OBJECTIVES: To assess the incidence, comorbidity, and patterns of resolution of DSM-IV mood, anxiety, and substance use disorders in individuals with traumatic brain injury (TBI). DESIGN: The Structured Clinical Interview for DSM-IV Diagnoses (SCID) was utilized. Diagnoses were determined for three onset points relative to TBI onset: pre-TBI, post-TBI, and current diagnosis. Contrasts of prevalence rates with community-based samples, as well as chi-square analysis and analysis of variance were used. Demographics considered in analyses included gender, marital status, severity of injury, and years since TBI onset. SETTING: Urban, suburban, and rural New York state. PARTICIPANTS: 100 adults with TBI who were between the ages of 18 and 65 years and who were, on average, 8 years post onset at time of interview. MAIN OUTCOME MEASURES: SCID Axis I mood diagnoses of major depression, dysthymia, and bipolar disorder; anxiety diagnoses of panic disorder, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), and phobia; and substance use disorders. RESULTS: Prior to TBI, a significant percentage of individuals presented with substance use disorders. After TBI, the most frequent Axis I diagnoses were major depression and select anxiety disorders (ie, PTSD, OCD, and panic disorder). Comorbidity was high, with 44% of individuals presenting with two or more Axis I diagnoses post TBI. Individuals without a pre-TBI Axis I disorder were more likely to develop post-TBI major depression and substance use disorders. Rates of resolution were similar for individuals regardless of previous psychiatric histories. Major depression and substance use disorders were more likely than were anxiety disorders to remit. CONCLUSION: TBI is a risk factor for subsequent psychiatric disabilities. The need for proactive psychiatric assessment and timely interventions in individuals post TBI is indicated.

Adult↗

PubMed1998

Master genes for bone growth, 1,25-dihydroxyvitamin D3 synthesis, and renal conservation of phosphate and calcium.

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25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

PubMed1998

Anticipation in Crohn's disease may be influenced by gender and ethnicity of the transmitting parent.

OBJECTIVE: We sought to examine whether anticipation (an earlier age of onset in succeeding generations) is observed in Crohn's disease (CD) patients within the New York metropolitan area, and whether there are differences in the degree of anticipation with respect to gender and ethnicity of the affected parent. METHODS: Sixty-one parent-child pairs both affected by CD were identified; about half of the pairs were of Ashkenazi Jewish descent. An additional 17 pairs of second-degree relatives with CD were also identified. The intergenerational difference in age at diagnosis (AAD) was used to perform regression analysis and the degree of anticipation among subsets of patients separated on the basis of gender and ethnicity of the transmitting parent was determined. RESULTS: The AAD was consistently (90% of the time) lower in the younger member of the 61 parent-child pairs (35.3+/-1.6 yr vs 20.8+/-1.1 yr, p = 0.0001). Furthermore, the degree of anticipation was significantly greater for father-child pairs (20.6+/-3.2 yr) than for mother-child pairs (11.7+/-2.1 yr). However, when the patient population where the parent had an AAD of < 28 was analyzed separately, there was a lack of clear-cut evidence of anticipation in the population as a whole. Only when the population was subdivided by ethnicity was there convincing evidence of anticipation in the Jewish population. CONCLUSION: Ascertainment bias may be responsible for the apparent anticipation observed in the CD population as a whole or in the nonJewish CD subgroup. However, the Jewish CD population displays strong evidence of anticipation even after correction for ascertainment bias.

Adult↗

PubMed1998

Murine leukemia virus envelope protein in transgenic-mouse serum blocks infection in vitro.

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Retraction Notice↗

PubMed1998

Calreticulin inhibits vitamin D's action on the PTH gene in vitro and may prevent vitamin D's effect in vivo in hypocalcemic rats.

1,25-dihydroxyvitaminD3 [1,25-(OH)2D3] and PTH both act to increase serum calcium. In addition, 1,25-(OH)2D3 decreases PTH gene transcription, which is relevant both to the physiology of calcium homeostasis and to the management of the secondary hyperparathyroidism of patients with chronic renal failure. In chronic hypocalcemia there is secondary hyperparathyroidism with increased levels of PTH mRNA and serum PTH despite markedly increased levels of 1,25-(OH)2D3. We have studied the role of calreticulin in this resistance to 1,25-(OH)2D3. Weanling rats fed a low-calcium diet were hypocalcemic and had increased PTH mRNA levels despite high serum 1,25-(OH)2D3 levels. 1,25-(OH)2D3 given by continuous minipump infusion to normal rats led to the expected decrease in PTH mRNA. The hypocalcemic rats had an increased concentration of calreticulin in the nuclear fraction of their parathyroids, but not in other tissues. Gel shift assays showed that a purified vitamin D receptor and retinoid X receptor-beta bound to the PTH promoter's chicken and rat vitamin D response element (VDRE), and this binding was inhibited by added pure calreticulin. Transfection studies with a PTH VDRE-chloramphenicol acetyltransferase (CAT) construct showed that 1,25-(OH)2D3 decreased CAT transcription. Cotransfection of PTH VDRE-CAT with a calreticulin expression vector in the sense orientation prevented the transcriptional effect of 1,25-(OH)2D3, but a calreticulin vector in the antisense orientation had no effect. These results show that calreticulin prevents the binding of vitamin D receptor-retinoid X receptor-beta to the PTH VDRE in gel retardation assays and prevents the transcriptional effect of 1,25-(OH)2D3 on the PTH gene. This is the first report of calreticulin inhibiting a down-regulatory function of a sterol hormone and may help explain the refractoriness of the secondary hyperparathyroidism of many chronic renal failure patients to 1,25-(OH)2D3.

