Effect of radon exposure on asthma morbidity in the School Inner-City Asthma study.

BACKGROUND: Radon may have a role in obstructive lung disease outside its known carcinogenicity. Little is known about radon's effects on asthma morbidity. OBJECTIVE: To determine the effect of radon on fractional exhaled nitric oxide (FE NO), asthma symptom-days, and lung function in inner-city asthmatic school children. METHODS: Two hundred ninety-nine school-aged asthmatic children enrolled in the School Inner-City Asthma Study (SICAS-1) were followed. One and two-month averaged radon was assessed using a spatiotemporal model predicting zip code-specific monthly exposures. FE NO and spirometry were measured twice during the academic year. Asthma symptoms were assessed four times during the academic year. The interaction between indoor radon exposure (Bq/m3 ) and seasonality predicting log-transformed FE NO, forced expiratory volume in 1 s (FEV1 ) % predicted, forced vital capacity (FVC) % predicted, FEV1 /FVC, and asthma symptom-days was evaluated. RESULTS: Participants with high radon exposure had greater change in FE NO from warm to cold periods compared to low radon exposure (interaction p = 0.0013). Participants with >50th percentile radon exposure experience significant FE NO increase from warm to cold weather ( ß $\beta $ = 0.29 [95% confidence interval [CI]: 0.04-0.54], p = 0.0240). We report a positive association between radon 1-month moving average (incidence rate ratio [IRR] = 1.01, p = 0.0273) and 2-month moving average (IRR = 1.01, p = 0.0286) with maximum asthma symptom-days (n = 299, obs = 1167). CONCLUSIONS: In asthmatic children, radon may be associated with increased asthma morbidity, suggesting radon may be a modifiable environmental risk factor for airway inflammation.

Clonal evolution in diffuse large B-cell lymphoma with central nervous system recurrence.

BACKGROUND: The prognosis of patients with secondary central nervous system lymphoma (SCNSL) is poor and despite massive advances in understanding the mutational landscape of primary diffuse large B-cell lymphoma (DLBCL), the genetic comparison to SCNSL is still lacking. We therefore collected paired samples from six patients with DLBCL with available biopsies from a lymph node (LN) at primary diagnosis and the central nervous system (CNS) at recurrence. PATIENTS AND METHODS: A targeted, massively parallel sequencing approach was used to analyze 216 genes recurrently mutated in DLBCL. Healthy tissue from each patient was also sequenced in order to exclude germline mutations. The results of the primary biopsies were compared with those of the CNS recurrences to depict the genetic background of SCNSL and evaluate clonal evolution. RESULTS: Sequencing was successful in five patients, all of whom had at least one discordant mutation that was not detected in one of their samples. Four patients had mutations that were found in the CNS but not in the primary LN. Discordant mutations were found in genes known to be important in lymphoma biology such as MYC, CARD11, EP300 and CCND3. Two patients had a Jaccard similarity coefficient below 0.5 indicating substantial genetic differences between the primary LN and the CNS recurrence. CONCLUSIONS: This analysis gives an insight into the genetic landscape of SCNSL and confirms the results of our previous study on patients with systemic recurrence of DLBCL with evidence of substantial clonal diversification at relapse in some patients, which might be one of the mechanisms of treatment resistance.

Effects of estradiol, progestogens, and of tibolone on breast proliferation and apoptosis.

