Modelling obesity outcomes: reducing obesity risk in adulthood may have greater impact than reducing obesity prevalence in childhood

A common policy response to the rise in obesity prevalence is to undertake interventions in childhood, but it is an open question whether this is more effective than reducing the risk of becoming obese during adulthood. In this paper, we model the effect on health outcomes of (i) reducing the prevalence of obesity when entering adulthood; (ii) reducing the risk of becoming obese throughout adult life; and (iii) combinations of both approaches. We found that, while all approaches reduce the prevalence of chronic diseases and improve life expectancy, a given percentage reduction in obesity prevalence achieved during childhood had a smaller effect than the same percentage reduction in the risk of becoming obese applied throughout adulthood. A small increase in the probability of becoming obese during adulthood offsets a substantial reduction in prevalence of overweight/obesity achieved during childhood, with the gains from a 50% reduction in child obesity prevalence offset by a 10% increase in the probability of becoming obese in adulthood. We conclude that both policy approaches can improve the health profile throughout the life course of a cohort, but they are not equivalent, and a large reduction in child obesity prevalence may be reversed by a small increase in the risk of becoming overweight or obese in adulthood.     

Indian Asians have poorer cardiovascular autonomic function than Europeans: this is due to greater hyperglycaemia and may contribute to their greater risk of heart disease

Aims/hypothesis  

A high prevalence of diabetes contributes to excess CHD in Indian Asians, but the underlying mechanisms are unclear. Heart rate, heart rate variability (HRV) and baroreflex sensitivity (BRS) are measures of cardiac autonomic function that are disturbed by hyperglycaemia and predict CHD. We compared these measures in Indian Asians and Europeans, and sought explanations for the observed differences.     

Thyroid carcinomas that express telomerase follow a more aggressive clinical course in children and adolescents

With each cell division, DNA is lost from the telomeres, limiting the number of divisions, and leading to senescence. Malignant tumors maintain immortality by expressing a specific DNA repair enzyme, telomerase, that replaces this DNA. We hypothesized that tumors which express telomerase would have the highest recurrence risk and we tested this by determining telomerase expression in 27 papillary thyroid carcinomas (PTC), 5 follicular thyroid carcinomas (FTC) and 13 benign thyroid lesions from children and adolescents. Patients were 6-21 yr of age (mean+/-SE=16.6+/-4.1 yr) and followed from 0-14.1 yr (mean+/-SE=4.71+/-3.5 yr). Original tumors were sectioned, and immunostained for telomerase. Telomerase-specific staining was determined by two independent, blind examiners and graded from absent (Grade 0) to intense (Grade 3). Telomerase was detected in a similar majority of benign (11/13, 85%) and malignant tumors (24/32, 75%). However, the intensity of telomerase expression was greater among FTC (mean+/-SE=2.4+/-0.5 relative intensity) followed by PTC (mean+/-SE=1.9+/-1.0 relative intensity) and benign tumors (mean+/-SE=1.8+/-1.0 relative intensity). Autoimmune lesions had lower telomerase expression (mean+/-SE=1.25+/-0.5 relative intensity) compared to FTC (p=0.01), PTC (p=0.06) and benign lesions (p=0.15). Among PTC, 19 (70%) expressed telomerase, and 8 (30%) did not. Direct invasion (no.=4, 21%), distant metastasis (no.=2, 10%) and recurrence (no.=7, 37%) developed exclusively in PTC that expressed telomerase (p=0.02). Disease-free survival was also shorter for PTC that expressed telomerase (p=0.06). Recurrence developed in 1/2 (50%) FTC that expressed telomerase. We conclude that childhood thyroid cancers which express telomerase have an increased risk of tissue invasion, metastasis, and recurrence.     

Cytoplasmic localization of the paired box gene, Pax-8, is found in pediatric thyroid cancer and may be associated with a greater risk of recurrence.

