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Biomedical subjects

A Nichols

Publications and source records attributed to A Nichols.

At least 19 recordsLinked to original sources
PubMed1998

Bax-induced cytochrome C release from mitochondria is independent of the permeability transition pore but highly dependent on Mg2+ ions.

Bcl-2 family members either promote or repress programmed cell death. Bax, a death-promoting member, is a pore-forming, mitochondria-associated protein whose mechanism of action is still unknown. During apoptosis, cytochrome C is released from the mitochondria into the cytosol where it binds to APAF-1, a mammalian homologue of Ced-4, and participates in the activation of caspases. The release of cytochrome C has been postulated to be a consequence of the opening of the mitochondrial permeability transition pore (PTP). We now report that Bax is sufficient to trigger the release of cytochrome C from isolated mitochondria. This pathway is distinct from the previously described calcium-inducible, cyclosporin A-sensitive PTP. Rather, the cytochrome C release induced by Bax is facilitated by Mg2+ and cannot be blocked by PTP inhibitors. These results strongly suggest the existence of two distinct mechanisms leading to cytochrome C release: one stimulated by calcium and inhibited by cyclosporin A, the other Bax dependent, Mg2+ sensitive but cyclosporin insensitive.

Animals↗
PubMed1998

Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase.

MAP kinase phosphatase-3 (MKP-3) dephosphorylates phosphotyrosine and phosphothreonine and inactivates selectively ERK family mitogen-activated protein (MAP) kinases. MKP-3 was activated by direct binding to purified ERK2. Activation was independent of protein kinase activity and required binding of ERK2 to the noncatalytic amino-terminus of MKP-3. Neither the gain-of-function Sevenmaker ERK2 mutant D319N nor c-Jun amino-terminal kinase-stress-activated protein kinase (JNK/SAPK) or p38 MAP kinases bound MKP-3 or caused its catalytic activation. These kinases were also resistant to enzymatic inactivation by MKP-3. Another homologous but nonselective phosphatase, MKP-4, bound and was activated by ERK2, JNK/SAPK, and p38 MAP kinases. Catalytic activation of MAP kinase phosphatases through substrate binding may regulate MAP kinase activation by a large number of receptor systems.

Amino Acid Sequence↗
PubMed1998

Inheritance and usefulness of AFLP markers in channel catfish (Ictalurus punctatus), blue catfish (I. furcatus), and their F1, F2, and backcross hybrids.

Eight primer combinations were used to investigate the application of amplified fragment length polymorphism (AFLP) markers in catfish for genetic analysis. Intraspecific polymorphism was low among channel catfish or blue catfish strains. Interspecific AFLP polymorphism was high between the channel catfish and blue catfish. Each primer combination generated from 70 to more than 200 bands, of which 38.6 75.7% were polymorphic between channel catfish and blue catfish. On average, more than 20 polymorphic bands per primer combination were produced as quality markers suitable for genetic analysis. All AFLP markers were transmitted into channel catfish x blue catfish F1 hybrids, except rare markers that were heterozygous in the parents and therefore were segregating in F1 hybrids. The two reciprocal channel catfish x blue catfish F1 hybrids (channel catfish female x blue catfish male; blue catfish female x channel catfish male) produced identical AFLP profiles. The AFLP markers were inherited and segregated in expected Mendelian ratios. At two loci, E8-b9 and E8-b2, markers were found at significantly lower frequencies than expected with F2 and backcross hybrids which had been selected for increased growth rates. The reproducibility of AFLP was excellent. These characteristics of the catfish AFLP markers make them highly useful for genetic analysis of catfish, especially for construction of genetic linkage and quantitative trait loci maps, and for marker-assisted selection.

Animals↗
PubMed1997

Medical superintendents with right of private practice in Queensland: practice, training and support.

This article presents the findings of a 1993 study into the work patterns, training and support needs of Medical Superintendents with Right of Private Practice (MSRPP), in Queensland funded by the Southern Queensland Rural Division of General Practice. These doctors form a small but significant subset of the medical workforce with a diverse range of duties, and until now there has been no formal study of their professional and family circumstances. Survey and interview data indicate that MSRPPs are a group subject to considerable professional and social pressure, usually in isolated practice and therefore vulnerable to attrition. This study aimed to provide a clearer identification of what MSRPPs do, what they need and how these needs can be met; and thus to contribute to more favourable retention rates for this sub-set of the rural medical workforce.

Adult↗
PubMed1996

Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease.

The presenilin 1 gene has recently been identified as the locus on chromosome 14 which is responsible for a large proportion of early onset, autosomal dominantly inherited Alzheimer's disease (AD). We have elucidated the intron/exon structure of the gene and designed intronic primers to enable direct sequencing of the entire coding region (10 exons) of the presenilin gene in a large number of families. This strategy has enabled us to find a further two novel mutations in the gene. We discuss the distribution of mutations and the proportions of autosomal dominant AD with a mean age of onset below 60 years caused by mutations in this gene.

