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Biomedical subjects

D Carpenter

Publications and source records attributed to D Carpenter.

At least 19 recordsLinked to original sources
PubMed2002

Brain monoglyceride lipase participating in endocannabinoid inactivation.

The endogenous cannabinoids (endocannabinoids) are lipid molecules that may mediate retrograde signaling at central synapses and other forms of short-range neuronal communication. The monoglyceride 2-arachidonoylglycerol (2-AG) meets several criteria of an endocannabinoid substance: (i) it activates cannabinoid receptors; (ii) it is produced by neurons in an activity-dependent manner; and (iii) it is rapidly eliminated. 2-AG inactivation is only partially understood, but it may occur by transport into cells and enzymatic hydrolysis. Here we tested the hypothesis that monoglyceride lipase (MGL), a serine hydrolase that converts monoglycerides to fatty acid and glycerol, participates in 2-AG inactivation. We cloned MGL by homology from a rat brain cDNA library. Its cDNA sequence encoded for a 303-aa protein with a calculated molecular weight of 33,367 daltons. Northern blot and in situ hybridization analyses revealed that MGL mRNA is heterogeneously expressed in the rat brain, with highest levels in regions where CB(1) cannabinoid receptors are also present (hippocampus, cortex, anterior thalamus, and cerebellum). Immunohistochemical studies in the hippocampus showed that MGL distribution has striking laminar specificity, suggesting a presynaptic localization of the enzyme. Adenovirus-mediated transfer of MGL cDNA into rat cortical neurons increased MGL expression and attenuated N-methyl-D-aspartate/carbachol-induced 2-AG accumulation in these cells. No such effect was observed on the accumulation of anandamide, another endocannabinoid lipid. The results suggest that hydrolysis by means of MGL is a primary mechanism for 2-AG inactivation in intact neurons.

Amino Acid Sequence↗
PubMed2001

Prolongation of allograft survival with viral IL-10 transfection in a highly histoincompatible model of rat heart allograft rejection.

BACKGROUND: The ability to express genes with potential immunoregulatory capacity could reduce the immunogenicity of allografts and result in long-term graft survival. In this study, we examine the feasibility of transferring viral interleukin-10 (vIL-10) gene into rat hearts using adenovirus by intracoronary administration. The subsequent effects of delivered vIL-10 alone or with subtherapeutic doses of cyclosporine A (CsA) on parameters of allograft rejection (AR) were also examined. METHODS: Recombinant adenovirus vectors containing vIL-10 (Ad-vIL-10) or beta-galactosidase (Ad-beta-gal) were derived from adenovirus type 5. vIL-10 expression in supernatants of transfected COS7 cell cultures and in transfected heart allografts were examined by enzyme immunoassay (EIA) and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. Rat heart transplants (LEWS->ACI) were performed in five groups [group 1: no treatment, group 2: Ad-beta-gal, group 3: AdvIL-10, group 4: CsA (10 mg/kg), and group 5: Ad-vIL10+CsA (10 mg/kg)]. Allograft survival was determined by palpating heartbeats. Allograft tissues were also submitted for histological study. RESULTS: vIL-10 expression was shown in both transfected COS7 cells and heart isografts. Animals transfected with vIL-10 showed prolongation of graft survival (19.6 vs. 12 days, P<0.001) when compared to beta-gal transfected controls. Animals treated with a single low dose injection of CsA showed no significant prolongation of graft survival compared to controls (11.7 vs. 10.5 days). Animals treated with both vIL-10 and CsA demonstrated a synergistic prolongation of allograft survival compared with controls and with animals treated with CsA or vIL-10 treatment alone (36.7 days vs. 11.7, P<0.001 or 36.7 vs.19.6, P<0.001, respectively). Histological study showed that allografts from untreated controls exhibited extensive AR with loss of graft architecture by day 7 posttransplant while those from the vIL-10 group showed less AR. The best pathological scores were seen in vIL-10 + CsA-treated animals. CONCLUSIONS: 1) Delivering Ad-vIL-10 into donor hearts by intracoronary perfusion results in overexpression of vIL-10 and significantly prolongs cardiac allograft survival in a highly histoincompatible rat model. 2) Subtherapeutic doses of CsA do not prolong allograft survival, but act synergistically with vIL-10 to significantly prolong graft survival beyond that achieved with either agent alone.

