Lymphotoxin-α Gene and Risk of Myocardial Infarction in 6,928 Cases and 2,712 Controls in the ISIS Case-Control Study

Lymphotoxin-α (LTA) is a pro-inflammatory cytokine that plays an important role in the immune system and local inflammatory response. LTA is expressed in atherosclerotic plaques and has been implicated in the pathogenesis of atherosclerosis and coronary heart disease (CHD). Polymorphisms in the gene encoding lymphotoxin-α (LTA) on Chromosome 6p21 have been associated with susceptibility to CHD, but results in different studies appear to be conflicting. We examined the association of seven single nucleotide polymorphisms (SNPs) across the LTA gene, and their related haplotypes, with risk of myocardial infarction (MI) in the International Study of Infarct Survival (ISIS) case-control study involving 6,928 non-fatal MI cases and 2,712 unrelated controls. The seven SNPs (including the rs909253 and rs1041981 SNPs previously implicated in the risk of CHD) were in strong linkage disequilibrium with each other and contributed to six common haplotypes. Some of the haplotypes for LTA were associated with higher plasma concentrations of C-reactive protein (p = 0.004) and lower concentrations of albumin (p = 0.023). However, none of the SNPs or related haplotypes were significantly associated with risk of MI. The results of the ISIS study were considered in the context of six previously published studies that had assessed this association, and this meta-analysis found no significant association with CHD risk using a recessive model and only a modest association using a dominant model (with narrow confidence intervals around these risk estimates). Overall, these studies provide reliable evidence that these common polymorphisms for the LTA gene are not strongly associated with susceptibility to coronary disease

Progress in prevention of mother-to-child transmission of HIV infection in Ukraine: results from a birth cohort study

<p>Abstract</p> <p>Background</p> <p>Ukraine was the epicentre of the HIV epidemic in Eastern Europe, which has the most rapidly accelerating HIV epidemic world-wide today; national HIV prevalence is currently estimated at 1.6%. Our objective was to evaluate the uptake and effectiveness of interventions for prevention of mother-to-child transmission (PMTCT) over an eight year period within operational settings in Ukraine, within the context of an ongoing birth cohort study.</p> <p>Methods</p> <p>The European Collaborative Study (ECS) is an ongoing birth cohort study in which HIV-infected pregnant women identified before or during pregnancy or at delivery were enrolled and their infants prospectively followed. Three centres in Ukraine started enrolling in 2000, with a further three joining in September 2006.</p> <p>Results</p> <p>Of the 3356 women enrolled, 21% (689) reported current or past injecting drug use (IDU). Most women were diagnosed antenatally and of those, the proportion diagnosed in the first/second trimester increased from 47% in 2000/01 (83/178) to 73% (776/1060) in 2006/07 (p < 0.001); intrapartum diagnosis was associated with IDU (Adjusted odds ratio 4.38; 95%CI 3.19–6.02). The percentage of women not receiving any antiretroviral prophylaxis declined from 18% (36/205) in 2001 to 7% in 2007 (61/843) (p < 0.001). Use of sdNVP alone substantially declined after 2003, with a concomitant increase in zidovudine prophylaxis. Median antenatal zidovudine prophylaxis duration increased from 24 to 72 days between 2000 and 2007. Elective caesarean section (CS) rates were relatively stable over time and 34% overall. Mother-to-child transmission (MTCT) rates decreased from 15.2% in 2001 (95%CI 10.2–21.4) to 7.0% in 2006 (95%CI 2.6–14.6). In adjusted analysis, MTCT risk was reduced by 43% with elective CS versus vaginal delivery and by 75% with zidovudine versus no prophylaxis.</p> <p>Conclusion</p> <p>There have been substantial improvements in use of PMTCT interventions in Ukraine, including earlier diagnosis of HIV-infected pregnant women and increasing coverage with antiretroviral prophylaxis and the initial MTCT rate has more than halved. Future research should focus on hard-to-reach populations such as IDU and on missed opportunities for further reducing the MTCT rate.</p

Mother-to-child transmission of human immunodeficiency virus in aten years period

