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M C White

Publications and source records attributed to M C White.

At least 55 records · Page 3Linked to original sources
PubMed1996

A 20-epi side chain restores growth-regulatory and transcriptional activities of an A ring-modified hybrid analog of 1 alpha, 25-dihydroxyvitamin D3 without increasing its affinity to the vitamin D receptor.

1 alpha-hydroxymethyl-25-hydroxyvitamin D3 and 1 beta-hydroxymethyl -3 alpha,25-hydroxyvitamin D3, two analogs with modifications restricted to the A ring, bind poorly to vitamin D receptor (VDR). The effective doses required for 50% of maximal binding activity (ED50) are 7 x 10(-7) M for the former and 8 x 10(-8) M for the latter, and the ED50 for their growth-inhibitory activities is greater than 10(-6) M. Unexpectedly, a hybrid analog with 20-epi configuration at its side chain and a 1 beta-hydroxymethyl group but not a 1 alpha-hydroxymethyl group inhibits malignant cell growth with an ED50 of 7 x 10(-9) M. To determine if the restored biological activity of the hybrid analog is associated with better binding to VDR, we performed competitive binding assays in vitro with calf thymus VDR and in vivo with recombinant human VDR. We found that the 20 epi side chain reduced the affinity of the 1 beta- and the 1 alpha-hydroxymethyl hybrid analogs for VDR in vitro and in vivo fourfold to tenfold. To determine whether the 1 beta-hydroxymethyl analogs induced a VDR-mediated transcription, we tested the induction of reporter gene expression through the osteocalcin vitamin D response element (VDRE) in ROS 17/2.8 cells and the induction of binding activity of VDR to VDRE in COS-1 cells. We found that the ED50 for transcriptional activity of 1 beta-hydroxymethyl-3 alpha,25-hydroxyvitamin D3 was greater than 10(-6) M, but its 1 alpha diastereomer had barely detectable transcriptional activity. The 20-epi side chain preferentially increased the transcriptional activity of the 1 beta-hydroxymethyl hybrid analog to an ED50 of 10(-8) M, but the 1 alpha-hydroxymethyl hybrid analog remained inactive. To confirm that this transcriptional activity was dependent on the VDR, we repeated the assay in VDR-negative CV-1 cells and compared ligand-dependent expression of the VDRE/growth hormone reporter in the presence of either wild-type or transcriptionally inactive mutant VDR expression vectors. Transcription was induced by the 1 beta-hydroxymethyl compounds only in the presence of wild-type VDR. Thus, we conclude that it is possible, by adding a 20 epi side chain, to restore growth-inhibitory and VDR-mediated transcriptional activities without increasing binding to the VDR of A ring-modified analogs.

Animals↗
PubMed1996

A comparative study of cytokine gene transcripts in normal and malignant breast tissue and primary cell cultures derived from the same tissue samples.

Using a differential centrifugation method followed by culture in selective medium, we have successfully isolated and maintained individual epithelial and stromal cells from normal (n = 10) and malignant (n = 6) human breast tissue and characterised their phenotype by immunocytochemistry. Further, we have studied expression of the cytokine genes IL-1beta, IL-6, IL-8 and TNF-beta in each cell fraction by RT-PCR and have compared these results with cytokine gene expression in tissue extracts from which primary cultures were derived. In breast tumours, there was near complete absence of IL-1beta in both whole tissue and cell fractions, and in normals it was present in only 3/10 tissue preparations, with increased expression in stromal (6/10) and epithelial (5/10) cell samples. IL-6 was constitutively expressed in all tumour-derived breast tissue samples but down-regulated in tumour cell cultures, with the opposite result in normal breast. Near identical levels of IL-8 expression were found throughout each preparation, irrespective of tissue origin. TNF-beta was expressed in all normal tissue samples, in 9/10 epithelial preparations but in only 6/10 stromal preparations. In tumours, TNF-beta was associated predominantly with whole tissue or stromal samples, with reduced expression in epithelial preparations. Our data confirm that primary cultures of normal and malignant human breast tissue can be successfully separated into epithelial and mesenchymal cell populations and their phenotype can be maintained in culture for up to 30 days. However, this cellular separation does alter the cytokine profiles; therefore, experimental findings with isolated cells should be treated with a caveat.

