Cerebral Palsy

PEPT1 is a high-capacity, low-affinity peptide transporter that mediates the uptake of di- and tripeptides in the intestine and kidney. PEPT1 also has significance in its ability to transport therapeutic agents and because of its potential as a target for anti-inflammatory therapies. To further understand the relevance of specific peptide transporters in intestinal physiology, pharmacology and pathophysiology, we have generated Pept1 null mice by targeted gene disruption. The Pept1 gene was disrupted by insertion of a lacZ reporter gene under the control of the endogenous Pept1 promoter. Phenotypic profiling of wild-type and Pept1 null mice was then performed, along with in vitro intestinal uptake, in situ intestinal perfusion and in vivo pharmacokinetic studies of glycylsarcosine (GlySar). Pept1 null mice lacked expression of PEPT1 protein in the intestine and kidney, tissues in which this peptide transporter is normally expressed. Pept1-deficient mice were found to be viable, fertile, grew to normal size and weight, and were without any obvious abnormalities. Nevertheless, Pept1 deletion dramatically reduced the intestinal uptake and effective permeability of the model dipeptide GlySar (i.e., by at least 80%), and its oral absorption following gastric gavage (i.e., by about 50%). In contrast, the plasma profiles of GlySar were almost superimposable between wild-type and Pept1 null animals after intravenous dosing. These novel findings provide strong evidence that PEPT1 has a major role in the in vivo oral absorption of dipeptides.

PURPOSE OF REVIEW: General anesthetics and sedatives are used in millions of children every year to facilitate surgical procedures, imaging studies, and sedation in operating rooms, radiology suites, emergency departments, and ICUs. Mounting evidence from animal studies suggests that prolonged exposure to these compounds may induce widespread neuronal cell death and neurological sequelae, seriously questioning the safety of pediatric anesthesia. This review presents recent developments in this rapidly emerging field. RECENT FINDINGS: In animals, all currently available anesthetics and sedatives that have been studied, such as ketamine, midazolam, diazepam, clonazepam, propofol, pentobarbital, chloral hydrate, halothane, isoflurane, sevoflurane, enflurane, nitrous oxide, and xenon, have been demonstrated to trigger widespread neurodegeneration in the immature brain. In humans, recent preliminary findings from epidemiological studies suggest an association between surgery and anesthesia early in life and subsequent learning abnormalities. SUMMARY: Neurodegeneration following exposure to anesthetics and sedatives has been clearly established in developing animals. However, while some of the biochemical pathways have been revealed, the phenomenon’s particular molecular mechanisms remain unclear. As the phenomenon is difficult to study in humans, clinical evidence is still scarce and amounts to associative and not causal relationships. Owing to the lack of alternative anesthetics, further animal studies into the mechanism as well as clinical studies defining human susceptibility are both urgently needed.

Background: Emotional interference tasks may be useful in probing anterior cingulate cortex (ACC) function to understand abnormal attentional study in individuals with specific phobia. Methods: In a 3 T functional MRI study, individuals with specific phobias of the animal subtype (SAP, n=12) and healthy comparison (HC) adults (n=12) completed an event-related emotional counting Stroop task. Individuals were presented phobia-related, negative, and neutral words and were instructed to report via button press the number of words displayed on each trial. Results: Compared to the HC group, the SAP group exhibited greater rostral ACC activation (i.e., greater response to phobia-related words than neutral words). In this same contrast, HCs exhibited greater right amygdala and posterior insula activations as well as greater thalamic deactivation than the SAP group. Both groups exhibited anterior cingulate, dorsomedial prefrontal cortex, inferior frontal gyrus/insula, and amygdala activations as well as thalamic deactivation. Psychophysiological interaction analysis highlighted a network of activation in these regions in response to phobia-related words in the SAP group. Conclusions: Taken together, these findings implicate a circuit of dysfunction, which is linked to attention abnormalities in individuals with SAP. Depression and Anxiety 0:1-10, 2009. Published 2009 Wiley-Liss, Inc.

OBJECTIVES: Tomographic ultrasound imaging has greatly simplified pelvic floor assessment. Abnormalities of the insertion of the levator ani can be documented in a single frame. In this study we aimed to determine which levels of the levator hiatus are associated with alterations in ultrasound parameters of pelvic organ support. METHODS: This was a subanalysis of a study conducted in 296 women seen before and after their first delivery. We analyzed postpartum changes in bladder neck descent and hiatal area as indicators of altered pelvic organ support. Tomographic ultrasound examination was performed on volumes obtained at maximal pelvic floor muscle contraction, at 2.5-mm slice intervals, from 5 mm below to 12.5 mm above the plane of minimal hiatal dimensions. RESULTS: Two hundred and eight recruits (70%) returned for a postnatal appointment. Of these, 130 had delivered vaginally and 26 (20%) were diagnosed with an avulsion injury. An abnormality in slices 3-8 was associated with increased bladder neck descent postpartum (P = 0.038 to P = 0.001) and increased hiatal area on Valsalva maneuver (P = 0.029 to P < 0.001). This was not the case for the two most distal slices. CONCLUSIONS: We found no association between levator ani defects observed on tomographic ultrasound imaging below the plane of minimal hiatal dimensions and indices of increased hiatal distension or bladder neck descent on Valsalva maneuver. This implies that defects observed below this plane are either irrelevant for pelvic organ support or artifactual. Copyright (c) 2009 ISUOG. Published by John Wiley & Sons, Ltd.

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&percnt; to 63.2&percnt;. 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.