Alzheimer Disease↗
PubMed1996

Fostering multidisciplinary research and approaches to rural health issues: the concept of an International Summer Institute.

The challenge of how best to provide equitable, accessible and affordable health care in rural and remote settings is an international concern. It has been acknowledged that a multidisciplinary approach to current rural health issues involving social scientists and health practitioners may be crucial in developing appropriate responses. One initiative designed to facilitate multidisciplinary research and greater collaboration between researchers and practitioners was an International Summer Institute sponsored by the Social Science and Humanities Research Council of Canada. This article outlines an Australian perspective on the rationale for, background to, and structure of this initiative, and evaluates it as one option for promoting multidisciplinary approaches to rural health research.

Allied Health Personnel↗
PubMed1996

Chemical approaches to improve the oral bioavailability of peptidergic molecules.

This review discusses both tools and strategies that may be employed as approaches towards the pursuit of orally active compounds from peptidergic molecules. Besides providing a review of these subjects, this paper provides an example of how these were utilized in a research programme at SmithKline Beecham involving the development of orally active GPIIb/IIIa antagonists. The tools for studying oral drug absorption in-vitro include variants of the Ussing chamber which utilize either intestinal tissues or cultured epithelial cells that permit the measurement of intestinal permeability. Example absorption studies that are described are mannitol, cephalexin, the growth hormone-releasing peptide SK&F 110679 and two GPIIb/IIIa antagonist peptides SK&F 106760 and SK&F 107260. With the exception of cephalexin, these compounds cross the intestine by passive paracellular diffusion. Cephalexin, on the other hand, crosses the intestine via the oligopeptide transporter. Structure-transport studies are reviewed for this transporter. The tools for studying oral drug absorption in-vivo involve animals bearing in-dwelling intestinal or portal vein catheters. A study of the segmental absorption of SK&F 106760 is provided. The review concludes with two chemical strategies that may be taken towards the enhancement of oral bioavailability of peptidergic molecules. The first strategy involves the chemical modification of peptides which enhance intestinal permeability, specifically the modification of amide bonds. The second strategy involves the design of compounds bearing nonpeptide templates, which are more amenable to the discovery of compounds with oral activity, from peptide pharmacophore models. An example is given regarding the discovery of SB 208651, a potent orally active GPIIb/IIIa antagonist, designed from the peptides SK&F 106760 and SK&F 107260.

Absorption↗
PubMed1995

TGF-beta 1 overexpression in murine pancreas induces chronic pancreatitis and, together with TNF-alpha, triggers insulin-dependent diabetes.

We have generated transgenic mice overexpressing TGF-beta 1 in pancreatic beta cells. This resulted in massive fibrosis of the pancreas; in adult mice, most of the acini were replaced by fibrotic and adipose tissues. A conspicuous disorganization of the islets of Langerhans was also observed; however, the number of beta cells was not decreased and the mice were normoglycemic. Backcrossing to transgenic mice overexpressing TNF-alpha in their islet beta cells (which also remain normoglycemic, (1)) yielded double transgenics, most of which became diabetic by the age of 4 months; histological analysis revealed a dramatic decrease in insulin-containing beta cells.

Amylases↗
PubMed1995

Candida tropicalis chorioamnionitis.

A case of Candida tropicalis chorioamnionitis at 25 weeks' gestation is presented, and the literature is reviewed. This is the first report, to our knowledge, of C. tropicalis diagnosed antenatally with confirmed congenital infection.

Adult↗
PubMed1995

Inhibition of Xhox1A gene expression in Xenopus embryos by antisense RNA produced from an expression vector read by RNA polymerase III.

Antisense inhibition of gene expression during Xenopus development was obtained by injecting, into the zygote, an expression vector carrying the adenovirus VAI gene read by RNA polymerase III. This vector yields high levels of antisense RNA in most embryonic cells between mid-blastula transition and tailbud stage. As a target we chose the Xenopus homeobox gene Xhox1A. A 26 bp long oligonucleotide, including the initiation codon of this gene, was inserted in opposite polarity into the vector. Antisense treatment reduces Xhox1A mRNA in embryos up to stage 22 and Xhox1A protein expression up to stage 30. Half of the antisense-treated embryos develop a characteristic phenotype with disorganized somites in the anterior trunk and delayed development of the intestinal tract.

Animals↗
PubMed1994

Ablation of islet endocrine cells by targeted expression of hormone-promoter-driven toxigenes.