<p>Abstract</p> <p>Objectives</p> <p>to evaluate mother-to-child transmission (MTCT) rates and related factors in HIV-infected pregnant women from a tertiary hospital between 2000 and 2009.</p> <p>Subjects and method</p> <p>cohort of 452 HIV-infected pregnant women and their newborns. Data was collected from recorded files and undiagnosed children were enrolled for investigation. Statistical analysis: qui-square test, Fisher exact test, Student <it>t </it>test, Mann-Whitney test, ANOVA, risk ratio and confidence intervals.</p> <p>Results</p> <p>MTCT occurred in 3.74%. The study population displayed a mean age of 27 years; 86.5% were found to have acquired HIV through sexual contact; 55% were aware of the diagnosis prior to the pregnancy; 62% were not using HAART. Mean CD4 cell-count was 474 cells/ml and 70.3% had undetectable viral loads in the third trimester. HAART included nevirapine in 35% of cases and protease inhibitors in 55%; Zidovudine monotherapy was used in 7.3%. Mean gestational age at delivery was 37.2 weeks and in 92% by caesarian section; 97.2% received intravenous zidovudine. Use of AZT to newborn occurred in 100% of them. Factors identified as associated to MTCT were: low CD4 cell counts, elevated viral loads, maternal AIDS, shorter periods receiving HAART, other conditions (anemia, IUGR (intra uterine growth restriction), oligohydramnium), coinfecctions (CMV and toxoplasmosis) and the occurrence of labor. Use of HAART for longer periods, caesarian and oral zidovudine for the newborns were associated with a decreased risk. Poor adhesion to treatment was present in 13 of the 15 cases of transmission; in 7, coinfecctions were diagnosed (CMV and toxoplasmosis).</p> <p>Conclusion</p> <p>Use of HAART and caesarian delivery are protective factors for mother-to-child transmission of HIV. Maternal coinfecctions and other conditions were risk factors for MTCT.</p

Clinical and genetic heterogeneity in familial focal segmental glomerulosclerosis

Clinical and genetic heterogeneity in familial focal segmental glomerulosclerosis.BackgroundFamilial forms of focal segmental glomerulosclerosis (FFSGS) that exhibit autosomal dominant or recessive patterns of inheritance have been described. The genetic basis of these hereditary forms of FSGS is unknown. One recent study of a kindred from Oklahoma with an autosomal dominant form of FSGS linked this disease to a region of chromosome 19q. In addition, polymorphisms in a gene in this region on chromosome 19q13 have been linked to congenital nephrotic syndrome of the Finnish type. We have ascertained and characterized a large family with autosomal dominant FFSGS (Duke 6530).MethodsFamilies were compared for clinical and genetic heterogeneity. To test for linkage of our family to this portion of chromosome 19, genomic DNA was isolated from 102 family members, and polymerase chain reaction was performed using eight microsatellite markers that spanned the area of interest on chromosome 19. Data were evaluated using two-point linkage analysis, multipoint analysis, and an admixture test.ResultsLinkage was excluded at a distance of ±5 to 10cm for all markers tested with two-point log10 of the odds of linkage (LOD) scores and from an approximate 60cm interval in this area of chromosome 19q via multipoint analysis.ConclusionFSGS has been called the “final common pathway” of glomerular injury, as it is a frequent pathological manifestation with diverse etiologies. This diversity likely correlates with the genetic heterogeneity that we have established. Thus, our data demonstrate that there are at least two genes responsible for this disease, and there is genetic as well as clinical heterogeneity in autosomal dominant FSGS

