Bayliss and Starling and the nascence of endocrinology.
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Endocrinology↗
Biomedical subjects
M Kidd
Publications and source records attributed to M Kidd.
Synaptic deficit in the temporal cortex of partial trisomy 16 (Ts65Dn) mice.
Down syndrome results from triplication of human chromosome 21. The distal end of mouse chromosome 16 shares a large region of genetic homology with the Down syndrome 'critical region' of human chromosome 21. Therefore, a partially trisomic mouse (Ts65Dn) that possesses a triplication of the distal region of chromosome 16 has been developed as a putative model for Down syndrome. Ts65Dn mice display learning and memory deficits. However, despite the importance of preserved synaptic integrity for learning and memory, the ultrastructure of neural connectivity has not yet been studied in Ts65Dn mice. Therefore, the density and apposition zone length of synapses in the temporal cortex of aged Ts65Dn mice (n=4) were compared with those in diploid controls (n=4), using quantitative electron microscopy. There were significantly less (30%) asymmetric synapses in the temporal cortex of Ts65Dn mice than in controls (t=-5.067; p=0.023). However, there was no significant difference between the mean density of symmetric synapses in Ts65Dn mice and control mice. In addition, the mean synaptic apposition lengths of both asymmetric (15%; t=9.812, p<0.0001) and symmetric (11%; t=5. 582; p<0.0001) synapses were significantly larger in Ts65Dn mice than in controls. These results suggest that excitatory synapses are preferentially affected in Ts65Dn mice and that there is an attempt to compensate for the deficit of asymmetric synapses by increasing the contact zone area of existing synapses. The results may also reveal the morphological basis for the learning and memory deficits observed in Ts65Dn mice and have a bearing on the cognitive deficits in Down syndrome in old age.
Animals↗
Gastrin-mediated alterations in gastric epithelial apoptosis and proliferation in a mastomys rodent model of gastric neoplasia.
BACKGROUND/AIMS: Hypergastrinemia secondary to low acid secretion is associated with gastric carcinoid formation in Mastomys. We investigated the effect of gastrin on oxyntic epithelial apoptosis and proliferation in this model. METHODS: Hypergastrinemia and mucosal hyperplasia were induced by irreversible H(2) receptor blockade with loxtidine. Gastrin levels were normalised in some animals by 10 days' loxtidine withdrawal. Serum gastrin was determined by radioimmunoassay, proliferative, enterochromaffin-like cells and Bcl-2 protein family expression by immunohistochemistry, and apoptotic cells by terminal deoxyuridine nucleotide nick end labeling (TUNEL). RESULTS: Proliferating cells were increased 4-fold in loxtidine-treated animals, and returned to normal upon loxtidine withdrawal. Enterochromaffin-like cell number increased 2-fold with loxtidine, and did not decrease after withdrawal. Apoptotic epithelial cells were located at the luminal surface and increased 1.8-fold with loxtidine, returning to control levels upon withdrawal. The ratio of proliferative to apoptotic cells was lower in the control and withdrawn groups than in the loxtidine group (0.26+/-0.05 and 0.26+/-0.08 vs. 0.77+/-0.12). With hypergastrinemia, the expression of Bcl-2 and Bak was increased and Bax decreased in the middle of the gland. CONCLUSION: Hypergastrinemia is associated with alterations in both proliferation and apoptosis in Mastomys gastric mucosa. This may contribute to the pathogenesis of mucosal hyperplasia in this model.
Animals↗
Prolonged expression of IFNgamma induced by protective blood-stage immunization against Plasmodium yoelii malaria.
Mice vaccinated with whole blood-stage antigens of Plasmodium yoelii develop protective, antibody-mediated immune responses to homologous challenge infection. In this model the level of protection induced by whole parasite antigen vaccination is dependent on antibody isotype, which can be influenced by adjuvant formulations. In this study the ability adjuvant formulations to affect cytokine production and protection against P. yoelii blood-stage infection was investigated. Survival of mice in groups vaccinated with P. yoelii antigens in an aqueous mix of copolymer P1005 + RaLPS was 100%. Mice vaccinated with either P. yoelii antigens alone or combined with a water-in-oil emulsion of copolymer P1005 + RaLPS demonstrated 83 or 50% survival, respectively. The fully protective aqueous vaccine group produced higher levels of interferon gamma (IFNgamma) and interleukin 4 (IL-4) than the water-in-oil vaccine group following a live parasite challenge infection. Furthermore, mice vaccinated with the aqueous vaccine displayed prolonged IFNgamma and IL-4 response as compared to mice that received the same antigens without adjuvants. These data support the hypothesis that both the Th1 cytokine IFNgamma, and the Th2 cytokine IL-4 are modulated by the vaccine vehicle and adjuvant used for vaccination, thus possibly affecting expression of protective immune responses. However, it is the long-lasting IFNgamma response following blood-stage P. yoelii parasite challenge that is associated with enhanced survival.
