Endothelial Cell-Targeted Deletion of PPARγ Blocks Rosiglitazone-Induced Plasma Volume Expansion and Vascular Remodeling in Adipose Tissue.

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor γ (PPARγ) agonists that represent an effective class of insulin-sensitizing agents; however, clinical use is associated with weight gain and peripheral edema. To elucidate the role of PPARγ expression in endothelial cells (ECs) in these side effects, EC-targeted PPARγ knockout (Pparg ΔEC) mice were placed on a high-fat diet to promote PPARγ agonist-induced plasma volume expansion, and then treated with the TZD rosiglitazone. Compared with Pparg-floxed wild-type control (Pparg f/f) mice, Pparg ΔEC treated with rosiglitazone are resistant to an increase in extracellular fluid, water content in epididymal and inguinal white adipose tissue, and plasma volume expansion. Interestingly, histologic assessment confirmed significant rosiglitazone-mediated capillary dilation within white adipose tissue of Pparg f/f mice, but not Pparg ΔEC mice. Analysis of ECs isolated from untreated mice in both strains suggested the involvement of changes in endothelial junction formation. Specifically, compared with cells from Pparg f/f mice, Pparg ΔEC cells had a 15-fold increase in focal adhesion kinase, critically important in EC focal adhesions, and >3-fold significant increase in vascular endothelial cadherin, the main component of focal adhesions. Together, these results indicate that rosiglitazone has direct effects on the endothelium via PPARγ activation and point toward a critical role for PPARγ in ECs during rosiglitazone-mediated plasma volume expansion.

Severe Ketoacidosis (pH ≤ 6.9) in Type 2 Diabetes: More Frequent and Less Ominous Than Previously Thought.

Diabetic ketoacidosis is a life-threatening acute metabolic complication of uncontrolled diabetes. Severe cases of DKA (pH ≤ 7.00, bicarbonate level ≤ 10.0, anion gap > 12, positive ketones, and altered mental status) are commonly encountered in patients with type 1 diabetes and are thought to carry an ominous prognosis. There is not enough information on the clinical course of severely acidotic type 2 diabetes (pH ≤ 6.9) patients with DKA, possibly because this condition is rarely seen in developed countries. In this series, we present 18 patients with type 2 diabetes, DKA, and a pH ≤ 6.9 that presented to a tertiary university hospital over the past 11 years. The objective was to describe their clinical characteristics, the triggering cause, and emphasis on treatment, evolution, and outcomes. The majority of the patients were female (61%). Mean age was 40.66 years (23-59). The patients had been first diagnosed with type 2 diabetes on average 5.27 ± 3.12 years before admission. Glutamic acid decarboxylase (GAD65) antibodies were negative in all patients. The origin of DKA could be attributed to two main causes: treatment omission in 8 (44.4%) patients and infections in 7 (38.8%) patients. The most common symptoms described were general malaise, dyspnea, altered mental status, and abdominal pain. Mean serum glucose on admission was 613.8 ± 114.5 mg/dL. Mean venous pH was 6.84 ± 0.03 with an anion gap of 30.3 ± 2.9 and a venous HCO3 level of 3.62 ± 1.35 mmol/L. All patients had acute renal failure on admission, with a mean serum creatinine of 1.57 ± 0.35 mg/dL compared to 0.55 ± 0.21 mg/dL at discharge. All patients received regular insulin infusion, aggressive fluid repletion, and 12 patients (66%) received bicarbonate infusion. Mean total insulin infusion dose was 181.7 ± 90.4 U (on average 0.14 ± 0.05 U/Kg/h). Mean time on infusion was 24.4 ± 12.6 hours. We recorded no mortality in this case series. Mean in-hospital stay was 5.0 ± 4.1 days. In conclusion, very severe DKA in type 2 diabetes is not uncommon in our population, shares many features with non-very-severe cases of DKA (bicarbonate therapy did not make a difference in mortality), and can be managed following standard published or institutional guidelines.

Nicotinic acid and DP1 blockade: studies in mouse models of atherosclerosis.

