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Biomedical subjects

R Harden

Publications and source records attributed to R Harden.

8 recordsLinked to original sources
PubMed2000

Task-based learning: the answer to integration and problem-based learning in the clinical years.

INTRODUCTION: Integrated teaching and problem-based learning (PBL) are powerful educational strategies. Difficulties arise, however, in their application in the later years of the undergraduate medical curriculum, particularly in clinical attachments. Two solutions have been proposed - the use of integrated clinical teaching teams and time allocated during the week for PBL separate from the clinical work. Both approaches have significant disadvantages. Task-based learning (TBL) is a preferred strategy. In TBL, a range of tasks undertaken by a doctor are identified, e.g. management of a patient with abdominal pain, and these are used as the focus for learning. Students have responsibility for integrating their learning round the tasks as they move through a range of clinical attachments in different disciplines. They are assisted in this process by study guides. METHOD: The implementation of TBL is described in one medical school. One hundred and thirteen tasks, arranged in 16 groups, serve to integrate the student learning as they rotate through 10 clinical attachments. RESULTS: This trans-disciplinary approach to integration, which incorporates the principles of PBL offers advantages to both teachers and students. It recognizes that clinical attachments in individual disciplines can offer rich learning opportunities and that such attachments can play a role in an integrated, as well as in a traditional, curriculum. In TBL, the contributions of the clinical attachments to the curriculum learning outcomes must be clearly defined and tasks selected which will serve as a focus for the integration of the students' learning over the range of attachments.

Clinical Clerkship↗
PubMed2000

Phylogeny and biogeography of Juglans (Juglandaceae) based on matK and ITS sequence data.

We investigated phylogenetic and biogeographic relationships within Juglans (walnuts), a Tertiary disjunct genus, using 15 species of Juglans and related (Juglandaceae) outgroups. The relationships were analyzed using nucleotide sequences of the chloroplast gene matK and its flanking spacers and of the internal transcribed spacers (ITS) and 5.8S gene of the nuclear ribosomal DNA. The DNA sequences provided 246 informative characters for parsimony analysis. ITS data supported as monophyletic groups the four generic sections, Cardiocaryon, Dioscaryon, Rhysocaryon, and Trachycaryon. Within Rhysocaryon, the temperate black walnuts and the tropical black walnuts were supported as monophyletic groups. When the two data sets were combined, J. cinerea was nested within Cardiocaryon. Combined analysis with published nuclear DNA restriction site data placed J. cinerea in a monophyletic group with Cardiocaryon. These analyses consistently supported Juglans as a monophyletic group and as the sister group to the genus Pterocarya. The results of this work are consistent with the known geological history of Juglans. The fossil record suggests that the butternuts had evolved by the early Oligocene in North America. The presence of butternuts in Eurasia could be the result of migration from North America to Eurasia during the warming trend of the mid Oligocene.

Journal Article↗
PubMed2000

Promotion by sodium barbital induces early development but does not increase the multiplicity of hereditary renal tumors in Eker rats.

Induced cell proliferation is important in the mode of action of many non-genotoxic renal carcinogens. Since Tsc2 mutant (Eker) rats are genetically predisposed to the development of renal cell tumors, they provide a useful animal model in which to study the action of renal carcinogens. Sodium barbital was used as a model non-genotoxic renal carcinogen to test whether a concentration that increased renal tubular proliferation without severe nephrotoxicity would enhance tumor induction in a hereditary tumor model. First, a subchronic concentration-response study was conducted in wild-type male Long-Evans rats to determine increased cell proliferation without severe nephrotoxicity. Rats were dosed with sodium barbital in the feed at 0, 50, 250, 500, 1000, 2000 or 4000 p.p.m. for 3 or 8 weeks. Cell proliferation within the cortex and nephrotoxicity were quantitated. Enhanced proliferation with minimal nephrotoxicity occurred at 500 p.p.m. A second study was conducted in male Tsc2 mutant rats given sodium barbital in the feed at 0, 100 or 500 p.p.m. from 9 weeks of age to either 6 or 12 months of age. An additional group of rats was treated with sodium barbital for 6 months and then provided control feed until 12 months of age. Rats necropsied at 6 months of age had a concentration-dependent increase in preneoplastic and total renal lesions. Sodium barbital-treated rats necropsied at 12 months of age had numbers of lesions that were not different from controls. Total combined preneoplastic and neoplastic lesions in the 6 month, high dose group was the same as the 12 month control group. These data show that sodium barbital caused progression to the stage of spontaneous renal lesions in Tsc2 mutant rats but did not increase their overall number. These data suggest that enhanced cell proliferation without significant cytotoxicity exerted a promotional influence in this hereditary model.

