Recent Northern Hemisphere stratospheric HCl increase due to atmospheric circulation changes.

The abundance of chlorine in the Earth's atmosphere increased considerably during the 1970s to 1990s, following large emissions of anthropogenic long-lived chlorine-containing source gases, notably the chlorofluorocarbons. The chemical inertness of chlorofluorocarbons allows their transport and mixing throughout the troposphere on a global scale, before they reach the stratosphere where they release chlorine atoms that cause ozone depletion. The large ozone loss over Antarctica was the key observation that stimulated the definition and signing in 1987 of the Montreal Protocol, an international treaty establishing a schedule to reduce the production of the major chlorine- and bromine-containing halocarbons. Owing to its implementation, the near-surface total chlorine concentration showed a maximum in 1993, followed by a decrease of half a per cent to one per cent per year, in line with expectations. Remote-sensing data have revealed a peak in stratospheric chlorine after 1996, then a decrease of close to one per cent per year, in agreement with the surface observations of the chlorine source gases and model calculations. Here we present ground-based and satellite data that show a recent and significant increase, at the 2σ level, in hydrogen chloride (HCl), the main stratospheric chlorine reservoir, starting around 2007 in the lower stratosphere of the Northern Hemisphere, in contrast with the ongoing monotonic decrease of near-surface source gases. Using model simulations, we attribute this trend anomaly to a slowdown in the Northern Hemisphere atmospheric circulation, occurring over several consecutive years, transporting more aged air to the lower stratosphere, and characterized by a larger relative conversion of source gases to HCl. This short-term dynamical variability will also affect other stratospheric tracers and needs to be accounted for when studying the evolution of the stratospheric ozone layer.

Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

Dietary patterns of university students in the UK: a cross-sectional study.

BACKGROUND: University represents a key transition into adulthood for many adolescents but there are associated concerns about health and behaviours. One important aspect relates to diet and there is emerging evidence that university students may consume poor quality diets, with potential implications for body weight and long-term health. This research aimed to characterise dietary patterns of university students in the UK and their sociodemographic and lifestyle antecedents. METHODS: An online, cross-sectional survey was undertaken with a convenience sample of 1448 university students from five UK universities (King's College London, Universities of St Andrews, Southampton and Sheffield, and Ulster University). The survey comprised a validated food frequency questionnaire alongside lifestyle and sociodemographic questions. Dietary patterns were generated from food frequency intake data using principal components analysis. Nutrient intakes were estimated to characterise the nutrient profile of each dietary pattern. Associations with sociodemographic variables were assessed through general linear modelling. RESULTS: Dietary analyses revealed four major dietary patterns: 'vegetarian'; 'snacking'; 'health-conscious'; and 'convenience, red meat & alcohol'. The 'health-conscious' pattern had the most favourable micronutrient profile. Students' gender, age, year of study, geographical location and cooking ability were associated with differences in pattern behaviour. Female students favoured the 'vegetarian' pattern, whilst male students preferred the 'convenience, red meat & alcohol' pattern. Less healthful dietary patterns were positively associated with lifestyle risk factors such as smoking, low physical activity and take-away consumption. The health-conscious pattern had greatest nutrient density. The 'convenience, red meat & alcohol' pattern was associated with higher weekly food spending; this pattern was also identified most consistently across universities. Students reporting greater cooking ability tended towards the 'vegetarian' and 'health-conscious' patterns. CONCLUSIONS: Food intake varied amongst university students. A substantial proportion of students followed health-promoting diets, which had good nutrient profiles obviating a need for dietary intervention. However, some students consumed poor diets, incurred greater food costs and practised unfavourable lifestyle behaviours, which may have long-term health effects. University policy to improve students' diets should incorporate efforts to promote student engagement in cooking and food preparation, and increased availability of low cost healthier food items.

Preparing and sharing food: a quantitative analysis of a primary school-based food intervention.

