Cerebral Palsy

Notch signaling plays an essential role in vascular development and human vascular diseases. In adults, mutations of the Notch3 gene cause a hereditary vascular degenerative disease known as cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL). CADASIL is characterized by recurrent strokes and cognitive impairment. Over the past decade, the number of CADASIL patients increased significantly with improvements in genetic testing and other diagnostic tools, but the true prevalence of CADASIL is still underestimated, especially in Asia. Basic studies suggest that Notch3 is essential for the development and survival of the vascular smooth muscle cells, but the mechanisms by which Notch3 mutations become pathogenic are still unclear. This article reviews the clinical features and possible pathogenesis of CADASIL. Efforts to improve the diagnostic accuracy and define the role of Notch3 mutation in brain damage and clinical presentations of CADASIL should be continued.

Insulin resistance is associated with type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). These abnormalities have been aggravated because of imbalanced and excess nutrition in developed countries, and rapid nutritional and lifestyle transition occurring in developing countries. This review presents evidence linking dietary nutrients with insulin resistance and its metabolic correlates, and also describes these issues from a Asian Indians and South Asian perspective. Despite possible influences from genetic and perinatal factors, diet and physical activity are likely to have greater and often overriding influence in pathogenesis of the insulin resistance, the metabolic syndrome, and T2DM. In animal studies, a link has been established between dietary nutrients and insulin resistance. However, in human studies evidence is not as strong as in animals. Data suggest that dietary omega-3 polyunsaturated fatty acids (PUFAs) improve lipid profile and may have beneficial effect on insulin resistance. Dietary saturated fatty acids intake is positively associated with insulin resistance. Also, low glycaemic index foods and whole grain intake decrease insulin resistance. Importantly, high carbohydrate diets increase plasma triglycerides, cause hyperinsulinaemia and decreases low-density lipoprotein cholesterol. Among micronutrients, high magnesium and calcium intake have been reported to decrease insulin resistance. High intake of dietary carbohydrate and omega-6 PUFAs, low intake of omega-3 PUFAs and fiber, and high omega -6/omega-3 PUFAs ratio have been reported in South Asians. Our recent investigations have shown that increased dietary omega-6 PUFAs and saturated fat intake are significantly associated with fasting hyperinsulinaemia and sub-clinical inflammation, respectively. Such imbalanced diets contribute to high prevalence of insulin resistance, the metabolic syndrome and T2DM in South Asians and Asian Indians.

Objectives: Hypoglycemia in young children with T1DM is an acute complication of intensive insulin therapy and is commonly observed in the absence of signs or symptoms. The effect of intensive treatment and patient age on sympatho-adrenal responses has not been established in youth with T1DM due to difficulties in testing procedures. Methods: We developed a standardized inpatient continuous subcutaneous insulin infusion protocol to produce a progressive fall in plasma glucose concentrations in insulin pump-treated patients. Plasma glucose and counter-regulatory hormone concentrations were measured in 14 young children (3 to <8 years, HbA1c 7.7 +/- 0.6%) vs. 14 adolescents (12 to <18 years, HbA1c 7.6 +/- 0.8%). Results: Plasma glucose decreased to similar nadir concentrations in the two groups. Four young children and 4 adolescents never had an epinephrine response. In the 4 young children and 5 adolescents who had a modest epinephrine response, this only occurred when plasma glucose fell to <60 mg/dL. In evaluating symptom scores, 29% of parents of young children felt that their child looked hypoglycemic even at the lowest plasma glucose concentrations. Adolescents were better able to detect symptoms of hypoglycemia. In comparison to our data, epinephrine response to hypoglycemia in 14 non-diabetic adolescents studied at the Children’s Hospital of Pittsburgh was higher. Conclusions: These data suggest that even young children and adolescents with T1DM are prone to develop hypoglycemia-associated autonomic failure regardless of duration. Whether these abnormalities can be reversed using continuous glucose monitoring and closed loop insulin delivery systems awaits further study.

