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Biomedical subjects

T Lehman

Publications and source records attributed to T Lehman.

18 recordsLinked to original sources
PubMed2005

Influence of Matrigel-overlay on constitutive and inducible expression of nine genes encoding drug-metabolizing enzymes in primary human hepatocytes.

1. Previous studies reported that rat hepatocytes overlaid with extracellular matrix components (Matrigel) maintain the expression and responsiveness of drug-metabolizing enzymes. However, whether Matrigel provides similar advantages in human hepatocytes remains largely uncertain.2. The influence of Matrigel-overlay on the constitutive and phenobarbital- and oltipraz-inducible expression of nine biotransformation enzymes, cytochrome P450s 1A1, 1A2, 2B6, 3A4, and glutathione S-transferases A1, A2, M1, T1, P1, in primary human hepatocytes was evaluated.3. Hepatocytes from five livers were maintained on a rigid collagen substratum with or without Matrigel overlay and treated for 48?h with two doses of each inducer. Quantitative RT-PCR, and for selected genes, immunoblot and enzyme activity analyses, demonstrated that human hepatocytes overlaid with Matrigel showed consistently higher constitutive and inducible expression of biotransformation genes. 4. Phenobarbital-mediated responsiveness of cytochrome P450 2B6, a potential indicator of hepatocyte differentiation status, was markedly higher in overlaid relative to non-overlaid hepatocytes. 5. It is concluded that an Matrigel overlay facilitates the maintenance and induction of xenobiotic metabolizing enzymes in primary cultures of human hepatocytes.

Adult↗
PubMed2001

The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series.

OBJECTIVE: To review all cases of septic shock treated with vasopressin to determine the effects on hemodynamic and renal function and to document any adverse effects. SETTING: A 14-bed mixed medical-surgical ICU of St. Paul's Hospital, a 450-bed tertiary referral hospital affiliated with the University of British Columbia. PATIENTS: All ICU patients who received vasopressin for treatment of severe septic shock between August 5, 1997, and March 21, 1999. RESULTS: We identified 50 patients: age 60 (+/-14); APACHE II score 27 (+/-7). Baseline data (T0) was compared to data at T4, T24 and T48 (4, 24 and 48 h) on infusion. Mean arterial pressure (MAP) increased by 18% from T0 to T4 and remained stable at T24 (p=0.006) and T48 (p=0.008). Systolic pulmonary artery pressure (PAP) was unchanged at 45+/-13 mmHg. Mean cardiac index (CI) decreased by 11% at T4 (p=0.03). Urine output increased 79% at T4 (p=0.005) and further increases were not significant at T24 and T48. Mean pressor dosage decreased by 33% at T4 (p=0.001), by 53% at T24 (p=0.002) and by 48% at T48 (p=0.01). Hospital mortality was 85%. There were six cardiac arrests; all but one occurred at a vasopressin dose of 0.05 U/min or more. CONCLUSIONS: In this group of patients with severe septic shock, vasopressin infusion increased MAP and urine output and decreased catecholamine requirements. Doses higher than 0.04 U/min were not associated with increased effectiveness and may have been associated with higher adverse effects.

Analysis of Variance↗
PubMed2001

UCN-01 induces cytotoxicity toward human CLL cells through a p53-independent mechanism.

OBJECTIVES: UCN-01, a novel protein kinase C inhibitor, is currently being tested in phase I clinical trials after being noted to induce apoptosis in lymphoid cell lines. We sought to study the in vitro activity of UCN-01 against human chronic lymphocytic leukemia (CLL) cells and potential mechanisms of action for inducing this cytotoxicity. METHODS: Detailed in vitro studies were performed from tumor cells derived from patients with CLL cells following attainment of written informed consent. RESULTS: The 50% loss of viability (LC(50)) in mononuclear cells from CLL patients (n = 10) following exposure to UCN-01 for 4 days was 0.4 microM (95% CI +/- 0.21; range 0.09-1.16). Loss of viability in human CLL cells correlated with early induction of apoptosis. Exposure of CLL cells to 0.4 and 5.0 microM of UCN-01 resulted in decreased expression of p53 protein. We therefore investigated the dependence of UCN-01 on intact p53 by exposing splenocytes from wild-type (p53(+/+)) and p53 null (p53(-/-)) mice, which demonstrated no preferential cytotoxicity when compared to the marked differential induced by F-Ara-A and radiation. CONCLUSIONS: UCN-01 has significant in vitro activity against human CLL cells that appears to occur independent of p53 status. While demonstration of in vitro cytotoxicity does not establish in vivo efficacy, the findings described support the early introduction of UCN-01 into clinical trials for patients with B-CLL.

