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Biomedical subjects

H Mitchell

Publications and source records attributed to H Mitchell.

At least 19 recordsLinked to original sources
PubMed2004

Differential trafficking of transforming growth factor-beta receptors and ligand in polarized epithelial cells.

Epithelial cells in vivo form tight cell-cell associations that spatially separate distinct apical and basolateral domains. These domains provide discrete cellular processes essential for proper tissue and organ development. Using confocal imaging and selective plasma membrane domain activation, the type I and type II transforming growth factor-beta (TGFbeta) receptors were found to be localized specifically at the basolateral surfaces of polarized Madin-Darby canine kidney (MDCK) cells. Receptors concentrated predominantly at the lateral sites of cell-cell contact, adjacent to the gap junctional complex. Cytoplasmic domain truncations for each receptor resulted in the loss of specific lateral domain targeting and dispersion to both the apical and basal domains. Whereas receptors concentrate basolaterally in regions of direct cell-cell contact in nonpolarized MDCK cell monolayers, receptor staining was absent from areas of noncell contact. In contrast to the defined basolateral polarity observed for the TGFbeta receptor complex, TGFbeta ligand secretion was found to be from the apical surfaces. Confocal imaging of MDCK cells with an antibody to TGFbeta1 confirmed a predominant apical localization, with a stark absence at the basal membrane. These findings indicate that cell adhesion regulates the localization of TGFbeta receptors in polarized epithelial cultures and that the response to TGFbeta is dependent upon the spatial distribution and secretion of TGFbeta receptors and ligand, respectively.

Adherens Junctions↗
PubMed2004

Randomized controlled trial evaluating rapid pre-screen of cervical cytology specimens.

A randomized controlled trial of 75,355 cervical cytology specimens was performed comparing rapid pre-screen with no pre-screen. While the percentage of cases receiving a final report of definite high-grade abnormality was higher in the no pre-screen arm (no pre-screen = 0.70%, pre-screen = 0.65%), the percentage of cases receiving a final report of possible or definite high-grade abnormality was essentially identical in the two arms of the trial (no pre-screen = 1.22%, pre-screen = 1.21%). In the randomized trial, one extra cytology report of definite high-grade abnormality was made for every 12,568 slides pre-screened. This level of benefit was reduced by about half when rapid pre-screen was adopted as a routine laboratory practice.

Adult↗
PubMed2004

Clinical features, diagnosis, treatment and molecular studies in paediatric Cushing's syndrome due to primary nodular adrenocortical hyperplasia.

BACKGROUND: Primary nodular adrenocortical hyperplasia (PNAH) is a well recognized, but infrequently studied cause of paediatric Cushing's syndrome (CS). OBJECTIVE: To assess presentation, diagnosis, radiological imaging, treatment and molecular analysis of patients with childhood-onset CS due to PNAH. PATIENTS: Four males and two females (median age 12.9 years, range 10.9-16.9 years) were studied. RESULTS: All had growth failure (mean height SDS -1.2; range -2.5-0.0), weight gain [mean body mass index (BMI) SDS 3.5; range 2.5-4.6] and clinical virilization, while five had hypertension [mean systolic blood pressure (SBP) 130 mmHg, diastolic blood pressure (DBP) 83 mmHg]. One patient had generalized lentigines, one had a tibial chondromyxomatous cyst and two had facial freckling. One patient had a family history of primary nodular adrenocortical disease. The diagnosis of CS was based on elevation of sleeping midnight serum cortisol and urinary free cortisol excretion, and impaired suppression of cortisol on both low- and high-dose dexamethasone suppression tests (DST). All patients had undetectable plasma ACTH with absent responses of both plasma ACTH and serum cortisol to an intravenous (i.v.) corticotrophin-releasing hormone (CRH) test. Computed tomography or magnetic resonance imaging showed normal or small adrenals, with nodules in two patients. All patients underwent bilateral adrenalectomy, performed by open (n = 2) or laparoscopic surgery (n = 4) at a mean of 0.4 years (range 0.2-0.8 years) from diagnosis. Hypercortisolaemia was treated preoperatively by metyrapone alone 0.50-0.75 g/day (n = 4), metyrapone 0.75-1.50 g/day + o'p'DDD/mitotane 1-2 g/day (n = 1), or ketoconazole (n = 1). Adrenal histology showed nodular cortical hyperplasia with shrinkage of intervening cortical tissue and pigmentation, present in four patients. Molecular analysis of the type 1-alpha regulatory subunit of protein kinase A (PRKAR1A) gene revealed a novel germline mutation in one patient. Postadrenalectomy, three patients, had catch-up growth with height velocities increasing from 3.0, 3.9 and 2.5-8.9, 8.3 and 9.0 cm/years, respectively. All six are well at a follow-up (mean 4.0 years; range 0.5-10.8 years). CONCLUSIONS: PNAH was associated with cushingoid features, virilization and hypertension with a lack of cortisol suppression on high DST, undetectable plasma ACTH and absent cortisol and ACTH responses to CRH. Adrenals were normal or small on imaging. PRKAR1A gene analysis may be helpful in the assessment of these patients.