AIM: To study the effects of estrogen therapy, alone or combined with progestogens, and of tibolone on the expression of proliferation and apoptosis markers in normal breast tissue. METHODS: Thirty 250-day-old Wistar rats were castrated and 3 weeks later received one of the following treatments by gavage for 5 weeks: (1) estradiol benzoate; (2) estradiol benzoate + medroxyprogesterone acetate; (3) estradiol benzoate + norethisterone acetate; (4) estradiol benzoate + dydrogesterone; (5) tibolone; (6) placebo. Following treatment, the expression of proliferating cell nuclear antigen (PCNA) and caspase-3 was analyzed by quantitative immunohistochemistry in the breast tissue, and proliferation and apoptosis were analyzed semiquantitatively by microscopic imaging. RESULTS: There was a statistically significant difference among the groups for PCNA, caspase-3 and the caspase-3 : PCNA ratio. Tibolone was associated with the lowest proliferative activity, followed by estradiol benzoate + dydrogesterone; however, estradiol benzoate + dydrogesterone showed the greatest rate of apoptosis. CONCLUSIONS: The various progestogens can have more or less proliferative and pro-apoptotic effects than estradiol alone. Among the treatment schemes analyzed, the estradiol + dydrogesterone combination resulted in a higher apoptosis rate in relation to the proliferation rate and tibolone was associated with the lowest proliferation.

Is expression of rat breast matrix components influenced by estrogen, progestins and tibolone?

AIM: To study the effects of estrogen therapy, alone or combined with progestogens, and of tibolone on the expression of heparanase (HSPE), extracellular matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), perlecan and proliferating cell nuclear antigen (PCNA) in normal breast tissue. METHODS: Thirty 250-day-old Wistar rats were castrated and 3 weeks later received one of the following treatments by gavage for 5 weeks: (1) estradiol benzoate; (2) estradiol benzoate + medroxyprogesterone acetate; (3) estradiol benzoate + norethisterone acetate; (4) estradiol benzoate + dydrogesterone; (5) tibolone; (6) placebo. Following treatment, the expressions of mRNA for HSPE, MMP-2 and MMP-9 were analyzed by real-time PCR and the protein expressions of HSPE, MMP-2, MMP-9, perlecan and PCNA were quantified by immunohistochemistry. RESULTS: There was a statistically significant difference among the groups for the expression of HSPE mRNA due to high levels in the tibolone group. The groups differed in terms of PCNA, with lower levels found in the tibolone group followed by the estradiol benzoate + dydrogesterone group. A statistically significant positive correlation was observed for PCNA versus perlecan and MMP-9. CONCLUSIONS: There was no difference in the effects of combinations of estradiol and different progestogens on extracellular matrix components, and breast cell proliferation was associated with increases in perlecan and MMP-9.

Gender differences in the association between stop-signal reaction times, body mass indices and/or spontaneous food intake in pre-school children: an early model of compromised inhibitory control and obesity.

BACKGROUND: Poor inhibitory control is associated with overeating and/or obesity in school-age children, adolescents and adults. The current study examined whether an objective and reliable marker of response inhibition, the stop-signal reaction time (SSRT), is associated with body mass index (BMI) z-scores and/or food intake during a snack test in pre-school children. METHODS: The current sample consisted of 193 pre-school children taking part in a longitudinal study of early brain development (Maternal Adversity, Vulnerability and Neurodevelopment (the MAVAN project)). Linear mixed-effect models were used to examine whether the SSRT measured at age 48 months associated with BMI z-scores and/or dietary intake during a laboratory-based snack test. RESULTS: After controlling for significant covariates including maternal BMI, there was a significant gender by SSRT interaction effect in predicting 48-month BMI z-scores. Post-hoc analysis revealed an association between longer SSRTs (poor response inhibition) and higher BMIs in girls but not boys. Across both girls and boys, longer SSRTs were associated with greater intake of carbohydrates and sugars during the snack test. The association between SSRT scores and BMI z-scores in girls was not statistically mediated by carbohydrate or sugar intake. CONCLUSIONS: At 48 months of age, slower response inhibition on the Stop-Signal Task associates with higher BMI z-scores in girls, and with higher intake of carbohydrates and sugars during a snack test across both genders. Ongoing follow-up of these children will help clarify the implications of these associations for longer term macronutrient intake, eating-related pathology and/or pathological weight gain over time.

Intravenous sildenafil i.v. as rescue treatment for refractory pulmonary hypertension in extremely preterm infants.

