Cerebral Palsy

We studied the effects of the presence of the HLA-DR15 allele on the experimental and clinical features of myelodysplastic syndrome (MDS) by assessing the clinical data of 136 patients with MDS. We observed that the frequency of HLA-DR15 expression in MDS patients (38.7%) was significantly higher than that in the healthy controls (p < 0.01). We noted the following observations with regard to disease progression: None of the 46 HLA-DR15 positive patients with international prognostic scoring system (IPSS) scores </=1 developed acute myeloid leukaemia (AML) during the follow-up period, while six of the 63 DR15-negative patients with the same IPSS score developed AML within a shorter follow-up period (p = 0.039). Furthermore, the incidence of poor chromosomal abnormalities, the percentage of patients with IPSS scores >/=1.5 and the presence of >/=5% blasts in the bone marrow in the DR15-positive patients were lower than the corresponding findings in the DR15-negative patients. In addition, we also recorded the following observations with regard to bone marrow (BM) failure: The bicytopenia/pancytopenia ratio in the DR15-positive patients was higher than that in the DR15-negative patients (92.4 vs. 78.3%; p = 0.029). The peripheral-neutrophil count and the platelet count in the DR15-positive patients were lower than those in the DR15-negative patients (p = 0.028 and p = 0.011, respectively). Moreover, hypocellularity was more easily detectable in the DR15-positive patients (26.4 vs. 16.9%). In addition, the BM CD4+ lymphocyte count and the CD4/CD8 ratio in the DR15-positive patients were higher than the corresponding values in the DR15-negative patients (p < 0.05 for both). However, there were no significant differences between the polarization of T-helper (T(h)) and T-cytotoxic (T(c)) cells and the cytokine levels in these two patient groups. We concluded that the presence of the HLA-DR15 allele is indicative of a genetic susceptibility to MDS and, the presence of the HLA-DR15 allele showed less association with disease progression and greater association with BM failure. Copyright (c) 2009 John Wiley & Sons, Ltd.

Spinocerebellar ataxia-1 (SCA1) is a late onset neurodegenerative disease caused by the expansion of a polyglutamine repeat within ataxin-1 protein. The toxic effects triggered by mutant ataxin-1 result in degeneration of the neurons in cerebellum, brain stem and spinocerebellar tracts. The targeted overexpression of mutant ataxin-1 in cerebellar Purkinje cells (PCs) of the SCA1 transgenic mice results in the formation of cytoplasmic vacuoles in PCs. These vacuoles appear early on before the onset of behavioral abnormalities. Interestingly, we found that vacoules contain S100B and vimentin proteins, which normally localize to neighboring Bergmann glia (BG). Further, immunohistochemical and specialized silver stain analysis revealed that vacuolar formation is associated with alterations in the morphology of dendritic spines of PCs. To gain insights into the mechanisms of vacuolar formation, we investigated if vacuoles in SCA1 PCs have an autophagic origin or are a consequence of some other event. We examined the expression levels (by Western blotting) of microtubule-associated protein light chain 3 (LC3)-I and LC3-II, and the degradation levels of p62 (a LC3 partner) in the cerebellar fractions prepared from pre-symptomatic SCA1 and age-matched wild-type mice. No p62 degradation was observed; however, LC3-II/(LC3-I + LC3-II) ratios were significantly altered in SCA1 mice indicating changes in the autophagic flux. In addition, LC3 localized to PC vacuoles. Further, we observed a co-localization of myo-inositol monophosphatase 1 (IMPA1) with S100B in PC vacuoles. IMPA1 is present in PC spines and has been implicated in autophagy. In vitro studies using purified IMPA1 and S100B demonstrated that S100B interacted with and activated IMPA1. Both apo and Ca(2+)-bound S100B were found to activate IMPA1, depending on substrate concentration. IMPA1 is regulated by another calcium-binding protein calbindin-D28k (CaB), since we reported earlier that the CaB levels are reduced in SCA1 PCs, the activation of IMPA1 by S100B may modulate CaB-dependent inositol signaling. This may cause BG-PC interface to degenerate resulting in vacuolar formation. In sum, these data indicate that vacuoles appearing early in SCA1 PCs could be developing through some unknown autophagic mechanism.

The following case report highlights about a Glioblastoma presenting with features of post stroke depression. The neuropsychological findings though initially was normal but on subsequent follow up showed gross abnormalities. The imaging studies revealed the tumor, involving the right parietal and temporal lobes with midline shift and high vascularity. The patient exhibited rapid downhill course and died within 4 weeks of initial presentation.

