Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement

Interleukin-1 (IL-1), a proinflammatory cytokine synthesized and released by activated microglia, can cause dopaminergic neurodegeneration leading to Parkinsons disease (PD). However, it is uncertain whether IL-1 can act directly, or by exacerbating the harmful actions of other brain insults. To ascertain the role of the IL-1 pathway on dopaminergic neurodegeneration and motor skills during aging, we compared mice with impaired [caspase-1 knockout (casp1(-/-))] or overactivated IL-1 activity [IL-1 receptor antagonist knockout (IL-1ra(-/-))] to wild-type (wt) mice at young and middle age. Their motor skills were evaluated by the open-field and rotarod tests, and quantification of their dopamine neurons and activated microglia within the substantia nigra were performed by immunohistochemistry. IL-1ra(-/-) mice showed an age-related decline in motor skills, a reduced number of dopamine neurons, and an increase in activated microglia when compared to wt or casp1(-/-) mice. Casp1(-/-) mice had similar changes in motor skills and dopamine neurons, but fewer activated microglia cells than wt mice. Our results suggest that the overactivated IL-1 pathway occurring in IL-1ra(-/-) mice in the absence of inflammatory interventions (e.g., intracerebral injections performed in animal models of PD) increased activated microglia, decreased the number of dopaminergic neurons, and reduced their motor skills. Decreased IL-1 activity in casp1(-/-) mice did not yield clear protective effects when compared with wt mice. In summary, in the absence of overt brain insults, chronic activation of the IL-1 pathway may promote pathological aspects of PD per se, but its impairment does not appear to yield advantages over wt mice.Funding Agencies|John Curtin School of Medical Research, The Australian National University</p

Identification of Methylated Genes Associated with Aggressive Bladder Cancer

Approximately 500,000 individuals diagnosed with bladder cancer in the U.S. require routine cystoscopic follow-up to monitor for disease recurrences or progression, resulting in over $2 billion in annual expenditures. Identification of new diagnostic and monitoring strategies are clearly needed, and markers related to DNA methylation alterations hold great promise due to their stability, objective measurement, and known associations with the disease and with its clinical features. To identify novel epigenetic markers of aggressive bladder cancer, we utilized a high-throughput DNA methylation bead-array in two distinct population-based series of incident bladder cancer (n = 73 and n = 264, respectively). We then validated the association between methylation of these candidate loci with tumor grade in a third population (n = 245) through bisulfite pyrosequencing of candidate loci. Array based analyses identified 5 loci for further confirmation with bisulfite pyrosequencing. We identified and confirmed that increased promoter methylation of HOXB2 is significantly and independently associated with invasive bladder cancer and methylation of HOXB2, KRT13 and FRZB together significantly predict high-grade non-invasive disease. Methylation of these genes may be useful as clinical markers of the disease and may point to genes and pathways worthy of additional examination as novel targets for therapeutic treatment

Congenital hypothyroidism

Congenital hypothyroidism (CH) occurs in approximately 1:2,000 to 1:4,000 newborns. The clinical manifestations are often subtle or not present at birth. This likely is due to trans-placental passage of some maternal thyroid hormone, while many infants have some thyroid production of their own. Common symptoms include decreased activity and increased sleep, feeding difficulty, constipation, and prolonged jaundice. On examination, common signs include myxedematous facies, large fontanels, macroglossia, a distended abdomen with umbilical hernia, and hypotonia. CH is classified into permanent and transient forms, which in turn can be divided into primary, secondary, or peripheral etiologies. Thyroid dysgenesis accounts for 85% of permanent, primary CH, while inborn errors of thyroid hormone biosynthesis (dyshormonogeneses) account for 10-15% of cases. Secondary or central CH may occur with isolated TSH deficiency, but more commonly it is associated with congenital hypopitiutarism. Transient CH most commonly occurs in preterm infants born in areas of endemic iodine deficiency. In countries with newborn screening programs in place, infants with CH are diagnosed after detection by screening tests. The diagnosis should be confirmed by finding an elevated serum TSH and low T4 or free T4 level. Other diagnostic tests, such as thyroid radionuclide uptake and scan, thyroid sonography, or serum thyroglobulin determination may help pinpoint the underlying etiology, although treatment may be started without these tests. Levothyroxine is the treatment of choice; the recommended starting dose is 10 to 15 mcg/kg/day. The immediate goals of treatment are to rapidly raise the serum T4 above 130 nmol/L (10 ug/dL) and normalize serum TSH levels. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and free T4 should be measured every 1-2 months in the first 6 months of life and every 3-4 months thereafter. In general, the prognosis of infants detected by screening and started on treatment early is excellent, with IQs similar to sibling or classmate controls. Studies show that a lower neurocognitive outcome may occur in those infants started at a later age (> 30 days of age), on lower l-thyroxine doses than currently recommended, and in those infants with more severe hypothyroidism

