Biomedical subjects

M A Wilson

Publications and source records attributed to M A Wilson.

At least 55 records · Page 3Linked to original sources

PubMed2000

Platelet-activating factor and bacteremia-induced pulmonary hypertension.

BACKGROUND: Acute lung injury is a common complication of gram-negative sepsis. Pulmonary hypertension and increased lung vascular permeability are central features of lung injury following experimental bacteremia. Platelet-activating factor is a prominent proinflammatory mediator during bacterial sepsis. Our previous studies have demonstrated that exogenous administration of platelet-activating factor (PAF) induces pulmonary edema without causing pulmonary hypertension. Interestingly, inhibition of PAF activity during Escherichia coli bacteremia prevents the development of both pulmonary hypertension and pulmonary edema. These data suggest that PAF contributes to pulmonary hypertension during sepsis, but that this is unlikely to be a direct vascular effect of PAF. The goal of the present study was to investigate the mechanism by which acute E. coli bacteremia induces pulmonary injury and to define the role that PAF plays in this injury. We hypothesized that the effects of PAF on pulmonary hypertension during bacteremia are due to the effects of PAF on other vascular mediators. Several studies suggest that PAF induces the expression of endothelin-1 (ET), a potent peptide vasoconstrictor. Further, our previous studies have implicated ET as a central mediator of systemic vasoconstriction during bacteremia. We therefore sought to assess whether ET is modulated by PAF. E. coli has also been demonstrated to increase endothelial production of nitric oxide (NO), which contributes to maintenance of basal vascular tone in the pulmonary circulation. We hypothesized that PAF might increase pulmonary vascular resistance during bacteremia by activating neutrophils, increasing expression of ET, and decreasing the tonic release of NO. Furthermore, we hypothesized that hypoxic vasoconstriction did not contribute to pulmonary vasoconstriction during the first 120 min of E. coli bacteremia. METHODS: Pulmonary artery pressure (PAP), blood pressure (BP), heart rate (HR), and arterial blood gases (ABG) were measured in anesthetized spontaneously breathing adult male Sprague-Dawley rats. E. coli (10(9) CFU/100 g body wt) was injected at t = 0, and hemodynamic data were obtained at 10-min intervals and ABG data at 30-min intervals for a total of 120 min. Sham animals were treated equally but received normal saline in place of E. coli. In treatment groups, a 2.5 mg/kg dose of WEB 2086, a PAF receptor antagonist, was administered intravenously 15 min prior to the onset of sepsis or sham sepsis. The groups were (1) intravenous E. coli (n = 5); (2) intravenous WEB 2086 pretreatment + intravenous E. coli (n = 5); (3) intravenous WEB 2086 alone (n = 5); and (4) intravenous normal saline (n = 6). Nitric oxide metabolites (NOx) and ET concentrations were assayed from arterial serum samples obtained at the end of the protocol. Lung tissue was harvested for measurement of myeloperoxidase (MPO) activity and pulmonary histology. RESULTS: E. coli bacteremia increased HR, PAP, and respiratory rate early during sepsis (within 20 min), while hypoxemia, hypotension, and hemoconcentration were not manifest until the second hour. Pretreatment with WEB 2086 completely abrogated all of these changes. E. coli bacteremia increased the activity of serum ET, lung MPO, and neutrophil sequestration in the lung parenchyma via a PAF-dependent mechanism. However, the mechanism of increased production of NO appears to be PAF independent. CONCLUSIONS: These data support the hypothesis that E. coli bacteremia rapidly induces pulmonary hypertension stimulated by PAF and mediated at least in part by endothelin-1 and neutrophil activation and sequestration in the lung. Microvascular injury with leak is also mediated by PAF during E. coli bacteremia, but the time course of resultant hypoxemia and hemoconcentration is slower than that of pulmonary hypertension. The contribution of hypoxic vasoconstriction in exacerbating pulmonary hypertension in gram-negative sepsis is probably a late

Animals↗

PubMed2000

Regulation of intestinal blood flow.

