Comparison of perometry-based volumetric arm measurements and bioimpedance spectroscopy for early identification of lymphedema in a prospectively-screened cohort of breast cancer patients.

Breast cancer-related lymphedema (BCRL) affects more than one in five women treated for breast cancer, and women remain at lifelong risk. Screening for BCRL is recommended by several national and international organizations for women at risk of BCRL, and multiple methods of objective screening measurement exist. The goal of this study was to compare the use of perometry and bioimpedance spectroscopy (BIS) for early identification of BCRL in a cohort of 138 prospectivelyscreened patients. At each screening visit, a patient's relative volume change (RVC) from perometer measurements and change in L-Dex from baseline (ΔL-Dex) using BIS was calculated. There was a negligible correlation between RVC and ΔL-Dex (r=0.195). Multiple thresholds of BCRL were examined: RVC ≥5% and ≥10% as well as and ΔL-Dex ≥6.5 and ≥10. While some patients developed an elevated RVC and ΔL-Dex, many demonstrated elevations in only one threshold category. Moreover, the majority of patients with RVC ≥5%, ΔL-Dex ≥6.5, or ΔL-Dex ≥10 regressed to non-elevated measurements without intervention. These findings suggest a role for combining multiple screening methods for early identification of BCRL; furthermore, BCRL diagnosis must incorporate patient symptoms and clinical evaluation with objective measurements obtained from techniques such as perometry and bioimpedance spectroscopy.

"Prostate cancer is far more hidden ": Perceptions of stigma, social isolation and help-seeking among men with prostate cancer.

The purpose of this study was to provide in-depth insight into men's experiences of prostate cancer, specifically: perceived stigma and self-blame, social isolation, unmet need and help-seeking. A qualitative descriptive approach was used. Semi-structured interviews were undertaken with 20 men diagnosed with prostate cancer, and thematic analysis was undertaken. Some participants perceived a stigma associated with prostate cancer and cancer in general, which sometimes acted as a barrier to disclosure. Self-blame and internalisation of cause was not a prominent issue. Participants' descriptions of emotional distress, social isolation and anxiety demonstrated the impact of prostate cancer. Social isolation was most commonly reported as a physical consequence of treatment and/or side effects. Participants felt both support and ongoing care were limited at post-treatment. Most did not seek or receive help for emotional or psychosocial problems from a formal source due to anticipated awkwardness, autonomous coping, not burdening others, unwanted sympathy and retaining privacy. Prostate cancer can cause considerable emotional and social burden for some men, and many are unlikely to seek or receive help. Men, and their support networks, require active encouragement throughout diagnosis, treatment and follow-up to overcome barriers and access additional support, particularly for sexual, emotional and psychosocial issues.

Coronary Artery Disease Associated Transcription Factor TCF21 Regulates Smooth Muscle Precursor Cells that Contribute to the Fibrous Cap.

TCF21 is a basic helix-loop-helix transcription factor that has recently been implicated as contributing to susceptibility to coronary heart disease based on genome wide association studies. In order to identify transcriptionally regulated target genes in a major disease relevant cell type, we performed siRNA knockdown of TCF21 in in vitro cultured human coronary artery smooth muscle cells and compared the transcriptome of siTCF21 versus siCONTROL treated cells. The raw (FASTQ) as well as processed (BED) data from 3 technical replicates per treatment has been deposited with Gene Expression Omnibus (GSE44461).

A novel, validated method to quantify breast cancer-related lymphedema (BCRL) following bilateral breast surgery.

