Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary ß-glucan-induced inflammatory adaptation.

The lung is constantly exposed to the outside world and optimal adaptation of immune responses is crucial for efficient pathogen clearance. However, mechanisms that lead to lung-associated macrophages' functional and developmental adaptation remain elusive. To reveal such mechanisms, we developed a reductionist model of environmental intranasal ß-glucan exposure, allowing for the detailed interrogation of molecular mechanisms of pulmonary macrophage adaptation. Employing single-cell transcriptomics, high-dimensional imaging and flow cytometric characterization paired with in vivo and ex vivo challenge models, we reveal that pulmonary low-grade inflammation results in the development of apolipoprotein E (ApoE)-dependent monocyte-derived alveolar macrophages (ApoE+CD11b+ AMs). ApoE+CD11b+ AMs expressed high levels of CD11b, ApoE, Gpnmb and Ccl6, were glycolytic, highly phagocytic and produced large amounts of interleukin-6 upon restimulation. Functional differences were cell intrinsic, and myeloid cell-specific ApoE ablation inhibited Ly6c+ monocyte to ApoE+CD11b+ AM differentiation dependent on macrophage colony-stimulating factor secretion, promoting ApoE+CD11b+ AM cell death and thus impeding ApoE+CD11b+ AM maintenance. In vivo, ß-glucan-elicited ApoE+CD11b+ AMs limited the bacterial burden of Legionella pneumophilia after infection and improved the disease outcome in vivo and ex vivo in a murine lung fibrosis model. Collectively these data identify ApoE+CD11b+ AMs generated upon environmental cues, under the control of ApoE signaling, as an essential determinant for lung adaptation enhancing tissue resilience.

Validity of the 12-item version of the General Health Questionnaire in detecting depression in the general population.

OBJECTIVES: The 12-item version of the General Health Questionnaire (GHQ-12) is frequently used to measure common mental disorder in public health surveys, but few population-based validations have been made. We validated the GHQ-12 against structured psychiatric interviews of depression using a population-based cohort in Stockholm, Sweden. METHODS: We used a population-based cohort of 484 individuals in Stockholm, Sweden (participation rate 62%). All completed the GHQ-12 and a semi-structured psychiatric interview. Last month DSM-III-R symptoms were used to classify major and minor depression. Three scoring methods for GHQ-12 were assessed, the Standard, Likert and Corrected method. Discriminatory ability was assessed with area under the receiver operating characteristic (ROC) curve. RESULTS: A total of 9.5% had a major or minor depression. The area under the ROC curve was for the Standard method 0.73 (0.65-0.82), the Likert method 0.80 (0.72-0.87) and the Corrected method 0.80 (0.73-0.87) when using major or minor depression as standard criterion. Adequate sensitivity and specificity for separating those with or without a depressive disorder was reached at ≥12 Likert scored points (80.4 and 69.6%) or ≥6 Corrected GHQ points (78.3 and 73.7%). Sensitivity and specificity was at ≥2 Standard scored points 67.4% and 74.2%. CONCLUSION: When scored using the Likert and Corrected methods, the GHQ-12 performed excellently. When scored using the Standard method, performance was acceptable in detecting depressive disorder in the general population. The GHQ-12 appears to be a good proxy for depressive disorder when used in public health surveys.

Mental disorder and long-term risk of mortality: 41 years of follow-up of a population sample in Stockholm, Sweden.

