Genetic variants of SLC11A1 are associated with both autoimmune and infectious diseases: systematic review and meta-analysis.

A systematic review and meta-analyses were undertaken to investigate the association of SLC11A1 genetic variants with disease occurrence. Literature searching indentified 109 publications to include in the meta-analyses assessing the association of 11 SLC11A1 variants with autoimmune and infectious disease. The (GT)n promoter alleles 2 and 3 (rs534448891), which alter SLC11A1 expression, were significantly associated with tuberculosis (OR=1.47 (1.30-1.66), OR=0.76 (0.65-0.89), respectively) and infectious disease (OR=1.25 (1.10-1.42), OR=0.83 (0.74-0.93), respectively). However, although no association was observed with autoimmune disease, a modest significant association was observed with type 1 diabetes (allele 2 OR=0.94 (0.89-0.98)). On the basis of a stronger association of (GT)n allele 2 with tuberculosis, compared with the protective effect of allele 3, we hypothesise that allele 2 is likely the disease-causing variant influencing disease susceptibility. Significant associations were observed between the 469+14G/C polymorphism (rs3731865) and autoimmune disease (OR=1.30 (1.04-1.64)) and rheumatoid arthritis (OR=1.60 (1.20-2.13)) and between the -237C/T polymorphism (rs7573065) and inflammatory bowel disease (OR=0.60 (0.43-0.84)). Further, significant associations were identified between the 469+14G/C, 1730G/A and 1729+55del4 polymorphisms (rs3731865, rs17235409 and rs17235416, respectively) and both infectious disease per se and tuberculosis. These findings show a clear association between variants in the SLC11A1 locus and autoimmune and infectious disease susceptibility.

The role of premorbid personality and cognitive factors in awareness of illness, memory, and behavioural functioning in Alzheimer's disease.

INTRODUCTION: Research has suggested an association between personality factors and awareness in patients with dementia, yet valid measurement of premorbid personality is problematic. The present study aimed to better reveal the relationship between premorbid personality and awareness by using improved methodology. Moreover, the study aims to contrast the strength of the relationship of premorbid personality and awareness with that of cognitive factors. METHODS: Awareness of illness, symptoms, mnemonic and behavioural impairments, and treatment compliance were measured in 27 patients with mild-to-moderate Alzheimer's disease (AD) diagnosed by standard criteria for probable AD. Participant premorbid personality was measured using average retrospective Neuroticism-Extroversion-Openness Inventory (NEO-FFI) scores from two informants. Correlations were performed to investigate the relationship between awareness and personality dimensions, as well as measures of cognitive style, neuropsychological function, mood, carer burden, and sociodemographic factors. RESULTS: There was little relationship between awareness and personality scores, but modest associations between awareness and mood, age, and age of onset of first symptoms. Awareness of memory was related to memory functioning. Increased carer burden was associated with lack of awareness of cognitive-behavioural deficits but there were only few and weak associations between awareness and measures of cognitive functioning. CONCLUSIONS: There was little support for an association between previous personality and awareness in dementia. However, increased carer burden was associated specifically with lack of awareness of cognitive-behavioural deficits not deficits in ADL, whereas lower awareness of ADL and not cognitive-behavioural deficits was associated with age. Awareness of memory appeared to be a metamemory capacity. Mood and age rather than personality and cognition are stronger predictors of awareness in early Alzheimer's disease.

Personal health records: a scoping review.

Electronic personal health record systems (PHRs) support patient centered healthcare by making medical records and other relevant information accessible to patients, thus assisting patients in health self-management. We reviewed the literature on PHRs including design, functionality, implementation, applications, outcomes, and benefits. We found that, because primary care physicians play a key role in patient health, PHRs are likely to be linked to physician electronic medical record systems, so PHR adoption is dependent on growth in electronic medical record adoption. Many PHR systems are physician-oriented, and do not include patient-oriented functionalities. These must be provided to support self-management and disease prevention if improvements in health outcomes are to be expected. Differences in patient motivation to use PHRs exist, but an overall low adoption rate is to be expected, except for the disabled, chronically ill, or caregivers for the elderly. Finally, trials of PHR effectiveness and sustainability for patient self-management are needed.