The paired box-8 protein (Pax-8) has been observed in the nucleus of normal adult thyroids, follicular adenomas, follicular thyroid cancers, and papillary thyroid cancers (PTC) but not undifferentiated thyroid cancers. To our knowledge, Pax-8 has not been studied in pediatric thyroid cancer. Because of the more favorable prognosis for PTC in children compared to young patients, we hypothesized that Pax-8 expression might be different in pediatric thyroid cancers. To test this, we stained 47 thyroid lesions from children and young patients for Pax-8. Pax-8 was located in the cytoplasm (cPAX) or nucleus (nPAX) in the majority of samples. There was no significant difference in nPAX between benign and malignant lesions. However, cPAX was more commonly seen in PTC than autoimmune diseases (p = 0.01) and the intensity of cPAX staining correlated with tumor size (p = 0.041), metastasis, age, completeness of resection, local invasion, and tumor size (MACIS) scores (p = 0.045), and the presence of invasion, metastasis, recurrence, or persistence (p = 0.012). Disease-free survival was significantly reduced for cancers with intense cPAX staining (p = 0.0003). These data show that cPAX is common in PTC, and although limited by small sample size, suggest an association with higher MACIS scores, an aggressive clinical course, and an increased risk of clinically evident recurrence for children and young patients.     

Soluble CD40 ligand, platelet surface CD40 ligand, and total platelet CD40 ligand in atrial fibrillation: relationship to soluble P-selectin, stroke risk factors, and risk factor intervention

BACKGROUND: Abnormal levels of soluble CD40 ligand (sCD40L) have been reported in patients with hypertension, coronary artery disease, diabetes mellitus, heart failure, and stroke, all of which are conditions that are associated with nonvalvular atrial fibrillation (AF). We hypothesized the following: (1) CD40 ligand (CD40L)-related indexes (ie, platelet surface expressed CD40L, the soluble fragment of CD40L [sCD40L], and the total amount of CD40L per platelet [pCD40L]) are elevated in patients with AF compared to control subjects; (2) these indexes correlate with soluble P-selectin (sP-selectin), which is an established platelet marker; and (3) these indexes differentiate "high-risk" from "low-risk" subjects. METHODS: We performed a case-control study of 121 AF patients, 71 "disease control subjects," and 56 "healthy control subjects." Peripheral venous levels of platelet surface-expressed CD40L were analyzed by flow cytometry, while levels of sCD40L, pCD40L, and sP-selectin were measured by enzyme-linked immunosorbent assay. RESULTS: AF patients had significantly higher sCD40L levels compared to healthy control subjects (p = 0.042), with no difference in platelet surface CD40L and pCD40L levels. A positive correlation was noted between levels of sCD40L and pCD40L, and not with sP-selectin. CD40L-related indexes failed to distinguish between high-risk and low-risk AF patients. AF patients receiving optimal antithrombotic therapy had significantly lower pCD40L levels (p < 0.001) compared to control subjects. Optimized AF management also resulted in significant reductions in the levels of sCD40L (p = 0.023) and pCD40L (p < 0.001). CONCLUSION: CD40L-related indexes are not useful in the risk stratification of AF patients, and abnormal sCD40L levels can be reduced by intense multifactorial risk management. While there is a significant, albeit modest, excess of platelet activation in AF patients (as measured by sCD40L levels) compared to healthy control subjects, this is not in excess of that seen in patients with underlying cardiovascular diseases.     

Women in Pakistan have a greater burden of clinical cardiovascular risk factors than men

AIMS: Migrant South Asian population in the West, particularly women, is more predisposed to central obesity and metabolic syndromes than native Caucasians. However, the burden of coexistence of clinical risk factors for cardiovascular disease (CVD) and associated gender disparities in native population of South Asia are not known. We analyzed the National Health Survey of Pakistan (NHSP) (1990-1994) data to study the same in the population of Pakistan. METHODS: Data from 9442 individuals age 15 years or over from the National Health Survey of Pakistan (NHSP) (1990-1994) was analyzed. The primary outcome was defined as the coexistence of at least two of the following five clinical risk factors for CVD. Hypertension (systolic blood pressure > or = 140 mm Hg, or diastolic blood pressure > or = 90 mm Hg, or current therapy with antihypertensive medications); diabetes (non-fasting blood glucose > or = 140 mg/dl (7.8 mmol/l), or known history of diabetes); proteinuria (dipstick urine protein > 1+); hyperlipidemia (random blood cholesterol > or = 200 mg/dl (5.17 mmol/l)), and central obesity (waist circumference of > or = 80 cm in women and > or = 90 cm in men. RESULTS: The overall prevalence (95% confidence intervals) of the coexistence of risk factors for CVD was 17.2% (16.4-18.0%): 13.0% (12.1-14.1%) in men and 20.9% (19.8-22.0%) in women (p < 0.001). Multivariate analysis revealed that men had at significantly lower odds of coexistence of risk factors than women with OR, 95% CI of 0.53, 0.47-0.61, and this difference increased in magnitude with age (interaction p < 0.001). In addition to Muhajir, Sindhi and Pashtun vs Punjabi ethnicity, factors independently associated with primary outcome were age (OR, 95% CI) (1.06, 1.05-1.06, for each one year increase), urban dwelling vs rural dwelling (1.45, 1.24-1.70), high (1.97, 1.61-2.45) and mid (1.44, 1.23-1.70) vs low socioeconomic status, body mass index (1.17, 1.15-1.18, for each one kg/m(2) increase), and high consumption of meat (1.77, 1.52-2.06) and ghee (1.26, 1.00-1.54). CONCLUSIONS: Potentially modifiable factors including obesity and saturated fat intake are associated with increased prevalence of CVD risk factors. The high burden of multiple CVD risk factors in women compared to men highlight the need for targeting this vulnerable segment of population in CVD prevention programs in Pakistan, and, possibly neighbouring countries.     