BACKGROUND: An increased mortality risk associated with mental disorder has been reported for patients, but there are few studies are based on random samples with interview-based psychiatric diagnoses. Part of the increased mortality for those with mental disorder may be attributable to worse somatic health or hazardous health behaviour - consequences of the disorder - but somatic health information is commonly lacking in psychiatric samples. This study aims to examine long-term mortality risk for psychiatric diagnoses in a general population sample and to assess mediation by somatic ill health and hazardous health behaviour. METHOD: We used a double-phase stratified random sample of individuals aged 18-65 in Stockholm County 1970-1971 linked to vital records. First phase sample was 32 186 individuals screened with postal questionnaire and second phase was 1896 individuals (920 men and 976 women) that participated in a full-day examination (participation rate 88%). Baseline examination included both a semi-structured interview with a psychiatrist, with mental disorders set according to the 8th version of the International Classification of Disease (ICD-8), and clinical somatic examination, including measures of body composition (BMI), hypertension, fasting blood glucose, pulmonary function and self-reported tobacco smoking. Information on vital status was obtained from the Total Population Register for the years 1970-2011. Associations with mortality were studied with Cox proportional hazard analyses. RESULTS: A total of 883 deaths occurred among the participants during the 41-year follow-up. Increased mortality rates were found for ICD-8 functional psychoses (hazard ratio, HR = 2.22, 95% confidence interval (95% CI): 1.15-4.30); psycho-organic symptoms (HR = 1.94, 95% CI: 1.31-2.87); depressive neuroses (HR = 1.71, 95% CI: 1.23-2.39); alcohol use disorder (HR = 1.91, 95% CI: 1.40-2.61); drug dependence (HR = 3.71, 95% CI: 1.80-7.65) and psychopathy (HR = 2.88, 95% CI: 1.02-8.16). Non-participants (n = 349) had mortality rates similar to participants (HR = 0.98, 95% CI: 0.81-1.18). In subgroup analyses of those with psychoses, depression or alcohol use disorder, adjusting for the potential mediators smoking and pulmonary function, showed only slight changes in the HRs. CONCLUSIONS: This study confirms the increased risk of mortality for several psychiatric diagnoses in follow-up studies on American, Finnish and Swedish population-based samples. Only a small part of the increased mortality hazard was attributable to differences in somatic health or hazardous health behaviour measured at baseline.

Improving the dietary intake of under nourished older people in residential care homes using an energy-enriching food approach: a cluster randomised controlled study.

BACKGROUND: To examine whether the nutritional status of aged undernourished residents in care could be improved through dietary modification to increase energy intake but not portion size. METHODS: A 12-week cluster randomised controlled trial was carried out in 21 residential care homes. Participants comprised undernourished residents with a body mass index (BMI) <18.5 kg m(-2) . All menus were analysed to evaluate nutrient provision. Energy and macronutrient intakes of undernourished residents were estimated using 3-day weighed food intake diaries. Those resident in homes randomised to intervention had their usual meals enriched with energy-dense foods to a maximum of +1673 kJ day(-1) . RESULTS: Of 445 residents screened, 41 (9%) had a BMI <18.5 kg m(-2) and entered the study. Despite adequate food provision, energy and macronutrient intakes were below UK dietary reference values. Mean (SEM) energy intake increased [+556 (372) kJ, P = 0.154] in residents allocated to intervention but fell in those residents in 'control homes' receiving usual care [-151 (351) kJ, P = 0.676]. Weight change [+1.3 (0.53) kg, P = 0.03] was seen in intervention residents but not in controls [-0.2 (1.5) kg, P = 0.536]. Between-group differences for changes in weight and energy intake were not significant (P = 0.08 and 0.20, respectively). Six residents allocated to the intervention increased their BMI >18.5 kg m(-2) (P = 0.018). CONCLUSIONS: Achieving weight gain in frail older people is difficult. These results suggest that enriching food could help address undernutrition and slow chronic weight loss. Interventions of a longer duration are needed to confirm or exclude the value of food enrichment.

The association between BMI value and long-term mortality.

