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Biomedical subjects

D Young

Publications and source records attributed to D Young.

At least 199 records · Page 11Linked to original sources
PubMed1997

Brain-derived neurotrophic factor is reduced in Alzheimer's disease.

Alzheimer's disease may be due to a deficiency in neurotrophin protein or receptor expression. Consistent with this hypothesis, a reduction in BDNF mRNA expression has been observed in human post-mortem Alzheimer's disease hippocampi. To further investigate this observation, we examined whether the alteration in BDNF expression also occurred at the protein level in human post-mortem Alzheimer's disease hippocampi and temporal cortices using immunohistochemical techniques. We observed a reduction in the intensity and number of BDNF-immunoreactive cell bodies within both the Alzheimer's disease hippocampus and temporal cortex when compared to normal tissue. These results support and extend previous findings that BDNF mRNA is reduced in the human Alzheimer's disease hippocampus and temporal cortex, and suggest that a loss of BDNF may contribute to the progressive atrophy of neurons in Alzheimer's disease.

Adult↗
PubMed1997

Acute inflammation, acute phase serum amyloid A and cholesterol metabolism in the mouse.

Acute inflammation results in a profound change in the apolipoprotein composition of high density lipoprotein (HDL). Several isoforms of the serum amyloid A (SAA) family, SAA1 and SAA2, become major components of HDL. This structural relationship has suggested that acute phase SAA plays some as yet unidentified role in HDL function, possibly related to cholesterol transport, during the course of acute inflammation. Using subcutaneous AgNO3 to induce a sterile abscess changes in plasma cholesterol and SAA were monitored over the subsequent 144 h. Total plasma cholesterol began to increase within 12 h of the induction of inflammation and reached a peak in 24 h. Thereafter its plasma levels fell returning to normal values by 96-120 h. The bulk of the increase in plasma cholesterol was found in the free cholesterol fraction of HDL. This pattern of cholesterol increase corresponds to the established temporal changes for acute phase SAA (AP-SAA). AP-SAA levels increased within 8 h of the induction of inflammation and reached a peak at 24 h. They began to decrease by 48 h with small quantites still present 120 h later. In concert, but inversely, with the changes in AP-SAA the apoA-I, apoA-II, and apo-E, content of HDL decreased during the AP-SAA increases and increased as AP-SAA levels fell. The plasma appearance of cholesterol from the periphery, and central parts of the inflammatory site was assessed by the use of radiolabelled cholesterol. The peripherally placed cholesterol rapidly reached a peak plasma concentration within 24 h of injection. Cholesterol placed in the central part of the sterile abscess, a site relatively inaccessible to the vasculature required 48 h to reach its peak and was 5-times lower than that placed peripherally. The influence of AP-SAA on neutral cholesterol ester hydrolase (nCEH) activity in mouse liver homogenates, mouse peritoneal macrophage homogenates, and a purified porcine pancreatic enzyme with nCEH activity was also assessed. Following optimization with regard to pH, bile salt concentration, protein concentration and incubation time, mouse peritoneal macrophages had a significantly higher nCEH specific activity than that found in liver (7-8 fold). Purified AP-SAA, assessed over a concentration range of 0-10 microg/ml, enhanced nCEH activity at concentrations above 2 microg/ml. The nCEH activity, regardless of its source, increased by 3-7 fold in the presence of AP-SAA. Equivalent concentrations of apolipoprotein A-I (apo A-I) and bovine serum albumin (BSA) failed to alter the activity of nCEH. The effect of AP-SAA on a purified form of nCEH suggests that AP-SAA may have a direct effect on the activity of this enzyme. The temporal correlation of circulating AP-SAA and plasma cholesterol and the significant stimulation of nCEH by AP-SAA (but not apoA-I or BSA) provides further evidence that AP-SAA plays a role in cholesterol metabolism during the course of acute inflammation.

Animals↗
PubMed1997

Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus.