Base Sequence↗
PubMed1996

RT-PCR detection of cytokine transcripts in a series of cultured human meningiomas.

The expression of cytokine transcripts has been investigated in a series of cultured human meningiomas using reverse transcriptase linked polymerase chain reaction (RT-PCR), which allowed simultaneous analysis of a range of cytokines. The main histological subgroups of meningioma were investigated; these included transitional, fibroblastic, and syncytial as well as atypical meningiomas. Meningiomas from each of the different histological subgroups were subjected to a standard tissue culture regime. Total RNA was extracted from representative cultures and reverse-transcribed to yield cDNA. PCR was performed using oligonucleotide primers designed to detect interleukin (IL)-1 alpha/beta to IL-8, transforming growth factor (TGF)beta 1-3, tumour necrosis factor (TNF)alpha/beta, and interferon (IFN)gamma. Transcripts for IL-3, IL-6, IL-8, and TGF beta 3 were detected in all cultures. Transcripts for the three isomers of TGF beta were expressed in the transitional and fibroblastic meningioma cells. TGF beta 2 and TGF beta 3 transcripts were expressed in the syncytial and TGF beta 1 and TGF beta 3 in the atypical meningioma cells. IL-1 beta transcripts were expressed in fibroblastic and atypical cultures and TNF beta transcripts were expressed in syncytial and transitional cultures only. Transcripts for IL-1 alpha, IL-2, IL-4, IL-5, IL-7, TNF alpha, or IFN gamma were not detected in any of the meningioma cultures. This investigation using cells cultured from a small number of tumours from each of the classic histological subtypes suggests that there is a distinct pattern of cytokine mRNA expression linked with histological classification.

Cytokines↗
PubMed1996

Tuberculosis mortality associated with AIDS and drug or alcohol abuse: analysis of multiple cause-of-death data.

The resurgence in tuberculosis morbidity in the mid-1980s has increased interest in tuberculosis mortality. We examined mortality in the United States, from tuberculosis in 1990, using multiple cause-of-death data to describe the impact of AIDS and substance abuse, defined as drug or alcohol abuse, on mortality from tuberculosis. Tuberculosis mortality by age showed a bimodal pattern, with a peak between ages 25 and 55; by race/ethnicity, black and Hispanic males had the highest mortality rates, and black females had rates close to those of Hispanic males. Although in each of the race/ethnicity categories the removal of deaths with AIDS resulted in mortality curves closer to those of 1980, the bimodal pattern remained for black and Hispanic deaths. When we examined deaths with tuberculosis and substance abuse, we found that substance abuse without AIDS may account for additional deaths contributing to the bimodal pattern seen.

AIDS-Related Opportunistic Infections↗
PubMed1996

Expression of the transferrin receptor in human anterior pituitary adenomas is confined to gonadotrophinomas.

OBJECTIVE: The human pituitary gland is affected selectively by conditions associated with iron deposition, but the mechanisms for this are unknown. In this study we have determined whether the transferrin receptor, which mediates iron uptake by cells, could be detected immunocytochemically in human pituitary adenomas in vitro. PATIENTS: Data were derived from 35 patients undergoing transsphenoidal surgery and included 13 with clinically non-functioning adenomas, 15 with acromegaly, 4 prolactinomas, 2 patients with Cushing's disease and one patient with Nelson's syndrome. MEASUREMENTS: Transferrin receptor immunopositivity was determined for each adenoma in dispersed cell culture using a specific monoclonal antibody. RESULTS: Eight of 13 clinically functionless adenomas showed immunopositive transferrin receptor expression, whilst adenomas from 15 patients with acromegaly, 4 prolactinomas, 2 Cushing's syndrome and one patient with Nelson's syndrome were negative. The eight transferrin receptor positive tumours were gonadotrophinomas and accounted for eight of the nine tumours which secreted and immunostained for FSH; all eight also secreted and immunostained for LH. CONCLUSIONS: These findings may reflect a special requirement for iron by gonadotrophin secreting cells in comparison to other pituitary cell types and this could underlie the reasons why in the normal pituitary these cells are especially susceptible to malfunction in iron overload syndromes such as genetic haemochromatosis and beta-thalassaemia.