The impact of ulcerative colitis is greater in unmarried and young patients.

GOALS: To determine whether the perceived impact of ulcerative colitis (UC) on activities of living (illness intrusiveness) is greater for people who are not living in a married or common-law relationship. BACKGROUND: In general, social and occupational achievement is not greatly impaired by UC, yet patients, especially young adults, often have interpersonal concerns. METHODS: One hundred fifty-five outpatients with UC were assessed for disease activity, and completed self-reports of marital status, income, social support and illness intrusiveness. RESULTS: Fifty-one patients (32.9%) were single, separated or divorced, and 104 patients (67.1%) were married or in common-law relationships. Compared with those who were married or in common-law relationships, single or separated patients were younger, had a lower household income, had lived with UC for fewer years and were less satisfied with social support. Among 135 patients in remission, marital status was significantly associated with illness intrusiveness, controlling for age, income and perceived social support (F=5.73; P=0.02). Low social support (F=4.94; P=0.03) and younger age (F=7.24; P=0.008) were independently associated with illness intrusiveness. Single patients in remission reported illness intrusiveness of similar severity to that reported by patients with active disease. CONCLUSIONS: The perceived impact of UC on the lives of patients is greater in those who are not married or living in common-law relationships. Youth, single status and lower social support commonly coexist, and exert additive effects on the functional impact of UC. Resources to improve social support should be directed toward this group of patients.     

Older women with age-related macular degeneration have a greater risk of falls: a physiological profile assessment study

OBJECTIVES: To determine whether older women with exudative age-related macular degeneration (AMD) are at greater risk of falls.
DESIGN: Cross-sectional study.
SETTING: A hospital-based ophthalmology clinic in Vancouver, Canada.
PARTICIPANTS: One hundred fifteen older (aged ≥70) community-dwelling women with exudative AMD (AMD cohort) and two control groups: 54 community-dwelling women without exudative AMD drawn from the same community (non-AMD cohort) and 341 community-dwelling Australian women (Australian normative cohort).
MEASUREMENTS: Participants were assessed for falls risk using the short-form Physiological Profile Assessment (PPA), which provides a fall risk index score and subcomponent measures of vision, proprioception, strength, reaction time, and postural sway.
RESULTS: The mean fall risk index score in the AMD cohort (3.20) was significantly greater than that of the non-AMD cohort (1.21; P <.001), and fall risk scores increased with age to a greater extent in the AMD cohort. The higher fall risk scores in the AMD cohort resulted from significantly worse performance on each PPA test, not just the test of vision. The AMD cohort also performed worse than the Australian normative cohort in tests of vision, reaction time, and postural sway.
CONCLUSION: Older women with AMD have impaired balance, slow visual reaction times, and poor vision, which in combination result in a significantly greater risk of falls than population norms. These deficits are clearly indicated in the physiological falls profile for the group. Strategies to enhance balance may be particularly beneficial to prevent falls in this group.     