We sought to develop a formula to quantify breast cancer-related lymphedema (BCRL) after bilateral breast surgery, which functions independently of the contralateral arm and accounts for fluctuations in patient weight. Perometer arm measurements from 265 unilateral breast surgery patients were analyzed. We assessed the relationship between change in patient weight and contralateral arm volume and developed a weight-adjusted volume change formula (WAC). The WAC formula and previously-established RVC formula were compared for classification of BCRL (> or = 10% volume increase) in unilateral breast surgery patients. We then evaluated BCRL incidence using the WAC formula in 225 bilateral mastectomy patients. Change in patient weight and contralateral arm volume demonstrated an approximately linear relationship. Weight-adjusted arm volume change (WAC) was therefore calculated as WAC = (A2*W1)/(W2*A1) - 1 where A1 is pre-operative and A2 is post-operative arm volume, and W1, W2 are the patient's corresponding weights. In the unilateral analysis, there was no significant difference in number of patients classified as having BCRL using the RVC and WAC formulas (p = 0.65). In bilateral mastectomy patients 11.1% (25/225) developed BCRL, defined as > or = 10% WAC. Independent risk factors for lymphedema included axillary lymph node dissection (ALND) and higher pre-operative BMI (p<0.05). Use of this weight-adjusted arm volume change formula should be of value for quantification of BCRL after bilateral breast surgery.

The evolving role of HER2 evaluation for diagnosis and clinical decision making for breast and gastric adenocarcinoma.

Clinical laboratory testing for human epidermal growth factor receptor-2 (HER2) in patients with newly diagnosed breast and gastric cancer is critically important for therapeutic decisions about adjuvant treatment. The HER2 pathway is a major molecular driver of disease progression in a subset of these solid tumors and the results of HER2 testing determine which patients are likely to respond to an expanding variety of therapies that target this important biologic pathway. Given the significant clinical impact of these test results on patient management and adjuvant treatment decisions, standardization of the assay for HER2 and assured reliability of these results are critical. We review highlights of the clinical rationale that underlies HER2 testing for both breast and gastric carcinomas, and describe some of the challenges associated with ensuring accurate test results.

Expression of nogo-a is decreased with increasing gestational age in the human fetal brain.

Nogo is a member of the reticulon family. Our understanding of the physiological functions of the Nogo-A protein has grown over the last few years, and this molecule is now recognized as one of the most important axonal regrowth inhibitors present in central nervous system (CNS) myelin. Nogo-A plays other important roles in nervous system development, epilepsy, vascular physiology, muscle pathology, stroke, inflammation, and CNS tumors. Since the exact role of Nogo-A protein in human brain development is still poorly understood, we studied its cellular and regional distribution by immunohistochemistry in the frontal lobe of 30 human fetal brains. Nogo-A was expressed in the following cortical zones: ependyma, ventricular zone, subventricular zone, intermediate zone, subplate, cortical plate, and marginal zone. The number of positive cells decreased significantly with increasing gestational age in the subplate and marginal zone. Using different antibodies, changes in isoform expression and dimerization states could be shown between various cortical zones. The results demonstrate a significant change in the expression of Nogo-A during the development of the human brain. The effects of its time- and region-specific regulation have to be further studied in detail.

HER2 testing in gastric and esophageal adenocarcinoma: new diagnostic challenges arising from new therapeutic options.

Adenocarcinomas of the esophagus and stomach constitute a substantial number of cancer cases worldwide. Most patients in the United States are diagnosed at an advanced or metastatic stage and, therefore, the prognoses have been poor. New treatments are needed to augment standard surgical and medical management. Recent studies have shown that a subset of esophageal and gastric adenocarcinomas overexpress the HER2 protein, similar to the overexpression seen in breast cancer. Because trastuzumab, a monoclonal antibody to the HER2 receptor, has been used with success in primary and HER2 positive metastatic breast cancers, the phase III ToGA trial was designed to assess the impact of trastuzumab in patients with HER2 positive gastric cancers. They have reported an increase in overall survival time for patients treated with chemotherapy and trastuzumab compared to those treated with chemotherapy alone. They have reported an increase in overall survival time for patients treated with chemotherapy and trastuzumab compared to those treated with chemotherapy alone. This means that accurate HER2 testing in gastric and esophageal carcinomas is necessary. While the breast cancer scoring system can be used to determine HER2 status in most cases, modifications are necessary to accommodate the heterogeneity and incomplete membrane staining that are observed more frequently in gastric cancers. An understanding of the scoring modifications is required for proper stratification of gastric cancer patients for treatment.

Impact on the Australian Quitline of new graphic cigarette pack warnings including the Quitline number.

