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Biomedical subjects

J Cornelius

Publications and source records attributed to J Cornelius.

At least 19 recordsLinked to original sources
PubMed2006

Oxalobacter sp. reduces urinary oxalate excretion by promoting enteric oxalate secretion.

The primary goal of this study was to test the hypothesis that Oxalobacter colonization alters colonic oxalate transport thereby reducing urinary oxalate excretion. In addition, we examined the effects of intraluminal calcium on Oxalobacter colonization and tested the hypothesis that endogenously derived colonic oxalate could be degraded by lyophilized Oxalobacter enzymes targeted to this segment of the alimentary tract. Oxalate fluxes were measured across short-circuited, in vitro preparations of proximal and distal colon removed from Sprague-Dawley rats and placed in Ussing chambers. For these studies, rats were colonized with Oxalobacter either artificially or naturally, and urinary oxalate, creatinine and calcium excretions were determined. Colonized rats placed on various dietary treatment regimens were used to evaluate the impact of calcium on Oxalobacter colonization and whether exogenous or endogenous oxalate influenced colonization. Hyperoxaluric rats with some degree of renal insufficiency were also used to determine the effects of administering encapsulated Oxalobacter lysate on colonic oxalate transport and urinary oxalate excretion. We conclude that in addition to its intraluminal oxalate-degrading capacity, Oxalobacter interacts physiologically with colonic mucosa by inducing enteric oxalate secretion/excretion leading to reduced urinary excretion. Whether Oxalobacter, or products of Oxalobacter, can therapeutically reduce urinary oxalate excretion and influence stone disease warrants further investigation in long-term studies in various patient populations.

Animals↗
PubMed2001

Inhibition of melanosome transfer from melanocytes to keratinocytes by lectins and neoglycoproteins in an in vitro model system.

We propose that some of the critical molecules involved in the transfer of melanosomes from melanocytes to keratinocytes include plasma membrane lectins and their glycoconjugates. To investigate this mechanism, co-cultures of human melanocytes and keratinocytes derived from neonatal foreskins were established. The process of melanosome transfer was assessed by two experimental procedures. The first involved labeling melanocyte cultures with the fluorochrome CFDA. Labeled melanocytes were subsequently co-cultured with keratinocytes, and the transfer of fluorochrome assessed visually by confocal microscopy and quantitatively by flow cytometry. The second investigative approach involved co-culturing melanocytes with keratinocytes, and processing the co-cultures after 3 days for electron microscopy to quantitate the numbers of melanosomes in keratinocytes. Results from these experimental approaches indicate significant transfer of dye or melanosomes from melanocytes to keratinocytes that increased with time of co-culturing. Using these model systems, we subsequently tested a battery of lectins and neoglycoproteins for their effect in melanosome transfer. Addition of these selected molecules to co-cultures inhibited transfer of fluorochrome by approximately 15-44% as assessed by flow cytometry, and of melanosomes by 67-93% as assessed by electron microscopy. Therefore, our results suggest the roles of selected lectins and glycoproteins in melanosome transfer to keratinocytes in the skin.

Cell Membrane↗
PubMed2001

Context-dependent memory under stressful conditions: the case of skydiving.

Two experiments examined the effect of differing levels of emotional arousal on learning and memory for words in matching and mismatching contexts. In Experiment 1, experienced skydivers learned words either in the air or on the ground and recalled them in the same context or in the other context. Experiment 2 replicated the stimuli and design of the first experiment except that participants were shown a skydiving video in lieu of skydiving. Recall was poor in air-learning conditions with actual skydiving, but when lists were learned on land, recall was higher in the matching context than in the mismatching context. In the skydiving video experiment, recall was higher in matching learn-recall contexts regardless of the situation in which learning occurred. We propose that under extremely emotionally arousing circumstances, environmental and/or mood cues are unlikely to become encoded or linked to newly acquired information and thus cannot serve as cues to retrieval. Results can be applied to understanding variations in context-dependent memory in occupations (e.g., police, military special operations, and Special Weapons and Tactics teams) in which the worker experiences considerable emotional stress while learning or recalling new information.