The gastrointestinal system anatomically is positioned to perform two distinct functions: to digest and absorb ingested nutrients and to sustain barrier function to prevent transepithelial migration of bacteria and antigens. Alterations in these basic functions contribute to a variety of clinical scenarios. These primary functions intrinsically require splanchnic blood flow at both the macrovascular and microvascular levels of perfusion. Therefore, a greater understanding of the mechanisms that regulate intestinal vascular perfusion in the normal state and during pathophysiological conditions would be beneficial. The purpose of this review is to summarize the current understanding regarding the regulatory mechanisms of intestinal blood flow in fasted and fed conditions and during pathological stress.

Animals↗

PubMed2000

Lazaroid and pentoxifylline suppress sepsis-induced increases in renal vascular resistance via altered arachidonic acid metabolism.

Early sepsis leads to renal hypoperfusion, despite a hyperdynamic systemic circulation. It is thought that failure of local control of the renal microcirculation leads to hypoperfusion and organ dysfunction. Of the many mediators implicated in the pathogenesis of microvascular vasoconstriction, arachidonic acid metabolites are thought to be important. Vasoconstriction may be due to excess production of vasoconstrictors or loss of vasodilators. Using the isolated perfused kidney model, we describe a sepsis-induced rise in renal vascular resistance and increased production of key arachidonic acid metabolites, both vasoconstrictors and vasodilators, suggesting excessive production of vasoconstrictors as a cause for microcirculatory hypoperfusion. There is evidence of increased enzymatic production of arachidonic acid metabolites as well as nonenzymatic, free radical, catalyzed conversion of arachidonic acid. Pentoxifylline (a phosphodiesterase inhibitor) and U74389G (an antioxidant) both have a protective effect on the renal microcirculation during sepsis. Both drugs appear to alter the renal microvascular response to sepsis by altering renal arachidonic acid metabolism. This study demonstrates that sepsis leads to increased renal vascular resistance. This response is in part mediated by metabolites produced by metabolism of arachidonic acid within the kidney. The ability of drugs to modulate arachidonic acid metabolism and so alter the renal response to sepsis suggests a possible role for these agents in protecting the renal microcirculation during sepsis.

Animals↗

PubMed2000

A lack of tolerance to the anxiolytic effects of diazepam on the plus-maze: comparison of male and female rats.

RATIONALE: The demonstration of tolerance to the anxiolytic effects of benzodiazepines remains inconsistent. OBJECTIVES: The present study tested the hypothesis that intact and gonadectomized male and female rats might exhibit differential tolerance to the anxiolytic effects of diazepam (DZ). METHODS: Following acute (3 days) or chronic (3 weeks) DZ exposure, all animals were tested on the elevated plus-maze and immediately sacrificed for analysis of corticosterone, adrenocorticotropin hormone, estrogen and progesterone levels in serum. In experiment 2, following acute or chronic DZ exposure, animals were treated with a DZ challenge dose on the test day. RESULTS: In experiment 1, both acute and chronic DZ treatment similarly enhanced percentage open arm time and entries, regardless of the hormonal status of the animal. The results of experiment 2 showed that both acute and chronic DZ-treated animals exhibited a significantly higher percentage open arm time than control animals after the DZ challenge dose, and males and females did not differ in their responses to DZ exposure. CONCLUSIONS: The findings from these experiments suggest that tolerance to the anxiolytic effects of DZ did not develop in males or females, and that the hormonal status of the animal does not significantly alter the anxiolytic effects of DZ following either acute or chronic exposure. Following plus-maze exposure, females had significantly higher corticosterone levels than males and acute DZ treatment diminished this stress response.

Adrenocorticotropic Hormone↗

PubMed2000

Gender and gonadal hormone effects in the olfactory bulbectomy animal model of depression.