Recent studies indicate that the proto-oncogene Bax, and other related proteins (eg Bcl-2) may play a major role in determining whether cells will undergo apoptosis under conditions which promote cell death. Increased expression of Bax has been found to promote apoptosis, while over-expression of Bcl-2 can inhibit apoptosis. To investigate the role of Bax in nerve cell death in the rat brain we examined the level of Bax expression in cells undergoing apoptosis, using a hypoxic-ischemic stroke model. We found that Bax was expressed at high levels in the nuclei of neurons in the hippocampus, cortex, cerebellum, and striatum on the control side, and that Bax levels increased in hippocampal neurons undergoing apoptosis on the stroke side, and then declined (correlating with cell loss). In the Alzheimer's disease hippocampi we found a concentrated localisation of Bax in senile plaques, which correlated with the localisation of beta-amyloid protein in adjacent sections from the same brains. beta-Amyloid positive plaques are thought to contribute to the Alzheimer's disease process, possibly via an apoptotic mechanism, and this may occur via an increase in Bax in these areas. Bax was also strongly stained in tau-positive tangles in Alzheimer's disease hippocampi, suggesting Bax may play a role in tangle formation. In addition, we observed a loss of Bax expression in the dentate granule cells of Alzheimer's disease hippocampi compared with moderate Bax expression in control hippocampi, and this loss may be related to the survival of these neurons in Alzheimer's disease. Finally, we observed substantially different staining patterns of Bax using three different commercially available antisera to Bax, indicating the need for caution when interpreting results in this area.

Adult↗
PubMed1997

Kainate/AMPA receptors expressed on human fetal astrocytes in long-term culture.

Long-term cultivation of primary human fetal brain cells has yielded a homogeneous population of glial progenitors of extended life span. These human astrocyte precursor (HAP-1) cells have been in culture for greater than 1 year, are diploid, and do not form colonies in soft agar. The culture was established in 10% fetal calf serum (FCS), although cells greatly increase their proliferative rate when both basic fibroblast growth factor and FCS are present in the culture media. HAP-1 cells express the cytoskeletal proteins glial fibrillary acidic protein, vimentin, and nestin. HAP-1 cells express the AMPA/kainate receptor subunit genes GluRs 1, 3, and 4 and the kainate receptor subunit genes GluR6, KA1, and KA2. Immunohistochemistry confirms the expression of GluR subunit proteins. HAP-1 cells demonstrate a kainate-responsive current found to be blockable by CNQX. HAP-1 cells will serve in the study of human glial cells and ligand-gated ion channels and in the identification of compounds which might act as agonists or antagonists at these receptor-ion channel complexes.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1997

Factors involved in long- and short-term mandibular plate exposure.

OBJECTIVES: To evaluate and to compare rates and timing of exposure of alloplastic mandibular plates by plate type and tissue reconstruction technique. DESIGN: A retrospective review series of 92 consecutive patients for 4 years (mean follow-up, 30 months). SETTING: National Cancer Institute-designated comprehensive cancer center in a freestanding cancer hospital. PATIENTS: Seventy-nine patients received alloplastic mandibular plates for segmental defects, and 13 patients received compression plates for mandibular osteotomies following ablative cancer surgery, including 21 titanium hollow osseointegrating reconstruction, 41 Storz, 16 Synthes, and 5 AO/ASIF (Arbeitsgemein schott fur Ostcosynthese fragen/Association for the Study of Internal Fixation) plates. Primary flap repair was provided by 71 pedicled soft tissue and 19 osseocutaneous free flaps, with primary closure in the remaining 2. INTERVENTION: Most of the reconstructions of the mandibular defect was with an alloplastic plate with musculocutaneous flap or revascularized bone graft. OUTCOME MEASURES: Clinically apparent intraoral or extraoral plate exposure. RESULTS: Plate exposure occurred in 25 cases. Nine plates were exposed extraorally, at a mean postoperative interval of 40 weeks. The remaining 16 plates were exposed intraorally at a mean postoperative interval of 16 weeks. There was no significant difference in the exposure rates of different plate types or methods of reconstruction. The titanium hollow osseointegrating reconstruction plate had a similar exposure rate compared with the other plates. Size and site of the defect were the only significant predictors of plate exposure Radiotherapy and postoperative complications did not affect the rate of exposure. CONCLUSIONS: Extraoral plate exposure occurs less commonly and later in the postoperative period than intraoral exposure, suggesting different causes. Plate type and type of flap reconstruction do not affect the rate of exposure. This may reflect long follow-up.

Bone Plates↗
PubMed1997

Flap selection as a determinant of success in pressure sore coverage.