Alkaloids↗
PubMed2001

Preventing sexual risk behaviors among gay, lesbian, and bisexual adolescents: the benefits of gay-sensitive HIV instruction in schools.

OBJECTIVES: This study compared sexual risk behaviors of gay, lesbian, and bisexual (GLB) and heterosexual adolescents and evaluated associations between gay-sensitive HIV instruction and risk behaviors of GLB youths. METHODS: A random sample of high school students and HIV education teachers completed surveys. Self-reported risk behaviors of heterosexual and GLB adolescents were compared, with control for student and community demographic characteristics. Sexual risk behaviors of GLB youths in schools with and without gay-sensitive instruction were compared. RESULTS: GLB youths reported more substance use, high-risk sexual behaviors, suicidal thoughts or attempts, and personal safety issues than did heterosexual youths (P < .001). Among those who were sexually active, GLB youths reported more lifetime and recent sexual partners than did heterosexuals (P < .001), and more of them reported alcohol use before last sex (P < .01) and a history of pregnancy (P < .001). GLB youths in schools with gay-sensitive instruction reported fewer sexual partners, less recent sex, and less substance use before last sex than did GLB youths in other schools (P < .05). CONCLUSIONS: The findings document increased risk behaviors among GLB youths and demonstrate the potential benefits of providing gay-sensitive HIV instruction in schools.

Adolescent↗
PubMed1999

Mutational activation of K-ras in nonneoplastic exocrine pancreatic lesions in relation to cigarette smoking status.

BACKGROUND: Cigarette smoking is among the few unequivocal risk factors for the development of pancreatic ductal adenocarcinoma (PDAC). Activating mutations in codon 12 of the K-ras protooncogene is a frequent and early molecular event in the pathogenesis of PDAC and a variety of nonmalignant ductal pancreatic lesions. The molecular epidemiologic relation between heavy cigarette smoking and mutational activation of K-ras in PDAC has been examined to a limited extent. The authors have examined the mutational status of K-ras in nonneoplastic pancreata in relation to cigarette smoking status. METHODS: Archival formalin fixed paraffin embedded specimens of nonneoplastic pancreata (n = 39) were obtained from the American Cancer Society and evaluated histopathologically. Specimens from age- and gender-matched individuals were stratified into three groups: 1) those who never smoked cigarettes (n = 16), 2) those who smoked 1-2 packs/day for more than 20 years (n = 10 cases), and 3) those who smoked more than 2 packs/day for 20 or more years (n = 13). Cases were preselected from 77 specimens based on the quality, suitability, and cellularity of the archival tissues for analyses. Furthermore, none of the patients died of primary PDAC or had evidence of pancreatic metastases from an extrapancreatic primary tumor. Tissue sections were microdissected and deparaffinized, and genomic DNA was purified by standard proteinase K-phenol-chloroform extraction techniques. Genomic DNA was analyzed for mutations in codon 12 of the K-ras protooncogene by two mutant-allele-enriched polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assays and by multiplex PCR-based ligase chain reaction (LCR) analyses. RESULTS: Analyses of multiple microdissected pancreata specimens from 39 cases revealed wild-type K-ras codon 12 sequences in both nonsmoking individuals and those who smoked 1-2 packs/day for 20 or more years. K-ras codon 12 mutations were confirmed by PCR-RFLP and PCR-LCR assays in 5 of 13 pancreata cases (39%) obtained from individuals who smoked more than 2 packs of cigarettes/day for 20 years or more (P < 0.005). The K-ras mutation spectra revealed two G-->T transversions, one G-->C transversion and two G-->A transitions. There was no clear relation between the incidence or spectra of mutations and pancreatic histopathology, as overtly normal pancreata as well as pancreata with squamous metaplasia, periductal fibrosis, and ductal atypia revealed reproducible K-ras alterations. Similarly, among those 34 cases in which a wild-type K-ras sequence was revealed by both approaches, a similar histopathologic profile was evident. CONCLUSIONS: Mutational activation of codon 12 of the K-ras protooncogene was confirmed reproducibly by mutant allele-enriched PCR-RFLP and multiplex PCR-LCR analyses in 39% (5 of 13) of archival nonneoplastic pancreata from age- and gender-matched individuals who smoked more than 2 packs of cigarettes/day for 20 or more years. The presence of a mutated or wild-type or K-ras was independent of the histopathologic profile of the 39 cases examined. The data provide further suggestive molecular epidemiologic evidence of an association between a major and unequivocal risk factor for PDAC (heavy cigarette smoking) and mutations in a molecular target (K-ras), the activation of which is an important and early event both in the pathogenesis of PDAC and in the development of a variety of nonneoplastic ductal pancreatic lesions.