Study of plasma levels of soluble CD40 ligand in systemic lupus erythematosus patients who have undergone plasmapheresis

We studied whether soluble CD40 ligands (sCD40L) are removed by means of double filtration plasmapheresis (DFPP), and the removal may help decrease activity of systemic lupus erythematosus (SLE). We studied 10 female patients with active SLE. Double filtration plasmapheresis was conducted one or two times per week. Plasma sCD40L levels were measured before and after each round of DFPP and throughout the treatment course. The plasma sCD40L level of SLE patients was significantly higher (14.09 +/- 18.88 ng/mL) than that of healthy individuals (0.19 +/- 0.20 ng/mL; P < 0.0001). In the SLE patients, plasma sCD40L levels were significantly lower following DFPP (P = 0.0251). The plasma waste from DFPP of an SLE patient was subjected to gel filtration, and the sCD40L concentration in each fraction was measured. We observed a peak in the fraction corresponding to > or =60 kDa. These results indicate that trimers and higher order complexes of sCD40L are removed during DFPP. Plasma sCD40L level and SLE disease activity index (SLEDAI) were decreased following the treatment course (mean 9.3 months). sCD40L exists as both a monomer and trimer in the plasma of SLE patients. The trimer as well as higher-order compounds can be removed via DFPP. It was thought that removal of sCD40L via DFPP may be useful for improving the overall condition of SLE.     

Thyroid acropachy: report of 40 patients treated at a single institution in a 26-year period

Thyroid acropachy is an extreme manifestation of autoimmune thyroid disease. It presents with digital clubbing, swelling of digits and toes, and periosteal reaction of extremity bones. It is almost always associated with ophthalmopathy and thyroid dermopathy. During a 26-yr period at our institution, of 178 patients with thyroid dermopathy, 40 had acropachy. Clubbing associated with thyroid dermopathy (pretibial myxedema) was seen in 35 patients. Clubbing usually was not a patient complaint and was noted only by clinical observers. Four of eight patients with hand and extremity radiographs had periosteal reaction. Seven had associated extremity and joint pain; this pain was absent at long-term follow-up. Half of the patients required systemic corticosteroid therapy, 53% required transantral or transfrontal orbital decompression for severe ophthalmopathy, and 18% had the elephantiasic form of dermopathy. Cigarette-smoking rates were 81% for women and 75% for men (mean, 28 pack-years). All 13 patients who had thyroid-stimulating Ig measurement had high titers. Long-term follow-up (median, 12.5 yr) revealed that acropachy was not a complaint in follow-up visits or questionnaires. The data suggest that thyroid acropachy is an indicator of severity of ophthalmopathy and dermopathy. It is a source of clinical concern only if dermopathy is persistent and severe.     

Crohn's disease: risk of recurrence and reoperation in a defined population.

Two hundred and ten patients with Crohn's disease (CD) were identified in an epidemiological survey of inflammatory bowel disease in the Leiden Health Care Region of the Netherlands. The survey included all patients with CD seen between 1979-1983. The duration of disease ranged from less than one year to 48 years. Of the 210 patients with CD, 118 (56%) underwent surgical resection. Sixty one had an ileocaecal resection, 14 a proctocolectomy, in seven cases as a two stage procedure; 12 a segmental colectomy with end-to-end anastomosis and eight a subtotal colectomy with ileostomy. Twenty-one of these 118 patients (18%) had recurrences requiring reoperation; in 11 because of recurrence at the anastomotic site. Life table analysis showed that after 10 years 17% of patients required further resection for recurrence and 8% for relapse. By 20 years the rate of recurrence had risen to 56%. Patients over the age of 30 at first resection were at 1.5 fold greater risk of requiring further surgery than younger patients. The initial site of disease played no role in recurrence and there was no evidence that preoperative disease duration, delay in diagnosis, or late surgery had any effect on recurrence rates. This is one of the few community based studies to measure recurrence and relapse. A balanced appraisal is that surgery is not permanently curative, but the need for further resection may be lower than previously suggested.     

CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency.

