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Biomedical subjects

D Paul

Publications and source records attributed to D Paul.

At least 91 records · Page 5Linked to original sources
PubMed1995

A transgenic mouse model for lung adenocarcinoma.

Lung cancer is a leading cause of tumor-related deaths in humans but its origin and development are poorly understood. To study the biology of these tumors, appropriate animal and cell culture models will be of eminent importance. Uteroglobin is a marker protein for the nonciliated epithelial Clara cells lining the respiratory and terminal bronchioli of the lung. We have used the promoter and 5'-flanking sequences of the rabbit uteroglobin gene to target expression of the SV40 T antigen to the lung of transgenic mice. All transgenic founders as well as the descendants from an established line, UT7.1, developed multifocal bronchioloalveolar adenocarcinomas originating from Clara cells. At least three different stages in tumor development with progressive loss of the differentiated phenotype can be distinguished by immunohistochemical data and in situ hybridization. Only in the initial stage did bronchiolar cells express both uteroglobin and SV40 T antigen, whereas at later stages, only SV40 T antigen was detected, and the most advanced tumors were negative for both proteins. Starting from the lungs of UT7.1 mice, a bronchiolar cell line was established that maintains the features of differentiated Clara cells. This system provides a useful model for further studying the development and progression of lung adenocarcinomas in vivo and in vitro.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1995

[The life of the couple and feelings of parental competence].

With the birth of their first child a couple must learn to adapt to their new role as parents. During this learning process, their degree of comfort with their new identities as mother and father is linked to how they develop as competent parents. According to the ecological approach to human development, several variables influence parental competency. The marital relationship and the family dynamics are of special interest to the nurse who often has to evaluate the family system and intervene during the transition period to parenthood. This descriptive-correlative study is in direct response to provincial priorities aimed at promoting parenthood and providing better support to parents. Surveys were mailed to 133 couples with a one-year-old child to determine the nature of the link between the marital relationship, the family dynamics and the feeling of parental competency. The results confirm the importance of the nurses involved in evaluating these variables so that effective interventions can be developed to support and assist the couple--thus reinforcing their feelings of parental competency.

Adult↗
PubMed1994

Characterization of single-stranded DNA binding proteins in rat glial-enriched nuclei.

Single-stranded DNA binding proteins (SSBs) are those proteins which preferentially bind single-stranded DNA as opposed to double-stranded DNA and are known to be involved in recombination, amplification, and repair of DNA. To characterize single-stranded DNA binding proteins of glial cells and to examine their potential involvement in induction of neurogenic tumors in rats, nuclei were isolated from target glia and non-target liver of carcinogenically sensitive Sprague-Dawley (SD) and resistant Berlin-Druckrey-IV (BD-IV) rats of various ages and rapidly proliferating glioma cells. Nuclei were fractionated into chromatin, a preribosomal RNA protein complex, heterogeneous nuclear ribonucleoprotein complex (hnRNP), and nucleoplasm. SSBs were isolated, quantitated, and characterized by electrophoresis. A comparison of the contents of SSBs relative to RNA and their electrophoretic profiles between chromatin and hnRNP revealed that SSBs of liver chromatin were mainly associated with RNA. However, it was found that glial chromatin, particularly that of juvenile rats, was enriched with a heterogeneous series of SSBs which were not found in liver chromatin and presumably associated with chromosomal DNA. Some of these SSBs were enriched in glial chromatin of sensitive SD rats compared with that of resistant BD-IV rats. High mobility group proteins (HMG) 1 and 2 constituted major SSB components in the nucleoplasm and a greater amount of these HMGs were found in juvenile glia, compared to adult glia and juvenile and adult liver. Fractionation of glial SSBs and determination of their biological functions may contribute to the further understanding of the role these proteins may play in the processes of carcinogenesis.

Animals↗
PubMed1994

Effects of lovastatin (20-80 mg daily) on lipoprotein fractions in patients with severe primary hypercholesterolemia.

