Biomedical subjects

J M Harvey

Publications and source records attributed to J M Harvey.

At least 19 recordsLinked to original sources

PubMed2005

Pathology reporting of breast cancer: trends in 1989-1999, following the introduction of mammographic screening in Western Australia.

BACKGROUND: A survey of pathology reporting of breast cancer in Western Australia in 1989 highlighted the need for improvement. The current study documents (1) changes in pathology reporting from 1989 to 1999 and (2) changes in patterns of histopathological prognostic indicators for breast cancer following introduction of mammographic screening in 1989. METHODS: Data concerning all breast cancer cases reported in Western Australia in 1989, 1994 and 1999 were retrieved using the State Cancer Registry, Hospital Morbidity data system, and pathology laboratory records. RESULTS: Pathology reports improved in quality during the decade surveyed. For invasive carcinoma, tumour size was not recorded in 1.2% of pathology reports in 1999 compared with 16.1% in 1989 (p<0.001). Corresponding figures for other prognostic factors were: tumour grade 3.3% and 51.6% (p<0.001), tumour type 0.2% and 4.1% (p<0.001), vascular invasion 3.7% and 70.9% (p<0.001), and lymph node status 1.9% and 4.5% (p = 0.023). In 1999, 5.9% of reports were not in a synoptic/checklist format, whereas all reports were descriptive in 1989 (p<0.001). For the population as a whole, the proportion of invasive carcinomas <1 cm was 20.9% in 1999 compared with 14.5% in 1989 (p<0.001); for tumours <2 cm the corresponding figures were 65.4% and 59.7% (p = 0.013). In 1999, 30.5% of tumours were histologically well-differentiated compared with 10.6% in 1989 (p<0.001), and 61.7% were lymph node negative in 1999 compared with 57.1% in 1989 (p = 0.006). Pure ductal carcinoma in situ (DCIS) constituted 10.9% and 7.9% of total cases of breast carcinoma in 1999 and 1989, respectively (p = 0.01). CONCLUSIONS: Quality of pathology reporting improved markedly over the period, in parallel with adoption of standardised synoptic pathology reports. By 1999, recording of important prognostic information was almost complete. Frequency of favourable prognostic factors generally increased over time, reflecting expected effects of mammographic screening.

Adenocarcinoma↗

PubMed2004

Inhibition of MCF-7 breast cancer cell proliferation by 5alpha-dihydrotestosterone; a role for p21(Cip1/Waf1).

Androgens inhibit the growth of breast cancer cells in vitro and in vivo by mechanisms that remain poorly defined. In this study, treatment of asynchronously growing MCF-7 breast cancer cells with the androgen, 5alpha-dihydrotestosterone (DHT), was shown to inhibit cell proliferation and induce moderate increases in the proportion of G1 phase cells. Consistent with targeting the G1-S phase transition, DHT pretreatment of MCF-7 cultures impeded the serum-induced progression of G1-arrested cells into S phase and reduced the kinase activities of cyclin-dependent kinase (Cdk)4 and Cdk2 to less than 50% of controls within 3 days. DHT treatment was associated with greater than twofold increases in the levels of the Cdk inhibitor, p27(Kip1), while p21(Cip1/Waf1) protein levels remained unchanged. During the first 24 h of DHT treatment, levels of Cdk4-associated p21(Cip1/Waf1) and p27(Kip1) were reduced coinciding with decreased levels of Cdk4-associated cyclin D3. In contrast, DHT treatment caused increased accumulation of Cdk2-associated p21(Cip1/Waf1), with no significant alterations in levels of p27(Kip1) bound to Cdk2 complexes. These findings suggest that DHT reverses the Cdk4-mediated titration of p21(Cip1/Waf1) and p27(Kip1) away from Cdk2 complexes, and that the increased association of p21(Cip1/Waf1) with Cdk2 complexes in part mediates the androgen-induced growth inhibition of breast cancer cells.

Breast Neoplasms↗

PubMed2001

Second transmembrane domains of ENaC subunits contribute to ion permeation and selectivity.

