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Biomedical subjects

S Naidu

Publications and source records attributed to S Naidu.

At least 73 records · Page 4Linked to original sources
PubMed1995

Diagnoses of neuronal ceroid-lipofuscinosis by immunochemical methods.

The neuronal ceroid-lipofuscinoses (NCL), also known as Batten disease, are a not uncommon group of disorders affecting infants, children, and young adults. The abnormal ultrastructural profiles seen in NCL are used for standard diagnosis; however, they can be missed, and are also found in other neurodegenerative conditions. Furthermore, there is an overlap between the types of inclusion profiles among the different forms of NCL. Therefore, a more specific and biochemically-based marker is necessary to confirm the diagnosis of NCL. Antibodies raised against the storage material from the ovine form of NCL (mitochondrial ATP synthase subunit c) were utilized to determine whether NCL could be distinguished from other metabolic-neurodegenerative disorders. By immunoblotting and immunohistochemistry, several brain samples of well-evaluated NCL cases confirmed increased accumulations in all NCL cases except in the brain of an infantile-onset NCL patient. The immunoblot studies of skin fibroblasts and brain were sensitive but not highly specific to NCL, due to the recognition of this material in normal controls as well as in other neurogenetic diseases. Immunocytochemistry of skin fibroblasts clearly distinguished LINCL and JNCL cases from controls, and with further refinement has the potential for becoming a diagnostic tool.

Adult↗
PubMed1995

Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups.

OBJECTIVE: To use the technique of complementation analysis to help define genotype and classify patients with clinical manifestations consistent with those of the disorders of peroxisome assembly, namely the Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata (RCDP). STUDY DESIGN: Clinical findings, peroxisomal function, and complementation groups were examined in 173 patients with the clinical manifestations of these disorders. RESULTS: In 37 patients (21%), peroxisome assembly was intact and isolated deficiencies of one of five peroxisomal enzymes involved in the beta-oxidation of fatty acids or plasmalogen biosynthesis were demonstrated. Ten complementation groups were identified among 93 patients (54%) with impaired peroxisome assembly and one of three phenotypes (ZS, NALD, or IRD) without correlation between complementation group and phenotype. Forty-three patients (25%) had impaired peroxisome assembly associated with the RCDP phenotype and belonged to a single complementation group. Of the 173 patients, 10 had unusually mild clinical manifestations, including survival to the fifth decade or deficits limited to congenital cataracts. CONCLUSIONS: At least 16 complementation groups, and hence genotypes, are associated with clinical manifestations of disorders of peroxisome assembly. The range of phenotype is wide, and some patients have mild involvement.

Acyltransferases↗
PubMed1995

Rett syndrome studies of natural history and search for a genetic marker.

The commonly held notion that Rett syndrome (RS) is a neurodegenerative disorder with normal early development was examined by an epidemiological survey and review of medical records and serial neurological and development evaluations. In some subjects, deviance from normal development was evident from the perinatal period, and gradually became more prominent with age. These findings are convincing when seen in conjunction with a reduction in velocity of brain growth, as early as 2-4 months of life, well before the recognition of gross neurological deficits. Neurodevelopmental evaluations provide no indication that there is progressive loss of adaptive behaviors, or communication skills to indicate a neurodegenerative process. Taken together with the known neuropathological and neurochemical changes in RS brain we hypothesize that RS is a neurodevelopmental disorder, which has a genetic basis, and affects subsets of neurons and their connections during a period of vigorous brain growth, when synapse formation and pruning are at a peak. Studies of mitochondrial (mt) DNA in brain to understand the genetic mechanisms underlying matrilineal inheritance in the few familial cases, and mt structural and enzyme deficiencies have been unrevealing to date.

Adolescent↗
PubMed1995

Abnormal expression of microtubule-associated protein 2 (MAP-2) in neocortex in Rett syndrome.