Ontogenic relationships between the different types of endocrine cells in the islets of Langerhans were explored by generating transgenic mouse embryos in which cells transcribing the glucagon, insulin, or pancreatic polypeptide genes were destroyed through the promoter-targeted expression of the diphtheria toxin A chain. Embryos lacking glucagon- or insulin-containing cells did not exhibit alterations in the development of the nontargeted islet cell types, whereas embryos lacking pancreatic polypeptide gene-expressing cells also lacked pancreatic insulin- and somatostatin-containing cells. These results show that neither glucagon nor insulin gene-expressing cells are essential for the differentiation of the other islet endocrine-cell types. These results also suggest that pancreatic polypeptide gene-expressing cells are indispensable for the differentiation of islet beta and delta cells because the former produce a necessary paracrine or endocrine factor and/or operate through a cell-lineage relationship.

Animals↗
PubMed1994

Training for rural general practice.

OBJECTIVE: To identify requirements for vocational training and continuing education programs in rural general practice. DESIGN: A questionnaire was sent to all 487 rural doctors and 140 metropolitan and 140 provincial city general practitioners (GPs) in Queensland. A sample of medical educators, health professional and consumer representatives and rural doctors was also interviewed. Responses were compared by geographical area, practice characteristics and level of postgraduate training. RESULTS: There are significant differences between rural and urban practice profiles. Rural doctors have to practise a range of clinical skills in an environment with restricted access to health professional support, although the need for advanced training in procedural or other skills depends on the type of rural practice. Rural and urban doctors want more influence in determining continuing medical education (CME) programs. Interactive learning methods were rated as the most effective education methods by both rural and urban GPs. Rural doctors were less likely to consider that they spent enough time on CME. CONCLUSION: Vocational training programs should accommodate various rural career objectives, including those requiring advanced levels of procedural work. There is a significant unmet demand for CME tailored to the needs of individual doctors, both rural and urban, but distance and isolation may make this more critical in rural practice. These issues need to be addressed as training opportunities can contribute to improved retention of the rural medical workforce.

Australia↗
PubMed1994

The value of hysteroscopy.

This study is a report of the first 200 diagnostic hysteroscopic procedures undertaken on 191 patients, in the GynaecoIogical Outpatient Department of a busy general hospital. One hundred and sixty examinations were conducted successfully. The study demonstrated that outpatient hysteroscopy is valuable to the patient by avoiding hospitalization and general anaesthesia, valuable to the nursing and medical staff by increasing job satisfaction and valuable to the hospital by reducing expensive inpatient costs. The potential reduction to the Australian national health budget, by the adoption of outpatient hysteroscopy instead of inpatient dilatation of the cervix and curettage, is calculated to be in excess of $60,000,000 per annum.

Cost-Benefit Analysis↗
PubMed1994

A sampling framework for rural and remote doctors.

A pilot survey by telephone interview, followed by a questionnaire of all rural doctors identified in Queensland, was used develop both a definition of rural practice that distinguishes it from urban general practice and a classification of rural and remote practice which assists in sampling of rural doctors. Questionnaire responses in specific geographic areas were compared using chi-square and Mantel-Haenszel chi-square tests. Several factors were found to differentiate rural from urban general practice consistently, thereby enabling a functional definition of rural practice to be developed. Within the broad group of rural doctors, gradients in practice characteristics were found to differentiate doctors in larger rural centres from those in smaller, more remote communities. These gradients were related to the distance and time of travel from support services. They formed the basis of a complex classification of rural and remote general practice. This functional definition of rural and remote medical practice should be considered by researchers of rural medicine issues when sampling rural and remote doctors. The strategies used in this study could be adapted for use in considering practice characteristics of other rural health professions.

Humans↗
PubMed1994

TGF-beta 1 influences the relative development of the exocrine and endocrine pancreas in vitro.

Pancreatic rudiments from E12.5 mouse embryos undergo extensive development and differentiation when cultured in three-dimensional gels of extracellular matrix proteins for up to 12 days. Whereas collagen gels promote the formation of numerous exocrine acini and relatively small clusters of endocrine cells, in basement membrane (EHS) matrices the development of endocrine cells is dramatically favoured over that of acinar tissue. Buds embedded in a collagen gel contiguous to an EHS gel also fail to develop acini, suggesting the involvement of diffusible factor(s). Addition of cytokines to cultures of pancreatic buds in collagen gels modifies the relative proportions of the epithelial components of the gland. In the presence of EGF the proportion of the tissue occupied by ducts overrides that of acinar structures, whereas the endocrine portion of the tissue is not significantly modified. TGF-beta 1 partially mimicks the effect of EHS matrix in inhibiting the development of acinar tissue without decreasing the amount of ducts and mesenchyme; TGF-beta 1 also promotes the development of endocrine cells, in particular of insulin-containing beta cells and of cells expressing genes of the PP-fold family. These results show that cytokines can modulate the development of the pancreas and suggest a role for TGF-beta 1 in regulating the balance between the acinar and endocrine portions of the gland in vivo. More generally, they are compatible with the notion that, during organogenesis, cytokines act as paracrine factors responsible for the development and maintenance of appropriate proportions of different tissue constituents.

Animals↗