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Biomedical subjects

D B Moore

Publications and source records attributed to D B Moore.

At least 19 recordsLinked to original sources
PubMed2000

Protein kinase C-dependent alpha-secretase competes with beta-secretase for cleavage of amyloid-beta precursor protein in the trans-golgi network.

The release of amyloidogenic amyloid-beta peptide (Abeta) from amyloid-beta precursor protein (APP) requires cleavage by beta- and gamma-secretases. In contrast, alpha-secretase cleaves APP within the Abeta sequence and precludes amyloidogenesis. Regulated and unregulated alpha-secretase activities have been reported, and the fraction of cellular alpha-secretase activity regulated by protein kinase C (PKC) has been attributed to the ADAM (a disintegrin and metalloprotease) family members TACE and ADAM-10. Although unregulated alpha-secretase cleavage of APP has been shown to occur at the cell surface, we sought to identify the intracellular site of PKC-regulated alpha-secretase APP cleavage. To accomplish this, we measured levels of secreted ectodomains and C-terminal fragments of APP generated by alpha-secretase (sAPPalpha) (C83) versus beta-secretase (sAPPbeta) (C99) and secreted Abeta in cultured cells treated with PKC and inhibitors of TACE/ADAM-10. We found that PKC stimulation increased sAPPalpha but decreased sAPPbeta levels by altering the competition between alpha- versus beta-secretase for APP within the same organelle rather than by perturbing APP trafficking. Moreover, data implicating the trans-Golgi network (TGN) as a major site for beta-secretase activity prompted us to hypothesize that PKC-regulated alpha-secretase(s) also reside in this organelle. To test this hypothesis, we performed studies demonstrating proteolytically mature TACE intracellularly, and we also showed that regulated alpha-secretase APP cleavage occurs in the TGN using an APP mutant construct targeted specifically to the TGN. By detecting regulated alpha-secretase APP cleavage in the TGN by TACE/ADAM-10, we reveal ADAM activity in a novel location. Finally, the competition between TACE/ADAM-10 and beta-secretase for intracellular APP cleavage may represent a novel target for the discovery of new therapeutic agents to treat Alzheimer's disease.

Amyloid Precursor Protein Secretases↗
PubMed2000

Physical activity and incidence of postmenopausal breast cancer.

Whether physical activity reduces the risk of postmenopausal breast cancer is uncertain; few studies have addressed this issue. We examined the association of leisure physical activity with breast cancer incidence among 37,105 postmenopausal participants in the Iowa Women's Health Study. Women reporting the highest level of physical activity at baseline compared with women with the lowest level of activity had an age-adjusted relative risk of breast cancer of 0.92 (95% confidence interval = 0.80-1.05). Women reporting any regular leisure-time physical activity had a relative risk of 0.97 (95% confidence interval = 0.87-1.08) compared with those reporting no such regular physical activity. Adjustment for potential confounders did not appreciably alter the findings. There is little evidence from this study that physical activity later in life is associated to any appreciable extent with breast cancer incidence.

Aged↗
PubMed1999

Ventricular asystole during vagus nerve stimulation for epilepsy in humans.

Electrical stimulation of the vagus nerve, a recently available option for patients with refractory epilepsy, has demonstrated safety and efficacy. We report four patients with refractory epilepsy who experienced ventricular asystole intraoperatively during initial testing for implantation of the vagus nerve stimulator. Acute intraoperative vagus nerve stimulation may create ventricular asystole in humans. Extracorporeal cervical vagus nerve stimulation testing with continuous EKG monitoring intraoperatively before generator implantation is warranted.

Adult↗
PubMed1999

Bcl-2 overexpression protects the neonatal cerebellum from ethanol neurotoxicity.

