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Biomedical subjects

J McDonald

Publications and source records attributed to J McDonald.

At least 145 records · Page 8Linked to original sources
PubMed1991

Ovarian sensitization to gonadotrophins by human growth hormone. Persistence of the effect beyond the treated cycle.

OBJECTIVE: To document the persistence of a sensitizing effect of human growth hormone on the ovarian responsiveness to human menopausal gonadotrophin in anovulatory patients resistant to standard gonadotrophin doses. DESIGN: We performed an open study of three patients given 4, 12 or 24 IU recombinant growth hormone on alternate days for 5-7 doses, concomitantly with gonadotrophin, and assessed gonadotrophin dose requirements before, during and after the cycle of growth hormone therapy. PATIENTS: We studied two with isolated gonadotrophin deficiency and primary amenorrhoea and one with a pituitary tumour and hyperprolactinaemia which normalized with bromocriptine but in whom there was persisting secondary amenorrhoea. MEASUREMENTS: We measured body mass index, FSH, LH, prolactin, growth hormone, insulin-like growth factor I (IGF-I), oestradiol and inhibin at baseline and growth hormone, IGF-I, oestradiol and inhibin during treatment. In addition we noted the numbers of ampoules (75 IU) and the last pre-hCG dose of gonadotrophin used before, during and after growth hormone therapy. RESULTS: Baseline growth hormone levels were low but IGF-I levels were normal. IGF-I increased by 20% in the subject given 4 IU growth hormone, and by 50-100% in the other two. Pretreatment daily gonadotrophin dosage of 8-11 ampoules pre-hCG was reduced to 3-6 ampoules during growth hormone and 3-4 post growth hormone. This effect persisted for 4 cycles over 7 months in one subject. CONCLUSION: Growth hormone causes persisting ovarian sensitization to gonadotrophin and may produce a substantial lowering of gonadotrophin requirement for ovulation induction in patients with large dosage needs.

Adult↗
PubMed1990

Clinical predictors for buserelin acetate treatment of uterine fibroids: a prospective study of 40 women.

Buserelin acetate, a luteinizing hormone-releasing hormone agonist, is known to be effective in the shrinkage of uterine fibroids. A prospective trial was undertaken (1) to compare the efficacy of intranasal (IN) and subcutaneous (SC) administration of buserelin acetate and (2) to assess if tumor regression correlated with fibroid size and/or patient age. Forty patients were randomly allocated to receive 6 months of either IN buserelin acetate (n = 21) or SC buserelin acetate (n = 19). Four patients did not complete the study and were excluded from statistical analysis. Fibroid regression occurred in all 36 patients. Overall regression to 66% or less of the initial fibroid volume occurred in 70% of subjects. There was no significant difference in fibroid shrinkage between the two administration routes. A significant positive correlation was found between initial fibroid size and subsequent fibroid regression, with larger tumors being more likely to shrink than smaller fibroids. No correlation was found between the patient's age and the extent of fibroid regression.

Administration, Intranasal↗
PubMed1990

Antioxidant-based inhibitors of leukotriene biosynthesis. The discovery of 6-[1-[2-(hydroxymethyl)phenyl]-1-propen-3-yl]-2,3-dihydro-5- benzofuranol, a potent topical antiinflammatory agent.

The leukotrienes, metabolites of arachidonic acid produced through the action of the enzyme 5-lipoxygenase, are important mediators of immediate hypersensitivity and inflammation. Among the variety of diseases in which the leukotrienes may play a symptomatic or causative role is the dermatological condition psoriasis, a chronic proliferative disease of the skin. This study reports the synthesis and comparative biological activities of various ortho-substituted phenols including 4-methoxyphenols, 6-hydroxy-1,2,3,4-tetrahydrobenzopyrans, 2,3-dihydro-5-benzofuranols, and 5-benzofuranols. The phenols prepared in this study were evaluated for their ability to inhibit the production of leukotriene B4(LTB4) in isolated human polymorphonuclear leukocytes (PMNs) and to inhibit a topical inflammatory response in the topical mouse ear (TME) model. In the former case, when the log IC50 was plotted versus the log of the octanol/water partition coefficient (log P), to eliminate the effect of lipophilicity, the 2,3-dihydro-5-benzofuranol ring system was shown to be more potent than the other ring systems examined throughout the range of partition coefficients studied. The ability to inhibit leukotriene production in vitro in human PMNs can be rationalized on the basis of a model that suggests that the observed inhibition is dependent on the kinetic ability of the inhibitor to reduce a radical species and on the fraction of inhibitor that is partitioned into the cell membrane. While the in vivo antiinflammatory activity as measured by the TME did not correlate with the in vitro data, it was felt that the TME represented a valuable measure of the ability of a compound to penetrate the skin to the site of an ongoing inflammatory response. Of the compounds synthesized in this study, 6-[1-[2-(hydroxymethyl)phenyl]-1-propen-3-yl]-2,3-dihydro-5-benzof uranol (1, L-651896) was chosen for further development.