OBJECTIVES: To study total mortality in different categories of BMI values, with adjustments for important covariates in a population-based 26-year mortality follow-up. Special interest will be given to gender differences and low BMI values. METHODS: From a stratified sample in 1969 of 32 185 individuals aged 18-64 years from Stockholm County, 2422 underwent a health examination, with complete data obtained for 1020 subjects. BMI was classified as underweight (<20), normal (20-24.9), overweight (25-29.9) or obesity (> or =30). Participants were followed up in the National Cause of Death Register until the end of 1996. Multivariate analysis was performed by Cox regression for men and women separately, with different models, with step-wise adjustment for age, care need category, heart rate, hypertension, blood glucose, alcohol intake and smoking, with hazard ratios (HR) and 95% confidence interval (CI) and with normal weight as reference. RESULTS: Among men, the age-adjusted HR was 1.68 (95% CI 1.10-2.57) for underweight and 1.62 (95% CI 1.08-2.43) for obesity, and among women it was 0.93 (95% CI 0.58-1.51) for underweight and 1.88 (95% CI 1.26-2.82) for obesity. In men, the significantly increased mortality remained when also adjusting for care need category, but not when adjusting for other factors, whereas the opposite was found regarding obesity. For women, underweight was significantly associated with decreased mortality when adjusting for smoking and for all factors together, whereas obesity was associated with increased mortality when adjusting for the different factors except for all factors together. CONCLUSIONS: Underweight was associated with higher mortality among men, but not when adjusting for covariates, whereas underweight was associated with lower mortality among women when adjusting for smoking.

The association between blood glucose value and long-term mortality.

This study aims at estimating the association between different fasting blood glucose levels (FBG) and total mortality during a long-term follow-up. In all 2,300 subjects were health examined, out of a stratified sample of 32,185 individuals aged 18-64 years drawn from the population in Stockholm County from the years 1969-70. FBG values were divided into following groups:<3.0, 3.0-4.4, 4.5-5.5, 5.66.0, 6.1-6.6, and > 6.6 mmol/l (corresponding to fasting plasma glucose, FPG,<3.5, 3.5-4.9, 5.0-6.0, 6.1-6.9, 7.0-7.7 and > 7.7 mmol/l), and known diabetes mellitus. All participants were followed up in the National Cause of Death Register up to the end of 1996. Multivariate analysis was performed by Cox regression, with three models, the first age- and sex-adjusted, the second also adjusted for care need category and hypertension, and the third with added BMI-category, with hazard ratios (HR) and 95% confidence interval (CI). Smoking habits were available for around half of the sample. Compared to the FBG showing the lowest mortality, i.e. FBG 5.6-6.0 mmol/l, we found an age- and sex-adjusted excess risk for subjects with known diabetes (HR 7.39, 95% CI 3.78-14.45), with FBG > 6.6 mmol/l (HR 2.30, 95% CI 1.20-4.39), and with FBG<3.0 mmol/l (HR 3.44, 95% CI 1.47-8.06). The excess risk persisted when adjusting for care need, hypertension, BMI, and also for smoking. The cause of the increased mortality risk with low FBG values is unclear, but low FBG value seems to be a risk marker of poor health.

Evidence that inhibited prostatic epithelial bud formation in 2,3,7,8-tetrachlorodibenzo-p-dioxin-exposed C57BL/6J fetal mice is not due to interruption of androgen signaling in the urogenital sinus.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits the androgen-dependent processes by which the urogenital sinus (UGS) of fetal mice forms prostatic epithelial buds. This inhibition is mediated by aryl hydrocarbon receptors in UGS mesenchyme and causes prostate lobes to develop abnormally. Experiments were conducted to test the hypothesis that TCDD inhibits prostatic budding in C57BL/6J mice by inhibiting androgen signaling. In utero TCDD exposure sufficient to inhibit budding (5 microg/kg maternal dose on gestation day [GD] 13) had no effect on testicular testosterone content on GD 16 or 18. Nor did it inhibit the conversion of testosterone to 5alpha-dihydrotestosterone (DHT) by the UGS. Both hydroxyflutamide (OH-flutamide; a competitive androgen receptor antagonist) and TCDD inhibited prostatic epithelial budding by UGSs cultured in vitro with DHT. To determine if TCDD inhibits responsiveness to androgens, primary mesenchymal cells prepared from UGSs cultured for three days with DHT were transiently transfected with an androgen-responsive reporter plasmid (MMTV-luciferase). OH-flutamide prevented DHT from increasing luciferase activity in these cells but TCDD did not. The same results were obtained when the mesenchymal cells were isolated from UGSs cultured with both DHT and TCDD. The lack of effect of TCDD on androgen-dependent gene expression was not due to inability of transfected UGS mesenchymal cells to respond to TCDD, as shown by significant increases in luciferase activity after transfection with plasmids containing CYP1A1 and CYP1B1 promoters. Finally, while OH-flutamide prevented DHT from altering androgen receptor and 5alpha-reductase type II mRNA expression in UGS organ culture, TCDD had no such effects. Collectively, these results suggest that TCDD inhibits prostatic epithelial bud formation without impairing the androgen receptor signaling pathway.