Animals↗
PubMed1998

Estrogen treatment enhances hereditary renal tumor development in Eker rats.

Hormonal influences are known to affect the development of renal cell carcinoma in man and laboratory animal models. We tested the hypothesis that estrogen treatment or ovariectomy of rats modulates renal tumor development using tuberous sclerosis 2 (Tsc2) heterozygous mutant (Eker) rats in which a germline mutation predisposes the animals to renal cell tumor development. Two-month-old female wild-type and Eker rats were ovariectomized or sham-operated and treated with placebo or 5 mg 17beta-estradiol in s.c. pellets for 6 or 10 months. Rats were examined at 8 or 12 months of age, at which time the numbers of renal tumors and preneoplastic foci were quantitated and the severity of nephropathy was assessed. In contrast to what may have been expected, prolonged estrogen treatment enhanced the development of hereditary renal cell tumors, with a 2-fold greater number of preneoplastic and neoplastic renal lesions compared with untreated Eker rats. Ovariectomized Eker rats had 33% fewer renal lesions than the unmanipulated control group. No tumors or preneoplastic lesions were present in wild-type rats at either time point. Estrogen treatment increased the severity of nephropathy in both wild-type and Eker rats, whereas ovariectomy was protective against nephropathic changes. Although estrogen is not a rat renal carcinogen, it enhanced the development of hereditary renal cell tumors when administered to Eker rats. Eker rats heterozygous for a mutation in the Tsc2 locus provide a good model in which to study how genetic and hormonal factors contribute to the development of renal cell tumors and to understand the influence genetic susceptibility has on the development of renal cell carcinoma.

Animals↗
PubMed1996

A non-bile duct origin for intestinal crypt-like ducts with periductular fibrosis induced in livers of F344 rats by chloroform inhalation.

To evaluate the toxic effects of prolonged exposure to chloroform vapors, female and male F344 rats were exposed to 0, 2, 10, 30, 90 and 300 p.p.m. chloroform by inhalation for 7 or 5 days/week for up to 13 weeks. The purpose of this study was to characterize a lesion that occurred in the livers of rats in the 300 p.p.m. exposure groups. Atypical glandular structures lined by intestinal-like epithelium and surrounded by dense connective tissue occurred in the livers of rats exposed to strongly hepatotoxic atmospheric concentrations of chloroform. Bile duct bromodeoxyuridine labeling indices as well as observations of the locations of the early lesions at the 3 and 6 week time points indicate that these lesions arose from a population of cells remote from the bile ducts. We refer to these lesions as intestinal crypt-like ducts with periductular fibrosis to distinguish them from true cholangiofibrosis. Here, intestinal crypt-like ducts with periductular fibrosis were seen only in rats exposed to 300 p.p.m. chloroform, and the multiplicity and severity of the lesions were greater in the right liver lobe. The lesion only occurred in association with liver necrosis and dramatic increases in hepatocyte labeling indices, while labeling indices in bile ducts in the same animals were not significantly different from controls. There was a treatment-related increase of transforming growth factor-alpha immunoreactivity in hepatocytes, bile duct epithelium, bile canaliculi and oval cells, and an increase in transforming growth factor-beta immunoreactivity in hepatocytes, bile duct epithelium and intestinal crypt-like ducts. Thus, intestinal crypt-like ducts with periductular fibrosis appeared to develop from a population of cells unrelated to bile ducts. Also, they occurred only in animals exposed to chloroform concentrations that induced significant hepatocyte necrosis and regenerative cell proliferation and were associated with increased growth factor expression or uptake.

