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Biomedical subjects

K A Smith

Publications and source records attributed to K A Smith.

At least 73 records · Page 4Linked to original sources
PubMed1997

Relapse of depression after rapid depletion of tryptophan.

BACKGROUND: Major depression is a common disorder but the pathophysiology is poorly understood. Current hypotheses implicate deficient function of brain serotonin pathways because drugs that selectively increase brain serotonin activity are effective antidepressants. However, there is no direct evidence that lowered serotonin function causes major depression. We aimed to assess whether lowering of brain serotonin activity by depletion of its amino acid precursor, tryptophan, could provoke a short-term relapse of clinically significant symptoms in women vulnerable to major depressive disorder. METHODS: We studied 15 women who had suffered recurrent episodes of major depression but had recovered and were no longer on drug treatment. Patients received two amino acid mixtures in a double-blind crossover design. One of the mixtures was nutritionally balanced and contained tryptophan and the other was identical except it contained no tryptophan. Participants were scored on the Hamilton rating scale for depression (HAMD) before and 7 h after drinking each mixture. They also completed hourly self-rated measures of mood during this period. Blood samples were also taken at baseline and 7 h for measurement of plasma tryptophan. FINDINGS: The tryptophan-free mixture produced a 75% reduction in plasma tryptophan concentration. After drinking the tryptophan-free mixture, ten of the 15 women experienced temporary but clinically significant depressive symptoms. The mean difference in total HAMD scores (7 h minus baseline) were significantly higher after the tryptophan-free mixture than after the nutritionally balanced mixture (7.3 vs 0.15 [95% CI 4.5-9.9]; p < 0.001). No changes in mood were seen after taking the nutritionally balanced mixture. INTERPRETATION: We conclude that rapid lowering of brain serotonin function can precipitate clinical depressive symptoms in well, untreated individuals who are vulnerable to major depressive disorder. The findings support a key role for deficient serotonin function in the aetiology of depression.

Adult↗
PubMed1997

Multiple mechanisms of N-phosphonacetyl-L-aspartate resistance in human cell lines: carbamyl-P synthetase/aspartate transcarbamylase/dihydro-orotase gene amplification is frequent only when chromosome 2 is rearranged.

Rodent cells resistant to N-phosphonacetyl-L-aspartate (PALA) invariably contain amplified carbamyl-P synthetase/aspartate transcarbamylase/dihydro-orotase (CAD) genes, usually in widely spaced tandem arrays present as extensions of the same chromosome arm that carries a single copy of CAD in normal cells. In contrast, amplification of CAD is very infrequent in several human tumor cell lines. Cell lines with minimal chromosomal rearrangement and with unrearranged copies of chromosome 2 rarely develop intrachromosomal amplifications of CAD. These cells frequently become resistant to PALA through a mechanism that increases the aspartate transcarbamylase activity with no increase in CAD copy number, or they obtain one extra copy of CAD by forming an isochromosome 2p or by retaining an extra copy of chromosome 2. In cells with multiple chromosomal aberrations and rearranged copies of chromosome 2, amplification of CAD as tandem arrays from rearranged chromosomes is the most frequent mechanism of PALA resistance. All of these different mechanisms of PALA resistance are blocked in normal human fibroblasts.

Aspartate Carbamoyltransferase↗
PubMed1997

Survey of veterinary professionals and other veterinary conference attendees for antibodies to Bartonella henselae and B quintana.

OBJECTIVE: To determine serologic and epidemiologic characteristics of an occupational group potentially at risk for Bartonella sp infection. DESIGN: Epidemiologic survey. SAMPLE POPULATION: 351 veterinarians, veterinary technicians, and other individuals attending a veterinary conference in Ohio. PROCEDURE: A serum sample was obtained from each individual and tested for antibodies to Bartonella henselae or B quintana. A 24-question survey also was administered regarding demographic, occupational, and exposure information. RESULTS: 25 (7.1%) individuals were seropositive for B henselae or B quintana. Forty-seven, of whom 5 were seropositive, reported a history of illness consistent with cat-scratch disease and 18, of whom 3 were seropositive, reported a previous diagnosis of cat-scratch disease. Of the variables analyzed, only years of experience with cats was correlated with seropositivity. CLINICAL IMPLICATIONS: The overall seroprevalence for 2 species of Bartonella in this occupational group was only slightly higher than that reported from other surveys. Seroprevalences among veterinarians, veterinary technicians, hospital staff, and others were essentially identical. Small sample groups, high percentage of cat ownership among participants, unknown duration of seropositivity, and unknown prevalence of infection among cats were potential confounders.