Adult↗
PubMed1999

Cardiocutaneous fistula.

Infection of the Teflon pledgets on the heart suture line after left ventricular aneurysm repair, presenting late with a fistulous tract connecting the heart with the skin (cardiocutaneous fistula) is an uncommon but potentially serious condition. The case is reported of a 73 year old man who developed a cardiocutaneous fistula extending through the left hemidiaphragm and draining at the abdominal wall, which developed six years after left ventricular aneurysmectomy. Following radiographic evaluation, which established the diagnosis, the Teflon pledgets and fistulous tract were successfully surgically removed. Prompt diagnosis depends on a high index of suspicion. Eradication of infection requires excision of infected material, which must be planned on an individual basis.

Aged↗
PubMed1994

p53 mutations at A:T base pairs in angiosarcomas of vinyl chloride-exposed factory workers.

Mutations in the p53 tumor suppressor gene are commonly found in the major human cancers and the mutational spectrum in some cancer types is consistent with the genotoxic effects of the associated environmental risk factors. Thus far there is little information on p53 mutations in cancers of factory workers with a history of carcinogen exposure in the workplace. Occupational exposure to vinyl chloride causes liver angiosarcomas (ASL) and also increases the risk of several other cancers. Loss of p53 function in osteo- and fibrosarcomas can occur by two different mechanisms, p53 mutation and amplification of the MDM2 gene. We examined tumors from five vinyl chloride-exposed patients, four with ASL and one with hepatocellular carcinoma (HCC), for evidence of MDM2 proto-oncogene amplification or p53 mutation in exons 5-8. Amplification of MDM2 was not found, but in two of the angiosarcomas an A:T to T:A missense mutation was detected. p53 sequence analysis of vinyl chloride associated cancers may provide valuable information on the relationship between carcinogen exposure and DNA damage in cancer-related genes.

Adenine↗
PubMed1993

Correlation of p53 mutations with epidermal growth factor receptor overexpression and absence of mdm2 amplification in human esophageal carcinomas.

Esophageal carcinomas from 24 patients, most of whom were smokers and consumed alcoholic beverages daily, were analyzed for mutations in exons 5-8 of the p53 tumor suppressor gene. Mutations were identified by polymerase chain reaction amplification and direct sequencing in 12 of 24 (50%) of the samples; almost half of the mutations were at A:T base pairs. Nuclear accumulation of p53 protein, determined by immunohistochemistry with the CM-1 polyclonal antibody, was observed in all cases in which a missense mutation in the p53 gene was detected. None of the 24 carcinomas had amplification of the mdm2 gene, an alternate pathway to p53 loss of function. Alterations involving three other cancer-related genes associated with human esophageal carcinogenesis, c-erbB-1/epidermal growth factor receptor (EGFR), c-myc, and retinoblastoma (Rb), were examined by Southern blot or immunohistochemical analysis in the same sample set to explore the possibility of a link between oncogene activation and loss of tumor suppressor function. While no associations were observed between amplification of the c-myc or EGFR genes and p53 abnormalities, a significant correlation (P < 0.01) was seen between the presence of p53 mutation and EGFR overexpression. Absence of Rb protein, measured immunohistochemically, was observed in four tumors, none of which had aberrations of the p53 gene.