BACKGROUND: Intravenous sildenafil treatment has recently shown promising results and good tolerability in the treatment of refractory pulmonary hypertension (PH) in term and near-term neonates, while comparable data in preterm infants are still lacking. However, for critically ill preterm infants suffering from PH refractory to conventional treatment, sildenafil may represent a last treatment resort. PATIENTS AND METHODS: We reviewed the records of 6 critically ill extremely preterm infants who had suffered from PH refractory to conventional treatment and had obtained intravenous sildenafil after careful consideration as ultima ratio treatment. AIM: To describe the responses to sildenafil in terms of hemodynamic and respiratory changes during treatment and outcome. RESULTS: 4/6 patients showed resolution of severe PH with full reversal of ductal shunt direction into pure left-to-right shunt within 82 ± 35 h after sildenafil start. Remarkably, 2/6 patients developed pulmonary hemorrhage at a time point when significant improvement of PH had already taken place, both of them survived. Overall 4/6 patients died, two deaths were related to treatment-refractory PH. CONCLUSION: Intravenous sildenafil treatment seems effective in improving severe PH and hemodynamic instability in extremely preterm infants with refractory PH. Pulmonary hemorrhage may represent a distinct adverse effect of sildenafil treatment in these patients, presumably due to sudden reversal of ductal shunt. Accordingly, sildenafil should be restricted to most severe and refractory cases in this population.

Better quality of mother-child interaction at 4 years of age decreases emotional overeating in IUGR girls.

BACKGROUND/OBJECTIVES: While most "fetal programming" area focused on metabolic disease, intrauterine growth restriction (IUGR) is also associated with a preference for less healthy food. Post-natal factors such as strained maternal-child interactions are equally related to obesogenic eating behaviors. We investigated if IUGR and the quality of the mother/child relationship affect emotional overeating in children. SUBJECTS/METHODS: Participants were 196 children from a prospective birth cohort (the MAVAN project). As part of the protocol at 4 years of age, mothers completed the Children Eating Behavior Questionnaire (CEBQ) and mother-child interactions were scored during a structured task. A GLM adjusted for BMI examined the interaction between the "Atmosphere" score (ATM) task, sex and IUGR on the emotional over-eating domain of the CEBQ. RESULTS: There was a significant interaction of BWR vs. sex vs. ATM (P = .02), with no effects of IUGR, sex or ATM. The model was significant for girls with low ATM scores (B = -2.035, P = .014), but not for girls with high (P = 0.94) or boys with high (P = .27) or low (P = .19) ATM scores. Only in IUGR girls, 48 months emotional over-eating correlated with BMI at that age (r = 0.560, P = 0.013) and predicted BMI in the subsequent years (r = 0.654, P = 0.006 at 60 months and r = 0.750, P = 0.005 at 72 months). CONCLUSIONS: IUGR and exposure to a negative emotional atmosphere during maternal-child interactions predicted emotional overeating in girls but not in boys. The quality of mother-infant interaction may be an important target for interventions to prevent emotional overeating and overweight in early development, particularly in girls with a history of IUGR.

Associations between autonomic dysfunction and pain in chemotherapy-induced polyneuropathy.

BACKGROUND: Autonomic neuropathy, a relatively common complication of several chemotherapy agents, can affect the vagus nerve and its pain inhibitory capacity, thus increasing sensitivity to pain. This study aimed to evaluate the relationships between autonomic parasympathetic function and the perception of (1) spontaneous pain; (2) experimental non-painful sensations; and (3) experimental painful sensations in chemotherapy-induced neuropathy patients. METHODS: Twenty-seven cancer patients with chemotherapy-induced polyneuropathy were enrolled (20 women, age 56.6 ± 7.9). Autonomic parameters of heart rate variability, deep-breathing and Valsalva ratios, experimental non-painful parameters of warm, cold and mechanical detection thresholds, and painful parameters of heat pain thresholds, pain rating of suprathreshold stimulus, mechanical temporal summation and conditioned pain modulation response were examined. RESULTS: Autonomic parameters and spontaneous pain levels were not associated, yet autonomic parameters were positively correlated with non-painful sensations - milder autonomic neuropathy was accompanied by milder sensory neuropathy as indicated by several parameters, e.g., lower Valsalva ratio was correlated with higher warmth detection threshold (r = -0.465; p = 0.033). Autonomic parameters were, however, negatively correlated with painful sensations - lower parasympathetic-vagal activity was associated with higher pain sensitivity as indicated by several parameters, e.g., lower Valsalva ratio was correlated with higher pain rating of suprathreshold stimulus (r = -0.559; p = 0.008). CONCLUSIONS: Diminished vagal function due to neuropathy is associated with, and may possibly underlie, pain disinhibition expressed as greater levels of experimental pain.

