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PubMed1980

[Changes in the chamber angle following ocular contusions (author's transl)].

In a retrospective study, 87 patients were reexamined after hospital treatment of ocular contusion. The relationships between intraocular pressure, outflow facility, and lesions of the anterior chamber angle were analyzed. In 52% of the cases, lesions were demonstrated in the anterior chamber angle; about half of these patients showed extension of 180 degrees or more. There was no statistical correlation between intraocular pressure and outflow facility or the extent of anterior chamber angle lesions, although clinical findings clearly indicated such correlations. Blunt ocular injuries evidently lead to higher intraocular pressure in elderly patients. The latency period also appears to play a role: the longer the period between trauma and examination, the higher the pressure measured in the injured eyes. We found secondary glaucoma in two cases (about 2%). Glaucoma was suspected in six patients (6.5%). There was an apparent risk of glaucoma in four patients (4.3%).

Aged↗
PubMed2002

The African-specific CYP2D617 allele encodes an enzyme with changed substrate specificity.

OBJECTIVE: The effects of the CYP2D6*17 and *29 alleles on substrate specificity and enzyme activity were studied by correlating CYP2D6 genotype to phenotype with 4 probe drugs (codeine, debrisoquine, dextromethorphan, metoprolol) in black Tanzanians and white Swedes. METHODS: The black Tanzanian subjects represented the following 6 genotypic groups: A, (CYP2D6*1 or *2)/(*1 or *2) (n = 13); B, CYP2D6*17 /*17 (n = 5); C, CYP2D6*29 /*29 (n = 4); D, CYP2D6*1 /*17 (n = 5); E, CYP2D6*5/*17 (n = 4); and F, various genotypes (n = 4). The white subjects were from 4 groups, as follows: A, (CYP2D6*1 or *2)/(*1 or *2) (n = 7); B, (CYP2D6*1 or *2)/(*3, *4, or *5) (n = 7); C, homozygous for defect alleles (n = 7); and D, duplicated CYP2D6 gene (n = 2). RESULTS: The metabolic ratios of the 4 probe drugs correlated significantly (r (s) = 0.69-0.92; P <.001) in both populations. Tanzanian subjects homozygous for the CYP2D6*17 allele were slower metabolizers when debrisoquine or dextromethorphan was used as the probe drug than when codeine or metoprolol was used, showing a different substrate specificity of CYP2D6.17 than of CYP2D6.1 and CYP2D6.2. This was confirmed with analysis of covariance of the different metabolic ratios for a subgroup of subjects carrying only the CYP2D6*17 mutated allele (n = 9) compared with all other subjects (n = 44). The metabolic ratios of dextromethorphan and metoprolol differed significantly among Tanzanian subjects homozygous for the CYP2D6*29 allele compared with those with CYP2D6*1 or *2 alleles. CONCLUSION: We found differences in the disposition of 4 CYP2D6 probe drugs in black Tanzanians compared with Swedes. The differences were caused by the presence of CYP2D6.17 and CYP2D6.29. The results show that CYP2D6.17 exhibits altered substrate specificity compared with CYP2D6.1 and CYP2D6.2.

Adrenergic Agents↗
PubMed2002

From reactants to products via simple hydrogen-bonding networks: Information transmission in chemical reactions.

The transmission of information is ubiquitous in nature and often occurs through supramolecular hydrogen bonding processes. Here we report that there is a remarkable correlation during synthesis between the efficiency of the hydrogen-bond-directed assembly of peptide-based [2]rotaxanes and the symmetry distortion of the macrocycle in the structure of the final product. It transpires that the ability of the flexible macrocycle-precursor to wrap around an unsymmetrical hydrogen bonding template affects both the reaction yield and a quantifiable measure of the symmetry distortion of the macrocycle in the product. When the yields of peptide rotaxane-forming reactions are high, so is the symmetry distortion in the macrocycle; when the yields are low, indicating a poor fit between the components, the macrocycle symmetry is relatively unaffected by the thread. Thus during a synthetic sequence, as in complex biological assembly processes, hydrogen bonding can code and transmit "information"--in this case a distortion from symmetry--between chemical entities by means of a supramolecularly driven multicomponent assembly process. If this phenomenon is general, it could have far reaching consequences for the use of supramolecular-directed reactions in organic chemistry.