Adult↗
PubMed1997

Esophageal candidiasis as a complication of inhaled corticosteroids.

BACKGROUND: Oropharyngeal candidiasis is a well-described side effect of inhaled corticosteroids. Nevertheless, few cases of esophageal candidiasis have been reported. OBJECTIVE: To present a patient with esophageal candidiasis associated with inhaled corticosteroids. METHODS: Case report. RESULTS: Our patient is a 70-year-old white woman with a 20-year history of intrinsic asthma, well controlled on triamcinolone acetonide 400 micrograms, ipratropium bromide 36 micrograms, and pirbuterol acetate 400 micrograms, each inhaled four times daily. She reported no oral steroid use for > 4 years and that she always rinsed her mouth following triamcinolone acetonide inhalation. The patient had gastritis with peptic ulcer disease in the past and developed worsening dyspeptic pain and heartburn. Following discontinuation of cimetidine and initiation of ranitidine without improvement, esophagogastroduodenoscopy was performed. Several small white patches in the mid and distal esophagus could not be removed with pressure. A biopsy confirmed the diagnosis of candidal esophagitis. Following a 4-week course of fluconazole, the patient was clinically improved and follow-up esophagogastroduodenoscopy was normal. There was no evidence of underlying cellular immunosuppression, malignancy, or diabetes mellitus and no history of recent antibiotic usage. Delayed skin tests revealed 5 x 5 mm induration to dermatophytin. Delayed hypersensitivity to Candida and mumps tests was absent. There was strong in vitro lymphocyte transformation and a positive immediate skin test response to Candida. ELISA for human immunodeficiency virus was negative. T and B cell counts were normal with CD4 = 630/mm3, CD8 = 520/mm3, and absolute B cell = 120/mm3. It is possible that this patient's immediate hypersensitivity response to Candida suppressed her delayed response. Candidal esophagitis is a rare, yet important, complication of inhaled corticosteroid use. CONCLUSION: Immunocompetent patients on inhaled corticosteroids with medically unresponsive symptoms of esophagitis should be investigated for esophageal candidiasis.

Administration, Inhalation↗
PubMed1997

Angiographic follow-up in 37 patients after radiosurgery for cerebral arteriovenous malformations as part of a multimodality treatment approach.

Modified Linac radiosurgery was utilized at our institution between 1990 and 1995 in 54 patients with cerebral arteriovenous malformations (AVMs) as part of a multimodality therapeutic approach. Most patients also underwent surgery and embolization of the AVMs prior to radiosurgery. The goal of the adjunctive radiosurgical treatment was the complete angiographic obliteration of the deep residual AVM after subtotal embolization and resection. Radiosurgery was used as the primary treatment of some small deep AVMs which were judged to have a high risk of morbidity if approached surgically. Of the 54 patients, 37 have had follow-up angiograms available for review. The median time interval between radiosurgery and the most recent angiogram was 22 months (range 5-66 months). This is a retrospective report on the angiographic follow-up available on this selected group of patients with difficult AVMs. All angiograms were evaluated for the presence of residual AVM. If any residual AVM was present, a decrease in size of more than 50% was noted as significant. The hospital and office charts of all patients were reviewed and the patients and families were contacted for up-to-date clinical follow-up. Prior to treatment, 11 patients had Spetzler-Martin grade 5 AVMs, 12 patients had grade 4 AVMs, and 14 patients had grade 3 AVMs. There were no grade 1 or 2 AVMs treated with radiosurgery. Of these 37 patients, 13 (35%) were completely obliterated on follow-up angiography. Three of the 11 (27%) grade 5 AVMs were completely obliterated. Seven of the 12 (58%) grade 4 AVMs were obliterated. Three of the 14 (21%) grade 3 AVMs have documented radiosurgical obliteration, however 8 others have had a significant decrease in size on the first posttreatment angiogram (median follow-up 14 months) and have further angiographic follow-up pending. There were 5 hemorrhages after radiosurgery, 1 was fatal and 1 resulted in permanent morbidity. Six patients have been reembolized since radiosurgery and 2 of those had their AVMs surgically resected thereafter. Only 1 patient of 6 (17%) in this series who was treated with radiosurgery alone has had documented AVM obliteration. None of 3 treated with embolization alone prior to radiosurgery have had complete obliteration. Three of the 5 patients (60%) who had only surgery prior to radiosurgery had their AVMs completely obliterated. Of the 23 patients who had all three treatments (embolization, surgery, and radiosurgery), 10 (43%) had complete obliteration of their AVMs. One patient (2%) developed moderate permanent neurological disability as a result of radiosurgery-induced necrosis. This patient did have complete obliteration of her AVM. These data support the use of radiosurgery for treatment of cerebral AVMs as part of a multimodality approach if the surgical risk of any residual AVM after embolization and microsurgical resection is deemed excessive. The adjunctive use of radiosurgery in this series resulted in the safe complete obliteration of many very difficult grade 4 and 5 AVMs. These data do not support the use of radiosurgery as the primary treatment of surgically resectable AVMs since there is a risk of interval hemorrhage and the obliteration rate is far inferior to that of microsurgical resection.

