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Biomedical subjects

Harvey B Sarnat

Publications and source records attributed to Harvey B Sarnat.

At least 19 recordsLinked to original sources
PubMed2006

Bilateral agenesis of the hippocampal dentate gyrus in a neurologically normal adult.

BACKGROUND: Ontogenic development of granule cells in the hippocampal dentate gyrus is influenced by genes including WNT3, EMX2, NEUROD, and LEF1. Dentate granule cells continue to be generated from stem cell precursors postnatally and during adult life, and are implicated in normal and abnormal neurological function. Developmental privation of dentate granule cells is rare and essentially always occurs in the context of other neurodevelopmental abnormalities. We have found no previous reports of severe, selective agenesis of dentate granule cells in humans. METHODS: A gross and microscopic examination of the brain included appropriate histochemical and immunohistochemical preparations and examination of the hippocampal formation at multiple levels bilaterally. RESULTS: This neurologically normal 82-year-old man was found to have bilateral agenesis of the hippocampal dentate gyrus, no identifiable dentate granule cells, and moderate disorganization of the pyramidal cell layer of Ammon's horn. We found no neurodevelopmental abnormalities outside the hippocampus. CONCLUSIONS: The hippocampal architectural alterations in this patient are similar to those associated with a murine Lef1 mutation, but our human case does not have the other congenital deficits reported in the Lef1-null mouse. Bilateral agenesis of the hippocampal dentate gyrus, and apparent failure of regeneration of dentate granule cells from stem cells in adult life, may occur without overt clinical neurological deficits.

Adult↗
PubMed2006

Population meta-analysis of low plasma glucose thresholds in full-term normal newborns.

There is extreme variation in the definition of low plasma glucose levels in newborn infants in the first postnatal days, ranging from < 30 to < or = 60 mg/dL. The goal of the present study was to define low thresholds (< or = 5th percentile) of plasma glucose concentrations in full-term normal newborns during the first 72 hours of life. Population meta-analysis was performed on published studies of neonatal hypoglycemia ascertained by MedLine search. One-way analysis of variance was computed across the studies for each of the following four postnatal time periods: 1 to 2 (physiological nadir), 3 to 23, 24 to 47, and 48 to 72 hours. The estimated < or = 5th percentiles of neonatal hypoglycemia during 1 to 2, 3 to 23, 24 to 47, and 48 to 72 hours after birth were < or = 28, < or = 40, < or = 41, and < or = 48 mg/dL, respectively. Based on this statistical definition, we recommend that low thresholds of plasma glucose levels of 28, 40, and 48 mg/dL be adopted in full-term normal newborns at 1 to 2, 3 to 47, and 48 to 72 hours of life, respectively.

Analysis of Variance↗
PubMed2006

Plasma glucose concentrations in profound neonatal hypoglycemia.

The study goal was to define low thresholds of plasma glucose concentrations that constitute profound hypoglycemia. Population analysis was performed on research publications on neonatal hypoglycemia ascertained by a Medline search. Eligible patients had neurological sequelae associated directly and primarily with hypoglycemia (profound hypoglycemia). Of 89 infants, more than 95% had plasma glucose levels of less than 25 mg/dL that were first detected at more than 10 hours of age. A breakdown of study patients according to those with or without neurological sequelae, who were exposed to a similar degree of hypoglycemia, showed a combined incidence of neurological injury of 21%, with 95% confidence interval from 14% to 27%.

Blood Glucose↗
PubMed2005

Pathology of mitochondrial encephalomyopathies.