The use of nicotinic acid to treat dyslipidemia is limited by induction of a "flushing" response, mediated in part by the interaction of prostaglandin D(2) (PGD(2)) with its G-protein coupled receptor, DP1 (Ptgdr). The impact of DP1 blockade (genetic or pharmacologic) was assessed in experimental murine models of atherosclerosis. In Ptgdr(-/-)ApoE(-/-) mice versus ApoE(-/-) mice, both fed a high-fat diet, aortic cholesterol content was modestly higher (1.3- to 1.5-fold, P < 0.05) in Ptgdr(-/-)ApoE(-/-) mice at 16 and 24 weeks of age, but not at 32 weeks. In multiple ApoE(-/-) mouse studies, a DP1-specific antagonist, L-655, generally had a neutral to beneficial effect on aortic lipids in the presence or absence of nicotinic acid treatment. In a separate study, a modest increase in some atherosclerotic measures was observed with L-655 treatment in Ldlr(-/-) mice fed a high-fat diet for 8 weeks; however, this effect was not sustained for 16 or 24 weeks. In the same study, treatment with nicotinic acid alone generally decreased plasma and/or aortic lipids, and addition of L-655 did not negate those beneficial effects. These studies demonstrate that inhibition of DP1, with or without nicotinic acid treatment, does not lead to consistent or sustained effects on plaque burden in mouse atherosclerotic models.

Peroxisome proliferator-activated receptor (PPAR)-alpha agonism prevents the onset of type 2 diabetes in Zucker diabetic fatty rats: A comparison with PPAR gamma agonism.

Peroxisome proliferator-activated receptor (PPAR)-gamma agonists are insulin sensitizers, whereas PPAR alpha agonists are lipid-lowering agents in humans. Chronic treatment with PPAR gamma agonists has been shown to prevent the onset of diabetes in young Zucker diabetic fatty (ZDF) rats; however, the effects of PPAR alpha agonists have not been well characterized in this model. Here we investigated chronic efficacy of PPAR alpha and nonthiazolidinedione (nTZD) PPAR gamma agonists on the onset of diabetes in 6-wk-old male ZDF rats. Whereas treatment with the nTZD PPAR gamma agonist completely prevented development of hyperglycemia, PPAR alpha activation was associated with lowering of food intake and body weight and reductions in fed and fasting hyperglycemia, with prevention of the hyperinsulinemic peak preceding the development of hyperglycemia in ZDF rats. Both compounds improved glucose tolerance during an oral glucose tolerance test with concomitant increases in insulin response. Such improvements of insulin secretion were associated with increased islet to total pancreatic area ratio and pancreatic insulin contents. Hyperinsulinemic-euglycemic clamp studies demonstrated that nTZD PPAR gamma reduced basal endogenous glucose production and increased insulin-stimulated glucose disposal, consistent with an improved insulin action as a cause of the improved glucose homeostasis. In contrast, activation of PPAR alpha did not significantly improve glucose metabolism during the hyperinsulinemic-euglycemic clamp. In conclusion, chronic treatment of ZDF rats with a PPAR gamma agonist completely prevented the onset of diabetes by improving both insulin action and secretion, whereas PPAR alpha agonism was partially effective, primarily by improving the pancreatic islet insulin response. Unlike the PPAR gamma agonist, the PPAR alpha agonist demonstrated efficacy without inducing body weight gain and cardiomegaly. This study suggests a possible role for PPAR alpha agonists in the prevention of type 2 diabetes mellitus.

Perinatal mortality and neonatal morbidity rates among twin pairs at different gestational ages: optimal delivery timing at 37 to 38 weeks' gestation.

OBJECTIVE: The aim of this study was to determine the gestational age at delivery associated with the lowest rates of perinatal mortality, respiratory distress syndrome, and long hospital stays among twins, with pair rates used to account for both infants in each twin pregnancy. STUDY DESIGN: We conducted a population-based retrospective study that analyzed linked birth certificates, fetal and infant death certificates, and hospital discharge data for 8150 twin pairs born in Washington State during 1987 through 1997. The chi2 or Fisher exact test was used to assess the statistical significance. RESULTS: The nadirs of perinatal mortality rate, respiratory distress syndrome incidence, and long hospital stay rate were seen at delivery dates of 39, 40, and 38 weeks' gestation, respectively. Restriction to pairs delivered vaginally without the induction of labor revealed that the perinatal mortality rate was lowest for delivery at 37 weeks' gestation, the gestational age at which the highest numbers of such spontaneously timed pairs were born. CONCLUSION: Induction of labor should be routinely considered for twins at 37 to 38 weeks' gestation.

Chronic rhinosinusitis: allergy and sinus computed tomography relationships.

