Cerebral Palsy

The goal of the present study was to investigate the effects of quercetin-filled phosphatidylcholine liposomes (PCL-Q) on the currents carried by large conductance Ca(2+)-dependent K(+) channels (BK(Ca)) in rat thoracic aorta following non-fatal whole-body ionizing irradiation. Using patch-clamp technique, it is found that the outward K(+) currents of isolated smooth muscle cells (SMCs) stimulated by depolarizing voltage steps were sensitive to BK(Ca) inhibitor, paxilline, and this kind of outward K(+) currents in SMCs from irradiated animals demonstrated a significant decrease in amplitude. Radiation-induced BK(Ca) suppression was evident 9 days post-irradiation and progressively increased over 30 days of experimental period. Thus, the vasorelaxing force of these SMCs may be diminished following irradiation. PCL-Q effectively restored BK(Ca) function in post-irradiated SMCs. It is noteworthy that the constituents of PCL-Q, i.e., free quercetin (Q) and “empty” liposomes (PCL), being taken separately, showed a decreased ability to recover BK(Ca) function as compared with combined composition. These results suggest that PCL-Q is able to regain normal function of BK(Ca) following irradiation. The protective effects of PCL-Q can be explained by its antioxidant and membrane repairing properties as well as its ability to inhibit protein kinase C activity. Thus, the lipid encapsulation of flavonoid, PCL-Q, appears to be a potential medication in the case of ionizing irradiation accident, and for the patients with neoplasm who have to receive external radiotherapy as well.

The pathophysiological processes responsible for acute coronary events in diabetic patients, in addition to the conventional factors associated with plaque rupture, include an enhanced prothrombotic state. This enhanced prothrombotic state results from multiple abnormalities of the coagulation system including platelet activation, impaired fibrinolysis and increased activity of the coagulation cascade. Studies have also demonstrated that severe hyperglycemia can result in an exacerbation of the underlying pro-thrombotic state, indicating that patients with extreme hyperglycemia are subject to an even greater thrombotic risk. The present case illustrates the thrombotic hazards associated with severe hyperglycemia.

BACKGROUND: Elevated values of mean platelet volume (MPV) and elevated white blood cell (WBC) count are predictors of an unfavourable outcome among survivors of ST segment elevation myocardial infarction (STEMI). However, their relationship with reperfusion abnormalities is less clear. OBJECTIVE: To evaluate the value of admission MPV and WBC count in predicting impaired reperfusion in patients with acute STEMI who are treated with primary percutaneous coronary intervention (PCI). METHODS: Blood samples were obtained on admission from 368 STEMI patients who underwent successful PCI. According to the 60th minute ST segment resolution ratio, patients were divided into impaired reperfusion and reperfusion groups. RESULTS: Impaired reperfusion was detected in 40% of study patients. Patients in the impaired reperfusion group had a higher admission MPV (9.8+/-1.3 fL versus 8.6+/-1.0 fL; P<0.001) and a higher WBC count (14.4+/-5.5 x 10(9)/L versus 12.1+/-3.8 x 10(9)/L; P<0.001) compared with the patients in the reperfusion group. In regression analysis, MPV (OR 2.21, 95% CI 1.69 to 2.91; P<0.001) and WBC count (OR 1.08, 95% CI 1.02 to 1.15; P=0.01) were found to be independently associated with impaired reperfusion. The best cut-off value of MPV for predicting impaired reperfusion was determined to be 9.05 fL, with a sensitivity of 74% and a specificity of 73%. CONCLUSIONS: The results indicate that leukocytes and platelets have a role in the mediation of reperfusion injury. In patients with STEMI who are undergoing PCI, admission MPV may be valuable in discriminating a higher-risk patient subgroup and thus, may help in deciding the need for adjunctive therapy to improve the outcome.

Placental abnormalities are associated with two of the most common and serious complications of human pregnancy, maternal preeclampsia (PE) and fetal intrauterine growth restriction (IUGR), each disorder affecting approximately 5% of all pregnancies. An important question for the use of the mouse as a model for studying human disease is the degree of functional conservation of genetic control pathways from human to mouse. The human and mouse placenta show structural similarities, but there have been no systematic attempts to assess their molecular similarities or differences. We collected protein and mRNA expression data through shot-gun proteomics and microarray expression analysis of the highly vascular exchange region, microdissected from the human and mouse near-term placenta. Over 7000 ortholog genes were detected with 70% co-expressed in both species. Close to 90% agreement was found between our human proteomic results and 1649 genes assayed by immunohistochemistry for expression in the human placenta in the Human Protein Atlas. Interestingly, over 80% of genes known to cause placental phenotypes in mouse are co-expressed in human. Several of these phenotype-associated proteins form a tight protein-protein interaction network involving 15 known and 34 novel candidate proteins also likely important in placental structure and/or function. The entire data are available as a web-accessible database to guide the informed development of mouse models to study human disease.

