Search PubMed⌕ Search

Biomedical subjects

K A Smith

Publications and source records attributed to K A Smith.

At least 55 records · Page 3Linked to original sources
PubMed1999

Symptomatic relapse in bulimia nervosa following acute tryptophan depletion.

BACKGROUND: Preclinical and clinical studies suggest that lowered brain serotonin neurotransmission may contribute to the pathophysiology of bulimia nervosa (BN). The aim of our study was to test this hypothesis by examining the psychological effects of a dietary-induced impairment in serotonin activity in subjects known to be at risk for manifestation of the clinical syndrome of BN. METHODS: An 85.8 g amino acid mixture lacking the serotonin precursor tryptophan and a balanced mixture were administered to 10 clinically recovered, medication-free female subjects with a history of BN in a double-blind, crossover design. Twelve healthy female subjects with no history of psychiatric disorder were studied as a comparison group. Observer and self-rated measures of mood and eating disorder cognitions were made for the 7 hours following administration of each amino acid mixture. RESULTS: Compared with healthy controls, subjects with a history of BN had significant lowering of mood, increases in ratings of body image concern, and subjective loss of control of eating following the tryptophan-free mixture. CONCLUSIONS: Our results suggest that diminished serotonin activity may trigger some of the cognitive and mood disturbances associated with BN. Our findings support suggestions that chronic depletion of plasma tryptophan may be one of the mechanisms whereby persistent dieting can lead to the development of eating disorders in vulnerable individuals.

Acute Disease↗
PubMed1999

Covariation of activity in habenula and dorsal raphé nuclei following tryptophan depletion.

Abnormal serotonergic function is implicated in the pathogenesis of affective disorders. We induced transient depressive relapses in volunteer patients by rapidly depleting plasma tryptophan, the precursor of serotonin (5-HT), and measured neural activity during different cognitive tasks using positron emission tomography (PET). Neural activity in several 5-HT-related brain areas, e.g., dorsal raphé, habenula, septal region, amygdala, and orbitofrontal cortex, covaried significantly with plasma levels of tryptophan and ratings of depressed mood. Task-specific responses in left amygdala and left anterior cingulate were attenuated by tryptophan depletion. We used these PET data to test the hypothesis that projections from the habenula modulate dorsal raphé activity and that this modulation is enhanced in patients experiencing a profound mood change following serotonergic challenge. A strong linear correlation (r(2) > 0.5) between habenula and raphé activity was observed in subjects with postdepletion ratings >/=10 on a modified Hamilton depression scale, whereas subjects experiencing milder changes in mood had weaker habenula-raphé coupling (r(2) < 0.5). These data support a model of the serotonergic system in which the habenula projection to the raphé represents a convergent feedback pathway that controls the release of 5-HT throughout the brain. In our experiment we were able to engage this system in patients who were sensitive to tryptophan depletion.

Adult↗
PubMed1999

Serotonin, dieting, and bulimia nervosa.

Dieting is a common behaviour which may trigger eating disorders such as bulimia nervosa in predisposed subjects. We found that in healthy women moderate dieting for 3 weeks lowered plasma concentrations of the 5-HT precursor, L-tryptophan (TRP) and impaired brain 5-HT neurotransmission as judged by 5-HT neuroendocrine tests. In recovered female subjects with a history of bulimia nervosa we found that TRP depletion produced by an amino acid mixture lacking TRP caused a temporary return of depressive symptoms together with concerns about weight and shape and fear of loss of control of eating. Taken together the data suggest that dieting-induced decreases in TRP availability may trigger the development of bulimia nervosa is susceptible individuals.

Bulimia↗
PubMed1999

Intrathecal morphine delivered via subcutaneous pump for intractable pain in pancreatic cancer.