In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in the C57BL/6J mouse prostate: lobe-specific effects on branching morphogenesis.

Branching morphogenesis is an essential component of prostate development. This study was conducted to test the hypothesis that in utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure differentially inhibits branching morphogenesis and ductal canalization in the ventral, dorsal, lateral, and anterior mouse prostate. Pregnant C57BL/6J mice were given TCDD (5 microg/kg, orally) or vehicle on gestation day (GD) 13 and their pups examined at 1, 7, 14, 21, 35, and 90 days of age. Prostate lobes were microdissected after incubation in 0.5% collagenase and the numbers of ductal tips, main ducts, and ductal tips per main duct were determined by examining photographs of microdissected, whole-mount specimens. Ductal canalization was determined using histological sections of the dorsolateral and anterior prostate lobes. TCDD inhibited branching morphogenesis in all prostate lobes. The ventral prostate (VP) was extremely small throughout development and never developed any ductal structure. TCDD reduced the numbers of ductal tips and main ducts in the dorsal (DP) and lateral prostate (LP), but reductions in ductal tip numbers appeared to result entirely from reductions in the number of main ducts. Dorsolateral prostate (DLP) weights were slightly reduced by TCDD, but there was no effect on ductal canalization in the dorsal, lateral, or anterior lobes. TCDD had no effect on main duct number in the anterior prostate, but weight, ductal tip number, and the number of ductal tips per main duct was substantially reduced. These results demonstrate that the severe inhibition in ventral prostate development caused by in utero and lactational TCDD exposure is accompanied by a complete absence of branching morphogenesis. The impairment in dorsal, lateral, and anterior prostate (AP) development is associated with a lobe-specific inhibition of the various processes involved in duct formation.

Leisure time activity as a determinant of survival: a 26-year follow-up of a Swedish cohort.

An individual's leisure time (pastime) engagements are in a way important for society. Irrespective of whether leisure time activities are causal determinants of health or health is a prerequisite for taking full part in society, the interaction is a challenge for Public Health. The first question is whether the sum of their influence results in coherence between enjoying good health and having leisure time activity. The aim of this study was to estimate their covariance.A random sample was drawn from the adult population of Stockholm County, Sweden. The residents were mailed a questionnaire regarding their social circumstances, their health complaints, the social repercussions of the complaints, and if they had any leisure time activity. Altogether, 7252 (about 93%) individuals responding to the questionnaire constituted our cohort. The individuals aged 18-65 y in November 1969 were followed up to the age of 65 y, or to 1996 as to mortality. The main outcome measure was mortality irrespective of cause of death. More than two-thirds of the respondents (71%) reported that they had some leisure time activity. Leisure time activity was a determinant of survival in the statistical sense. The risk ratio was 0.77 and its 95% confidence interval was 0.68-0.87 for those reporting leisure time activity when age, sex, baseline health and baseline alcohol consumption was discounted. The conclusion was that having leisure time activity, unspecified, covaried with health. Further studies should specify the pastime activities.