Adolescent↗
PubMed2000

A comparison of apoptosis and necrosis induced by hepatotoxins in HepG2 cells.

7H-Dibenzo[c,g]carbazole (DBC), an N-heterocyclic aromatic hydrocarbon, is cytotoxic and carcinogenic in rodent liver. While DBC leads to necrotic lesions in the liver, the induction of apoptosis by DBC has not been investigated. The focus of this study was to determine the degree to which apoptosis and necrosis contributed to DBC cytotoxicity in a human hepatoma cell line (HepG2). To determine if these effects were unique to DBC, the results were compared to another hepatotoxin, aflatoxin B(1) (AFB(1)). DBC produced a distinct biphasic LDH release curve within 24 h of exposure. During the same time period lower concentrations of DBC (<10 microM) induced the formation of DBC-DNA adducts and increased p53 protein levels followed by apoptotic cell death. However, increasing the concentration of DBC to 80 microM led to lower DNA adduct and p53 protein levels. At this concentration, intracellular ATP levels were rapidly depleted followed by cell swelling and loss of membrane integrity consistent with necrotic cell death. In contrast to DBC, a biphasic LDH release curve was not observed for AFB(1). Instead, AFB(1) induced a concentration-dependent increase in apoptosis that reached two- to threefold higher levels than DBC. These results suggest that differences exist in the extent and type of cell death induced by DBC and AFB(1) at equimolar concentrations. Apoptosis and necrosis result from low and high concentrations of DBC, respectively, and may be dependent upon intracellular ATP levels.

Adenosine Triphosphate↗
PubMed2000

Mutant alleles at the brown locus encoding tyrosinase-related protein-1 (TRP-1) affect proliferation of mouse melanocytes in culture.

Tyrosinase related protein-1 (TRP-1) is a melanocyte-specific gene product involved in eumelanin synthesis. Mutation in the Tyrp1 gene is associated with brown pelage in mouse and oculocutaneous albinism Type 3 in humans (OCA3). It has been demonstrated that TRP-1 expresses DHICA oxidase activity in the murine system. However, its actual function in the human system is still unclear. The study was designed to determine the effects of mutation at two Typr1 alleles, namely the Tyrp1b (brown) and Tyrp1b-cj (cordovan) compared with wild type Tyrp1B (black) on melanocyte function and melanin biosynthesis. The most significant finding was that both of the Tyrp1 mutations (i.e. brown expressing a point mutation and cordovan expressing decreased amount of TRP-1 protein) resulted in attenuation of cell proliferation rates. Neither necrosis nor apoptosis was responsible for the observed decrease in cell proliferation rates of the brown and cordovan melanocytes. Ultrastructural evaluation by electron microscopic analysis revealed that both mutations in Tyrp1 affected melanosome maturation without affecting its structure. These observations demonstrate that mutation in Tyrp1 compromised tyrosinase activity within the organelle. DOPA histochemistry revealed differences in melanosomal stages between black and brown melanocytes but not between black and cordovan melanocytes. There were no significant differences in tyrosine hydroxylase activities of tyrosinase and TRP-1 in wild type black, brown and cordovan melanocyte cell lysates. We conclude that mutations in Tyrp1 compromise cell proliferation and melanosomal maturation in mouse melanocyte cultures.

Alleles↗
PubMed1999

Improvement of rat lung structure and function after preservation with celsior.