Estimation of the burden of cardiovascular disease attributable to modifiable risk factors and cost-effectiveness analysis of preventative interventions to reduce this burden in Argentina

Background. Cardiovascular disease (CVD) is the primary cause of mortality and morbidity in Argentina representing 34.2% of deaths and 12.6% of potential years of life lost (PYLL). The aim of the study was to estimate the burden of acute coronary heart disease (CHD) and stroke and the cost-effectiveness of preventative population-based and clinical interventions. Methods. An epidemiological model was built incorporating prevalence and distribution of high blood pressure, high cholesterol, hyperglycemia, overweight and obesity, smoking, and physical inactivity, obtained from the Argentine Survey of Risk Factors dataset. Population Attributable Fraction (PAF) of each risk factor was estimated using relative risks from international sources. Total fatal and non-fatal events, PYLL and Disability Adjusted Life Years (DALY) were estimated. Costs of event were calculated from local utilization databases and expressed in international dollars (I$). Incremental cost-effectiveness ratios (ICER) were estimated for six interventions: reducing salt in bread, mass media campaign to promote tobacco cessation, pharmacological therapy of high blood pressure, pharmacological therapy of high cholesterol, tobacco cessation therapy with bupropion, and a multidrug strategy for people with an estimated absolute risk > 20$ 2,908 per DALY saved), mass media campaign to promote tobacco cessation amongst smokers (I$3,186 per DALY saved), and lowering cholesterol with statin drug therapy (I$ 14,432 per DALY saved); and one intervention was not found to be cost-effective: tobacco cessation with bupropion (I$ 59,433 per DALY saved). Conclusions. Most of the interventions selected were cost-saving or very cost-effective. This study aims to inform policy makers on resource-allocation decisions to reduce the burden of CVD in Argentina.Centro de Endocrinología Experimental y Aplicada (CENEXA

Promoting optimal parenting and children’s mental health : a preliminary evaluation of the How-to Parenting Program

Parenting quality is widely accepted as a primary predictor of children’s mental health. The present study examined the effectiveness of a parenting program in fostering optimal parenting and child mental health. The selected program was How to talk so kids will listen & listen so kids will talk (How-to Parenting Program). This program was selected because its content corresponds closely to what the parenting style literature suggests is optimal parenting (i.e., includes structure, affiliation and autonomy support). Eleven groups of six to twelve parents were conducted in 7 local grade schools. The program, offered by two trained leaders, consisted of eight weekly sessions and taught a total of 30 skills. A total of 82 parents completed questionnaires both prior to and after the program. Participants’ children between eight and 12 years old (N = 44) completed questionnaires at school, at both assessment points. Repeated measures ANOVAs using parent reports indicated that structure, affiliation and autonomy support were increased after the program, compared to baseline. The level of child internalizing and externalizing problems also decreased significantly. Importantly, children reports confirmed that parental autonomy support increased from pre to post-test and child-reported well-being improved as well. The preliminary evidence from this pre-test versus post-test repeated measures design suggests that the How-to Parenting Program is effective in improving parenting style and in promoting children’s mental health and that future evaluation research examining the potential of this program is warranted

Iliocaval venous obstruction, cardiac preload reserve, and exercise limitation

Cardiac output during exercise increases by as much as five-fold in the untrained man, and by as much as eight-fold in the elite athlete. Increasing venous return is a critical but much overlooked component of the physiological response to exercise. Cardiac disorders such as constrictive pericarditis, restrictive cardiomyopathy and pulmonary hypertension are recognised to impair preload and cause exercise limitation, however the effects of peripheral venous obstruction on cardiac function have not been well described. This manuscript will discuss how obstruction of the iliocaval venous outflow can lead to impairment in exercise tolerance; how such obstructions may be diagnosed, the potential implications of chronic obstructions on sympathetic nervous system activation, and relevance of venous compression syndromes in heart failure with preserved ejection fraction