Adolescent↗
PubMed1997

Highly sensitive method to detect mRNAs in individual cells by direct RT-PCR using Tth DNA polymerase.

A new method for detecting the expression of low-abundance mRNA molecules has been developed that combines the sensitivity of PCR, the high efficiency and specificity of reverse transcription (RT) using Tth DNA polymerase at high temperature, and the enhancement of sensitivity and specificity of nested PCR. This method is highly sensitive, reproducible and allows the detection of mRNAs in individual cells by direct RT-PCR.

Animals↗
PubMed1997

Rational interleukin-2 therapy.

The administration of cytokines that augment the function of the immune system can be accomplished safely and without toxicity, provided a rational approach is used. Such a therapeutic method should be based upon the principles of pharmacology and the structure-activity relationships of the cytokine-receptor interaction. Thus, the therapeutic index should be determined, and the goal should be to augment the function of the immune system in a variety of clinical situations, not necessarily focused on eradicating a particular disease process such as metastatic cancer that may or may not be influenced by the immune system.

HIV Infections↗
PubMed1996

Rational interleukin 2 therapy for HIV positive individuals: daily low doses enhance immune function without toxicity.

When administered in high doses to HIV positive (HIV+) individuals, interleukin 2 (IL-2) causes extreme toxicity and markedly increases plasma HIV levels. Integration of the information from the structure-activity relationships of the IL-2 receptor interaction, the cellular distribution of the different classes of IL-2 receptors, and the pharmacokinetics of IL-2 provides for the rationale that low IL-2 doses should circumvent toxicity. Therefore, to identify a nontoxic, but effective and safe IL-2 treatment regimen that does not stimulate viral replication, doses of IL-2 from 62,500 to 250,000 IU/m2/day were administered subcutaneously for 6 months to 16 HIV+ individuals with 200-500 CD4+ T cells/mm3. IL-2 was already detectable in the plasma of most HIV+ individuals even before therapy. Peak plasma IL-2 levels were near saturating for high affinity IL-2 receptors in 10 individuals who received the maximum nontoxic dose, which ranged from 187,500 to 250,000 IU/m2/day. During the 6 months of treatment at this dose range, plasma levels of proinflammatory cytokines remained undetectable, and plasma HIV RNA levels did not change significantly. However, delayed type hypersensitivity responses to common recall antigens were markedly augmented, and there were IL-2 dose-dependent increases in circulating Natural Killer cells, eosinophils, monocytes, and CD4+ T cells. Expanded clinical trials of low dose IL-2 are now warranted, especially in combination with effective antivirals to test for the prevention of immunodeficiency and the emergence of drug-resistant mutants and for the eradication of residual virions.

Adult↗
PubMed1996

The selective GABAB antagonist CGP-35348 blocks spike-wave bursts in the cholesterol synthesis rat absence epilepsy model.

Slow IPSPs, which are believed to be involved in generation of the wave of spike-wave epileptiform discharges, are mediated by the GABAB receptor. We therefore examined the effect of the GABAB antagonist, Ciba Geigy Product, CGP-35348, in the cholesterol synthesis inhibitor model of absence epilepsy in rat. Rats received Ayerst-9944 (AY-9944), from 6-45 mg i.p. in the first few weeks of life. By 2 months after AY-9944 administration these rats exhibited recurrent spike-waves and behavioral arrests. In 10 such animals CGP-35348 was administered intraperitoneally in doses of 0 (vehicle), 10, 25 or 100 mg/kg. EEG recordings were obtained via previously implanted bone screws. Technologists blinded to treatment group counted spike-waves over a 4 h period post-injection. The average number of spike-wave burst seconds per 4 h of recording for all dosages and times was 52.4 +/- 81.4 (mean +/- S.D.) s. Mean burst times (seconds) were vehicle = 93.5 +/- 106.5; 10 mg/kg = 69.9 +/- 79.7; 25 mg/kg = 30.8 +/- 46.9; 100 mg/kg = 15.2 +/- 54, a mean 84% reduction at 100 mg/kg (ANOVA regression significant at 0.0001). Spike-waves were suppressed for at least 4 h after injection of CGP-35348. These findings supplement similar findings in other absence models, and support a potential role for GABAB antagonists in treatment of absence seizures.