Ischemia/reperfusion-induced increase in pulmonary microvascular permeability was shown to be reduced after preservation with Celsior. We investigated reimplantation-induced lung injury in isolated, reperfused rat lungs after preservation via the pulmonary artery with Celsior, Celsior + prostacyclin, and reduced-potassium (40 mmol) Euro-Collins solution (40 ml/kg/body wt each) followed by 2 h of cold ischemia. Arterial and veneous oxygen tensions were recorded during 50 min of in vitro reperfusion after which the lungs (10 right lungs per experimental group) were fixed by vascular perfusion. The tissue was further processed for microscopy, and histological changes were quantified stereologically. Lung preservation with Celsior resulted in a significantly higher volume of air-filled alveolar space with a large proportion of widely distended alveoli compared with the other groups. In the Euro-Collins group the fraction of atelectatic alveoli exceeded that observed in Celsior-preserved lungs. In accordance, the difference between arterial and venous oxygen tensions was significant among Euro-Collins- and Celsior-protected lungs, with improved oxygenation values in the Celsior group. In contrast, addition of prostacyclin to Celsior treatment resulted in rather variable structural as well as functional data. There were no differences in the volumes of intraalveolar edema among the groups tested. However, the volume of alveolar tissue was increased in the Euro-Collins group. In conclusion, compared with Euro-Collins and Celsior + prostacyclin solutions, preservation with Celsior resulted in improved structural characteristics which in combination with improved oxygenation parameters supports the prospective advantage of Celsior in clinical organ preservation.

Animals↗
PubMed1999

Stereological estimation of the volume weighted mean volumes of alveoli and acinar pathways in the rat lung to characterise alterations after ischaemia/reperfusion.

The aim of this study was to characterise pulmonary reimplantation injury in isolated, perfused rat lungs following 2 h of cold ischaemia, and 50 min. of in vitro reperfusion. The effects of 2 differently composed lung preservation solutions (low potassium Euro-Collins and Celsior; each n = 5) were examined in comparison with untreated, nonischaemic control lungs (n = 3). After fixation by vascular perfusion and tissue collection by systematic random sampling, the volume weighted mean volume (Vv) of alveoli and acinar pathways was estimated by light microscopic stereology using the method of point sampled intercepts in plastic embedded, Azan-stained material. Significantly higher Vv of alveoli and acinar paths was found in the Celsior group than in Euro-Collins preserved lungs. However, in the controls the size of acinar pathways was similar to Celsior preserved lungs whereas alveolar size was comparable to preservation with Euro-Collins. The between-animal coefficient of variation of alveoli was very low in controls and Celsior preserved but higher in the Euro-Collins group. Size distribution of alveoli and acinar paths in 15 size classes was largely homogeneous in all groups tested. In the Euro-Collins group the fractions of both class 1-alveoli and class 1-acinar paths significantly exceeded those of the other groups. Widely expanded alveoli (size classes 13-15) only occurred after preservation with Celsior whereas wider acinar paths (size class 15) were found in the Celsior group and in the controls. It is concluded that lung preservation with low-potassium Euro-Collins and Celsior solutions may act differently on distinct spaces in the distal gas-exchange regions of lungs. This may be due to selective effects on pulmonary surfactant activity and on elastic tissue elements in the alveolar ducts, respectively. Additionally, the method of point sampled intercepts is considered to be an efficient tool to evaluate the effects of different preservation solutions on lung parenchyma.

Animals↗
PubMed1999

Altered gene expression in melanocytes exposed to 4-tertiary butyl phenol (4-TBP): upregulation of the A2b adenosine receptor 1.

Exposure to phenolic agents contributes to the development of occupational vitiligo. Proposed as a causative factor for leukoderma in vivo, the para-substituted phenol 4-tertiary butyl phenol was chosen to investigate early cellular events responsible for selective disappearance of melanocytes from the epidermis of individuals sensitive to such agents. To this end, differential display of melanocyte mRNA isolated from three separate cultures was performed following a 12 h exposure of cells to 250 microM 4-tertiary butyl phenol or to vehicle alone. Fragments of cDNA representing differentially expressed messages were cloned and subsequently confirmed by reverse dot blotting. Alignment analysis revealed that the L30 ribosomal protein was upregulated by the treatment, potentially reflecting altered levels of protein synthesis in response to stress. In addition, a gene sequence upregulated following exposure to 4-tertiary butyl phenol was identified as the A2b receptor (a P1 receptor for adenosine). Differential expression of this gene was confirmed in an RNase protection assay. By reverse transcription-polymerase chain reaction, the gene was shown to be expressed in keratinocytes and fibroblasts as well. Flow cytometry confirmed differential expression in melanocytes and fibroblasts, but not in keratinocytes. Interestingly, it has been reported that P1 purinoceptor stimulation can induce apoptosis. This is in concordance with results reported elsewhere demonstrating induction of apoptosis by 4-tertiary butyl phenol in human melanocytes, as well as with morphologic changes observed in this study in cells exposed to 250 microM 4-tertiary butyl phenol for 72 h. In conclusion, differential display is useful to establish melanocyte components involved in the cellular response to phenolic agents.