The efficacy of milbemycin oxime against pre-adult Spirocerca lupi in experimentally infected dogs.

The aim of this investigation was to determine the efficacy of milbemycin oxime in preventing the oesophageal encapsulation of Spirocerca lupi, following the experimental infection of dogs. Two studies were conducted which involved a total of 21 purpose-bred Beagles. Each dog was infected with approximately 40, third stage infective S. lupi larvae. The larvae were dissected from scarabaeid beetles that had been collected from areas endemic for spirocercosis. In the first study, milbemycin oxime (minimum dose 0.5mg/kg body weight) was administered to seven dogs on day 30 post-infection. Seven other dogs served as untreated controls. In the second study, milbemycin oxime (also at a minimum dose of 0.5mg/kg body weight) was administered to four of seven infected dogs on day 28 post-infection. Treatment was repeated at 14- or 28-day intervals. All of the dogs, from both studies, were euthanized 168 or 169 days after infection. All S. lupi were recovered, and lesions in the thoracic aorta and oesophagus were described and quantified. A single treatment with milbemycin oxime was 79.8% effective in preventing the establishment of S. lupi in the oesophagus. This treatment significantly (p<0.05) reduced both the number of S. lupi within the oesophagus and the size of the oesophageal nodules. The efficacy of anthelmintic treatment was increased to 100% when repeat doses of milbemycin oxime were administered at 14- or 28-day intervals. These repeat treatments completely prevented the establishment of S. lupi within the oesophagus and thereby averted the development of oesophageal nodules. As expected, none of the treatment protocols reduced S. lupi related damage within the aorta because the administration of milbemycin oxime only began after the larvae had completed their first stage of migration.

A Multiple Indicators Multiple Causes (MIMIC) model of Behavioural and Psychological Symptoms in Dementia (BPSD).

INTRODUCTION: Although there is evidence for distinct behavioural sub-phenotypes in Alzheimer's disease (AD), their inter-relationships and the effect of clinical variables on their expression have been little investigated. METHODS: We have analysed a sample of 1850 probable AD patients from the UK and Greece with 10 item Neuropsychiatric Inventory (NPI) data. We applied a Multiple Indicators Multiple Causes (MIMIC) approach to investigate the effect of MMSE, disease duration, gender, age and age of onset on the structure of a four-factor model consisting of "psychosis", "moods", "agitation" and "behavioural dyscontrol". RESULTS: Specific clinical variables predicted the expression of individual factors. When the inter-relationship of factors is modelled, some previously significant associations are lost. For example, lower MMSE scores predict psychosis, agitation and behavioural dyscontrol factors, but psychosis and mood predict the agitation factor. Taking these associations into account MMSE scores did not predict agitation. CONCLUSIONS: The complexity of the inter-relations between symptoms, factors and clinical variables is efficiently captured by this MIMIC model.

The use of milbemycin oxime in a prophylactic anthelmintic programme to protect puppies, raised in an endemic area, against infection with Spirocerca lupi.