The effects of femoral external derotational osteotomy on frontal plane alignment.

PURPOSE: Femoral osteotomies are the preferred treatment in significant torsional deformity of the femur. The influence of torsional osteotomies on frontal plane alignment is poorly understood. Therefore, the aim of the present study was to evaluate the effects of external derotational osteotomies on proximal, mid-shaft and distal levels onto frontal plane alignment. METHODS: The effect of rotation around the anatomical axis of the femur on frontal plane alignment was determined with a 3D computer model, created from CT data of a right human cadaver femur. Virtual torsional osteotomies of 10°, 20° and 30° were performed at proximal, mid-shaft and distal levels under five antecurvatum angles of the femur. The change of the frontal plane alignment was expressed by the mechanical lateral femoral angle. RESULTS: Proximal derotational osteotomies resulted in an increased mechanical lateral distal femoral angle (mLDFA) of 0.8°-2.6° for 10°, of 1.6°-5.1° for 20° and of 2.3-7.9° for 30° derotational osteotomy, indicating an increased varus angulation. Supracondylar derotational osteotomy resulted in a decreased mLDFA of -0.1° to -1.7° for 10°, of -0.2 to -3.7° for 20° and of -0.7 to -6.9° for 30° derotational osteotomy, indicating an increased valgus angulation. The effect increased with the amount of torsional correction and virtually increased antecurvatum angles. Mid-shaft torsional osteotomies had the smallest effect on frontal plane alignment. CONCLUSION: This three-dimensional computer model study demonstrates the relationship between femoral torsional osteotomies and frontal plane alignment. Proximal external derotational osteotomies tend to result in an increased varus angulation, whilst distal external derotational osteotomies tend to result in an increased valgus angulation. As a clinical consequence, torsional osteotomies have an increased risk of unintentional implications on frontal plane alignment.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for the treatment of advanced epithelial ovarian carcinoma: upfront therapy, at first recurrence, or later?

AIM: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) has been proposed as treatment for advanced epithelial ovarian carcinoma (EOC). No consensus exists on when to administer CRS+HIPEC during the natural history of the disease, namely, as upfront therapy, at first recurrence, or at second or subsequent recurrence. PATIENTS AND METHODS: We analyzed a series of patients with advanced EOC collected prospectively in an institution with a peritoneal malignant disease treatment program. Patients were treated with CRS+HIPEC upfront, at first recurrence, and at second or subsequent recurrence. RESULTS: We treated 42 patients: 15 upfront, 19 at first recurrence, and 8 at second or subsequent recurrence. Cytoreduction was complete (CC0) in 75% of cases; residual disease was <2.5 mm (CC1) in 25%. Severe morbidity (CTCAE v.3.0, grade 3-4) was 26%, and hospital mortality was 7%. After a median follow-up of 24 months, median overall survival was 77.8 months for patients treated upfront, 62.8 months for patients treated at first recurrence, and 35.7 months for patients treated at second or subsequent recurrence. Disease-free survival was 21.1 months, 18 months, and 5.7 months, respectively. Overall survival in the upfront and first recurrence groups was similar, and statistically significant differences with the second recurrence group were identified (p<0.03). CONCLUSIONS: Treatment of advanced EOC using CRS+HIPEC is promising in terms of overall survival and disease-free survival when administered as upfront and at first recurrence therapy. These results warrant further evaluation in a randomized trial.

Conservative management for an entero-adnexal fistula at initial presentation of advanced ovarian carcinoma.

