Analysis of speech fluency in Williams syndrome

Williams syndrome (WS) is a neurodevelopmental genetic disorder, often referred as being characterized by dissociation between verbal and non-verbal abilities, although the number of studies disputing this proposal is emerging. Indeed, although they have been traditionally reported as displaying increased speech fluency, this topic has not been fully addressed in research. In previous studies carried out with a small group of individuals with WS, we reported speech breakdowns during conversational and autobiographical narratives suggestive of language difficulties. In the current study, we characterized the speech fluency profile using an ecologically based measure - a narrative task (story generation) was collected from a group of individuals with WS (n = 30) and typically developing group (n = 39) matched in mental age. Oral narratives were elicited using a picture stimulus - the cookie theft picture from Boston Diagnosis Aphasia Test. All narratives were analyzed according to typology and frequency of fluency breakdowns (non-stuttered and stuttered disfluencies). Oral narratives in WS group differed from typically developing group, mainly due to a significant increase in the frequency of disfluencies, particularly in terms of hesitations, repetitions and pauses. This is the first evidence of disfluencies in WS using an ecologically based task (oral narrative task), suggesting that these speech disfluencies may represent a significant marker of language problems in WS. (C) 2011 Elsevier Ltd. All rights reserved.

Purine nucleoside phosphorylase: A potential target for the development of drugs to treat T-cell- and apicomplexan parasite-mediated diseases

Purine nucleoside phosphorylase (PNP) catalyzes the reversible phosphorolysis of nucleosides and deoxynucleosides, generating ribose 1-phosphate and the purine base, which is an important step of purine catabolism pathway. The lack of such an activity in humans, owing to a genetic disorder, causes T-cell impairment, and thus drugs that inhibit human PNP activity have the potential of being utilized as modulators of the immunological system to treat leukemia, autoimmune diseases, and rejection in organ transplantation. Besides, the purine salvage pathway is the only possible way for apicomplexan parasites to obtain the building blocks for RNA and DNA synthesis, which makes PNP from these parasites an attractive target for drug development against diseases such as malaria. Hence, a number of research groups have made efforts to elucidate the mechanism of action of PNP based on structural and kinetic studies. It is conceivable that the mechanism may be different for PNPs from diverse sources, and influenced by the oligomeric state of the enzyme in solution. Furthermore, distinct transition state structures can make possible the rational design of specific inhibitors for human and apicomplexan enzymes. Here, we review the current status of these research efforts to elucidate the mechanism of PNP-catalyzed chemical reaction, focusing on the mammalian and Plamodium falciparum enzymes, targets for drug development against, respectively, T-Cell and Apicomplexan parasites-mediated diseases.

Atherosclerosis morphology and pathogenesis

Atherosclerosis is a very common and important disease being the most important cause of mortality in Brazil. Indeed, in 1995, 23.3% of deaths, all ages, in our country, were the consequence of atherosclerosis. This percentage grows to 26.3% for S. Paulo and 32.7% for Rio Grande do Sul. Morphologically, there are 3 main types of lesions: fatty streaks, fibrous plaques, and complicated lesions. Fatty streaks are inocuous and occur early in life. In some persons, with age, they change into fibrous plaques that may lead to stenosis. They also may become complicated by erosion, calcification, hemorrhage and thrombosis. Atherosclerosis is initiated by endothelial functional alterations responsible for increase in permeability to macromolecules, adhesion, and migration of monocytes-macrophages and lymphocytes plus recruitment of platelets and smooth-muscle medial cells. Adhesion molecules, cytokines, growth factors, and free radicals are locally synthesized, favoring proliferation of extracellular matrix and progression of the lesion. Experimental, clinical, and epidemiological evidence point to the importance of lipids, mainly cholesterol-rich low-density lipoprotein (LDL), as one of the most important molecules involved in the genesis and progression of atherosclerosis. Patients with a genetic disorder of cholesterol metabolism (familial hyperlipidemia), caused by a decrease in the availability of receptors for LDL, develop severe atherosclerosis early in life. A series of other factors, such as age, diabetes melitus, diet, hypertension, lack of exercise, elevated hemocysteinemia, immunological disorders, and coagulation instability, are related to the progression of atherosclerosis. All of them are capable of altering the endothelium or increasing the offer of LDL. All the above-mentioned factors are systemic; but atherosclerosic lesions are focal, located at preferential sites such as the emergence of colaterals, bifurcations, and curvatures of arteries, all areas in which the laminar flow is disturbed. In these areas shear stress is diminished favoring the prolongation of permanence time of lipid particles, cells, cytokines, growth factors, etc., in the vicinity of the endothelium. Moreover, the endothelium has sensors that act as transducers of mechanical forces in biological responses. Experimental data demonstrate that the number and quality of adhesion molecules, cytokines, and growth factors synthetized, as well as the local production of radicals, and pro and anticoagulation factors may change with shear stress favoring or not the local establishment and progression of atherosclerotic lesions.

