Search PubMed⌕ Search

Biomedical subjects

E W Johnson

Publications and source records attributed to E W Johnson.

At least 37 records · Page 2Linked to original sources
PubMed1998

CaBPs and other immunohistochemical markers of the human vomeronasal system: a comparison with other mammals.

After more than two centuries of almost sporadic inquiry as to the existence and function of the human vomeronasal system (VNS), the last decade has seen a resurgent interest in it. The principal question vexing many laboratories is whether adult humans retain the VNS that clearly develops during fetal growth. Additional questions are whether the structurally defined fetal VNS has any function role, and if this structure and function extend into postnatal life. One research tool that has been successfully used to identify key components of the mammalian VNS has been immunohistochemistry (IHC). This technique has clearly defined the vomeronasal receptor neurons in the vomeronasal organ, the vomeronasal nerve that projects into the central nervous system, and the target of this nerve, the accessory olfactory bulb. This review will discuss immunohistochemical studies that have identified these features in the mammalian VNS, and relate them to structural and IHC studies of the fetal and adult human VNS. Suggestions as to future studies to clarify the status of the human VNO also are offered.

Adult↗
PubMed1998

Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B.

Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures. Segregation analysis suggests the majority of cases have complex inheritance but rare families show apparent autosomal dominant inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified. We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures. We now report linkage, in another large GEFS+ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Co-expression of the mutant beta1 subunit with a brain Na+-channel alpha subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns.

Amino Acid Sequence↗
PubMed1998

Evidence for a novel gene for familial febrile convulsions, FEB2, linked to chromosome 19p in an extended family from the Midwest.

Febrile convulsions are a common form of childhood seizure. It is estimated that between 2 and 5% of children will have a febrile convulsion before the age of 5. It has long been recognized that there is a significant genetic component for susceptibility to this type of seizure. Wallace, Berkovic and co-workers recently reported linkage of a putative autosomal dominant febrile convulsion gene to chromosome 8q13-21. We report here another autosomal dominant febrile convulsion locus on chromosome 19p. Linkage analysis in this large multi-generational family gave a maximum pairwise lod score of 4.52 with marker Mfd120 at locus D19S177. Linkage to the chromosome 8 locus was excluded in this family. Haplotype analysis using both affected and unaffected family members indicates that this febrile convulsion gene, which we call FEB2 , can be localized to an 11.7 cM, 1-2 Mb section of chromosome 19p13.3, between loci D19S591 and D19S395.

Chromosome Mapping↗
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↗
PubMed1997

Human natural killer cells account for non-MHC class I-restricted cytolysis of porcine cells.

Despite similarities in the cellular response to allografts and xenografts, some aspects of the xenogeneic immune response are unique. We find that both freshly isolated and primed human peripheral blood lymphocytes manifest MHC unrestricted cytolysis of porcine cells. While natural antibody-mediated mechanisms account for variable levels of cytotoxicity, reproducible killing in the absence of human serum is attributable to natural killer (NK) cells. This was shown by cold target inhibition with K562 cells, increased antiporcine cytotoxicity after enrichment for CD56+ cells, and significantly reduced lytic activity after depletion of CD56+ cells. Increased anti-porcine cytotoxicity after mixed culture of human and porcine cells was due to differentiation of NK cells to lymphokine-activated killer (LAK) cells and was IL-2 dependent. After depletion of NK cells, T-cell-mediated anti-porcine cytotoxicity could also be demonstrated. We conclude that the human anti-porcine cellular cytotoxic response is due to multiple cell types that include T cells in addition to NK and LAK cells.

Animals↗
PubMed1997

Protein gene product 9.5-like and calbindin-like immunoreactivity in the nasal respiratory mucosa of perinatal humans.

BACKGROUND: Protein gene product 9.5 (PGP) and calbindin-D28k (calbindin) are neuroendocrine markers that have been localized to neuroendocrine cells in the developing tracheobronchial epithelium. Neuroendocrine cells may play some role in the development of the tracheobronchial epithelium. Little is known about the development of the nasal respiratory epithelium (RE). METHODS: Nasal respiratory mucosa from fetal and newborn humans was examined to determine immunoreactivity for PGP and calbindin. RESULTS: At all stages studied, cells of different morphologies displayed PGP-like immunoreactivity (-LI) and calbindin-LI. Columnar immunoreactive cells for both markers predominated, but labeled cells of different shapes were also observed. Most labeled columnar cells were in the RE at its border with olfactory epithelium (OE); a few similarly labeled columnar cells also appeared in this OE. In the lamina propria, PGP-LI was also seen in numerous thin branching fibers. Some of these branches penetrated into the epithelium, where fiber varicosities appeared to contact cells, some of which also exhibited PGP-LI. CONCLUSION: This study demonstrates that during development the human nasal RE contains different cell types, as illustrated by the assortment of epithelial cells displaying PGP-LI and calbindin-LI among unlabeled cells. Because PGP and calbindin immunoreactivities were found within neuroendocrine cells in previous studies, the present results indicate that the developing human nasal RE also may support a number of neuroendocrine cells. Furthermore, at least some of these cells may form synaptic contacts with nerve fibers from outside the epithelium.