Major depressive disorder (MDD) affects women to a greater extent then men; however, the few studies that have examined the role of gender in an animal model of depression have shown inconsistent results. The purpose of the present study was to determine if the gonadal hormone milieu of the animal modulated behavioral changes following olfactory bulbectomy (OBX), a well-documented animal model of depression. Body weight, sucrose preference levels and open-field activity levels were measured once a week for a period of 2 weeks in gonadally intact and gonadectomized male and female rats. Following these baseline measurements, animals underwent either OBX or sham surgery. Body weight, sucrose preference and activity levels were assessed for 4 weeks post-OBX surgery. OBX-gonadectomized animals exhibited higher activity levels than OBX gonadally intact and control animals. This effect of gonadectomy was more robust in males. OBX-females (both intact and gonadectomized) exhibited significantly lower sucrose preference levels than OBX-males (both intact and gonadectomized) and control animals. These results suggest that the gonadal hormone milieu of the animal plays a role in modulating sucrose preference and activity levels following OBX.

Animals↗

PubMed2000

Overexpression of proenkephalin in the amygdala potentiates the anxiolytic effects of benzodiazepines.

To elucidate the role of opioid peptides in control of the anxiety-like behavior and anxiety-reducing actions of benzodiazepines, a recombinant, replication-defective herpes virus (SHPE) carrying human preproenkephalin cDNA was delivered to rat amygdala. Viral infection resulted in a strong, localized transgene expression after 2-4 days which diminished after one week. Anxiety-like behavior and the anxiolytic effect of diazepam were assessed three days after gene delivery using the elevated plus maze test. While SHPE infection alone did not reduce anxiety-like behavior, rats infected with SHPE exhibited a greater response to the anxiolytic effect of diazepam when compared to rats infected with a control virus (SHZ.1) containing the lacZ gene. The enhancement of diazepam action by SHPE was naloxone reversible, region-specific, and correlated with the time course of preproenkephalin expression. The findings implicate amygdalar opioid peptides in regulating the anxiolytic effects of benzodiazepines. This study also demonstrates the usefulness of recombinant herpes virus in evaluating the role of single gene products within specific brain sites in pharmacological responses and complex behaviors.

Amygdala↗

PubMed2000

Formation of temporal memory requires NMDA receptors within CA1 pyramidal neurons.

In humans the hippocampus is required for episodic memory, which extends into the spatial and temporal domains. Work on the rodent hippocampus has shown that NMDA receptor (NMDAR) -mediated plasticity is essential for spatial memory. Here, we have examined whether hippocampal NMDARs are also needed for temporal memory. We applied trace fear conditioning to knockout mice lacking NMDARs only in hippocampal CA1 pyramidal cells. This paradigm requires temporal processing because the conditional and unconditional stimuli are separated by 30 s (trace). We found that knockout mice failed to memorize this association but were indistinguishable from normal animals when the trace was removed. Thus, NMDARs in CA1 are crucial for the formation of memories that associate events across time.

Animals↗

PubMed2000

Experience-dependent asymmetric shape of hippocampal receptive fields.

We propose a novel parameter, namely, the skewness, or asymmetry, of the shape of a receptive field to characterize two properties of hippocampal place fields. First, a majority of hippocampal receptive fields on linear tracks are negatively skewed, such that during a single pass the firing rate is low as the rat enters the field but high as it exits. Second, while the place fields are symmetric at the beginning of a session, they become highly asymmetric with experience. Further experiments suggest that these results are likely to arise due to synaptic plasticity during behavior. Using a purely feed forward neural network model, we show that following repeated directional activation, NMDA-dependent long-term potentiation/long-term depotentiation (LTP/LTD) could result in an experience-dependent asymmetrization of receptive fields.

Action Potentials↗

PubMed2000

High-resolution solid state 13C nuclear magnetic resonance spectra of 3,4-methylenedioxyamphetamine hydrochloride and related compounds and their mixtures with lactose.