Administration, Inhalation↗
PubMed1996

Cell proliferation and regulation of negative growth factors in mouse liver foci.

Foci of altered hepatocytes are preneoplastic lesions capable of progressing to hepatocellular carcinomas. To characterize the growth of preneoplastic hepatic lesions, size of hepatic foci was analyzed with regard to growth factor regulation and hepatocyte proliferation in focal and non-focal hepatocytes. Twelve-day-old female B6C3F1 mice were initiated with a single dose of the potent mutagen N-nitrosodiethylamine (DEN) (5 mg/kg body weight). Beginning at 6 weeks of age, mice were exposed for 16 weeks to 2038 p.p.m. unleaded gasoline (UG) vapor or 1 p.p.m. ethinyl estradiol (EE) in the diet. Analysis of hepatic foci demonstrated that UG significantly increased, but EE significantly decreased the size of DEN-initiated foci. Hepatic labeling index (LI), as measured by the incorporation of 5-bromo-2'-deoxyuridine, was similar in non-focal hepatocytes at 16 weeks in all groups (0.4-0.8%) and greatly increased in hepatic foci. Hepatocyte LI was significantly increased in DEN/UG foci (29%, n = 41) and significantly decreased in DEN/EE foci (6%, n = 23) relative to DEN/control focal hepatocytes (18%, n = 25). The mean LI of foci correlated with the focal size differences observed in the treatment groups. Immunohistochemical analysis with antibodies directed to the negative growth regulator transforming growth factor-beta 1 (TGF-beta1) demonstrated a consistent decrease of TGF-beta 1 in DEN/Ct and DEN/UG hepatic foci relative to non-lesion hepatocytes. Similar results were seen with mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF-II R), which facilitates activation of latent TGF-beta 1. In contrast, only 50% of DEN/EE foci had decreased levels of TGF-beta 1 and M6P/IGF-II R relative to non-focal hepatocytes. These data suggest that proliferative responses observed in hepatic foci may be correlated with foci size. In contrast, chemically induced proliferative responses in non-focal hepatocytes after subchronic exposure cannot necessarily be used to predict proliferative effects in preneoplastic cell populations. Furthermore, these studies suggest that hepatic foci may occur by M6P/IGF-II R enhancing activation of latent TGF-beta 1 in non-focal hepatocytes but not in the focal hepatocytes, thereby affording focal hepatocytes a selective growth advantage.

Air Pollutants↗
PubMed1994

Nasal toxicity of chloroform in male F-344 rats and female B6C3F1 mice following a 1-week inhalation exposure.

Chloroform is an important environmental water and air pollutant. Inhalation exposure of female B6C3F1 mice and F-344 rats for 6 hr/day for 7 consecutive days to 0, 1, 3, 10, 30, 100, or 300 ppm of chloroform resulted in concentration-dependent lesions in the nasal passages. Chloroform-induced changes included increased epithelial mucosubstances in the respiratory epithelium of the nasopharyngeal meatus, primarily in the rats. A complex set of responses was seen in specific regions of the ethmoid turbinates, predominantly in the rats. These lesions in the ethmoid region, which involved all of the endo- and ectoturbinates, were most severe peripherally and generally spared the tissue adjacent to the medial airways. These changes were characterized by atrophy of Bowman's glands, increased numbers of vimentin-positive cells in the periosteum, new bone formation, and increased numbers of periosteal cells in S phase as determined by bromodeoxyuridine incorporation. Additional changes were site-specific loss of mucosubstances and loss of immunocytochemical staining of acini and ducts of Bowman's glands for P450-2E1 and pancytokeratin, and loss of P450-2E1 immunostaining of the olfactory epithelium. The only change noted in the mice was increased cell proliferation without the osseous hyperplasia. The no-observed-effect level for these responses ranged from 3 to 100 ppm, with histological changes and induced cell proliferation being the most sensitive parameters. It is proposed that the osseous changes induced by chloroform exposure may be secondary to primary degeneration of adjacent Bowman's glands. The relevance of these changes to human health risks include potential damage to the sense of smell, but such effects would not be expected at the low levels of chloroform commonly encountered in the environment.

Administration, Inhalation↗