BACKGROUND: Pain secondary to unresectable pancreatic cancer is frequently severe and extremely difficult to control with traditional methods of analgesia. This retrospective study reports the analgesic effects of intrathecal morphine sulfate by implanted infusion pumps in nine patients with unresectable adenocarcinoma of the pancreas. METHODS: Nine patients were implanted over a 2-year period. Preoperative morphine i.v. equivalents were a mean of 81.51 mg/day, with a range of 20-140 mg/day. Patients were hospitalized for a trial dose of 1-2 mg of intrathecal Duramorph, 1 mg/ml, via lumbar puncture to assess whether adequate pain relief could be achieved and whether there would be drug-related side effects. RESULTS: All patients who received a trial dose experienced excellent pain relief, and subsequently underwent implantation of a lumbar subarachnoid catheter and infusion pump during the same hospitalization. The mean number of days from diagnosis to pump implant was 119, with a range of 3-587 days. The mean maximum daily dose was 21.28 mg, with a range of 3-73.10 mg. No patient experienced respiratory depression or excess sedation which prevented achievement of pain control. Minor supplemental narcotic use was documented in three of the nine patients. Assessment of pain control was made by the level of activity and the analog pain scale, with 0 being no pain and 10 being the worst pain imaginable. All of the patients experienced good to excellent relief of pain. The mean duration of intrathecal morphine sulfate use until death was 137.3 days, with a range of 52-354 days. CONCLUSIONS: This series of nine patients indicates that long-term administration of intrathecal morphine via implanted infusion pump in patients with pancreatic cancer is both efficacious and safe. All patients and their families reported an improved quality of life with an increased level of activity.

Adenocarcinoma↗
PubMed1999

c-Rel is crucial for lymphocyte proliferation but dispensable for T cell effector function.

The TCR signals are essential for T cell activation and proliferation, primarily through the induction of cytokine and cytokine receptors. Several transcription factor families, including NF-kappaB/Rel, have been implicated in the regulation of cytokine gene expression in T cells in response to antigen, cytokine and mitogenic stimulation. In this study, we show that the mice with a null mutation in the lymphoid-specific c-Rel gene have normal development of lymphoid tissues and T cell compartment. However, T cells derived from the c-Rel knockout mice have several functional abnormalities. The c-Rel-deficient T lymphocytes fail to respond to activation and proliferation signals mediated by the TCR and mitogens in vitro. This is attributed to an impaired production of cytokines IL-2, IL-3 and granulocyte macrophage colony stimulating factor. In addition, the induction of IL-2R alpha chain is impaired in the c-Rel(-/-) T cells. The poor expression of cytokines and IL-2R alpha chain correlates with a reduced nuclear translocation of NF-kappaB components in c-Rel(-/-) T cells. Since activation is prerequisite for differentiation into effector cells, c-Rel(-/-) T cells failed to differentiate into cytotoxic T cells or Th cells without rescuing cytokines. However, upon supplement with exogenous IL-2, the c-Rel(-/-) cytotoxic T lymphocytes are able to execute cytotoxicity and the c-Rel(-/-) Th cells are capable of providing help to normal B cells. These data suggest that c-Rel is important for inducible cytokine and cytokine receptor expression, and a key regulator of early activation and proliferation in T cells.

Animals↗
PubMed1999

Allelic variation of the 5-HT2C receptor (HTR2C) in bulimia nervosa and binge eating disorder.

The 5-HT2C (serotonin-2C, HTR2C) receptor is implicated in the pathophysiology of eating disorders. There is a common polymorphism of the human 5-HT2C receptor at codon 23 (cys23ser) which has been reported to be a risk factor for certain psychiatric disorders and a predictor of their pharmacotherapeutic response. We examined whether this variant was associated with the eating disorder bulimia nervosa or binge eating disorder in a well-characterized community sample of 163 women, aged 16-35 years. Genotype and allele frequencies were entirely unaltered in both groups, compared to screened healthy controls from the same population. We conclude that allelic variation does not account for the involvement of the 5-HT2C receptor in these eating disorders.

Adolescent↗
PubMed1999

Gamma knife radiosurgery for trigeminal neuralgia: experience at the Barrow Neurological Institute.