Differences between solution and solid state 13C nuclear magnetic resonance spectra of some amphetamines namely, 3,4-methylenedioxyamphetamine HCI, (R.S)-MDA HCI, the methyl derivative 3,4-methylenedioxy-N-methylamphetamine x HCI, (R,S)-MDMA x HCI, the ethyl derivative, (R,S)-MDEA x HCI, and the analogues (R,S)-methamphetamine HCI, (-)-ephedrine x HCI (the 3R,2S enantiomer as numbered here), and (+)-pseudo-ephedrine x HCI (the 3S,2S enantiomer as numbered here) have been studied and related to their crystal structure. For (R,S)-MDMA x HCI, an interesting new finding is that the observed solid state chemical shifts changed when lactose monohydrate was added as a dry powder and thoroughly mixed at room temperature. This experiment mimicked the illicit production of "Ecstasy" tablets. The mixing phenomena with lactose observed for (R.S)-MDMA x HCI was not seen for the other compounds studied. The results are discussed in terms of hydrogen bonding and possible polymorphs. It appears that lactose affects crystal packing by reducing conformational rigidity so that the molecule more closely resembles that in solution.

3,4-Methylenedioxyamphetamine↗

PubMed2000

Evolution in the management of hepatic trauma: a 25-year perspective.

OBJECTIVE: To define the changes in demographics of liver injury during the past 25 years and to document the impact of treatment changes on death rates. SUMMARY BACKGROUND DATA: No study has presented a long-term review of a large series of hepatic injuries, documenting the effect of treatment changes on outcome. A 25-year review from a concurrently collected database of liver injuries documented changes in treatment and outcome. METHODS: A database of hepatic injuries from 1975 to 1999 was studied for changes in demographics, treatment patterns, and outcome. Factors potentially responsible for outcome differences were examined. RESULTS: A total of 1,842 liver injuries were treated. Blunt injuries have dramatically increased; the proportion of major injuries is approximately 16% annually. Nonsurgical therapy is now used in more than 80% of blunt injuries. The death rates from both blunt and penetrating trauma have improved significantly through each successive decade of the study. The improved death rates are due to decreased death from hemorrhage. Factors responsible include fewer major venous injuries requiring surgery, improved outcome with vein injuries, better results with packing, and effective arterial hemorrhage control with arteriographic embolization. CONCLUSIONS: The treatment and outcome of liver injuries have changed dramatically in 25 years. Multiple modes of therapy are available for hemorrhage control, which has improved outcome.

Cause of Death↗

PubMed2000

Should trauma surgeons do general surgery?

OBJECTIVE: Many trauma centers have separated emergency and general surgery from trauma care. However, decreased trauma volume and more frequent nonoperative management may limit operative experience and the economic viability of the trauma service. Trauma surgeons at our Level I trauma center have long provided all emergency surgical care and elective surgery. We sought to determine the impact of this policy. METHODS: We reviewed all admissions to the trauma service from June of 1992 to July of 1998 and cross-referenced this with our trauma registry. The number of major and minor procedures performed was also determined, and we reviewed all operative procedures by the trauma service for June of 1996 to October of 1998. RESULTS: Total admissions by the trauma service averaged 3,003 patients/year (range, 2,798-3,198 patients). Nontrauma patients accounted for 34% of all trauma service admissions (range, 26-40%). During this time period, there was no change in volume of operative or intensive care unit procedures, whereas minor procedures recently decreased from a peak of 141/month to 50/month. This was largely due to decreased use of diagnostic peritoneal lavage (surgeon reimbursable) and an increased use of computed tomographic scan and ultrasound (not presently reimbursed) to evaluate blunt abdominal trauma. During the past 2 years, nontrauma cases accounted for 33% of all operative procedures by the trauma service. CONCLUSIONS: Maintenance of emergency and general surgical care by the trauma service has allowed us to buffer impact of variations in trauma volume and to maintain operative skills in an era of increased nonoperative management of many injuries.

Abdominal Injuries↗

PubMed2000

Regulation and developmental expression of the divalent metal-ion transporter in the rat brain.