Carcinoma, Squamous Cell↗
PubMed1992

Rigidity of half-pins for the Ilizarov external fixator.

The success of the Ilizarov technique is due to the combination of the biomechanics of its external fixator and the biology of distraction osteogenesis. The stability and stiffness of the conventional Ilizarov fixator is attributed to its use of a K-wire cross structure. The disadvantages of this structure include pain, and possible neurologic and vascular injuries when the wires are introduced into crucial neurovascular areas, as well as increased frame complexity and construction. Reducing the number of wires decreases these problems, but also decreases the stiffness of the system. Hybrid (wire and half-pins) Ilizarov fixators and half-pin fixators are also being used in an attempt to alleviate these problems. Half-pins have been described by Fleming et al. and Green as causing minimal transfixation of the surrounding soft tissues and capable of and being inserted into anatomically safe areas. The stiffnesses of the hybrid systems have not been measured. This study reports on the stiffness of different wire and half-pin systems that were biomechanically tested in axial loading, anterior-posterior bending, medial-lateral bending, and torsional loading. The results demonstrated that the conventional Ilizarov fixator with wires possesses a high axial stiffness, whereas the fixator with half-pins possesses higher stiffness under bending and torsional loads. To obtain adequate stability, the use of hybrid Ilizarov frames with one wire and two or more half-pins (5 or 6 mm in diameter), or larger half-pin frames (5 or 6 mm) with three pins is recommended.

Biomechanical Phenomena↗
PubMed1991

Subtrochanteric femur fractures: a comparison of the Zickel nail, 95 degrees blade plate, and interlocking nail.

Seventy-nine nonconsecutive patients with subtrochanteric femur fractures were divided into three groups based on the method of fracture fixation. Group I consisted of 21 patients treated with a Zickel nail, Group II comprised 25 patients treated with a 95 degrees blade plate, and Group III included 33 patients treated with an interlocking nail. All patients in Group I and Group II had open reduction and internal fixation of their fractures. Ninety-four percent of the patients in Group III were treated by closed intramedullary nailing. The average operating times for Groups I, II, and III were 212, 272, and 181 min, respectively, while blood loss averaged 900, 1,500, and 600 ml for each group, respectively. Group I had one infection, ten malunions, and one nonunion. Group II had one infection, six malunions, and two nonunions. Group III had no infections, two malunions, and one nonunion. We conclude that closed interlocking nailing is the treatment of choice for acute nonpathologic subtrochanteric femur fractures in adults. There is decreased blood loss, reduced operating time, and fewer complications than with either the Zickel nail or the 95 degrees blade plate regardless of the fracture pattern or the degree of fracture comminution.

Adult↗
PubMed1989

Development of neoplastic phenotype following transfection of HNF cells with sarcoma DNA.

DNA isolated from chondrosarcoma cells effectively transformed NIH-3T3 cells and human foreskin fibroblasts. The transfected NIH-3T3 cells, directly implanted three or four passages later, formed progressively growing tumors (greater than or equal to 2.0 cm in diameter) subcutaneously in nude mice. No metastasis was evident upon pathological examination of the tumor bearing mice. Transfected human foreskin fibroblasts that exhibited anchorage independent growth formed only small tumors in nude mice (less than 0.6 cm in diameter). The transfected human cells which exhibited anchorage independent growth reacted with the monoclonal antibody 345.134S, specific for an epitope expressed by human sarcoma cells. The transfected NIH-3T3 cells did not exhibit reactivity with the same monoclonal antibody. Southern blot analysis of the DNA prepared from the transfected NIH-3T3 cells, that developed as a progressively growing tumor in a nude mouse, revealed the presence of human repetitive DNA sequences.

