Bermans J. Iskandar
University of Wisconsin-Madison
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Featured researches published by Bermans J. Iskandar.
Nature Neuroscience | 2001
Howard M. Bomze; Ketan R. Bulsara; Bermans J. Iskandar; Pico Caroni; J. H. Pate Skene
In contrast to peripheral nerves, damaged axons in the mammalian brain and spinal cord rarely regenerate. Peripheral nerve injury stimulates neuronal expression of many genes that are not generally induced by CNS lesions, but it is not known which of these genes are required for regeneration. Here we show that co-expressing two major growth cone proteins, GAP-43 and CAP-23, can elicit long axon extension by adult dorsal root ganglion (DRG) neurons in vitro. Moreover, this expression triggers a 60-fold increase in regeneration of DRG axons in adult mice after spinal cord injury in vivo. Replacing key growth cone components, therefore, could be an effective way to stimulate regeneration of CNS axons.
Journal of Veterinary Internal Medicine | 2006
Clare Rusbridge; Dan Greitz; Bermans J. Iskandar
Syringomyelia is a condition that results in fluid-containing cavities within the parenchyma of the spinal cord as a consequence of altered cerebrospinal fluid dynamics. This review discusses the history and the classification of the disorder, the current theories of pathogenesis, and the advanced imaging modalities used in the diagnosis. The intramedullary pulse pressure theory (a new pathophysiologic concept of syringomyelia) also is presented. In addition, the current understanding of the painful nature of this condition is discussed and the current trends in medical and surgical management are reviewed.
Environmental Health Perspectives | 2006
Abee L. Boyles; Ashley V. Billups; Kristen L. Deak; Deborah G. Siegel; Lorraine Mehltretter; Susan Slifer; Alexander G. Bassuk; John A. Kessler; Michael C. Reed; H. Frederik Nijhout; Timothy M. George; David S. Enterline; John R. Gilbert; Marcy C. Speer; Joanna Aben; A. Alysworth; Joann Bodurtha; Timothy Brei; Connie Buran; Bermans J. Iskandar; Joy Ito; Nicole Lasarsky; Philip Mack; Elli Meeropol; Joanne Mackey; David G. McLone; W. J. Oakes; Cynthia M. Powell; Kathleen Sawin; Michael Walker
Background Folate metabolism pathway genes have been examined for association with neural tube defects (NTDs) because folic acid supplementation reduces the risk of this debilitating birth defect. Most studies addressed these genes individually, often with different populations providing conflicting results. Objectives Our study evaluates several folate pathway genes for association with human NTDs, incorporating an environmental cofactor: maternal folate supplementation. Methods In 304 Caucasian American NTD families with myelomeningocele or anencephaly, we examined 28 polymorphisms in 11 genes: folate receptor 1, folate receptor 2, solute carrier family 19 member 1, transcobalamin II, methylenetetrahydrofolate dehydrogenase 1, serine hydroxymethyl-transferase 1, 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homo-cysteine methyltransferase, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase, betaine-homocysteine methyltransferase (BHMT), and cystathionine-beta-synthase. Results Only single nucleotide polymorphisms (SNPs) in BHMT were significantly associated in the overall data set; this significance was strongest when mothers took folate-containing nutritional supplements before conception. The BHMT SNP rs3733890 was more significant when the data were stratified by preferential transmission of the MTHFR rs1801133 thermolabile T allele from parent to offspring. Other SNPs in folate pathway genes were marginally significant in some analyses when stratified by maternal supplementation, MTHFR, or BHMT allele transmission. Conclusions BHMT rs3733890 is significantly associated in our data set, whereas MTHFR rs1801133 is not a major risk factor. Further investigation of folate and methionine cycle genes will require extensive SNP genotyping and/or resequencing to identify novel variants, inclusion of environmental factors, and investigation of gene–gene interactions in large data sets.
Journal of Clinical Investigation | 2010
Bermans J. Iskandar; Elias Rizk; Brenton Meier; Nithya Hariharan; Teodoro Bottiglieri; Richard H. Finnell; David F. Jarrard; Ruma Banerjee; J. H. Pate Skene; Aaron D. Nelson; Nirav Patel; Carmen Gherasim; Kathleen Simon; Thomas Cook; Kirk Hogan
The folate pathway plays a crucial role in the regeneration and repair of the adult CNS after injury. Here, we have shown in rodents that such repair occurs at least in part through DNA methylation. In animals with combined spinal cord and sciatic nerve injury, folate-mediated CNS axon regeneration was found to depend on injury-related induction of the high-affinity folate receptor 1 (Folr1). The activity of folate was dependent on its activation by the enzyme dihydrofolate reductase (Dhfr) and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons was biphasic and dose dependent and correlated closely over its dose range with global and gene-specific DNA methylation and with expression of both the folate receptor Folr1 and the de novo DNA methyltransferases. These data implicate an epigenetic mechanism in CNS repair. Folic acid and possibly other nontoxic dietary methyl donors may therefore be useful in clinical interventions to promote brain and spinal cord healing. If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries.