Background: Primary schools are increasingly used as arenas for public health initiatives. The aim of this study was to assess a primary school-based food intervention. Methods: The intervention comprised timetabled kitchen classroom sessions (90 min, fortnightly). Pupils prepared and cooked food, which they then ate together. Children's relationship with food, including food enjoyment, experience and food neophobia, were addressed at the intervention school (baseline n = 154; follow-up n = 164) and at a matched control school (baseline n = 171; follow-up n = 174). Results: Pupils at the intervention school scored significantly higher (M = 3.90, SD = 1.81) for scores on Kitchen Equipment, compared to the control school (M = 3.06, SD = 2.12); and again scored significantly higher (M = 9.34, SD = 3.79) for the overall Cooking Experience Score compared to the control school (M = 7.98, SD = 4.57). Shifts accompanying the intervention in three outcome measures for pupils (taste description, liking for cooking and helping with cooking at home) were also revealed. No main intervention effect for food neophobia and fussiness was found; a close to significant time by intervention interaction (P = 0.053) was evident. Conclusions: The study indicates limited but encouraging changes, and contributes to the growing literature regarding school-based food initiatives.

Food choice and nutrient intake amongst homeless people.

BACKGROUND: Homeless people in the UK and elsewhere have typically been found to consume a nutritionally inadequate diet. There is need for contemporary research to update our understanding within this field. The present study aimed to provide an insight into the nutrient intake and food choice of a sample of homeless adults. METHODS: In this mixed-methods study, 24 homeless individuals accessing two charitable meal services in Sheffield, UK, participated in up to four 24-h dietary recalls between April and August 2012. Twelve individuals took part in a semi-structured interview focusing on food choice. RESULTS: Energy intake was significantly lower than the estimated average requirement. Median intakes of vitamin A, zinc, magnesium, potassium and selenium were significantly lower than reference nutrient intakes. Contributions of saturated fat and nonmilk extrinsic sugars to total energy intake were significantly higher, whereas dietary fibre was significantly lower, than population average intakes. Charitable meals made an important contribution to intakes of energy and most micronutrients. Thematic analysis of interview transcripts revealed three major themes: food aspirations; constraints over food choice; and food representing survival. CONCLUSIONS: The present study reveals risk of dietary inadequacies amongst homeless people alongside a lack of control over food choices. Charitable meal services are suggested as a vehicle for improving the dietary intake and nutritional health of homeless people.

Modified Valsalva test differentiates primary from secondary cough headache.

BACKGROUND: The current definition of cough headache includes provocation of the symptom by Valsalva manoeuvre, and it is generally believed that all cough headache results from a sudden increase in intracranial pressure. We sought to question that presumption and to determine whether the Valsalva test might distinguish primary from secondary cough headache. METHODS: We examined 16 consecutive cough headache patients using a modified Valsalva test (exhalation into the connecting tube of a standard anaeroid sphygmomanometer to 60 mm Hg for 10 seconds). A positive response was recorded if the manoeuvre provoked headache. All patients subsequently underwent brain MRI. RESULTS: None of the patients had neurological signs. Eleven had positive modified Valsalva tests. Ten were found subsequently to have posterior fossa pathologies (secondary cough headache: 8 Chiari Type 1 malformations, 2 posterior fossa meningiomas). The cough headache was relieved following surgery in all cases. One patient with a positive Valsalva test had an apparently normal brain MRI but measurements of hindbrain and posterior fossa dimensions were consistent with 'posterior fossa crowdedness'. The remaining 5 patients had negative (4 patients) or equivocal (1 patient) Valsalva tests and normal MRI scans (primary cough headache). CONCLUSIONS: These findings suggest that secondary cough headache results from a transient increase in intracranial CSF pressure during exertion in the presence of obstruction to normal cerebrospinal fluid dynamics. The modified Valsalva test can also determine whether tonsillar herniation found on brain MRI is symptomatic. Primary cough headache appears to be caused by a different mechanism, possibly through congestion of the orbital venous plexus in the presence of jugular venous incompetence and a reduced threshold for trigeminal sensory activation.

On limb radiance calculations and convergence of relaxation type retrieval algorithms.

Several approaches to the solution of the radiative transfer equation assume either Curtis-Godson average or linear change of the source function across grid segments. When such solutions are used for calculating limb radiances, the peak radiance response to the source function perturbation at tangent point i is displaced down to the tangent point i+1. This effect is explained through a geometric argument. Temperature profile retrievals performed by applying the ratio of signals at level i+1 for correcting temperature at level i demonstrate dramatic convergence acceleration of the iterative relaxation scheme.