Patients who present with acute coronary syndromes, particularly ST-segment elevation myocardial infarction (STEMI), have abnormalities in platelet size and function that predispose to thrombotic events. Both preprocedural platelet reactivity and mean platelet volume are directly correlated with the occurrence of adverse ischemic events and impaired microvascular reperfusion following primary percutaneous coronary intervention (PCI) for STEMI. The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial demonstrated a similar ischemic event rate to 30 days with a significantly lower bleeding event rate (enhanced net clinical benefit) in favor of bivalirudin monotherapy (with provisional platelet glycoprotein [GP] IIb/IIIa receptor blockade) in comparison with unfractionated heparin plus GP IIb/IIIa blockade in patients undergoing primary PCI for STEMI. The bivalirudin monotherapy was associated with a highly significant greater incidence of acute stent thrombosis. This observation provides the opportunity for strategies that enhance periprocedural platelet inhibition to reduce stent thrombosis and to potentially improve the safety and efficacy of periprocedural adjunctive pharmacotherapy above that achieved by bivalirudin monotherapy alone.

The incidence of hypertension is increasing as the number of patients with obesity and diabetes mellitus increases. Hypertension results when the peripheral vascular resistance is increased, the blood viscosity is elevated and/or the flow of blood through the main arteries is impeded. Chronic hypertension results in an enlarged heart, myocardial damage and lung and renal abnormalities. While some causative factors, such as obesity, can be controlled, others, for example genetics, are more difficult to treat because often there is more than one factor involved. This article explores how essential and secondary factors contribute to the incidence of hypertension and the physiological changes resulting from raised blood pressure. It proposes that although traditional treatment has some success, nurse-led clinics are having better success not only in controlling raised blood pressure but also in reducing cardiac, pulmonary and renal morbidity. Nurse-led clinics are more cost-effective, staff are more productive and clients are more compliant with treatment.

Cardiac disease is a major contributor to disease-related death in Churg-Strauss syndrome (CSS). We conducted the current study to determine the prevalence and clinical impact of cardiac involvement in CSS patients. We performed a multicenter, cross-sectional analysis of patients diagnosed with CSS. Cardiac workup included electrocardiography, echocardiography, cardiac magnetic resonance imaging (MRI), and endomyocardial biopsy.We analyzed 49 patients with CSS: 22 patients had clinical evidence of cardiac involvement. A negative antineutrophil cytoplasmic antibodies (ANCA) test and much higher eosinophil counts (9947 vs. 3657/microL, respectively, p < 0.001) distinguished patients with cardiac involvement from those without. Impaired left ventricular function (50%), mild to severe valvular insufficiencies (73%), and pericardial effusions (41%) were common findings in these patients. Endomyocarditis was found in 13 patients (59%) as detected by cardiac MRI, cardiac thrombus formation, and endomyocardial biopsy, and was associated with impaired cardiac function. After a mean follow-up of 47 months, most patients had regained or maintained good cardiac function. However, patients with endomyocarditis had a more severe outcome. Two patients died (61 and 99 mo after diagnosis, respectively), both due to severe cardiomyopathy and heart failure.Cardiac involvement is common in patients with CSS and is associated with the absence of ANCA and high eosinophil counts. Endomyocarditis may represent the most severe manifestation eventually causing fatal outcome. A structured clinical assessment incorporating cardiac imaging with echocardiography and MRI can identify impaired cardiac function and endomyocardial abnormalities.

Giant cell arteritis (GCA) and Takayasu arteritis (TAK) have been considered distinct disorders based on their clinical features, age of onset, and ethnic distribution. However, on closer examination, these disorders appear more similar than different. The histopathology of arterial lesions in these diseases may be indistinguishable. Imaging studies have revealed large vessel inflammation in at least 60% of patients with GCA. We questioned whether the distinctions between these diseases might in part be an artifact due to bias in gathering historical and physical data. We postulated that signs and symptoms of GCA and polymyalgia rheumatica occur in patients with TAK but have been under-reported as a result of this bias.We performed a retrospective review of 75 patients with TAK and 69 patients with GCA (per American College of Rheumatology criteria). Signs and symptoms attributable to disease within the year before and following diagnosis, treatment and interventional outcomes, and mortality were recorded using a standardized database. All cases were evaluated by a single physician, using identical history and physical examination forms for patients with both diseases.Patients were predominantly female (TAK 91%, GCA 82%) and white (TAK 88%, GCA 95%). New headache was a presenting symptom in 52% of TAK and in 70% of GCA patients. All TAK patients underwent vascular imaging studies and were demonstrated to have large vessel abnormalities. However, only a subset of patients with GCA (43/69, 62%) was similarly studied. Among this group, 73% of GCA patients had at least 1 arterial lesion identified. In both TAK and GCA, the most common sites of involvement were the aorta (TAK 77%, GCA 65%) and subclavian (TAK 65%, GCA 37%) arteries. Compared to patients with TAK, patients with GCA had a greater prevalence of jaw claudication (GCA 33%, TAK 5%), blurred vision (GCA 29%, TAK 8%), diplopia (GCA 9%, TAK 0%), and blindness (GCA 14%, TAK 0%).Symptoms, signs, and imaging abnormalities that are characteristic of GCA or TAK are often present, albeit in differing frequencies, in both disorders. These findings lend support to the hypothesis that these diseases may not be distinct entities, but represent skewed phenotypes within the spectrum of a single disorder. Differences in frequencies of manifestations may reflect a significant bias in how data are gathered for patients with each disease, as well as the influence of vascular and immunologic senescence.