Immunocytochemical evaluations of the neocortex of three classical Rett syndrome (RS) individuals revealed a selective abnormality in the expression of microtubule-associated protein 2 (MAP-2). MAP-2 immunoreactivity (ir) was reduced throughout the neocortex of all three RS cases with a reversal of the normal pattern of more intense staining in deep cortical layers. This anomaly was selective for MAP-2 because nonphosphorylated neurofilament (SMI-32) labeling of deep pyramidal neurons and calbindin (CaBP)-stained GABAergic cells remained unchanged. Moreover, MAP-2 ir was virtually undetected in white matter while GABAergic and, particularly, peptidergic (neuropeptide Y: NPY) profiles were easily recognized. These results demonstrate a marked disruption of a major cytoskeletal component in neocortex in RS which seems to affect, predominantly, pyramidal projection and white matter neurons. MAP-2 expression appears early in neuronal maturation of the neocortex, particularly in the subplate region, the future superficial white matter, suggesting that these reported abnormalities in RS represent a developmental disturbance. Considering that MAP-2 expression is regulated by several neurotransmitter systems in adult cerebral cortex, particularly dopaminergic and cholinergic afferents that are deficient in RS, these neurochemical alterations could be related to this anomalous MAP-2 expression.

Adult↗
PubMed1995

Abnormalities of thyroid function and glucose control in subjects with Rett syndrome.

We have identified subtle abnormalities of thyroid function and glucose control in patients with Rett syndrome. The mean serum total thyroxine (T4) concentration was significantly lower in a group of subjects with Rett syndrome (6.9 +/- 1.5 microgram/dl, n = 34; p < 0.001) than the adult reference range (8.5 +/- 1.75 microgram/dl, n = 200). This differences remained significant even for the 17 subjects not taking anticonvulsants (7.6 +/- 1.5 microgram/dl; p < 0.05 vs. adult reference). The difference was more marked when compared to age-adjusted normals, with 10 subjects having a serum total T4 concentration below normal for age including 3 of 17 of the subjects not taking anticonvulsants. This decrease in serum total T4 concentration was not due to changes in binding proteins as measured by 3,5,3'-triiodothyronine resin uptake, and was associated with a decreased concentration of thyroid-stimulating hormone (1.7 +/- 1.6 mU/l, n = 23 vs. 2.5 +/- 1.0 mU/l, n = 200; p < 0.01). Oral glucose tolerance tests were performed in 10 of the subjects with Rett syndrome. They had a delay in the peak glucose and insulin concentrations. Glucose levels were elevated at 1 and 2 hours (p < 0.05), and insulin levels were elevated at 1, 2, and 3 hours (p < 0.05). Two subjects fulfilled criteria for impaired glucose tolerance.

Adolescent↗
PubMed1995

Effects of housing density on mouse physiology and behavior in the NASA Animal Enclosure Module simulators.

Space flight studies using the Animal Enclosure Module (AEM) make it possible to investigate the role of microgravity on animal physiology and behavior. In this study, we compared the health and well-being of mice housed at different densities in AEM simulators (AEMS), to vivarium shoebox (control) cages (VSBC). A stress assessment battery (SAB) of measures was developed to evaluate mouse health and well-being, and to determine if any of the population sizes resulted in a stressful environment. The SAB was based, in part, on recommendations of a NASA Workshop on Rodent Cage Sizing. It includes: 1) General assessment of appearance, 2) Behavioral assessment (video), 3) Food and water consumption, 4) Body weight changes, 5) Thymus, adrenal, spleen, heart and kidney weights, 6) Plasma corticosterone concentration, 7) Total plasma protein concentration, 8) Total blood leukocyte count, 9) Differential leukocyte count: neutrophil/lymphocyte ratio; eosinophil count, 10) Gastric histology.

Animals↗
PubMed1995

Studies of X inactivation and isodisomy in twins provide further evidence that the X chromosome is not involved in Rett syndrome.