Adenoviridae↗
PubMed2001

Treatment of depression in women: a summary of the expert consensus guidelines.

Women constitute two-thirds of patients suffering from common depressive disorders, making the treatment of depression in women a substantial public health concern. However, high-quality, empirical data on depressive disorders specific to women are limited, and there are no comprehensive evidence-based practice guidelines on the best treatments for these illnesses. To bridge the gap between research evidence and key clinical decisions, the authors developed a survey of expert opinion concerning treatment of four depressive conditions specific to women: premenstrual dysphoric disorder, depression in pregnancy, postpartum depression in a mother choosing to breast-feed, and depression related to perimenopause/menopause. The survey asked about 858 treatment options in 117 clinical situations and included a broad range of pharmacological, psychosocial, and alternative medicine approaches. The survey was sent to 40 national experts on women's mental health issues, 36 (90%) of whom completed it. The options, scored using a modified version of the RAND Corporation's 9-point scale for rating appropriateness of medical decisions, were assigned one of three categorical rankings-first line/preferred choice, second line/alternate choice, third line/usually inappropriate-based on the 95% confidence interval of each item's mean rating. The expert panel reached consensus (defined as a non-random distribution of scores by chi-square "goodness-of-fit" test) on 76% of the options, with greater consensus in situations involving severe symptoms. Guideline tables indicating preferred treatment strategies were then developed for key clinical situations. The authors summarize the expert consensus methodology they used and then, for each of the four key areas, review the treatment literature and summarize the experts' recommendations and how they relate to the research findings. For women with severe symptoms in each area we asked about, the first-line recommendation was antidepressant medication combined with other modalities (generally psychotherapy). These recommendations parallel existing guidelines for severe depression in general populations. For initial treatment of milder symptoms in each situation, the panel was less uniform in recommending antidepressants, and either gave equal endorsement to other treatment modalities (e.g., nutritional or psychobehavioral approaches in PMDD; hormone replacement in perimenopause) or preferred psychotherapy over medication (during conception, pregnancy, or lactation). In all milder cases, however, antidepressants were recommended as at least second-line options. Among antidepressants, selective serotonin reuptake inhibitors (SSRIs) were recommended as first-line treatment in all situations. The specific SSRIs that were preferred depended on the particular clinical situation. Tricyclic antidepressants were highly rated alternatives to SSRIs in pregnancy and lactation. In evaluating many of the treatment options, the experts had to extrapolate beyond controlled data in comparing treatment options with each other or in combination. Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide some direction for addressing common clinical dilemmas in women, and can be used to inform clinicians and educate patients regarding the relative merits of a variety of interventions.

Journal Article↗
PubMed2001

Pharmacotherapy of depression in older patients: a summary of the expert consensus guidelines.

