Arterial Stiffness in a Cohort of Young People Living With Perinatal HIV and HIV Negative Young People in England.

Background: Antiretroviral therapy (ART) has increased life expectancy and consequently the risk of cardiovascular disease (CVD) in adults living with HIV. We investigated the levels and predictors of arterial stiffness in young people (YP) living with perinatal HIV (PHIV) and HIV negative YP in the Adolescents and Adults Living with Perinatal HIV (AALPHI) study. Methods: AALPHI was a prospective study evaluating the impact of HIV infection and exposure to ART on YP living with PHIV (aged 13-21 years) who had known their HIV status for at least 6 months, and HIV negative YP (aged 13-23 years) who either had a sibling, friend or parent living with HIV. Participants were enrolled from HIV clinics and community services in England. Two hundred and thirteen PHIV and 65 HIV negative YP (42% siblings of PHIV) had pulse wave velocity (PWV) measurements taken (Vicorder software) from the supra-sternal notch to the middle of the thigh cuff, at their second interview in the study between 2015 and 2017. Average PWV was calculated from the three closest readings (≥3 and ≤ 12 m/s) within 0.6 m/s of each other. Linear regression examined predictors of higher (worse) PWV, including age, sex, HIV status and height as a priori, ethnicity, born outside UK/Ireland, alcohol/nicotine/drug use, weight, waist-to-hip-ratio, mean arterial pressure (MAP), caffeine 2 h before PWV and nicotine on day of PWV. A separate PHIV model included CD4, viral load, years taking ART and ART regimen. Findings: One hundred and twenty eight (60%) PHIV and 45 (69%) HIV negative YP were female (p = 0.18), with median (IQR) age 18 (16, 20) and 18 (16, 21) years (p = 0.48) respectively. Most PHIV were taking a combination of three ART drugs from two classes. There was a trend toward higher (worse) mean PWV in the PHIV group than the HIV negative group [unvariable analysis 6.15 (SD 0.83) m/s vs. 5.93 (0.70) m/s, respectively, unadjusted p = 0.058], which was statistically significant in the multivariable analysis [adjusted p (ap) = 0.020]. In multivariable analysis being male (ap = 0.002), older age (ap < 0.001), higher MAP (ap < 0.001) and nicotine use on day of measurement (ap = 0.001) were also predictors of higher PWV. The predictors were the same in the PHIV model. Interpretation: By late adolescence PHIV had worse PWV in comparison to HIV negative peers, and traditional risk factors for CVD (higher arterial pressure, being male and older age) were associated with higher PWV values. Regular detailed monitoring of cardiovascular risk factors should become standard of care for every young person with PHIV worldwide.

Acute intravenous exposure to silver nanoparticles during pregnancy induces particle size and vehicle dependent changes in vascular tissue contractility in Sprague Dawley rats.

The use of silver nanoparticles (AgNP) raises safety concerns during susceptible life stages such as pregnancy. We hypothesized that acute intravenous exposure to AgNP during late stages of pregnancy will increase vascular tissue contractility, potentially contributing to alterations in fetal growth. Sprague Dawley rats were exposed to a single dose of PVP or Citrate stabilized 20 or 110nm AgNP (700µg/kg). Differential vascular responses and EC50 values were observed in myographic studies in uterine, mesenteric arteries and thoracic aortic segments, 24h post-exposure. Reciprocal responses were observed in aortic and uterine vessels following PVP stabilized AgNP with an increased force of contraction in uterine artery and increased relaxation responses in aorta. Citrate stabilized AgNP exposure increased contractile force in both uterine and aortic vessels. Intravenous AgNP exposure during pregnancy displayed particle size and vehicle dependent moderate changes in vascular tissue contractility, potentially influencing fetal blood supply.

Vascular Tissue Contractility Changes Following Late Gestational Exposure to Multi-Walled Carbon Nanotubes or their Dispersing Vehicle in Sprague Dawley Rats.

