Biomedical subjects

Carl J Schmidt

Publications and source records attributed to Carl J Schmidt.

13 recordsLinked to original sources

PubMed2006

Distinctive profiles of gene expression in the human nucleus accumbens associated with cocaine and heroin abuse.

Drug abuse is thought to induce long-term cellular and behavioral adaptations as a result of alterations in gene expression. Understanding the molecular consequences of addiction may contribute to the development of better treatment strategies. This study utilized high-throughput Affymetrix microarrays to identify gene expression changes in the post-mortem nucleus accumbens of chronic heroin abusers. These data were analyzed independently and in relation to our previously reported data involving human cocaine abusers, in order to determine which expression changes were drug specific and which may be common to the phenomenon of addiction. A significant decrease in the expression of numerous genes encoding proteins involved in presynaptic release of neurotransmitter was seen in heroin abusers, a finding not seen in the cocaine-abusing cohort. Conversely, the striking decrease in myelin-related genes observed in cocaine abusers was not evident in our cohort of heroin subjects. Overall, little overlap in gene expression profiles was seen between the two drug-abusing cohorts: out of the approximately 39,000 transcripts investigated, the abundance of only 25 was significantly changed in both cocaine and heroin abusers, with nearly one-half of these being altered in opposite directions. These data suggest that the profiles of nucleus accumbens gene expression associated with chronic heroin or cocaine abuse are largely unique, despite what are thought to be common effects of these drugs on dopamine neurotransmission in this brain region. A re-examination of our current assumptions about the commonality of molecular mechanisms associated with substance abuse seems warranted.

Adult↗

PubMed2006

Fatal bromethalin poisoning.

Bromethalin is a neurotoxin found in some rodenticides. A delusional 21-year-old male presented to a hospital with altered mental status the day after ingesting a bromethalin-based rodenticide. He died 7 days after his self-reported exposure to c. 17 mg bromethalin (equivalent to 0.33 mg bromethalin/kg). His clinicopathologic course was characterized by altered mental status, obtundation, increased cerebrospinal fluid pressure, cerebral edema, death, and diffuse histologic vacuolization of the white matter in the central nervous system seen on microscopic examination at autopsy. The presence of a demethylated form of bromethalin in the patient's liver and brain was confirmed by gas chromatography with mass spectrometry. Clinical signs and lesions observed in this patient are similar to those seen in animals poisoned with bromethalin. This case illustrates the potential for bromethalin ingestion to result in fatal human poisoning.

Adult↗

PubMed2006

Nuclear localization and dynamic properties of the Marek's disease virus oncogene products Meq and Meq/vIL8.

Marek's disease virus (MDV) is an avian herpesvirus that causes T-cell lymphomas and immune suppression in susceptible chickens. At least one gene product, MDV Eco Q-encoded protein (Meq), is essential for the oncogenicity of MDV. Alternative splicing permits the meq gene to give rise to two major transcripts encoding proteins designated Meq and Meq/vIL8. Meq is a basic leucine zipper protein capable of modulating transcription. The Meq/vIL8 protein retains a modified leucine zipper, along with the mature receptor-binding portion of vIL8, but lacks the domain of Meq responsible for transcriptional modulation. In this report, we describe studies using fusions between either Meq or Meq/vIL8 and fluorescent proteins to characterize the distribution and properties of these products in chicken embryo fibroblasts (CEFs). Meq and Meq/vIL8 both localized to the nucleoplasm, nucleoli, and Cajal bodies of transfected cells. Similar distributions were found for fluorescent fusion proteins and native Meq or Meq/vIL8. Fluorescence recovery after photobleaching and photoactivatable green fluorescent protein revealed that Meq exhibited mobility properties similar to those of other transcription factors, while Meq/vIL8 was far less mobile. In addition, fluorescence resonance energy transfer studies indicated the formation of Meq/vIL8 homodimers in CEFs. Time lapse studies revealed the coordinated elimination of a portion of Meq and Meq/vIL8 from the nucleus. Our data provide new insight regarding the dynamic cellular properties of two forms of a herpesvirus-encoded oncoprotein and suggest that these forms may have fundamentally different functions in MDV-infected cells.

Alternative Splicing↗

PubMed2005

Apparent suicidal carbon monoxide poisonings with concomitant prescription drug overdoses.