Regulation of murine intestinal inflammation by reactive metabolites of oxygen and nitrogen: divergent roles of superoxide and nitric oxide.

Several reports have implicated reactive oxygen and nitrogen metabolites (RONS) in the initiation and/or progression of inflammatory bowel diseases (IBDs). We have investigated the role of three key RONS-metabolizing enzymes (inducible nitric oxide synthase [iNOS], superoxide dismutase [SOD], nicotinamide adenine dinucleotide phosphate [NADPH] oxidase) in a murine model of IBD. Mice genetically deficient ((-/-)) in either iNOS or the p47phox subunit of NADPH oxidase, transgenic (Tg) mice that overexpress SOD, and their respective wild-type (WT) littermates were fed dextran sulfate sodium (DSS) in drinking water for 7 days to induce colitis. In addition, the specific iNOS inhibitor 1400W was used in DSS-treated WT and p47phox(-/-) mice. WT mice responded to DSS feeding with progressive weight loss, bloody stools, elevated serum NO(X) and colonic mucosal injury with neutrophil infiltration. Both the onset and severity of colitis were significantly attenuated in iNOS(-/-) and 1400W-treated WT mice. While the responses to DSS did not differ between WT and p47phox(-/-) mice, enhanced protection was noted in 1400W-treated p47phox(-/-) mice. Interestingly, SOD(Tg) mice exhibited more severe colitis than their WT littermates. These findings reveal divergent roles for superoxide and iNOS-derived NO in intestinal inflammation.

Active transport of potassium and chloride in an identifiable molluscan neuron.

Direct measurements of intracellular K(+) and Cl(-)activities before and after blockage of cellular metabolic processes indicate that K(+) is actively transported inwardly and Cl(-)is actively transported outwardly from the giant cell of the abdominal ganglion of Aplysia. The rewarming of cells that have been cooled to 1 degrees +/- 1 degrees C causes K(+) to be taken up and Cl(-) to be extruded against electrochemical gradients.

A Reevaluation of the Ozone Budget with HALOE UARS Data: No Evidence for the Ozone Deficit.

Recently, additional ozone production mechanisms have been proposed to resolve the ozone deficit problem, which arises from greater ozone destruction than production in several photochemical models of the upper stratosphere and lower mesosphere. A detailed ozone model budget analysis was performed with simultaneous observations of O(3), HCl, H(2)O, CH(4), NO, and NO(2) from the Halogen Occultation Experiment (HALOE) on the Upper Atmosphere Research Satellite (UARS) under conditions with the strongest photochemical control of ozone. The results indicate that an ozone deficit may not exist. On the contrary, the use of currently recommended photochemical parameters leads to insufficient ozone destruction in the model.

The long and winding road: the journey taken by headache sufferers in search of help.

AimTo outline the pathways a cohort of first attendees to our headache clinics had taken over the years in search of explanations and treatment for their headaches. To establish a greater awareness of the shortcomings and failures in their medical journey in the hope that better headache management will emerge in primary care. BACKGROUND: At first attendance in primary care most headache sufferers will not receive a firm diagnosis. Treatments provided are often ineffective and so many patients embark on a somewhat random self-made journey searching for a remedy. If they reach a Headache Clinic the most common diagnoses are 'chronic migraine' and 'medication overuse headache'. They are either no better or worse than when their headaches first started despite their efforts. METHOD: We undertook a prospective questionnaire-based study of over 200 patients on first attendance at each of our headache clinics, three based in District General Hospitals and one in a tertiary referral centre. We documented the patients' headache characteristics, the 'burden' of their headaches, functional handicap and the financial costs incurred seeking help before referral. We also documented what our patients understood about their headache disorder and the treatments previously tried.FindingsMost patients had not been given a formal diagnosis in primary care and many remained unconvinced of the benign nature of their headache problem and wanted further investigations. A few had sought help from headache charities. Many had unrealistic attitudes to their problem and medication overuse was rife. A few patients had been offered triptans in primary care. Key deficiencies in the primary care management of these patients included failure to provide a formal headache diagnosis, inadequate understanding of the nature and mechanism of headaches and failure to follow a resilient management strategy. We provide a more effective management pathway in primary care.