Divalent metal ion transporter 1 (DMT1) is a recently identified metal-ion transporter that appears to mediate the absorption of iron in the intestine. DMT1 mRNA is also present in discrete areas of the brain. In this study, we examined the expression of DMT1 mRNA in developing rat brain. DMT1 mRNA was found by in situ hybridization in the striatum, cortex, hippocampus and cerebellum. During development, DMT1 mRNA was found in Purkinje and granule cells in the cerebellum at post-natal day (PND) 14 and PND 30. DMT1 mRNA was also expressed in the external granular layer of the cerebellum at PND 14. No change in the level of DMT1 mRNA was observed by Northern analysis in the cerebellum at different ages between PND 1 and 21. DMT1 was found by Northern analysis in cultures of rat astrocytes. Activation of protein kinase C increased the expression of DMT1 in kidney epithelial cells but not astrocytes from newborn rats. Because DMT1 is expressed in a wide variety of types of cells, we suggest that it plays an important role in metal homeostasis in the brain.

Animals↗

PubMed2000

Current medical and surgical treatment options for gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is one of the most common disorders in medicine. The options of medical versus surgical therapies have been highlighted by more potent acid suppression medications and by the introduction of minimally invasive surgery for GERD. Many factors will impact on the treatment selection for each individual patient: the underlying pathophysiology, typical vs atypical symptoms, presence of reflux complications, and success and limitations of medical and surgical treatments. Medical antireflux therapy is very effective and safe, but long-term maintenance therapy is required for most patients. Minimally invasive antireflux surgery has provided excellent results, but outcome is dependent on patient selection and surgical expertise. Careful pre-operative evaluation is essential to determine the optimal treatment and surgical approach.

Adult↗

PubMed2000

A clinical evaluation of Class II composites placed using a decoupling technique.

PURPOSE: This study was undertaken to evaluate the three-year clinical performance of Class II restorations of a fine particle hybrid composite placed using a decoupling placement technique, whereby polymerization shrinkage stresses at the cervical tooth-restoration interface were minimized by separating the initial gingival increment of composite from the body of the restoration using a polyurethane varnish. MATERIALS AND METHODS: The study was a practice-based explanatory, single-center clinical trial. A minimum of 40 Class II restorations of the material under investigation (Tetric) was required to be placed in predominantly molar teeth in selected patients. The restorations were placed using a decoupling incremental technique, bonding being accomplished using Syntac and Heliobond. The restorations were reviewed within 1 month of placement, thereafter at 18 months, then at 2 and 3 to 4 years using predetermined codes and criteria. Impressions and photographic records were used to obtain retrospective, third-party assessments of the restorations. RESULTS: Of 43 restorations originally placed and found to have ideal characteristics at baseline review, 41 (95%) were reviewed at 18 months, 36 (84%) at two years, and 31 (74%) at 3 to 4 years. None of the restorations were found to have suffered significant deterioration, notwithstanding three restorations having been lost to the study because of the replacement of part of the restored tooth for causes other than the catastrophic failure of the material. No secondary caries or postoperative sensitivity was recorded. CONCLUSION: It was concluded that the findings support the use of the material under investigation in the restoration of moderate- to large-sized Class II preparations in selected patients. The decoupling placement technique employed may be found to be an effective means to limit postoperative sensitivity and to contribute to the favorable in-service performance of restorations of the type investigated. Good practice would now require a multicentered, randomized controlled trial to investigate the effectiveness of the material and, in particular, the decoupling technique under the conditions of everyday practice.

Acrylates↗

PubMed1999

Interaction between spike waveform classification and temporal sequence detection.

In vivo extracellular recordings have allowed researchers to study the response properties of neurons to behaviorally relevant stimuli. In this paper we use multiple tetrode recordings from the hippocampus of the freely behaving rat to show that the action potential amplitude of a given cell can vary in a systematic and activity dependent manner over behaviorally relevant time scales. Since the discrimination algorithms used by experimenters to isolate cells from extracellular recordings are based on differences in waveforms, we show how these systematic changes in waveform shape can lead to non-random errors in single cell isolation. We further demonstrate that these non-random errors can lead to apparent temporal ordering effects between neurons in the absence of any specific temporal relationship. A firm understanding of these naturally occurring physiological changes is therefore critical for the evaluation of higher order phenomena such as the temporally correlated firing of ensembles of neurons.

Action Potentials↗

PubMed1999

Changes in nociceptive and anxiolytic responses following herpes virus-mediated preproenkephalin overexpression in rat amygdala are naloxone-reversible and transient.