The developing nervous system is extremely sensitive to ethanol, and exposure often produces a condition known as the fetal alcohol syndrome. Although mechanisms underlying developmental ethanol toxicity have long been sought, they remain poorly understood. In this study, we examined the ability of the cell death repressor gene bcl-2 to protect against ethanol neurotoxicity. Transgenic mice overexpressing bcl-2 in neurons were exposed to ethanol vapor on postnatal days 4 and 5, which is the peak period of vulnerability of cerebellar Purkinje cells to ethanol. While exposure of wild-type animals to ethanol resulted in significant loss of Purkinje cells by P5, similar exposure of homozygous and heterozygous transgenics had no effect on the number of these neurons. This study suggests that bcl-2 can protect neurons from ethanol neurotoxicity and that modulation of cell death effector or repressor gene products may play a significant role in developmental ethanol neurotoxicity.

Analysis of Variance↗
PubMed1999

Neurotrophic factors BDNF and GDNF protect embryonic chick spinal cord motoneurons from ethanol neurotoxicity in vivo.

Maternal consumption of ethanol is widely recognized as a leading cause of mental and physical deficits. Many populations of the central nervous system are affected by the teratogenic effects of ethanol. Neurotrophic factors (NTFs) have been shown to protect against ethanol neurotoxicity in culture, although there have been no demonstrations of such protection in vivo, in specific neuronal populations. Previous studies have demonstrated that ethanol is toxic to developing chick embryo motoneurons when administered from embryonic day 10 (E10) to E15. NTFs such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) have been shown to support developing spinal cord motoneurons, and when exogenously applied, decrease naturally occurring cell death, and protect against axotomy. The concurrent delivery of BDNF or GDNF with ethanol to the embryonic chick from E10 to E15 was designed to examine the capacity of these NTFs to provide in vivo neuroprotection for this ethanol-sensitive motoneuron population. Analysis of motoneuron numbers indicated that both BDNF and GDNF provided protection to developing spinal cord motoneurons from ethanol toxicity, restoring motoneuron numbers to control levels. This study represents the first demonstration of in vivo neuroprotection from ethanol toxicity with respect to specific neuronal populations.

Animals↗
PubMed1999

Neonatal ethanol exposure alters bcl-2 family mRNA levels in the rat cerebellar vermis.

BACKGROUND: The objective of the present work was to determine whether ethanol-induced cerebellar cell death during development is related to alterations in the expression of bcl-2 family genes. METHODS: Rats were exposed to ethanol or control conditions during the neonatal period and transcript levels of bcl-2 family members relative to cyclophilin were determined. Pups exposed in parallel were taken for cerebellar cell counts. RESULTS: Ethanol exposure during the first postnatal week significantly reduced Purkinje and granule cell numbers by postnatal day 21 (P21). Acute first postnatal week ethanol exposure up-regulated mRNA transcripts encoding the cell death-promoting molecules bax and bcl-xs as measured on P4. An additional day of exposure on P5 resulted in no further alterations in bcl-2 family transcripts, likely because Purkinje cell death was detectable as early as P5. To determine whether proapoptotic gene expression changes were specific to first postnatal week ethanol neurotoxicity, we examined bcl-2 family mRNA levels in rats exposed to ethanol during a developmental period of cerebellar insusceptibility, the second postnatal week. Exposure on P7 to P8 produced no change in cerebellar cell number, but also resulted in increased levels of bax, although only after 2-day ethanol exposure and not after acute exposure on P7. CONCLUSIONS: These data implicate altered expression of proapoptotic members of the bcl-2 gene family in acute ethanol-mediated cerebellar cell death during the first postnatal week. They also suggest that the differential survival of cerebellar neurons after ethanol exposure during more mature developmental stages may be related to more successful suppression of proapoptotic processes.

Animals↗
PubMed1998

Prenatal ethanol exposure reduces parvalbumin-immunoreactive GABAergic neuronal number in the adult rat cingulate cortex.