Depression in older adults increases disability, medical morbidity, mortality, suicide risk, and healthcare utilization. Most studies of antidepressants are conducted in younger adults, and clinicians often have to extrapolate from findings in populations that do not present the same problems as older patients. Older patients often have serious coexisting medical conditions that may contribute to or complicate treatment of depression; they tend to take multiple medications, some of which may contribute to depression or interact with antidepressants; and they metabolize medications slowly and are more sensitive to side effects than younger patients. To address clinical questions not definitively answered in the research literature, the authors surveyed 50 experts on the pharmacotherapy of depressive disorders in older patients. The survey contained 64 questions with 857 options: 618 of the options were scored using a modified version of the RAND 9-point scale for rating appropriateness of medical decisions; for the other 239 options, the experts were asked to write in answers or check a box. The experts reached consensus on 89% of the options rated on the 9-point scale. Categorical rankings (first line/preferred, second line/alternate, third line/usually inappropriate) were assigned to each option based on the 95% confidence interval around the mean rating. Guideline tables indicating preferred treatment strategies were then developed for common and important clinical scenarios. The authors summarize the expert consensus methodology and the experts' recommendations and discuss how they relate to research findings. The experts recommend including both antidepressant medication and psychotherapy in treatment plans for nonpsychotic unipolar major depressive disorder of any severity, as well as for dysthymic disorder or persistent minor depressive disorder. They would also consider using either medication or psychotherapy alone for milder depression. For unipolar psychotic major depression, the treatment of choice is an antidepressant plus one of the newer atypical antipsychotics, with electroconvulsive therapy another first-line option. If the patient has a comorbid medical condition that is contributing to the depression, the experts recommend treating both the depression and the medical condition from the outset. The SSRIs were the top-rated antidepressants for all types of depression, with highest ratings for efficacy and tolerability given to citalopram and sertraline. Paroxetine was another first-line option, and fluoxetine was rated high second line. The preferred psychotherapy techniques for treating depression in older patients are cognitive-behavioral therapy, supportive psychotherapy, problem-solving psychotherapy, and interpersonal psychotherapy. The experts also recommended use of psychosocial interventions (e.g., psychoeducation, family counseling, visiting nurse services) in addition to pharmacotherapy and psychotherapy. Within limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide direction concerning common clinical dilemmas in older patients. They cannot address the complexities of each individual patient's care and can be most helpful in the hands of experienced clinicians.

Journal Article↗
PubMed2001

Superoxide dismutase and catalase do not affect the pulmonary hypertensive response to group B streptococcus in the lamb.

The purpose of this study was to determine whether treatment with conjugated antioxidant enzymes could attenuate or abolish pulmonary hypertension induced by group B streptococcus (GBS). Lambs, 3-7 d old, were anesthetized and ventilated. Intravascular catheters were placed in the left ventricle, descending aorta, right atrium, and pulmonary artery for continuous monitoring of intravascular pressures. Cardiac output was measured with radiolabeled microspheres. Measurements were obtained at baseline and 15 and 60 min into a 60-min GBS infusion, and 60 min after GBS was stopped. Blood gas values were held constant and PaO(2) was maintained >100 mm Hg. The control group received saline vehicle only (n = 6), the GBS group received GBS infusion only (n = 9), the enzymes (ENZ) group received polyethylene glycol-superoxide dismutase (PEG-SOD) and polyethylene glycol-catalase (PEG-CAT) treatment only (n = 6), and the ENZ+GBS group received PEG-SOD and PEG-CAT then GBS (n = 9). Plasma samples were obtained to confirm increased superoxide dismutase and catalase activities in the groups receiving enzymes. Compared with baseline, pulmonary vascular resistance increased by 119% and 101% at 15 min and 87% and 81% at 60 min in the GBS and ENZ+GBS groups, respectively. Sixty minutes after the termination of the GBS infusion, PVR returned to baseline in the GBS group but did not in the ENZ+GBS group. Enzyme infusions resulted in at least a ninefold increase in plasma enzyme activities. As opposed to previously published data from endotoxin models, PEG-CAT and PEG-SOD were ineffective in altering the GBS-induced pulmonary hypertensive response in this model. This suggests that acute administration of antioxidant enzymes may not be effective in ameliorating GBS-induced pulmonary hypertension.

Animals↗
PubMed2001

Polyinosinic acid and polycationic liposomes attenuate the hepatic clearance of circulating plasmid DNA.