Rett syndrome (RS), a progressive encephalopathy with onset in infancy, has been attributed to an X-linked mutation, mainly on the basis of its occurrence almost exclusively in females and its concordance in female MZ twins. The underlying mechanisms proposed are an X-linked dominant mutation with male lethality, uniparental disomy of the X chromosome, and/or some disturbance in the process of X inactivation leading to unequal distributions of cells expressing maternal or paternal alleles (referred to as a "nonrandom" or "skewed" pattern of X inactivation). To determine if the X chromosome is in fact involved in RS, we studied a group of affected females including three pairs of MZ twins, two concordant for RS and one uniquely discordant for RS. Analysis of X-inactivation patterns confirms the frequent nonrandom X inactivation previously observed in MZ twins but indicates that this is independent of RS. Analysis of 29 RS females reveals not one instance of uniparental X disomy, extending the observations previously reported. Therefore, our findings contribute no support for the hypothesis that RS is an X-linked disorder. Furthermore, the concordant phenotype in most MZ female twins with RS, which has not been observed in female twins with known X-linked mutations, argues against an X mutation.

Child↗
PubMed1994

Sex- and tissue-specific Bkm(GATA)-binding protein in the germ cells of heterogametic sex.

The ZZ male/ZW female system of sex determination (female heterogamety) is found in snakes and birds whereas XY male/XX female system of sex determination (male heterogamety) operates in mammals including humans. The W and Y chromosomes are largely heterochromatic and undergo cycles of condensation and decondensation in the germ cells of ovary and testis, respectively, whereas they remain highly condensed and transcriptionally inactive in all somatic cells. Both chromosomes have enriched stretches of GATA repeats along their entire length (which is identified as banded krait minor satellite DNA and called Bkm) that are highly conserved through widely separated orders of eukaryotes. Here we report the existence of a factor, which specifically binds to Bkm, in the germ cells of the heterogametic sex (ovary in female heterogamety and testis in male heterogamety) where decondensation (activation) of the W and Y chromosomes, respectively, occurs; it has been purified as a polypeptide of 57.5 kDa from the rat snake ovary and designated as Bkm-binding protein (BBP) by virtue of its binding to GATA repeats of Bkm. Such a sex- and tissue-specific BBP is also present in the ovary of other species of snakes and in the testis of mouse and human where the Y chromosome is highly decondensed. We suggest that GATA repeats of Bkm brings about a coordinated decondensation of the W and Y sex chromosomes in the germ cells of the heterogametic sex in response to BBP which may serve as a "switch" for the activation of the genes present on the W and Y chromosomes.

Animals↗
PubMed1994

Cytosolic compartmentalization of hepatic alanine:glyoxylate aminotransferase in patients with aberrant peroxisomal biogenesis and its effect on oxalate metabolism.

Two patients with atypical manifestations of aberrant peroxisomal biogenesis are described. Contrary to previous studies, which had shown that Zellweger syndrome patients usually have normal levels of urinary oxalate excretion, the patients in the present study had evidence of abnormal oxalate metabolism in the form of hyperoxaluria and, in one of the patients, calcium oxalate urolithiasis. Activity of the liver-specific peroxisomal enzyme alanine:-glyoxylate aminotransferase (AGT), which is a major determinant of the level of endogenous oxalate synthesis in humans, was normal in one patient and markedly supranormal in the other. Using the technique of post-embedding protein A-colloidal gold immunoelectron microscopy, AGT was found to be mainly cytosolic in the livers of both patients, with significant amounts also localized in the nuclei. In a small minority of the hepatocytes of one patient, who was homozygous for the more common (major) AGT allele, large numbers of unidentified fibrillar arrays were found in the cytosol, which labelled heavily for immunoreactive AGT. The background cytosolic AGT labelling was markedly reduced in such cells when compared to the majority of cells that did not contain fibrils. In the other patient, who was heterozygous for the major and minor AGT alleles, there appeared to be low levels of mitochondrial AGT labelling. In the light of these data, the possible metabolic function of cytosolic AGT in the livers of panperoxisomal disease patients is discussed.

Alanine Transaminase↗
PubMed1994

Polysomnographic characteristics of patients with Rett syndrome.