Spirocerca lupi is primarily a parasite of dogs and other carnivores. Clinical signs of infection are regurgitation, vomiting, weight loss, coughing and dyspnoea. Sudden death can also occur due to a ruptured aortic aneurysm. In this study, the Eastern Cape Province of South Africa was identified as an area with a high prevalence of S. lupi. A subsequent investigation, to evaluate the efficacy of milbemycin oxime as a prophylactic agent for canine spirocercosis, involved 58 puppies that were raised in this area in accordance with local husbandry procedures. Approximately half of the puppies served as untreated controls. Puppies in the treatment group received milbemycin oxime (minimum dose of 0.5mg/kg body weight) when they were between 2 and 6 weeks old. They then received five further treatments at approximately 28-day intervals. The treatment was orally administered in tablet form. After the sixth treatment, puppies from both the treated and control groups were euthanized and post-mortem examinations were performed. Twenty-four out of 27 dogs in the untreated control group had become infected by S. lupi. In comparison, only 19 out of 31 dogs in the treatment group had evidence of spirocercosis as demonstrated by aortic nodules. The prophylactic regimen reduced the severity of aortic lesions and prevented 86.5% of S. lupi from becoming established in the thoracic aorta. It also prevented 89.4% of S. lupi from becoming established in the oesophagus and significantly reduced the number of oesophageal nodules. Milbemycin oxime markedly reduced the level and severity of S. lupi infection in treated puppies raised in an endemic area of South Africa. It deserves further evaluation as a potential prophylactic treatment for spirocercosis.

Midlife Neuroticism and the age of onset of Alzheimer's disease.

BACKGROUND: There may be important public health implications of increasing our knowledge of factors associated with age of dementia onset. The pre-morbid personality domain of Neuroticism constituted an interesting and theoretically plausible, yet uninvestigated, candidate for such an association. We aimed to examine whether midlife Neuroticism was associated with earlier age of onset of Alzheimer's disease (AD). METHOD: This was a case-comparison study of 213 patients with probable AD. Detailed clinical information was collected for all patients including age of onset of dementia symptoms. One or two knowledgeable informants rated each patient's midlife personality retrospectively using the Neuroticism, Extraversion, Openness Five-Factor Inventory (NEO-FFI) questionnaire. The relationship between midlife Neuroticism and age of dementia onset was evaluated using both correlational analysis and backward linear regression analysis. RESULTS: Midlife Neuroticism predicted younger age of dementia onset in females but not in males. The association found in females was independent of pre-morbid history of affective disorder. CONCLUSIONS: This finding and its potential mechanism warrant further investigation.

Hypocalcaemia and vitamin D deficiency: an important, but preventable, cause of life-threatening infant heart failure.

BACKGROUND: In recent large paediatric cardiomyopathy population studies from North America and Australia, vitamin D deficiency was not identified as a cause of infant heart failure. However, rickets is resurgent in developed countries. OBJECTIVE: To review the prevalence of this cardiomyopathy in paediatric cardiology units of southeast England and determine the prognosis. METHODS AND RESULTS: A retrospective review from 2000 to 2006 in southeast England. Sixteen infants (6 Indian subcontinent, 10 black ethnicity) were identified: median (range) age at presentation was 5.3 months (3 weeks-8 months). All had been breast fed. Ten presented at the end of the British winter (February-May). Median shortening fraction was 10% (range 5-18%) and median left ventricular end diastolic dimension z score was 4.1 (range 3.1-7.0). Six had a cardiac arrest; three infants died. Eight were ventilated, two required mechanical circulatory support and 12 required intravenous inotropic support. Two were referred for cardiac transplantation. Median (range) of biochemical values on admission was: total calcium 1.5 (1.07-1.74) mmol/l; alkaline phosphatase 646 (340-1057) IU/l; 25-hydroxyvitamin D 18.5 (0-46) nmol/l (normal range >35) and parathyroid hormone 34.3 (8.9-102) pmol/l (normal range <6.1). The clinical markers and echocardiographic indices of all survivors have improved. The mean time from diagnosis to achieve normal fractional shortening was 12.4 months. CONCLUSIONS: Vitamin D deficiency and consequent hypocalcaemia are seen in association with severe and life-threatening infant heart failure. That no infant or mother was receiving the recommended vitamin supplementation highlights the need for adequate provision of vitamin D to ethnic minority populations.

Interaction between the ADAM12 and SH3MD1 genes may confer susceptibility to late-onset Alzheimer's disease.