The effect of lovastatin on lipids, lipoproteins and apolipoproteins was studied in 10 patients with primary hypercholesterolemia. After four weeks diet/placebo alone, patients received diet plus lovastatin at daily doses of 20 mg (weeks 1-4), 40 mg (weeks 5-8) and 80 mg (weeks 9-12). Twelve weeks of treatment with lovastatin resulted in a lowering of total cholesterol and LDL-cholesterol by 34% and 41%, respectively. Triglycerides and VLDL-cholesterol decreased by 19% and by 42%, respectively. HDL-cholesterol and HDL2-cholesterol increased, whereas HDL3-cholesterol was not affected. IDL-cholesterol decreased by 50%, suggesting that the clearance of remnant lipoproteins was enhanced by lovastatin. In the VLDL and the IDL fraction, the triglyceride to cholesterol mass ratio increased significantly after twelve weeks of therapy. Lipoprotein(a) was not affected. Lovastatin was well tolerated and the data shows that lovastatin exerts favorable effects on plasma lipoprotein fractions. It may, therefore, prove a useful drug in the primary and secondary prevention of atherosclerotic vessel diseases.

Adult↗
PubMed1994

The uteroglobin promoter targets expression of the SV40 T antigen to a variety of secretory epithelial cells in transgenic mice.

Adenocarcinomas derived from the lining epithelia of various organs are the most common malignant tumors in human pathology and about 50% are hormone dependent. The tissue-specific and hormally regulated expression of the rabbit uteroglobin gene is secretory epithelial cells could provide a means of establishing in vivo models for a variety of human tumors originating from such tissues. We have generated trangenic mice inheriting a hybrid gene containing 4.7 kb of the rabbit uteroglobin 5'-flanking sequences fused to the SV40 T antigen encoding region. All transgenic founders examined exhibited bronchio-alveolar adenocarcinomas, probably due to expression of the transgene in Clara cells. Most founders also developed tumors of the submandibular salivary gland, and adenocarcinomas of the stomach. Adenocarcinomas and dysplasias in epithelial cells of the male and female genital tract were found in single founders. Immunohistochemical analysis showed that T antigen expression interfered with stable maintenance of the differentiated phenotype as documented by expression of the endogenous uteroglobin gene. One founder gave rise to a mouse line, UT7.1. Transgenic descendants of UT7.1 developed lung adenocarcinomas and, depending on the genetic background, exhibited tumors of the stomach, the salivary gland and the pancreas. Sporadically male descendants developed prostatic adenocarcinoma whereas females developed dysplasias and adenocarcinomas of the uterus and the oviduct. Thus, the UT7.1 mouse line could be a useful model for several epithelial neoplasias.

Adenocarcinoma↗
PubMed1993

[Long-term treatment of mucoviscidosis. Results with a microencapsulated pancreatic enzyme preparation].

METHODS: In 30 children suffering from cystic fibrosis, the long-term effect (2 years) of treatment with an acid-protected micro-encapsulated pancreatin preparation was investigated in comparison with prior enzyme replacement with a conventional pancreatin preparation given over a period of years. Assessment criteria was the development of body length and body weight, lung function (vital capacity, FEF1) and the Shwachman-Kulczycki score. RESULTS: The therapeutic efficacy of the acid-protected micro-encapsulated preparation is considered to be higher than that of conventional preparations, since the same effect was achieved with only one-quarter to one-third of the pancreatin dose of the conventional preparation (average: 6.5 +/- 2.9 g pancreatin/d, as compared with 1.6 +/- 0.6 g pancreatin in the case of the acid-protected micro-encapsulated preparation). However, none of the clinical parameters investigated revealed any significant changes during the course of the observation period. The results indicate that, if the general state of health and nutritional status of patients with cystic fibrosis is to be improved further, in addition to a special diet, attempts must be made to achieve further optimization of the intraluminal digestion.

Adolescent↗
PubMed1993

Expression of c-fos and c-myc protooncogenes in an immortalized hepatocyte line harbouring SV40 T antigen and hGH as transgenes.