During wakefulness, patients with Rett syndrome have disordered breathing. To understand further this ventilatory control disorder, we performed polysomnography in 30 patients with Rett syndrome and 30 control subjects (female subjects with primary snoring). The median age was 7 years (range, 1 to 32 years) for Rett syndrome and 6 years (range, 1 to 17 years) for control subjects. During periods of wakefulness, 67% of patients with Rett syndrome had the characteristic pattern of disordered breathing (i.e., episodes of hyperventilation followed by central apnea and desaturation). No such events occurred during sleep. Sleep efficiency and sleep architecture were similar for both groups. During sleep, there was no difference in duration of periodic breathing, number of episodes of central apnea with desaturation, or number of episodes of obstructive apnea or end-tidal carbon dioxide tension between the two groups. Although arterial oxygen saturation during rapid eye movement (REM) sleep was slightly lower in patients with Rett syndrome (nadir, 94% +/- 2% vs 96% +/- 2%), it remained within the normal range. Parental history reflected the awake respiratory findings in most cases. We conclude that patients with Rett syndrome have normal breathing during non-rapid eye movement (NREM) sleep. We speculate that patients with Rett syndrome have normal brain-stem control of ventilation, and that the disordered breathing seen during wakefulness is due to an abnormality of the cortical influence on ventilation.

Adolescent↗
PubMed1994

Raynaud's phenomenon and cold stress testing: a new approach.

There are a number of methods of evaluating digital blood flow in the vascular laboratory but none fulfills the criteria of providing a quick and reproducible diagnostic test for Raynaud's phenomenon. We present our experience with the use of high frequency ultrasound to provide direct real time imaging of the digital arteries. Using this method and a standardised cold challenge test, consisting of exposure of the hand to a temperature of 10 degrees C for 5 minutes, it is possible to distinguish patients with Raynaud's phenomenon from normal controls on the basis of extent of digital artery closure. The mean fall in digital artery diameter on cold challenge, expressed as a percentage of the original diameter, was 92.4% (S.D. = 16.4, S.E.M. = 2.1) in patients with Raynaud's phenomenon as against 8.7% (S.D. = 11.5, S.E.M. = 2.5) in a group of normal volunteers. Using a 45% fall in digital artery diameter as the diagnostic cut-off point, the test has a specificity of 100% and a sensitivity of 96.6% in differentiating patients with Raynaud's phenomenon from controls. It is suggested that the test could be used as objective confirmation of a clinical diagnosis and to assess the efficacy of therapeutic interventions.

Adolescent↗
PubMed1994

Peroxisomal disorders.

Disorders of peroxisome function result in severe and progressive neurologic deficits. Knowledge of these disorders and their role in neurodegenerative disorders has been growing rapidly over the last 40 years. Noninvasive diagnostic tests can identify all of the peroxisomal disorders, many of them prenatally. The genetic basis of some of these peroxisomal disorders is being established, which will advance understanding of their pathobiology and provide clues for therapeutic interventions.

Adolescent↗
PubMed1994

Neurofibromatosis type 1: the evolution of deep gray and white matter MR abnormalities.

PURPOSE: To investigate the evolution of deeply located high-signal-intensity abnormalities of the brain on T2-weighted MR images of patients with neurofibromatosis type 1 (NF-1). METHODS: The study consists of two patient groups: 1) retrospective evaluation of MR scans of 24 symptomatic NF-1 patients, 10 of whom were sequentially studied, and 2) prospective MR evaluations of 20 asymptomatic NF-1 subjects from 14 families; 2 of these families were sequentially studied. RESULTS: Deeply located, high-signal-intensity abnormalities on T2-weighted images were noted in 34 of 44 NF-1 subjects (77%). If NF-1 patients are grouped according to age, 28 of 30 subjects (93%) younger than 15 years had the lesions, whereas 4 of 7 subjects (57%) between 16 and 30 years, and 2 of 7 subjects (29%) older than 31 years had lesions. High-signal lesions in basal ganglia and brain stem were demonstrated in all decades with relatively high frequency. Lesions in the cerebellar white matter and dentate nuclei were mainly found in the patients younger than 10 years, and never found after the third decade. In 13 sequential studies (mean interval, 24 months), lesions appeared to increase in size in 3, remain unchanged in size in 2, and decrease in size in 7. One subject showed a mixed pattern of lesion size change. CONCLUSIONS: Deeply located high-signal-intensity lesions on T2-weighted MR images are more evident in young NF-1 patients. The underlying brain abnormality, while pathologically unproved, is probably transient.

