PubMed Health⌕ Search

Biomedical subjects

R Alexander

Publications and source records attributed to R Alexander.

At least 19 recordsLinked to original sources
PubMed1998

Induction of prostate apoptosis by doxazosin in benign prostatic hyperplasia.

PURPOSE: The molecular mechanisms underlying the therapeutic effect of the alpha1 blocker, doxazosin, on benign prostatic hyperplasia (BPH) are poorly understood. We evaluated the effect of doxazosin on cell proliferation and apoptosis in the prostatic glandular epithelium and stroma of patients with BPH. MATERIALS AND METHODS: We examined proliferative and apoptotic activities in prostate specimens of 22 men a mean of 65 years old with BPH before and after doxazosin treatment within the normal therapeutic range. Proliferative and apoptotic indexes were determined using Ki-67 nuclear antigen staining and the terminal transferase end labeling assay, respectively. The smooth muscle cell content in prostatic specimens was identified by smooth muscle alpha-actin, and desmin immunoreactivity and apoptotic indexes were correlated with prostatic stromal tissue regression and improvement in BPH symptoms. RESULTS: In response to doxazosin treatment there were no significant changes in the kinetics of cell proliferation in the prostatic epithelial or stromal cell population. Mean pretreatment baseline apoptosis was 1.9 and 1.0% for the epithelial and stromal prostate components, respectively. Mean apoptotic indexes significantly increased after 3 months of doxazosin treatment in the glandular epithelial (6%) and smooth muscle cells (15%). By 12 months after treatment epithelial apoptosis had decreased to constitutive levels, while the apoptotic index of prostatic stroma cells remained high. Doxazosin induced smooth muscle cell apoptosis correlated with prostatic stromal degeneration, decreased alpha-smooth muscle actin expression and improved BPH symptoms. CONCLUSIONS: These findings implicate the induction of prostate apoptosis by doxazosin as a potential molecular mechanism underlying the acute and chronic therapeutic responses of BPH to alpha1 blockade.

Adrenergic alpha-Antagonists↗
PubMed1997

Altered proliferative response by T lymphocytes of Ly-6A (Sca-1) null mice.

Ly-6A is a murine antigen which is implicated in lymphocyte activation and may be involved in activation of hematopoietic stem cells. Antibody cross-linking studies and antisense experiments have suggested that Ly-6A is a lymphocyte coactivation molecule. To better understand the function of Ly-6A, we used gene targeting to produce Ly-6A null mice which are healthy and have normal numbers and percentages of hematopoietic lineages. However, T lymphocytes from Ly-6A-deficient animals proliferate at a significantly higher rate in response to antigens and mitogens than wild-type littermates. In addition, Ly-6A mutant splenocytes generate more cytotoxic T lymphocytes compared to wild-type splenocytes when cocultured with alloantigen. This enhanced proliferation is not due to alterations in kinetics of response, sensitivity to stimulant concentration, or cytokine production by the T cell population, and is manifest in both in vivo and in vitro T cell responses. Moreover, T cells from Ly-6A-deficient animals exhibit a prolonged proliferative response to antigen stimulation, thereby suggesting that Ly-6A acts to downmodulate lymphocyte responses.

Animals↗
PubMed1997

Evaluation of a commercial polymerase chain reaction assay for the detection of Chlamydia trachomatis.

Cell culture has traditionally been considered the most sensitive method for detecting Chlamydia trachomatis from clinical specimens, but depends upon the organisms being viable at the time of cell inoculation. Furthermore, cell culture is slow and labor intensive. Even when a special transport medium is used, there is a progressive loss of viability of C. trachomatis during transport. The detection of C. trachomatis by cell culture is more rapid when immunofluorescence is used to detect early antigen, but requires considerable experience to interpret. The Amplicor C. trachomatis system is a commercial polymerase chain reaction (PCR)-based assay combined with nucleic acid hybridization for the direct detection of C. trachomatis in urine and swabs of appropriate sites, with results available within 6 h. All specimens for C. trachomatis received by the Royal Perth Hospital Department of Microbiology during the period 1 July 1994 to 30 June 1995 that were suitable for culture and Amplicor PCR were tested by both methods (2029 specimens). Discordant results were obtained in nine cases and resolved by additional testing. Seventy-one specimens were confirmed as true positives, of these Amplicor PCR correctly detected 67 (sensitivity 94.4%) and culture correctly detected 62 (sensitivity 87.3%). The Amplicor PCR assay was found to be more sensitive and as specific as culture. It had the added advantages of ease of use, rapid availability of results, standardization and was more suited than culture to processing large number of specimens.

Cells, Cultured↗
PubMed1997

The laryngeal mask airway and the tracheal route for drug administration.