Adjuvants, Immunologic↗
Children with HIV: the challenge for general practice.
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Child↗
beta-Amyloid immunoreactivity in astrocytes in Alzheimer's disease brain biopsies: an electron microscope study.
The deposition of amyloid beta (A beta) protein plays a central role in the neuropathology of Alzheimer's disease (AD) and it constitutes the core of classical senile plaques. However, little is known about its intracellular distribution. An immunogold electron microscope study was therefore carried out on biopsies of brain tissue from patients with AD using a monoclonal antibody raised against residues 8 to 17 of the A beta protein. Specific A beta immunogold labeling was observed over extracellular amyloid fibrils associated with senile plaques. In addition, widespread intracellular A beta immunolabeling was observed adjacent to granular structures (30-40 nm in diameter) within membrane-bound processes. Pretreatment of some sections with amylase or omission of lead citrate staining from others strongly suggests that the electron-dense granular structures associated with A beta immunoreactivity are glycogen. Some of the A beta-immunolabeled processes contained gliofilaments and immunolabeling of alternate sections for glial fibrillary acidic protein confirmed that the A beta-immunolabeled processes were astrocytic. A beta immunolabeling was not observed over neuronal or microglial processes. Whether the presence of A beta protein in astrocytes is the result of synthetic or degradation processes requires further investigation.
Adult↗
The luminati of Leiden: from Bontius to Boerhaave.
In the glittering canopy of the history of great medical centers of Europe, none was more viviscent than Leiden. Although wealthy nations nurtured great medical establishments in Padua, Salerno, Montpellier, and Paris, it was from a diminutive market town in The Netherlands that a group of medical cognoscenti arose whose intellectual prowess blazed across the intellectual firmament of seventeenth and eighteenth century Europe. The tradition of medical excellence established by Bontius was amplified by the surgeon Peter Paaw, whose stewardship of the Anatomical Theater guided it to heights comparable to those achieved at Padua. At the same time, Clusius established a botanical garden that would have no rival for two centuries. The multitalented Sylvius educated some of the greatest minds of the generation, accepted the Harveian theories of circulation, and succeeded in fostering an intellectual environment characterized by novel ideas and tolerance of thought. van Horne defined and chartered the existence of lymphatic circulation, and Bartholin destroyed the myth of the liver as a source of blood. Exalting in the freedom of thought, the cabal of Ruysch, Steensen, de Graaf, and Swammerdam banded together under Sylvius and van Horne and made significant advances in pancreatic, lymphatic, reproductive, and respiratory physiology. There is little doubt, however, that of all the great names linked with Leiden, it is Boerhaave's that is universally held to be synonymous with that of the city. As a clinician, scientist, and teacher, the aura of his knowledge and fame spread to the farthest corners of Europe. Without doubt, the great medical schools of Edinburgh, Vienna, and Gottingen owe their subsequent potency to him. Thus the legacy of Leiden provides the richest of all earthly concepts-an appreciation of the unique spiritual power and intellectual wealth that devolves from the pursuit of the life of the mind.
General Surgery↗
Pituitary adenylate cyclase-activating polypeptide modulates gastric enterochromaffin-like cell proliferation in rats.