Animals↗
PubMed1996

Interleukin-2 is indispensable for development of immunological self-tolerance.

Interleukin-2-deficient mice (IL-2(-/-)) manifest severe immune system abnormalities characterized by an uncontrolled activation and proliferation of lymphocytes. A systemic autoimmune syndrome results, and hemolytic anemia leads to early death especially in mice derived from a BALB/c genotype. Remarkably, IL-2 treatment prevents both the activation of the immune system and the development of autoimmune disease. Moreover, adoptive transfer of lymphocytes from IL-2-treated IL-2(-/-) animals confers protection to IL-2(-/-) mice, suggesting that IL-2 induces a postnatal differentiation/maturation of regulatory cells necessary for self- and non-self-discrimination.

Anemia, Hemolytic, Autoimmune↗
PubMed1996

Inefficient growth arrest in response to dNTP starvation stimulates gene amplification through bridge-breakage-fusion cycles.

Cells often acquire resistance to the antiproliferative agents methotrexate (MTX) or N-phosphonacetyl-L-aspartate (PALA) through amplification of genes encoding the target enzymes dihydrofolate reductase or carbamylphosphate synthetase/aspartate transcarbamylase/dihydroorotase (CAD), respectively. We showed previously that Syrian hamster BHK cells resistant to selective concentrations of PALA (approximately 3 x ID50) arise at a rate of approximately 10(-4) per cell per generation and contain amplifications of the CAD gene as ladder-like structures on one of the two B9 chromosomes, where CAD is normally located. We now find that BHK cells resistant to high concentrations of PALA (approximately 15 x ID50) appear only after prior exposure to selective concentrations of PALA for approximately 72 h. Furthermore, in contrast to untreated cells, BHK cells pretreated with selective concentrations of MTX give colonies in high concentrations of PALA, and cells pretreated with selective concentrations of PALA give colonies in high concentrations of MTX or 5-fluorouracil. As judged by measuring numbers of cells and metaphase cell pairs, BHK cells do not arrest completely when starved for pyrimidine nucleotides by treatment with selective concentrations of PALA for up to 72 h. We propose that DNA damage, caused when cells fail to stop DNA synthesis promptly under conditions of dNTP starvation, stimulates amplification throughout the genome by mechanisms--such as bridge-breakage-fusion cycles--that are triggered by broken DNA. Amplified CAD genes were analyzed by fluorescence in situ hybridization both in cells where amplification was induced by PALA pretreatment and in cells in which the amplification occurred spontaneously, before selection with PALA. The ladder-like structures that result from bridge-breakage-fusion cycles were observed in both cases.

Animals↗
PubMed1996

Nitric oxide involvement in the toxicity of hydroxyguanidine in leukaemia HL60 cells.

The free-radical intermediates and the stable products formed on one-electron oxidation of hydroxyguanidine (HOG) were investigated in order to suggest a mechanistic basis for HOG-induced cytotoxicity and cytostasis in leukaemia HL60 cells. The azide radical (generated radiolytically) reacted with HOG to produce a carbon-centred radical which in the absence of oxygen decays by a first-order process (k = 3.2 x 10(3) s-1) to yield nitric oxide (NO) and urea. Although the HOG radical reacts rapidly with oxygen (rate constant for O2 addition, k = 4.2 x 10(8) dm3 mol-1 s-1) this neither prevented the elimination of NO. nor generated alternative nitrogen oxides (e.g. peroxynitrite) capable of contributing to cellular oxidative stress. The detection of NO. in HL60 cells corroborated mechanistic studies that oxidative denitrification of HOG does not require catalysis by nitric oxide synthase. Quantitation of NO. by electron paramagnetic resonance (EPR) spectroscopy (utilising a NO. -selective probe) shows higher amounts of NO. under anoxic conditions, reflecting competition for NO. with molecular oxygen in oxic cells. Inhibition of cytochrome P450 and myeloperoxidase activity decreased NO. production thereby identifying these enzyme systems as capable of oxidizing HOG in vitro. A correlation exists between the intracellular levels of NO. with both the cytotoxic and cytostatic effects of HOG within HL60 cells. A higher toxicity was observed with hypoxic than with oxic cells. The lower levels of NO. associated with aerobic conditions caused a G1 --> S block in the cell cycle which under anoxia potentiated NO. -induced apoptotic cell death.

Antineoplastic Agents↗