BACKGROUND: In March 2006, Australia introduced graphic pictorial warnings on cigarette packets. For the first time, packs include the Quitline number. OBJECTIVE: To measure the combined effect of graphic cigarette pack warnings and printing the Quitline number on packs on calls to the Australian Quitline service. METHODS: Calls to the Australian Quitline were monitored over 4 years, 2 years before and after the new packets were introduced. RESULTS: There were twice as many calls to the Quitline in 2006 (the year of introduction), as there were in each of the preceding 2 years. The observed increase in calls exceeds that explained by the accompanying television advertising alone. While call volume tapered back in 2007, it remained at a level higher than before the introduction of new packets. No change was observed in the proportion of first time callers. CONCLUSION: Introducing graphic cigarette packet warnings and the Quitline number on cigarette packets boosts demand for Quitline services, with likely flow on effects to cessation.

Using a quitline plus low-cost nicotine replacement therapy to help disadvantaged smokers to quit.

OBJECTIVES: To trial an intervention in a real-life setting to motivate low-income smokers to try to quit. The intervention under trial was the addition of subsidised nicotine replacement therapy (NRT) to a standard population quitline service. DESIGN: Participants were low-income smokers, recruited "cold" via either a letter in the mail or a flyer inserted in a local newspaper. The intervention group received the usual service of multisession counselling from the quitline plus access to heavily subsidised NRT. A comparison group received the usual quitline service only. Participants were followed up at 3, 6, and 12 months. Trial participants were also compared with a sample of general callers to the quitline. RESULTS: The offer of subsidised NRT recruited more than twice as many low-income smokers than the offer of the cessation service alone (intervention group n = 1000; comparison group n = 377). 63% were first-time callers to the quitline. Intervention respondents showed higher levels of nicotine dependence than comparison group respondents. Comparisons of quitting data were confounded by the differences in the respondents at baseline. 73.5% of smokers in the intervention group tried to quit compared to 61.0% in the comparison group. Unadjusted quit rates were higher in the intervention group than in the comparison group at 3 months and 6 months but not at 12 months. CONCLUSIONS: Disadvantaged smokers were easily engaged to call the quitline, particularly when offered subsidised NRT. Disadvantaged smokers using the quitline, with and without subsidised NRT, achieved cessation outcomes comparable to other studies of "mainstream" smokers.

Quality control for microarray analysis of human brain samples: The impact of postmortem factors, RNA characteristics, and histopathology.

The quality of results from microarray studies depends on RNA quality, which can be significantly influenced by postmortem factors. The aim of this study was to determine which postmortem factors and/or RNA electropherogram characteristics best correspond to microarray output and can be used to prospectively screen RNA prior to microarray analysis. Total RNA was extracted (N=125) from gray and white matter of postmortem frontal and occipital lobe tissue, acquired from normal controls, and patients with schizophrenia, bipolar disorder or major depression. Electropherograms were generated by the Agilent BioAnalyzer 2100, allowing calculation of the 28S/18S ratio, the 18S/baseline peak ratio and the RNA Integrity Number (RIN). These values were compared to post-hybridization image analysis of Affymetrix microarrays. The postmortem variables correlated with some quality measures but could not be used as effective screening tools. Logistic regression demonstrated that all three electropherogram measures were predictive for microarray quality, and that the RIN threshold predictive of "good quality" (>35% present calls) was most consistent with that of prior studies. The optimal RIN must be determined by the investigator's specifications for false inclusion and false exclusion. In contrast to RIN, the quality threshold for the 28S/18S ratio has proven unacceptably variable, due to sensitivity to slight differences in protocol and/or tissue source. In conclusion, the measures we found useful as screening criteria do not replace the need to exclude samples after a microarray analysis is performed, as an acceptable percent call rate and other measures of microarray quality represent the desired endpoint.

Inadequacies in antiretroviral therapy use among Aboriginal and other Canadian populations.