Administration, Topical↗
PubMed1990

Modulation of experimental cyclosporine nephrotoxicity by inhibition of thromboxane synthesis.

The clinical usefulness of Cyclosporine is limited by its intrinsic nephrotoxicity. A potential mechanism of CsA-mediated renal injury may involve an alteration in the prostaglandin-thromboxane (PG-TX) cascade. In our studies, pharmacological manipulation of the PG-TX system in normal and nephrotoxic animals was conducted using a specific thromboxane synthetase inhibitor U63,557A, and the cyclooxygenase inhibitor indomethacin. Administration of CsA 50 mg/kg/day for 7 days to Sprague Dawley rats resulted in a 99% increase in urinary thromboxane B2 excretion compared with controls (48.2 +/- 3.1 vs. 24.2 +/- 2.6 ng/24 hr, P less than 0.001), while plasma levels remained unchanged. Glomerular and tubular function was significantly reduced at this time, with a 48% decrease in creatinine clearance (CCr), and a 25% reduction in the fractional excretion of sodium (FeNa) (P less than 0.001). Histological injury included cortical tubular vacuolization and necrosis. Administration of indomethacin 8 mg/kg/day to both normal and CsA-treated rats resulted in a significant reduction in prostanoid excretion. Indomethacin alone had no adverse effect on glomerular function; however, when coadministered with CsA an exaggerated decrease in renal function was observed. CCr in this group fell by a further 27% compared with the CsA-50 group, while FeNa decreased by 76% (P less than 0.001). Histologic injury intensified, with an increase in vacuolization and necrosis. In contrast, coadministration of U63,557A with CsA prevented the rise in urinary TXB2 excretion, improved CCr by 20% (P less than 0.05), and restored FeNa to control levels. The severity of CsA-induced vacuolization was significantly diminished. Selective inhibition of thromboxane production may therefore be valuable in mitigating the clinical nephrotoxicity of CsA.

Animals↗
PubMed1990

Enhanced radiometric detection of Mycobacterium paratuberculosis by using filter-concentrated bovine fecal specimens.

A commercial radiometric medium, BACTEC 12B, was modified by addition of mycobactin, egg yolk suspension, and antibiotics (vancomycin, amphotericin B, and nalidixic acid). Decontaminated bovine fecal specimens were filter concentrated by using 3-microns-pore-size, 13-mm-diameter polycarbonate filters, and the entire filter was placed into the radiometric broth. Comparison of the radiometric technique with conventional methods on 603 cattle from 9 Mycobacterium paratuberculosis-infected herds found that of 75 positive specimens, the radiometric technique detected 92% while conventional methods detected 60% (P less than 0.0005). Only 3.9% of radiometric cultures were contaminated. To measure the effect of filter concentration of specimens on the detection rate, 5 cattle with minimal and 5 with moderate ileum histopathology were sampled weekly for 3 weeks. M. paratuberculosis was detected in 33.3% of nonfiltered specimens and 76.7% of filtered specimens (P less than 0.005). Detection rates were directly correlated with the severity of disease, and the advantage of specimen concentration was greatest on fecal specimens from cattle with low-grade infections. Detection times were also correlated with infection severity: 13.4 +/- 5.9 days with smear-positive specimens, 27.9 +/- 8.7 days with feces from cows with typical subclinical infections, and 38.7 +/- 3.8 days with fecal specimens from cows with low-grade infections. Use of a cocktail of vancomycin, amphotericin B, and nalidixic acid for selective suppression of nonmycobacterial contaminants was better than the commercial product PANTA (Becton Dickinson Microbiologic Systems, Towson, Md.) only when specimens contained very low numbers of M. paratuberculosis. Radiometric culture of filter-concentrated specimens generally doubled the number of positive fecal specimens detected over conventional methods, making it a useful tool for diagnosis and control of bovine paratuberculosis.

Animals↗
PubMed1990

Chemistry, biology, and toxicology of domoic acid and its isomers.