Huntington's disease: a clinical review

Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia. Prevalence in the Caucasian population is estimated at 1/10,000-1/20,000. Mean age at onset of symptoms is 30-50 years. In some cases symptoms start before the age of 20 years with behavior disturbances and learning difficulties at school (Juvenile Huntington's disease; JHD). The classic sign is chorea that gradually spreads to all muscles. All psychomotor processes become severely retarded. Patients experience psychiatric symptoms and cognitive decline. HD is an autosomal dominant inherited disease caused by an elongated CAG repeat (36 repeats or more) on the short arm of chromosome 4p16.3 in the Huntingtine gene. The longer the CAG repeat, the earlier the onset of disease. In cases of JHD the repeat often exceeds 55. Diagnosis is based on clinical symptoms and signs in an individual with a parent with proven HD, and is confirmed by DNA determination. Pre-manifest diagnosis should only be performed by multidisciplinary teams in healthy at-risk adult individuals who want to know whether they carry the mutation or not. Differential diagnoses include other causes of chorea including general internal disorders or iatrogenic disorders. Phenocopies (clinically diagnosed cases of HD without the genetic mutation) are observed. Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis. Preimplantation diagnosis with in vitro fertilization is offered in several countries. There is no cure. Management should be multidisciplinary and is based on treating symptoms with a view to improving quality of life. Chorea is treated with dopamine receptor blocking or depleting agents. Medication and non-medical care for depression and aggressive behavior may be required. The progression of the disease leads to a complete dependency in daily life, which results in patients requiring full-time care, and finally death. The most common cause of death is pneumonia, followed by suicide

Amlodipine versus angiotensin II receptor blocker; control of blood pressure evaluation trial in diabetics (ADVANCED-J)

BACKGROUND: The coexistence of type 2 diabetes mellitus and hypertension increases the risk of cardiovascular diseases. The U.K. Prospective Diabetes Study has shown that blood pressure control as well as blood glucose control is efficient for prevention of complications in hypertensive patients with diabetes mellitus. However, some reports have shown that it is difficult to control the blood pressure and the concomitant use of a plurality of drugs is needed in hypertensive patients with diabetes mellitus. In recent years renin-angiotensin system depressants are increasingly used for the blood pressure control in diabetic patients. Particularly in Japan, angiotensin II (A II) antagonists are increasingly used. However, there is no definite evidence of the point of which is efficient for the control, the increase in dose of A II antagonist or the concomitant use of another drug, in hypertensive patients whose blood pressure levels are inadequately controlled with A II antagonist. METHODS/DESIGN: Hypertensive patients of age 20 years or over with type 2 diabetes mellitus who have been treated by the single use of AII antagonist at usual doses for at least 8 weeks or patients who have been treated by the concomitant use of AII antagonist and an antihypertensive drug other than calcium channel blockers and ACE inhibitors at usual doses for at least 8 weeks are included. DISCUSSION: We designed a multi-center, prospective, randomized, open label, blinded-endpoint trial, ADVANCED-J, to compare the increases in dose of A II antagonist and the concomitant use of a Ca-channel blocker (amlodipine) and A II antagonist in hypertensive patients with diabetes mellitus, whose blood pressure levels were inadequately controlled with A II antagonist. This study is different from the usual previous studies in that home blood pressures are assessed as indicators of evaluation of blood pressure. The ADVANCED-J study may have much influence on selection of antihypertensive drugs for treatment in hypertensive patients with diabetes mellitus. It is expected to give an important hint for considering the validity of selection of antihypertensive drugs from the aspects not only of the antihypertensive effect but medical cost-effectiveness

Treating the acute stroke patient as an emergency: current practices and future opportunities

Developments in acute stroke therapy have followed advances in the understanding of the evolving pathophysiology in both ischaemic stroke and intracerebral haemorrhage (ICH). In ischaemic stroke, rapid reperfusion of the ischaemic penumbra with thrombolysis within 3 h of symptom onset is of proven benefit, but few patients currently receive therapy, mainly due to the short-time window and lack of stroke expertise. In ICH, a recent study indicated that a haemostatic agent can limit ongoing bleeding and improve outcomes when administered within 4 h of stroke onset. These advances in acute stroke therapy underlie the concept that ‘time is brain’ and that urgent intervention can limit cerebral damage. Neuroprotective therapy could offer the prospect of a greater proportion of stroke patients receiving treatment, potentially before imaging and even in the ambulance setting. Virtually all stroke patients would benefit from receiving multidisciplinary care in acute stroke units

Effects of intraoperative hypothermia on neuropsychological outcomes after intracranial aneurysm surgery