Adolescent↗
PubMed2003

Squamous cell carcinoma antigen: a role in the early identification of nodal metastases in men with squamous cell carcinoma of the penis.

OBJECTIVE: To evaluate whether serum squamous cell carcinoma antigen (SCCAg) measurements may be of use in identifying nodal metastases in patients with SCC of the penis after treating the primary tumour. PATIENTS AND METHODS: The levels of SCCAg were analysed in 11 men with penile SCC between 1994 and 2001. RESULTS: An elevated SCCAg level had a sensitivity of 57% (95% confidence interval, CI, 18-90%) and a specificity of 100% (CI 40-100%) for nodal metastases. Levels of SCCAg increased exponentially in patients who developed nodal metastases after treatment of the primary tumour, and were elevated before clinical or radiological evidence of nodal disease. CONCLUSION: Either the absolute level or the rate of rise of SCCAg may be a useful tool with which to follow patients after excision of the primary tumour. It may be more sensitive than computed tomography and magnetic resonance imaging in detecting recurrence, but further evaluation is needed.

Antigens, Neoplasm↗
PubMed2001

Abnormal cervical cytology in bone marrow transplant recipients.

Particular human papillomavirus (HPV) subtypes are implicated in the genesis of abnormal cervical cytology and cervical cancer. While most immunocompetent hosts clear HPV infection with no sequelae, some develop premalignant cytological changes of whom a minority subsequently progress to overt carcinoma. Immunocompromised patients, such as renal allograft recipients and HIV-infected individuals, have a higher rate of cytological abnormalities. This is thought to be due to prolonged persistence of virus due to impaired clearance by the immune system. We undertook a retrospective review of the cervical cytology of all women who underwent BMT at two transplant centres and who had cervical smears performed between 1990 and 1998. The rate of cytological abnormalities was significantly higher than in the general population before BMT (age-adjusted odds ratio (OR) 2.2, P = 0.02) and after BMT (OR 7.0, P < 0.0001). After BMT, allogeneic recipients had a higher rate of abnormalities than did autologous patients (OR 2.6, P = 0.02) although only allogeneic recipients had a higher rate of abnormalities post-BMT compared to pre-BMT (allogeneic OR 6.8, P = 0.004). These observations suggest that pre-transplant disease and treatment factors increase the risk of cytologic abnormalities and that transplant-related factors such as conditioning therapy and immunosuppression further increase this risk. These data suggest that more frequent screening may be required in these at-risk groups, especially allogeneic recipients. Prospective studies are required to further evaluate cytological abnormalities and HPV shedding in these populations.

Adult↗
PubMed2001

Helicobacter pylori--an African perspective.

Helicobacter pylori is ubiquitous in Africa, with acquisition in childhood the rule. Despite the prevalence of a virulent strain (in Soweto, most H. pylori organisms are cagA- and vacAS(1)-positive) H. pylori-associated pathology (duodenal ulcer, gastric ulcer and gastric cancer) has a variable, often low distribution in sub-Saharan Africa that does not parallel H. pylori prevalence in the population, suggesting a different natural history from that seen in developed countries. Progression to atrophic gastritis in Africans does not appear to differ from that reported in other regions, but as yet unidentified factors may play a role in inhibiting progression to gastric cancer. Studies have suggested that the specific IgG subclass response to H. pylori is predominately IgG1 (suggestive of a Th2 response), and the Th2 response may provide a protective effect against development of gastric cancer. Host immune mechanisms may be the key to different responses to H. pylori in the developed and developing worlds.

Africa↗
PubMed2001

Gastric cancer in sub-Saharan Africa.

Gastric cancer has a variable but generally low prevalence in black populations of sub-Saharan Africa, despite a high prevalence of Helicobacter pylori (the 'African enigma'). Evidence from Soweto indicates that the host response to H. pylori may be protective against a virulent organism and that, in most people, H. pylori does not lead to more serious sequelae. This suggests that there may be host protective/inhibitory factors present, which prevent the progression of H. pylori-induced chronic active gastritis to cancer.

Aged↗
PubMed2001

Predictors of early rescreening in the National Cervical Screening Program, Australia.