Adolescent↗
PubMed1994

Growth plate matrix vesicle biogenesis. The role of intracellular calcium.

Isolated bovine growth plate chondrocytes suspended in a synthetic cartilage buffer containing 10(-7) to 10(-3) M concentrations of calcium were treated with 1 microM ionomycin to induce changes in intracellular ionized calcium as measured by Fura-2 fluorescence. An increase in intracellular calcium of 10(-6) to 10(-4) M calcium resulted in the secretion of vesicles that contain alkaline phosphatase. An increase in intracellular calcium above 10(-4) M resulted in nonspecific cell fragmentation because of cell damage. Electron microscopy of the secreted vesicles demonstrated that their structure resembled matrix vesicles. Isolated cells treated with ionomycin (synthetic cartilage buffer with 10(-6) M calcium) demonstrated intact cell membranes, normal intracellular architecture, and numerous plasma membrane processes undergoing vesiculation. The plasma membrane of these isolated cells and the isolated vesicles demonstrated a positive stain for alkaline phosphatase. Fresh growth plate tissue demonstrated plasma membrane staining for alkaline phosphatase at the lower proliferative and upper hypertrophic cell zone, and an increasing number of alkaline phosphatase stained matrix vesicles in the matrix of the lower hypertrophic cell zone. The data indicate that an increase in intracellular calcium in the lower proliferative and hypertrophic cell zones of the growth plate induces the secretion of plasma membrane derived matrix vesicles.

Alkaline Phosphatase↗
PubMed1993

Neurochemical alterations in Rett syndrome.

The Rett syndrome (RS) is a neurological disorder associated with severe mental deficiency and neurological manifestations of cortical and extrapyramidal dysfunction. The present report is (1) a postmortem brain study that compares the levels of choline acetyltransferase (ChAT) activity and the binding density of selected neurotransmitter receptors in four cases of RS and five normal controls of similar age and (2) a study of cerebrospinal fluid (CSF) concentrations of the endogenous tridecapeptide neurotensin in 12 RS patients and 8 controls of similar age. The level of ChAT activity was lower in many cortical and subcortical regions in the RS brains as compared to control levels. The number of NMDA, AMPA, mu opioid and neurotensin binding sites, as well as CSF concentrations of neurotensin, did not differ significantly from control levels. The results suggest that changes in specific neurotransmitter systems, particularly cholinergic neurons, in the thalamus, cerebellum and basal ganglia may underlie the progressive deterioration in motor and cognitive function characteristic of this disorder.

Adolescent↗
PubMed1993

Neuroanatomy of Rett syndrome: a volumetric imaging study.

Rett syndrome is a pediatric neurological disorder of unknown etiology defined by the presence of severe neurodevelopment decline, acquired microcephaly, dementia, abnormalities of movement, autistic behavior, and seizures in young female children. In this study, the neuroanatomy of 11 females with Rett syndrome and 15 age- and gender-matched control subjects was investigated in vivo with quantitative neuroimaging techniques. Compared to control subjects, the patients with Rett syndrome were found to have significantly reduced cerebral volume; evidence of greater loss of gray matter in comparison to white matter; regional variation in cortical gray matter, with the frontal regions showing the largest decrease; and reduced volume of the caudate nucleus and midbrain, even when taking into account general reduction in the size of the brain. In addition, there was no evidence of an ongoing degenerative process in this sample of girls with Rett syndrome. The consistency of these data with results from neuropathological investigations points to the need for continued quantitative neuroimaging studies of children with this condition. In particular, research employing serial longitudinal scans of very young children manifesting early signs of the clinical syndrome holds promise for helping to elucidate the neuropathological pathways leading to the debilitating clinical manifestations of Rett syndrome.

Adolescent↗