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Biomedical subjects

D Steele

Publications and source records attributed to D Steele.

At least 19 recordsLinked to original sources
PubMed2006

BRCA1 dysfunction in sporadic basal-like breast cancer.

Basal-like breast cancers form a distinct subtype of breast cancer characterized by the expression of markers expressed in normal basal/myoepithelial cells. Breast cancers arising in carriers of germline BRCA1 mutations are predominately of basal-like type, suggesting that BRCA1 dysfunction may play a role in the pathogenesis of sporadic basal-like cancers. We analysed 37 sporadic breast cancers expressing the basal marker cytokeratin 5/6, and age- and grade-matched controls, for downregulation of BRCA1. Although BRCA1 promoter methylation was no more common in basal-like cancers (basal 14% vs controls 11%, P=0.72), BRCA1 messenger RNA expression was twofold lower in basal-like breast cancers compared to matched controls (P=0.008). ID4, a negative regulator of BRCA1, was expressed at 9.1-fold higher levels in basal-like breast cancer (P<0.0001), suggesting a potential mechanism of BRCA1 downregulation. BRCA1 downregulation correlated with the presence of multiple basal markers, revealing heterogeneity in the basal-like phenotype. Finally, we found that 63% of metaplastic breast cancers, a rare type of basal-like cancers, had BRCA1 methylation, in comparison to 12% of controls (P<0.0001). The high prevalence of BRCA1 dysfunction identified in this study could be exploited in the development of novel approaches to targeted treatment of basal-like breast cancer.

BRCA1 Protein↗
PubMed2006

Basal-like breast carcinomas: clinical outcome and response to chemotherapy.

BACKGROUND: Grade-III invasive ductal carcinomas of no special type (IDCs-NST) constitute a heterogeneous group of tumours with different clinical behaviour and response to chemotherapy. As many as 25% of all grade-III IDCs-NST are known to harbour a basal-like phenotype, as defined by gene expression profiling or immunohistochemistry for basal cytokeratins. Patients with basal-like breast carcinomas (BLBC) are reported to have a shorter disease-free and overall survival. MATERIAL AND METHODS: A retrospective analysis of 49 patients with BLBC (as defined by basal cytokeratin expression) and 49 controls matched for age, nodal status and grade was carried out. Histological features, immunohistochemical findings for oestrogen receptor (ER), progesterone receptor (PgR) and HER2, and clinical outcome and survival after adjuvant chemotherapy were compared between the two groups. RESULTS: It was more likely for patients with BLBCs to be found negative for ER (p<0.0001), PgR (p<0.0001) and HER2 (p<0.01) than controls. Patients with BLBCs were found to have a significantly higher recurrence rate (p<0.05) and were associated with significantly shorter disease-free and overall survival (both p<0.05). In the group of patients who received anthracycline-based adjuvant chemotherapy (BLBC group, n = 47; controls, n = 49), both disease-free and overall survival were found to be significantly shorter in the BLBC group (p<0.05). CONCLUSIONS: BLBCs are a distinct clinical and pathological entity, characterised by high nuclear grade, lack of hormone receptors and HER2 expression and a more aggressive clinical course. Standard adjuvant chemotherapy seems to be less effective in these tumours and new therapeutic approaches are indicated.

Adult↗
PubMed2006

Identification of viral agents causing diarrhea among children in the Eastern Center of Tunisia.