Forty-three patients with trigeminal neuralgia (TN) unresponsive to pharmacologic treatment and/or prior invasive procedures underwent stereotactic radiosurgery with the Gamma Knife (GK). Outcome was evaluated by a standardized questionnaire mailed to each patient. The mean follow-up was 9 months. Fifteen patients (35%) reported no trigeminal pain and were no longer taking medication. Three patients (7%) experienced occasional pain, but were no longer taking medication. In 15 patients (35%), pain improved and was adequately controlled by medication, often in lower dosages than preoperatively. Pain was reduced in 9 patients (21%), but their symptoms were still inadequately controlled by drug therapy, and 1 patient (2%) reported no pain relief after treatment. Three patients (7%) described new facial numbness, but in none was this bothersome. GK radiosurgery for TN appears to have minimal morbidity, although the success rate may be slightly lower than that of other operative procedures. More patients and longer follow-up are needed before drawing final conclusions regarding efficacy and complications.

Aged↗
PubMed1999

Development and evaluation of a direct immunofluorimetric assay for urinary growth hormone.

We describe a two-site immunofluorimetric assay for urinary growth hormone that is resistant to interference from a wide range of urinary constituents and therefore eliminates the need for sample pre-treatment. A microtitre plate format is used with specific orientation of capture antibody on a polystyrene surface carrying a hydrazide group. Europium-labelled F(ab)2 is the fluorophore and time-resolved fluorimetry with co-fluorescence enhancement the signal detection system. Inter-assay precision was 11.3% at 5.2 ng/L and 10.3% at 44.3 ng/L, minimum detection limit (22% coefficient of variation, CV) was < 1.0 ng/L, working range (< 10% CV) was 0-100 ng/L and quantitative recovery and good parallelism were demonstrated. This convenient and sensitive assay is suitable for the routine measurement of human growth hormone (hGH) in urine.

Child↗
PubMed1999

Brain mechanisms associated with depressive relapse and associated cognitive impairment following acute tryptophan depletion.

BACKGROUND: Acute tryptophan depletion lowers brain serotonin synthesis and results in a transient, but striking, clinical relapse in recovered depressed patients. AIMS: To identify brain regions which change their activity as an acute depressive relapse evolves and to determine how pathological mood might modulate neural activity during a cognitive task. METHOD: We used H2(15)O positron-emission tomography (PET) to study eight recovered depressed men after tryptophan depletion and after a control procedure. During both PET scan sessions, subjects performed a paced verbal fluency task which alternated with a control verbal repetition task. RESULTS: Increasing levels of depression after tryptophan depletion were associated with diminished neural activity in the ventral anterior cingulate, orbitofrontal cortex and caudate nucleus regions. In addition, depressive relapse attenuated cognitive task-related activation in the anterior cingulate cortex. CONCLUSIONS: Our data indicate that changes in neural activity in distinct brain regions mediate the clinical phenomena of depression and depression-related cognitive impairment following acute tryptophan depletion. These changes could be associated with the widespread distribution of serotonin neurons in brain pathways associated with the expression of affect and cognitive performance.

Adult↗
PubMed1999

Restoration of immunity with interleukin-2 therapy.

HIV replication can now be effectively suppressed using antiretroviral combination regimens. The search continues, however, for ways to restore the immune response and eliminate reservoirs of latent infection. Interleukin-2 (IL-2) may augment the immune response in HIV-infected persons. This article discusses the rationale for using IL-2 in those with HIV disease and reviews key trials of IL-2 treatment regimens.

Antiretroviral Therapy, Highly Active↗
PubMed1998

Neutrophils deficient in PU.1 do not terminally differentiate or become functionally competent.