The causative agent of toxicity in cultured mussels from a localized area of eastern Prince Edward Island has been identified as domoic acid, a neuroexcitatory amino acid. The toxin was isolated by a number of different bioassay-directed separation techniques including high-performance liquid chromatography (HPLC), high-voltage paper electrophoresis (HVPE), and ion-exchange chromatography, and characterized by a number of spectroscopic techniques including ultraviolet, infrared, mass spectrometry, and nuclear magnetic resonance. The isolation and purification methods are described in detail and some new analytical data for domoic acid are reported. A plankton bloom at the time of the outbreak gave positive mouse bioassays and consisted almost entirely of the pennate diatom, Nitzschia pungens f. multiseries. A positive correlation was found between the number of N. pungens cells and the concentration of domoic acid in the plankton. N. pungens f. multiseries isolated from Cardigan Bay produced domoic acid de novo during stationary phase culture at levels (1 to 10 pg/cell) comparable to values estimated for N. pungens in the plankton samples. We conclude that N. pungens was the major source of the domoic acid in toxic mussels in eastern Prince Edward Island. The recurrence, in November 1988, of a monospecific bloom of N. pungens and the presence of domoic acid in plankton and mussels reinforces this conclusion.

Animals↗
PubMed1989

Chlamydia trachomatis infections in infants.

In recent years considerable progress has been made in understanding chlamydial infections. The spectrum of pediatric Chlamydia trachomatis infection includes neonatal inclusion conjunctivitis, infantile pneumonia, occasional respiratory or genital tract infections in older children and sexually transmitted diseases in adolescents. The role of maternal chlamydial infection in prematurity and in perinatal death is currently an area of active study. We outline the current knowledge of the biologic characteristics of C. trachomatis, the epidemiologic features of chlamydial infection, and the clinical aspects, diagnosis and treatment of neonatal chlamydial infections.

Chlamydia Infections↗
PubMed1989

Activation of the erythropoietin gene due to the proximity of an expressed gene.

The erythroleukemic cell line IW32 has a normal erythropoietin (epo) gene and one which has undergone rearrangement and amplification. The rearranged epo locus consists of a breakpoint approximately 1 kb upstream from an otherwise structurally unchanged epo gene. DNase I hypersensitivity studies had suggested that the rearranged gene is the transcriptionally active one. To understand this transcriptional activation more fully we have sequenced the upstream regions of both the normal and the rearranged epo genes, the latter encompassing the rearrangement breakpoint. Sequence analysis showed that the new sequence past the breakpoint at the rearranged locus contained all the promoter components needed for a gene in opposite transcriptional orientation to the epo gene. Subsequent Northern blot analysis showed that this gene is transcriptionally active. No homology was found between this gene and any sequence in the data banks. It appears that the transcriptional activation of the rearranged epo gene in IW32 cells has been mediated by a translocation event which has served to bring the epo gene into close juxtaposition to this transcriptionally active gene.

Animals↗
PubMed1989

Studies of the constitutive expression of the mouse erythropoietin gene.

The IW32 and NN10 cell lines are erythroleukemic cell lines which secrete erythropoietin (epo) into the culture medium constitutively. IW32 cells have a rearranged and amplified epo gene in addition to the normal gene. NN10 cells contain only the normal epo gene. DNase I hypersensitivity studies suggested that, in IW32 cells, it is the rearranged gene which is transcriptionally active. Sequence analysis of the upstream region of the rearranged epo gene suggests that the rearrangement has served to introduce a transcriptionally active gene close to the epo gene. This juxtaposition may explain the transcriptional activation of the epo gene at the rearranged locus.

Animals↗
PubMed1989

Craniopharyngiomas: fluctuation in cyst size following surgery and radiation therapy.

Patients with craniopharyngiomas who demonstrate cyst enlargement after surgery and radiation are often presumed to be treatment failures. Therapeutic approaches in various centers include repetitive cyst aspirations, surgical reexcision, and installation of cytotoxic agents such as methotrexate, 32P, or 198Au. Each intervention has associated severe or even lethal side effects. Not all patients with craniopharyngioma who have cystic enlargement after primary therapy require an intervention, as demonstrated by 4 patients recently managed in the University of Rochester Medical Center. Since 1978, when computed tomography was routinely in use, we have managed 11 patients with craniopharyngiomas who were treated with surgery followed by radiation therapy. Three of these patients demonstrated post-irradiation enlargement of the residual cystic component followed by a decrease in size without surgical intervention. An additional patient showed cystic growth followed by stabilization of size. It is noteworthy that the cyst enlarged within the first 5 months after radiation therapy in the 3 patients who subsequently demonstrated a diminution in the size of their cysts. This suggests that the mechanism for cyst formation remained intact and subsequently abated because of a radiation-induced lesion. We conclude that after treatment with surgery and radiation therapy, the cystic component of craniopharyngiomas may increase and, without intervention, subsequently decrease in size. Thus, in the asymptomatic patient who demonstrates cystic growth soon after primary therapy, close observation alone may be warranted.

