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Biomedical subjects

M J Berg

Publications and source records attributed to M J Berg.

At least 19 recordsLinked to original sources
PubMed2001

Opposite effects of lithium on proximal and distal caspases of immature and mature primary neurons correlate with earlier paradoxical actions on viability.

To provide an explanation for earlier paradoxical findings of lithium on survival of mature and immature neurons, this study monitors changes in cytosolic caspases in rat cerebellar granule cells (CGC) grown 2-7 days in vitro (DIV), or in murine E-17 cortical neurons. Data show Li+ protects mature 7-DIV CGC parallel to a decrease in proximal and distal caspases but increases levels for immature 2-DIV-CGC or E-17 cortical neurons. Caspases mirror viability based on morphological analyses (dye uptake, phase-contrast, DNA fragmentation), and suggest protection occurs by suppressing activation of a cascade resulting in distal effectors that destroy proteins essential for neuronal survival. Protection was dose-dependent with EC50 3.0 mM and extended to 64 h in K+-serum deprived apoptotic media. Neuronal extracts contain a spectrum of proximal (-2, -8, -9) and distal (-3, -6) caspases sensitive to Li+ on assay with preferred peptide substrates and by immunoblotting. The lack of direct effect on activated cytosols indicates Li+ acts upstream only on intact cells, at sites for recruitment of pivotal procaspases. Alterations of procaspase-9 p46 and membrane-bound cytochrome c (Apaf-1) point to interaction with an intrinsic Mt-mediated pathway as one of the targets. The opposite effects on caspases and viability of immature or embryological neurons point to existence of alternative pathways that alter during neurite outgrowth suggesting the use of Li+ as a probe to unravel events relevant to neurogenesis.

Animals↗
PubMed2001

Differential expression of carnosine, homocarnosine and N-acetyl-L-histidine hydrolytic activities in cultured rat macroglial cells.

N-acetyl-L-histidine (NAH) and N-acetyl-L-aspartate (NAA) are representatives of two series of substances that are synthesized by neurons and other cells in the vertebrate central nervous system (CNS). Histidine containing homologs of NAH are beta-alanyl-L-histidine or carnosine (Carn) and gamma-aminobutyrl-L-histidine or homocarnosine (Hcarn). A homolog of NAA is N-acetylaspartylglutamate (NAAG). These substances belong to a unique group of osmolytes in that they are synthesized in cells that may not to be able to hydrolyze them, and are released in a regulated fashion to a second compartment where they can be rapidly hydrolyzed. In this investigation, the catabolic activities for NAH, Carn, and Hcarn in cultured macroglial cells and neurons have been measured, and the second compartment for NAH and Hcarn has been identified only with astrocytes. In addition, oligodendrocytes can only hydrolyze Carn, although Carn can also be hydrolyzed by astrocytes. Thus, astrocytes express hydrolytic activity against all three substrates, but oligodendrocytes can only act on Carn. The cellular separation of these hydrolytic enzyme activities, and the possible nature of the enzymes involved are discussed.

Amidohydrolases↗
PubMed2000

Pharmacogenetic screening for susceptibility to fetal malformations in women.