Adenoma↗
PubMed1996

Cytokine expression in human anterior pituitary adenomas.

OBJECTIVE: There is increasing evidence for the role of cytokines in pituitary differentiated function and tumorigenesis, but the spectrum of cytokines found in the pituitary is unknown. Therefore profiles of cytokine expression were determined in different human anterior pituitary adenoma sub-types. DESIGN: The reverse transcriptase-linked polymerase chain reaction (PCR) was used to identify the presence of cytokine mRNA within human pituitary adenomas. PATIENTS: Seventeen pituitary adenoma biopsies removed at transsphenoidal surgery were examined: 4 somatotrophinomas, 7 non-functional adenomas, 4 prolactinomas, one case of Cushing's disease and one case of Nelson's syndrome. MEASUREMENTS: RNA was extracted from each adenoma biopsy and reverse transcribed into cDNA. This was specifically amplified in a PCR using oligonucleotide primers complementary to each cytokine. The cytokines investigated were interleukin (IL)-I alpha, IL-I beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, tumour necrosis factor (TNF)-alpha, TNF-beta and transforming growth factor (TGF)-beta 1, beta 2 and beta 3. The products of each PCR were visualized using agarose gel electrophoresis. RESULTS: All 17 adenomas expressed IL-8 transcripts, but no expression of IL-2, IL-5 or IL-7 was found. IL-6 was expressed in all 4 somatotrophinomas, 3 of 7 non-functional tumours, 2 of 4 prolactinomas and in the single case of Nelson's syndrome. At least one of the 3 isoforms of TGF-beta was found in all but 2 tumours; one prolactinoma and one non-functional adenoma. IL-1 alpha, IL-beta, IL-4, TNF-alpha and TNF-beta were expressed sporadically by individual adenomas. CONCLUSION: These data suggest that whilst IL-8 may be important, the local expression of the cytokines IL-2, IL-5 and IL-7 is not important in human anterior pituitary tumorigenesis.

Adenoma↗
PubMed1996

11 beta-hydroxylase deficiency: management of a difficult case by laparoscopic bilateral adrenalectomy.

A 14-year-old girl presented with short stature and progressive virilization. She had not undergone the menarche. On investigation, she had elevated testosterone, androstenedione, dihydroepiandrosterone sulphate and 17 alpha-hydroxyprogesterone levels, which were all suppressed by overnight dexamethasone to within their normal ranges. An initial diagnosis of 21-hydroxylase deficiency was revised to 11 beta-hydroxylase deficiency after a tetracosactrin stimulation test, which showed only a modest rise in 17 alpha-hydroxyprogesterone level (from 92 nmol/l at baseline to 133 nmol/l at 60 minutes) and measurement of the basal 11-deoxycortisol, which was grossly elevated. Treatment with dexamethasone 0.5 mg nocte resulted in suppression of androgens in the daytime, but not in the evening, particularly androstenedione. Treatment with hydrocortisone 10 mg b.d. failed to suppress testosterone or androstenedione over a 24-hour period. Addition of cyproterone and oestrogen supplements had no effect and significant virilization persisted. Laparoscopic bilateral adrenalectomy was therefore performed as definitive treatment and resulted in remarkable clinical and biochemical improvement. This case illustrates difficulties in correct diagnosis, choice of appropriate steroid regimen and monitoring efficacy of treatment in congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. More aggressive management with earlier bilateral adrenalectomy may be appropriate in selected cases.

Adolescent↗
PubMed1996

Effects of air pollution on the respiratory health of asthmatic children living in Mexico City.