Gastrointestinal fistulae can occur in ovarian cancer patients, usually in the setting of advanced relapsed disease. Treatment typically involves immediate surgery.Here, we describe a case of an abscess resulting from an intestinal fistula as the first manifestation of advanced epithelial ovarian cancer, and we review the current literature on this subject. The patient was successfully treated with a combination of chemotherapy, antibiotics, and delayed surgery. Optimal debulking was achieved without a need for bowel resection.This report is the first of conservative management of a fistula in an ovarian cancer patient in the chemotherapy-naïve setting.

Effect of estrogen therapy on vascular perlecan and metalloproteinases 2 and 9 in castrated rats.

AIM: To study the effects of estrogen therapy on the expression of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) and perlecan in the vascular wall. METHODS: Twenty 180-day-old Wistar rats were castrated and treated 1 week later for a period of 4 weeks with one of the following: (1) placebo; (2) 0.5 µg/day estradiol benzoate (E(2)B); (3) 5 µg/day E(2)B; (4) 50 µg/day E(2)B. A fifth group consisted of rats that had not been castrated. Following treatment, expression of MMP-2 and MMP-9 mRNA (MMP-2([RNA]) and MMP-9([RNA]), respectively) was analyzed by real-time PCR, and expression of MMP-2 (MMP-2([IH])), MMP-9 (MMP-9([IH])) and perlecan was quantified by immunohistochemistry, in carotid walls. RESULTS: There were no differences among castrated groups for MMP-2([RNA]) (p = 0.1969) and for MMP-9([RNA]) (p = 0.1828); however, a correlation was observed between E(2)B dose and MMP-9([RNA]) levels (r = 0.471, p = 0.018). Differences among groups were observed for MMP-2([IH]), MMP-9([IH]) and perlecan (p < 0.0001), wherein higher levels were observed in animals treated with estrogen therapy, correlating with E(2)B doses in the case of MMP-9 (r = 0.441, p = 0.026) and perlecan (r = 0.574, p = 0.005). CONCLUSIONS: Estrogen therapy correlates with higher levels of MMP-2, MMP-9 and perlecan in the extracellular matrix of carotid walls in castrated rats, in a dose-dependent manner. There was a dose-response effect of E(2)B on the expression of MMP-9 mRNA and, possibly, MMP-2 mRNA.

Major ethnic group differences in breast cancer screening uptake in Scotland are not extinguished by adjustment for indices of geographical residence, area deprivation, long-term illness and education.

BACKGROUND: Breast cancer screening data generally show lower uptake in minority ethnic groups. We investigated whether such variations occur in Scotland. METHODS: Using non-disclosive computerised linkage we combined Scottish breast screening and Census 2001 data. Non-attendance at first breast-screening invitation (2002-2008) was compared between 11 ethnic groups using age-adjusted risk ratios (RR) with 95% confidence intervals (CI), multiplied by 100, using Poisson regression. RESULTS: Compared with the White Scottish (RR=100), non-attendance was similar for Other White British (99.5, 95% CI 96.1-103.2) and Chinese (112.8, 95% CI 96.3-132.2) and higher for Pakistani (181.7, 95% CI 164.9-200.2), African (162.2, 95% CI 130.8-201.1), Other South Asian (151.7, 95% CI 118.9-193.7) and Indian (141.7, 95% CI 121.1-165.7) groups. Adjustment for rural vs urban residence, long-term illness, area deprivation and education, associated with risk of non-attendance, increased the RR for non-attendance except for Pakistani women where it was modestly attenuated (RR=164.9, 149.4-182.1). CONCLUSION: Our data show important inequality in breast cancer screening uptake, not attenuated by potential confounding factors. Ethnic inequalities in breast screening attendance are of concern especially given evidence that the traditionally lower breast cancer rates in South Asian groups are converging towards the risks in the White UK population. Notwithstanding the forthcoming review of breast cancer screening, these data call for urgent action.