OBJECTIVE: To present a review of the literature and research on the pharmacogenetics of congenital defects, with a focus on the need for predictive maternal genotype assays. DATA SOURCE: MEDLINE searches (January 1985-January 1999), past reference reviews, and unpublished research. STUDY SELECTION: Review of relevant human, animal, and basic science studies. DATA EXTRACTION: Data on research on polymorphisms, genotyping, cytochrome P450 enzyme systems, epoxide hydrolase, folate metabolism, metabolism of anticonvulsant medications, molecular genetics of neural tube defects, variations in drug metabolism, and environmental exposures were evaluated. DATA SYNTHESIS: Data synthesis includes not only a review of the literature but suggests ways such data might be used to facilitate the development of maternal genotype assays, with the goal of preventing birth defects. CONCLUSIONS: Individuals vary in how they metabolize drugs and handle toxic environmental exposures. In an ideal pregnancy, there is no or limited exposure to medications and environmental agents. However, in women with chronic medical conditions such as heart disease and seizures, this is often not possible. Unfortunately, no techniques have been available to identify those at risk in this population. Gene polymorphisms for a specific enzyme may result in an absence or reduction in the level of enzyme activity or in no change at all, with little effect on the structure/function of the gene product(s); they are not associated with clinical phenotypes in either the mother or the fetus. Other polymorphisms may be only markers. Thus, developing genotyping assays for women that are predictive of phenotype expression in the fetus is the key to screening for polymorphisms. As more mutations are identified and clinical, pharmacologic, biologic, and pharmacokinetic relationships are established, using these polymorphisms to develop a genotyping assay for women may become a clinical reality, possibly leading to preventive prepregnancy or prenatal treatment that may play an increasingly effective role in maternal care.

Congenital Abnormalities↗
PubMed2000

Genetic and neuroradiological heterogeneity of double cortex syndrome.

Mutations in the X-linked doublecortin gene appear in many sporadic cases of double cortex (DC; also known as subcortical band heterotopia), a neuronal migration disorder causing epilepsy and mental retardation. The purpose of this study was to examine why a significant percentage of sporadic DC patients had been found not to harbor doublecortin mutations and to determine whether clinical features or magnetic resonance imaging scan appearance could distinguish between patients with and without doublecortin mutations. Magnetic resonance imaging scan analysis differentiated patients into the following four groups: anterior biased/global DC with doublecortin mutation (16 of 30; 53%), anterior biased/global DC without mutation (8 of 30; 27%), posterior biased DC without mutation (3 of 30; 10%), and limited/unilateral DC without mutation (3 of 30; 10%). The presence of these atypical phenotypes suggests that other genetic loci or mosaicism at the doublecortin locus may be responsible for this diversity of DC cases.

Adolescent↗
PubMed1999

Characterization of mutations in the gene doublecortin in patients with double cortex syndrome.

Mutations in the X-linked gene doublecortin, which encodes a protein with no dear structural homologues, are found in pedigrees in which affected females show "double cortex" syndrome (DC; also known as subcortical band heterotopia or laminar heterotopia) and affected males show X-linked lissencephaly. Mutations in doublecortin also cause sporadic DC in females. To determine the incidence of doublecortin mutations in DC, we investigated a cohort of eight pedigrees and 47 sporadic patients with DC for mutations in the doublecortin open reading frame as assessed by single-stranded conformational polymorphism analysis. Mutations were identified in each of the eight DC pedigrees (100%), and in 18 of the 47 sporadic DC patients (38%). Identified mutations were of two types, protein truncation mutations and single amino acid substitution mutations. However, pedigrees with DC displayed almost exclusively single amino acid substitution mutations, suggesting that patients with these mutations may have less of a reproductive disadvantage versus those patients with protein truncation mutations. Single amino acid substitution mutations were tightly clustered in two regions of the open reading frame, suggesting that these two regions are critical for the function of the Doublecortin protein.

Brain Diseases↗
PubMed1999

Recent advances on neuronal caspases in development and neurodegeneration.

In view of a large and growing literature, this overview emphasizes recent advances in neuronal caspases and their role in cell death. To provide historical perspective, morphology and methods are surveyed with emphasis on early studies on interleukin converting enzyme (ICE) as a prototype for identifying zymogen subunits. The unexpected homology of ICE (caspase-1) to Caenorhabditis elegans death gene CED-3 provided early clues linking caspases to programmed cell death, and led later to discovery of bcl-2 proteins (CED-9 homologs) and 'apoptosis associated factors' (Apafs). Availability of substrates, inhibitors, and cDNAs led to identification of up to 16 caspases as a new superfamily of unique cysteine proteinases targeting Asp groups. Those acting as putative death effectors dismantle neurons by catabolism of proteins essential for survival. Caspases degrade amyloid precursor protein (APP), presenilins (PS1, PS2), tau, and huntingtin, raising questions on their role in neurodegeneration. Brain contains 'inhibitors of apoptosis proteins' (IAPs) survivin and NAIP associated also with some neuronal disorders. Apoptotic stress in neurons initiates a chain of events leading to activation of distal caspases by pathways that remain to be fully mapped. Neuronal caspases play multiple roles for initiation and execution of cell death, for morphogenesis, and in non-mitotic neurons for homeostasis. Recent studies focus on cytochrome c as pivotal in mediating conversion of procaspase-9 as a major initiator for apoptosis. Identifying signaling pathways and related events paves the way to design useful therapeutic remedies to prevent neuronal loss in disease or aging.