The management of chronic or recurrent rhinosinusitis problems is multifaceted and should include consideration of contributory and potentially correctable medical and anatomic factors. To date, the relationship between allergy and rhinosinusitis has not been clearly defined. The purpose of this study is to improve understanding of the relative roles of perennial and seasonal allergens in the cause of chronic rhinosinusitis. A retrospective review of 200 consecutive patients was carried out on patients who had chronic rhinosinusitis refractory to medical therapy and who subsequently underwent functional endoscopic sinus surgery. All of these patients had allergy testing for common perennial and seasonal inhalant allergens before surgery. Each patient had sinus CT imaging before undergoing the surgery. The CT scans of each patient were staged according to a validated, standardized grading system by investigators blinded to allergic profile. Allergy testing indicated that 84% of all patients tested positive for allergies. Moreover, 60% of all patients had significant allergic sensitivity; 52% of all patients had multiple allergen sensitivities. Furthermore, there was a predominance of perennial allergens, especially house dust mite over seasonal allergens. The vast majority of our patients undergoing functional endoscopic sinus surgery had concomitant allergy. This study highlights the potential contribution of perennial allergies to the development of rhinosinusitis. Given this direction, future studies may reveal that in the care of patients with perennial allergic rhinitis, early intervention with identification of the offending allergen(s), and subsequent treatment through avoidance, pharmacotherapy, and/or immunotherapy may help in the prevention of recurrent and chronic rhinosinusitis.

Maternal birth weight and cesarean delivery in four race-ethnic groups.

OBJECTIVE: We hypothesized that maternal birth weight was associated with the risk of cesarean delivery for nulliparous women. STUDY DESIGN: In a population-based cohort study, maternal birth data were linked to a Washington State database, including the birth certificates of 18,905 first-born singleton infants (1987-1995). RESULTS: Among non-Hispanic white subjects, maternal birth weight of 2500 to 3999 g was associated with a 20.9% risk of cesarean delivery, which was the lowest risk, compared with 24.5% for a maternal birth weight <2500 g (P <.05) and 24.0% for a maternal birth weight > or =4000 g (P <.05). Similar patterns of risk were noted among Hispanic and Native American subjects, although the associations did not reach statistical significance. Risk of cesarean delivery was not associated with maternal birth weight among African American subjects. Among non-Hispanic white subjects, the risk of cesarean delivery was 3.23 times greater with a maternal birth weight <2500 g and an infant birth weight > or =4000 g compared with pregnancies with both maternal and infant birth weights between 2500 and 3999 g (P <. 001). Adjustment for socioeconomic factors did not alter these results. CONCLUSION: Low and high maternal birth weights exert an intergenerational risk of cesarean delivery in nulliparous non-Hispanic white women.

Respiratory distress syndrome and maternal birth weight effects.

OBJECTIVE: To study traditional risk factors and the intergenerational risk factor maternal low birth weight (LBW) for respiratory distress syndrome (RDS) in infants in multiple ethnic groups. METHODS: The population-based database consists of hospital records linked to Washington state maternal and infant vital records. Four racial-ethnic groups were studied, whites, blacks, Native Americans, and Hispanics. Poisson regression models were used to estimate relative risks of various factors for RDS. RESULTS: Rates for RDS were whites 1.2%, blacks 1.9%, Native Americans 1.3%, and Hispanics 1.0%. Maternal LBW was associated with increased relative risk (RR) for RDS in whites (2.6, 95% confidence interval [CI] 1.6, 4.2) and blacks (3.3, 95% CI 1.9, 5.6) for infants born vaginally. Compared with mothers of normal infants, birth weights of mothers of infants with RDS and delivered vaginally were significantly lower in whites, blacks, and Native Americans. The association of maternal LBW with RDS persisted in blacks even when multiple risk factors were added to the model (RR 2.4; 95% CI 1.1, 5.1). CONCLUSION: The association of maternal LBW with RDS is probably due in part to the association of maternal LBW with infant LBW and preterm birth. The strong persistent association of maternal LBW with RDS in blacks suggests that improvement of perinatal outcomes in that group will require improvement of long-term birth weight distribution.

Early-life risk factors and the development of Alzheimer's disease.

