Cerebral Palsy

Heart failure (HF) is characterized by molecular and cellular defects which jointly contribute to decreased cardiac pump function. During the development of the initial cardiac damage which leads to HF, adaptive responses activate physiological countermeasures to overcome depressed cardiac function and to maintain blood supply to vital organs in demand of nutrients. However, during the chronic course of most HF syndromes, these compensatory mechanisms are sustained beyond months and contribute to progressive maladaptive remodeling of the heart which is associated with a worse outcome. Of pathophysiological significance are mechanisms which directly control cardiac contractile function including ion- and receptor-mediated intracellular signaling pathways. Importantly, signaling cascades of stress adaptation such as intracellular calcium (Ca(2+)) and 3′-5′-cyclic adenosine monophosphate (cAMP) become dysregulated in HF directly contributing to adverse cardiac remodeling and depression of systolic and diastolic function. Here, we provide an update about Ca(2+) and cAMP dependent signaling changes in HF, how these changes affect cardiac function, and novel therapeutic strategies which directly address the signaling defects.

Introduction: Renal transplantation is the treatment of choice for children with end-stage renal failure (ESRF). The paediatric renal transplant programme in Singapore was initiated in 1989. This study aimed to examine our outcomes over the 19-year period from 1989 to 2007. Materials and Methods: A total of 38 renal transplants were performed at our centre. Another 4 patients with overseas transplants who returned within 3 weeks post-transplant were included. The proportion of living donor (LD) transplants was 61.9%. Structural abnormalities and glomerulopathies were the most common aetiologies comprising 33% each. Median age at transplant was 13.9 years and median waiting time was 2.2 years. LD transplant recipients were younger and had a shorter waiting time than deceased donor (DD) recipients. Results: Overall patient survival rates were 95%, 92%, 86% and 86% at 1, 5, 10 and 15 years, respectively. There were 4 deaths, of which 3 were due to infections. Graft survival rates at 1, 5, 10 and 15 years for LD and DD transplants were 100%, 89.5%, 67.3%, 67.3% and 80.8%, 56.5%, 42.2%, 28.3% respectively, and were significantly higher in LD transplants. The main cause of graft loss was rejection following non-adherence. Multivariate analysis showed male gender, late acute rejections and acute tubular necrosis as predictors of graft failure. There was a high incidence of early bacterial infections (42.9%) and cytomegalovirus disease (16.7%). Conclusion: Our graft survival rates for LD transplants were comparable to North American rates, although our DD transplant rates were slightly worse, probably a reflection of the prevailing transplant policies.

Lung cancer-predominantly non-small cell lung cancer (NSCLC)-is the leading cause of death from cancer in most industrialized countries. Patients with early-stage NSCLC are at substantial risk for recurrence and death even after potentially curative surgery. Multiple large randomized trials have demonstrated that adjuvant chemotherapy using modern cisplatin-based regimens can significantly improve 5-year survival in carefully selected patients with NSCLC.The current staging system is inadequate for predicting the outcome of treatment and the prognosis in an individual patient. Molecular markers may provide additional information about the likelihood of relapse beyond that obtained from pathologic staging. They may also have value in determining which patients will benefit from adjuvant platinum-based chemotherapy.This is a review focused on approaches and specific markers under study, including gene expression profiles, DNA repair pathways, class III beta-tubulin expression, abnormalities in the k-ras oncogene and p53 tumor suppressor gene, and DNA methylation markers. Additional studies will be required to determine whether these markers are useful in selecting patients for adjuvant platinum-based chemotherapy.

Meiotic behavior was analyzed in 6 progenies from 3 artificially induced tetraploid (2n = 4x = 36) sexual genotypes (C31, C41, and C48) of the normally apomictic Brachiaria brizantha (Hochst. ex A. Rich.) Stapf., syn. Urochloa brizantha (Hochst. ex A. Rich.) R. Webster. These are key plants to allow intraspecific hybridization of this important forage species, widely used for pastures in the tropics. The percentage of abnormal cells among the plants ranged from 39.8% to 63.2%. In the single plant derived from C48, only the common meiotic abnormalities typical of polyploids were observed, while in plants derived from C31 and C41, a distinct behavior was found. In the majority of cells of those plants, the chromosomes remained scattered in the cytoplasm in the first division, without forming a metaphase plate. This abnormality blocked chromosome movements at anaphase I. Several micronuclei of various sizes were formed and, after the occurrence of an irregular first cytokinesis, the meiocytes progressed normally to the second division, generating polyads with unbalanced microspores. Pollen viability was not correlated with meiotic abnormalities. The importance of these findings to the Brachiaria breeding program is discussed. The sexual progeny of C48 seems most suitable as female parents to be used in intra- and interspecific hybridization.