American Journal of Medical Genetics Part A | 2006
Abee L. Boyles; David S. Enterline; Preston Hammock; Deborah G. Siegel; Susan Slifer; Lorraine Mehltretter; John R. Gilbert; Diane Hu-Lince; Dietrich A. Stephan; Ulrich Batzdorf; Edward C. Benzel; Richard G. Ellenbogen; Barth A. Green; Roger W. Kula; Arnold H. Menezes; Diane M. Mueller; John J. Oro; Bermans J. Iskandar; Timothy M. George; Thomas H. Milhorat; Marcy C. Speer
Chiari type I malformation (CMI; OMIM 118420) is narrowly defined when the tonsils of the cerebellum extend below the foramen magnum, leading to a variety of neurological symptoms. It is widely thought that a small posterior fossa (PF) volume, relative to the total cranial volume leads to a cramped cerebellum and herniation of the tonsils into the top of the spinal column. In a collection of magnetic resonance imagings (MRIs) from affected individuals and their family members, we measured correlations between ten cranial morphologies and estimated their heritability in these families. Correlations between bones delineating the PF and significant heritability of PF volume (0.955, P = 0.003) support the cramped PF theory and a genetic basis for this condition. In a collection of 23 families with 71 affected individuals, we performed a genome wide linkage screen of over 10,000 SNPs across the genome to identify regions of linkage to CMI. Two‐point LOD scores on chromosome 15 reached 3.3 and multipoint scores in this region identified a 13 cM region with LOD scores over 1 (15q21.1‐22.3). This region contains a biologically plausible gene for CMI, fibrillin‐1, which is a major gene in Marfan syndrome and has been linked to Shprintzen–Goldberg syndrome, of which CMI is a distinguishing characteristic. Multipoint LOD scores on chromosome 9 maximized at 3.05, identifying a 40 cM region with LOD scores over 1 (9q21.33‐33.1) and a tighter region with multipoint LOD scores over 2 that was only 8.5 cM. This linkage evidence supports a genetic role in Chiari malformation and justifies further exploration with fine mapping and investigation of candidate genes in these regions.
Spine | 2002
Ketan R. Bulsara; Bermans J. Iskandar; Alan T. Villavicencio; J. H. P. Skene
Introduction. Neurons surviving spinal cord injury undergo extensive reorganization that may result in the formation of functional synaptic contacts. Many neurons, however, fail to activate the necessary mechanisms for successful regeneration. In this review, we discuss the implications of growth cone genes that we have correlated with successful spinal cord axonal regeneration. Method. Factors that inhibit regeneration, and activation of genes that promote it are discussed. Results/Discussion. The early progress n understanding mechanisms that seem to promote or inhibit regeneration in the central nervous system may have significant clinical utility in the future.
Annals of Neurology | 2004
Bermans J. Iskandar; Aaron D. Nelson; Daniel K. Resnick; J. H. Pate Skene; Peng Gao; Chenara Johnson; Thomas Cook; Nithya Hariharan
Folic acid supplementation has proved to be extremely effective in reducing the occurrence of neural tube defects (NTDs) and other congenital abnormalities in humans, suggesting that folic acid can modulate key mechanisms for growth and differentiation in the central nervous system (CNS). To prevent NTDs, however, supplemental folate must be provided early in gestation. This suggests that the ability of folic acid to activate growth and differentiation mechanisms may be confined to the early embryonic period. Here, we show that folic acid can enhance growth and repair mechanisms even in the adult CNS. Using lesion models of CNS injury, we found that intraperitoneal treatment of adult rats with folic acid significantly improves the regrowth of sensory spinal axons into a grafted segment of peripheral nerve in vivo. Regrowth of retinal ganglion cell (RGC) axons into a similar graft also was enhanced, although to a smaller extent than spinal axons. Furthermore, folic acid supplementation enhances neurological recovery from a spinal cord contusion injury, showing its potential clinical impact. The results show that the effects of folic acid supplementation on CNS growth processes are not restricted to the embryonic period, but can also be effective for enhancing growth, repair, and recovery in the injured adult CNS. Ann Neurol 2004;56:221–227
Journal of Biomechanical Engineering-transactions of The Asme | 2010
Bryn A. Martin; Richard Labuda; Thomas J. Royston; John N. Oshinski; Bermans J. Iskandar; Francis Loth