Relationship between oral health and mortality in cardiovascular diseases.

BACKGROUND, AIMS: The purpose of the study was to investigate the relationship between periodontal health and fatal cardiovascular diseases (CVD). METHODS: The investigation was conducted on a sample of 1393 individuals in the County of Stockholm. The subjects were examined in an epidemiological study in 1970 with respect to dental health. At a follow-up in 1997, the mortality rate of the sample during the years 1970-1996 was registered as well as cause of death according to the death certificate. Stepwise logistic regression analysis was performed in order to evaluate the influence of the investigated variables on the incidence of death from CVD. RESULTS: The interactional effect between plaque and oral health score (a sum of scores for number of missing teeth, apical lesions, caries lesions and marginal bone loss), adjusted for age, gender, smoking and CVD at baseline, was significantly correlated to fatal coronary events. For individuals younger than 45 years of age, the age-adjusted incidence odds ratio of death due to CVD was 2.7 (p=0.04) if subjects with mean marginal bone loss of >10% were compared with subjects with mean marginal bone loss < or =10 %. If the stratum of individuals <45 years of age is confined to smokers, the odds ratio was found to be 3.4 (p=0.03). CONCLUSION: Dental health was found to be a risk indicator of death due to CVD, especially in combination with another risk factor, smoking habits.

Effects of drop out in a longitudinal study of musculoskeletal disorders.

OBJECTIVES: The drop out rates in different longitudinal studies of musculoskeletal disorders range between 7% and 57%, and little is known about the characteristics of the subjects who dropped out. The aim was to analyse various consequences of drop out in a longitudinal study of musculoskeletal disorders and occupational risk factors during 1969-97. METHOD: Data about occupational conditions and health in 1969 and in 1993 were analysed. Differences between those who participated throughout (participants) and drop out subjects in these analyses formed the basis for recalculations of earlier reported analyses of associations between occupational conditions and low back pain. In the recalculation the data were weighted to compensate for the differences. RESULTS: More female and male drop out subjects than participants in 1993 had monotonous work, fewer women and more male drop out subjects had heavy lifting in 1969. In 1997, more female and male drop out subjects had had heavy lifting and low stimulation at work in 1993. At both occasions, there were differences between the drop out subjects and participants in occurrence of musculoskeletal disorders. The weighted analyses resulted in changes in risk ratio of 0.1-0.2. CONCLUSIONS: Differences in occupational conditions and health among participants and drop out subjects in a longitudinal study of musculoskeletal disorders and occupational risk factors during 1969-97 did not markedly influence the risk ratios.

The effects of alcohol consumption on mortality and morbidity: a 26-year follow-up study.

OBJECTIVE: To investigate the long-term effects of the consumption of alcohol on mortality and morbidity. METHOD: A sample of 32,185 (50.5% female) individuals was randomly selected from the 450,000 inhabitants of Stockholm County, Sweden, in 1969. Alcohol consumption data were obtained from postal questionnaires; response rate was 87% (n = 28,001). Data on mortality and morbidity were obtained from the National Cause of Death Register, the Cancer Register and the Inpatient Register 1971-1996. RESULTS: The reference groups were moderate consumers of alcoholic beverages. High-consumption men had increased risks of mortality from cardiovascular diseases (relative risk ratio [RR] = 1.28; 95% confidence interval [CI]: 1.12-1.46), accidents or poisoning (RR = 2.10; CI: 1.67-2.65) and gastrointestinal diseases (RR = 4.65; CI: 2.93-7.36). High-consumption women had an increased risk of mortality only from accidents or poisoning (RR = 2.95; CI: 1.82-4.78) and gastrointestinal diseases (RR = 3.60; CI: 1.40-9.24). For low-consumption women, there was an increased risk of mortality from cardiovascular diseases (RR = 1.25; CI: 1.07-1.47). Low-consumption men also had an increased mortality from cardiovascular diseases (RR = 1.23; CI: 1.05-1.44). The results with respect to morbidity almost mirrored the results for mortality, with one exception; for low-consumption men, the morbidity from cardiovascular diseases was not increased. CONCLUSIONS: The mortality and morbidity associated with different levels of alcohol consumption are associated with the same diseases, which suggests that alcohol may be one of the causative factors for these diseases. The reasons for the differences between genders, regarding responses to the negative effects of alcohol consumption, are still unknown.