Objective: To investigate the association of the dietary pattern with the presence of newly diagnosed glucose tolerance abnormalities among Chinese adults. Research Design and Methods: A total of 20,210 adults aged 45-69 yrs from the 2002 China National Nutrition and Health Survey were included. Information on dietary intake was collected using a validated food frequency questionnaire. Factor analysis and cluster analysis were used to identify the food factors and dietary pattern clusters. Results: Four dietary pattern clusters were identified (”Green Water”, “Yellow Earth”, “Western Adopter”, and “New Affluence”). The prevalence of glucose tolerance abnormalities ranged from 3.9% in the Green Water to 8.0% in the New Affluence. After adjustment for area, age, sex, current smoking and physical activity, subjects in the Yellow Earth cluster (PR 1.22, CI: 1.04-1.43) and New Affluence cluster (PR 2.05 CI: 1.76-2.37) had significantly higher prevalence rates compared with the Green Water. After further adjustment for BMI and waist to height ratio, the elevated risk in the New Affluence remained statistically significant Conclusions: Dietary patterns and food factors are associated with the presence of glucose tolerance abnormalities in China, even independent of obesity. A New Affluence diet are important modifiable risk factors which need attention from the prevention point of view.

The ligatation behaviour of sulphonylurea glibenclamide drug is studied in order to give an idea about its potentiality towards some transition metals in vitro systems. Metal complexes of glibenclamide (GCA; H(3)L) drug are prepared and characterized based on elemental analyses, IR, diffused reflectance, magnetic moment, molar conductance and thermal analysis (TG and DTG) techniques. From the elemental analyses data, the complexes are proposed to have the general formulae [M(H(3)L)Cl(n)(H(2)O)(m)].yH(2)O (where M=Cr(III) (n=3, m=1, y=3); Mn(II) (n=2, m=0, y=1); Fe(III) (n=3, m=1, y=0), Co(II) (n=2, m=2, y=0); Ni(II) (n=2, m=2, y=3); Cu(II) (n=2, m=2, y=2) and Zn(II) (n=2, m=0, y=0). The molar conductance data reveal that all the metal chelates are non-electrolytes. IR spectra show that GCA is coordinated to the metal ions in a neutral bidentate manner with OO donor sites of the amide-O and sulphone-O. From the magnetic and solid reflectance spectra, it is found that the geometrical structures of these complexes are octahedral except Mn(II) and Zn(II) complexes which have tetrahedral structure. The thermal behaviour of these chelates is studied using thermogravimetric analysis (TG and DTG) technique. The activation thermodynamic parameters are calculated using Coats-Redfern method. The GCA drug, in comparison to its metal complexes also is screened for its biological activity against house fly, Musca domestica (Diptera-Muscidae). Dose of 5mug/insect of GCA is topically applied against 3 days old larval instar of M. domestica. Survival of pupal and adult stages has been affected by the complexes of GCA more than larval instars. Morphogenic abnormalities of larvae, pupae and adults are studied. On the other hand pupation and adult emergence program is deteriorated by the effect of different chemicals.

Gardner’s syndrome (GS) is a hereditary autosomal dominant disease of the colon that presents with extra-colonic manifestations such as osteomas, skin lesions and dental abnormalities. Osteomas are commonly found in the skull, jaws and the paranasal sinuses. We present a family of four sisters affected with GS with a wide range of anomalies. The role of Cone beam computed tomography (CBCT) in the early detection and evaluation of osteomas and dental anomalies with precise assessment of their relationship to adjacent anatomic structures is described here in detail. The careful interpretation of CBCT may be of a great value in surgical and orthodontic treatment planning in the presence of jaw lesions. Management of dental problems in GS may be challenging due to the presence of odontomas and increased bone density. A multidisciplinary approach in the management of GS can achieve the best treatment results.

AIMS: To study the impact of genetic factor on pancreatic beta-cell function in the Chinese population. METHODS: 233 first-degree relatives of patients with type 2 diabetes (T2D) with no history of blood glucose abnormalities and their 190 spouses, who did not have a family history of T2D, underwent a 75-g oral glucose tolerance test (OGTT). Based upon the OGTT, these two groups were further divided into three subgroups, including groups with normal glucose tolerance (NGT), impaired glucose regulation (IGR), and type 2 diabetes. Insulin resistance (IR) was evaluated using the homeostasis model assessment-IR (HOMA-IR), beta-cell function indices of basal and first-phase were measured by DI1 (HOMA-beta/HOMA-IR) and DI2 (DeltaI30/DeltaG30/HOMA-IR), respectively. RESULTS: Among the first-degree relatives and their spouses, the HOMA-IR was highest in the T2D group and lowest in the NGT group. However, the HOMA-beta, DI1 and DI2 declined significantly with progressive reductions in glucose tolerance (P<0.01 or 0.05). DI1 and DI2 of the NGT group of first-degree relatives (FNGT) were significantly lower than those of the spouse NGT (SNGT) group (P<0.05). DI1 and DI2 of the IGR of first-degree relatives (FIGR) group were significantly lower than those of the spouse IGR (SIGR) group. CONCLUSIONS: Defects in pancreatic beta-cell function exist in the first-degree relatives, who have different glucose tolerance statuses, of T2D patients. These defects are more profound in FNGT and FIGR when compared to their spouses in corresponding glucose tolerance subgroups. However, there is no difference in IR between the corresponding glucose tolerance subgroups of the first-degree relatives and their spouses. It suggests that the genetic factor possibly aggravates beta-cell lesion.