BACKGROUND:: Folic acid is known to reduce risk of neural tube defects (NTDs). Even so, NTDs continue to occur despite individual supplementation or population fortification with folic acid. We investigated other nutrients related to one-carbon metabolism that may affect NTD risk. METHODS:: This prospective study included data from more than 180,000 pregnant women in California from 2003 through 2005. Midpregnancy serum specimens were linked with delivery information regarding the presence of a NTD, another structural malformation, or no malformation in the fetus. We identified 80 NTD-affected pregnancies (cases) and we randomly selected 409 pregnancy controls. Serum specimens were tested for methylmalonic acid, homocysteine, cysteine, methionine, total choline, betaine, cystathionine, vitamin B6, folate, vitamin B12, riboflavin, and creatinine. RESULTS:: We observed elevated NTD risks associated with lower levels of total choline, and reduced risks with higher levels of choline. Specifically, we observed an odds ratio of 2.4 (95% confidence interval = 1.3-4.7) associated with the lowest decile and an odds ratio of 0.14 (0.02-1.0) associated with the highest decile, both relative to the 25th-74th percentiles of the control distribution. These data did not show meaningful differences between cases and controls for any other analytes. CONCLUSIONS:: This is the first study to investigate total choline in NTD-affected pregnancies. Our findings for choline, for which low levels were a risk factor and higher levels were a protective factor for NTDs, may offer a useful clue toward understanding the complex etiologies of NTDs in an era of folic acid fortification of the food supply.

The cardiac conduction system comprises a specialized tract of electrically coupled cardiomyocytes responsible for impulse propagation through the heart. Abnormalities in cardiac conduction are responsible for numerous forms of cardiac arrhythmias, but relatively little is known about the gene regulatory mechanisms that control the formation of the conduction system. We demonstrate that a distal enhancer for the connexin 30.2 (Cx30.2, also known as Gjd3) gene, which encodes a gap junction protein required for normal atrioventricular (AV) delay in mice, is necessary and sufficient to direct expression to the developing AV conduction system (AVCS). Moreover, we show that this enhancer requires Tbx5 and Gata4 for proper expression in the conduction system, and Gata4(+/-) mice have short PR intervals indicative of accelerated AV conduction. Thus, our results implicate Gata4 in conduction system function and provide a clearer understanding of the transcriptional pathways that impact normal AV delay.

Disruption of the integrity of the blood-brain barrier (BBB) is an important mechanism of cerebrovascular diseases, including neonatal cerebral hypoxia-ischemia (HI). Although both tissue-type plasminogen activator (tPA) and matrix metalloproteinase-9 (MMP-9) can produce BBB damage, their relationship in neonatal cerebral HI is unclear. Here we use a rodent model to test whether the plasminogen activator (PA) system is critical for MMP-9 activation and HI-induced brain injury in newborns. To test this hypothesis, we examined the therapeutic effect of intracerebroventricular injection of plasminogen activator inhibitor-1 (PAI-1) in rat pups subjected to unilateral carotid artery occlusion and systemic hypoxia. We found that the injection of PAI-1 greatly reduced the activity of both tPA and urokinase-type plasminogen activator after HI. It also blocked HI-induced MMP-9 activation and BBB permeability at 24 h of recovery. Furthermore, magnetic resonance imaging and histological analysis showed the PAI-1 treatment reduced brain edema, axonal degeneration, and cortical cell death at 24-48 h of recovery. Finally, the PAI-1 therapy provided a dose-dependent decrease of brain tissue loss at 7 d of recovery, with the therapeutic window at 4 h after the HI insult. Together, these results suggest that the brain PA system plays a pivotal role in neonatal cerebral HI and may be a promising therapeutic target in infants suffering hypoxic-ischemic encephalopathy.