Epithelial sodium channels (ENaC) are composed of three structurally related subunits (alpha, beta, and gamma). Each subunit has two transmembrane domains termed M1 and M2, and residues conferring cation selectivity have been shown to reside in a pore region immediately preceding the M2 domains of the three subunits. Negatively charged residues are interspersed within the M2 domains, and substitution of individual acidic residues within human alpha-ENaC with arginine essentially eliminated channel activity in oocytes, suggesting that these residues have a role in ion permeation. We examined the roles of M2 residues in contributing to the permeation pore by individually mutating residues within the M2 domain of mouse alphaENaC to cysteine and systematically characterizing functional properties of mutant channels expressed in Xenopus oocytes by two-electrode voltage clamp. The introduction of cysteine residues at selected sites, including negatively charged residues (alphaGlu(595), alphaGlu(598), and alphaAsp(602)) led to a significant reduction of expressed amiloride-sensitive Na(+) currents. Two mutations (alphaE595C and alphaD602C) resulted in K(+)-permeable channels whereas multiple mutations altered Li(+)/Na(+) current ratios. Channels containing alphaD602K or alphaD602A also conducted K(+) whereas more conservative mutations (alphaD602E and alphaD602N) retained wild type selectivity. Cysteine substitution at the site equivalent to alphaAsp(602) within beta mENaC (betaD544C) did not alter either Li(+)/Na(+) or K(+)/Na(+) current ratios, although mutation of the equivalent site within gamma mENaC (gammaD562C) significantly increased the Li(+)/Na(+) current ratio. Mutants containing introduced cysteine residues at alphaGlu(595), alphaGlu(598), alphaAsp(602), or alphaThr(607) did not respond to externally applied sulfhydryl reagent with significant changes in macroscopic currents. Our results suggest that some residues within the M2 domain of alphaENaC contribute to the channel's conduction pore and that, in addition to the pore region, selected sites within M2 (alphaGlu(595) and alphaAsp(602)) may have a role in conferring ion selectivity.

Amino Acid Sequence↗

PubMed2000

The effect of mammographic screening on invasive breast cancer in Western Australia.

OBJECTIVE: To determine whether mammographic screening has affected the presentation of invasive breast cancer in Western Australia. DESIGN: Population-based reviews of the presentation of all invasive breast cancers diagnosed in Western Australia in 1989 and 1994. SETTING: Western Australia (population 1.8 million). Active recruitment of women aged 50-69 years for mammographic screening began in 1989. MAIN OUTCOME MEASURES: Size and stage of invasive breast cancers at diagnosis. RESULTS: From 1989 to 1994, the age-standardised incidence rose from 109 to 123 per 100,000 woman-years, based on 584 and 750 cases, respectively. The proportion of all invasive breast cancers detected as a result of a mammogram increased from 9.2% in 1989 to 34.5% in 1994. Among the cases where relevant information was recorded, the proportion of "impalpable" tumours increased from 7.7% in 1989 to 27.6% in 1994, and the average size of palpable tumours fell. There was an unexpected increase in the proportion of tumors that were negative on assays for oestrogen and progesterone receptors. CONCLUSIONS: A relatively simple and inexpensive clinical review has boosted confidence that the outlay of public monies required to establish and conduct screening in Australia appears likely to yield the reductions in mortality from breast cancer that would be predicted on the basis of the earlier controlled trials of mammography.

Age Distribution↗

PubMed2000

Comparison of vascularity and angiogenesis in primary invasive mammary carcinomas and in their respective axillary lymph node metastases.

It is well established that the ability of a neoplasm to induce a blood supply from a pre-existing circulation (angiogenesis) is a major factor in tumour growth, invasion and metastasis. However, the angiogenic potential of metastases and their subsequent growth have not been extensively studied. The question arises: can metastatic clones induce the same level of angiogenesis as in the primary neoplasm they emanated from? In this study it is hypothesised that in the same patient the level of vascularity and angiogenesis is the same in both the primary invasive ductal carcinoma and in the axillary lymph node metastasis at the time of surgery, according to Kerbels theory of clonal-dominance. To directly address the hypothesis, morphological measures of the established blood/lymphatic circulation (vascularity) as well as estimates of angiogenesis (endothelial cell proliferation) were measured in primary tumours and directly compared to the same parameters in the corresponding lymph node metastasis in a case by case basis (n = 17). The results demonstrate varying associations between the level of vascularity and angiogenesis between matched individual tumours and their metastatic lymph nodal deposits. It is possible that either variations in the angiogenic characteristics of the metastasising clone or local or systemic promoters or inhibitors of angiogenesis influence tumour angiogenesis at the different sites.