Calbindin 1↗
PubMed1996

Familial cerebral cavernous angioma: a gene localized to a 15-cM interval on chromosome 7q.

Cerebral cavernous angiomas are collections of closely clustered vessels without intervening normal brain parenchyma, with microscopic evidence of hemorrhage, frequently multiple; they are best visualized with magnetic resonance imaging. Familial cerebral cavernous angioma occurs as an autosomal dominant disorder, although carriers of the gene are often asymptomatic. Recently, a gene responsible for familial cerebral cavernous angioma in a large Hispanic kindred was mapped to human chromosome 7q11-22, representing a large segment of DNA containing approximately 33 cM (about 33 million base pairs). This distance did not allow more restricted isolation of the region containing the familial cerebral cavernous angioma gene. In this report, we present a large white kindred with familial cerebral cavernous angioma and confirm the mapping to 7q11-22, including the genetic markers D7S558/D7S1789 and D7S804. Recombination between several markers in the region suggests that the candidate region is distal to D7S804. Combining our results with those previously published, we suggest that the gene is likely to reside within a 15-cM region bounded by markers D7S660 and D7S558/D7S1789. These results should assist the further refinement of the candidate region for familial cerebral cavernous angioma and facilitate the search for the gene.

Brain↗
PubMed1995

New seizure frequency QTL and the complex genetics of epilepsy in EL mice.

EL/Suz (EL) mice experience recurrent seizures that are similar to common partial complex epilepsy in humans. In the mice, seizures occur naturally at 90-100 days of age, but can be induced in younger mice and analyzed as a semi-quantitative trait after gentle rhythmic stimulation. A previous genetic mapping study of EL backcrosses to the strains ABP/LeJ or DBA/2J showed two quantitative trait loci (QTL) with large effects on seizure frequency (El1, Chr 9; El2, Chr 2) and implied the existence of other QTL with lesser effects. To further the understanding of EL-derived seizure alleles, we examined intercross progeny of EL and the strains ABP/LeJ and DDY/Jcl, and also a backcross of (EL x DDY)F1 hybrids to DDY. A new large-effect seizure frequency QTL was found (El5, Chr 14), a more minor QTL confirmed (El3, Chr 10), and two additional QTL proposed (El4, Chr 9; El6, Chr 11). The serotonin receptor gene, Htr2a, maps near and is a candidate for El5, and linkages of other serotonin receptor genes to seizure frequency QTL are noted. In addition, a strong gender effect was revealed, and epistasis was found between Chr 9 and Chr 14 markers. Despite this progress, however, our results revealed a more complex determinism of epilepsy in EL mice than previously described. In particular, no single El locus or pair was essential for frequent seizures, as QTL with large effects, such as El5, El2, and El1, were highly dependent on genetic context. Our studies highlight the importance of gene interaction in some complex mammalian traits defined by natural variation.

Animals↗
PubMed1995

Congenic strains reveal effects of the epilepsy quantitative trait locus, El2, separate from other El loci.

Congenic mouse strains made by transferring epilepsy predisposing alleles El1, El2, and El3 from the EL/Suz strain to the ABP/Le recipient were tested for seizure frequency following gentle rhythmic stimulation. Mice homozygous for El2, but not El1 or El3, experienced seizures much more frequently than ABP controls, while respective El1 homozygotes and El2 heterozygotes had only a modest increase over ABP, and El3 homozygotes showed no increase. Association between marker genotypes and seizure frequency in small intra-strain crosses showed that the phenotypic effects of El2 map to the selected interval, and that segregation of El2 accounts for virtually all genetic effects. However, in separating El2 from other EL susceptibility alleles, the seizure frequency phenotype was weaker and less heritable than in crosses between parental strains. These results confirm El2 as an important QTL and show that it has significant phenotypic effects in the absence of other EL-derived alleles, including El1. In addition, the present localization of El2 on Chr 2 suggests several potential candidate genes for El2, including the beta subunit of phospholipase-C. The approach to dissecting complex traits by making congenic strains for individual QTL is discussed.