We undertook a study to observe if a preformed curved plastic cannula, the Trachojet, could be passed blindly down a laryngeal mask airway into the trachea in 100 anaesthetized patients. Using air aspiration and a fibreoptic scope to confirm placement of the cannula, it passed into the trachea in only 27% of patients. The air aspiration technique used for detecting tracheal cannulation was 100% successful when the cannula was inserted fully. We conclude that it may not be possible to gain access to the trachea with a Trachojet for drug administration if a laryngeal mask airway is used to maintain the patient's airway.

Administration, Oral↗
PubMed1997

Comparison of ondansetron, metoclopramide and placebo as premedicants to reduce nausea and vomiting after major surgery.

In a randomised, double-blind study, we have compared the incidence of postoperative nausea and vomitting in 124 patients undergoing major lower limb orthopaedic surgery following oral premedication with temazapam and ondansetron 8 mg, metoclopramide 10 mg or placebo. They received a standardised epidural and general anaesthetic. An epidural mixture containing bupivacaine 0.1% and fentanyl 10 mg.ml-1 was infused postoperatively. The occurrence of nausea and vomiting was assessed every 4 h for 24 h. The incidence of vomiting significantly decreased from 55% and 43% in the placebo and metoclopramide groups, respectively, to 26% in the ondansetron group (p = 0.03). The incidence of nausea and vomiting in patients who had previously suffered was also significantly reduced from 67% and 68% in the placebo and metoclopramide groups, respectively, to 29% in the ondansetron group (p = 0.035). We conclude that oral premedication with ondansetron 8 mg was superior to metoclopramide 10 mg and placebo in preventing postoperative nausea and vomiting following major orthopaedic surgery in patients given epidural opioid analgesia.

Adolescent↗
PubMed1996

Phase II trial of topotecan in advanced or metastatic adenocarcinoma of the pancreas.

PURPOSE: A phase II trial of topotecan, an inhibitor of topoisomerase I, was conducted in patients with advanced or metastatic adenocarcinoma of the pancreas to determine the activity and toxicity of topotecan. PATIENTS AND MATERIALS: 35 patients, previously untreated with chemotherapy, received topotecan 1.5 mg/m2/d for five days intravenously and repeated every 21 days. Patients were assessed for response after 3 cycles. Those with either clinical response or stable disease received additional cycles of the drug until toxicity developed or disease progression occurred. RESULTS: Among 30 patients evaluable for response there were no complete responses and 3 partial responses (10%) for a total response rate of 10% (95% confidence interval = 0-20.6%). Stable disease for at least eight weeks was seen in 11 patients (36%). Median survival was 19 weeks (95% confidence interval 11 to 26 weeks). Therapy was generally well tolerated, with reversible granulocytopenia being the most common toxicity. CONCLUSION: Topotecan given on a 5 day, short infusion schedule, demonstrated limited activity in pancreatic carcinoma with minimal toxicity. Further exploration of topotecan in pancreatic carcinoma using different dosing schedules is warranted.

Adenocarcinoma↗
PubMed1996

Recognition of vitreoschisis in proliferative diabetic retinopathy. A useful landmark in vitrectomy for diabetic traction retinal detachment.

INTRODUCTION: In the late stages of proliferative diabetic retinopathy (PDR) the vascularized posterior cortical gel (PCG) contracts leading to a partial posterior hyaloidal separation, hemorrhage, and traction retinal detachment (TRD). "Additional epiretinal membranes" have been described previously. These are thin, usually transparent epiretinal membranes which extend anteriorly from the point of attachment of the elevated posterior cortical gel to the edge of the TRD. The origin and frequency of the occurrence as well as the clinical significance of such additional epiretinal membranes are the subjects of controversy. PURPOSE: To quantitate the authors' clinical impression that additional epiretinal membranes are common in advanced PDR, to characterize them immunohistochemically, and to demonstrate the rationale for the authors' surgical approach. METHODS: Intraoperative observations for all patients undergoing diabetic vitrectomy and delamination over the last 2 years were reviewed retrospectively. The presence of additional epiretinal membrane was searched for in the initial stages of vitrectomy. When identified, their apparent continuity with the elevated portion of the PCG was confirmed. Surgical specimens were obtained from nine patients for immunohistochemical study. RESULTS: Additional epiretinal membranes were observes in 145 (81%) of 179 consecutive eyes with PDR that underwent surgery for macular TRD. Immunohistochemical staining with type II collagen antibody was positive in all specimens, suggesting that these membranes were of vitreous origin. CONCLUSIONS: It is likely that the additional epiretinal membranes represent the posterior leaf of a split PCG, the anterior leaf being the elevated portion of the PCG. The two leaves remain fused in the main, fibrovascular portion of the epiretinal membrane. These findings help explain the clinical experience that once the posterior leaf of the PCG is identified and elevated, it provides an accurate point of entry into the surgical plane facilitating delamination of the fused (vascularized) portion of the PCG from the detached retina.