The neuropathology of Alzheimer's disease (AD) is characterized by intracellular neurofibrillary tangles and the extracellular deposition of beta-amyloid (Abeta) in senile plaques. Abeta has been shown to mediate neurodegenerative and inflammatory changes associated with amyloid plaques, although the pathological mechanism of Abeta remains largely unknown. Recent evidence suggests that the FISH adapter protein binds to, and potentially regulates, ADAM12 (a disintegrin and metalloprotease 12) to mediate a neurotoxic effect of Abeta. The ADAM12 gene lies on chromosome 10q26.3, and the gene encoding FISH, SH3MD1, lies within a region of linkage to late-onset AD (LOAD) on 10q25.1. This study investigates whether there is a relationship between variation in ADAM12 and SH3MD1 and susceptibility to LOAD in a sample of 1,051 AD cases and 1,269 matched controls. We observe significant interactions between variants in the two genes that may influence susceptibility to LOAD. The most significant statistical interaction is between rs3740473, a synonymous single nucleotide polymorphism (SNP) in SH3MD1 and rs11244787, an intronic SNP in ADAM12 (effect size = 2.1 for interaction term, P = 0.006).

The effects of commonly prescribed drugs in patients with Alzheimer's disease on the rate of deterioration.

BACKGROUND: Prescribed drugs in patients with Alzheimer's disease may affect the symptomatic progression of their disease, both positively and negatively. AIM: To examine the effects of drugs on the progression of disease in a representative group of patients with Alzheimer's disease. METHODS: Patients with the diagnosis of probable Alzheimer's disease were recruited from the community. The prescribed drugs taken by 224 patients (mean age 82.3 years) were recorded at initial assessment and then correlated in logistic regression analysis with progression of the disease, defined as an increase of one point or more in the Global Deterioration Scale over the next 12-month period. RESULTS: Patients who were taking antipsychotic drugs and sedatives had a significantly higher risk of deterioration than those who were taking none (odds ratios (ORs) 2.74 (95% confidence interval (CI) 1.17 to 6.41) and 2.77 (95% CI 1.14 to 6.73), respectively). Higher risk of deterioration was observed in those who were taking both antipsychotic and sedative drugs together (OR 3.86 (95% CI 1.28 to 11.7). Patients taking drugs licensed for dementia, drugs affecting the renin-angiotensin system and statins had a significantly lower risk of deterioration than those who were not taking any of these drugs (ORs 0.49 (95% CI 0.25 to 0.97), 0.31 (95% CI 0.11 to 0.85) and 0.12 (95% CI 0.03 to 0.52), respectively). CONCLUSION: Our findings have implications for both clinicians and trialists. Most importantly, clinicians should carefully weigh any potential benefits of antipsychotics and benzodiazepines, especially in combination, against the risk of increased decline. Researchers need to be aware of the potential of not only licensed drugs for dementia but also drugs affecting the renin-angiotensin system and statins in reducing progression in clinical trials.

Proteome-based plasma biomarkers for Alzheimer's disease.

Alzheimer's disease is a common and devastating disease for which there is no readily available biomarker to aid diagnosis or to monitor disease progression. Biomarkers have been sought in CSF but no previous study has used two-dimensional gel electrophoresis coupled with mass spectrometry to seek biomarkers in peripheral tissue. We performed a case-control study of plasma using this proteomics approach to identify proteins that differ in the disease state relative to aged controls. For discovery-phase proteomics analysis, 50 people with Alzheimer's dementia were recruited through secondary services and 50 normal elderly controls through primary care. For validation purposes a total of 511 subjects with Alzheimer's disease and other neurodegenerative diseases and normal elderly controls were examined. Image analysis of the protein distribution of the gels alone identifies disease cases with 56% sensitivity and 80% specificity. Mass spectrometric analysis of the changes observed in two-dimensional electrophoresis identified a number of proteins previously implicated in the disease pathology, including complement factor H (CFH) precursor and alpha-2-macroglobulin (alpha-2M). Using semi-quantitative immunoblotting, the elevation of CFH and alpha-2M was shown to be specific for Alzheimer's disease and to correlate with disease severity although alternative assays would be necessary to improve sensitivity and specificity. These findings suggest that blood may be a rich source for biomarkers of Alzheimer's disease and that CFH, together with other proteins such as alpha-2M may be a specific markers of this illness.