Thalidomide is a potent teratogen that induces a range of birth defects, most commonly of the developing limbs. The mechanisms underpinning the teratogenic effects of thalidomide are unclear. Here we demonstrate that loss of immature blood vessels is the primary cause of thalidomide-induced teratogenesis and provide an explanation for its action at the cell biological level. Antiangiogenic but not antiinflammatory metabolites/analogues of thalidomide induce chick limb defects. Both in vitro and in vivo, outgrowth and remodeling of more mature blood vessels is blocked temporarily, whereas newly formed, rapidly developing, angiogenic vessels are lost. Such vessel loss occurs upstream of changes in limb morphogenesis and gene expression and, depending on the timing of drug application, results in either embryonic death or developmental defects. These results explain both the timing and relative tissue specificity of thalidomide embryopathy and have significant implications for its use as a therapeutic agent.

We used data from the National Birth Defects Prevention Study, a population-based, case-control study, to examine whether previously reported associations between antihypertensive medications and cardiovascular malformations could be confirmed and to explore whether new associations might be identified. Cases (n=5021) were ascertained through birth defects surveillance systems from 1997 through 2003 in 10 US states. Controls (n=4796) were live births without birth defects selected randomly from birth certificates or hospital discharge listings in the same geographic regions. Logistic regression was used to examine the relationship between antihypertensive medication treatment and the occurrence of cardiovascular malformations while controlling for confounding variables. First-trimester treatment with antihypertensive medication was associated with pulmonary valve stenosis (odds ratio [OR]: 2.6; 95% CI: 1.3 to 5.4), Ebstein malformation (crude OR: 11.4; exact 95% CI: 2.8 to 34.1), coarctation of the aorta (OR: 3.0; 95% CI: 1.3 to 6.6), and secundum atrial septal defects (OR: 2.4; 95% CI: 1.3 to 4.4). Treatment initiated after the first trimester was associated with pulmonary valve stenosis (OR: 2.4; 95% CI: 1.1 to 5.4), perimembranous ventricular septal defects (OR: 2.3; 95% CI: 1.2 to 4.6), and secundum atrial septal defects (OR: 2.4; 95% CI: 1.3 to 4.4). Untreated hypertension was associated with Ebstein malformation (OR: 2.1; 95% CI: 1.0 to 4.3) and secundum atrial septal defects (OR: 1.3; 95% CI: 1.0 to 1.6). Antihypertensive medication use and/or the underlying hypertension might increase the risk of having an infant with specific left and right obstructive and septal defects. Additional studies with adequate power will be needed to confirm these findings.

OBJECTIVE: To assess the relationship between baseline dietary fatty acids and 10-year incident age-related macular degeneration (AMD). METHODS: In an elderly Australian cohort, 3654 participants were examined at baseline and 2454 were examined 5 and/or 10 years later. We assessed AMD from retinal photographs. Participants completed a semiquantitative food frequency questionnaire. RESULTS: After adjusting for age, sex, and smoking, 1 serving of fish per week was associated with reduced risk of incident early AMD (relative risk, 0.69 [95% confidence interval, 0.49-0.98]), primarily among participants with less than the median linoleic acid consumption (0.57 [0.36-0.89]). Findings were similar for intake of long-chain omega-3 polyunsaturated fatty acids. One to 2 servings of nuts per week was associated with reduced risk of incident early AMD (relative risk, 0.65 [95% confidence interval, 0.47-0.91]). Protective associations between the intake of nuts and reduced risk of pigmentary abnormalities were seen among nonsmokers, participants with less than the median ratio of serum total to high-density lipoprotein cholesterol, and those with beta carotene intake greater than the median level. CONCLUSIONS: This study provides evidence of protection against early AMD from regularly eating fish, greater consumption of omega-3 polyunsaturated fatty acids, and low intakes of foods rich in linoleic acid. Regular consumption of nuts may also reduce AMD risk. Joint effects from multiple factors are suggested.