Multi-walled carbon nanotubes (MWCNTs) are increasingly used in industry and in nanomedicine raising safety concerns, especially during unique life-stages such as pregnancy. We hypothesized that MWCNT exposure during pregnancy will increase vascular tissue contractile responses by increasing Rho kinase signaling. Pregnant (17-19 gestational days) and non-pregnant Sprague Dawley rats were exposed to 100 µg/kg of MWCNTs by intratracheal instillation or intravenous administration. Vasoactive responses of uterine, mesenteric, aortic and umbilical vessels were studied 24 hours post-exposure by wire myography. The contractile responses of the vessel segments were different between the pregnant and non-pregnant rats, following MWCNT exposure. Maximum stress generation in the uterine artery segments from the pregnant rats following pulmonary MWCNT exposure was increased in response to angiotensin II by 4.9 mN/mm2 (+118%), as compared to the naïve response and by 2.6 mN/mm2 (+40.7%) as compared to the vehicle exposed group. Following MWCNT exposure, serotonin induced approximately 4 mN/mm2 increase in stress generation of the mesenteric artery from both pregnant and non-pregnant rats as compared to the vehicle response. A significant contribution of the dispersion medium was identified as inducing changes in the contractile properties following both pulmonary and intravenous exposure to MWCNTs. Wire myographic studies in the presence of a Rho kinase inhibitor and RhoA and Rho kinase mRNA/protein expression of rat aortic endothelial cells were unaltered following exposure to MWCNTs, suggesting absent/minimal contribution of Rho kinase to the enhanced contractile responses following MWCNT exposure. The reactivity of the umbilical vein was not changed; however, mean fetal weight gain was reduced with dispersion media and MWCNT exposure by both routes. These results suggest a susceptibility of the vasculature during gestation to MWCNT and their dispersion media-induced vasoconstriction, predisposing reduced fetal growth during pregnancy.

Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials.

BACKGROUND: REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma. PATIENTS AND METHODS: Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect. RESULTS: RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival. CONCLUSIONS: The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.

Bevacizumab with peri-operative epirubicin, cisplatin and capecitabine (ECX) in localised gastro-oesophageal adenocarcinoma: a safety report.

BACKGROUND: Peri-operative chemotherapy and surgery is a standard treatment of localised oesophagogastric adenocarcinoma; however, the outcomes remain poor. PATIENTS AND METHODS: ST03 is a multicentre, randomised, phase II/III study comparing peri-operative ECX with or without bevacizumab (ECX-B). The primary outcome measure of phase II (n = 200) was safety, specifically gastrointestinal (GI) perforation rates and cardiotoxicity. RESULTS: Two hundred patients were randomised between October 2007 and April 2010. Ninety-one/101 (90%) ECX and 86/99 (87%) ECX-B patients completed pre-operative chemotherapy; 7 ECX and 9 ECX-B patients stopped due to toxicity. Gastrointestinal perforations (3 ECX, 1 ECX-B), cardiac events (1 ECX, 4 ECX-B) and venous thromboembolic events (VTEs, 8 ECX, 7 ECX-B) were uncommon. Arterial thromboembolic events (ATEs, myocardial infarction (MI) or cerebrovascular accident) were more frequent with ECX-B (5 versus 1 with ECX). Delayed wound healing, anastomotic leaks and GI bleeding rates were similar. More asymptomatic left ventricular ejection fraction (LVEF) falls (≥15% and/or to <50%) occurred with ECX-B (21.2% versus 11.1% with ECX). Clinically significant falls (≥10% to below lower limit of normal, LLN) occurred in (15.3%) and (8.9%) respectively, with no associated cardiac failure (median 22 months follow-up). CONCLUSIONS: Addition of bevacizumab to peri-operative ECX chemotherapy is feasible with acceptable toxicity and no negative impact on surgical outcomes.

Effect of HER2 on prognosis and benefit from peri-operative chemotherapy in early oesophago-gastric adenocarcinoma in the MAGIC trial.