Breast Neoplasms↗

PubMed2000

Morphogenesis during asexual reproduction in Pygospio elegans Claparede (Annelida, Polychaeta).

The spionid Pygospio elegans reproduces both asexually and sexually. Using scanning electron and bright field microscopy, we examined morphogenesis following asexual reproduction to determine how "lost" body regions were regenerated after a worm spontaneously divided. Asexual reproduction occurred through transverse fission and divided the parent worm into 2 to 6 fragments (architomy). All fragments retained their original anterior-posterior polarity. Regeneration in all fragments followed a specific series of events: wound healing (day 1); extension of the blastema to generate lost body regions-specifically, the head and thorax for posterior fragments and the tail and pygidium for anterior fragments (days 2-3); segmentation (days 3-6); and differentiation of segment- or region-specific structures (days 4-8). This pattern occurred regardless of where the original division took place. Subsequent growth occurred through addition of terminal setigers anterior to the pygidium followed by differentiation of tail setigers into abdominal setigers, leaving the tail region about 6 to 10 setigers in size. Division rates were compared in worms from three populations in Nova Scotia, Canada. Worms from two populations (Conrad's Beach, Starr's Point) divided more frequently (about 1.2 and 1.3 weeks between divisions, respectively) than worms from Bon Portage Island (3.5 weeks between divisions). Fragments containing the original head (original mouth intact, generally much larger fragment) had a higher survivorship than fragments containing the original tail.

Animals↗

PubMed1999

Placental pathology and neurodevelopment of the infant with intrauterine growth restriction.

The placentas of 68 infants with intrauterine growth restriction (IUGR) were examined for evidence of impaired uteroplacental circulation and compared with those of 65 appropriately grown infants. Infarcts and/or accelerated villous maturation were present in the placentas in 27 (40%) of the infants with IUGR compared with seven (11%) of the infants without IUGR (P<0.001). The infants were followed-up at 4 and 12 months of age and growth parameters recorded. Medical and developmental assessments and neuromotor developmental examinations were also performed. The 23 infants in the IUGR group with placentas with evidence of impaired uteroplacental circulation were compared with the 31 infants with IUGR with normal placentas. There was no difference between the groups in growth, cognitive development, or neuromotor abnormality. It was concluded that IUGR is strongly associated with placental markers of impaired uteroplacental blood flow while it would appear that there is no association between placental pathology and growth or neurodevelopment in the first year.

Child Development↗

PubMed1999

Executive function of children with extremely low birthweight: a case control study.

This study examines the executive function (EF) skills of extremely-low-birthweight (ELBW) children at school compared with their peers. Thirty children with ELBW and 50 control children (both with a mean age of 62+/-4 months) were administered tests of EF including the Tower of Hanoi task, Finger Sequencing task, and Tapping Test. Children with ELBW, including those who scored more than 1 SD below the mean on the Peabody Picture Vocabulary Test-Revised, scored significantly lower than their peers on all executive tasks. There was limited correlation between EF and previous general quotient index scores obtained at routine assessment using the McCarthy Scales of General Ability at 4 years of age for the children with ELBW. Results suggest that children with ELBW are at risk for deficits in 'executive' behaviours including planning, sequencing, and inhibition which may have implications for later learning.

Case-Control Studies↗

PubMed1999

High density of small vessels expressing the tyrosine kinase receptor KDR in primary invasive breast carcinoma correlates with axillary lymph node metastases.

Although it is generally accepted that tumour growth is angiogenesis dependent, little is known about the role of angiogenesis in the metastatic process. Recent evidence suggests that the angiogenic tyrosine kinase receptor KDR is pivotal in new vessel formation. To investigate, therefore, the association between new vessel formation in primary breast carcinoma and axillary lymph node metastasis we have used computer assisted video analysis to assess the vascular distribution as well as the level of expression of KDR in individual vessels in sections of invasive breast carcinomas, some of which had metastasized to the axillary lymph nodes and some that had not. We specifically assessed the frequency distribution, perimeter, area, and density of KDR positive vessels in the same sections of tumours. Our results show that in invasive mammary carcinoma KDR is expressed exclusively on the surface and cytoplasm of endothelial cells of approximately 71% of vessels, but the level of expression in individual vessels does not correlate with the presence of axillary lymph node metastases (P > 0.10). However, we found that small vessels express higher levels of KDR (P < 0.02) than larger vessels and that there is a significantly higher frequency of relatively small (< 90 microm in perimeter) KDR positive vessels in breast tumours that had metastasized to the axillary lymph nodes than those that had not (P < 0.001). In conclusion, increased density and frequency of KDR positive small vessels in primary invasive breast carcinoma correlates with axillary lymph node metastases.