BACKGROUND & AIMS: Gastric carcinoids (types I and II) involve the transformation of naive enterochromaffin-like (ECL) cells to the neoplastic state and are associated primarily with hypergastrinemia. In this study, we evaluated the effects of two related neuropeptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP), on ECL cell proliferation and characterized the receptor subtype(s) and signal transduction pathways that mediate this effect. METHODS: Purified rat ECL cells were analyzed in culture for DNA synthesis as measured by 24-hour 5-bromo-2-deoxyuridine (BrdU) uptake. Reverse-transcription polymerase chain reaction (RT-PCR) with gene-specific oligonucleotide primers was performed to characterize the PACAP/VIP receptor subtype(s). RESULTS: PACAP/VIP neuropeptide-stimulated BrdU uptake was significantly greater (3.4-3.8-fold greater than control) than that at the maximal dose of gastrin (2.2-fold greater than control). PACAP-stimulated ECL cell proliferation (EC50, approximately 3 x 10(-)14 mol/L) was approximately 100-fold more potent than VIP (EC50, approximately 3x 10(-)12 mol/L). The stimulated BrdU uptake by both PACAP and VIP was competitively inhibited by PACAP-receptor antagonist (IC50, 10(-)9 mol/L, 3 x 10(-)9 mol/L, respectively) and VIP-receptor antagonist (IC50, 3 x 10(-)7 mol/L, 5 x 10(-)7 mol/L, respectively). RT-PCR identified the presence of the PACAP-specific but not PACAP/VIP receptor subtypes. The PACAP-stimulated BrdU uptake was inhibited (70%-80%) by inhibitors of adenosine 3',5'-cyclic monophosphate, phosphatidylinositol 3 kinase, and protein tyrosine kinase as well as mitogen-activated protein kinase. CONCLUSIONS: PACAP/VIP-related peptides are more potent modulators of ECL cell proliferation than gastrin, and their effect is mediated by a PACAP-specific receptor whose activation is transduced by multiple intracellular messenger systems.
Androstadienes↗
Helicobacter pylori in Africa: observations on an 'enigma within an enigma'.
BACKGROUND: We conducted a retrospective literature review of all the data published on Helicobacter pylori in Africa in order to test whether the prevalence of diseases associated with this organism differs from that in developed nations. METHODS: Both sero-epidemiological (n = 8) as well as prospective endoscopic studies in subjects with either dyspepsia or epigastric pain (n = 23) and one retrospective study were available for analysis. RESULTS: Sero-epidemiology confirmed both the early age of acquisition in children (50% by 10 years) as well as the high prevalence of the organism (61%) in adult asymptomatic individuals. Endoscopic studies in dyspeptic individuals revealed the presence of the organism in 72%. Duodenal ulceration was noted in 26% of 3473 cases and in these, H. pylori was present in 90%. An association of gastric metaplasia with duodenal ulceration was identified in the one study in which it was investigated. Gastric ulceration occurred approximately four-fold less frequently (7% of 2286 cases) than duodenal ulceration and the organism was evident in 75% of the gastric ulceration cases. Findings of intestinal metaplasia (14%) and gastric cancer (3.4%) were not infrequent, but the paucity of accurate epidemiological data made it difficult to establish a correlation between the two. CONCLUSION: It would appear that prospective endoscopic-based studies in African subjects may question the standard dogma of a low prevalence of H. pylori-associated diseases in Africa. Further research is clearly required.
Adolescent↗
Rarity of colon cancer in Africans is associated with low animal product consumption, not fiber.
OBJECTIVE: To investigate whether the rarity of colon cancer in black Africans (prevalence, < 1:100,000) can be accounted for by dietary factors considered to reduce risk, and by differences in colonic bacterial fermentation. METHODS: Samples of the adult black South African population were drawn from several rural and urban regions. Food consumption was assessed by home visits, food frequency questionnaires, computerized analysis of 72-h dietary recall, and blood sampling. Colonic fermentation was measured by breath H2 and CH4 response to a traditional meal, and to 10-g of lactulose. Cancer risk was estimated by measurement of epithelial proliferation indices (Ki-67 and BrdU) in rectal mucosal biopsies. Results were evaluated by comparison to measurements in high-risk white South Africans (prevalence, 17:100,000). RESULTS: Epithelial proliferation was significantly lower in rural and urban blacks than whites. The diets of all the black subgroups were characterized by a low animal product and high boiled maize-meal content, whereas whites consumed more fresh animal products, cheese, and wheat products. Blacks consumed below RDA quantities of fiber (43% of RDA), vitamin A (78%), C (62%), folic acid (80%) and calcium (67%), whereas whites consumed more animal protein (177% of RDA) and fat (153%). Fasting and food-induced breath methane production was two to three times higher in blacks. CONCLUSIONS: The low prevalence of colon cancer in black Africans cannot be explained by dietary "protective" factors, such as, fiber, calcium, vitamins A, C and folic acid, but may be influenced by the absence of "aggressive" factors, such as excess animal protein and fat, and by differences in colonic bacterial fermentation.
Adult↗
Heterogeneity in the Helicobacter pylori vacA and cagA genes: association with gastroduodenal disease in South Africa?