2,3,7,8-tetrachlorodibenzo-p-dioxin inhibits luminal cell differentiation and androgen responsiveness of the ventral prostate without inhibiting prostatic 5alpha-dihydrotestosterone formation or testicular androgen production in rat offspring.

In utero and lactational exposure to a single maternal dose of 1 microg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg causes some overt toxicity and impairs prostate growth in male offspring. As similar effects on the ventral prostate can be caused by decreased testosterone production during perinatal development, we determined whether intratesticular testosterone content, testicular responsiveness to gonadotropin stimulation, or plasma testosterone concentrations were reduced in fetal and newborn rats. Because these endpoints were not affected, the ability of TCDD exposure to inhibit synthesis of the proximal androgen in prostate development, 5alpha-dihydrotestosterone (DHT), from the circulating precursor testosterone and 5alpha-androstane-3alpha,17ss-diol (3alpha-Diol), was studied on postnatal days (PNDs) 14, 21, and 32. The ability of the ventral prostate to form DHT from 3alpha-Diol was slightly impaired on PND 14, but this transient effect was not statistically significant, and recovery was evident by PND 21. Subsequent experiments used organ culture to study the effects of in vivo TCDD exposure on androgen metabolism, androgen responsiveness, androgen receptor expression, and luminal epithelial cell differentiation after in vitro exposure to graded androgen concentrations. In utero and lactational TCDD exposure had no effect on DHT formation in organ culture, but transiently reduced the androgen -induced expression of prostatic-binding protein subunit C3, decreased ventral prostate epithelial cell androgen receptor expression, and inhibited the formation of androgen responsive luminal epithelial cells. These results suggest that TCDD exposure impairs prostate growth and androgen responsiveness by inhibiting prostatic epithelial cell differentiation.

A moderate intake of wine is associated with reduced total mortality and reduced mortality from cardiovascular disease.

OBJECTIVE: The aim of this study was to investigate the effects of the consumption of wine, beer and distilled spirits on total mortality and on mortality from cardiovascular disease. METHOD: The consumption of wine, beer and distilled spirits was assessed in 1,828 individuals by a psychiatrist. Subjects were selected according to expected level of need for health services, from a random sample of 24,043 individuals aged 18-65 years. Mortality was recorded after 22 years and the results related to those for the individuals not exposed to the factor examined. The results were adjusted for age, expected level of need for health services, total alcohol consumption, gender, body-mass index, tobacco use and social class. RESULTS: Intake of wine once a week or more (compared with intake of wine less than once a week or not at all) was associated with a relative risk ratio of 0.58 for total mortality (95% CI: 0.40-0.84) and a relative risk ratio of 0.49 for mortality from cardiovascular disease (95% CI: 0.27-0.90). The risk reduction seemed to be confined to those consumers of wine who had an intake of less than 140 grams of alcohol per week and consumed the beverage once a week. Ex-drinkers had an increased relative risk ratio in total mortality compared with lifelong abstainers and individuals who consumed less than 50 grams of alcohol per week (relative risk ratio = 2.64; 95% CI: 1.56-4.49). CONCLUSIONS: A low to moderate intake of wine seems, unlike the consumption of distilled spirits and beer, to be associated with reduced total mortality and reduced mortality from cardiovascular disease.

Validity of two questions on alcohol use in a health survey questionnaire.