TGFbeta activated kinase 1 (TAK1), a member of the MAPKKK family, controls diverse functions ranging from innate and adaptive immune system activation to vascular development and apoptosis. To analyse the in vivo function of TAK1 in cartilage, we generated mice with a conditional deletion of Tak1 driven by the collagen 2 promoter. Tak1(col2) mice displayed severe chondrodysplasia with runting, impaired formation of secondary centres of ossification, and joint abnormalities including elbow dislocation and tarsal fusion. This phenotype resembled that of bone morphogenetic protein receptor (BMPR)1 and Gdf5-deficient mice. BMPR signalling was markedly impaired in TAK1-deficient chondrocytes as evidenced by reduced expression of known BMP target genes as well as reduced phosphorylation of Smad1/5/8 and p38/Jnk/Erk MAP kinases. TAK1 mediates Smad1 phosphorylation at C-terminal serine residues. These findings provide the first in vivo evidence in a mammalian system that TAK1 is required for BMP signalling and functions as an upstream activating kinase for Smad1/5/8 in addition to its known role in regulating MAP kinase pathways. Our experiments reveal an essential role for TAK1 in the morphogenesis, growth, and maintenance of cartilage.

BACKGROUND:: The ThinPrep Imaging System (TIS) was implemented at Brooke Army Medical Center (BAMC) in February 2006 and has been a crucial part of the ability of the Department of Pathology and Laboratory Services ability to improve efficiency and turnaround times for Papanicolaou (Pap) test reporting. The increased detection rate of squamous abnormalities, specifically high-grade squamous intraepithelial lesions (HSIL), has been well documented by many studies. In addition, the TIS has increased productivity for many laboratories. The objective of this study was to evaluate the effects of implementing the TIS at BAMC, a tertiary military medical center. Specifically, the following were assessed: 1) whether the detection of squamous abnormalities was increased with the TIS, 2) how the rate of high-risk human papillomavirus (HR-HPV) detection in atypical squamous cells (ASC) of undetermined significance (ASC-US) cases changed (or did not change) before and after implementation of the TIS, and 3) how the TIS influenced productivity. METHODS:: All gynecologic cytology at BAMC has been collected and processed using the ThinPrep system since 2002. Before February 2006 and before implementation of the TIS, Pap tests were screened manually by the cytotechnologists. Detection rates of squamous abnormalities were compared between the period from February 2005 to December 2005 (manual screening) and the period from February 2006 to December 2006 (image-assisted screening). Squamous abnormalities included ASC-US; ASC, cannot rule out HSIL (ASC-H); low-grade squamous intraepithelial lesion (LSIL); HSIL; glandular abnormalities; and malignancies (squamous or glandular). In addition, the rates of HR-HPV-positive, HR-HPV-negative, and HR-HPV-quantity not sufficient were compared for the same periods. During both periods, testing for HR-HPV was performed only on ASC-US Pap tests. HR-HPV was tested with Digene Hybrid Capture 2 methodology. Productivity was calculated as the change in average slides screened per hour before and after imager implementation. RESULTS:: In total, 107,647 Pap tests were analyzed in the 2005 (54,438 Pap tests) and 2006 (53,209 Pap tests) timeframes. Increases in the detection of ASC-H, atypical glandular cells (AGC), LSIL, and HSIL were statistically significant. The proportion of negative for intraepithelial lesion or malignancy (NILM) and unsatisfactory cases decreased significantly with implementation of the TIS. The ASC to squamous intraepithelial lesion (ASC:SIL) ratio decreased from 1.5 to 1.0 after TIS implementation. Decreases in the ASC-US HR-HPV-positive proportion and increases in the ASC-US HR-HPV-negative proportion after implementation of the TIS were statistically significant. In our laboratory, a 60% increase in productivity was noted with use of the TIS. CONCLUSIONS:: Implementation of the TIS at BAMC significantly increased the detection of ASC-H, AGC, LSIL, and HSIL but had no significant impact on the ASC-US detection rate. Although the ASC-US rate did not change, both the HR-HPV-positive rate and the ASC:SIL ratio decreased. The data from the current study suggested that, at least initially, the use of imager-directed screening may increase the number of clinically insignificant ASC-US Pap tests. Cancer (Cancer Cytopathol) 2009. Published 2009 by the American Cancer Society.