Flow Cytometry↗
PubMed1998

Activation of the cyclic AMP pathway by alpha-melanotropin mediates the response of human melanocytes to ultraviolet B radiation.

A hallmark of sun exposure is increased melanin synthesis by cutaneous melanocytes which protects against photodamage and photocarcinogenesis. Irradiation of human keratinocytes or melanocytes with ultraviolet (UV) rays stimulates the synthesis and release of alpha-melanotropin (alpha-MSH) and adrenocorticotropic hormone (ACTH), which induce cyclic AMP (cAMP) formation and increase the proliferation and melanogenesis of human melanocytes. We report that stimulation of cAMP formation is obligatory for the melanogenic response of cultured normal human melanocytes to UVB radiation. In the absence of cAMP inducers, UVB radiation inhibited, rather than stimulated, melanogenesis. UVB radiation (28 mJ/cm2) arrested melanocytes in the G1 phase of the cell cycle, and concomitant treatment with 0.1 microM alpha-MSH enhanced their proliferation but did not increase the surviving fraction. Irradiation with UVB, with or without alpha-MSH, caused prolonged expression of p53 and p21(waf-1, cip-1), maintained pRB in a hypophosphorylated state, and reduced the expression of Bcl2. However, alpha-MSH allowed UVB-irradiated melanocytes to enter S phase, suggesting that alpha-MSH acts as a mitogen rather than a survival factor, and that overexpression of p53 is mainly a signal for cell death. Our results underscore the importance of the cAMP pathway and its physiological inducers in mediating the response of human melanocytes to UV radiation.

Cyclic AMP↗
PubMed1998

Characterization of the changing lymphocyte populations and cytokine expression in the exocrine tissues of autoimmune NOD mice.

NOD mice develop chronic lymphocytic invasion of the pancreas, submandibular, and lacrimal glands leading to loss of insulin secretion, salivary flow, and tear production. In this study, we have used flow cytometric analyses and RT-PCR to track glandular lymphocyte populations and cytokine expression spanning the initiation of autoimmune infiltration through the development of widespread autoimmune destruction of the salivary and lacrimal glands of NOD mice. Results demonstrate a predominance of CD4+ to CD8+ lymphocytes and a similar predominance of T-cells versus B-cells in both the submandibular and lacrimal gland infiltrates. A temporal increase in memory (CD3+CD45RBlo) T-cells was also detected; however, naive (CD3+CD45RBhi) T-cell populations as well as a CD3+, CD4-/CD8- double negative population were also present. In addition, a skewing of the TCR Vbeta repertoire toward Vbeta6+ and Vbeta8+ lymphocytes was evident in both glandular infiltrates. Analyses of cytokine mRNA expression in the submandibular glands demonstrated an increase between 12 and 16 wk of age of several proinflammatory cytokines including IL-1beta, IL-6, IL-7, IL-10, IFNgamma, TNFalpha, and inducible Nitric Oxide Synthase (iNOS). IL-4 synthesis was notably absent in both tissues. Cytokine mRNA transcripts detected in lacrimal tissue were similar to those seen in the submandibular glands but appeared both earlier and more intensely. These findings depict the progressive development of autoimmune exocrinopathy and can be used as a foundation to explore the similarities and potential differences in the immunopathogenic lesions of several distinct tissues within the same host.

Animals↗
PubMed1998

Endothelin-1 is a paracrine growth factor that modulates melanogenesis of human melanocytes and participates in their responses to ultraviolet radiation.