OBJECTIVE: To establish a treatment algorithm for the long-term surgical management of pressure sores. DESIGN: Retrospective case series. SETTING: University-based teaching hospital. PATIENTS: From March 1979 to July 1995, 280 unselected pressure sore reconstructions (113 ischial, 94 sacral, and 73 trochanteric sores) were performed in 201 patients (130 men and 71 women; age range, 16-90 years; mean, 50 years). Of the patients, 90% had severe spinal cord injuries (paraplegia or quadriplegia). Forty-one percent of the wounds were chronic (present longer than 3 months). MAIN OUTCOME MEASURES: Length of stay, postoperative morbidity and mortality, and flap success (defined as a completely healed wound). RESULTS: Overall, 89% of the flaps healed primarily (ischium, 83% [94/113]; sacrum, 91% [86/94]; trochanter, 93% [68/73]). Three fourths of cases were treated in a single stage (debridement and reconstruction). The inferior gluteus maximus island flap (ischium) (94% [32/ 34]), the V-Y gluteus maximus advancement flap (sacrum) (97% [36/37]), and the tensor fascia lata flap (trochanter) (95% [42/44]) had the highest success rates. Flap success was not significantly affected by the size of the pressure sore or the number of previous flaps used. Postoperative hospital stays averaged 20 days. The overall complication rate was 28%, most commonly from a slight wound edge dehiscence. CONCLUSIONS: Flap selection and the appropriate short- and long-term sequence of flap use significantly improve success rates for pressure sore coverage. Reconstruction can be reliably performed in a single stage with a relatively short hospitalization.

Adolescent↗
PubMed1997

Similar mutant frequencies observed between pairs of monozygotic twins.

The relative contribution of both genetic and environmental factors to spontaneous mutation frequency in humans is unknown. We have investigated the contribution of genetic factors to this phenomenon by determining the in vivo mutant frequency at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus in circulating T-lymphocytes obtained from pairs of monozygotic twins. hprt mutant frequencies were determined three times over fourteen days in six sets of monozygotic male twins (mean age 30) taking part in a Russian Space Program inclined bed rest experiment. Blood samples were obtained prior to, during, and immediately following the experiment. Mononuclear cells were separated, frozen, and flown to Canada for analysis using the hprt T-lymphocyte clonal assay. There is no evidence within this data set to demonstrate that the period of inclined bed rest to simulate the effects of weightlessness had any effect on the observed mutant frequency. However, the average mutant frequency for the six sets of Russian twins was found to be three times higher than that of Western counterparts. More surprisingly, the spontaneous mutant frequency of monozygotic twins was found to be much more similar within pairs than between pairs of twins. These data suggest that the contribution of genetics in the determination of mutation frequency is substantial. However, whether high concordance within twin pairs reflects shared environmental experience as well as common genetic factors is not entirely clear. More data will be required to distinguish genetic from environmental factors and to determine the degree to which mutant frequency is genetically determined.

Adult↗
PubMed1997

Thiabendazole-induced cytogenetic abnormalities in mouse oocytes.

Of the various classes of human genetic disorders, aneuploidy is the most prevalent. Besides its association with maternal age and its predominant origin during maternal meiosis I, little is known about the etiology of aneuploidy. Although various classes of chemicals have been shown to induce aneuploidy in experimental systems, there is no definitive evidence for the role of chemically induced aneuploidy and adverse human health effects, particularly germ cell effects. Thus, it is important to understand the potential of chemicals for inducing aneuploidy in germ cells. There are conflicting data in the literature about the ability of thiabendazole (TBZ) to induce aneuploidy; therefore, we investigated the potential of TBZ for inducing aneuploidy in oocytes. Superovulated ICR female mice were administered 0, 50, 100, or 150 mg/kg TBZ by intraperitoneal injection. The frequencies and percentages of hyperploid oocytes were 0/472 (0), 2/410 (0.5), 6/ 478 (1.3), and 3/427 (0.7) for control, 50, 100, and 150 mg/kg TBZ, respectively. The difference between controls and the 100 mg/kg dose was statistically significant. Also, the proportions of ovulatory mice and the number of oocytes collected per ovulatory female were reduced in the TBZ groups relative to controls. Based on these results, we conclude that TBZ induces a small, but significant increase in the frequency of aneuploid oocytes at toxic doses that also impair ovulation.