Endosymbiotic bacteria of the genus Wolbachia are widespread among arthropods and cause a variety of reproductive abnormalities, such as cytoplasmic incompatibility, thelytokous parthenogenesis, male-killing, and host feminization. In this study, we used three sets of Wolbachia-specific primers (16S rDNA, ftsZ, and wsp) in conjunction with the polymerase chain reaction (PCR), cloning and sequencing to study the infection of fruit flies (Anastrepha spp. and Ceratitis capitata) by Wolbachia. The flies were collected at several localities in Brazil and at Guayaquil, Ecuador. All of the fruit flies studied were infected with Wolbachia supergroup A, in agreement with the high prevalence of this group in South America. Phylogenetic analysis showed that the wsp gene was the most sensitive gene for studying the relationships among Wolbachia strains. The Wolbachia sequences detected in these fruit flies were similar to those such as wMel reported for other fruit flies. These results show that the infection of Anastrepha fruit flies by Wolbachia is much more widespread than previously thought.

Epilepsy is the most common neurological disorder affecting young people. The etiologies are multiple and most cases are sporadic. However, some rare families with Mendelian inheritance have provided evidence of genes’ important role in epilepsy. Two important but apparently different groups of disorders have been extensively studied: epilepsies associated with malformations of cortical development (MCDs) and epilepsies associated with a structurally normal brain (or with minimal abnormalities only). This review is focused on clinical and molecular aspects of focal cortical dysplasia, polymicrogyria, periventricular nodular heterotopia, subcortical band heterotopia, lissencephaly and schizencephaly as examples of MCDs. Juvenile myoclonic epilepsy, childhood absence epilepsy, some familial forms of focal epilepsy and epilepsies associated with febrile seizures are discussed as examples of epileptic conditions in (apparently) structurally normal brains.

The excessive hyperventilation seen during exercise in chronic heart failure (CHF) contributes to the limited exercise capacity in this condition. The hyperactivation of reflexes originating, independently, from muscle (ergoreflex) and from chemoreceptors (chemoreflex) has been suggested to play an important part in the mediation of the CHF ventilatory abnormalities. In this study we aimed to assess the ventilatory responses to the combined activation of the muscle ergoreflex and the ventilatory chemoreflex, achieved by post-exercise circulatory occlusion (PECO) and euoxic hypercapnia (end-tidal PCO(2) = 7 mmHg above normal), respectively.Three healthy women and three healthy men (29.33 +/- 1.28 yrs; mean +/- SD) undertook four trials, in random order, separated from each other by 30 min of rest: 2 min of isometric handgrip exercise followed by 2 min of PECO with hypercapnia, 2 min of isometric handgrip exercise followed by 2 min of PECO while breathing room air, 4 min of rest with hypercapnia and 4 min of rest while breathing room air.Ventilation (V(E)) was significantly elevated by the ventilatory chemoreflex and it was further elevated by 5.13+/-0.83 L/min (P<0.05) when the muscle ergoreflex was superimposed upon it. The response to the combination of these stimuli was significantly greater than the sum of the responses to the two stimuli when given independently (P<0.05).The results indicate that the interaction between the two reflexes has an additional stimulatory effect on ventilation and consequently could be involved in the limited exercise capacity in CHF.

Individuals with neurofibromatosis type 1 (NF1) are prone to developoptic pathway gliomas that can result in significant visual impairment. To explore the cellular basis for the reduced visual functionresulting from optic glioma formation, we used a genetically engineered mouse model of Nf1 optic glioma (Nf1+/-CKO mice). We performed multimodal functional and structural analyses both before and after the appearance of macroscopic tumors. At 6weeks of age, before obvious glioma formation, Nf1+/-CKO mice had decreased visual-evoked potential amplitudes and increased optic nerve axon calibers. By 3 months of age, Nf1+/-CKO mice exhibited pronounced optic nerve axonopathy and apoptosis ofneurons in the retinal ganglion cell layer. Magnetic resonance diffusion tensor imaging showed a progressive increase in radial diffusivity between 6 weeks and 6 months of age in the optic nerve proximal to the tumor indicating ongoing deterioration of axons. These data suggest that optic glioma formation results in early axonaldisorganization and damage, which culminates in retinal ganglion cell death. Collectively, this study shows that Nf1+/-CKO mice can provide a useful model for defining mechanisms of visual abnormalities in children with NF1 and lay the foundations for future interventional studies aimed at reducing visual loss.