Objective Subarachnoid hemorrhage and surgical obliteration of ruptured intracranial aneurysms are frequently associated with neurological and neuropsychological abnormalities. We reported that intraoperative cooling did not improve neurological outcome in good-grade surgical subarachnoid hemorrhage patients, as assessed by the Glasgow Outcome Scale score or other neurological and functional measures (National Institutes of Health Stroke Scale, Rankin Disability Scale, Barthel Activities of Daily Living). We now report the results of neuropsychological testing in these patients. Methods A total of 1,001 patients who bled ≤14 days before surgery were randomly assigned to intraoperative hypothermia (t = 33°C) or normothermia (37°C). Outcome was assessed approximately 3 months after surgery. Patients underwent the Benton Visual Retention, Controlled Oral Word Association, Rey–Osterrieth Complex Figure, Grooved Pegboard, and the Trail Making tests. T -scores for each test were calculated from normative data. T -scores were averaged to calculate a Composite Score. A test result (or the Composite Score) was considered “impaired” if the T -score was two or more standard deviations below the norm. A Mini-Mental State Examination was also performed. Results Neurological outcome data were available in 1,000 patients. Sixty-one patients died. Of the 939 survivors, 873 completed 3 or more tests (exclusive of the Mini-Mental State Examination). Patients with poor neurological outcomes were less likely to complete testing; only 3.9% of Good Outcome (Glasgow Outcome Scale score = 1) patients were untested, compared with 38.6% of patients with Glasgow Outcome Scale scores of 3 and 4. There were no prerandomization demographic differences between the two treatment groups. For hypothermic patients, 16.8% were impaired from their Composite Score versus 20.0% of patients in the normothermic group ( p = 0.317). For patients in the hypothermic group, 54.5% were impaired on at least one test, compared with 55.5% of patients in the normothermic group ( p = 0.865). Similar results were seen in patients with baseline WFNS scores = I. Mini-Mental State Examination scores in the hypothermic and normothermic groups were 27.4 ± 3.8 and 26.8 ± 4.5, respectively. Interpretation This is the largest prospective evaluation of neuropsychological function after subarachnoid hemorrhage to date. Testing was completed in a high fraction of patients, demonstrating the feasibility of such testing in a large trial. However, the frequent inability to complete testing in poor-outcome patients suggests that testing may be best used to refine outcome assessments in good-grade patients. Many patients showed impairment on at least one test, with global impairment present in 17 to 20% of patients (18–21% of survivors). This was true even among the patients with the best preoperative condition (WFNS = 1). There was no difference in the incidence of impairment between hypothermic and normothermic groups. Ann Neurol 2006;60:518–527Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55889/1/21018_ftp.pd

Pre-hospital ECG for acute coronary syndrome in urban India: A cost-effectiveness analysis

<p>Abstract</p> <p>Background</p> <p>Patients with acute coronary syndrome (ACS) in India have increased pre-hospital delay and low rates of thrombolytic reperfusion. Use of ECG could reduce pre-hospital delay among patients who first present to a general practitioner (GP). We assessed whether performing ECG on patients with acute chest pain would improve long-term outcomes and be cost-effective.</p> <p>Methods</p> <p>We created a Markov model of urban Indian patients presenting to a GP with acute chest pain to compare a GP's performing an ECG versus not performing one. Variables describing the accuracy of a GP's referral decision in chest pain and ACS, ACS treatment patterns, the effectiveness of thrombolytic reperfusion, and costs were derived from Indian data where available and other developed world studies. The model was used to estimate the incremental cost-effectiveness ratio (ICER) of the intervention in 2007 US dollars per quality adjusted life years (QALY) gained.</p> <p>Results</p> <p>Under baseline assumptions, the ECG strategy cost an additional $12.65 per QALY gained compared to no ECG. Sensitivity analyses around the cost of the ECG, cost of thrombolytic, and referral accuracy of the GP yielded ICERs for the ECG strategy ranging between cost-saving and$1124/QALY. All results indicated the intervention is cost-effective under current World Health Organization recommendations.</p> <p>Conclusions</p> <p>While direct presentation to the hospital with acute chest pain is preferable, in urban Indian patients presenting first to a GP, an ECG performed by the GP is a cost-effective strategy to reduce disability and mortality. This strategy should be clinically studied and considered until improved emergency transport services are available.</p