Chemistry↗
PubMed1975

Somatic cell hybrids between mouse peritoneal macrophages and simian-virus-40-transformed human cells: II. Presence of human chromosome 7 carrying simin virus 40 genome in cells of tumors induced by hybrid cells.

Cells derived from tumors induced in "nude" mice after injection of cells that were hybrids between mouse peritoneal macrophages and simian virus 40 (SV40)-transformed human cells were found to retain the human chromosome 7 carrying the SV40 genome, and indicate that the presence of human chromosome 7 carrying the SV40 genome is responsible for the expression of the tumorigenic phenotype in the hybrid cells.

Animals↗
PubMed1982

Synthesis and secretion of alpha 2-plasmin inhibitor by established human liver cell lines.

The site of synthesis of alpha 2-plasmin inhibitor (alpha 2-PI), a physiologic inhibitor of plasmin, is not known with certainty. We have studied the production and secretion of alpha 2-PI by three established human liver cell lines derived from hepatocellular carcinoma and hepatoblastoma (Hep G2, Hep 3B, and PLC/PRF/5). As measured by a specific radioimmunoassay, the titer of alpha 2-PI increased in the medium of Hep G2 and Hep 3B cells with time, but no significant amount of alpha 2-PI was found in the medium of PLC/PRF/5. There was no evidence for a significant intracellular pool of this protein. On immunodiffusion against anti-alpha 2-PI serum, alpha 2-PI secreted by Hep G2 (G2 alpha 2-PI) formed a simple precipitin line of complete identity with the alpha 2-PI present in plasma (plasma alpha 2-PI). G2 alpha 2-PI behaved similarly to plasma alpha 2-PI in Sephadex G-150 gel filtration, sucrose density-gradient centrifugation, and crossed immunoelectrophoresis. G2 alpha 2-PI inhibited plasmin activity instantaneously in a functional assay and formed a complex with plasmin demonstrable by crossed immunoelectrophoresis. De novo synthesis of alpha 2-PI was shown by the presence of specific immunoprecipitable radioactivity in the medium after 5 hr of labeling of the cells with [35S]methionine. Analysis of the immunoprecipitates by NaDodSO4/polyacrylamide gel electrophoresis showed a single peak of radioactivity corresponding to Mr 68,000. These results indicate that the liver is a site of alpha 2-PI production.

Carcinoma, Hepatocellular↗
PubMed1984

Translocated c-myc oncogene of Burkitt lymphoma is transcribed in plasma cells and repressed in lymphoblastoid cells.

We examined somatic cell hybrids between Burkitt lymphoma cells and either human lymphoblastoid cells or mouse plasmacytoma cells for the expression of the translocated c-myc oncogene. The results of this study indicate that the translocated c-myc oncogene is transcribed in plasma cells but is repressed in lymphoblastoid cells. Thus, the factors necessary for translocated c-myc transcription are present in plasma cells and Burkitt lymphoma cells but are absent or inactive in lymphoblastoid cells. Since the distance between the rearranged immunoglobulin loci and the c-myc oncogene can even exceed 30-50 kilobases, we speculate that the translocated c-myc oncogene is under the transcriptional control of enhancer-like elements capable of acting over long distances. The activity of this long-range enhancer may depend on the interaction with transacting factors that are active in plasma cells and in Burkitt lymphoma cells but are not active in lymphoblastoid cells. We also examined the transcription of the first exon of the c-myc oncogene, which becomes separated from the second and third exon because of the chromosomal break involving the first intron. This exon is transcribed at high levels in ST486 Burkitt lymphoma cells with the t(8;14) chromosome translocation. Hybrids between lymphoblastoid and ST486 cells expressed high levels of transcripts of the first exon, whereas hybrids between plasma cells and ST486 cells did not. Thus, transcription of the separated first exon can be enhanced in lymphoblastoid and Burkitt lymphoma cells because of its close proximity to the heavy chain enhancer that is normally located between the joining and the switch region of the C mu gene. Such enhancement, however, does not occur in plasma cells, possibly because these cells are able to suppress completely the c-myc oncogene, unless it has been placed in the proximity of a rearranged immunoglobulin constant region gene.