OBJECTIVE: To investigate the association of early-life factors with AD. BACKGROUND: The early-life environment and its effect on growth and maturation of children and adolescents are linked to many adult chronic diseases (heart disease, stroke, hypertension, and diabetes mellitus), and these effects are also linked to maternal reproduction. AD may have an early-life link. The areas of the brain that show the earliest signs of AD are the same areas of the brain that take the longest to mature during childhood and adolescence. A poor-quality childhood or adolescent environment could prevent the brain from reaching complete levels of maturation. Lower levels of brain maturation may put people at higher risk for AD. METHODS: In a community-based case-control study (393 cases, 377 controls), we investigated the association of early-life factors and AD. Early-life variables include mother's age at patient's birth, birth order, number of siblings, and area of residence before age 18 years. Patient education level and apolipoprotein E (APOE) genotypes were also included in the analysis. RESULTS: Area of residence before age 18 years and number of siblings are associated with subsequent development of AD. For each additional child in the family the risk of AD increases by 8% (OR = 1.08, 95% CI = 1.01 to 1.15). More controls compared with cases grew up in the suburbs (OR = 0.45, 95% CI = 0.25 to 0.82). APOE epsilon 4 and the patient's education level did not confound or modify the associations. CONCLUSIONS: The early-life childhood and adolescent environment is associated with the risk of AD.

A population-based cohort study of the relation between maternal birthweight and risk of gestational diabetes mellitus in four racial/ethnic groups.

Intrauterine growth retardation and low birthweight have been associated with an increased risk of insulin resistance and type II diabetes later in life. We hypothesised that maternal low birthweight is associated with an increased risk of gestational diabetes mellitus (GDM). Study subjects comprised women giving birth in Washington State between 1987 and 1995. Information for 21,528 births to non-Hispanic white women, 6359 to African-American women, 7456 to Native American women and 6496 to Hispanic women was available for analysis. All information was derived from statewide computerised vital records and hospital discharge summaries of obstetric and neonatal admissions with linkage to birth certificates of mothers. Maternal birthweight was collected from subjects' birth certificates. Information from both the birth certificates and the obstetric and neonatal admissions database was used to determine whether subjects developed GDM. Poisson regression models were estimated to calculate unadjusted and adjusted risk ratios (RRs) and 95% confidence intervals (CIs) for GDM by categories of maternal birthweight. The cumulative incidence of GDM among non-Hispanic white, African-American, Native American and Hispanic women was 2.8, 2.6, 2.7 and 3.0% respectively. After adjusting for maternal age, parity, cigarette smoking, history of chronic hypertension and participation in the Medicaid programme, non-Hispanic white women with a birthweight < 2000 g were 1.7 times more likely to have had their pregnancy complicated by GDM (RR = 1.7; 95% CI 0.8, 3.3) than those with a birthweight 3000-3999 g. The corresponding adjusted RRs for African-American, Native American, and Hispanic women were 2.8 [95% CI 1.2, 6.1], 3.1 [95% CI 1.2, 8.2] and 2.4 [95% CI 0.9, 6.0] respectively. Among African-American women, those with a birthweight > or = 4000 g also experienced a twofold increased risk of GDM (RR = 2.1; 95% CI 1.0, 4.1). This association of high birthweight and increased GDM risk was not found among women in the other three racial/ethnic groups. These findings suggest that individuals with low birthweight constitute a group at increased risk for GDM.

The Washington State Intergenerational Study of Birth Outcomes: methodology and some comparisons of maternal birthweight and infant birthweight and gestation in four ethnic groups.

A statewide database of vital records and hospital discharge summaries of obstetric and neonatal admissions for Washington State in 1987-95 was linked to the birth certificates of mothers born in the state. A total of 46,000 births to mothers of four racial/ethnic groups were studied: Whites, African-Americans, Native Americans and Hispanics. For all four groups inverse associations were found between maternal birthweight and infant low birthweight and preterm birth. The birthweight distribution of African-American mothers was displaced markedly downwards compared with the Whites; this difference in maternal birthweight is offered as a partial explanation of the greater prevalence of suboptimal pregnancy outcomes in the former. In contrast, the maternal birthweight distributions of Whites, Native Americans and Hispanics are similar; differences in pregnancy outcomes are probably more related to maternal preconceptional and postnatal factors in these groups as well as differences in pregnancy-related factors. Mothers' birthweight may have clinical value in identifying high-risk pregnancies.

Birthweight and blood pressure among children in Harare, Zimbabwe.