The relation between air pollution and the exacerbation of childhood asthma was studied in a panel of 71 children (aged 5 to 7 yr) with mild asthma who resided in the northern part of mexico City. During the follow-up, ambient measures of particulate matter less than 10 microns (PM10, 24-h average) and ozone (1-h maximum) frequently exceeded the Mexican standards for these contaminants. The peak expiratory flow rate (PEFR) was strongly associated with PM10 levels and marginally with ozone levels. Respiratory symptoms (coughing, phlegm production, wheezing, and difficulty breathing) were associated with both PM10 and ozone levels. An increase of 20 micrograms/m3 of PM10 was related to an 8% increase in lower respiratory illness (LRI) among children on the same day (95% confidence interval [CI] = 1.04-1.15), and an increase of 10 micrograms/m3 in the weekly mean of particulate matter less than 2.5 microns (PM2.5) was related to a 21% increase in LRI (95% CI = 1.08-1.35). A 50 parts per billion (ppb) increase in ozone was associated with a 9% increase in LRI (95% CI = 1.03-1.15) on the same day. We concluded that children with mild asthma are affected by the high ambient levels of particulate matter and ozone observed in the northern part of Mexico City.

Air Pollutants↗
PubMed1996

Hyponatraemia secondary to cerebral salt wasting syndrome following routine pituitary surgery.

A female aged 53 years was found to have a suprasellar lesion, which was shown to be a Rathke's cyst after removal by transsphenoidal surgery. She presented 16 days postoperatively, and following two grand mal seizures was found to be profoundly hyponatraemic (sodium 101 nmol/l). She was initially thought to have the syndrome of inappropriate antidiuretic hormone and was treated accordingly, but central venous pressure measurement revealed the hypovolaemia of cerebral salt wasting syndrome. The patient subsequently developed severe neurological sequelae after the correction of her hyponatraemia, following the development of extrapontine myelinolysis. Cerebral salt wasting syndrome is a rare cause of hyponatraemia following pituitary transsphenoidal surgery, which may mimic the syndrome of inappropriate antidiuretic hormone secretion. This case emphasizes the poor prognosis that may result from the rapid correction of profound hyponatraemia.

Brain↗
PubMed1995

Sensitivity and specificity of photography and direct ophthalmoscopy in screening for sight threatening eye disease: the Liverpool Diabetic Eye Study.

OBJECTIVE: To evaluate different methods for community based screening for sight threatening diabetic eye disease. DESIGN: Prospective study. SETTING: Mobile screening unit visiting inner city community clinics; hospital assessment clinic (tertiary centre). SUBJECTS: 395 diabetic patients registered with four general practices in an inner city location. INTERVENTIONS: Community based photography with mydriasis and direct ophthalmoscopy through dilated pupils by an experienced ophthalmologist, both compared with reference standard of slit lamp biomicroscopy by a consultant specialist in medical retinal disease. MAIN OUTCOME MEASURES: Sensitivity and specificity of screening method and prevalence of sight threatening diabetic eye disease (moderate preproliferative retinopathy, circinate maculopathy, exudate within 1 disc diameter of fixation, other diabetes related eye disease). RESULTS: 358 subjects underwent photography, 326 attended hospital clinic for ophthalmoscopy, and six were ungradable on photographs and biomicroscopy, leaving 320 for analysis. Of these 295 (91%) attended clinic within four months of photography. Sensitivity of detection of eye disease by photography was 89% (95% confidence interval 80% to 98%), significantly better than for direct ophthalmoscopy (65% (51% to 79%)). Analysis of patients with false negative results indicated possible improvement of photographic sensitivity to 93% by addition of stereoscopic macular pair photographs. Specificity of detection of sight threatening eye disease was 86% (82% to 90%) for photography and 97% (95% to 99%) for direct ophthalmoscopy. CONCLUSIONS: Since high sensitivity is essential for an effective screening programme, a photographic method should be considered as preferred option in national, community based screening programmes. Even in the hands of an experienced ophthalmologist, direct ophthalmoscopy is limited by weaknesses inherent to the instrument.