We undertook this study to provide a profile of Aboriginal people initiating antiretroviral therapy and their response to treatment. Aboriginal peoples were identified through self-report. Baseline socio-demographics and risk factors were compared between Aboriginal and non-Aboriginal participants as were baseline factors associated with two consecutive plasma viral load measures below 500 copies/ml using contingency table analysis. Multivariate survival analysis of the prognostic factors associated with time to two consecutive plasma viral load measures below 500 copies/ml among eligible participants was undertaken to characterize response to antiretroviral therapy. There were 892 participants with available data for this analysis, of those 146 (16%) self-identified as Aboriginal. Aboriginal participants were more likely to be female (p < or = 0.001), have lower baseline plasma viral loads (p = 0.010), be co-infected with HCV (p < 0.001), live in unstable housing (p < or = 0.001), and report an income of >10K CDN (p < or = 0.001) per annum. Aboriginal people were less likely to report men who have sex with men (p < or = 0.001) and more likely to report injection drug use (p < or = 0.001) as a risk factor for HIV infection. Aboriginal participants were more likely to receive double versus triple combination antiretroviral therapy (p = 0.002), be less adherent in the first year on therapy (p = 0.001) and to have a physician less experienced with treating HIV (p < or = 0.001). When these factors were controlled for, Aboriginal people treated with triple combination therapy were as likely to respond and suppress their viral load below 500 copies. In the era of HAART, our results indicate that Aboriginal people living with HIV/AIDS were less likely to receive optimal therapy. However, when Aboriginals did receive triple drug therapy they suppressed just as well as non-Aboriginals.

Effect of H-7 and Lat-B on retinal physiology.

PURPOSE: To investigate the effects of H-7 and Latrunculin B (Lat-B) on retinal vascular permeability and electrophysiology at concentrations that increase outflow facility in monkeys. METHODS: One eye of 1 rhesus and 22 cynomolgus monkeys received an intravitreal bolus injection of H-7 or Lat-B; the opposite eye received vehicle. Multifocal electroretinograms (mfERGs), and photopic and scotopic full-field electroretinograms (ffERGs, sERGs) were recorded in subsets of monkeys at baseline and at multiple time-points post-H-7 or Lat-B. Vitreous fluorophotometry (VF) and fluorescein angiography (FA) were also performed. RESULTS: No differences between the H-7 or Lat-B treated and control eyes were found in ffERGs, mfERGs, sERGs, or in FAs in any monkey. No significant difference was found in vitreous fluorescein levels between H-7 treated or Lat-B treated vs. control eyes. CONCLUSIONS: No effect on retinal vascular permeability or retinal electrophysiology was apparent after intravitreal administration of H-7 or Lat-B at doses that increase outflow facility and lower IOP when given intracamerally.

Uptake and effectiveness of the Australian telephone Quitline service in the context of a mass media campaign.

OBJECTIVES: Since June 1997, Australia has run its first nationally coordinated mass media anti-smoking campaign, with all States collaborating to offer a standard Quitline service. An overview of the Australian national Quitline service is presented as well as two studies describing (a) the relationship between television advertising and call volume and type, and (b) the quit rates of callers over time. DESIGN: Data on extent of advertising, as measured by weekly television target audience rating points (TARPs), is compared with weekly call volume and disposition. A randomly selected sample of callers was followed up at 3 weeks, 6 months and 12 months to assess caller appraisal and quit rates. SETTING: The Australian Quitline service, in the context of a nationally coordinated, major anti tobacco campaign. RESULTS: In a one year period from June 1997, 3.6% of adult Australian smokers called the Quitline. Weekly call volume was strongly related to TARPs and increased further when an advertisement specifically promoting the Quitline was broadcast. Calls involving requests for counselling, as opposed to brief calls to request quit materials, were more likely with lower TARPs. Of the cohort who were smoking at baseline, 28% reported they had quit smoking at a one year follow up and 5% had been quit for an entire year. CONCLUSIONS: In the context of a national mass media campaign, this study illustrates that it is possible to bring together differing State based services to provide an accessible, acceptable, and effective quit smoking service.

The NS2 protein generated by the parvovirus minute virus of mice is degraded by the proteasome in a manner independent of ubiquitin chain elongation or activation.