We report four separate suicides by apparent motor vehicle-related carbon monoxide (CO) poisoning in which complete toxicological analysis showed the absence of, or lower than expected, percent carboxyhemoglobin saturation and high concentrations of concomitant prescription drugs. These cases, within a population of 71 apparent CO suicides from the Wayne County Medical Examiner's Office over 1998-2004, represent cases where additional factors are in play. Multiple modalities (CO poisoning and drug overdose) and/or undetectable carbon dioxide poisoning from the vehicle exhaust of cars manufactured after laws regulating vehicle emissions were enacted are examples of additional factors that require consideration in these selected cases. All four cases demonstrated some degree of decomposition, so the possible loss of CO could not be ruled out. The need for full toxicological analysis in apparent suicidal CO poisoning is emphasized.

Adult↗

PubMed2005

Blunt force injury of the abdomen complicating previously undiagnosed peliosis hepatis in a 2-year-old female.

Peliosis hepatis is an abnormal accumulation of blood-filled lakes in the liver that is most commonly seen in adults and is generally associated with chronic wasting diseases, use of androgenic steroids or bacterial infection. Few cases have been reported in children. We report a case of a 2-year-old female with no past medical history who presented with homicidal blunt force abdominal injury. The autopsy revealed lacerations in the liver and previously undiagnosed peliosis hepatis.

Abdominal Injuries↗

PubMed2004

Transcription factors specifying dopamine phenotype are decreased in cocaine users.

During development, survival of midbrain dopamine neurons and specification of their phenotype are dependent upon the intracellular expression of a number of transcription factors, including Engrailed 1, Pitx3, and Nurr1. The role of these transcription factors in the maintenance of the dopaminergic phenotype is less clear. In the present study, we show that each of these transcription factors is robustly expressed in adult dopamine neurons in human midbrain, and that cocaine abuse is associated with a significant decrease in the abundance of Nurr1 and Pitx3 in these cells. These data suggest that cocaine abuse leads to a partial loss of dopaminergic phenotype.

Cocaine-Related Disorders↗

PubMed2004

Herpesvirus of turkeys: microarray analysis of host gene responses to infection.

Herpesvirus of turkeys (HVT) provides an economically important live vaccine for prevention of Marek's disease (MD) of chickens. MD, characterized by both immunosuppression and T-cell lymphoma, is caused by another herpesvirus termed Marek's disease virus (MDV). Microarrays were used to investigate the response of chicken embryonic fibroblasts (CEF) to infection with HVT. Genes responding to HVT infection include several induced by interferon along with others modulating signal transduction, transcription, scaffolding proteins, and the cytoskeleton. Results are compared with earlier studies examining the responses of CEF cells to infection with MDV.

Animals↗

PubMed2004

Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin.

Chronic cocaine abuse induces long-term neural adaptations as a consequence of alterations in gene expression. This study was undertaken to identify those transcripts differentially regulated in the nucleus accumbens of human cocaine abusers. Affymetrix microarrays were used to measure transcript abundance in 10 cocaine abusers and 10 control subjects matched for age, race, sex, and brain pH. As expected, gene expression of cocaine- and amphetamine-regulated transcript (CART) was increased in the nucleus accumbens of cocaine abusers. The most robust and consistent finding, however, was a decrease in the expression of a number of myelin-related genes, including myelin basic protein (MBP), proteolipid protein (PLP), and myelin-associated oligodendrocyte basic protein (MOBP). The differential expression seen by microarray for CART as well as MBP, MOBP, and PLP was verified by RT-PCR. In addition, immunohistochemical experiments revealed a decrease in the number of MBP-immunoreactive oligodendrocytes present in the nucleus accumbens and surrounding white matter of cocaine abusers. These findings suggest a dysregulation of myelin in human cocaine abusers.

Adult↗

PubMed2003

GoFigure: automated Gene Ontology annotation.

SUMMARY: We have developed a web tool to predict Gene Ontology (GO) terms. The tool accepts an input DNA or protein sequence, and uses BLAST to identify homologous sequences in GO annotated databases. A graph is returned to the user via email. AVAILABILITY: The tool is freely available at: http://udgenome.ags.udel.edu/frm_go.html/

Documentation↗

PubMed2003

Characterization of vnr-13, the first alphaherpesvirus gene of the bcl-2 family.