Viral diarrhea remains a major cause of childhood morbidity and mortality worldwide. In Tunisia, no comprehensive studies of all viral agents related to diarrhea in children have yet been conducted. The present study was performed to investigate the role of enteric viruses in acute diarrhea in the country. Six hundred thirty-eight stool samples were collected from children under 5 years of age seeking medical care for acute diarrhea between October 2003 and September 2005 in hospitals from the Eastern-Center Tunisia. All samples were tested for rotavirus, astrovirus, and adenovirus using commercial antigen enzyme immunoassays (EIAs). Positive samples for rotavirus and astrovirus were confirmed by an "in-house" reverse transcriptase-polymerase chain reaction (RT-PCR). Samples positive for adenovirus antigen were subjected to further EIA screening for species F enteric adenovirus types 40 and 41. At least one viral agent was found in 30% of the specimens. The frequency of rotavirus, astrovirus, and adenovirus was 20%, 7%, and 6%, respectively. Of the stool samples containing adenovirus, 57% (20/35) were found to be positive for species F adenovirus types 40/41. Dual infections were found in 9% (17/191) of the positive samples. Enteric viruses appear to play an important role in pediatric diarrhea in Tunisia. The introduction of affordable viral diagnosis in pediatric hospitals will improve patient care by reducing the unnecessary use of antibiotics.

Acute Disease↗
PubMed2006

Cognitive impairment and fMRI in major depression.

Cognitive impairment in depression may be one of the more practically important aspects of the illness, responsible for much of its morbidity. It also is at the heart of its psychopathology, may contribute to strategies of treatment, and may give us a more easily quantifiable measure of impaired function to correlate with brain activity. Functional magnetic resonance imaging (fMRI) is ideally suited to examine brain function in depression. It has the correct time window to repeatedly sample cognitive task performance; it does not require exposure to radioactive tracers and can therefore be repeated many times; it also can be linked with high resolution structural images acquired in the same imaging session that help identify the regions of activation and support the spatial transformation necessary to compare the scans of different subjects. fMRI has already produced a series of consistent results in depression, identifying increased activity of rostral anterior cingulate and other medial prefrontal structures during effortful tasks and on occasion also increased dorsolateral prefrontal activity, suggesting increased possibly compensatory activity to maintain task performance. Investigating the interplay between limbic (orbitomedial) and 'cognitive' dorsolateral structures clearly has the potential to clarify important illness mechanisms of depressive illness.

Brain↗
PubMed2006

Metaplastic breast carcinomas are basal-like tumours.

AIMS: Recently, an immunohistochemical panel comprising antibodies against HER2, oestrogen receptor (ER), epidermal growth factor receptor (EGFR) and cytokeratin (CK) 5/6 was reported to identify basal-like breast carcinomas, as defined by cDNA microarrays. Our aim was to analyse a series of metaplastic breast carcinomas (MBCs) using this panel plus two other basal markers (CK14 and p63) and progesterone receptor (PR), to define how frequently MBCs show a basal-like immunophenotype. METHODS AND RESULTS: Sixty-five cases were retrieved from the pathology archives of the authors' institutions and reviewed by three of the authors. Immunohistochemistry with antibodies for HER2, ER, EGFR, CK5/6, CK14 and p63 was performed according to standard methods. All but six cases (91%) showed the typical immunoprofile of basal-like tumours (ER- and HER2-, EGFR+ and/or CK5/6+). When CK14 and p63 were added to the panel, two additional cases could be classified as basal-like. The majority of MBCs lacked PR, except 4/19 (21%) carcinomas with squamous metaplasia. CONCLUSIONS: Our results demonstrate that MBCs show a basal-like phenotype, regardless of the type of metaplastic elements. Moreover, as these neoplasms frequently overexpress EGFR (57%), patients with MBC may benefit from treatment with anti-EGFR drugs.

Biomarkers, Tumor↗
PubMed2006

Outcome of post-prostatectomy radiotherapy in one institution.