Muscle biopsy provides the best tissue to confirm a mitochondrial cytopathy. Histochemical features often correlate with specific syndromes and facilitate the selection of biochemical and genetic studies. Ragged-red fibres nearly always indicate a combination defect of respiratory complexes I and IV. Increased punctate lipid within myofibers is a regular feature of Kearns-Sayre and PEO, but not of MELAS and MERRF. Total deficiency of succinate dehydrogenase indicates a severe defect in Complex II; total absence of cytochrome-c-oxidase activity in all myofibres correlates with a severe deficiency of Complex IV or of coenzyme-Q10. The selective loss of cytochrome-c-oxidase activity in scattered myofibers, particularly if accompanied by strong succinate dehydrogenase staining in these same fibres, is good evidence of mitochondrial cytopathy and often of a significant mtDNA mutation, though not specific for Complex IV disorders. Glycogen may be excessive in ragged-red zones. Ultrastructure provides morphological evidence of mitochondrial cytopathy, in axons and endothelial cells as well as myocytes. Abnormal axonal mitochondria may contribute to neurogenic atrophy of muscle, a secondary chronic feature. Quantitative determinations of respiratory chain enzyme complexes, with citrate synthase as an internal control, confirm the histochemical impressions or may be the only evidence of mitochondrial disease. Biological and technical artifacts may yield falsely low enzymatic activities. Genetic studies screen common point mutations in mtDNA. The brain exhibits characteristic histopathological alterations in mitochondrial diseases. Skin biopsy is useful for mitochondrial ultrastructure in smooth erector pili muscles and axons; skin fibroblasts may be grown in culture. Mitochondrial alterations occur in many nonmitochondrial diseases and also may be induced by drugs and toxins.

Axons↗
PubMed2005

Embryology of the neural crest: its inductive role in the neurocutaneous syndromes.

Neural crest cells are first recognized at the lateral margin of the neural placode shortly after gastrulation, although they are not committed to their diverse fates until later. After dorsal closure of the neural tube, neural crest cells separate and migrate throughout the embryo to form many structures of ectodermal origin (eg, dorsal root and autonomic ganglia, peripheral nerve sheaths) and mesodermal origin (eg, blood vessels, melanocytes, adipose tissue, membranous bone, connective tissue, most of the ocular globe). Terminal differentiation occurs after migration is complete. Three regions of the neural tube generate neural crest: rhombencephalon, mesencephalon, and prosencephalon, each with a different migratory pattern. The most important genes promoting neural crest differentiation and migration are those with a dorsalizing influence in the vertical axis of the neural tube (eg, PAX3, BMP4, ZIC2), some segmentation genes (eg, WNT1), genes that inhibit neural crest (eg, EGR2), and neural crest-specific differentiating genes (eg, SLUG, SOX10). In the neurocutaneous syndromes, diverse features result from abnormal neural crest differentiation, providing a more encompassing embryologic basis for these disorders than the traditional view that these syndromes are somehow related to skin and brain because both are ectodermal derivatives. Abnormal angiogenesis, areas of abnormal pigmentation that sometimes follow the lines of Blashko, nerve sheath proliferations, disorders of chromaffin tissue, lipomes and benign and malignant tumors are frequent features. Many defective genes in neurocutaneous syndromes have an additional function as tumor suppressors. Interactions between genes associated with these disorders and others essential to neural crest formation, migration, and differentiation, are a likely molecular genetic basis for these diseases. The craniofacial abnormalities associated with many cerebral malformations and cutaneous lesions in some neurocutaneous syndromes emphasize an important inductive role of the neural tube in the development of non-neural tissues, mediated through neural crest.

Cell Differentiation↗
PubMed2005

Neurologic aspects of neonatal hypoglycemia.

Profound neonatal hypoglycemia is one of the leading causes of brain injury. Hypoglycemic encephalopathy is caused by lack of glucose availability to brain cells. Although sharing a similar pathogenesis with hypoxic-ischemic encephalopathy, hypoglycemic brain insult has distinctive metabolic, brain imaging, electroencephalographic and histopathologic findings.

Brain Diseases↗
PubMed2004

Integrative classification of morphology and molecular genetics in central nervous system malformations.

We propose a scheme to classify central nervous system (CNS) malformations that integrates morphology and genetics by using patterns of genetic expression as its basis. The precise genetic mutations are not necessary to know in all cases. The premises of this classification are (1) genetic expression in the neural tube follows gradients in the axes that are established at the time of gastrulation: vertical (dorsoventral and ventrodorsal); rostrocaudal; mediolateral. (2) Overexpression in one of these gradients generally results in duplication or hyperplasia of structures, or ectopic segmental (i.e., neuromeric) expression. (3) Underexpression in a gradient generally results in hypoplasia, noncleavage in the midline of paired structures or segmental deletion of neuromeres. These gradients may also affect the formation and migration of neural crest tissue, affecting non-neural structures such as the face in the case of the mesencephalic neural crest, or induction of paraxial mesodermal in the posterior fossa. Additional criteria of the new classification allow for other genetic influences on developmental processes, such as cellular lineage, exemplified by tuberous sclerosis, and hemimegalencephaly. It is essential that the CNS be considered as a whole and classification not be regionalized, as to the cerebral cortex, because the limit of the rostrocaudal gradient may account for variability in clinical manifestations.