The effect of prenatal ethanol exposure on the number of parvalbumin-immunoreactive (PA+) GABAergic neurons in the adult rat anterior cingulate cortex was determined. Pregnant Long-Evans rats were maintained on one of three diets throughout gestation: an ethanol-containing liquid diet, a similar, control liquid diet with the isocaloric substitution of sucrose for ethanol, or a lab chow control diet. Offspring were euthanized on postnatal day 60 and brains were prepared for parvalbumin immunocytochemistry. Rats exposed to the ethanol-containing diet contained 45% fewer PA+ neurons in the anterior cingulate cortex compared with sucrose and chow controls. This reduction occurred in the absence of changes in structure volume, and occurred in the absence of changes in PA+ neuronal size.

Animals↗
PubMed1998

A comparative study of ethanol, hypoglycemia, hypoxia and neurotrophic factor interactions with fetal rat hippocampal neurons: a multi-factor in vitro model developmental ethanol effects.

Fetal alcohol syndrome (FAS) is characterized by numerous central nervous system anomalies, with the hippocampus being particularly vulnerable to developmental ethanol exposure. In addition to direct ethanol neurotoxicity, other conditions resulting from maternal ethanol consumption, such as hypoglycemia and hypoxia, may also contribute to FAS. The present study used a tissue culture system to model multiple conditions which may relate to in vivo FAS, and assessed their relative neurotoxicity with MTT assays. Gestational day 18 rat hippocampal cultures were exposed to varying ethanol concentrations, glucose withdrawal-induced hypoglycemic (gwHG, 16 h) or acute hypoxic (aHP, 2 h) conditions alone, as well as to co-treatments with ethanol and gwHG or aHP. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) have previously been shown to ameliorate ethanol-, hypoglycemia- and hypoxia-induced neurotoxicity. Therefore, their neuroprotective potential, along with ciliary neurotrophic factor (CNTF), was examined. Neuronal viability was reduced dose-dependently by ethanol, alone or with hypoglycemia or hypoxia. Ethanol + gwHG or aHP was not uniformly additive. NGF treatment provided the most extensive neuroprotection, being effective against ethanol (200 and 400 mg/dl), gwHG, and aHP, alone and combined. BDNF afforded similar protection, but not against ethanol + gwHG. CNTF protected only against aHP. CNTF + BDNF, previously shown to act synergistically, protected against ethanol + aHP up to 800 mg/dl ethanol, but not, paradoxically, against ethanol alone, gwHG, or ethanol + gwHG, all conditions BDNF alone protected against. This study demonstrated that several neurotrophic factors are capable of mitigating neurotoxicity associated with ethanol, hypoglycemia and hypoxia.

Animals↗
PubMed1998

Effects of neonatal ethanol exposure on cholinergic neurons of the rat medial septum.

The objective of this study was to determine the long-term effects of neonatal ethanol exposure on the cholinergic neurons in the medial septum (MS) of the rat. On postnatal day 4 (P4) pups were assigned to one of three groups: an ethanol-receiving, gastrostomized group (EtOH); a pair-fed, gastrostomized control group (GC); and a dam-reared suckle control group (SC). Gastrostomized pups were infused with ethanol-containing or control diet as a 9.1% v/v solution for two feedings on each day from P4 to P10. Choline acetyltransferase (ChAT) immunocytochemistry was analyzed at P60. Ethanol treatment resulted in long-lasting microencephaly in P60 EtOH animals. Ethanol exposure did not directly reduce ChAT-expressing (ChAT+) neuronal number, nor were changes noted in MS volume, mean area/section, or cell density as a result of ethanol treatment. Ethanol exposure reduced ChAT+ neuronal size in EtOH males compared with GC males but not SC males. No differences in ChAT+ neuronal size were noted in females. Thus, neonatal ethanol exposure, whereas producing long-lived microencephaly, has little effect on the cholinergic neurons of the adult rat MS.

Animals↗
PubMed1997

Ethanol influences on the chick embryo spinal cord motor system. II. Effects of neuromuscular blockade and period of exposure.