Animals↗
PubMed1999

Gangliosides attenuate ethanol-induced apoptosis in rat cerebellar granule neurons.

Ethanol significantly enhances cell death of differentiated rat cerebellar granule neurons on culture in a serum-free medium containing a depolarizing concentration of KCl (25 mM), 5 microM MK-801 (an NMDA receptor antagonist), and 20-200 mM ethanol for 1-4 days. Cell death augmented by ethanol was concentration- and time-dependent with neurons displaying hallmark apoptotic morphology and DNA fragmentation that correlated with the activation of cytosolic caspase-3. Inclusion of 5 microM MK-801 or 100 microM glycine in culture media did not alter rates of cell death indicating ethanol toxicity is mediated via an NMDA receptor-independent pathway. Preincubation with 50 microM gangliosides GM1, GD1a, GD1b or GT1b for 2 h, or preincubation with 10 microM LIGA20 (a semisynthetic GM1 with N-dichloroacetylsphingosine) for 10 min, attenuated caspase-3 activity and ethanol-induced cell death. Data show native gangliosides and a synthetic derivative are potently neuroprotective in this model of ethanol toxicity, and potentially serve as useful probes to further unravel the mechanisms relevant to neuronal apoptosis.

Animals↗
PubMed1998

The semisynthetic glycosphingolipid LIGA20 potently protects neurons against apoptosis.

LIGA20 (a semisynthetic GM1 with n-dichloroacetyl sphingosine) having antinecrotic properties was evaluated as an antiapoptotic agent using cerebellar granule cells as a neuronal model. Neurons exposed to medium containing 5 mM K+ in absence of serum (apoptotic medium) for up to 22 h resulted in 65% cell death, accompanied by oligonucleosomal laddering, and a 15-fold-increase in caspase-3 activity. The relationships between times required for enzyme activation and cell death suggests a linkage between these two events. Pretreatment with 10 microM LIGA20 for 10 min significantly attenuated the aforementioned apoptotic changes. LIGA20 also attenuated apoptosis induced by Pb2+, ethanol, and C6-ceramide. Data show that LIGA20 is a versatile neuroprotective agent protecting cells from multiple pathways of cell death.

Animals↗
PubMed1998

Activation of caspase-3 and apoptosis in cerebellar granule cells.

Caspase-3 activity increased dramatically in cytosolic extracts of rat cerebellar granule cells exposed to apoptotic conditions (basal medium Eagle (BME) containing 5 mM K+ without serum) when assayed with Ac-DEVD-amc, but not with Ac-YVAD-afc, a preferred substrate for caspase-1. This provided a basis to examine relationships between enzyme activity and cell viability for purposes of selecting an optimal time for comparing neuroprotective agents or strategies. Exposure of neurons to an apoptotic medium containing 5 mM K+ in absence of serum led to a rapid 5- to 10-fold increase in caspase-3 within 2-4 hr but without significant cell loss, or morphological alterations. Exposure to apoptotic medium followed by replacement with maintenance medium containing 25 mM K+ and serum led to a rapid fall in caspase-3 and prevention of cell death. This strategy was not effective after 13 hr exposure despite a large fall in enzyme activity. These temporal changes infer systems for rapid enzyme turnover and/or activation of cytoplasmic components linked to later DNA degradation. The effects of cycloheximide point to requirements for protein synthesis, and those of Glu exclude a caspase-3 dependent pathway for necrotic cell damage. Brief treatment with 10 microM LIGA20, an anti-necrotic agent, also attenuated cell loss and caspase-3 activity, indicating a broad spectrum of neuroprotection. Rapid and long-lasting effects, together with its biophysical properties, suggest that this semisynthetic ganglioside acted upstream at or near a membrane site. As such, gangliosides provide useful agents to further probe pathways relevant to neuronal death in culture.