We present a retrospective study to evaluate the outcome of postoperative radiotherapy for biochemical or clinical recurrent prostate cancer. Twenty-six patients (median age 60 years) underwent radiotherapy after radical prostatectomy between January 1997 and January 2004. Seven patients received adjuvant radiotherapy and 19 received salvage radiotherapy. The median prostate-specific antigen at diagnosis was 8.6 (0.9-89) and most (23 patients) presented with T(3)N(0) disease. The median follow up was 19.5 months (5-84 months). All patients received a dose of 61.2 Gy at 1.8 Gy per fraction, 20 initially receiving 45 Gy to the lesser pelvis. The median dose to the bladder, rectum and left femoral head were 55.6, 57.5 and 33.8 Gy, respectively. All patients were managed radiotherapeutically by the first author. Twenty-four patients are alive. Two patients have died, one from oesophageal cancer and the second from metastatic prostate cancer. Two other patients also developed metastatic disease. Four asymptomatic patients with a rising prostate-specific antigen are under observation. None of the 26 patients has developed a local recurrence. Seven patients have developed grade 1 late bowel effects and three a grade 2 late effect. Eight patients suffer from grade 1 late genitourinary effects and two from grade 2 effects. One patient developed impotence, whereas 23 patients were rendered impotent postoperatively. There were no grade 3/4 late effects. Postoperative radiotherapy is well tolerated and provides effective local control.

Aged↗
PubMed2003

Limits on diffuse fluxes of high energy extraterrestrial neutrinos with the AMANDA-B10 detector.

Data from the AMANDA-B10 detector taken during the austral winter of 1997 have been searched for a diffuse flux of high energy extraterrestrial muon neutrinos. This search yielded no excess events above those expected from background atmospheric neutrinos, leading to upper limits on the extraterrestrial neutrino flux measured at the earth. For an assumed E-2 spectrum, a 90% classical confidence level upper limit has been placed at a level E2Phi(E)=8.4 x 10(-7) cm(-2) s(-1) sr(-1) GeV (for a predominant neutrino energy range 6-1000 TeV), which is the most restrictive bound placed by any neutrino detector. Some specific predicted model spectra are excluded. Interpreting these limits in terms of the flux from a cosmological distributions of sources requires the incorporation of neutrino oscillations, typically weakening the limits by a factor of 2.

Journal Article↗
PubMed2001

Observation of high-energy neutrinos using Cerenkov detectors embedded deep in Antarctic ice.

Neutrinos are elementary particles that carry no electric charge and have little mass. As they interact only weakly with other particles, they can penetrate enormous amounts of matter, and therefore have the potential to directly convey astrophysical information from the edge of the Universe and from deep inside the most cataclysmic high-energy regions. The neutrino's great penetrating power, however, also makes this particle difficult to detect. Underground detectors have observed low-energy neutrinos from the Sun and a nearby supernova, as well as neutrinos generated in the Earth's atmosphere. But the very low fluxes of high-energy neutrinos from cosmic sources can be observed only by much larger, expandable detectors in, for example, deep water or ice. Here we report the detection of upwardly propagating atmospheric neutrinos by the ice-based Antarctic muon and neutrino detector array (AMANDA). These results establish a technology with which to build a kilometre-scale neutrino observatory necessary for astrophysical observations.

Journal Article↗
PubMed2001

What did we learn about student and faculty "backlash" to the Interdisciplinary Generalist Curriculum Project?

There was student and faculty backlash against the Interdisciplinary Generalist Curriculum (IGC) Project innovations at all ten schools involved. Students may react strongly to requirements and experiences they find onerous, and often reacted to being "preached at" and being told what they should value and believe. Backlash was not limited to students. A complaint heard in virtually all schools was that the basic science faculty barely had enough time to adequately cover their topics as it was, and now they were being asked to give up time for clinical experiences and topics. Despite the backlash, the authors point out that the vast majority of students endorsed the value of the preceptorship experience and that reaction to the IGC Project did not necessarily translate into negative perceptions of primary care medicine. Each IGC Project school made strategic decisions in response to backlash. Among the various efforts undertaken were enhanced communication and clarification, persistence and "watchful waiting," programmatic changes, and elimination of program components that were not working. These various efforts appear to have paid off, as most schools reported that backlash diminished over time. Lessons learned about backlash against new curricular innovations were that (1) backlash, however defined, is inevitable; (2) communication, coordination, and cooperation are essential; (3) flexibility, compromise, and willingness to change are essential; and (4) "watchful waiting" can be an effective response to some forms of backlash.