DNA that enters the circulation is rapidly cleared both by tissue uptake and by DNase-mediated degradation. In this study, we have examined the uptake of linear plasmid DNA in an isolated perfused liver model and following intra-arterial administration to rats. We found that the DNA was rapidly taken up by the isolated perfused liver without degradation. The single-pass extraction ratio was 0.76 +/- 0.05, the mean transit time was 15.3 +/- 3.6 s, and the volume of distribution was 0.29 +/- 0.07 ml/g. Hepatic uptake was saturable and was inhibited by polyinosinic acid or polycationic liposomes but not by condensation of the DNA with polylysine. When the linear plasmid DNA was administered in vivo, plasma half-life was 3.1 +/- 0.2 min, volume of distribution was 670 +/- 85 ml/kg, and clearance was 32 +/- 4 ml/min. Coadministration of cationic liposomes decreased the volume of distribution to 180 +/- 28 ml/kg as well as the half-life (2.6 +/- 0.2 min). By contrast, polyinosinic acid significantly increased the circulating half-life (7.7 +/- 0.5 min), decreased the volume of distribution (95 +/- 17 ml/kg), and partially inhibited DNA degradation. When administered along with the liposomes and the polyinosinic acid, the distribution of plasmid-derived radioactivity decreased in the liver and increased in most other peripheral tissues. This study shows that pharmacological manipulation of the uptake and degradation of DNA can alter its distribution and clearance in vivo. These results may be useful in optimizing gene delivery procedures for in vivo gene therapy.

Animals↗
PubMed2001

Our overburdened ERs.

Like meteorologists tracking powerful weather systems, hospital officials have watched uneasily for some time as pressures built. The rising number of uninsured, a nursing shortage, lower reimbursements, and more and sicker hospital patients all brought turbulence. Now a convergence of these and other factors poses a serious challenge to emergency rooms, raising concerns about the stability of the nation's health care delivery system.

Crowding↗
PubMed2001

The Expert Consensus Guideline Series. Treatment of depression in women.

OBJECTIVES: Women constitute two-thirds of patients suffering from common depressive disorders. The treatment of depression in women is therefore a substantial public health concern. High-quality, empirical data on depressive disorders specific to women are limited. As a result, there are no comprehensive evidence-based practice guidelines on the best treatment approaches for these illnesses. We conducted a consensus survey of expert opinion on the treatment of 4 depressive conditions specific to women: premenstrual dysphoric disorder (PMDD), depression in pregnancy, postpartum depression in a mother choosing to breast-feed, and depression related to perimenopause/menopause. METHOD: After reviewing the literature and convening a work group of leading experts, we prepared a written survey covering a total of 858 treatment options in 117 specific clinical situations. Depression severity (mild to severe) was specified for most clinical situations. Treatment options included a broad range of pharmacological, psychosocial, and alternative medicine approaches. Most options were scored using a modified version of the RAND 9-point scale for rating appropriateness of medical decisions. We identified 40 national experts, 36 (90%) of whom completed the survey. Consensus on each option was defined as a non-random distribution of scores by chi-square "goodness-of-fit" test. We assigned a categorical rank (first line/preferred choice, second line/alternate choice, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean rating. Guideline tables indicating preferred treatment strategies were then developed for key clinical situations. RESULTS: The expert panel reached consensus on 76% of the options, with greater consensus in situations involving severe symptoms. For women with severe symptoms in each of the 4 central disorder areas we asked about, the first-line recommendation was for antidepressant medication combined with other modalities (generally psychotherapy), paralleling existing guidelines for severe depression in general populations. For milder symptoms in each situation, the panel was less uniform in recommending antidepressants. For the initial treatment of milder symptoms, the panel either gave equal endorsement to other treatment modalities (e.g., nutritional or psychobehavioral approaches in PMDD; hormone replacement in perimenopause) or preferred psychotherapy over medication (in conception, pregnancy, or lactation). In all milder cases, however, antidepressants were recommended as at least second-line options. Among antidepressants, selective serotonin reuptake inhibitors (SSRIs) as a class were recommended as first-line treatment in all situations. The specific SSRIs that were preferred depended on the particular clinical situation. Tricyclic antidepressants were highly rated alternatives to SSRIs in pregnancy and lactation. CONCLUSIONS: The experts reached a high level of consensus on the appropriateness of including both antidepressant medication, specifically SSRIs, and nonpharmacological modalities in treatment plans for severe depression in 4 key clinical situations unique to women. To evaluate many of the treatment options in this survey, the experts had to extrapolate beyond controlled data in comparing modalities with each other or in combination. Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide some direction for addressing common clinical dilemmas in women. They can be used to inform clinicians and educate patients regarding the relative merits of a variety of interventions.

Antidepressive Agents↗