The Bcl-2 family, including antiapoptotic and proapoptotic members, plays key regulating roles in programmed cell death. We report the characterization of a new member of the bcl-2 family, encoded by herpesvirus of turkeys (HVT). The product of this gene shares 80% homology with Nr-13, an apoptosis inhibitor, which is overexpressed in avian cells transformed by the v-src oncogene. This new gene, that we propose to call vnr-13, is the first member of the bcl-2 family to be isolated among alpha-herpesviruses. Results from cells expressing the HVT-vnr-13 gene product show that the encoded protein inhibits apoptosis and also reduces the rate of cellular proliferation. Contrary to all bcl-2 homologues found in gamma-herpesvirus, which are intronless, vnr-13 has the same organization as the cellular nr-13 gene. Hence, the HVT vnr-13 gene may have been acquired from a reverse transcriptase product of an unspliced precursor RNA, or via direct recombination with the host chromosomal DNA.

Alphaherpesvirinae↗

PubMed2002

Decreased expression of the transcription factor NURR1 in dopamine neurons of cocaine abusers.

Chronic exposure to cocaine induces long-term adaptations that are likely to involve changes in transcription factor expression. This possibility has not been examined in the cocaine-exposed human brain. The transcription factor nurr1 is highly expressed in rodent midbrain dopamine neurons and is essential for their proper phenotypic development. Here we show that human NURR1 gene expression is robust within control subjects and reduced markedly within the dopamine neurons of human cocaine abusers. NURR1 is known to regulate transcription of the gene encoding the cocaine-sensitive dopamine transporter (DAT). We show here that DAT gene expression also is reduced markedly in the dopamine neurons of NURR1-deficient cocaine abusers, suggesting that NURR1 plays a critical role in vivo in controlling human DAT gene expression and adaptation to repeated exposure to cocaine.

Adult↗

PubMed2002

Marek's disease virus VP22: subcellular localization and characterization of carboxyl terminal deletion Mutations.

Marek's disease virus (MDV) is an alphaherpesvirus that causes T cell lymphoma and severe immunosuppression in chickens. The MDV UL49 gene, which encodes the tegument viral protein 22 (VP22), has been expressed as a green fluorescent protein (GFP) fusion protein in chicken embryonic fibroblasts to examine its subcellular localization. As with both human herpesvirus 1 and bovine herpesvirus 1VP22-GFP fusion proteins, the MDV VP22-GFP product binds to microtubules and heterochromatin. In addition, the MDV protein also binds to the centrosomes. During mitosis, VP22-GFP binds to sister chromatids, but dissociates from the centrosomes and the microtubules of the mitotic spindle. A series of VP22 carboxy terminal truncation mutants were constructed to define regions responsible for these binding properties. These mutants identified separable domains or motifs responsible for binding microtubules and heterochromatin.

Amino Acid Sequence↗

PubMed2001

The genome of herpesvirus of turkeys: comparative analysis with Marek's disease viruses.

The complete coding sequence of the herpesvirus of turkeys (HVT) unique long (U(L)) region along with the internal repeat regions has been determined. This allows completion of the HVT nucleotide sequence by linkage to the sequence of the unique short (U(S)) region. The genome is approximately 160 kbp and shows extensive similarity in organization to the genomes of Marek's disease virus serotypes 1 and 2 (MDV-1, MDV-2) and other alphaherpesviruses. The HVT genome contains 75 ORFs, with three ORFs present in two copies. Sixty-seven ORFs were identified readily as homologues of other alphaherpesvirus genes. Seven of the remaining eight ORFs are homologous to genes in MDV, but are absent from other herpesviruses. These include a gene with similarity to cellular lipases. The final, HVT-unique gene is a virus homologue of the cellular NR-13 gene, the product of which belongs to the Bcl family of proteins that regulate apoptosis. No other herpesvirus sequenced to date contains a homologue of this gene. Of potential significance is the absence of a complete block of genes within the HVT internal repeat that is present in MDV-1. These include the pp38 and meq genes, which have been implicated in MDV-1-induced T-cell lymphoma. By implication, other genes present in this region of MDV-1, but missing in HVT, may play important roles in the different biological properties of the viruses.

Amino Acid Sequence↗