Attitude↗
PubMed2001

The Interdisciplinary Generalist Project at the University of Nebraska Medical Center.

The Interdisciplinary Generalist Curriculum (IGC) Project at the University of Nebraska College of Medicine (Nebraska) had three goals: (1) to increase first- and second-year students' exposure to primary care practice in the community; (2) to develop specific educational programs introducing these students to the principles and practices of primary care medicine; and (3) to establish a generalist coordinating council to provide leadership and to nurture generalist educational initiatives in the College of MEDICINE: Students at Nebraska were already required to spend three half-days a semester in a longitudinal clinical experience (LCE) and to complete a three-week primary care block experience in the summer between the first and second years. IGC Project funds were used increase the number of required LCE visits to five a semester and to develop curricular enhancements that would maximize the educational potential of community-based clinical experiences for first- and second-year students. Curricular elements developed included a focus on faculty development for preceptors and development of the Primary Care Introduction to Medicine Curriculum, an eight-week, interdisciplinary module scheduled late in the first year to help prepare students for intensive summer rotations. Other developments were the implementation of a pediatric physical examination experience for first-year students and the implementation of instruction in community-oriented primary care in the second year. Lessons learned are related to: (1) the value and power of early clinical experiences; and (2) the enhancing effect of a holistic, longitudinal view of the curriculum on the planning of early clinical experiences.

Curriculum↗
PubMed2001

Prevalence of unusual human rotavirus strains in Ghanaian children.

Sixty-seven rotavirus-positive fecal samples, collected between January and April 1999, from children with diarrhea in the Upper East Region of Ghana were examined for rotavirus VP7 and VP4 types. Sufficient viral RNA could be obtained from 46 (68.7%) of the samples and all the isolates had short electrophoretic pattern and typed as subgroup I rotaviruses by subgroup ELISA. Three rotavirus strains with G8 specificity were identified for the first time in Ghana. G and P typing by PCR identified two distinct strains, P[6]G2 (50%) and P[6]G8 (4.3%). Eighty-two percent of the isolates (n = 38) were of the "putative" neonatal P[6] genotype. Two of these G8 isolates carried the VP4 P[6] genotype whereas the third could not be assigned a P type. Mixed infections of G1, G2, G3 and G8 were detected amongst the stool samples. The presence of these unusual strains, especially the high incidence of G2 rotavirus strains in Ghana, reinforces the need to put in place a surveillance system for the detection of new and exotic rotavirus strains, that will provide information on the spread of these strains in West Africa as well as useful data for the formulation of the next generation of rotavirus vaccines.

Acute Disease↗
PubMed2000

Characterisation of rotavirus G9 strains isolated in the UK between 1995 and 1998.

G9P[6] and G9P[8] rotavirus strains were identified during 1995/96 through the molecular epidemiological surveillance of rotavirus strains circulating in the UK between 1995 and 1998. An increase in the incidence and spread of sporadic infections with rotavirus genotype G9P[8] across the UK was detected in the two following seasons. Partial sequencing of the VP7 gene showed that all the UK strains shared a high degree of homology and were related very closely to G9 strains from the US and from symptomatic infections in India (> or =96% homology). The UK strains were related more distantly to the apathogenic Indian strain 116E (85-87.8% homology). Phylogenetic analysis revealed clustering of the UK strains into 3 different lineages (I to III) and into two sub-lineages within lineage I. There were correlations between VP7 sequence clustering, the P type and the geographical origin of the G9 strains. Partial sequencing of the VP4 gene showed high degree of homology (>98%) among all the P[6] strains, and the sequences obtained from the P[8] strains clustered into 2 of the 3 global lineages described for P[8] strains associated with other G types. These data suggest that G9 strains may be a recent importation into the UK, and that G9P[8] strains may have emerged through reassortment in humans between G9P[6] strains introduced recently and the more prevalent cocirculating G1, G3 and G4 strains that normally carry VP4 genes of P[8] type.