Journal Article↗

PubMed1999

Clinical versus polysomnographic profiles in children with obstructive sleep apnoea.

OBJECTIVE: To examine the clinical and polysomnographic (PSG) profiles of neurologically normal and abnormal children with obstructive sleep apnoea (OSA) and explore the relationship between these profiles. METHODOLOGY: We enrolled 56 children with persistent snoring and OSA for the study, 16 of whom were neurologically abnormal. All children were examined clinically and attended an overnight PSG study. Total clinical scores, PSG scores, and mild/moderate or severe ratings were derived for each child. RESULTS: Comparison of individual PSG parameters with neurological status demonstrated that the abnormal children had significantly increased obstructive apnoea indices, increased desaturation events and lower mean arousal indices compared to their neurologically normal OSA peers. For the neurologically abnormal children, there was a significant correlation between severity ratings of disease according to clinical and PSG profiles (r = 0.56, P = 0.03, sensitivity 82%) using the clinical summary as the gold standard, although the association was less marked in the neurologically normal children (r = -0.08, P = NS, sensitivity 69%). CONCLUSION: Neurologically abnormal children are likely to have more severe abnormalities in selected polysomnographic indices and overall scores. However, the clinical assessment is only likely to reflect this at the severe end of the spectrum. These relationships are not seen in the neurologically normal child, where little or no reliance can be placed upon predicting the severity of the polysomnographic findings from the clinical data. Decisions regarding the severity of disease and treatment should be based on the combined findings of the clinical and PSG data rather than overall clinical and polysomnographic scores or selected clinical and polysomnographic parameters.

Arousal↗

PubMed1999

Six-month follow-up of children with obstructive sleep apnoea.

OBJECTIVES: This study examined prospectively changes in development, temperament and sleep related behaviour in children referred for obstructive sleep apnoea (OSA) and polysomnographic sleep study, some of whom had surgical intervention. METHODOLOGY: Using a prospective cohort study design, parents of 56 children referred for OSA completed sleep and temperament questionnaires and their child was assessed developmentally at the time of the polysomnographic sleep study. Forty (72%) of the children were neurologically normal. At 6 months, 42 children were reassessed using sleep and temperament questionnaires and a developmental assessment. After excluding the primary snorers, subjects were categorised as having had intervention (n = 24) or not (n = 15), and differences over the 6-month period in Griffiths scores, temperament and sleep related behaviour were examined. RESULTS: Regardless of intervention status, there was an improvement in night-time and day-time sleep behaviour for the total group, though the extent of improvement was more marked in the intervention group. For the neurologically normal children, improvement in the sleep behaviour was only significant for the intervention group (P < 0.05). Intervention did not result in any significant changes in Griffiths developmental score or temperament. CONCLUSION: Surgical intervention improves sleep behaviour in children though not temperament or development.

Adenoidectomy↗

PubMed1999

Aetiological factors and development in subjects with obstructive sleep apnoea.

OBJECTIVE: To examine whether maternal pregnancy complications, adverse birth events, respiratory illnesses, or developmental difficulty were increased in neurologically normal children with obstructive sleep apnoea (OSA) and whether severity of OSA adversely affects the child's development and temperament. METHODOLOGY: Maternal report of perinatal events, respiratory illness and developmental difficulty in 37 children with OSA was contrasted with a comparison group (n = 67). Children with OSA were assessed developmentally (Griffiths Scales), had a parental rating of temperament (Australian Temperament Scale) and attended an overnight polysomnographic sleep study. RESULTS: Children with OSA had an increased prevalence of adverse maternal pregnancy and perinatal events, respiratory disease and developmental concerns. Limited associations were found between the severity of OSA and development or temperament difficulty. CONCLUSIONS: This study suggests a relationship between OSA, though not its severity, and pre/perinatal adversity and child development. Polysomnographic and detailed developmental assessment of community-based samples of children with OSA and control children are necessary to confirm these findings.