These results using herpes virus-mediated gene transfer to overexpress enkephalin in the amygdala support the role of amygdalar opioids in the anxiolytic actions of benzodiazepines and supraspinal nociception (see ref. 1). These studies also demonstrate the usefulness of recombinant herpes virus in evaluating the role of single gene products within specific brain sites in pharmacological responses and complex behaviors.

Amygdala↗

PubMed1999

Decreased alpha-adrenergic response in the intestinal microcirculation after "two-hit" hemorrhage/resuscitation and bacteremia.

BACKGROUND: The two-hit theory of multiple organ dysfunction syndrome proposes that an initial insult primes the host for an altered response to subsequent stimuli. We have previously documented enhanced dilator tone in the small intestine after a two-hit insult; however, the effects on vasoconstrictor function are unknown. We postulated that prior hemorrhage and resuscitation followed by bacteremia would alter microvascular responsiveness to alpha-adrenergic stimulation. METHODS: Male Sprague-Dawley rats underwent fixed-volume hemorrhage with resuscitation (H/R) or sham procedure (Sham). At 24 or 72 h, in vivo videomicroscopy of the small intestine was performed (inflow A1 and premucosal A3 arterioles). Constrictor function was assessed by topical application of norepinephrine (NE; 10(-8)-10(-6) M) before and 1 h after intravenous Escherichia coli or saline. RESULTS: Sham, 24 or 72 h H/R, and E. coli alone produced no significant changes in A1 or A3 response to NE. Sequential H/R + E. coli resulted in decreased constrictor response in both A1 (72 h H/R + E. coli-38% from baseline vs Sham - 54%, P < 0.05) and A3 arterioles (-8% vs -51%, P < 0.05) at high doses of NE (10(-6) M). CONCLUSIONS: Prior H/R primes the intestinal microvasculature for an altered response during a subsequent stress and these effects persist for up to 72 h following H/R. Sequential insults in this two-hit model caused marked hyporesponsiveness to NE. These alterations in control of microvascular tone might contribute to the hemodynamic compromise of sepsis, impair mucosal blood flow, and contribute to the development of MODS.

Adrenergic alpha-Agonists↗

PubMed1999

Glucose and glutamine gavage increase portal vein nitric oxide metabolite levels via adenosine A2b activation.

INTRODUCTION: Postprandial intestinal hyperemia is a complex vascular response during nutrient absorption. Many mediators have been studied including enteric reflexes, GI hormones, and absorption-stimulated metabolic mediators such as pH and adenosine. We have shown that nitric oxide (NO) mediates premucosal arteriolar dilation during glucose absorption and that glucose-induced portal vein NO metabolite production requires adenosine A2b receptor activation. We hypothesize that Na+-linked absorption of l-glutamine or l-glycine might also stimulate NO release in the enteroportal circulation via adenosine A2b receptors. METHODS: Male Sprague-Dawley rats (190-220 g) were anesthetized with urethane/alpha-chloralose and cannulated for hemodynamic monitoring and blood sampling. A right paramedian abdominal incision was made for access to both the stomach (gavage) and the portal vein (blood sampling). Animals received intragastric nutrient gavage (saline, d-glucose, l-glutamine, racemic glycine, or oleic acid) with and without adenosine A2b receptor blockade. NO metabolites (NOx) were measured by a fluorescent modified-Greiss assay at baseline and 30 min after nutrient gavage. RESULTS: Glucose and glutamine gavage increased portal NOx levels compared to baseline, while glycine and oleic acid gavage did not. Adenosine A2b antagonism returned NOx levels to baseline in both glucose and glutamine gavage animals, but did not alter portal NOx levels in glycine- or oleic acid-treated animals. CONCLUSIONS: These data suggest that nutrient-induced adenosine is involved in a signaling process from the intestinal epithelium to nitric oxide-producing cells elsewhere in the vasculature. Adenosine A2b receptors are required for NO production during Na+-linked glucose or glutamine absorption.

Administration, Oral↗