Molecular and Cytogenetic Analyses on Brazilian Youths with Pervasive Developmental Disorders

The Pervasive Developmental Disorders (PDDs) constitute a group of behavioral and neurobiological impairment conditions whose main features are delayed communicative and cognitive development. Genetic factors are reportedly associated with PDDs and particular genetic abnormalities are frequently found in specific diagnostic subgroups such as the autism spectrum disorders. This study evaluated cytogenetic and molecular parameters in 30 youths with autism or other PDDs. The fragile X syndrome was the most common genetic abnormality detected, presented by 1 patient with autism and 1 patient with PPD not-otherwise specified (PPD-NOS). One girl with PDD-NOS was found to have tetrasomy for the 15q11-q13 region, and one patient with autism exhibited in 2/100 metaphases an inv(7)(p15q36), thus suggesting a mosaicism 46,XX/46,XX,inv(7)(p15q36) or representing a coincidental finding. The high frequency of chromosomopathies support the hypothesis that PDDs may develop as a consequence to chromosomal abnormalities and justify the cytogenetic and molecular assessment in all patients with PDDs for establishment of diagnosis.

Kinetics and crystal structure of human purine nucleoside phosphorylase in complex with 7-methyl-6-thio-guanosine

Purine nucleoside phosphorylase (PNP) catalyzes the reversible phosphorolysis of nucleosides and deoxynucleosides, generating ribose 1-phosphate and the purine base, which is an important step of purine catabolism pathway. The lack of such an activity in humans, owing to a genetic disorder, causes T-cell impairment, and drugs that inhibit this enzyme may have the potential of being utilized as modulators of the immunological system to treat leukemia, autoimmune diseases, and rejection in organ transplantation. Here, we describe kinetics and crystal structure of human PNP in complex with 7-methyl-6-thio-guanosine, a synthetic substrate, which is largely used in activity assays. Analysis of the structure identifies different protein conformational changes upon ligand binding, and comparison of kinetic and structural data permits an understanding of the effects of atomic substitution on key positions of the synthetic substrate and their consequences to enzyme binding and catalysis. Such knowledge may be helpful in designing new PNP inhibitors. © 2005 Elsevier Inc. All rights reserved.

Maxi-K channels contribute to urinary potassium excretion in the ROMK-deficient mouse model of Type II Bartter's syndrome and in adaptation to a high-K diet

Type II Bartter's syndrome is a hereditary hypokalemic renal salt-wasting disorder caused by mutations in the ROMK channel (Kir1.1; Kcnj1), mediating potassium recycling in the thick ascending limb of Henle's loop (TAL) and potassium secretion in the distal tubule and cortical collecting duct (CCT). Newborns with Type II Bartter are transiently hyperkalemic, consistent with loss of ROMK channel function in potassium secretion in distal convoluted tubule and CCT. Yet, these infants rapidly develop persistent hypokalemia owing to increased renal potassium excretion mediated by unknown mechanisms. Here, we used free-flow micropuncture and stationary microperfusion of the late distal tubule to explore the mechanism of renal potassium wasting in the Romk-deficient, Type II Bartter's mouse. We show that potassium absorption in the loop of Henle is reduced in Romk-deficient mice and can account for a significant fraction of renal potassium loss. In addition, we show that iberiotoxin (IBTX)-sensitive, flow-stimulated maxi-K channels account for sustained potassium secretion in the late distal tubule, despite loss of ROMK function. IBTX-sensitive potassium secretion is also increased in high-potassium-adapted wild-type mice. Thus, renal potassium wasting in Type II Bartter is due to both reduced reabsorption in the TAL and K secretion by max-K channels in the late distal tubule. © 2006 International Society of Nephrology.

Clinical manifestations and oral findings in fraser syndrome

This article is the first known case report of Fraser syndrome in the dental literature. Its purpose was to present the clinical manifestations, oral findings, and dental treatment of a 14-year, 10-month-old female patient. Fraser syndrome is a rare recessive autosomal genetic disorder characterized by multisystemic malformation, usually comprising cryptophthalmos, syndactyly, and renal defects. The child presented with: (1) hydrocephaly; (2) face asymmetry; (3) low-inserted ears; (4) flat nose bridge; (5) cryptophthalmos; (6) bilateral absence of eyeballs; (7) hypertelorism; (8) syndactyly on the left fingers and toes; (9) skeletal defects; and (10) lower limb asymmetry. The intraoral examination revealed: (1) complete primary denture; (2) malocclusion; (3) tooth crowding; (4) ogival palate; (5) normal labial frena; (6) absence of lingual frenum (not compromising the tongue movements); (7) parched lips; (8) supragingival calculus adhered to all tooth surfaces; and (9) moderate gingivitis. The dental treatment consisted of periodic monitoring of the patient's oral health status and supragingival scaling associated with topical applications of 0.12% chlorhexidine digluconate gel at 2-week intervals to reduce gingivitis.