Australia↗

PubMed1999

Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer.

PURPOSE: Immunohistochemistry (IHC) is a newer technique for assessing the estrogen receptor (ER) status of breast cancers, with the potential to overcome many of the shortcomings associated with the traditional ligand-binding assay (LBA). The purpose of this study was to evaluate the ability of ER status determination by IHC, compared with LBA, to predict clinical outcome-especially response to adjuvant endocrine therapy-in a large number of patients with long-term clinical follow-up. PATIENTS AND METHODS: ER status was evaluated in 1,982 primary breast cancers by IHC on formalin-fixed paraffin-embedded tissue sections, using antibody 6F11 and standard methodology. Slides were scored on a scale representing the estimated proportion and intensity of positive-staining tumor cells (range, 0 to 8). Results were compared with ER values obtained by the LBA in the same tumors and to clinical outcome. RESULTS: An IHC score of greater than 2 (corresponding to as few as 1% to 10% weakly positive cells) was used to define ER positivity on the basis of a univariate cut-point analysis of all possible scores and disease-free survival (DFS) in patients receiving any adjuvant endocrine therapy. Using this definition, 71% of all tumors were determined to be ER-positive by IHC, and the level of agreement with the LBA was 86%. In multivariate analyses of patients receiving adjuvant endocrine therapy alone, ER status determined by IHC was better than that determined by the LBA at predicting improved DFS (hazard ratios/P = 0.474/.0008 and 0.707/.3214, respectively) and equivalent at predicting overall survival (0.379/.0001 and 0.381/.0003, respectively). CONCLUSION: IHC is superior to the LBA for assessing ER status in primary breast cancer because it is easier, safer, and less expensive, and has an equivalent or better ability to predict response to adjuvant endocrine therapy.

Adult↗

PubMed1998

Assessment of vascularity in breast carcinoma by computer-assisted video analysis (CAVA) and its association with axillary lymph node status.

Case-control methodology was used to evaluate the significance of vascularity in small breast carcinomas with regard to the presence or absence of axillary lymph node metastases. Vascularity was assessed in 32 axillary node positive primary breast tumours (LN+ve) less than 2 cm in size and compared with 56 control axillary node negative primary tumours (LN-ve), which were matched for histological type and grade and tumour size. This study design employed computer-assisted video analysis (CAVA) to assess the total blood vessel perimeter (BVP), total blood vessel area (BVA), and total blood vessel density (BVD) throughout a tissue section that encompassed an entire cross section of the tumour and its immediate periphery. The BVA and BVD in these tumours were not significantly different between LN+ve and LN-ve groups. The LN-ve carcinomas had, on average, a significantly (P<0.05) higher total BVP (3355 microm/mm2) than LN+ve tumours (2771 microm/mm2). 'Hot spot' areas were also independently assessed by two pathologists and the same areas measured by CAVA. A strong correlation (P<0.001) between the two methods of assessment of BVD of the neovascular 'hot spots' was found; however, no association with axillary lymph node metastasis was found using either method of assessment. In conclusion, vascularity assessed by either blood vessel density or blood vessel size in primary invasive breast cancers less than 2 cm in diameter showed no association with axillary lymph node metastasis; in fact a negative association was found with total BVP of whole tumour sections and BVD in 'hot spots' using CAVA. Further, this study has established a computer-assisted method of quantifying vascularity in solid neoplasms and is a positive step towards a standardised approach to this diverse and methodologically variable area.

Axilla↗

PubMed1998

Prognostic and predictive factors in breast cancer by immunohistochemical analysis.