A clonal hepatocyte line (FMH-202-2), derived from livers of fetal transgenic mice harbouring human growth hormone (hGH) and SV40 T antigen as transgenes, was used in the investigation of protooncogene expression involved in liver-specific growth control and/or in hepatocellular transformation. In this model system, representing an immortalized, yet untransformed phenotype, the transgenes hGH and SV40 T antigen were expressed constitutively. The c-fos protooncogene was induced by incubation with insulin, epidermal growth factor (EGF) and insulin-like growth factor (IGF-I) in a transient manner comparable to its expression in primary murine hepatocytes. Elucidation of second messenger mechanisms demonstrated that c-fos induction by hepatotrophic growth factors was not mediated by protein kinase C. In contrast to primary hepatocytes, the c-myc protooncogene exhibited a constitutive expression pattern which was independent of growth factor stimulation. These results indicate that apart from hGH and SV40 T antigen, c-myc may play a role in cellular immortalization, but that constitutive expression of these genes, even in combined coexpression, does not suffice to induce the transformed phenotype.

Animals↗
PubMed1993

Molecular analysis of radiation-induced albino (c)-locus mutations that cause death at preimplantation stages of development.

Deletion mutations at the albino (c) locus have been useful for continuing the development of fine-structure physical and functional maps of the Fes-Hbb region of mouse chromosome 7. This report describes the molecular analysis of a number of radiation-induced c deletions that, when homozygous, cause death of the embryo during preimplantation stages. The distal extent of these deletions defines a locus, pid, (preimplantation development) genetically associated with this phenotype. The proximal breakpoints of eight of these deletions were mapped with respect to the Tyr (tyrosinase; albino) gene as well as to anonymous loci within the Fah-Tyr region that are defined by the Pmv-31 viral integration site and by chromosome-microdissection clones. Rearrangements corresponding to the proximal breakpoints of two of these deletions were detected by Southern blot analysis, and a size-altered restriction fragment carrying the breakpoint of one of them was cloned. A probe derived from this deletion fusion fragment defines a locus, D7Rn6, which maps within (or distal to) the pid region, and which discriminates among the distal extents of deletions eliciting the pid phenotype. Extension of physical maps from D7Rn6 should provide access both to the pid region and to loci mapping distal to pid that are defined by N-ethyl-N-nitrosourea-induced lethal mutations.

Albinism↗
PubMed1993

Development of short-term mutagenicity test systems in vitro: metabolic activation of indirectly acting mutagens by three immortal rat hepatocyte lines.

The metabolic capacity to activate the indirectly acting promutagens aflatoxin B1, cyclophosphamide, benzo[a]-pyrene, 7,12-dimethylbenz[a]anthracene and dimethylnitrosamine into DNA-reactive metabolites was investigated in three immortalized rat hepatocyte cell lines (NRL cl-B, NRL cl-C and ARL) by analysing chromosome aberrations and sister chromatid exchange (SCE). In all three cell lines a significant clastogenic and SCE inducing response was observed after exposure to each test compound. Furthermore, activities of the two enzymes aryl hydrocarbon hydroxylase and aldrin-epoxidase, which play major roles in the cytochrome P450-dependent metabolism, could be determined in all cell lines. In contrast to the hepatocyte lines in V79 Chinese hamster cells, which were used as a reference cell line without any cytochrome P450 metabolizing capacity, no arylhydrocarbon hydroxylase or aldrinepoxidase activities were detected. A cytogenetic response to the test compounds was only observed in the presence of the exogenous activating system S9 mix. Due to the wide, efficient and stable spectrum of their metabolizing capacities, the tested rat hepatocyte lines offer promising perspectives as alternative assay systems for the detection of indirectly acting mutagens.

Animals↗
PubMed1993

Differential expression of gap junction connexins in endocrine and exocrine glands.

We have investigated the expression of three gap junction proteins and their corresponding mRNAs by secretory cells of a variety of endocrine and exocrine rat glands. By immunostaining cryostat sections (indirect immunofluorescence) with antibodies against connexins (Cx) 26, 32, and 43 and by hybridizing total glandular RNA (Northern blot) with cRNAs for these proteins, we have found that several endocrine glands (pituitary, parathyroid, pancreatic islets, and adrenal) express Cx43, variable levels of Cx26, and no Cx32, whereas several exocrine glands (lacrimal gland, salivary glands, pancreas, prostate, and seminal vesicle) express high levels of Cx32 and variable levels of Cx26, but no Cx43. Thus, different sets of proteins comprise the gap junctions of endocrine and exocrine glands. Together with the findings that an endocrine gland (thyroid) that discharges secretory products extracellularly before releasing them in the vascular compartment expresses both Cx43 and Cx32 and that an exocrine gland (preputial gland) that has a pheromonal role expresses Cx43, these observations suggest that the differential expression of gap junction connexins may be required to specify the endocrine or exocrine differentiation of a secretory cell.