Aged↗
PubMed2000

Distribution of rotavirus VP7 serotypes and VP4 genotypes circulating in Sousse, Tunisia, from 1995 to 1999: emergence of natural human reassortants.

Rotavirus strains circulating in Sousse, Tunisia, between 1995 and 1999 were characterized antigenically by monoclonal antibodies to the VP6 subgroup and the VP7 serotype. The VP4 genotype was determined by reverse transcription-PCR, as were the strains with untyped VP7. Only 17% of 375 children were shedding rotavirus as determined by latex agglutination assay. Most rotavirus strains were G1P[8] (50%), followed by G4P[8] and G4P[6]. Reassortant G1P[4] strains emerged in Sousse during the 1998-1999 season.

Antigens, Viral↗
PubMed2000

Use of nitric oxide inhalation in chronic obstructive pulmonary disease.

BACKGROUND: Inhalation of nitric oxide with oxygen could be a promising treatment in patients with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension. However, the current methods of delivery of NO are cumbersome and unsuitable for long term use. The present study was undertaken to investigate the safety and efficacy of a mixture of nitric oxide (NO) and oxygen administered via a nasal cannula for 24 hours in patients with oxygen dependent COPD. METHODS: Twenty five parts per million (ppm) of NO was administered by inhalation combined with supplemental oxygen at a flow rate of 2 l/min via a nasal cannula for 24 hours to 11 ambulatory men with stable, oxygen dependent COPD. Room air with supplemental oxygen at 2 l/min was administered in an identical manner for another 24 hours as control therapy in a randomised, double blind, crossover fashion to all patients. Pulmonary function tests, exercise tolerance, dyspnoea grade, and lung volumes were measured at baseline, 24, and 48 hours. Pulmonary artery pressure (PAP), cardiac output (CO), pulmonary vascular resistance (PVR), arterial blood gas tensions, and minute ventilation were measured at baseline, after 30 minutes and 24 hours of breathing NO and oxygen. Venous admixture ratio (Qs/Qt) and dead space ratio (Vd/Vt) were also calculated. Concentrations of nitrogen dioxide (NO(2)) and NO in the inhaled and ambient air were monitored continuously. Differences in pulmonary function, arterial blood gas tensions, pulmonary haemodynamics, exercise tolerance, and dyspnoea between oxygen and NO breathing periods were analysed for significance using paired t tests. RESULTS: A significant (p<0.05) fall was observed in PVR (183.1 (116.05) and 137.2 (108.4) dynes.s.cm(-3) before and after breathing NO for 24 hours, respectively) with NO administration without significant changes in symptoms, pulmonary function, arterial oxygen tension, or exercise tolerance. CONCLUSIONS: NO at a concentration of 25 ppm blended with oxygen can be safely administered by nasal cannula for 24 hours without significant adverse effects and lowers PVR in stable patients with COPD receiving long term oxygen therapy.

Administration, Inhalation↗
PubMed2000

Analysis of physician ability in the measurement of pulsus paradoxus by sphygmomanometry.