[SIPS--screening instrument for premenstrual symptoms. The German version of Premenstrual Symptoms Screening Tool to assess clinically relevant disturbances]. / SIPS--Screening-Instrument für prämenstruelle Symptome. Die deutsche Version des Premenstrual Symptoms Screening Tool zur Erfassung klinisch relevanter Beschwerden.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) and severe premenstrual syndrome (PMS) are common, yet often remain unrecognized and not adequately treated. One reason for this is the lack of a valid German screening instrument. The aim of the present study was to create a German version of the English "Premenstrual Symptoms Screening Tool (PSST)" and to verify its applicability. MATERIAL AND METHODS: The German version of the PSST was created as "Screening-Instrument für prämenstruelle Symptome (SIPS)" and its reliability and validity determined based on data from 47 women with and without PMDD/severe PMS using Internet-based daily symptom ratings. RESULTS: The retest reliability of the SIPS was r=0.69, and Cronbach's alpha was 0.924. As an indicator of the convergent validity of the SIPS, there were significant differences between women with and without PMDD/severe PMS as identified by the SIPS with regard to prospectively assessed premenstrual symptomatology (F[2,44]=4.52, p<0.001) and symptom change (F[2,44]=25.23, p<0.001). CONCLUSIONS: The SIPS is reliable and valid and may help to improve the identification of women who require treatment for their premenstrual symptoms.

Integrative oncology in the Middle East: from traditional herbal knowledge to contemporary cancer care.

BACKGROUND: Based on traditional, historical, ethnobotanical, laboratory, and clinical findings, we present research framework aiming to identify Middle Eastern herbs that are worthy of further research for their anticancer potential. METHODS: A comprehensive research project was developed by a multinational team comprising family physicians, medicine specialists, oncologists, an Islamic medicine history specialist, a traditional medicine ethnobotanist, and a basic research scientist. The project followed two consecutive phases: (i) historical and ethnobotanical search for cancer-related keywords and (ii) Medline search for in vitro and in vivo studies. RESULTS: This search yielded 44 herbs associated with cancer care. The Medline search yielded 34 herbs of which 9 herbs were reported in various clinical studies. CONCLUSIONS: This multidisciplinary survey was found to be a valuable way to identify herbs with potential clinical significance in cancer care. Based on this pilot study, it is suggested that the Middle East can serve as a valuable region for future multicultural-oriented cancer research.

Effect of abrupt discontinuation versus gradual dose reduction of postmenopausal hormone therapy on hot flushes.

OBJECTIVE: To compare the effects of the abrupt discontinuation of postmenopausal hormone therapy (HT) and reduction of the daily dosage of the hormone on climacteric symptoms. METHODS: The study included Brazilian postmenopausal women who were using estrogen-progestogen hormone therapy in full doses previously prescribed for vasomotor symptoms. The patients were randomized to receive one of three treatments: placebo for 6 months; estradiol (E2) 1 mg/day + norethisterone acetate (NETA) 0.5 mg/day for 2 months, followed by placebo for 4 months; or E2 1 mg/day + NETA 0.5 mg/day for 4 months, followed by placebo for 2 months. The climacteric symptoms were assessed by the Blatt-Kupperman Menopausal Index at baseline and at 2, 4 and 6 months. Statistical evaluation was performed using the chi(2) or Fisher's test for categorical data, the Kruskal-Wallis test for numerical data, and ANOVA for time and group relationship with the Blatt-Kupperman Menopausal Index. RESULTS: We randomized 60 women (20 in each group), and 54 completed the study. It was observed that both the full Blatt-Kupperman Menopausal Index and the hot flush score did not change significantly in the HT group during low-dose therapy compared with baseline; however, the evaluation performed at 2 months after low-dose-HT cessation showed that the full Blatt-Kupperman Menopausal Index and the hot flush score were similar to those of the group who stopped HT abruptly and significantly higher than at baseline (hot flush scores: p < 0.001 for all three groups at months 2, 4 and 6, respectively, vs. baseline). CONCLUSION: Discontinuation of HT by reducing the daily dose of estrogen for a period of 2 or 4 months did not differ in its effect from that of abrupt cessation with regard to vasomotor symptoms.