Adrenal Glands↗
PubMed1993

[Concepts and attitudes of parents of adolescents in regard to suicide].

In the context of parents reacting with surprise to the suicidal tendencies of their teenage child, the authors prepared a questionnaire for 380 parents of adolescents to gauge the realism of their perceptions on the topic. The authors noted differences of opinion between fathers and mothers among parents who have experienced a variety of situations related to suicide and others who have received information on the matter. These differing points of view concern the impulsive nature of the gesture, the age of the suicidal person, the opportunity to intervene and the level of acceptance of suicide. In addition, this study underscores the importance of implementing prevention programs that go beyond the simple distribution of information.

Adolescent↗
PubMed1993

Alpha adrenergic and mu-2 opioid receptors are involved in morphine-induced suppression of splenocyte natural killer activity.

The immunosuppressive effects following acute morphine administration have been mapped to opioid receptors in the central nervous system, specifically to the periaqueductal gray matter of the mesencephalon. The mesencephalon is associated with sympathetic neuronal processes, and the spleen is innervated with sympathetic neurons that are in direct apposition with lymphocytes in the periarteriolar lymphatic sheath. Accordingly, we investigated adrenergic involvement following morphine administration on natural killer (NK) activity by splenic lymphocytes. Acute morphine administration (25 mg/kg s.c.) suppresses (30-50%) NK activity by murine splenic immunocytes as measured in a 4-hr 51Cr-release assay. The suppression is blocked by phentolamine (4 mg/kg) and propranolol (10 mg/kg) in a dose-dependent fashion. However, phentolamine (2 mg/kg), but not propranolol (5 mg/kg), can also effectively antagonize morphine-induced immunosuppression. In addition, phentolamine (4 mg/kg) and prazocin (1 mg/kg), but not yohimbine (1 mg/kg), antagonizes morphine-elicited suppression of splenic NK activity. Selective opioid receptor antagonists were also utilized to determine the type or subtype of receptor activated following morphine administration. beta-Funaltrexamine (40 mg/kg) but not naloxonazine (35 mg/kg), naltrindole (20 mg/kg) or norbinaltorphimine (10 mg/kg) effectively blocks morphine-induced suppression of splenic NK activity. Collectively, morphine interacts with 1) mu-2 opioid receptors (most probably centrally) and 2) activates both alpha and beta adrenergic pathways.

Animals↗
PubMed1993

Mycobacterium marinum skin infections: two case reports.

Most infections of soft tissue injury sites are caused by Staphylococcus or Streptococcus and respond to beta-lactam antibiotics. Occasionally, a patient does not respond to routine antibiotics, and other possibilities must be considered. A detailed history of the event that caused the soft tissue injury can be important in the diagnosis. Two cases of Mycobacterium marinum soft tissue infection (ie, fish tank granuloma) are presented.

Female↗
PubMed1992

Analgesic potency of TRIMU-5: a mixed mu 2 opioid receptor agonist/mu 1 opioid receptor antagonist.