CONTEXT: Measurement of pulsus paradoxus (PP) is one of several measures previously advocated in the National Heart, Lung, and Blood Institute asthma management guidelines: a pulsus of > 12 mm Hg warranted hospital admission. It is one of only a few measures that is not effort dependent and therefore important in the evaluation of patients with asthma. OBJECTIVE: Determination of physician accuracy in measuring PP. DESIGN: A model of induced PP in a trained healthy subject without respiratory disease was constructed with a fixed inspiratory resistance with measurement of inspiratory air pressure and beat-to-beat BP noninvasively. SETTING: Laboratory. PARTICIPANTS: Attending physicians from emergency medicine and critical care disciplines who served as consecutive examiners of the trained reference subject generating known PP. INTERVENTIONS: A total of 19 attending physicians were assessed for ability in measuring PP by sphygmomanometry and by palpation. The reference subject generated 4 degrees of PP sequentially, with each examiner blinded to the value of negative inspiratory pressure and PP. Examiners first assessed PP qualitatively by palpation, followed by its measurement within 2 min. MAIN OUTCOME MEASURE: Proximity of physician-measured PP (PPm) to true PP (PPt). RESULTS: At inspiratory pressures of - 10, - 15, - 20, and - 25 mm Hg, PPt was 13.7, 16.2, 19.1, and 20.7 mm Hg, respectively (F = 14.8, p < 0. 0001; analysis of variance [ANOVA]). At the same pressures, PPm was 13.1, 17.5, 17.7, and 18.0 mm Hg (p > 0.10; ANOVA). Linear regression of PPm against PPt for each examiner revealed a slope (SE) of 0.53 (0.23), and not a 1:1 relationship. CONCLUSIONS: Past and present guidelines do not account for the challenges in measuring PP, especially in tachypneic patients. Sphygmomanometric determination of PP should be augmented by new aids developed through technological innovation.

Adult↗
PubMed1998

Determination of a specific 5-HT2a antagonist (M100907) in rat and dog plasma at the femtomole/milliliter level by gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric method for the determination of R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)-4-p iperdinemethanol] (M100907), I, in rat and dog plasma is described. I, a specific 5-HT2a receptor antagonist and the internal standard were concentrated from plasma by C1 solid-phase extraction. Following derivatization to their TMS ethers, they were separated by capillary GC and detection was by mass specific detection in single-ion monitoring mode. The validation range was from 0.1 to 10 ng/ml. The day-to-day coefficient of variation for the calibration standards over the concentration range varied from 9.5 to 14.9% in dog plasma and 1.7 to 13.4% in rat plasma. Quality control standards were measured at three concentrations (0.5, 2.5 and 7.5 ng/ml) in plasma from both species; the day-to-day coefficient of variation ranged from 1.8 to 14.2% in dog plasma and 1.6 to 15.1% in rat plasma. The method is both specific and sensitive down to the picomolar level in plasma.

Animals↗
PubMed1998

The construction and utility of an amniocentesis trainer.

OBJECTIVE: Our goal was to design an inexpensive amniocentesis trainer for instruction and practice with ultrasonography-assisted needle guidance and the freehand technique. STUDY DESIGN: The amniocentesis trainer was constructed from a commercially available 5.3-L storage box (No. 5805; Rubbermaid Incorporated, Wooster, Ohio). Sonodense sperical targets 2.3 cm in diameter were taped to the bottom, and the box was filled with a gelatin mixture. The box was covered with a rubber membrane from a pelviscopy trainer (United States Surgical Corp, Norwalk, Conn). After the gelatin mixture set overnight at 40 degreesF, the amniocentesis trainer was ready for use. RESULTS: When a needle is introduced through the membrane into the gelatin, the ultrasonographic image is a reasonable simulation of an amniocentesis. The trainer improved the ability of an operator to perform a freehand amniocentesis, orient the ultrasound transducer, follow a needle with continuous ultrasonographic guidance, and hit a 2-cm target. The gelatin also allows for evaluation of improvement between amniocentesis attempts because a faint image of the needle track from prior attempts remains visible. Once basic amniocentesis skills are mastered, the trainer is easily modifiable so that obstacles can be added that could simulate umbilical cord and fetal extremities. CONCLUSIONS: We were able to construct an inexpensive amniocentesis trainer that facilitates instruction in the freehand amniocentesis technique. This trainer enables an operator to master the skills necessary to perform the technique of freehand ultrasonography-guided amniocentesis under direct ultrasonographic visualization without putting a patient through the discomfort of participating in the learning curve.

Amniocentesis↗