We designed our study to investigate the efficacy of a new therapeutic approach to late onset hypertension in patients after surgical repair of aortic coarctation. Several studies have shown a higher incidence of hypertension during daily activities, and during exercise, in patients after surgical correction of coarctation. To the best of our knowledge, however, no data exists concerning haemodynamics, the response of arterial pressures, and the effects of medications for lowering blood pressure during exercise or during daily activities.We studied 128 patients, aged 15.6 +/- 4.3 years, to determine the response of blood pressure as we administered treatment in the attempt to achieve a normotensive state. We excluded patient with associated cardiac abnormalities, apart from those with bicuspid aortic valves. We evaluated blood pressure at rest in both the right arm and leg to establish presence of any gradient, as well as the blood pressure in the arm during exercise testing, and by 24-hour ambulatory monitoring.Atenolol was prescribed for those with elevated values of blood pressure but with a normal increment of heart rate during exercise. We prescribed Candesartan for those with elevated levels of blood pressure but with reduced increments of heart rate, specifically maximal heart rates of less than 85% of their predicted value. Both drugs were used when one alone was not effective. We found that, in young patients, candesartan provided better control of blood pressure with no side-effects, especially as demonstrated using 24-hour ambulatory monitoring, while atenolol was less effective, with more side-effects. Our experience suggests that both drugs should be used in patients who are non-responsive to monotherapy.

Scinderin, the closest homologue of the actin-severing protein, gelsolin, has two similar paralogs (Scinla and Scinlb) in zebrafish. Scinla is abundant in the adult cornea; Scinlb comprises considerably less corneal protein. Here, we show that scinla is expressed in the nose, lens, brain, cornea and annular ligament of the iridocorneal angle; by contrast, scinlb is expressed in the hatching gland, floor plate, notochord, otic vesicle, brain, pharynx, cartilage, swim bladder and cornea. Activity of scinla and scinlb promoter fragments driving the EGFP reporter gene in transgenic zebrafish resembled scinla or scinlb expression. Previously, we showed that reduction of scinla by injection of antisense morpholino oligonucleotides ventralized embryos; here, specific reduction of scinlb expression led to subtle brain abnormalities associated with increased cell death, decreased shhb expression in the floor plate, and slightly reduced eye distance. Thus, scinla and scinlb have different expression patterns and developmental roles during zebrafish development. Developmental Dynamics, 2009. Published 2009 Wiley-Liss, Inc.

A contrarian view suggests that the ectodermal dysplasias, including more than 200 different disorders, represent clinical variability and molecular heterogeneity as well as complex multigene heritable conditions often characterized by dysmorphogenesis of derivatives of embryonic ectoderm and beyond. Controversy exists over which syndromes do or do not belong in the classification of the clinical features that characterize ectodermal dysplasias. For example, Ellis-van Creveld syndrome is characterized by abnormalities of the teeth and hair, as well as of the skeleton and the cardiovascular system. Precision in diagnosis often is a preamble for improved patient diagnosis, treatment and desired outcomes. In tandem, molecular studies of complex epithelial-mesenchymal interactions required for ectodermal derivatives (e.g., hair, nail, skin, teeth, and exocrine glands) continue to identify and explain many signal transduction pathways and networks related to ectodermal dysplasias. Meanwhile, major international investments in fundamental biomedical research continue to yield significant benefits to the larger society. The convergence of informatics, nanotechnology, genomics, and epigenetic studies with clinical medicine and dentistry promise major progress for special needs patients such as ectodermal dysplasias. For example, investments in the molecular biology of genes and their regulation and function now provide more than 30 candidates for specific biomarkers to improve diagnosis, prognosis, treatments, therapeutics, and biomaterials for ectodermal dysplasias. Innovations in high throughput genotyping, gene mapping, single nucleotide polymorphisms (SNPs), interference RNA treatments, bioimaging, tissue engineering and related biomimetic approaches to design and fabricate biomaterials, offer enormous promise for the future of ectodermal dysplasias. (c) 2009 Wiley-Liss, Inc.