Common variable immunodeficiency (CVI) is characterized by hypogammaglobulinemia and recurrent bacterial infections due to failure of CVI B cells to differentiate in vivo into immunoglobulin-secreting plasma cells. We hypothesized that T-cell dysfunction resulting in abnormal contact-mediated B-cell activation may play a prominent role in the failure of CVI B cells to produce specific antibody. We have previously shown that B-cell proliferation and IgE production after stimulation with anti-CD40 and interleukin (IL) 4 were normal in 22 CVI patients evaluated, indicating that CVI B cells respond to signals delivered via CD40. Here we report that CD40 ligand (gp39) mRNA expression by activated lymphocytes from CVI patients (n = 31) as a group was significantly depressed (P < 0.0001) compared with normal controls (n = 32). gp39 mRNA expression by activated lymphocytes from 13 CVI patients fell below the normal control range. T-cell surface expression of functional gp39 protein was correspondingly low in those patients with gp39 mRNA levels below normal control range and normal in patients with gp39 mRNA levels within normal control range. In CVI patients as a group, gp39 mRNA levels correlated with IL-2 mRNA levels (P < 0.002, r = 0.6) and production (P < 0.001, r = 0.7) but not with gene expression or production of other lymphokines evaluated, suggesting an as-yet-undetermined association between gp39 and IL-2 gene regulation. Of the 13 patients whose activated T cells exhibited gp39 mRNA expression below the normal control range, 2 had normal T-cell-derived lymphokine production, whereas the remaining 11 exhibited broader T-cell dysfunction, resulting in IL-2 deficiency, and in some patients deficient production of other lymphokines as well, reflecting a heterogeneity in the underlying mechanisms leading to depressed gp39 expression in these patients. The observation that both gene and surface expression of gp39 by activated T cells is depressed in a subgroup of CVI patients suggests that inefficient signaling via CD40 may be responsible, in part, for failure of B-cell differentiation in these patients.     

CD40 ligand and risk of ischemic stroke or coronary events in patients with chronic coronary heart disease

BACKGROUND: CD40 ligand (CD40L) is a trimeric, transmembrane protein of the tumor necrosis factor family and together with its receptor CD40 is an important contributor to the inflammatory processes that lead to atherosclerosis, plaque destabilization, and thrombosis. METHODS: In order to assess the association between serum concentrations of CD40 ligand (CD40L) and risk of future ischemic stroke and coronary events among patients with chronic CHD, we obtained baseline serum samples from patients (n = 3090) with chronic CHD enrolled in a secondary prevention trial. With a prospective nested case-control design, we measured baseline CD40L concentration in sera of patients who subsequently developed myocardial infarction, sudden cardiac death or ischemic stroke during follow-up (cases, n = 233) and in 233 age- and gender-matched pairs without any subsequent cardiovascular events. RESULTS: Relative odds for recurrent cardiovascular events per one natural log unit difference of CD40L were 0.97 (95%CI, 0.82-1.16). No increase in relative odds for recurrent cardiovascular events was observed per increasing quartiles of CD40L concentrations. In analysis for individual end-points, different trends of risks were observed beyond the 95 percentile for ischemic stroke (OR 2.22; 95%CI, 0.46-12.5) and for recurrent coronary events (OR 0.35; 95%CI, 0.07-1.37), but falling short of statistical significance. CONCLUSION: High serum concentrations of CD40L were not associated with increased risk of ischemic stroke or coronary events in patients with chronic coronary heart disease.     

Sensitivity of testicular germ cells to toxicant-induced apoptosis in gld mice that express a nonfunctional form of Fas ligand

Germ cell apoptosis in testis is essential for functional spermatogenesis. Recent evidence suggests that the Fas signaling system is critical for the regulation of testicular germ cell apoptosis. To further evaluate the Fas signaling system in testis, we examined the incidence of germ cell apoptosis in gld mice that lack a functional Fas-signaling pathway. gld mice have a small, but significant, increase in testis weight and numbers of spermatid heads per testis compared with wild-type mice. In addition, gld mice have a small increase in the spontaneous incidence of germ cell apoptosis, as indicated by characteristic DNA fragmentation via the terminal deoxynucleotidyl-transferase-mediated deoxy-UTP nick end labeling assay. To test the role of the Fas system in toxicant-induced germ cell apoptosis, mice were exposed to either a Sertoli cell- or germ cell-specific toxicant [mono-(2-ethylhexyl)phthalate (MEHP; 1 g/kg) or 5 Gy radiation, respectively]. These two exposure paradigms induced extensive increases in germ cell apoptosis in wild-type mice. However, exposure of gld mice to MEHP caused only a minimal increase in germ cell apoptosis, whereas they were as sensitive as wild-type mice to radiation exposure. These data indicate that the Fas signaling pathway is 1) involved in regulating the numbers of germ cells in the testis, 2) crucial for the initiation of germ cell apoptosis after MEHP-induced Sertoli cell injury, and 3) differentially active in the cell-specific regulation of germ cell apoptosis that occurs as a consequence of Sertoli cell vs. germ cell injury.