Ambulatory Care↗
PubMed1995

1 alpha,25-dihydroxyvitamin D3 analogs featuring aromatic and heteroaromatic rings: design, synthesis, and preliminary biological testing.

Aromatic compounds 2a-c, analogs of 1 alpha, 25-dihydroxyvitamin (calcitriol, 1), and heteroaromatic compounds 4a-c and 5a-c, analogs of 19-nor-1 alpha, 25-dihydroxyvitamin D3 (3), were designed to simulate the topology of their biologically potent parent compounds while avoiding previtamin D equilibrium. Convergent and facile total syntheses of the analogs (+)-2b, (+)-2c, (-)-4b, and (-)-5b were achieved via carbonyl addition of regiospecifically formed organolithium nucleophiles to the enantiomerically pure C,D-ring ketone (+)-17, characteristic of natural calcitriol (1). Likewise, hybrid analogs 20a-c were prepared to determine whether incorporation of a known potentiating side chain would lead to increased biological activity. Preliminary in vitro biological testing showed that aromatic analogs (+)-2b, (+)-2c, and 20a-c as well as heteroaromatic analogs (-)-4b and (-)-5b have very low affinities for the calf thymus vitamin D receptor but considerable antiproliferative activities in murine keratinocytes at micromolar concentration. No biological advantage was observed in this keratinocyte assay for the doubly modified hybrid analogs 20a-c over the singly modified parent (+)-2b. Analog (+)-2b, but surprisingly not the corresponding analog 20b differing from (+)-2b only in the side chain, showed considerable activity in nongenomic opening of calcium channels in rat osteosarcoma cells.

Animals↗
PubMed1995

Interleukin-3: a putative protective factor against breast cancer which is secreted by male but not female breast fibroblasts.

The enzyme 17 beta-hydroxysteroid dehydrogenase (17-HSD) is a key regulator of intracellular 17 beta-estradiol (E2), which is associated with breast cancer and is influenced by paracrine factors released by breast-cancer fibroblasts. Since the incidence of breast cancer is much higher in females than in males, we have used an in vitro cell culture system to investigate whether male fibroblasts may inhibit breast-cancer genesis by restricting the intracellular accumulation of E2. Fibroblasts were obtained from normal males and females undergoing reduction mammoplasty, and from females with benign or malignant breast lesions. Fibroblast-conditioned medium (CM) was incubated with the established breast-cancer cell line, MCF-7, and its effects on 17-HSD activity were assessed. CM (25% v/v) from male breast fibroblasts had a significant inhibitory effect on reductive 17-HSD, decreasing E2 production. This was in direct contrast to the effects of CM from female breast fibroblasts, which had a powerful stimulatory effect on reductive 17-HSD. RT-PCR allowing simultaneous detection of a range of cytokines was performed on each type of fibroblast. IL-3 mRNA was consistently detected in fibroblasts from male but not female breast tissue. Addition of rhIL-3 to cultures of MCF-7 caused a reduction in 17-HSD activity and addition of a polyclonal antibody directed against IL-3 to male CM completely reversed the inhibitory effects of CM. Thus, male breast fibroblasts may be responsible for secreting IL-3-like factors which, given the considerably lower incidence rates of breast cancer in men, may have a protective effect against breast cancer.

17-Hydroxysteroid Dehydrogenases↗
PubMed1995

Effects of urban air pollutants on emergency visits for childhood asthma in Mexico City.

The metropolitan area of Mexico City, Mexico, has serious air pollution problems. Although air contaminants may contribute to clinical asthma, there are at present no data on the relation between air pollution exposure and childhood asthma in Mexico City. The authors reviewed data on emergency visits from January to June 1990 at one major pediatric hospital in Mexico City. They used a Poisson regression model to study the relation between the number of daily emergency visits for asthma and air pollutant levels. The levels of ozone and sulfur dioxide-exposure were significantly associated with the number of emergency visits for asthma. After adjustment for potential confounding factors, the multivariate regression model predicted that an increase of 50 ppb in the 1-hour maximum ozone level would lead to a 43% increase in the number of emergency visits for asthma on the following day. Exposure to high ozone levels (> 110 ppb) for 2 consecutive days increased the number of asthma-related emergency visits by 68 percent. The results of this study suggest that ozone exposure is positively associated with the number of children's emergency visits for asthma in Mexico City.