Central Nervous System↗
PubMed2004

Watershed infarcts in the fetal and neonatal brainstem. An aetiology of central hypoventilation, dysphagia, Möibius syndrome and micrognathia.

Watershed zone infarcts of the human cerebral cortex at the overlapping junctions of the anterior and middle cerebral arterial territories are well known. Another watershed zone exists in the brainstem tegmentum, between the terminal perfusion zones of the paramedian penetrating and long circumferential arteries, which are paired segmental vessels arising from the basilar artery. The vertebrobasilar circulation achieves its mature configuration and caudorostral flow by 9 weeks gestation. Systemic hypotension and other conditions of reduced basilar perfusion in the fetus, either early or late in gestation, may result in symmetrical longitudinal columns of infarction in the midbrain and tegmentum of the pons and medulla oblongata and laminar necrosis of the midbrain tectum. Within this zone are cranial nerve nuclei III-XII, the nucleus and tractus solitarius or central pneumotaxic center, as well as the nucleus ambiguus and other somatic motor nuclei that subserve muscles of swallowing, mastication and tongue movement. Watershed infarcts in the human fetal and neonatal brainstem are clinically expressed as multiple cranial neuropathies, failure of central respiratory drive and apnea, dysphagia and aspiration, Möbius syndrome and Pierre Robin sequence. MRI is sometimes helpful, but most of the involved neuroanatomical structures are beneath the resolution of present imaging techniques, and the diagnosis during life depends upon clinical neurological examination of the neonate, sometimes supported by evoked potential studies. Postmortem examination confirms the diagnosis and dates the lesions, but also contributes to better understand transient or persistent vascular insufficiencies in the fetal and neonatal brainstem.

Brain Stem Infarctions↗
PubMed2004

Lack of long-term histopathologic changes in brain and skeletal muscle of mice treated with a ketogenic diet.

Although there is increasing awareness of adverse effects associated with use of the high-fat ketogenic diet, very little is known regarding its long-term clinical consequences, especially in relation to cardiovascular health. Recent reports have highlighted rare but significant cardiac problems in patients treated with the ketogenic diet. Given the inherent limitations in conducting detailed pathologic assessments in patients, we asked whether histologic changes might develop in the brain and skeletal muscle of mice fed a high-fat diet for 2 to 3 months. We found no evidence of gross morphologic or histochemical alterations in muscle or brain after administration of the ketogenic diet. Further, there was no abnormal lipid storage or mitochondrial enzymatic staining. Our data suggest that patients chronically treated with a ketogenic diet are not likely to develop a lipid myopathy or neuronal inclusions.

Animals↗
PubMed2003

Probing striated muscle mitochondrial phenotype in neuromuscular disorders.

Multisystemic disorders with predominantly neurologic manifestations often present with mitochondrial abnormalities in striated muscle biopsies. Decreased respiratory complex activities and abnormalities in mitochondrial structure and DNA constitute the spectrum of mitochondrial changes used as diagnostic and prognostic indicators in patients with neuromuscular disorders. This study assessed mitochondrial defects present in a cohort of 154 young patients to determine diagnostic efficiency and probe the relationship of mitochondrial to clinical phenotype. Striated muscle biopsies were analyzed for mitochondrial structure and number, levels of enzyme activities of complex I-V and citrate synthase, mitochondrial DNA and specific mitochondrial DNA deletions, and presence of 15 pathogenic mitochondrial DNA point mutations. Reduced complex I, III, IV, and V activities were the most ubiquitous finding, with complex III most commonly affected. Mitochondrial structural defects (39%) included changes in mitochondria sizes/shapes and number and aberrant cristae formation. Mitochondrial DNA deletions were evident in 15 patients, three displayed mitochondrial DNA depletion, and only two harbored pathogenic point mutations. Reductions in specific enzyme activities may be the most sensitive diagnostic indicator, whereas defects in ultrastructure and mitochondrial DNA integrity were frequently accompanied by the full spectrum of mitochondrial abnormalities. Some phenotypes displayed specific mitochondrial abnormalities; however, most clinical phenotypes displayed little specificity with regard to mitochondrial phenotype.

Adolescent↗