Animals↗
PubMed1998

Failure of standard magnetic resonance imaging in patients with refractory temporal lobe epilepsy.

OBJECTIVE: To compare the sensitivity of standard magnetic resonance imaging (MRI) scans done outside an epilepsy center with that of special protocol MRI scans done at an epilepsy center in delineating relevant lesions of the temporal lobe. SUBJECTS: Eighty-four consecutive patients who had temporal lobe resections for refractory temporal lobe epilepsy between January 1, 1993, and February 1, 1996. DESIGN: The reports of findings on standard MRI scans done outside an epilepsy center were compared with the findings of special protocol MRI scans done with 1.5-mm T1-weighted coronal and 3-mm T2-weighted coronal images (no gaps) on a 1.5-T system. Both sets of MRI findings were compared with findings on histologic examination of the resected tissue. RESULTS: Of the 84 patients, 51 had standard MRI scans done outside an epilepsy center; of these, there were 34 patients with normal results, 10 with tumors, 2 with vascular malformations, 2 with hippocampal atrophy, 2 with unclassified abnormalities, and 1 with cortical malformation. In 32 of the 34 patients with normal results of an MRI scan done outside an epilepsy center, abnormalities were found on our special protocol MRI scans. These included hippocampal atrophy in 27 patients, tumors in 2, and cortical malformations in 1. Additionally, all 17 of the abnormalities detected on the standard MRI scans done outside the epilepsy center were identified on our special protocol MRI scans. Important pathologic abnormalities of the temporal lobe were identified in 16 (35%) of the 46 patients with standard MRI scans done outside an epilepsy center and in 44 (96%) with our special protocol MRI scans. In the 29 patients for whom adequate surgical specimens were available and results of standard MRI scans were normal, our special protocol MRI scans showed the abnormality in 27 (93%). CONCLUSIONS: Conventional neuroimaging studies are inadequate for diagnosing hippocampal sclerosis although they fairly readily detect low-grade tumors and vascular malformations. Magnetic resonance imaging scans for the evaluation of patients with refractory temporal lobe epilepsy should be done with a special temporal lobe protocol and read by physicians experienced with the findings in hippocampal sclerosis. Health care dollars are wasted on neuroimaging done for refractory temporal lobe epilepsy outside epilepsy centers.

Atrophy↗
PubMed1998

Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27.

Cerebral cavernous malformation (CCM) is a Mendelian model of stroke, characterized by focal abnormalities in small intracranial blood vessels leading to hemorrhage and consequent strokes and/or seizures. A significant fraction of cases is inherited as an autosomal dominant trait with incomplete penetrance. Among Hispanic Americans, virtually all CCM is attributable to a founder mutation localized to 7q ( CCM1 ). Recent analysis of non-Hispanic Caucasian kindreds, however, has excluded linkage to 7q in some, indicating at least one additional CCM locus. We now report analysis of linkage in 20 non-Hispanic Caucasian kindreds with familial CCM. In addition to linkage to CCM1, analysis of linkage demonstrates linkage to two new loci, CCM2 at 7p13-15 and CCM3 at 3q25.2-27. Multilocus analysis yields a maximum lod score of 14.11, with 40% of kindreds linked to CCM1, 20% linked to CCM2 and 40% linked to CCM3, with highly significant evidence for linkage to three loci (linkage to three loci supported with an odds ratio of 2.6 x 10(5):1 over linkage to two loci and 1.6 x 10(9):1 over linkage to one locus). Multipoint analysis among families with high posterior probabilities of linkage to each locus refines the locations of CCM2 and CCM3 to approximately 22 cM intervals. Linkage to these three loci can account for inheritance of CCM in all kindreds studied. Significant locus-specific differences in penetrance are identified. These findings have implications for genetic testing of this disorder and represent an important step toward identification of the molecular basis of this disease.