Persistent pulmonary hypertension late after neonatal aortic valvotomy: a consequence of an expanded surgical cohort.

BACKGROUND: Survival of neonates with critical aortic stenosis has improved over the past decade. Models based on morphological characteristics have been designed to help determine whether early survival is more likely after biventricular repair (surgical or balloon aortic valvotomy) or after a single ventricle staged palliative surgical strategy. However, late follow up data are lacking. OBJECTIVE: To report follow up data on survivors of neonatal aortic valvotomy who had persistent pulmonary hypertension caused by restriction to left ventricular filling. RESULTS: Of four medium term survivors of neonatal valvotomy for critical aortic stenosis who had persistent pulmonary hypertension, one died aged 4 years and the other three have severe limitation of effort tolerance. CONCLUSIONS: This previously unreported late complication of "successful" biventricular repair for neonatal critical aortic stenosis is an important consideration in determining the initial management.

Prenatal diagnosis of coarctation of the aorta improves survival and reduces morbidity.

OBJECTIVE: To investigate whether antenatal diagnosis of coarctation of the aorta results in reduced mortality and improved preoperative haemodynamic stability compared with postnatal diagnosis. DESIGN: Retrospective review of all cases of coarctation of the aorta presenting to a tertiary fetal and neonatal cardiology service from January 1994 to December 1998. METHODS: Prenatal, postnatal, and necropsy records were reviewed to determine survival in the two groups. Markers of preoperative illness severity were recorded, including presence of femoral pulse, collapse, left ventricular function, ductal patency on echocardiography, coagulation status, duration of intensive care unit and total hospital stay, heart rate, respiratory rate, plasma creatinine, plasma potassium, and right upper limb blood pressure. A univarate and multivariate analysis was conducted on all variables and a cumulative score was created and subjected to logistic regression analysis. RESULTS: Both collapse and death were more common in the postnatally diagnosed group (p < 0.05). Femoral pulses were more likely to be palpable and there was echocardiographic evidence of duct patency in the antenatally diagnosed infants (p < 0.001 and p < 0.05, respectively). An increased respiratory rate was associated with postnatal presentation (p < 0.05). Infants with haemodynamic instability preoperatively were more likely to have been diagnosed postnatally (p < 0.01). CONCLUSIONS: Antenatal diagnosis of coarctation of the aorta is associated with improved survival and preoperative clinical condition.

Closure of the ductus arteriosus and development of pulmonary branch stenosis in babies of less than 32 weeks gestation.

AIMS: To define how often transient pulmonary branch stenosis (PBS) develops after closure of a patent ductus arteriosus (PDA) in babies born at less than 32 weeks gestation; to describe the natural history of PBS and the relation between PBS and a cardiac murmur. METHODS: Fifty three preterm infants born at a gestational age less than 32 weeks and who had PDA diagnosed on echocardiography were recruited. An echocardiogram was performed on alternate days until the ductus arteriosus closed. If PBS was diagnosed, the baby was followed up until PBS resolved. RESULTS: In 59%, PBS developed in one or both branches after closure of the PDA. In 21%, both pulmonary branches were affected. In 79%, the left pulmonary artery alone was involved but the right side was never affected alone. PBS had resolved in 74% by the time the infants reached 40 weeks, in 95% at a corrected age of 6 weeks, and in 100% at a corrected age of 3 months. There is a better correlation between a cardiac murmur and PBS than between a murmur and PDA. CONCLUSIONS: PBS in preterm infants is usually not present at birth but develops after closure of a PDA. PBS resolves by a corrected age of 3 months. The presence of a murmur after closure of a PDA is usually related to PBS and not to reopening of the ductus arteriosus.