BACKGROUND: Helicobacter pylori infection is universally associated with gastritis, but only sometimes with clinically significant disease. Candidate virulence markers seem to be useful in identifying the pathogenic infections in some populations. AIMS: To investigate the association between putative virulence markers and disease in an African population. METHODS: Fifty nine H pylori strains isolated from dyspeptic patients (11 with peptic ulceration, eight with gastric adenocarcinoma, and 28 with no pathology other than gastritis) were studied for differences in the genes vacA and cagA. RESULTS: Forty seven (80%) of 59 strains had the vacA signal sequence genotype s1 (one s1a, 46 s1b) and 12 (20%) had subtype s2. vacA mid-region analysis revealed that 40 (68%) strains were vacA m1 and 19 (32%) were m2. All 14 strains from patients with peptic ulceration were vacA s1, in contrast to 23 (66%) of 35 strains from patients with gastritis alone (p<0.01). vacA s2 was found exclusively in patients with gastritis alone (p<0.01). All strains isolated from patients with gastric adenocarcinoma were s1b/m1 (p<0. 005 versus gastritis alone). cagA was detectable in 56 (95%) of 59 isolates. Strains from patients with peptic ulceration (12/13 versus 19/30 with gastritis alone, p=0.05) had the shortest fragment length in the 3' region of cagA, while 4/10 strains from patients with gastric cancer had the longest fragment length in this region (p<0. 02 versus gastritis alone). CONCLUSION: In this study, the vacA s1 genotype, and fragment length of the 3' region of cagA identified isolates associated with significant clinical disease. The vacA s1bm1 genotype seems to be strongly associated with gastric cancer.
Adenocarcinoma↗
Gastrin-regulated expression of p53 in transformed enterochromaffin-like cells in the African rodent mastomys.
The tumor suppressor p53 functions at the G1/S-phase checkpoint of the cell cycle to direct cells that have accumulated somatic mutations toward apoptosis and away from mitosis. The p53 gene is commonly mutated in human cancers, but the molecular mechanisms regulating this event are not clear. The African rodent mastomys exhibits a genetic predisposition to develop gastric carcinoids derived from enterochromaffin-like (ECL) cells. The ECL cell transformation can be accelerated by acid inhibition-induced hypergastrinemia. This study evaluates the alteration of p53 during the rapid ECL cell transformation. Hypergastrinemia was generated by the irreversible histamine-2 receptor antagonist loxtidine for 8 weeks (hyperplasia) and 16 weeks (neoplasia). p53 expression was evaluated in fundic mucosa from different stages of transformation by Western blot analysis and immunohistochemistry using monoclonal antibodies against wild-type p53. RT-PCR and molecular sequence analysis of p53 were undertaken with mRNA isolated from purified ECL cells. Overproduction of the wild type of p53 was evident in ECL cells during hypergastrinemia, and the molecular characteristics of p53 were determined in naive and transformed ECL cells. p53 was mutated at the C-terminus in ECLoma induced by hypergastrinemia. Therefore, p53 is altered from overproduction to mutation during the development of hypergastrinemia-induced ECLoma and it may therefore play a role in the cell transformation.
Amino Acid Sequence↗
A polyamine pathway-mediated mitogenic mechanism in enterochromaffin-like cells of Mastomys.
We have previously demonstrated that in Mastomys species proliferation of gastric enterochromaffin-like (ECL) cells is predominantly regulated by gastrin and by transforming growth factor-alpha (TGF-alpha) in the naive and neoplastic state, respectively. In this study we examined whether these intracellular mitogenic responses are mediated by polyamines and ornithine decarboxylase (ODC), the rate-limiting enzyme for polyamine biosynthesis. An ECL cell preparation of high purity was used to measure the effect of the polyamine derivatives putrescine, spermidine, and spermine on DNA synthesis by bromodeoxyuridine uptake. Both putrescine and spermidine augmented gastrin-stimulated, but not basal, DNA synthesis in naive cells. This proliferative response correlated with an increase in ODC activity that was partially inhibited (20%) by difluoromethylornithine (DFMO), an inhibitor of ODC (IC50, 30 pM). In contrast, all polyamines increased both basal and TGF-alpha-stimulated DNA synthesis as well as ODC activity in tumor ECL cells. DFMO completely inhibited the proliferative response of TGF-alpha (IC50, 3 pM). Thus polyamine biosynthesis is involved in proliferation of ECL cells and in particular the mitogenesis of tumor cells, suggesting a role for this pathway in the regulation of ECL cell transformation.
Animals↗
A century of Helicobacter pylori: paradigms lost-paradigms regained.