Animals↗

PubMed1997

Role of Thy-1 in T cell development.

Tolerance to self proteins is accomplished in part by elimination of autoreactive immature T cells as they develop in the thymus. Although many investigators have studied the cellular interactions that regulate this important process, the specific molecules involved in negative selection are still not well understood. Thy-1 is a glycosyl-phosphatidylinositol-linked protein that is expressed at high levels on immature thymocytes, and recent evidence suggests that it is involved in thymocyte apoptosis. Correspondingly, we have found that Abs to Thy-1 block Ag-dependent thymocyte deletion in an in vitro culture system. Thus, we investigated the role of Thy-1 in T cell development by using Thy-1 -deficient mice containing a TCR transgene specific for a class II MHC-restricted Ag. With this system, the role of Thy-1 in Ag-specific self-restriction and self-tolerance could be analyzed. Thy-1-null mice were found to undergo normal negative selection in three different models: the in vitro culture system, anti-CD3-induced thymocyte deletion in vivo, and Ag-induced thymocyte deletion in vivo. Self-restriction to MHC class II also appeared to occur normally in Thy-1-null mice. These results therefore suggest that Thy-1 is not essential for either self-restriction or self-tolerance to MHC class II-restricted Ags. This finding is discussed in light of recent data regarding the role of other glycosyl-phosphatidylinositol-linked proteins in thymocyte development.

Age Factors↗

PubMed1997

Comparison of HIV-1 envelope-specific CD4+ T cell lines simultaneously established from peripheral blood mononuclear cells and lymph node biopsy in HIV-1-infected individuals.

HIV-1 envelope-specific CD4+ T cell lines were established simultaneously from PBMC and lymph node mononuclear cells of two HIV-1-infected patients. Three recombinant envelope proteins were used to establish the CD4+ T cell lines: gp160NL4-3, gp120IIIB, and gp120MN. Six T cell lines were established from the first patient, one for each Ag from each compartment, and four T cell lines, two per compartment, were established from the second patient. Each line was challenged with a panel of overlapping peptides spanning the entire gp120 sequence to define its T cell epitope specificity. The pattern of recognition for all the lines from any given patient was similar between compartments. Each patient had a different pattern of peptide recognition. TCR analysis showed a heterogeneous usage of Vbeta between lines with same peptide specificity and established from different compartments. These data suggest that the cellular immune response does not phenotypically vary between the peripheral blood and lymph node compartments, but demonstrates genotypic heterogeneity, showing possible redundancy of the immune response to HIV-1 gp160.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Nanoliter scale PCR with TaqMan detection.

We monitored PCR in volumes of the order of 10 nl in glass microcapillaries using a fluorescence energy transfer assay in which fluorescence increases if product is made due to template-dependent nucleolytic degradation of an internally quenched probe (TaqMan assay). This assay detected single starting template molecules in dilutions of genomic DNA. The results suggest that it may be feasible to determine the number of template molecules in a sample by counting the number of positive PCRs in a set of replicate reactions using terminally diluted sample. Since the assay system is closed and potentially automatable, it has promise for clinical applications.

Actins↗

PubMed1997

Widespread neuronal ectopia associated with secondary defects in cerebrocortical chondroitin sulfate proteoglycans and basal lamina in MARCKS-deficient mice.

