Register based follow up study. SUBJECTS: The population covered by the 1985 and 1990 censuses, aged > or = 20 in the follow up period 1987-93. MAIN OUTCOME MEASURES: Total mortality and alcohol related mortality from all causes, from diseases, and from accidents and violence according to socioeconomic position. The excess mortality among other classes compared with upper non-manual employees and differences in life expectancy between the classes were used to measure mortality differentials. RESULTS: Alcohol related mortality constituted 11% of all mortality among men aged > or = 20 and 2% among women and was higher among manual workers than among other classes. It accounted for 14% of the excess all cause mortality among manual workers over upper non-manual employees among men and 4% among women and for 24% and 9% of the differences in life expectancy, respectively. Half of the excess mortality from accidents and violence among male manual workers and 38% among female manual workers was accounted for by alcohol related deaths, whereas in diseases the role of alcohol was modest. The contribution of alcohol related deaths to relative mortality differentials weakened with age. CONCLUSIONS: Class differentials in alcohol related mortality are an important factor in the socioeconomic mortality differentials in Finland, especially among men, among younger age groups, and in mortality from accidents and violence.     

Dietary protein energy supplementation of pregnant Asian mothers at Sorrento,Birmingham. I: Unselective during second and third trimesters.

At Sorrento Maternity Hospital Asian mothers whose babies had grown poorly in utero had anthropometric and biochemical evidence suggesting an inadequate nutritional state. To test this hypothesis further the effect of unselective dietary protein energy supplementation was studied. A total of 153 Asian mothers received one of three supplements from the 18th to 38th weeks of pregnancy: (a) vitamins only--vitamin C 30 mg daily, iron 3 mg daily; (b) energy--42-80 MJ; (10 000-19 000 kcal)/trimester, all from carbohydrate, plus vitamins; (c) protein energy--energy and vitamins as before, but with 5-11% of energy from milk protein. By the 28th week mothers receiving the protein energy supplement had put on more weight and more fat than the vitamin-only group. Neither protein energy nor energy supplementation alone enhanced intrauterine growth. It is concluded that dietary supplementation of all pregnant mothers does not enhance intrauterine growth.     

Genetic separation of third and fourth whorl functions of AGAMOUS.

AGAMOUS (AG) is an Arabidopsis MADS box gene required for normal development of the third and fourth whorls of the flower. In previously described ag mutants, the third whorl stamens are replaced by petals, and the fourth whorl is replaced by another (mutant) flower. We describe two new ag alleles, ag-4 and AG-Met205, retaining partial AG activity. Both produce flowers with stamens in the third whorl and indeterminate floral meristems; however, ag-4 flowers contain sepals in the fourth whorl, and AG-Met205 produces carpels. The ag-4 mutation results in partial loss of the C terminus of the K domain, a putative coiled coil, and AG-Met205 contains a site-directed mutation that causes a single amino acid change in this same region of the K box. Two models that might explain how these changes in AG result in the separation of different AG activities are discussed.     

Structural variability of rabbit secretory components. Allotype-associated differences in the third, fourth, and fifth domains

We have previously shown (Frutiger, S., Hughes, G. J., Hanly, W. C., Kingzette, M., and Jaton, J.-C. (1986) J. Biol. Chem. 261, 16673-16681) that limited tryptic digestion of the high Mr form of rabbit secretory component of allotypes t61, t62, and t63 generates two major fragments, the NH2-terminal domain and a 40-kDa fragment encompassing domains 3, 4, and 5. Similarly, from the low Mr form of secretory component, (SC) the NH2-terminal domain, together with a 30-kDa fragment containing domains 4 and 5, were released. These fragments were used as inhibitors in a sensitive competitive binding radioimmunoassay with noncross-reactive rabbit alloantisera to study the distribution and localization of the major allotype-specific allotopes within the SC polypeptide. The 40-kDa fragments were shown to inhibit the 125I-labeled intact SC/anti-SC allotype reaction to the extent of 90%, i.e. nearly as well as the intact homologous high Mr SC form. In contrast, the NH2-terminal fragments (domain 1) were not inhibitory. The low Mr SC of each allotype was less inhibitory on a molar basis than the homologous high Mr SC polypeptide, an observation compatible with the deletion of domains 2 and 3 in the smaller polypeptide (Deitcher, D. L., and Mostov, K. E. (1986) Mol. Cell. Biol. 6, 2712-2715; Frutiger, S., Hughes, G. J., Fonck, Ch., and Jaton, J.-C. (1987) J. Biol. Chem. 262, 1712-1715). The structural correlates of the allotypic specificities were evaluated by comparative peptide mapping of the 40-kDa fragments (allotypes t61, t62, and t63). The data suggest that the t61 allotype structure differs significantly from the t62 and t63 structures, the latter two being much more related to each other than to t61. These findings are in full agreement with the serological data. The inhibition results suggest that the major allotype-specific, noncross-reactive allotopes of SC are distributed throughout domains 3, 4, and 5, even though domain 4 appears to be more conserved than domains 3 and 5 between the allotypes t61 and t63. Seven amino acid substitutions between t61 and t63 have been detected within domains 3, 4, and 5.