The aim of this study was to investigate whether consumers of high and low levels of alcohol could be identified by two questions about alcohol use in a postal questionnaire survey. A sample of 2,300 persons aged 18 64 years from Stockholm county were sent a masked postal questionnaire comprising 30 questions about their health and functioning. Two questions concerned their alcohol consumption. One year later the subjects underwent a psychiatric health examination, which included an assessment of their alcohol use. The two questions about alcohol consumption identified high alcohol consumers with a relatively high sensitivity and specificity, of 64% and 87%, respectively, and thus are useful for identifying high alcohol consumers in health surveys using questionnaires.

Effects of an assessment of needs for medical and social services on long-term mortality: a randomized controlled study.

BACKGROUND: The aim of this study was to investigate the long-term effects of one general health screening on mortality. METHOD: After stratification and randomization of a population of 450,000 inhabitants, two groups were formed, an intervention group of 3064 people and a control group of 29,122 people. From the National Cause of Death Register, data were collected as regards death and causes of deaths for 1970-1990. RESULTS: Multivariate analysis was used to correct for known confounders. We then found no differences between the groups regarding deaths from all causes, cardiovascular diseases, cancer or accidents and poisoning. CONCLUSIONS: One general health screening seems to have little, if any value in preventing fatal diseases.

In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin: effects on development of the male and female reproductive system of the mouse.

To evaluate effects of in utero and lactational 2,3,7,8-tetrachlorodibenzo-rho-dioxin (TCDD) exposure on male and female reproductive system development of the mouse, the offspring of pregnant ICR mice administered 0, 15, 30, or 60 microg TCDD/kg on Gestation Day (GD) 14 were examined at the postweanling, pubertal, young adult, and adult stages of development. Dam and offspring body weights and prenatal and postnatal mortality were unaffected by TCDD exposure. The most sensitive endpoints in male offspring were decreased ventral prostate, coagulating gland, and thymus weights, accelerated eye opening, and hydronephrosis. Decreases in pituitary gland weight and epididymal sperm numbers were also found in TCDD-exposed male offspring. Testis, epididymis, and dorsolateral prostate weights, anogenital distance, latencies to testis descent and to preputial separation, and serum testosterone concentrations were unaffected. At the highest maternal TCDD dose uterus weights were decreased in female offspring evaluated during estrus and diestrus. No morphologic changes in the external genitalia of female offspring were found, nor were there alterations in ovary or pituitary gland weights. Cross-species comparisons showed that the mouse was not as sensitive to TCDD-induced developmental reproductive toxicity as the rat and hamster. Many endpoints affected by TCDD in rat and hamster offspring were either not affected or were less sensitive in mouse offspring. Endpoints of androgenic status were not affected in the mouse, decreases in accessory sex organ weights were restricted to fewer organs in the mouse, and decreases in daily sperm production were not found in the mouse. The only developmental reproductive endpoint observed in all three species was a reduction in epididymal sperm numbers.

Effect of metabolic control on 24-h ambulatory blood pressure in elderly non-insulin-dependent diabetic patients.

OBJECTIVES: To assess the effect of improved metabolic control with insulin therapy on blood pressure (BP) in elderly non-insulin-dependent diabetes mellitus (NIDDM) patients having secondary failure of oral antidiabetic drug therapy. METHODS: Elderly NIDDM patients on maximal sulfonylurea treatment and showing poor metabolic control, but without symptoms of decompensation, were studied in a randomized prospective trial. One group was treated with insulin and the other was kept on oral treatment. Ambulatory BP measurements over 24 h were performed at the start and after 6 and 12 months. RESULTS: Metabolic control in the insulin-treated, but not in the sulfonylurea-treated group, improved significantly. Body weight increased in the insulin-treated and decreased in the sulfonylurea-treated group. We found no changes in BP in the two treatment groups, whether studied during the 24-h period or during the daytime or night time when divided into longer (22.00 to 06.00 hours) or shorter (01.00 to 07.00 hours) time periods in the night. CONCLUSIONS: No change in BP was noted in elderly diabetic patients when the metabolic control was improved by insulin treatment. Their weight gain may have counteracted the effect of the improved metabolic control on BP. Thus, elderly NIDDM patients seem not to have any benefits from insulin treatment as regards BP control.