PU.1 is an ets family transcription factor that is expressed specifically in hematopoietic lineages. Through gene disruption studies in mice we have previously shown that the expression of PU.1 is not essential for early myeloid lineage or neutrophil commitment, but is essential for monocyte/macrophage development. We have also shown that PU.1-null (deficient) neutrophils have neutrophil morphology and express neutrophil-specific markers such as Gr-1 and chloroacetate esterase both in vivo and in vitro. We now demonstrate that although PU.1-null mice develop neutrophils, these cells fail to terminally differentiate as shown by the absence of messages for neutrophil secondary granule components and the absence or deficiency of cellular responses to stimuli that normally invoke neutrophil function. Specifically, PU.1-deficient neutrophils fail to respond to selected chemokines, do not generate superoxide ions, and are ineffective at bacterial uptake and killing. The failure to produce superoxide could, in part, be explained by the absence of the gp91 subunit of nicotinamide adenine dinucleotide phosphate oxidase, as shown by our inability to detect messages for the gp91(phox) gene. Incomplete maturation of PU.1-deficient neutrophils is cell autonomous and persists in cultured PU.1-deficient cells. Our results indicate that PU.1 is not necessary for neutrophil lineage commitment but is essential for normal development, maturation, and function of neutrophils.

Animals↗
PubMed1998

Antigen-specific cytolysis by neutrophils and NK cells expressing chimeric immune receptors bearing zeta or gamma signaling domains.

TCR- and IgG-binding Fc receptors (Fc gamma R) mediate a variety of critical biologic activities including cytolysis via the structurally related zeta- and gamma-chains. In previous studies, we have described chimeric immune receptors (CIR) in which the ligand-binding domain of a heterologous receptor or Ab is fused directly to the cytoplasmic domain of the TCR zeta-chain. Such zeta-CIRs efficiently trigger cytotoxic function of both T and NK cells in a target-specific manner. In this report, we compared the ability of both zeta- and gamma-CIRs to activate the cytolytic function of two distinct classes of Fc gamma R-bearing effectors, NK cells and neutrophils. Mature neutrophils expressing zeta- and gamma-CIR were generated in vivo from murine hemopoietic stem cells following transplantation of syngeneic mice with retrovirally transduced bone marrow or in vitro from transduced human CD34+ progenitors following differentiation. Both zeta- and gamma-based CIRs were capable of activating target-specific cytolysis by both NK cells and neutrophils, although the zeta-CIR was consistently more efficient. The experimental approach described is a powerful one with which to study the role of nonlymphoid effector cells in the host immune system and permits the rational design of immunotherapeutic strategies that rely on harnessing multiple immune cell functions via CIR-modified hemopoietic stem cells or progenitors.

Adult↗
PubMed1998

Myeloid development is selectively disrupted in PU.1 null mice.

The ets family transcription factor PU.1 is expressed in monocytes/macrophages, neutrophils, mast cells, B cells, and early erythroblasts, but not in T cells. We have recently shown that PU.1 gene disruption results in mice with no detectable monocytes/macrophages and B cells but T-cell development is retained. Although neutrophil development occurred in these mice, it was delayed and markedly reduced. We now proceed to demonstrate that PU. 1 null hematopoietic cells fail to proliferate or form colonies in response to macrophage colony-stimulating factor (M-CSF), granulocyte CSF (G-CSF), and granulocyte/macrophage CSF (GM-CSF). In contrast, PU.1 null cells did proliferate and form colonies in response to interleukin-3 (IL-3), although the response was reduced as compared with control littermates. Compared with control cells, PU.1 null cells had minimal expression of G- and GM-CSF receptors and no detectable M-CSF receptors. The size of individual myeloid colonies produced from PU.1 null primitive and committed myeloid progenitors in the presence of IL-3, IL-6, and stem cell factor (SCF) were reduced compared with controls. Under these conditions, PU.1 null progenitors produced neutrophils but not monocytes/macrophages. These observations suggest that PU.1 gene disruption induces additional cell-autonomous effects that are independent of the alterations in myeloid growth factor receptor expression. Our results demonstrate that PU.1 gene disruption affects a number of developmentally regulated hematopoietic processes that can, at least in part, explain the changes in myeloid development and reduction in myeloid and neutrophil expansion observed in PU.1 null mice.

Animals↗
PubMed1998

Oxidative denitrification of the antitumour drug hydroxyguanidine.