TRIMU-5 (Tyr-D-Ala-Gly-NH-(CH2)2CH(CH3)2) is a potent enkephalin analog with analgesic actions. Detailed studies show high affinity for both mu 1 and mu 2 sites, with poor affinity for delta, kappa 1 and kappa 3 receptors. Of all the mu ligands examined in binding assays, TRIMU-5 was the most mu-selective. In mice, TRIMU-5 administered either intracerebroventricularly (i.c.v.) or intrathecally elicited analgesia which was readily reversed by the mu-selective antagonist beta-funaltrexamine (beta-FNA). However, the analgesia observed following i.c.v. injections differed from traditional mu ligands: (1) the dose of drug required for analgesic activity i.c.v. was 100-fold greater than those following intrathecal administration; (2) although sensitive to beta-FNA, the analgesia was not antagonized by naloxonazine; and (3) the analgesia was reversed by an opioid antagonist given intrathecally (i.t.) but not i.c.v. Thus, TRIMU-5 analgesia appeared to be mediated spinally through mu 2 receptors. TRIMU-5 did have supraspinal actions, inhibiting gastrointestinal transit, another mu 2 action. In binding studies TRIMU-5 had high affinity for mu 1 sites, but pharmacological studies revealed antagonist actions at this receptor. In mice, the analgesia produced by morphine given i.c.v. was antagonized by coinjection of a low TRIMU-5 dose which was inactive alone. Similarly, TRIMU-5 coadministered with morphine into the periaqueductal gray of rats reversed the analgesia seen with morphine alone. Thus, TRIMU-5 is a highly selective mixed mu 2 opioid receptor agonist/mu 1 opioid receptor antagonist.

Analgesics↗
PubMed1992

Potentiation of opioid analgesia by the antidepressant nefazodone.

Nefazodone is a new antidepressant related structurally to trazodone. In addition to its activity in preclinical assays for antidepressant activity, nefazodone was a potent analgesic in the mouse hotplate assay. At 50 mg/kg s.c. nefazodone doubled baseline latencies in 40% of mice but was inactive in the tailflick test at any dose tested. The hotplate analgesia seen with nefazodone alone was not reversed by naloxone (10 mg/kg s.c.). In the tailflick assay, nefazodone (50 mg/kg s.c.) enhanced morphine's analgesic response, shifting morphine's ED50 from 3.1 mg/kg alone to 0.86 mg/kg in conjunction with nefazodone (P less than 0.05). Two days after implantation of a morphine pellet (75 mg) no mice remained analgesic in the tailflick assay. Administration of nefazodone (50 mg/kg s.c.) restored analgesia to 60% of mice (P less than 0.03). In selective analgesic assays, nefazodone enhanced mu 1, mu 2 and delta analgesia, but not kappa 1 or kappa 3 analgesia. Nefazodone did not affect morphine's LD50 and, in assays of gastrointestinal transit, nefazodone increased morphine's potency only slightly. In conclusion, nefazodone alone is analgesic in certain animal models. In conjunction with morphine, nefazodone potentiated analgesia with no effect on lethality and little effect on gastrointestinal transit, resulting in an increase in morphine's therapeutic index. These results suggest that nefazodone and similar agents may have a significant role in the management of pain.

Analgesia↗
PubMed1992

Transcriptional control in hepatocytes of normal and c14CoS albino deletion mice.

The transcription rates of the albumin and alpha-fetoprotein (alpha FP) genes were reduced to marginally detectable levels in livers of newborn or fetal c14CoS albino deletion mutant mice, which lack the hepatocyte specific developmental regulation (hsdr-1) locus on chromosome 7 and die shortly after birth. However, steady-state levels of these two mRNAs in livers of mutant mice were similar to those in normal mice, where these genes are actively transcribed. In c14CoS mice, transcription rates of transcription factor genes HNF-1, C/EBP and HNF-4 were reduced, albeit to different extents. These effects are specific because transcription of the HNF-3, DBP, LAP and Jun-B genes remained normal in mutant mice. Steady-state levels of all of these mRNAs reflected the transcriptional activities. Levels of HNF-1 and HNF-4 mRNAs showed much greater depression than that of C/EBP in mutant liver. The availability of this group of transcription factors may be reduced in c14CoS hepatocytes and therefore caused depressed transcription rates of their target genes such as those encoding albumin and alpha FP. However, the normal steady-state levels of albumin and alpha FP mRNAs in mutant mice remains unexplained. Fetal c14CoS hepatocytes in primary culture did acquire competence for glucocorticoid inducible transcription of the albumin, alpha FP, HNF-4 and metallothionein genes but not of the tyrosine aminotransferase (TAT) gene. These results indicate that the hsdr-1 locus is dispensable for the glucocorticoid induced transcription of these genes but not of TAT. The effects caused by the c14CoS deletion are pleiotropic in controlling the expression of numerous genes at distinct levels in the liver.

Albinism↗