B-Lymphocytes↗
PubMed2001

Antiepileptic drugs increase plasma levels of 4beta-hydroxycholesterol in humans: evidence for involvement of cytochrome p450 3A4.

The major cholesterol oxidation products in the human circulation are 27-hydroxycholesterol, 24-hydroxycholesterol, and 7alpha-hydroxycholesterol. These oxysterols are formed from cholesterol by specific cytochrome P450 enzymes, CYP27, CYP46, and CYP7A, respectively. An additional oxysterol present in concentrations comparable with 7alpha- and 24-hydroxycholesterol is 4beta-hydroxycholesterol. We now report that patients treated with the antiepileptic drugs phenobarbital, carbamazepine, or phenytoin have highly elevated levels of plasma 4beta-hydroxycholesterol. When patients with uncomplicated cholesterol gallstone disease were treated with ursodeoxycholic acid, plasma 4beta-hydroxycholesterol increased by 45%. Ursodeoxycholic acid, as well as the antiepileptic drugs, are known to induce cytochrome P450 3A. Recombinant CYP3A4 was shown to convert cholesterol to 4beta-hydroxycholesterol, whereas no conversion was observed with CYP1A2, CYP2C9, or CYP2B6. The concentration of 4alpha-hydroxycholesterol in plasma was lower than the concentration of 4beta-hydroxycholesterol and not affected by treatment with the antiepileptic drugs or ursodeoxycholic acid. Together, these data suggest that 4beta-hydroxycholesterol in human circulation is formed by a cytochrome P450 enzyme.

Adult↗
PubMed2006

Design principles for developing an efficient clinical anatomy course.

The exponential growth of medical knowledge presents a challenge for the medical school curriculum. Because anatomy is traditionally a long course, it is an attractive target to reduce course hours, yet designing courses that produce students with less understanding of human anatomy is not a viable option. Faced with the challenge of teaching more anatomy with less time, we set out to understand how students employ instructional media to learn anatomy inside and outside of the classroom. We developed a series of pilot programs to explore how students learn anatomy and, in particular, how they combine instructional technology with more traditional classroom and laboratory-based learning. We then integrated what we learned with principles of effective instruction to design a course that makes the most efficient use of students' in-class and out-of-class learning. Overall, we concluded that our new anatomy course needed to focus on transforming how medical students think, reason, and learn. We are currently testing the hypothesis that this novel approach will enhance the ability of students to recall and expand their base of anatomical knowledge throughout their medical school training and beyond.

Anatomy↗
PubMed1992

Pathogenicity of two strains of Newcastle disease virus in the grey-breasted helmet guinea fowl.

Thirty-five 6-week-old guinea fowl keets, seronegative for maternal antibodies to Newcastle disease virus, were infected with Herts strain (33/56) and Kumarov strain of Newcastle disease virus intramucularly (IM) or intranasally (IN). Clinical signs were first noticed four days post infection (PI) in the group infected IM but five days PI in the group infected IN with Herts strain of Newcastle disease virus. These clinical signs were similar in both groups and included anorexia, droopiness, huddling together, greenish diarrhoea and marked cachexia. Prominent nervous signs, including spasms of the head and neck, were observed in groups infected with Herts strain. The major gross lesions observed were emaciation with prominent keel bone, empty intestinal tract and distended gall bladder in most keets. The histological lesions were characterised by meningoencephalitis, necrosis and loss of lymphocytes from splenic and lymphoid aggregates. There was muscular degeneration and necrosis in the gizzard and mild pulmonary congestion and oedema in some keets. Neither gross or microscopic lesions were observed in keets that had received the Kumarov strain.