Endothelin (ET)-1, alpha-melanocyte stimulating hormone (alpha-melanotropin; alpha-MSH), and basic fibroblast growth factor (bFGF) are keratinocyte-derived factors that interact synergistically to stimulate human melanocyte proliferation. ET-1 has a dose-dependent mitogenic effect on human melanocytes and a biphasic effect on melanogenesis: a stimulatory effect at subnanomolar concentrations, and an inhibitory effect at concentrations equal to or higher than 1 nM. Human melanocytes express ET B receptors. Brief treatment of melanocytes with ET-1 caused up-regulation of alpha-MSH receptor mRNA but did not alter ET B receptor mRNA level. ET-1 modulates the response of human melanocytes to UV rays (UVRs). Treatment of melanocytes with 10 nM ET-1 immediately after exposure to UVRs enabled them to overcome the G1 growth arrest. However, ET-1 did not inhibit p53 accumulation or p21(Waf-1/SDI-1/Cip-1) overexpression, nor did it reverse the hypophosphorylated state of pRb or the reduction in Bcl2 level in irradiated melanocytes. These results substantiate the role of ET-1 as a paracrine regulator that modulates the response of human melanocytes to UVRs.

Cell Division↗
PubMed1996

Pharmacokinetics of aminoguanidine administration and effects on the diabetes frequency in nonobese diabetic mice.

In vitro studies suggest that intra-islet nitric oxide production may contribute to the pathogenesis of autoimmune insulin-dependent diabetes mellitus. We tested whether aminoguanidine (AG), a competitive inhibitor of inducible nitric oxide synthase, might block beta cell destruction and prevent insulin-dependent diabetes mellitus in vivo. A total of 50 female nonobese diabetic mice, from the time of weaning until 32 wk of age, received injections (i.p.) twice daily with 50 mg AG/kg body weight and received AG in drinking water (350 mg/liter). A total of 50 littermates treated with vehicle alone served as controls. A 24-hr pharmacokinetic analysis showed that AG was readily absorbed after i.p. administration, peaked in plasma (9.0 micrograms/ml) at 0.5 hr and had a half-life of 1.88 hr. Steady-state values for the area under the curve for the therapeutic regimen were 20.51 and 16.35 (micrograms)(hr)/ml for the 0000 to 1600 and 1600 to 2400 hr, respectively. In terms of therapy, life-table analysis indicated the frequency of insulin-dependent diabetes mellitus (6/30 AG-treated vs. 11/31 vehicle-treated, P = .25) and insulitis scores (2.0 +/- 1.1 vs. 2.4 +/- 1.2 in nondiabetic AG- and vehicle-treated mice at 32 wk, respectively, P = .20) were similar in both groups. Flow cytometric analysis revealed no quantitative differences in islet infiltrating macrophages, CD4+ or CD8+ T lymphocytes between groups of animals randomly killed at 8, 16 and 32 wk. Although not eliminating a role for nitric oxide in the pathogenesis of insulin-dependent diabetes mellitus, prophylactic treatment with AG did not significantly impact the onset of insulitis or diabetes in nonobese diabetic mice.

Animals↗
PubMed1995

Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-gamma transcription.

We reported previously that daily injections of isophane insulin prevented both hyperglycemia and insulitis in nonobese diabetic (NOD) mice (Atkinson, M., N. Maclaren; and R. Luchetta. 1990. Diabetes. 39:933-937). The possible mechanisms responsible include reduced immunogenicity of pancreatic beta-cells from "beta-cell rest" and induced active immunoregulation to insulin (Aaen, IK., J. Rygaard, K. Josefsen, H. Petersen, C. H. Brogren, T. Horn, and K. Buschard. 1990. Diabetes. 39:697-701). We report here that intermittent immunizations with insulin or its metabolically inactive B-chain in incomplete Freund's adjuvant also prevent diabetes in NOD mice, whereas immunizations with A-chain insulin or with BSA do not. Adoptive transfer of splenocytes from B-chain insulin-immunized mice prevented diabetes in recipients co-infused with diabetogenic spleen cells, an effect that was abolished by prior in vivo elimination of either CD4+ or CD8+ cells. Insulin immunization did not reduce the extent of intraislet inflammation (insulitis); however, it did abolish expression of IFN-gamma mRNA within the insulitis lesions. Immunizations with insulin thus induce an active suppressive response to determinants on the B-chain that converts the insulitis lesion from one that is destructive to one that is protective.