Aged↗
PubMed1996

The inhibition of antigen-induced eosinophilia and bronchoconstriction by CDP840, a novel stereo-selective inhibitor of phosphodiesterase type 4.

1. The novel tri-aryl ethane CDP840, is a potent and selective inhibitor of cyclic AMP phosphodiesterase type 4 (PDE 4) extracted from tissues or recombinant PDE 4 isoforms expressed in yeast (IC50S: 4-45 nM). CDP840 is stereo-selective since its S enantiomer (CT 1731) is 10-50 times less active against all forms of PDE 4 tested while both enantiomers are inactive (IC50S: > 100 microM) against PDE types 1, 2, 3 and 5. 2. Oral administration of CDP840 caused a dose-dependent reduction of interleukin-5 (IL-5)-induced pleural eosinophilia in rats (ED50 = 0.03 mg kg-1). The eosinophils in pleural exudates from CDP840-treated animals contained higher levels of eosinophil peroxidase (EPO) than cells from control animals, suggesting a stabilizing effect on eosinophil degranulation. CDP840 was approximately equi-active with the steroid dexamethasone in this model and was 10-100 times more potent than the known PDE 4-selective inhibitors rolipram and RP73401. The activity of CDP840 was not influenced by adrenalectomy, beta-sympathomimetics or beta-sympatholytics. 3. Antigen-induced pulmonary eosinophilia in sensitized guinea-pigs was reduced dose-dependently by CDP840 (0.01-1 mg kg-1, i.p.) and intracellular EPO levels were significantly higher. CDP840 was more potent in these activities than CT1731 or rolipram and comparable in potency to RP73401. 4. Rolipram or CDP840 were less active than dexamethasone in preventing neutrophil accumulation, or exudate formation in carrageenan-induced pleurisy in rats and thus do not exhibit general anti-inflammatory activity. 5. In sensitized guinea-pigs, aerosols of the antigen ovalbumin caused a dose-dependent bronchoconstriction demonstrated by an increase in pulmonary inflation pressure. Administration of CDP840 (0.001-1.0 mg kg-1, i.p.), 1 h before antigen challenge, resulted in dose-dependent reduction in response to antigen. This activity was not due to bronchodilatation since higher doses of CDP840 (3 mg kg-1) did not significantly change the bronchoconstrictor response to histamine. Rolipram was approximately 10 times less active than CDP840 in preventing antigen-induced bronchoconstriction. 6. These results confirm the observations that selective PDE 4 inhibitors reduce antigen-induced bronchoconstriction and pulmonary eosinophilic inflammation. CDP840 is more potent than rolipram in inhibiting native or recombinant PDE 4. Unlike the recently described potent PDE 4 inhibitor RP73401, CDP840 is more active than rolipram in the rat IL-5 model following oral administration. The novel series of tri-aryl ethanes, of which CDP840 is the lead compound, could be the basis of an orally active prophylactic treatment for human asthma.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1996

The pathology of cornea in Tangier disease (familial high density lipoprotein deficiency).

AIMS: To clarify the underlying causes of corneal opacification in Tangier disease. METHODS: Both corneas were removed at death from a 62 year old man with Tangier disease, and were examined by direct and transmission electron microscopy, histochemistry, biochemical analysis by thin-layer and gas-liquid chromatography after extraction, and by differential scanning calorimetry. RESULTS: Membranous inclusions in the stroma were seen on transmission electron microscopy. Direct analysis confirmed enrichment with phospholipids and cholesterol, with acyl patterns and proportions as ester broadly similar to those of normal cornea. Tangier cornea showed major thermotropic phase transitions in the range 28-37 degrees C, peak 30-33 degrees C, extending above profiles of normal clear cornea and without the complexity of those seen with cornea with heavy arcus involvement. CONCLUSIONS: Lipid accumulation underlies corneal opacification in Tangier disease. The excess material is mainly phospholipid and cholesterol esters. As at other sites which are below body core temperature, notably tonsil, accumulation may be enhanced by local impaired mobilisation of material as the phase transitions of the excess lipid present extend above ambient corneal temperatures.

Calorimetry, Differential Scanning↗
PubMed1996

Mechanisms of facilitation in primed perceptual identification.

We investigated the mechanism that produces priming in perceptual identification. In Experiment 1, subjects studied a series of compound words (e.g., OUTDOOR, SIDELINE); in Experiment 2, subjects studied a series of pictures (photographs) of objects. All subjects later received perceptual identification tests in which old (primed) and new (unprimed) words (Experiment 1) or pictures (Experiment 2) were presented for varying durations and masked. In both experiments, performance for primed and unprimed stimuli was predicted essentially perfectly by a model that assumes that prior exposure to a stimulus results in increased visual information-acquisition rate when it is subsequently encountered. An ancillary purpose of Experiment 1 was to test whether or not priming occurs for recombined words (e.g., OUTLINE); there was no evidence for such priming at any exposure duration.

Adult↗