Animals↗
PubMed1994

Diarrhoea among children in rural Somalia. Maternal perceptions, management and mortality.

Diarrhoea was the second most common symptom of disease in a longitudinal study of 431 children under 5 years of age in rural Somalia. Most mothers perceived diarrhoea as a condition in which oral rehydration therapy (ORT) and feeding were logical parts of its management. During 1 year of observation, ORT was used in the household in one-third of the episodes of diarrhoea, mostly by non-farming, young and literate mothers. Infants were treated more often than older children, as were also children in smaller households. In a 3-year demographic surveillance in the same area (1219 person years), the under-5 mortality from diarrhoea in children of literature and illiterate mothers was 43 per 1000 (95% CI 0-84) and 93 per 1000 (95% CI 60-101), respectively. The findings suggest that the use of ORT is associated with a mother's ability to allocate time to health care and her general position in the household.

Adult↗
PubMed2007

Cellular mechanisms of mainstream cigarette smoke-induced lung epithelial tight junction permeability changes in vitro.

Mainstream cigarette smoke increases the permeability of human airways; however, the mechanism for this increased permeability is poorly defined. Tight junctions between adjacent epithelial cells constitute the physiological barrier to fluid and macromolecules in epithelium. These structures are highly regulated by phosphorylation and their association with the cytoskeleton. The goal of these studies was to identify the signal transduction pathways that regulate smoke-induced permeability. Using a physiologically relevant air-liquid interface exposure system, electrically tight monolayers of the human bronchial epithelial cell-line Calu-3 were exposed to fresh, whole mainstream cigarette smoke. This exposure results in a regulated, dose-dependent loss of epithelial barrier function in the lung epithelial monolayers. With cigarette smoke exposure, transepithelial electrical resistance (TER) is decreased and albumin flux is increased, indicating a loss in barrier function to ions and macromolecules, respectively; however, both largely recover in 30 min. Smoke-induced losses of macromolecular barrier function are the result of multicellular junctional reorganization, resulting in increased leak volume rather than leak frequency. Inhibiting Rho kinase (ROCK) significantly reduces the smoke-induced permeability to both ions and macromolecules, while inhibiting protein tyrosine kinases (PTK) only reduces smoke-induced macromolecular permeability. Interestingly, inhibiting myosin light chain kinase (MLCK) exacerbates smoke-induced permeability, indicating that MLCK and ROCK have opposing regulatory roles. Our results demonstrate that the smoke-induced loss of epithelial barrier function in human bronchial epithelium is a regulated process rather than a cytotoxic response. Additionally, our results indicate that activation of PTK and ROCK and inactivation of MLCK contribute to the increased airway permeability caused by mainstream cigarette smoke.

Amides↗
PubMed1977

Complement-mediated antiserum cytotoxic reactions to human chromosome 7 coded antigen(s): immunoselection of rearranged human chromosome 7 in human-mouse somatic cell hybrids.

Immunoselection via complement-dependent lysis of human-mouse somatic cell hybrids containing chromosome 7, with antisera reactive to cell surface antigen(s) coded for by chromosome 7, has resulted in growth of somatic cell hybrids containing rearranged human chromosome 7s. Investigation of these hybrids has localized the gene(s) coding for the relevant cell surface antigen(s) to the short arm of human chromosome 7. The simian virus 40 integration site and the gene coding for human beta-glucuronidase appear to be localized to the long arm of chromosome 7 in this hybrid clone.

Animals↗
PubMed2002

Respiratory tract deposition efficiencies: evaluation of effects from smoke released in the Cerro Grande forest fire.