Most recent decisions for breast cancer patients are made on the basis of prognostic and predictive factors. In addition to the traditional tumor/nodal/metastasis staging variables, estrogen and progesterone receptor status as assessed by biochemical ligand-binding assays are the only other factors that have been adequately validated and recommended for routine clinical use. Pathologists today, however, are evaluating estrogen and progesterone receptors almost exclusively by immunohistochemical means. Although many studies suggest that these tests might have equivalent or even superior abilities to predict patient outcome, there are important methodologic shortcomings to resolve before this technology achieves the clinical and technical validation necessary to justify its routine use. Many laboratories are also evaluating other factors for clinical use by immunohistochemical techniques, including, in particular, c-erbB-2, p53, and Ki-67 proliferation indices. Although available studies suggest that these factors might indeed be helpful in making treatment decisions, their clinical usefulness is still controversial, and, like the assessment of hormone receptors, there are important unresolved technical issues, such as how to prepare the tissue, which reagents to use and, most importantly, how to interpret the results. A few laboratories have gone to considerable effort to develop reproducible methods for evaluating these factors, and they have performed comprehensive studies demonstrating the prognostic and predictive significance of their results. Nonetheless, most laboratories offering these tests have not adequately validated them and might not even be aware of the issues needing attention. Unless laboratories validate their tests or follow the procedures of others who have, they run the risk of reporting meaningless and potentially harmful results. In the future, these and other factors will be incorporated into a prognostic index that will better reflect the biologic diversity of breast cancer and that will more accurately predict clinical outcome.

Biomarkers, Tumor↗

PubMed1997

Detection of p53 gene mutation by rapid PCR-SSCP and its association with poor survival in breast cancer.

We examined the association between mutation of the p53 gene and survival in a large cohort of breast cancer patients. Using a rapid, non-isotopic single-strand conformation polymorphism (SSCP) method we screened for mutations in exons 4-10 of the p53 gene in 375 primary breast cancers from patients with a median follow-up of 57 months. Mutations were found in 19% of tumours. Statistically significant associations were found between p53 mutation and histological grade, hormone receptor status, ploidy and S-phase fraction. No association was found between p53 mutation and axillary lymph node involvement, histological type, tumour size, vascular invasion or patient age. In univariate survival analysis, p53 mutation was strongly associated with poor prognosis. This was maintained in the lymph node-negative and hormone receptor-positive patient subgroups. In multivariate analysis, p53 mutation was associated with poor survival independent of lymph node status, estrogen receptor status and S-phase fraction. Our results demonstrate the feasibility of using a rapid and simple polymerase chain reaction-SSCP screening procedure to detect p53 gene mutation in breast cancer for the provision of prognostic information.

Adolescent↗

PubMed1997

Characteristics at four months follow-up of infants born small for gestational age: a controlled study.

This prospective study compared 65 small-for-gestational-age (SGA) (birth weight < 3rd centile) and 71 control infants at a corrected age of 4 months. It was hypothesised that differences would exist in growth, development, temperament and minor neurological signs and that these would be predicted by type (proportional/disproportional) of growth restriction at birth and maternal mood disturbance at birth or at 4 months. Infants had a Griffith's developmental test and neuromotor assessment. Maternal mood and infant temperament were surveyed. Few differences were found between SGA and control infants. SGA infants showed catch-up growth with 63% being above the third percentile and 43% being above the tenth percentile for weight. SGA infants had lower Griffith's GQ scores (97 vs. 102, P = 0.02) and they were rated in temperament as more manageable than controls. There were no differences in subtle neuromotor signs. Neither type of SGA nor maternal mood disturbance at birth had prognostic significance for infant catch up growth, neuromotor scores, or temperament though level of maternal stress and anxiety at 4 months were related to lower GQ scores in SGA infants.

Body Height↗

PubMed1997

Prevalence of maternal depression and its relationship to ADL skills in children with developmental delay.

OBJECTIVE: To determine the prevalence of maternal affective symptoms in children with developmental problems compared to a control group, and to examine their relationship to the child's Activities of Daily Living (ADL), socialization skills and behaviour. METHODOLOGY: This study examined prospectively the prevalence of symptoms of maternal depression, maternal anxiety, stress and adverse life events in 65 mothers whose children were attending a Child Development Clinic. ADL and socialization skills were measured using the Vinelands Adaptive Behaviour Scales, and behaviour using a checklist. RESULTS: Symptoms of maternal depression (P = 0.04), maternal anxiety (P = 0.01) and number of adverse life events (P = 0.03) were increased in the study compared to control mothers. Presence of maternal symptoms was unrelated to ADL or socialization skills though was associated with increased behavioural symptoms in the child. CONCLUSION: Affective disturbance in mothers of children with developmental problems are common and should be addressed as part of a comprehensive assessment of such children.

Activities of Daily Living↗