OBJECTIVE: To identify variables that predict early rescreening after a negative Pap smear report. METHODS: Cohort study using the records of a statewide Cervical Cytology Registry in Victoria, Australia. The cohort comprised 31,082 women who had a negative Pap smear report during the first half of 1996 and who were rescreened within the subsequent 36 months. Early rescreening was defined as a further Pap smear within 21 months. RESULTS: The strongest predictor of early rescreening was a recommendation at the time of issuing the negative Pap smear report by the laboratory for retesting before two years (adjusted odds ratio = 3.81, 95% confidence interval (CI) 3.58-4.05). Mention of reactive or inflammatory change as part of the negative Pap smear report was also a powerful predictor (adjusted odds ratio = 1.67, 95% CI 1.50-1.85). Significant predictors associated with the women were young age, high socio-economic status and residence in the capital city. Significant predictors associated with the practitioner were if either the index or subsequent smear was collected by an obstetrician/ gynaecologist or a hospital-based clinic, or if the practitioner collecting the index smear was a female. The population-attributable risk per cent associated with the laboratory recommendation was 27%. CONCLUSIONS: This data suggests that a multifaceted strategy targeting pathology laboratories, practitioners and women may be needed to reduce early rescreening. IMPLICATIONS: Early rescreening is wasteful of health resources. New screening programs should be designed to avoid this problem.

Adult↗
PubMed2001

Effects of physical interventions on house dust mite allergen levels in carpet, bed, and upholstery dust in low-income, urban homes.

House dust mite allergen exposure is a postulated risk factor for allergic sensitization, asthma development, and asthma morbidity; however, practical and effective methods to mitigate these allergens from low-income, urban home environments remain elusive. The purpose of this study was to assess the feasibility and effectiveness of physical interventions to mitigate house dust mite allergens in this setting. Homes with high levels of house dust mite allergen (Der f 1 + Der p 1 > or = 10 microg/g dust by enzyme-linked immunosorbent assay) in the bed, bedroom carpet, and/or upholstered furniture were enrolled in the study. Carpets and upholstered furniture were subjected to a single treatment of either dry steam cleaning plus vacuuming (carpet only) or intensive vacuuming alone. Bed interventions consisted of complete encasement of the mattress, box spring, and pillows plus either weekly professional or in-home laundering of nonencased bedding. Dust samples were collected at baseline and again at 3 days (carpet and upholstery only) and 2, 4, and 8 weeks posttreatment. We compared pretreatment mean allergen concentrations and loads to posttreatment values and performed between-group analyses after adjusting for differences in the pretreatment means. Both dry steam cleaning plus vacuuming and vacuuming alone resulted in a significant reduction in carpet house dust mite allergen concentration and load (p < 0.05). Levels approached pretreatment values by 4 weeks posttreatment in the intensive vacuuming group, whereas steam cleaning plus vacuuming effected a decrease that persisted for up to 8 weeks. Significant decreases in bed house dust mite allergen concentration and load were obtained in response to encasement and either professional or in-home laundering (p < 0.001). Between-group analysis revealed significantly less postintervention house dust mite allergen load in professionally laundered compared to home-laundered beds (p < 0.05). Intensive vacuuming and dry steam cleaning both caused a significant reduction in allergen concentration and load in upholstered furniture samples (p < 0.005). Based on these data, we conclude that physical interventions offer practical, effective means of reducing house dust mite allergen levels in low-income, urban home environments.

Allergens↗
PubMed2001

Utility of commonly used commercial human chorionic gonadotropin immunoassays in the diagnosis and management of trophoblastic diseases.