Developmental and reproductive toxicity of dioxins and related compounds: cross-species comparisons.

Developmental toxicity to TCDD-like congeners in fish, birds, and mammals, and reproductive toxicity in mammals are reviewed. In fish and bird species, the developmental lesions observed are species dependent, but any given species responds similarly to different TCDD-like congeners. Developmental toxicity in fish resembles "blue sac disease," whereas structural malformations can occur in at least one bird species. In mammals, developmental toxicity includes decreased growth, structural malformations, functional alterations, and prenatal mortality. At relatively low exposure levels, structural malformations are not common in mammalian species. In contrast, functional alterations are the most sensitive signs of developmental toxicity. These include effects on the male reproductive system and male reproductive behavior in rats, and neurobehavioral effects in monkeys. Human infants exposed during the Yusho and Yu-Cheng episodes, and monkeys and mice exposed perinatally to TCDD developed an ectodermal dysplasia syndrome that includes toxicity to the skin and teeth. Toxicity to the central nervous system in monkey and human infants is a potential part of the ectodermal dysplasia syndrome. Decreases in spermatogenesis and the ability to conceive and carry a pregnancy to term are the most sensitive signs of reproductive toxicity in male and female mammals, respectively.

Response of the antral mucosa of the rat stomach to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) produces a striking hypergastrinemia in rats that is thought to mediate the antiatrophy effect of TCDD on the oxyntic gland mucosa of the stomach. However, effects of TCDD on the antral mucosa, which is the origin of most physiologically released gastrin and is not a target for the trophic action of gastrin, has yet to be thoroughly investigated. Also gastrin release from gastrin-containing cells (i.e., G-cells) in the antral mucosa is inhibited by the paracrine secretion of somatostatin from D-cells in the antrum. Our purpose was to determine if the antral mucosa is affected by the trophic influence of TCDD and if alterations in antral mucosa levels of gastrin or somatostatin cause the hypergastrinemia. TCDD (100 micrograms/kg, Day 14 post-treatment) had a trophic effect on the antral mucosa. This was demonstrated histologically and by significant increases in antral wet weight and antral mucosa height. In contrast, pair-fed control rats that lost the same amount of body weight developed antral mucosa atrophy. With respect to serum and antral levels of gastrointestinal hormones, TCDD produced a 7- to 10-fold increase in serum gastrin concentrations that was not detected until Day 14 post-treatment. In contrast, serum gastrin concentrations in pair-fed control rats were comparable to those of control rats. The number of G-cells in the antral mucosa was not affected by either TCDD treatment or paired-feed restriction. These findings demonstrate that hypergastrinemia in TCDD-treated rats is not caused by reduced feed intake or antral G-cell hyperplasia. A major finding was that antral mucosa levels of both gastrin and somatostatin were decreased significantly in TCDD-treated rats. However, the temporal development and dose-dependence of these TCDD effects on antral hormone levels were quite different than those for hypergastrinemia. TCDD-induced decreases in antral levels of gastrin and somatostatin were detected 1 week earlier than hypergastrinemia. Also, the ED50 of TCDD on Day 14 post-treatment for the decrease in antral mucosa content and concentration of gastrin (29 and 22 micrograms/kg, respectively) and somatostatin (24 and 19 micrograms/kg, respectively) was less than that for hypergastrinemia (46 micrograms/kg). These time- and dose-dependent differences demonstrate that hypergastrinemia in TCDD-treated rats is not a consequence of reduced antral levels of gastrin or somatostatin. We conclude that the antral mucosa, an epithelial tissue not responsive to the proliferative effect of gastrin, is nevertheless a target for the trophic influence and gastrointestinal hormone-altering effects of TCDD.