What's the signification of nuclear vacuoles in human sperm?

The aim of this study was to determine the extent of DNA fragmentation and the presence of single/denatured or double stranded of DNA in sperm with large nuclear vacuoles (LNV) selected by high-magnification. A total of 30 patients had fresh semen samples prepared by discontinuous concentration gradient. Sperm with normal nucleus (NN) and LNV were selected at 8400x magnification and placed in different slides. DNA fragmentation was determined by TUNEL assay. Denatured and double stranded DNA was identified by acridine orange fluorescence method. The percentage of DNA fragmentation in LNV sperm (29%) was significantly higher (P<0.001) than NN sperm (15.8%). Therefore, cleavage of genomic DNA in low molecular weight DNA fragments (mono and oligonucleosomes), and single strand breaks (nicks) in high molecular weight DNA occur more frequently in LNV. Identically, the percentage denatured stranded DNA in sperm with LNV (67.9%) was significantly higher (P <0.0001) than NN sperm (33%). The high level of denatured DNA in sperm with LNV suggests precocious decondensation and disaggregation of sperm chromatin fibers. Our results support an association between LNV sperm and DNA damage, and the routine selection and injection of morphological motile sperm at high magnification for ICSI. The adverse effect (DNA fragmentation or denaturation) leads to concern particularly about the possibility of iatrogenic transmission of genetic abnormalities. Copyright - SBRA - Sociedade Brasileira de Reprodução Assistida.

SED-brachydactyly and distinctive speech: Report of a new familial case

Background: Spondyloepiphyseal dysplasia-brachydactyly and distinctive speech (SED-BDS) is a syndrome characterized by short stature, disproportionately short limbs, peculiar face, thick and abundant hair, high-pitched and coarse voice, small epiphyses, brachymetacarpalia, brachymetatarsalia and brachy-phalangia of fingers and toes, small pelvis and delayed carpal bone age, among other features. Case Report: We report a Brazilian patient with father, brother and sister presenting with the same typical features of the syndrome. Clinically, he showed disproportionately short stature, rhizo-meso-acromelic shortness of the extremities, short hands and feet, a peculiar distinctive high-pitched voice, peculiar facies, and other features already reported as characteristic of this syndrome. Radiographic fndings included shape anomalies of the vertebral bodies such as cuboid-shaped vertebral bodies, mild scoliosis, short and broad tubular bones, brachymetacarpalia, brachymetatarsalia, and brachy-dactyly, lumbar hyperlordosis, generalized osteopenia, and hypoplastic iliac wings. Conclusions: Few cases have been described, as this is a rare skeletal dysplasia. This paper describes a new familial case of SED-BDS. © The American Journal of Case Reports.

Idade masculina: Qualidade do sêmen e fertilidade: Idade masculina X qualidade seminal

The man's age seems to affect reproductive function but to a lower degree compared with the woman's age. In fact, the effect of paternal age on semen quality has been discussed, but the results are contradictory. Considering the differences in the results of studies, this review aimed to analyze the literature regarding the effect of paternal age on semen parameters (volume, concentration, motility and morphology) in sperm DnA damage in assisted reproduction results and genetic diseases.

Assessment of clinical scoring systems for the diagnosis of Williams-Beuren syndrome

Williams-Beuren syndrome (WBS) is a genetic disorder characterized by physical and intellectual developmental delay, associated with congenital heart disease and facial dysmorphism. WBS is caused by a microdeletion on chromosome 7 (7q11.23), which encompasses the elastin (ELN) gene and about 27 other genes. The gold standard for WBS laboratory diagnosis is FISH (fluorescence in situ hybridization), which is very costly. As a possible alternative, we investigated the accuracy of three clinical diagnostic scoring systems in 250 patients with WBS diagnosed by FISH. We concluded that all three systems could be used for the clinical diagnosis of WBS, but they all gave a low percentage of false-positive (6.0-9.2%) and false-negative (0.8-4.0%) results. Therefore, their use should be associated with FISH testing. © FUNPEC-RP.

Frequência dos mutantes C282Y e H63D do gene HFE e sua influência no metabolismo do ferro e na expressão da beta talassemia heterozigota

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

A síndrome de Williams-Beuren: contribuições à avaliação clínica e genômica

Pós-graduação em Ciências Biológicas (Genética) - IBB

Derivados de poli(L-lisina) com fosforilcolina para transferência gênica não-viral

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Allele frequency of hereditary equine regional dermal asthenia in American Quarter horses in Brazil determined by quantitative real-time PCR with high resolution melting analysis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)