Animals↗
PubMed1995

Distribution of OMP-, PGP 9.5- and CaBP-like immunoreactive chemoreceptor neurons in the developing human olfactory epithelium.

We have examined the distribution of olfactory marker protein (OMP), protein gene product 9.5 (PGP 9.5) and calcium-binding protein D-28k (CaBP) in the olfactory epithelium of mid- to late fetal and newborn humans using immunocytochemistry. Olfactory chemoreceptor neurons (ORNs) in a 24-week-old female fetus, a 31-week-old male fetus and a newborn male were examined. OMP-like immunoreactivity (-LI) and PGP 9.5-LI were distributed throughout ORNs at all ages. CaBP-like immunoreactivity, however, was found only in clustered or isolated fetal ORNs; in the newborn, CaBP-LI was seen only in isolated ORNs sparsely distributed throughout the OE. These findings demonstrate that human ORNs express OMP-LI nearly 4 weeks earlier in development than previously reported. PGP 9.5-LI is coincidentally abundant within these cells, suggesting it may have an important role in mature ORNs. Because the number of ORNs expressing CaBP-LI decreases during perinatal development, CaBP may be important in intracellular calcium regulation during ORN growth and maturation in the developing OE.

Calbindins↗
PubMed1995

Refined localization of the cerebral cavernous malformation gene (CCM1) to a 4-cM interval of chromosome 7q contained in a well-defined YAC contig.

Cerebral cavernous malformations (CCM) are vascular lesions present in some 20 million people worldwide that are responsible for seizures, migraine, hemorrhage, and other neurologic problems. Familial cases ofCCM can be inherited as an autosomal dominant disorder with variable expression. A gene for CCM (CCM/)was recently mapped to a 33-cM segment of chromosome 7q in a large Hispanic family (Dubovsky et al.1995). Here, the collection of several new short tandem repeat polymorphisms (STRPs) within the region of interest on 7q and the refinement of the marker order in this region using both linkage analysis in CEPH families and especially YAC-based STS content mapping are described. Affected members of three Hispanic families share allele haplotypes indicating a common ancestral mutation within these families. Using the shared haplotype information along with analysis of crossovers in affected individuals from both the Hispanic and Caucasian families, the region likely to contain the CCMI gene has been reduced to a 4-cM segment of 7q between D7S2410 and D7S689. All markers within the refined chromosomal segment were located on a single YAC contig estimated to be approximately 2 Mb in size. Four potential candidate genes have been mapped to this region.

Base Sequence↗
PubMed1994

Protein gene product 9.5 in the developing and mature rat vomeronasal organ.

Protein gene product 9.5 (PGP 9.5) was immunocytochemically identified in structures of the developing and mature rat vomeronasal organ (VNO). This study started with embryos at 17 days of gestation. By this stage, PGP 9.5 was immunolocalized within both the receptor cells of the neuroepithelium and cells of the receptor-free epithelium, located on the opposite side of the lumenal space. Nerve fibers surrounding the nascent vomeronasal vein also showed PGP 9.5 immunoreactivity. Labeling was retained in the neuroepithelium and nerve fibers around the vein during development and into adulthood. Within the pool of receptor cells of the adult neuroepithelium, labeling was observed within the cytoplasm of the somata and dendrites; some receptor cells also expressed nuclear labeling. The number of immunoreactive cells in the receptor-free epithelium appeared to increase postnatally but by adulthood immunoreactivity virtually was absent. These results suggest a role for PGP 9.5 in development and maturation of the VNO and a continuing role within the steadily renewing receptor cell population found in the mature neuroepithelium. The findings of this study also suggest that PGP 9.5 is localized within the nerve fibers surrounding the vomeronasal vein from early in development through adulthood.

Aging↗
PubMed1994

Calbindin-like immunoreactivity in epithelial cells of the newborn and adult human vomeronasal organ.

The vomeronasal organs (VNOs) of two humans, a male neonate and a female adult, were examined for immunolocalization of calbindin-D28k (calbindin) which has been immunolocalized to VNO receptor cells in other mammals. The present study demonstrates that epithelial cells within the VNOs of both subjects expressed calbindin-like immunoreactivity. These results suggest that human VNO epithelial cells of both genders express calbindin during development and in the adult.

Adult↗
PubMed1994

A preventable cause of foot drop during childbirth.

Compression of the peroneal nerve is an uncommon complication of labor and delivery. We describe a case of common peroneal nerve injury associated with positioning the knees in hyperflexion during delivery. The pathophysiologic mechanisms, clinical course, and possible prevention of this uncommon complication are discussed.

Adult↗