Aneuploidy↗
PubMed1997

Social interaction alters attraction to competitor's odour in the mouse Mus spretus Lataste

When animals defend territories that are large and structurally complex, scent marks alone are unlikely to be reliable signals of a resident's dominance and competitors should require initial proof through direct interaction. This was tested using freshly captured Mus spretus which occupy large non-overlapping ranges in grassland but are strongly attracted to substrate odours from unfamiliar competitors. Choice tests measured time spent investigating and chewing to gain access to paired nestboxes when the entrances were blocked with mesh. Experiment 1 established that mice of both sexes were more strongly attracted to their own odour than to a clean site. Experiment 2 examined choice between the subject's own odour and that of an unfamiliar same-sex competitor both before and after meeting the competitor in a neutral (clean) arena. Prior to interaction, males exerted much effort to gain access to both their own and their unfamiliar competitor's odour. Once relative dominance had been established through agonistic interaction, subordinates avoided their dominant competitor's odour in favour of their own while dominants continued to be attracted to both. There was little aggressive competition between unfamiliar females and relative status did not affect their attraction to a competitor's odour. Females tended to be more attracted to a competitor's odour than to their own prior to interaction but showed less attraction to a competitor's odour post-interaction. A third experiment showed that the odour of an unfamiliar male was more attractive than that from an unfamiliar female, especially to males. The consequences of these responses for maintaining spatial dispersion in this species are discussed.Copyright 1997 The Association for the Study of Animal Behaviour1997The Association for the Study of Animal Behaviour

Journal Article↗
PubMed1997

Setting dissolution specifications for modified-release dosage forms.

Dissolution specifications are used for quality assurance and may also serve as a surrogate for in vivo bioavailability. These limits can guide formulation development and eliminate the need for bioavailability studies for scale up and post approval changes. Several methods for setting dissolution specifications have been reviewed in this chapter. A summary of the advantages and disadvantages for each method can be found in Table 1. When choosing a method for setting dissolution specifications, it is important to 1) have a discriminating dissolution system, 2) incorporate in vivo data, 3) include intersubject variability, and 4) predict plasma concentration-time profiles. Predicting plasma concentration curves allows one to see how the change in formulation or dissolution limits perform in vivo. Dissolution specifications should be set so that all formulations that have dissolution profiles within the limits of the specifications are bioequivalent. This can be assured if the boundaries are tested for bioequivalence. Minimally, the formulations that have dissolution profiles within the limits of the specifications should be bioequivalent to the pivotal batch. A population prediction of the plasma concentration-time profiles for the upper and lower limit would incorporate the true intersubject variability for the formulation.

Data Interpretation, Statistical↗
PubMed1997

A co-twin study of the effect of calcium supplementation on bone density during adolescence.

The effect of calcium supplementation on bone mineral density (BMD) was evaluated in female twin pairs aged 10-17 years with a mean age of 14 years. Forty-two twin pairs (22 monozygotic, 20 dizygotic; (including one monozygotic pair from a set of triplets) completed at least 6 months of the intervention: 37 pairs to 12 months and 28 pairs to 18 months. BMD was measured by dual-energy X-ray absorptiometry (DXA). In a double-blind manner, one twin in each pair was randomly assigned to receive daily a 1000 mg effervescent calcium tablet (Sandocal 1000), and the other a placebo tablet similar in taste and appearance to the calcium supplement but containing no calcium. Compliance (at least 80% tablets consumed), as measured by tablet count, was 85% in the placebo group and 83% in the calcium group over the 18 months of the study, on average increasing dietary calcium to over 1600 mg/day. There was no within-pair difference in the change in height or weight. When the effect of calcium supplementation on BMD was compared with placebo at approximately 6, 12 and 18 months, it was found that there was a 0.015 +/- 0.007 g/ cm2 greater increase in BMD (1.62 +/- 0.84%) at the spine in those on calcium after 18 months. At the end of the first 6 months there was a significant within-pair difference of 1.53 +/- 0.56% at the spine and 1.27 +/- 0.50% at the hip. However, there were no significant differences in the changes in BMD after the initial effect over the first 6 months. Therefore, we found an increase in BMD at the spine with calcium supplementation in females with a mean age of 14 years. The greatest effect was seen in the first 6 months; thereafter the difference was maintained, but there was no accelerated increase in BMD associated with calcium supplementation. The continuance of the intervention until the attainment of peak bone mass and follow-up after cessation of calcium supplementation will be important in clarifying the optimal timing for increased dietary calcium and the sustained, long-term effects of this intervention.