Plasma ammonia response to incremental cycling and walking tests in COPD.

OBJECTIVE: It is well documented that plasma ammonia accumulates during exercise under conditions of metabolic stress. Metabolic stress (when skeletal muscle ATP supply fails to meet demand) occurs at low work rates during cycling in patients with COPD, but not been described during walking. Walking is an important activity for many patients with COPD and is commonly prescribed in pragmatic outpatient pulmonary rehabilitation programmes. In this study we explored whether metabolic stress occurs during incremental walking at the low work rates these patients achieve. METHODS: Twenty-nine subjects with stable COPD [mean(SD) age 68(7)years, FEV(1) 50(19)% predicted] performed maximal cardiopulmonary exercise tests on a cycle ergometer and treadmill. Plasma ammonia concentration was measured at rest, 1 and 2min of exercise, peak exercise and 2min recovery. RESULTS: Subjects achieved mean(SD) cycle work rate of 57(20)W with VO(2max) 15.5(4.6)ml/min per kg, and treadmill distance 284(175)m with VO(2peak) 16.8(4.2)ml/min per kg. Plasma ammonia concentration rose significantly (p<0.001) with walking [mean(SEM) change 24.7(3.8)micromol/l] and cycling [mean(SEM) change 35.2(4.3)micromol/l], but peak exercise ammonia was lower in walking (p<0.01). In a subgroup of subjects (n=7) plasma ammonia did not rise during either cycling or walking despite similar lactate rise and peak exercise indices. CONCLUSION: Our data indicate that failure of muscle ATP re-synthesis to meet demand and development of metabolic stress can occur during walking in COPD patients at the low work rates these patients achieve. This may therefore be a factor contributing to exercise limitation independent of ventilatory limitation.

Interleukin-6 overexpression induces pulmonary hypertension.

Inflammatory cytokine interleukin (IL)-6 is elevated in the serum and lungs of patients with pulmonary artery hypertension (PAH). Several animal models of PAH cite the potential role of inflammatory mediators. We investigated role of IL-6 in the pathogenesis of pulmonary vascular disease. Indices of pulmonary vascular remodeling were measured in lung-specific IL-6-overexpressing transgenic mice (Tg(+)) and compared to wild-type (Tg(-)) controls in both normoxic and chronic hypoxic conditions. The Tg(+) mice exhibited elevated right ventricular systolic pressures and right ventricular hypertrophy with corresponding pulmonary vasculopathic changes, all of which were exacerbated by chronic hypoxia. IL-6 overexpression increased muscularization of the proximal arterial tree, and hypoxia enhanced this effect. It also reproduced the muscularization and proliferative arteriopathy seen in the distal arteriolar vessels of PAH patients. The latter was characterized by the formation of occlusive neointimal angioproliferative lesions that worsened with hypoxia and were composed of endothelial cells and T-lymphocytes. IL-6-induced arteriopathic changes were accompanied by activation of proangiogenic factor, vascular endothelial growth factor, the proproliferative kinase extracellular signal-regulated kinase, proproliferative transcription factors c-MYC and MAX, and the antiapoptotic proteins survivin and Bcl-2 and downregulation of the growth inhibitor transforming growth factor-beta and proapoptotic kinases JNK and p38. These findings suggest that IL-6 promotes the development and progression of pulmonary vascular remodeling and PAH through proproliferative antiapoptotic mechanisms.

Improvement of modelling capabilities for assessing urban contamination: the EMRAS Urban Remediation Working Group.

The Urban Remediation Working Group of the International Atomic Energy Agency's Environmental Modelling for Radiation Safety (EMRAS) programme was established to improve modelling and assessment capabilities for radioactively contaminated urban situations, including the effects of countermeasures. An example of the Working Group's activities is an exercise based on Chernobyl fallout data in Ukraine, which has provided an opportunity to compare predictions among several models and with available measurements, to discuss reasons for discrepancies, and to identify areas where additional information would be helpful.