Cerebrovascular Disorders↗
PubMed1998

X-linked female band heterotopia-male lissencephaly syndrome.

We report a family with band heterotopia in a mother and daughter and lissencephaly in a son (X-linked inheritance pattern). Postmortem examination of the boy revealed classical lissencephaly and, among other findings, simplified and discontinuous inferior olives without inferior olivary heterotopia. The absence of inferior olivary heterotopia may distinguish X-linked lissencephaly from other conditions with classic lissencephaly such as Miller-Dieker syndrome.

Adult↗
PubMed1998

Drug and environmental factors associated with adverse pregnancy outcomes. Part II: Improvement with folic acid.

OBJECTIVE: To provide a comprehensive review of periconceptional folic acid supplementation and factors affecting folate supplementation trials. DATA SOURCES: A MEDLINE search was conducted through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included folate, folic acid, neural tube defect, spina bifida, and anencephaly. STUDY SELECTION: Relevant animal and human studies examining the effects of folate were reviewed. DATA EXTRACTION: Data collected included: type of study, folate dosing, dietary folate intake, serum and red blood cell folate concentrations, type of defect(s) studied, vitamin usage, parental risk factors, factors affecting trial results. DATA SYNTHESIS: Nine key factors have been identified that affect outcomes of folic acid supplementation trials. Daily doses of 0.8 mg decreased the occurrence and doses of 4 mg decreased the recurrence of neural tube defects in randomized clinical trials. Since lower folic acid doses were effective in nonrandomized trials, research is needed to determine the lowest effective dosage. Other benefits involving pregnancy outcome are suggested. CONCLUSIONS: Women of childbearing age should take a daily folic acid supplement to reduce the risk of pregnancies resulting in infants with a neural tube defect and other potential adverse pregnancy outcomes. Further health benefits from folic acid supplementation are reviewed in Part III of this series.

Animals↗
PubMed1998

Drug and environmental factors associated with adverse pregnancy outcomes. Part III: Folic acid: pharmacology, therapeutic recommendations, and economics.

OBJECTIVE: To review folic acid's mechanism of action, adverse effects, therapeutic recommendations, compliance, and cost. DATA SOURCES: A MEDLINE search was conducted through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included folate, folic acid, neural tube defect, homocysteine, and methylenetetrahydrofolate reductase. STUDY SELECTION: Animal and human studies examining the effects of folate were reviewed. DATA EXTRACTION: Data collected included mechanism of action, safety issues, dosing recommendations, compliance with recommendations, and economics. DATA SYNTHESIS: Folic acid decreases neural tube defect risk through an effect on methionine-homocysteine metabolism. In addition, increased folate intake may reduce cardiovascular morbidity and mortality. Since toxicity is minimal, everyone can potentially benefit from increased folate consumption. To help achieve this, the Food and Drug Administration has mandated that cereal grain be fortified with 140 micrograms of folic acid per 100 g of grain, which will add approximately 0.1 mg of folate to the average diet. Studies recommend supplementing with 0.2 mg to promote optimal homocysteine concentrations and for preventing neural tube defects. CONCLUSIONS: Despite fortification, most women will still receive less folate than the 0.4 mg/d recommended by the Public Health Service. All population groups would benefit from increased folate intake. Current studies indicate 200 micrograms/d may be the minimum effective amount of fortification needed for normalizing homocysteine concentrations and preventing a significant number of neural tube defects; thus, a higher level of food fortification may be warranted.

Environmental Exposure↗