Adolescent↗
PubMed1988

Temporal study of metabolic change when poorly controlled noninsulin-dependent diabetics change from low to high carbohydrate and fiber diet.

Thirteen poorly controlled noninsulin-dependent diabetic subjects ingested in succession over 5.5 wk their usual low-carbohydrate, low-fiber diet (LCF) for 3 d, a high-carbohydrate, high-fiber diet (HCF) for 3 wk, and the LCF diet again for 2 wk. All diets were designed to be individually isoenergetic. Fasting plasma glucose fell significantly during the HCF diet and then rose significantly during the last LCF diet. Dietary change rather than hospitalization had its full effect by 18 d. Urinary glucose excretion rose transiently on the HCF diet before also falling significantly. Similarly, pancreatic immunoreactive glucagon (IRG) fell significantly on the HCF diet and increased significantly on the LCF diet. No significant differences were observed in plasma insulin, serum free fatty acids, or monocyte insulin binding activity between the two diets. Reduction in circulating IRG may in part explain the lower fasting (or basal) plasma glucose observed on HCF diets.

Blood Glucose↗
PubMed1988

Effect of cyclosporine on urinary prostanoid excretion, renal blood flow, and glomerulotubular function.

The clinical usefulness of cyclosporine (CsA) in organ transplantation and autoimmune diseases is limited by its intrinsic nephrotoxicity. The mechanism of this renal impairment was examined utilizing an animal model in which male Sprague-Dawley rats were administered oral CsA in doses of 25, 37.5, and 50 mg/kg/day for 7 days and 50 mg/kg/day for 2, 4, and 7 days. Urinary thromboxane B2 (TXB2) excretion increased from 30.6 +/- 2.3 to 60.8 +/- 4.4 ng/24 hr P less than 0.001, following 48 hr of CsA dosing. In addition, a concomitant rise in proximal tubular sodium reabsorption was observed with fractional excretion of sodium decreasing from 0.502 +/- 0.091 to 0.223 +/- 0.037% P less than 0.05. Urinary prostaglandin E2 and 6-keto-prostaglandin F1 alpha excretion increased two-fold, although plasma levels of all 3 prostanoids did not vary from controls. Functional changes included decreases in the relative renal blood flow of 53% P less than 0.05, and the clearance of creatinine and urea of 46% and 42%, respectively on day 7 of treatment, while renal morphology showed severe vacuolization and necrosis confined to the proximal tubular region of the cortex. Thromboxane A2, the active precursor of TXB2, is a potent vasoconstrictor and promoter of platelet aggregation and may alter proximal tubular handling of sodium. The rise in urinary TXB2 excretion may contribute to the renal vasoconstriction leading to functional impairment and histologic injury.

Brain↗
PubMed1988

Protective effects of the thromboxane receptor antagonists BM 13.177 and BM 13.505 against U 46619-induced sudden death in rats.

The purpose of this study was to evaluate the pharmacology and pharmacodynamics of the thromboxane receptor antagonists, BM 13.177 and BM 13.505, for prevention of U 46619-induced sudden death in anesthetized male Sprague-Dawley rats. The injection of U 46619 (100 micrograms/kg i.v.) produced sudden death typically between 5 and 15 min. Administration of 0.01 mg/kg BM 13.505 (i.v.) 0.1 h prior to the U 46619 challenge did not protect against sudden death, while doses of 0.03 mg/kg or greater protected completely (100% survival). A dose of 1 mg/kg BM 13.505 afforded protection to 2 h but not to 24 h, while a single dose of 30 mg/kg administered 24 h prior to the U 46619 challenge provided complete protection against the lethal event. Administration of BM 13.177 (30 mg/kg, i.v. or i.p.) blocked the effects of U 46619 when administered 0.1 h before the challenge, but not when given 2 or 3 h prior to the challenge with U 46619. Pretreatment with indomethacin did not block the effects of U 46619, indicating that formation of endogenous thromboxane does not play a major role in the lethal effects of U 46619, and that blockade of the lethal effects of U 46619 was specific for thromboxane receptor antagonists. These data demonstrate that BM 13.177 and BM 13.505 prevented sudden death produced by the injection of U 46619. At comparable doses of 30 mg/kg, the duration of action for BM 13.505 was was significantly greater than for BM 13.177. These data suggest that BM 13.177 and BM 13.505 may be useful for the investigation of diseases where thromboxane is involved.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