BACKGROUND: Patients with trophoblastic diseases produce ordinary and irregular forms of human chorionic gonadotropin (hCG; e.g., nicked hCG, hCG missing the beta-subunit C-terminal segment, hyperglycosylated hCG, and free beta subunit) that are recognized to differing extents by automated immunometric hCG (or hCG beta) assays. This has led to low or false-negative results and misdiagnosis of persistent disease. False-positive hCG immunoreactivity has also been detected, leading to needless therapy for trophoblastic diseases. Here we compare seven commonly used hCG assays. METHODS: Standards for five irregular forms hCG produced in trophoblastic diseases, serum samples from 59 patients with confirmed trophoblastic diseases, and serum samples from 12 women with previous false-positive hCG results (primarily in the Abbott AxSYM assay) were blindly tested by commercial laboratories in the Beckman Access hCG beta, the Abbott AxSYM hCG beta, the Chiron ACS:180 hCG beta, the Baxter Stratus hCG test, the DPC Immulite hCG test, the Serono MAIAclone hCG beta tests, and in the hCG beta RIA. RESULTS: Only the RIA and the DPC appropriately detected the five irregular hCG standards. Only the Beckman, DPC, and Abbott assays gave results similar to the RIA in the patients with confirmed trophoblastic diseases (values within 25% of RIA in 49, 49, and 54 of 59 patients, respectively). For samples that were previously found to produce false-positive hCG results, no false-positive results were detected with the DPC and Chiron tests (5 samples, median <2 IU/L), but up to one-third of samples were false positive (>10 IU/L) in the Beckman (1 of 5), Serono (2 of 9), and Baxter assays (1 of 5), and the hCG beta RIA (3 of 9; median for all assays, <5 IU/L). These samples, which produced false-positive results earlier in the Abbott AxSYM assay, continued to produce high values upon reassessment (median, 81 IU/L). CONCLUSIONS: Of six frequently used hCG immunometric assays, only the DPC detected the five irregular forms of beta hCG, agreed with the RIA, and avoided false-positive results in the samples tested. This assay, and similarly designed assays not tested here, seem appropriate for hCG testing in the diagnosis and management of trophoblastic diseases.

Choriocarcinoma↗
PubMed2000

Hormone replacement therapy and accuracy of mammographic screening.

BACKGROUND: Hormone replacement therapy (HRT) is commonly used and may affect the accuracy of mammographic screening. METHODS: We examined the sensitivity, specificity, and small-cancer detection rate according to HRT use in 103,770 women in Victoria, Australia, who attended first-round screening in 1994 and who did not have a personal history of breast cancer or a breast lump or a bloodstained or watery nipple discharge at the time of screening. BreastScreen Victoria provides mammography to women aged 40 years and older every 2 years. Unconditional logistic modelling was used to adjust for age, family history, and symptom status. FINDINGS: The sensitivity of screening mammography for a 2-year screening interval was lower in HRT users (64.8% [95% CI 58-72]) than non-users (77.3% [74-81]). In the target group (50-69 years), the sensitivity was 64.3% (57-72) in HRT users and 79.8% (76-84) in non-users. Among women who were diagnosed with cancer during the 2-year screening interval, HRT users were more likely to have a false negative result than non-users (odds ratio 1.60 [1.04-2.21]) after adjusting for potential confounding factors. Specificity was 0.6% lower in HRT users compared with non-users. Among women who did not have cancer diagnosed in the interval, HRT users were more likely to have a false positive result (adjusted odds ratio 1.12 [1.05-1.19]). INTERPRETATION: We show that HRT use reduces the sensitivity of mammographic screening. In countries where HRT use is widespread, the reduction in sensitivity with HRT use may undermine the capacity of population-based mammographic-screening programmes to realise their potential mortality benefit.

Adult↗
PubMed2000

Undetectable ultrasensitive PSA after radical prostatectomy for prostate cancer predicts relapse-free survival.

Radical retropubic prostatectomy is considered by many centres to be the treatment of choice for men aged less than 70 years with localized prostate cancer. A rise in serum prostate-specific antigen after radical prostatectomy occurs in 10-40% of cases. This study evaluates the usefulness of novel ultrasensitive PSA assays in the early detection of biochemical relapse. 200 patients of mean age 61. 2 years underwent radical retropubic prostatectomy. Levels < or = 0.01 ng ml-1 were considered undetectable. Mean pre-operative prostate-specific antigen was 13.3 ng ml-1. Biochemical relapse was defined as 3 consecutive rises. The 2-year biochemical disease-free survival for the 134 patients with evaluable prostate-specific antigen nadir data was 61.1% (95% CI: 51.6-70.6%). Only 2 patients with an undetectable prostate-specific antigen after radical retropubic prostatectomy biochemically relapsed (3%), compared to 47 relapses out of 61 patients (75%) who did not reach this level. Cox multivariate analysis confirms prostate-specific antigen nadir < or = 0.01 ng ml-1 to be a superb independent variable predicting a favourable biochemical disease-free survival (P < 0.0001). Early diagnosis of biochemical relapse is feasible with sensitive prostate-specific antigen assays. These assays more accurately measure the prostate-specific antigen nadir, which is an excellent predictor of biochemical disease-free survival. Thus, sensitive prostate-specific antigen assays offer accurate prognostic information and expedite decision-making regarding the use of salvage prostate-bed radiotherapy or hormone therapy.

Adult↗
PubMed2000

Cognitive-behavioral predictors of asthma morbidity in inner-city children.