Adolescent↗
PubMed1995

Isolated adrenocorticotropin deficiency presenting as primary infertility.

A 31 year old female presented with primary infertility and gave a two year history of amenorrhea without symptoms or signs of endocrine dysfunction. Examination was normal and investigation showed low oestradiol and progesterone levels with decreased LH pulsatility. The cortisol responses were impaired following hypoglycaemic stress and a short synacthen test, but the cortisol response to a prolonged synacthen test was normal. An inadequate ACTH response to CRF testing confirmed the diagnosis of isolated ACTH deficiency. Hydrocortisone therapy was followed by an ovulatory menstrual cycle. Amenorrhea again ensued following the reduction of the steroid dose and normal menses resumed on normal steroid replacement therapy. Six hourly gonadotrophin pulsatility showed a significant increase in both pulse amplitude and mean LH and FSH levels following steroid treatment. Isolated ACTH deficiency is a rare but treatable cause of hypogonadism and infertility, and this case gives further insight on the role of cortisol on the hypothalamo-pituitary gonadal axis.

Adrenocorticotropic Hormone↗
PubMed1995

Urinary catheter-related infections among home care patients.

Urinary catheterization is a common indication for home care nursing services among older adults, and catheter-related urinary tract infections commonly occur among these patients. The purpose of this study was to determine the rate of urinary catheter-related infections among a group of elderly adults cared for in the home, the characteristics of those who acquire urinary tract infections as opposed to those who do not become infected, and the influence of the interval between catheter changes on the incidence of urinary tract infections.

Aged↗
PubMed1995

Effects of quinagolide (CV 205-502), a selective D2-agonist, on vascular reactivity in patients with a prolactin-secreting adenoma.

BACKGROUND: Quinagolide (CV 205 502) is a dopamine D2-receptor agonist which has proved effective in the treatment of prolactinomas, reducing both serum PRL and tumour size. Some of its D2-receptor effects are mediated via alpha-adrenoceptors, which have a major influence on the control of vascular tone. The aim of this study was to examine the influence of quinagolide on in-vivo dorsal hand vein vascular responses to noradrenaline in patients with a prolactinoma. DESIGN AND PATIENTS: Seven female patients with prolactinomas (age 37 (28-46) years), intolerant of bromocriptine, were studied before and after 3 months treatment with quinagolide (0.75-1.5 mg/day). Patients were otherwise disease free, were taking no other medication, and had been on no other medication (including bromocriptine) for at least 3 months prior to enrollment into the study. MEASUREMENTS: Vascular responses to locally infused noradrenaline were measured in dorsal hand veins using an established technique. PRL, oestradiol, FSH, LH, blood pressure and body mass index were also measured before and after 3 months treatment. RESULTS: Quinagolide significantly reduced PRL in all 7 patients (1795 (696-4680) (mean (range)) vs 488 (290-868) mU/l, P = 0.001), with no effect on the other parameters, including mean arterial pressure (88 (2) vs 87 (4) mmHg, P = 0.6). Vascular reactivity to noradrenaline was significantly increased after 3 months therapy: log10 dose estimated to cause 50% vasoconstriction (ED50) 1.37 (0.12) vs 0.85 (0.12) ng/min (P = 0.003; a lower ED50 indicates less noradrenaline is required to constrict the vein by 50%). CONCLUSIONS: Vasoconstrictor responses to noradrenaline were increased in all patients after 3 months treatment with quinagolide. Peripheral veins carry alpha-adrenoceptors analogous to those of systemic resistance vessels. If this increased vasoconstrictor response in patients with prolactinomas was occurring in hypophyseal vessels, it would lead to reduced tumour blood supply. Quinagolide may therefore reduce tumour blood flow, which may be one factor responsible for its effectiveness in these patients.

Adult↗