BACKGROUND: Alterations in cerebrospinal fluid (CSF) tau and beta-amyloid peptide 1-42 (Abeta(42)) levels and rates of cerebral glucose metabolism (CMRglu) on fluorodeoxyglucose positron emission tomography (FDG-PET) occur years before clinical symptoms of Alzheimer disease (AD) become manifest, but their relationship remains unclear. OBJECTIVE: To determine whether CSF AD biomarker levels and CMRglu in healthy individuals correlate in brain structures affected early in AD. DESIGN: Cohort study. SETTING: Alzheimer disease research center. PARTICIPANTS: Twenty individuals without dementia aged 46 to 83 years. INTERVENTIONS: Lumbar CSF sampling and FDG-PET imaging of CMRglu. The CSF Abeta(42), tau, and tau phosphorylated at threonine 181 (ptau(181)) levels were measured using immunobead-based multiplex assays. MAIN OUTCOME MEASURES: Correlations between CMRglu and CSF biomarker levels were analyzed via voxel-based and volume-of-interest approaches. RESULTS: Voxel-based analyses demonstrated significant negative correlations between CSF tau and ptau(181) levels and CMRglu in the posterior cingulate, precuneus, and parahippocampal regions. In contrast, a limited positive correlation was found between CSF Abeta(42) levels and CMRglu in the inferior temporal cortex. Volume-of-interest analyses confirmed negative associations between CSF tau and ptau(181) levels and CMRglu in the parietal and medial parietal lobes and a positive association between CSF Abeta(42) levels and CMRglu in the parahippocampal gyrus. CONCLUSIONS: In healthy individuals, higher CSF tau and ptau(181) concentrations were associated with more severe hypometabolism in several brain regions affected very early in AD, whereas lower CSF Abeta(42) concentrations were associated with hypometabolism only in the medial temporal lobe. This suggests that early tau and Abeta abnormalities may be associated with subtle synaptic changes in brain regions vulnerable to AD. A longitudinal assessment of CSF and FDG-PET biomarkers is needed to determine whether these changes predict cognitive impairment and incipient AD.

BACKGROUND: Diffuse abnormalities in the white matter (WM), ie, the so-called diffusely abnormal WM (DAWM), as observed on magnetic resonance imaging (MRI), may contribute to the development of clinical disability in multiple sclerosis (MS). Underlying pathologic and MRI characteristics of DAWM are largely unknown. OBJECTIVES: To explore and describe the histopathologic and radiologic characteristics of DAWM in chronic MS. DESIGN: An MRI and histopathologic postmortem correlative study. METHODS: We analyzed 17 formalin-fixed hemispheric brain slices from 10 patients with chronic MS using histopathologic analysis and qualitative and quantitative MRI. A region-of-interest approach was applied to compare radiologically defined DAWM, normal-appearing WM, and focal WM lesions and to correlate quantitative MRI measures with histopathologic findings. MAIN OUTCOME MEASURES: The DAWM consisted of extensive axonal loss, decreased myelin density, and chronic fibrillary gliosis, all of which were substantially abnormal compared with normal-appearing WM and significantly different from focal WM lesion pathology. Increased T1- and T2-relaxation times and decreased fractional anisotropy values were found in DAWM regions of interest, in association with extensive axonal loss and reduced myelin density. Increased T1- and T2-relaxation times were associated with chronic gliosis. CONCLUSIONS: This study classifies DAWM in chronic MS as an abnormality that is different from normal-appearing WM and focal WM lesions, most likely resulting from the cumulative effects of ongoing inflammation and axonal pathology. As such, DAWM is likely to substantially contribute to disease progression and may prove to be an important new disease marker in clinical trials focusing on the neurodegenerative aspects of MS.

Use of a nasogastric tube is one means of administering antifungal therapy to critically ill patients unable to receive medication via the oral route. This was a phase 1, open-label, single-center, randomized, crossover study of posaconazole administered via nasogastric tube in healthy volunteers. Each subject received 2 single doses of posaconazole 400 mg, one administered orally and one administered by nasogastric tube, with a 7-day washout period between each dose. Posaconazole was administered 5-10 minutes after subjects received a nutritional supplement. Blood samples for pharmacokinetic analysis were obtained up to 120 hours post-dose. The analysis of variance (ANOVA) estimate of the study population suggests that posaconazole nasogastric tube administration least square mean values of Cmax, AUC(tf), and AUC(I) were 81%, 76%, and 77%, respectively, of the corresponding oral administration values. The reason for lower Cmax and AUC values when posaconazole is administered via the nasogastric tube route is not known. Oral and nasogastric tube administration of a single dose of posaconazole suspension 400 mg was safe and well tolerated in healthy adult subjects. The incidence and nature of treatment-emergent adverse events were similar with both administration routes, and no serious adverse events, clinically significant laboratory, or vital sign abnormalities were reported. Obtaining plasma posaconazole concentrations may be warranted when posaconazole is given to patients via a nasogastric tube to ensure adequate posaconazole exposure. Strategies that have been shown to enhance posaconazole exposure (such as splitting the dose and minimizing the use of proton pump inhibitors) may also be used.