The study described below was performed as a continuation of a previous study in which we found reduced motoneuron number in lumbar spinal cord of the chick embryo following chronic ethanol administration from embryonic day 4 (E4) to E11. We sought to determine whether this reduction was due to primary ethanol toxicity or to enhancement of naturally occurring cell death (NOCD) and to determine whether administration of ethanol at a later period of development could also reduce motoneuron number. Earlier studies have shown that curare suspends NOCD in the chick embryo. By administering both ethanol and curare to these embryos from E4 to E11 and examining the lumbar spinal cord on E12, we determined that ethanol was directly toxic to motoneurons and reduced motoneuron number in the absence of NOCD. By administering ethanol from E10 to E15 and examining the lumbar spinal cord on E16, we determined that ethanol can reduce motoneuron number without altering spinal cord length during more than one stage of chick embryo development, and that ethanol toxicity is not dependent on NOCD. In addition, we demonstrated that ethanol does not affect the neurotrophic content of chick muscle when it is administered from E10 to E15.

Animals↗
PubMed1997

Effects of prenatal ethanol exposure on parvalbumin-expressing GABAergic neurons in the adult rat medial septum.

Exposure of human fetuses to ethanol often results in the fetal alcohol syndrome. Animal models of fetal alcohol syndrome have been developed and used to examine the consequences of prenatal ethanol exposure on the central nervous system. The objective of this study was to determine the long-term effects of prenatal ethanol exposure on parvalbumin-expressing (PA+) GABAergic neurons of the rat medial septum. Pregnant Long-Evans rats were maintained on 1 of 3 diets from gestational day 0 to 21: an ethanol-containing liquid diet in which ethanol accounted for 35% of the total calories, a similar diet with the isocaloric substitution of sucrose for ethanol, or a lab chow control diet. Offspring were killed on postnatal day 60, and their brains were prepared for parvalbumin immunocytochemistry. Female rats exposed to the ethanol-containing diet during gestation had 42% fewer PA+ neurons in the medial septum and reduced PA+ cell density when compared with female rats exposed to the sucrose diet. Ethanol females also had fewer PA+ neurons per unit volume than sucrose females. Male rats exposed to ethanol did not display a similar reduction in PA+ neurons or density. No effect of prenatal diet was found on the area or volume of the medial septum, nor were cell diameters affected. As such, prenatal exposure to ethanol seems to reduce permanently the number of PA+ neurons in the female rat medical septum without affecting area, volume, or neuronal size. Functional implications and possible relations to the fetal alcohol syndrome are discussed.

Animals↗
PubMed1988

Simple ligation vs stump inversion in appendectomy.

The records of 886 patients who had appendectomy performed by the same surgeons within a five-year period were used to contrast appendiceal stump inversion vs simple ligation. Our analysis contrasted inversion vs simple ligation techniques as related to postoperative complications, hospital stay, and pathologic diagnosis. Adhesions requiring repeated operation to relieve bowel obstruction occurred in five of 87 patients with acute gangrenous appendicitis treated by inversion. Of 106 patients with acute gangrenous appendicitis treated with simple ligation, postoperative obstruction developed in none. No other statistically significant differences existed between the two techniques. These data suggest that simple ligation is at least as good as and probably better than inversion of the appendiceal stump.

Acute Disease↗
PubMed1987

The effect of rapid resuscitation upon cardiac index following thermal trauma in a porcine model.

Minipigs were divided into four experimental groups: nonburned control (C); burn, minimal resuscitation (MR); burn, standard resuscitation (SR); and burn, rapid resuscitation (RR). Resuscitation was begun 30 minutes postburn and hemodynamics were measured through 24 hours postburn. At 30 minutes postburn, the three burn groups demonstrated a significant decrease in cardiac index % (CI%). At 1 1/2 hours postburn, the RR group CI% was significantly greater than for the SR group and not significantly different from that of controls. At 2 hours postburn, fluid was abruptly decreased in the RR group and the salutary effect on CI promptly dissipated. In this model, the early decrement in CI following thermal injury is responsive to rapid resuscitation, concluding that the etiology of decreased CI following thermal trauma is at least partially due to inadequate volumes of fluid administration in the early postburn period.

Animals↗