BACKGROUND: Perioperative epirubicin, cisplatin and fluorouracil (ECF) chemotherapy improves survival in operable oesophago-gastric cancer [Adjuvant Gastric Cancer Infusional Chemotherapy (MAGIC) trial HR 0.75 (0.6-0.93)]. HER2 amplification is reported to predict enhanced benefit from anthracyclines in breast cancer. We sought to define whether HER2 predicts benefit from ECF in oesophago-gastric cancer. PATIENTS AND METHODS: Diagnostic biopsies and/or resection specimens were collected from 415 of 503 MAGIC trial patients (82.5%). HER2 was evaluated by immunohistochemistry (IHC) and brightfield dual in situ hybridisation (BDISH) in tissue microarrays. The prognostic and predictive impact of HER2 status was investigated. RESULTS: Concordance between HER2 over-expression (IHC3+) and amplification was 96%. Results of HER2 assessment in biopsy and resection specimens were concordant in 92.9% (145/156). HER2 positive rate (IHC3+, or IHC2+/BDISH positive) was 10.9% in the whole cohort and 10.4% in resection specimens. A further 4.0% of resections were IHC negative/BDISH positive. HER2 status was neither prognostic, nor (in pre-treatment biopsies) predicted enhanced benefit from chemotherapy [HER2 positive HR 0.74 (0.14-3.77); HER2 negative HR 0.58 (0.41-0.82), interaction P = 0.7]. However, the power of the predictive analysis was limited by the small number of HER2 positive pre-treatment biopsies. CONCLUSIONS: HER2 status is not an independent prognostic biomarker in early oesophago-gastric adenocarcinoma.

Chemotherapy dose reductions in obese patients with colorectal cancer.

BACKGROUND: In cancer patients with a large Body Surface Area, chemotherapy drug doses are often reduced, as studies have suggested that their pharmacokinetics may be altered. However, this strategy may result in underdosing obese patients. PATIENTS AND METHODS: In three Medical Research Council trials of chemotherapy for advanced colorectal cancer, dose reductions were not mandated. This provided the opportunity to compare the toxicity levels in those obese patients fully dosed and to investigate if those under dosed experienced a worse survival. Body Mass Index (BMI) was used to classify patients as normal weight (BMI < 25), overweight (BMI 25-29), or obese (BMI 30+). RESULTS: Of the 4781 patients, 2158 (45%) were classified as normal weight, 1753 (37%) as overweight, and 870 (18%) as obese. There was no evidence that, in those patients fully dosed, obese patients experienced more toxicity or that dose-reducing obese patients resulted in less toxicity. However, there was a suggestion that those obese patients who were given reduced doses had a worse progression-free survival [hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.06-1.39, P = 0.006] and a slightly worse overall survival (HR 1.12, 95% CI 0.96-1.30, P = 0.152). CONCLUSION: These results, although not a randomised comparison, do not support the policy of reducing chemotherapy doses for obese patients with colorectal cancer.

A Randomized Controlled Trial of Metronidazole Vaginal Cream in the Treatment of Papanicolaou Smears Showing Atypical Squamous Cells of Undetermined Significance (ASCUS).

OBJECTIVE: To compare topical metronidazole gel vs. placebo to assess resolution to normal in subsequent Pap smears of patients with ASCUS. MATERIALS AND METHODS: Patients with ASCUS pap smears were randomized to metronidazole or placebo. Resolution of ASCUS vs. persistence, or progression, was the endpoint. A subanalysis stratified patients for bacterial vaginosis (BV) to determine if this population responded differently. Discrete variables were compared using chi-square analysis. RESULTS: Forty-nine patients received metronidazole and 52 received placebo. The rate of resolution in the placebo group were 60%, and 67% in the metronidazole group. With BV, the rate of resolution in the placebo group was 67%, and 70% in the metronidazole group. These were not significantly different. CONCLUSIONS: Treatment of ASCUS Pap smears using topical metronidazole did not demonstrate a significant increase in the rate of resolution in subsequent Pap smears in the overall group nor in a subgroup with BV.

Localization of telomerase hTERT protein and hTR in benign mucosa, dysplasia, and squamous cell carcinoma of the cervix.