AIM: To determine whether poor uterine growth may be associated with increased blood pressure and subsequent hypertension in adulthood. METHODS: A retrospective cohort study of 756 schoolchildren (mean age 6.5 years) was carried out in six low income areas in Harare city, Zimbabwe. Indices of intrauterine growth and blood pressure were assessed. RESULTS: Adjusted for current weight, the children's systolic blood pressure was inversely related to their birthweight; for each decreasing kg of birthweight, systolic blood pressure rose by 1.73 mm Hg (95% CI; 0.181 to 3.28). After adjustment for current weight, systolic blood pressure was also inversely associated with occipito-frontal circumference, but not with birth length or gestational age. Diastolic blood pressure was not associated with any of the intrauterine indices. CONCLUSION: Fetal size may be inversely related to systolic blood pressure in childhood in an African population.

In vitro testing for allergy diagnosis. Comparison of methods in common use.

In vitro assays for the measurement of specific IgE have been available for the last 30 years. Over this time there have been significant changes in their technology, ranging from a long 3-day test to a short 3-hour test and from a labor intensive test to a fully automated test. These new innovations have enabled today's in vitro assays to be far more efficient, reliable, and reproducible.

Maternal and perinatal risk factors for later delinquency.

BACKGROUND: The early identification of risk factors for juvenile offending is one important step in preventing youth violence and offending. This cohort study examined whether perinatal circumstances predicted offending during adolescence. METHODS: Washington State birth certificates from 1974 to 1975 were linked to juvenile justice data to identify all individuals adjudicated between 10 and 17 years of age. Thirteen thousand five hundred seventy-three offenders were compared with a sample of 38 387 nonoffenders matched on gender and birth order. RESULTS: Both male and female children of mothers who were teenagers at the child's birth or at her first birth, or who were born to unmarried mothers, had significantly increased risk for any juvenile offending, and for being adjudicated for five or more crimes (chronic offending). Males born to unmarried mothers under 18 years old had an 11-fold increased risk of chronic offending compared with males born to married mothers >/=20 years old. Low birth weight and preterm gestational age carried no increased risk for juvenile offending. CONCLUSIONS: Birth to teenage or unmarried mothers are strongly associated with later risk of juvenile delinquency. Although there are multiple, interrelated risk factors for juvenile delinquency, prevention of births to teenage and/or unmarried mothers may help to prevent subsequent juvenile delinquency.

Juvenile delinquency and adolescent trauma: how strong is the connection?

OBJECTIVES: To determine whether youth convicted of juvenile offenses have a greater risk of injury resulting in hospitalization compared with nonoffending adolescents. DESIGN: A statewide hospital discharge database was linked to juvenile justice records to identify all hospitalizations occurring at ages 13 to 17 years for juvenile offenders and nonoffenders. SUBJECTS: Juvenile offenders and nonoffenders in Washington State during 1989 through 1992. MAIN OUTCOME MEASURES: Incidence of hospitalizations attributable to injury, analyzed by cause of injury and intent. RESULTS: The prevalence of delinquency was 19.1% of male and 9.5% of female adolescents. Hospitalization for injury was 2.7-fold greater for male and 1.6-fold greater for female offenders compared with nonoffenders. The greatest risk of hospitalization was for intentional injury, especially that attributable to firearms, and for drug overdoses. CONCLUSIONS: Juvenile offenders are much more likely to be hospitalized for an injury than nonoffenders. Admission to the hospital for trauma may serve as an opportunity for health providers to intervene with youth exhibiting high-risk behavior.

Perinatal factors and risk of breast cancer.

A high level of endogenous estrogen in utero has been hypothesized to be a possible risk factor for breast cancer. We used information from two population-based case-control studies to investigate the relation between perinatal factors and risk of invasive breast cancer among women age 21-45 years (746 cases, 960 controls) and women age 50-64 years (401 cases, 439 controls). Breast cancer cases were ascertained through a population-based cancer registry, and controls were selected by random digit dialing. After adjustment for age, menopausal status, and maternal smoking, the birthweight-breast cancer association in women age 21-45 years followed a J-shaped curve, with women whose birthweight was less than 2,500 gm [odds ratio (OR) = 1.3; 95% confidence interval (CI) = 0.9-2.0] and 4,000 gm or more (OR = 1.7; 95% CI = 1.1-2.5) at increased risk. Women age 50-64 years who were 4,000 gm or more at birth appeared to be at slightly reduced risk of breast cancer (OR = 0.6; 95% CI = 0.3-1.1). With the exception of maternal smoking, there was little effect of other perinatal factors on breast cancer risk in either group. These results support the hypothesized association between intrauterine estrogen exposure and subsequent risk of breast cancer.