Adolescent↗
PubMed1997

Uptake and processing of 59Fe-labelled and 125I-labelled rat transferrin by early organogenesis rat conceptuses in vitro.

The delivery of iron to the early organogenesis rat embryo has been studied, using 59Fe- and 125I-labelled rat transferrin. Rat conceptuses at 9.5 days postconception were cultured for 27 or 51 h in whole rat serum. Rat transferrin labelled with 59Fe was added for the final 0.1, 0.5, 6, 24 or 48 h of culture. Radioactivity accumulated progressively in both the embryo and the visceral yolk sac. Similar results were obtained when unconjugated 59Fe3+ was added to the rat serum used as culture medium. Both acid-soluble and acid-insoluble 59Fe were substantially present in the embryo and yolk sac after all exposure periods. When conceptuses were cultured in the presence of 125I-labelled rat transferrin, acid-soluble radioactivity was progressively released into the culture medium, but accumulation into the embryo and visceral yolk sac was slight and did not change with duration of exposure to the labelled protein. Similar findings were obtained using 125I-labelled bovine serum albumin. In these experiments, there was a close correspondence between the amount of iron accumulated by the embryo and visceral yolk sac in the final 24 h of a 51-h culture and the amount of transferrin converted into acid-soluble products in the same period. Visceral yolk sacs from 17.5-day pregnant rats were explanted and cultured in the presence of 59Fe-labelled rat transferrin, 125I-labelled rat transferrin or 125I-labelled bovine serum albumin, for periods up to 3 h. Again uptake of 59Fe increased with time of incubation, and the 125I-labelled proteins were digested to acid-soluble products which were released into the culture medium. The results indicate that transferrin delivers iron for incorporation into both the embryo and the visceral yolk sac, and are consistent with a mechanism involving receptor-mediated endocytosis of iron-laden transferrin by the cells of the visceral yolk sac. The transferrin itself appears to be quantitatively degraded, following delivery of iron to the yolk sac cells, a result that differs from findings in other cell types, in which the protein is not degraded but returns to the plasma membrane to participate in further cycles of iron acquisition and delivery.

Animals↗
PubMed1997

Changes in collagen phenotypes during progression and regression of cardiac hypertrophy.

OBJECTIVE: Excessive deposition of collagen has been implied to be responsible for abnormal stiffness and altered cardiac function during hypertrophy and heart failure. In the present paper we studied the changes in collagen and their phenotypes during development of cardiac hypertrophy in spontaneously hypertensive rats (SHR) compared to age- and sex-matched Wistar Kyoto (WKY). We also studied the changes in collagen after regression of hypertrophy, with antihypertensive therapy with ACE inhibitors, captopril (C) and lisinopril (L). METHOD: Collagen was extracted from the heart tissue by cyanogen bromide (CNBr) digestion. Collagen phenotypes were separated and quantified by SDS-polyacrylamide gel electrophoresis. The transcript levels(mRNA) of collagen phenotypes were determined by Northern analysis. RESULTS: Our studies showed that the ventricular collagen and their phenotypes did not alter in SHR during the first 6 months of progression of hypertrophy when compared to WKY. After 40 weeks, however, in SHR there was an unexpected rise in collagen content and the distribution of collagen phenotype differs compared to WKY, especially during the chronic phase of hypertrophy (65 weeks of age). In WKY during the aging process there was a gradual increase in type III collagen, whereas in SHR it plateaus after 40 weeks of age. Treatment with antihypertensive drugs captopril and lisinopril showed a similar degree of reduction in blood pressure (P < 0.001), regressed hypertrophy (P < 0.001), and reduced collagen, whereas decrease in type I to III ratio was found with captopril only, but not with lisinopril. This decrease in type I to III ratio due to captopril treatment is primarily due to an increase in type III collagen (both protein and transcript level) in SHR. CONCLUSION: Our data showed, for the first time, that during the chronic phase of hypertrophy in SHR there is a gradual reduction in type I to III ratio, primarily due to a lack of increase in type III collagen during chronic phase of hypertrophy. This suggests that quality of collagen is an important factor in determining the degree of cardiac stiffness. Our data also showed that not all ACE inhibitors have similar actions on collagen phenotype production. This suggests that perhaps the mechanism of action of ACE inhibitors on collagen are independent of its effect on angiotensin II formation.

Aging↗