The oxidative denitrification of the antitumour agent hydroxyguanidine (HOG) has been investigated by radiolysis methods and EPR spectroscopy. The azide radical (N3.), a model one-electron oxidant, reacts with HOG with the rate constant 5.1 x 10(9) dm3 mol(-1) s(-1) to yield the guanidino carbon-centred radical (HOG.) which rapidly eliminates nitric oxide (k = 3.1 x 10[3] s[-1]) with the concomitant formation of urea. The HOG. undergoes conjugation with molecular oxygen to form a peroxyl radical (HOGOO.) with a rate constant 8.8 x 10(8) dm3 mol(-1) s(-1). The HOGOO. radical also eliminates nitric oxide but may act as a precursor to the peroxynitrite (ONOO-) ion. The oxidation of HOG by the dibromide radical (Br2.-) was found to release nitric oxide with a yield of 95% relative to Br2.- as determined from the combined yields of inorganic nitrite, nitrate and a HOG/nitric oxide-adduct. This study provides a possible mechanistic basis for the oxidative denitrification of HOG which may contribute to the observed toxicity of the drug both in vitro and in vivo and for the oxidation of nonphysiological hydroxyguanidines to NO. via nitric oxide synthase-independent pathways.

Antineoplastic Agents↗
PubMed1998

Distal posterior cerebral artery revascularization in multimodality management of complex peripheral posterior cerebral artery aneurysms: technical case report.

UNLABELLED: OBJECTIVES AND IMPORTANCE: Although controversial, revascularization of the distal posterior cerebral artery (PCA) may become necessary in treating complex PCA aneurysms before proximal parent vessel sacrifice. The revascularization of the distal PCA territories of two patients with peripheral PCA aneurysms is presented. CLINICAL PRESENTATIONS: One patient had an aneurysm of the P2-P3 segment and failed a selective P2 balloon occlusion test by developing homonymous hemianopia before planned parent vessel sacrifice. The other patient with a giant P2 segment aneurysm presented with visual field deficits. TECHNIQUE: The distal segment of PCA was revascularized before the aneurysms were trapped by surgical clipping or coil occlusion of the distal P2 segment, proximal to the aneurysms. In both cases, the occipital artery was used as the "donor" vessel. Temporary occlusion times were 22 and 20 minutes, respectively. Both grafts were patent on postoperative angiography, and both patients had full visual fields at the time of their follow-up examinations. CONCLUSION: De novo distal P2 sacrifice, advocated for treating peripheral PCA aneurysms, leads to visual field deficits in some patients. Revascularization of the distal segment of the PCA, less technically demanding than bypass to other PCA segments, preserves blood flow, thus sparing vision in this subset of patients.

Adult↗
PubMed1998

A case-control study of verocytotoxigenic Escherichia coli infection in cats with diarrhea.

The objectives of this study were to determine the prevalence of enteric verocytotoxigenic E. coli (VTEC) infection in a population of cats in Ontario, and to determine whether an association exists between the presence of VTEC and feline diarrhea. Fecal samples from 179 cats, representing 113 cats with diarrhea and 66 cats with normal feces, were cultured for E. coli. The fecal cultures were screened for verocytotoxin activity with a Vero cell assay. Confirmation of the presence of verocytotoxin (VT) genes was done with polymerase chain reaction (PCR) amplification; the frequency of occurrence of the genes for generic VT, VT1, and VT2 was determined. VTEC-positive samples were defined as those that demonstrated cytotoxicity on the Vero cell assay and yielded E. coli possessing one or more of the VT genes. All VTEC-positive isolates were serotyped. The overall prevalence of enteric VTEC infection in the cats was 12.3% (22/179). Statistical analysis of the case-control data showed no significant association between VTEC infection and diarrheal illness. The majority of the cats with VT-positive E. coli were positive for the presence of the generic VT, rather than for VT1 or VT2; it is therefore possible that a novel verocytotoxin gene may exist in E. coli isolated from cats. Eight VTEC strains were identified by serotyping; 4 of these serotypes have previously been isolated from humans, and 2 from cattle, suggesting that cats may be capable of acting as reservoirs for human and bovine VTEC serotypes.

Animals↗