The investigation of gastric bacteria properly began in the latter half of the nineteenth century when microscope resolution had sufficiently advanced. Whilst a bacterial etiology was demonstrated for dysentery, tuberculosis and syphilitic ulcers, problems in the isolation and culture of pure strains circumvented a role for bacteria in gastric pathology. Furthermore, dogma and the intellectual chorus were in harmony advocating that gastric acid was critical in ulcer disease. The consideration of a role for a pathogen or pepsin was regarded as whimsical in the context of mucosal ulceration. Indeed, the effects of acid inhibitory agents were held as gospel truth whilst the use of antibiotics or metallic ions were deemed to be quackery or at least ill judged. Nonetheless, spiral-shaped bacteria had been identified in both mucosa and gastric contents of patients as early as 1889. Elegant studies had documented the infectivity of these organisms, and suggested but not proven a causative role in gastric disease. The prescient identification by Doenges of organisms associated with gastritis in both man and monkey, was buried by the observations of Palmer, and an opportunity for early progress lost. It required two decades and Antipodean pathological perspicacity to elucidate the warren of previous archaic gastric bacterial misinformation. The subsequent marshalling of clinical and pathological data established the fatal flaw in the mucosa to be bacteria and not only acid on the mucus shore. It is now widely apparent that Helicobacter is ubiquitous, pathological and, a century after its initial discovery, still remains a paradox of as yet incompletely determined biological consequence. It is of note that an organic helical configuration has twice in this century provided biological information of unique import.
Gastrointestinal Diseases↗
Gastrin and the enterochromaffin-like cell: an acid update.
Gastrin is synthesized and secreted mostly in a heptadecapeptide form from neurocrine G cells located in the antrum. The biologically active sequence of the molecule is a C-terminal pentapeptide, which has been conserved across many species. Transcriptional regulation of gastrin mRNA synthesis is positively regulated by transforming growth factor-alpha (TGF-alpha) and inhibited by somatostatin (SST). The inactive precursor form is converted to the active molecule by several post-translation processing steps which include cleavage, C-terminal amidation, glycosylation, phosphorylation and sulfation. Aberrations in processing steps generate incompletely processed forms, particularly glycosylated progastrin, which may act as autocrine growth factors for gastrointestinal neoplasms. Gastrin release is stimulated by luminal aromatic amino acids and inhibited by a decrease in luminal pH. Other gastrin agonists include beta-adrenergic agents, acetylcholine, gastrin-releasing peptide (bombesin), TGF-alpha, and possibly the gastric pathogen, Helicobacter pylori. The principal peptide inhibitor of gastrin release is SST. The major physiological roles of gastrin include stimulation of acid secretion, regulation of mucosal cell lineage and mucosal cell proliferation. The fundic enterochromaffin-like (ECL) cell is the principal cellular transducer of the gastrin-acid signal. Activation of its gastrin/CCKB receptor results in histamine synthesis and release with consequent activation of the fundic parietal cell H2 receptor. An increase in luminal pH caused by acid inhibitory pharmacotherapy agents (particularly proton pump inhibitors) results in hypergastrinemia and ECL cell hyperplasia. Gastric carcinoids however appear occur in patients with multiple endocrine neoplasia type I syndrome, suggesting that an associated genomic defect is necessary. Gastrin is thus both a potent gastrointestinal trophic and histamine secretory agent. As a hormone it is a paradigm in the elucidation of both cellular secretory and growth factor induced cell proliferation.
Enterochromaffin-like Cells↗
The Asia Pacific Association for Medical Informatics (APAMI) and World Organisation of Family Doctors (WONCA) Consortium on General and Family Practice Informatics--a statement of intent.
This paper describes the establishment of a consortium to advance health and medical informatics in general/family practice in the Asia Pacific Region. The objectives, current activities currently taking place in the region and key activities planned will be outlined.
Asia↗
Methodology for developing educational hypermedia systems.
Hypermedia has the potential to greatly enhance teaching. It can, however, be difficult to develop hyperdocuments which provide medical students with the full benefit of the technology. We wish to resolve this problem by providing a methodology for creating educational hypermedia systems with specific emphasis on the medical domain, but applicable across disciplines. This paper examines some of the specific issues involved in educational hypermedia, and outlines a series of practical guidelines, drawing together the disparate disciplines necessary to the development process. We illustrate the methodology with our own experience in creating and updating the HIV Hypermedia Medical Education Software over a period of two years.
Computer-Assisted Instruction↗
Family medicine for all the family? Discrimination in Australian general practice.
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Attitude of Health Personnel↗