Animals↗
PubMed1989

Comparative stages of expression of human squamous carcinoma cells and carcinogen transformed keratinocytes.

The mouse monoclonal antibody OSU 22-3 was prepared using cells from a squamous cell carcinoma (SCC) as an immunogen. This antibody reacts with an antigen found on squamous cell carcinomas but does not react with normal keratinocytes. This antibody and two antibodies that react with normal keratinocytes were used as markers of malignant and normal phenotypes. These markers were used to evaluate several spontaneous and carcinogen initiated SCC tumors and to identify the expression of an antigen associated with a malignant phenotype. A variety of subpopulations in carcinogen initiated tumors and spontaneous SCC tumors were noted. The subpopulations that reacted only with MoAb OSU 22-3 exhibited features of anchorage independent growth and cellular invasiveness, and formed progressively growing tumors in nude mice. Other SCC spontaneous tumor cell subpopulations reacted with the antibodies associated with normal keratinocytes. These cells did not proliferate in vitro and did not form tumors in the nude mouse. There were other carcinogen transformed cells which reacted with MoAb OSU 22-3 but not with the antibodies associated with normal keratinocytes. These cells exhibited anchorage independent growth and cellular invasiveness but did not form tumors in nude mice. We conclude from this work that human SCC tumors contain multiple cell populations. These cell populations have varied growth properties and express surface antigens that may indicate their malignant vigor. Carcinogen transformed keratinocytes do exhibit some of the characteristics of SCC tumor phenotypes but not the property of malignant progressively growing cells on a routine and consistent basis. This feature is transiently and inconsistently expressed in a surrogate host by populations prepared from spontaneous SSC tumors.

Animals↗
PubMed1988

Reverse lithotomy: modified prone position for simultaneous nephroscopic and ureteroscopic procedures in women.

Occasionally there is need for nephroscopic and ureteroscopic access during the same surgical procedure. Patient positioning is problematic and usually the patient must be turned from supine to prone position or vice versa. Simultaneous access is possible by placing the patient in a prone position with the thighs and knees cradled laterally in a "boot" type stirrup. Thus access is afforded to a percutaneous nephrostomy tract and to the urethra for nephroscopic and ureteroscopic procedures, and at the same time adequate operator comfort is maintained. This approach has been used four times in 3 patients and has been a valuable factor in the endoscopic removal of massive renal and ureteral calculi.

Adult↗
PubMed1981

Stereotypy and striatal dopamine receptor changes with 1-alpha-acetylmethadol (LAAM).

Narcotics like morphine and methadone produce effects on striatal dopaminergic mechanisms as evidenced by changes in a stereotyped behavior induced by apomorphine and binding or radioactive ligands to dopamine (DA) receptors. LAAM may replace methadone in the treatment of narcotic addiction. We investigated the effect of LAAM on apomorphine induced stereotypy and the binding of 3H-spiroperidol to dopamine receptors isolated from mouse and guinea pig striata. Chronic LAAM treatment produced a behavioral supersensitivity to apomorphine. The biochemical expression of the behavioral effect was a significant increase in the number of dopamine receptor binding sits in mouse and guinea pig striata. These effects can be due to either a direct chronic blockade or postsynaptic dopamine receptors or stimulation of a presynaptic receptor which acts to reduce the amount of dopamine released during nerve activity. Work is in progress to determine the mechanism of this effect.

Animals↗
PubMed1978

Naloxone-reversible analgesic action of SKF 525-A in mice.

SKF 525-A, given i.p. to mice at doses from 50 to 100 mg/kg, had analgesic activity approximately 40% the analgesic potency of d-propoxyphene HCl, a chemically similar narcotic. While the analgesia produced by propoxyphene was totally antagonized by naloxone, however, that produced by SKF 525-A was only partly reversed. We suspect that SKF 525-A may exert its antinociceptive actions partly by an interaction with CNS narcotic receptors and partly by a nonspecific sedating action.

Analgesics↗