Telomerase has been detected by telomerase repeat amplification protocol (TRAP) assay in cervical dysplasia and squamous cell carcinoma but not in most normal cervical tissues. In the present study, the cellular localization of the protein catalytic subunit of telomerase (hTERT) and the RNA component (hTR) were investigated by a sensitive immunohistochemical technique and by in situ hybridization, respectively. hTERT protein was detected in all diagnostic categories of cervical specimens. hTERT was localized predominantly to the lower suprabasal levels of normal squamous mucosa but was detected throughout virtually all levels of the lesional epithelium in low-grade squamous intraepithelial lesions (LSILs), high-grade squamous intraepithelial lesions (HSILs), and squamous cell carcinoma (SCC). Telomerase expression correlated with hTERT detection in SCC and HSIL but was not detected by TRAP assay in most samples of normal mucosa or LSIL. The distribution of hTR correlated with the localization of hTERT in HSIL and SCC but was restricted to the basal and suprabasal cell layers in normal mucosa and LSIL.

Health-related quality of life in Australian men remaining disease-free after radical prostatectomy.

OBJECTIVE: To determine the health-related quality of life (HRQOL) of Australian men after radical prostatectomy. DESIGN: Cross-sectional study. SETTING: Private and public practices of three urologists in south-east Queensland, July 1989 to June 1995. PARTICIPANTS: 140 men with no evidence of disease recurrence 1 to 6 years after radical prostatectomy. MAIN OUTCOME MEASURES: Voiding and erectile potency and HRQOL. Recall of preoperative status and status at survey were established by an independently administered multi-item questionnaire. RESULTS: 112 men (80%) completed the study questionnaire. Difficulty with bladder control before the operation was reported by 25 (22%; 95% confidence interval [CI], 15%-31.2%), and the incontinence rate after treatment was 22/112 (20%; 95% CI, 12.7%-28.2%). Men with incontinence after operation were more likely to recall preoperative urinary symptoms. Eighty-four (75%) men were happy or coping with their sexual function after radical prostatectomy despite an erectile potency rate of only 12% (95% CI, 7%-20%). Twenty-eight (25%) had tried penile injections and three have had penile prostheses since their operation. Impotence was reported more frequently (40%) as the treatment-related problem most affecting life, followed by "concern about cancer" (12%) and incontinence (8%). Impotence was also the most common cause given for diminished HRQOL. CONCLUSIONS: Loss of sexual function after radical prostatectomy is more commonly perceived as a major problem and is more likely than urinary incontinence to adversely affect HRQOL. Loss of sexual function and its effect on HRQOL needs to be given greater emphasis in counselling before radical prostatectomy.

Telomerase expression in normal epithelium, reactive atypia, squamous dysplasia, and squamous cell carcinoma of the uterine cervix.

Telomerase activity has been detected in a broad range of human malignant neoplasms, and its expression may represent an essential step in the malignant transformation of tissues; however, the expression of telomerase in premalignant lesions remains relatively unexplored. We tested tissue sections of cervical squamous cell carcinomas and squamous intraepithelial lesions, samples of benign reactive atypia, and normal cervical mucosa from hysterectomy and cone biopsy specimens for the expression of telomerase. Mirror-image sections from each sample were paraffin embedded and processed for histologic analysis. The test samples of cervical tissue were crushed under liquid nitrogen, and telomerase activity was determined by the telomeric repeat amplification protocol. Telomerase activity was detected in 18 of 18 cases (100%) of invasive squamous cell carcinoma. Twenty-five of 26 samples (96%) of high-grade squamous intraepithelial lesion also tested positively for telomerase activity, including 10 of 10 samples of moderate dysplasia, 12 of 13 samples of severe dysplasia, and 3 of 3 samples of carcinoma in situ. Telomerase activity was detected in 14 of 25 samples (56%) of low-grade squamous intraepithelial lesion and in 10 of 18 samples (56%) of reactive atypia but was detected in only 9 of 50 samples (18%) of histologically normal cervical mucosa. These results suggest that telomerase expression may be a marker of premalignant and malignant squamous cell lesions of the uterine cervix, although it is also expressed in a high proportion of cases of reactive atypia.

Captopril inhibits tumour growth in a xenograft model of human renal cell carcinoma.