Asthma is a growing health problem among children in the United States, particularly in urban, inner-city areas. This article examines the relationship between cognitive-behavioral aspects of asthma management (caretaker asthma knowledge, expectations, and problem-solving) and asthma morbidity in a sample of 1,376 inner-city children with physician-diagnosed asthma. In the analyses, baseline symptom severity served as a covariate, and the average of the 3-, 6-, and 9-month follow-up data served as the outcome measure. Children of caregivers with ineffective problem-solving strategies had significantly more days of wheezing over a 14-day period. Ineffective problem-solving capabilities were also associated with poorer functional status; however, positive caregiver expectations were associated with better functional status. Of the cognitive-behavioral factors studied in a high-risk urban population, caregiver problem-solving skills and expectations emerged as meriting further investigation and possible intervention.

Asthma↗
PubMed2000

The sensitivity, specificity, and positive predictive value of screening mammography and symptomatic status.

OBJECTIVE: To examine whether the accuracy of screening mammography varies according to symptomatic status reported at the time of screening. SETTING: Victoria, Australia, where free biennial screening is provided to women aged 40 and older. METHODS: We examined the sensitivity, specificity, and the positive predictive value of screening mammography by symptom status in 106,826 women from Victoria, who attended for first round mammography in 1994 and who did not have a personal history of breast cancer. Symptomatic status was divided into the following categories: asymptomatic; significant symptoms, if the woman reported a breast lump and/or blood stained or watery nipple discharge; and other symptoms, if reported. Unconditional logistic regression modelling was used to adjust for age, use of hormone replacement therapy (HRT), and family history. RESULTS: Sensitivity was lower for women with other symptoms (60.0%) than asymptomatic women (75.6%), or women with significant symptoms (80.8%). Specificity was lower for women with significant symptoms (73.7%) than asymptomatic women (94.9%), or women with other symptoms (95.4%). Among women who had invasive cancer detected during screening interval, women with other symptoms were more likely to get a false negative result (odds ratio 1.79, 95% confidence interval 1.03 to 3.04) than asymptomatic women, after adjusting for age, use of HRT, and family history. CONCLUSION: The lower sensitivity in women with other symptoms requires further investigation. Possible explanations include increased breast density and poor image quality. The high sensitivity in women with significant symptoms is probably due to more cautious radiological practice, which has also resulted in low specificity in this group.

Adult↗
PubMed2000

Do obese inner-city children with asthma have more symptoms than nonobese children with asthma?

OBJECTIVE: To test whether obesity is associated with decreased peak expiratory flow rates (PEFR), increased asthma symptoms, and increased health service use. DESIGN/METHODS: Secondary analysis of data from a cross-sectional convenience sample. SETTING: Emergency departments (EDs) and primary care clinics in 8 inner-city areas in 7 cities. PARTICIPANTS: One thousand three hundred twenty-two children aged 4 to 9 years with asthma. MEASURES: Obesity was defined as a body mass index (BMI, weight/height(2)) >95th percentile. Nonobese children were those with a BMI between the 5th and 95th percentile. Underweight children with a BMI <5th percentile were eliminated from the study. Demographic and anthropometric data were obtained during a baseline interview with the primary caretaker and the child. Symptoms, health service use data and measurements of PEFR were obtained by parental report during the baseline interview and at 3-month intervals by telephone interview over the following 9-month period. RESULTS: Obese (n = 249) and nonobese (n = 1073) children did not differ in terms of age, gender, family income, passive smoke exposure, caretaker's mental health, and skin test reactivity to indoor allergens. Obese children were more often Latino (28% vs 17%) and, in the 3 months before the baseline interview, were more likely to have used oral steroids (30% vs 24%). There were no differences between groups in terms of baseline PEFR scores. During the 9 months after baseline assessment, the obese group had a higher mean number of days of wheeze per 2-week period (4.0 vs 3.4), and a greater proportion of obese individuals had unscheduled ED visits (39% vs 31%). There were no differences between the groups in terms of frequency of hospitalization, or in nocturnal awakening. CONCLUSIONS: In our sample of inner-city children with asthma, obese children used more medicine, wheezed more, and a greater proportion had unscheduled ED visits than the nonobese children.

Asthma↗
PubMed1999

Inverse relation between prostate-specific antigen and insulin-like growth factor-binding protein 3 in bone metastases and serum of patients with prostate cancer.

The usual osteoblastic phenotype of metastatic prostate cancer is unexplained. Here we show that tissue and serum concentrations of prostate-specific antigen (PSA)-vary inversely with a substrate protein that binds a growth factor known to activate osteoblasts. These findings suggest that PSA may contribute to the osteoblastic phenotype, and could thus represent a new drug target devoid of antiandrogenic toxicity.

Biomarkers, Tumor↗