Animals↗
PubMed1994

Risk factors for suicidal behavior in borderline personality disorder.

OBJECTIVE: This study identified potential risk factors for suicidal behavior in patients with borderline personality disorder defined by the Diagnostic Interview for Borderline Patients and by DSM-III-R criteria for patients who did and did not attempt suicide. METHOD: Histories of suicide attempts and attempt characteristics were obtained by Schedule for Affective Disorders and Schizophrenia interviews from 84 patients with borderline personality disorder and were related to severity of borderline pathology, diagnostic comorbidity, and state and trait symptoms. RESULTS: There were 61 patients with a lifetime history of suicide attempts (72.6%), with an average of 3.39 (SD = 2.87) attempts per patient. Attempters were significantly older than nonattempters, with more impulse actions, antisocial personality disorder comorbidity, and state depression. State depression was significantly less severe in patients who had attempted suicide in the present episode (or past year) than in patients who had attempted suicide only in the past. A comorbid diagnosis of major depression, alcoholism, or drug use disorder did not distinguish attempters from nonattempters. Suicide attempt in the present episode was best predicted by the number of prior lifetime attempts. A highly serious intent to commit suicide was predicted by the number of lifetime attempts and subjective depression, while a low intent was predicted by a mixed subtype of borderline personality disorder plus schizotypal personality disorder and paranoid ideation. A high degree of medical lethality was predicted by number of lifetime attempts, older age, and hysteroid dysphoria, while low lethality attempts were associated with high degrees of anger. CONCLUSIONS: Risk factors for suicidal behavior in patients with borderline personality disorder include older age, prior suicide attempts, antisocial personality, impulsive actions, and depressive moods but not comorbid affective disorder, alcoholism, or drug use disorders.

Adult↗
PubMed1993

Efficacy of phenelzine and haloperidol in borderline personality disorder.

OBJECTIVE: To compare the efficacy of a neuroleptic (haloperidol) to a monoamine oxidase inhibitor antidepressant (phenelzine sulfate) against the affective, cognitive, and impulsive-aggressive symptoms of criteria-defined borderline inpatients in an effort to dissect apart affective and schizotypal symptom patterns or subtypes using medication response. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Inpatient unit of a tertiary care university psychiatric hospital serving a large public catchment area. PATIENTS: One hundred eight consecutively admitted borderline inpatients defined by Gunderson's Diagnostic Interview for Borderline Patients and DSM-III-R criteria, randomly assigned to 38 phenelzine, 36 haloperidol, and 34 placebo trials. INTERVENTIONS: Following 1 week free of medication, haloperidol (average dose, 4 mg/d), phenelzine sulfate (average dose, 60 mg/d), or placebo were given for 5 weeks with weekly symptom ratings and plasma drug level determinations. MAIN OUTCOME MEASURES: Efficacy was measured on depression (Hamilton Rating Scale, Beck Depression Inventory), global severity (Global Assessment Scale, Symptom Checklist-90 items [SCL-90]), anxiety, anger-hostility (SCL-90, Inpatient Multidimensional Psychiatric Scale [IMPS], Buss-Durkee Hostility Inventory), psychoticism (Schizotypal Symptom Inventory, SCL-90, IMPS), impulsivity (Ward Scale, Barratt Impulsiveness Scale, Self-Report Test of Impulse Control), and borderline psychotherapy (Borderline Syndrome Index). RESULTS: Three-way comparisons between groups indicated superior efficacy for phenelzine, followed by placebo and haloperidol on measures of depression, borderline psychopathologic symptoms, and anxiety. Pairwise comparisons between medication and placebo revealed significant efficacy for phenelzine against anger and hostility but no efficacy against atypical depression or hysteroid dysphoria. We were unable to replicate prior reports of efficacy for the neuroleptic. CONCLUSIONS: Pharmacologic dissection of borderline personality disorder patients into affective and schizotypal subtypes could not be demonstrated.

Adult↗