The NS2 protein generated by the parvovirus minute virus of mice is very labile, having a half-life during infection of approximately 90 min. The degradation of NS2 is blocked by proteasome inhibitors but is likely ubiquitin independent: NS2 does not form detectable higher molecular weight ubiquitin-containing conjugates, and NS2 degradation requires neither ubiquitin chain elongation nor intracellular ubiquitin activation. We have also identified a region in the carboxyl half of NS2 that is required for its proteasome-mediated degradation.

Distinct role of gp130 activation in promoting self-renewal divisions by mitogenically stimulated murine hematopoietic stem cells.

Previous studies have demonstrated hematopoietic stem cell amplification in vitro after the activation of three cell-surface receptors: flt3/flk2, c-kit, and gp130. We now show flt3-ligand and Steel factor alone will stimulate >85% of c-kit(+)Sca-1(+)lin(-) adult mouse bone marrow cells to proliferate in single-cell serum-free cultures, but concomitant retention of their stem cell activity requires additional exposure to a ligand that will activate gp130. Moreover, this response is restricted to a narrow range of gp130-activating ligand concentrations, above and below which hematopoietic stem cell activity is lost. These findings indicate a unique contribution of gp130 signaling to the maintenance of hematopoietic stem cell function when these cells are stimulated to divide with additional differential effects dictated by the intensity of gp130 activation.

Signaling induced by erythropoietin and stem cell factor in UT-7/Epo cells: transient versus sustained proliferation.

UT-7/Epo cells are human factor-dependent erythroleukemic cells, requiring erythropoietin (Epo) for long-term growth. Stem cell factor (SCF) stimulates proliferation of UT-7/Epo only transiently, for three to five days. An investigation of the signal transduction pathways activated by these cytokines in UT-7/Epo cells may identify those signals specifically required for sustained growth. Proliferation assays demonstrate that SCF generates a substantial growth response in UT-7/Epo cells; however, the cells do not multiply or survive past five to seven days. While Epo induces the activation of JAK2 and STAT5, SCF stimulation shows no activation of JAK2 or STATs 1, 3, or 5. The activation of MAPK (p42/44) by SCF was transient, lasting only 30 min, in contrast to Epo, which stimulated phosphorylation of p42/44 for up to 2 h. The expression of the early response genes c-fos, egr1, and cytokine-inducible SH2 protein (CIS) in response to SCF or Epo stimulation demonstrated that the transient expression of p42/44 correlated with the transient expression of c-fos and egr1. In addition, CIS was activated by Epo but not SCF. These data indicate that EpoR, JAK2, and STAT5 activation are not required for the initiation of proliferation of these erythroid cells, that the transient activation of p42/44 correlates with the transient gene expression of c-fos and egr1, and sustained expression of c-fos and egr1 as seen in UT-7/Epo cells continuously grown in Epo may be necessary for long-term proliferation.

Successful treatment of oral squamous cell carcinoma with intralesional fluorouracil in a Malayan tapir (Tapirus indicus).

An oral mass was observed in a Malayan tapir (Tapirus indicus). Squamous cell carcinoma was diagnosed by histologic examination of a biopsy specimen. A series of intralesional injections using fluorouracil resulted in complete regression of the neoplasm with no recognized adverse effects.

Cue sensitivity in women with cardiac disease.

The purpose of this study was to discover factors that influenced the healthcare seeking behavior of women cardiac patients. Interviews included 10 women with cardiac disease, two women at risk for cardiac disease, three advanced nurse practitioners, and one cardiologist. Participants were interviewed on two occasions. Taped transcripts were reviewed using a grounded theory approach. Analysis revealed a core process of cardiac cue sensitivity that originated in the period prior to entry into the healthcare system. The stages of this process included: cue apprehension, cue assimilation, and medical consultation. Cues were signs, symptoms, or self risk appraisal. Decisions to discount or attend to cues was dependent on the nature, intensity, and specificity of the cue to cardiac disease as well as the woman's knowledge and experience with cardiac disease and validation with others. A sensitivity to the subjective cue experiences of women and a recognition of public attitudes regarding women and cardiac disease facilitates their entry into the healthcare system and improves outcomes for women with cardiac disease.