Mice deficient in MARCKS, a prominent neural substrate for protein kinase C (PKC), die before or shortly after birth. They exhibit high frequencies of exencephaly, universal agenesis of forebrain commissures, and abnormalities of cerebral cortical and retinal lamination. We show here that these mice have wide-spread and severe neuronal ectopia in the outer layers of the developing forebrain, manifested by the migration of clusters of developing neuroblasts through the basal lamina and often through the pial membrane and into the subarachnoid space. This abnormality became apparent by Embryonic Day (E) 13 or 14, shortly after the formation of the early marginal zone. MARCKS deficiency was associated with decreased staining for marginal zone chondroitin sulfate proteoglycans; this decrease was detectable earlier in development than the neuronal ectopia. Later in development, there was also marked disruption of the basal lamina at the pial-glial interface, as evidenced by gross abnormalities in laminin and reticulin staining; however, the basal lamina appeared normal at E9.5. These data indicate that MARCKS is required for the prevention of neuronal ectopia during development. Potential mechanisms responsible for the neuronal ectopia in the MARCKS-deficient mice include decreased expression or increased proteolytic destruction of basal lamina proteins and marginal zone chondroitin sulfate proteoglycans in the developing brain.

Animals↗

PubMed1997

Expression of full-length trkB receptors by reactive astrocytes after chronic CNS injury.

Growth factors, including members of the neurotrophin family, are expressed by neuronal and glial elements following injury to the CNS. In order to assess the capacity for glial cells to respond to neurotrophins at sites of chronic injury, full-length trkB receptors were localized following implantation of a nitrocellulose filter into the cerebral cortex for 30 days. Northern analysis demonstrated that filter implants contained cells expressing transcripts for full-length and truncated trkB receptors, in contrast to the predominant expression of truncated trkB receptors by cultured astrocytes. In situ hybridization and immunohistochemistry using probes to the trkB kinase domain colocalized full-length receptors with GFAP-immunopositive reactive astrocytes adjacent to and within the filter implant. In contrast, OX-42-immunopositive microglia/macrophages were not stained for full-length trkB. These data indicate that reactive astrocytes can express functional trkB receptors following a chronic insult to the cerebral cortex and support the hypothesis that neurotrophins may regulate astrocytic responses to injury.

Animals↗

PubMed1997

Activated macrophages and the blood-brain barrier: inflammation after CNS injury leads to increases in putative inhibitory molecules.

The cellular responses to spinal cord or brain injury include the production of molecules that modulate wound healing. This study examined the upregulation of chondroitin sulfate proteoglycans, a family of molecules present in the wound healing matrix that may inhibit axon regeneration in the central nervous system (CNS) after trauma. We have demonstrated increases in these putative inhibitory molecules in brain and spinal cord injury models, and we observed a close correlation between the tissue distribution of their upregulation and the presence of inflammation and a compromised blood-brain barrier. We determined that the presence of degenerating and dying axons injured by direct trauma does not provide a sufficient signal to induce the increases in proteoglycans observed after injury. Activated macrophages, their products, or other serum components that cross a compromised blood-brain barrier may provide a stimulus for changes in extracellular matrix molecules after CNS injury. While gliosis is associated with increased levels of proteoglycans, not all reactive astrocytes are associated with augmented amounts of these extracellular matrix molecules, which suggests a heterogeneity among glial cells that exhibit a reactive phenotype. Chondroitin sulfate also demarcates developing cavities of secondary necrosis, implicating these types of boundary molecules in the protective response of the CNS to trauma.

Animals↗

PubMed1997

Richard Bunge.

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History, 20th Century↗

PubMed1997

Glial cell extracellular matrix: boundaries for axon growth in development and regeneration.

Astrocytes and other glia in the central nervous system are now thought to produce molecules that negatively modulate axon growth, thereby influencing axon pathfinding in both development and regeneration. The relevant evidence for glial cell boundaries and the inhibitory molecules present in these extracellular matrix structures is discussed in this minireview.

Animals↗

PubMed1997

Leiden factor V mutation in four patients with small bowel infarctions.

The Leiden factor V mutation is observed in 20% of unexplained lower limb venous thromboses and involves substitution of the arginine residue at position 506 by glutamine (R506Q). It is known to decrease the anticoagulant activity of activated protein C. This case report describes 4 cases of small bowel infarction (SBI) associated with the presence of this mutation. Two cases of arterial and 2 cases of venous SBI were observed. Extensive assessment excluded the usual causes of SBI and plasma hypercoagulation syndrome (antithrombin III, protein C, and protein S deficiency and myeloproliferative syndrome). An abnormal resistance to activated protein C was observed. Molecular analysis consisting of polymerase chain reaction amplification and digestion with MnlI showed that 2 patients were heterozygous and 2 were homozygous for the R506Q mutation. Despite familial history of thrombosis in only 1 patient, first- and second-degree relatives of 2 patients also had the presence of the mutation. Examination for the presence of abnormal resistance to activated protein C should be part of the etiological assessment of SBI. Its presence may warrant consideration of long-term anticoagulant therapy, especially for patients with shortened small bowel who are treated by home parenteral nutrition with deep venous access.

Adult↗