Forest-fire smoke inhaled by humans can cause various health effects. This smoke contains toxic chemicals and naturally occurring radionuclides. In northern New Mexico, a large wildfire occurred in May 2000. Known as the Cerro Grande Fire, it devastated the town of Los Alamos and damaged Los Alamos National Laboratory (LANL). Residents were concerned about the possible dissemination of radionuclides from LANL via smoke from the fire. To evaluate potential health effects of inhaling radionuclides contained in the smoke from the Cerro Grande Fire, it was first necessary to evaluate how much smoke would deposit in the human respiratory tract. The purpose of this study was to evaluate respiratory-tract deposition efficiencies of airborne forest-fire smoke for persons of different ages exposed while inside their homes. Potential non-radiological health effects of a forest fire are reviewed. The deposition efficiencies presented can be used to evaluate in-home smoke deposition in the respiratory tract and expected radionuclide intake related to forest fires. The impact of smoke exposure on firemen fighting a forest fire is quantitatively discussed and compared. They primarily inhaled forest-fire smoke while outdoors where the smoke concentration was much higher than inside. Radionuclides released at the LANL site via the Cerro Grande Fire were restricted to naturally occurring radionuclides from burning trees and vegetation. Radiation doses from inhaled airborne radionuclides to individuals inside and outside the Los Alamos area were likely very small.

Adult↗
PubMed1983

Identification of human hepatoma-defined cell surface molecules.

BALB/c mouse splenocytes from mice immunized with cells of the human hepatoma line Hep G2 were fused with SP2/0-Ag 14 mouse myeloma cells. Two monoclonal antibodies recognizing antigenic determinants (Hag-1, Hag-2) of hepatoma cell surface molecules were investigated. Analysis of immunoprecipitates by sodium dodecyl sulfate (SDS) gel electrophoresis revealed that the Hag-1 antigenic determinant is born ona 115, kD MW glycoprotein, and that the second antibody immunoprecipitates a group of surface proteins with MW of 230 kD, 79 kD, 23 kD, and 20 kD from human hepatoma cells. These antigenic determinants are present on cell lines derived from other human tumors, thus neither of the antibodies is hepatoma-specific; cross-reactivity with human colorectal carcinoma and some mammary carcinoma cell lines is notable. Using indirect immunofluorescence on frozen sections Hag-1 was detected in one of three liver biopsies tested whereas Hag-2 was demonstrated in all three. Both antigens were detected in sections of human kidney with Hag-2 localized to the proximal tubules.

Animals↗
PubMed1980

Metabolic activation of benzo[a]pyrene by a human hepatoma cell line.

The liver-derived human cell line, Hep G2, has high benzo[a]pyrene-metabolizing activity and converts benzo[a]pyrene to intermediates that are mutagenic and that bind to DNA. This cell line will be useful for studying metabolic activation of polycyclic aromatic hydrocarbons and other xenobiotics by human tissue and as an activation system in short-term screening assays for identifying compounds with carcinogenic potential for humans.

Animals↗
PubMed1977

Tumorigenicity of intraspecific somatic cell hybrids in nude mice.

Intraspecific somatic cell hybrids between normal mouse peripheral blood lymphocytes and a highly tumorigenic L-cell line (C1-1D) produced tumors in nude mice. While the hybrid cells were tumorigenic, the length of time necessary for tumor appearance and the size of the tumor varied. Correlation between the growth rate of the parenteral and hybrid cells in vitro or their plating efficiency in methyl cellulose with the rapidly of tumor growth in vivo was not found.

Animals↗
PubMed1977

Pathology of human-mouse somatic cell hybrid tumors.

Somatic cell hybrids between mouse peritoneal macrophages and simian virus 40-transformed human cells injected sc into nude mice resulted in a formation of tumors with two distinct growth rates and growth patterns: 1) rapid growing, irregularly circumscribed, with necrotic foci and prominent vascular channels lined by tumor cells and 2) slow growing, small, well-circumscribed, and nonvascular. Individual tumor cells were ultrastructurally classified as undifferentiated mesenchymal cells indistinguishable within these two tumor types. Characteristics of each tumor type were retained during subsequent passages in nude mice.

Animals↗