The effect of captopril on tumour growth was examined in a xenograft model of human renal cell carcinoma (RCC). Inoculation of the human RCC cell line SN12K-1 (10(6) cells) under the left kidney capsule of severe combined immunodeficient (SCID) mice resulted in the growth of large tumours, with an increase in weight of the inoculated kidney of 3.69+/-1.63-fold (mean+/-s.d.) when compared with the contralateral normal kidney. In mice treated with captopril (19 mg kg(-1) day(-1) or 94 mg kg(-1) day(-1) administered in the drinking water), there was a significant dose-related reduction in tumour development; the tumour bearing kidneys weighed 1.9+/-0.42 and 1.55+/-0.42 times the normal kidneys, respectively (P< 0.05 compared with untreated animals). In vitro, captopril at clinically achievable doses (0.1-10 microM) had no significant effect on the incorporation of [3H]thymidine into SN12K-1 cells. Thus, this highly significant attenuation by captopril of in vivo tumour growth does not appear to be due to a direct effect on the proliferation of the tumour cells. Further studies are required to determine the mechanism of inhibition of tumour growth by captopril, in particular to evaluate the role of angiotensin II in this process.

Moving health care education into the community.

The A+ Asthma Club, an educational program developed for elementary school children in inner-city schools, is offered through a series of six sessions during school hours with an additional three booster sessions. This article describes how the program was designed, its theoretical basis, the curriculum and its staffing.

Maintaining competent practice: information settings for the gastroenterology nurse.

Professional standards of practice for the gastroenterology nurse address the nurse's need to maintain and enhance professional competency through knowledge acquisition. With the rapidly increasing knowledge base in the nursing profession, it is increasingly important for the nurse to "keep current." In this article, the authors present information settings that assist the gastroenterology nurse in information retrieval and management.

Home environmental risk factors in urban minority asthmatic children.

Urban minority families with children with asthma often live in homes with allergen and irritant exposures harmful to these children. We enrolled 392 African-American asthmatic children, male and female, aged 5 to 12, from 42 schools in Washington, DC and Baltimore, MD. The project is designed to test the effectiveness of school-based asthma education interventions, community-based asthma health workers' programs, and the combination on these children. Baseline telephone interviews were carried out with the primary home care-givers for demographic data and for environmental home exposures that exacerbated asthma. Exposures stated to cause wheezing in the children were cigarette smoke in 72%, dust in 53%, cats in 34%, dogs in 27%, and roach exposure in 15%. Fifty-six percent of children live with cigarette smoke exposure, 73% of which is from mothers. This was a highly symptomatic group with 44% reporting two or more days per week of restricted activity and 62% reporting two or more episodes of night symptoms per week. Those with mattress covers on beds had significantly fewer emergency department visits in the past 6 months than those without covers. Over one-third of parents reported children taking two bronchodilators without anti-inflammatory agents. Less than 20% were reported using anti-inflammatory medications. Decreasing asthma severity in this population entails the prevention and control of known risk factors in the home environment. Emphasis must be placed on cigarette smoking cessation programs, covering mattresses, and dust and animal dander control. Primary care physicians require education on the role of anti-inflammatory medications.

Sarcomatoid carcinoma of the urinary bladder.

Sarcomatoid carcinoma of the urinary bladder is a rare malignancy of an aggressive nature usually seen in patients in the seventh to eighth decade of life. A case of sarcomatoid carcinoma of the bladder in a 37 year old male presenting with gross haematuria is reported. A potency-preserving radical cystoprostatectomy with ileal conduit was performed.

Two peaks of interleukin 1 expression in human leukocytes cultured with tobacco glycoprotein.

We have previously shown that tobacco glycoprotein (TGP), a polyphenol-rich glycoprotein isolated from tobacco or from cigarette smoke, affects the immune system. In this study we show that TGP induces human PBL and adherent cells to produce IL-1 alpha and IL-1 beta. Two peaks of IL-1 activity were observed; one at 18-24 h, the second at 4-6 d after initiation of culture. A similar pattern was observed for the steady state level of IL-1 mRNA. These data suggest that the production of IL-1 by cells stimulated with TGP might be a factor in cardiovascular disease associated with cigarette smoking.