Full explanation for the pathogenesis of syringomyelia (SM), a neuropathology characterized by the formation of a cystic cavity (syrinx) in the spinal cord (SC), has not yet been provided. It has been hypothesized that abnormal cerebrospinal fluid (CSF) pressure, caused by subarachnoid space (SAS) flow blockage (stenosis), is an underlying cause of syrinx formation and subsequent pain in the patient. However, paucity in detailed in vivo pressure data has made theoretical explanations for the syrinx difficult to reconcile. In order to understand the complex pressure environment, four simplified in vitro models were constructed to have anatomical similarities with post-traumatic SM and Chiari malformation related SM. Experimental geometry and properties were based on in vivo data and incorporated pertinent elements such as a realistic CSF flow waveform, spinal stenosis, syrinx, flexible SC, and flexible spinal column. The presence of a spinal stenosis in the SAS caused peak-to-peak cerebrospinal fluid CSF pressure fluctuations to increase rostral to the stenosis. Pressure with both stenosis and syrinx present was complex. Overall, the interaction of the syrinx and stenosis resulted in a diastolic valve mechanism and rostral tensioning of the SC. In all experiments, the blockage was shown to increase and dissociate SAS pressure, while the axial pressure distribution in the syrinx remained uniform. These results highlight the importance of the properties of the SC and spinal SAS, such as compliance and permeability, and provide data for comparison with computational models. Further research examining the influence of stenosis size and location, and the importance of tissue properties, is warranted.
Clinical Genetics | 1999
Marcy C. Speer; Jeffrey S. Nye; David G. McLone; Gordon Worley; Elizabeth C. Melvin; Kristi D. Viles; Amy Franklin; Courtney R. Drake; Joanne Mackey; Timothy M. George; David S. Enterline; Herbert E. Fuchs; Robert D. Fitch; Jeffery M. Vance; Margaret A. Pericak-Vance; W. Jerry Oakes; Colleen McLaughlin; Cindy Powell; Arthur S. Aylsworth; Marion L. Walker; Paula Peterson; Timothy Brei; Connie Buran; Bonnie Ohm; Bermans J. Iskandar
Neural tube defects are a common, complex disorder with genetic and environmental components to risk. We investigated the previously reported interaction between homozygosity for the thermolabile variant at the methylenetetrahydrofolate reductase and heterozygosity for the 844ins68 allele at the cystathionine β‐synthase loci in cases with lumbosacral myelomeningocele and their parents. Using control allele frequencies from our sample pooled with those published in the literature, we confirm a marginally significant interaction at these two loci. This finding suggests that additional, larger studies are warranted to investigate this possible interaction in more detail.
Birth Defects Research Part A-clinical and Molecular Teratology | 2008
Kristen L. Deak; Deborah G. Siegel; Timothy M. George; Simon G. Gregory; Allison E. Ashley-Koch; Marcy C. Speer; Joanna Aben; Arthur S. Aylsworth; Cynthia M. Powell; Joanne Mackey; Gordon Worley; Timothy Brei; Connie Buran; Joann Bodurtha; Kathleen Sawin; Mark S. Dias; Philip Mack; Elli Meeropol; Nicole Lasarsky; David G. McLone; Joy Ito; W. Jerry Oakes; Marion L. Walker; Paula Peterson; Bermans J. Iskandar
BACKGROUND Neural tube defects (NTDs), including spina bifida and anencephaly, are the second most common birth defect with an incidence of 1/1000. Genetic factors are believed to contribute to NTD risk and family-based studies can be useful for identifying such risk factors. METHODS We ascertained 1066 NTD families (1467 affected patients), including 307 multiplex NTD families. We performed pedigree analysis to describe the inheritance patterns, pregnancy outcomes, and recurrence risks to relatives of various types. RESULTS Myelomeningocele or spina bifida (66.9%) and cranial defects (17.7%) were the most common NTD subtypes observed. The overall male:female ratio for affected individuals was 0.82, and there were even fewer males among individuals with an upper level NTD (0.62). Among twins, 2 of the 5 monozygotic twins and only 3 of 35 dizygotic twins were concordant, while 27% of the same sex twins were concordant, but none of the different sex twins. The estimated 6.3% recurrence risk to siblings (CI 0.04-0.08) is consistent with previous reports. Families with two or more affected individuals show a higher proportion of female transmitters (p = 0.0002). Additionally, the number of affected relatives in maternal compared to paternal lineages was more than double (p = 0.006). There were significantly more miscarriages, infant deaths, and stillborn pregnancies of the maternal aunts and uncles (p < 0.0001) and of first cousins (p = 0.04). CONCLUSIONS Our data provide several lines of evidence consistent with a maternal effect, as well as a sex-influenced effect, in the etiology of NTDs.