A systematic review of antioxidant treatment for amyotrophic lateral sclerosis/motor neuron disease.

Free radical accumulation and oxidative stress have been proposed as contributing to the progression of amyotrophic lateral sclerosis (motor neuron disease). A range of antioxidant medications is available, and has been studied. We aimed to examine the effects of antioxidant medication in the treatment of people with amyotrophic lateral sclerosis, and searched the Cochrane Neuromuscular Disease Group Trials register (August 2005), MEDLINE (January 1966 to August 2005), EMBASE (January 1980 to August 2005) and other sources. Selection criteria were all randomized or quasi-randomized controlled trials of antioxidant treatment for amyotrophic lateral sclerosis. The authors independently applied the selection criteria, assessed study quality and two authors performed independent data extraction. The search identified 23 studies for consideration but only nine studies met the inclusion criteria. Only two studies used our predetermined primary outcome measure as the primary outcome measure (survival at 12 months treatment). However, sufficient data were available from four studies to allow analysis of this outcome measure, and a meta-analysis was performed. In the individual studies no significant effect was observed for vitamin E 500 mg twice daily; vitamin E 1 g five times daily; acetylcysteine 50 mg/kg daily subcutaneous infusion; or a combination of L-methionine 2 g, vitamin E 400 International Units, and selenium 0.03 mg three times daily (Alsemet). No significant effect on the primary outcome measure was observed in a meta analysis of all antioxidants combined. No significant differences were demonstrated in any of the secondary outcome measures. In the opinion of the reviewers, there is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect, but this was not supported by the analysis we used. Generally, the studies were poorly designed, and underpowered, with low numbers of participants and of short duration. Further well-designed trials of medications such as vitamin C and E are unlikely to be performed. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trial. The high tolerance and safety, and relatively low cost of vitamins C and E, and other considerations related to the lack of other effective treatments for amyotrophic lateral sclerosis, explain the continuing use of these vitamins by physicians and people with amyotrophic lateral sclerosis. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.

A non-inferiority comparison of duloxetine and venlafaxine in the treatment of adult patients with generalized anxiety disorder.

The present study is a non-inferiority comparison of duloxetine 60-120 mg/day and venlafaxine extended-release (XR) 75-225 mg/day for the treatment of adults with generalized anxiety disorder (GAD). The non-inferiority test was a prespecified plan to pool data from two nearly identical 10-week, multicentre, randomized, placebo-controlled, double-blind studies of duloxetine 60-120 mg/day and venlafaxine 75-225 mg/ day for the treatment of GAD. An independent expert consensus panel provided six statistical and clinical criteria for determining non-inferiority between treatments. Response was defined as > or =50% reduction in Hamilton Anxiety Rating Scale (HAMA) total score. In the pooled sample, patients were randomly assigned to duloxetine (n = 320), venlafaxine XR (n = 333) or placebo (n = 331). For the non-inferiority analysis, the per-protocol patients who were treated with duloxetine (n = 239) or venlafaxine XR (n = 262) improved significantly more (mean HAMA reductions were -15.4 and -15.2, respectively) than placebo-treated patients (n = 267; -11.6, P < or = 0.001, both comparisons). Response rates were 56%, 58% and 40%, respectively. Discontinuation rate because of AEs was significantly higher for duloxetine (13.4%, P < or = 0.001) and venlafaxine XR (11.4%, P < or = 0.01) groups compared with placebo (5.4%). Duloxetine 60-120 mg/day met all statistical and clinical criteria for non-inferiority and exhibited a similar tolerability profile compared with venlafaxine XR 75-225 mg/day for the treatment of adults with GAD.

NAD(P)H oxidase-derived superoxide mediates hypercholesterolemia-induced leukocyte-endothelial cell adhesion.

Experimental animals placed on a high-cholesterol diet for 2 or more weeks exhibit an inflammatory response in postcapillary venules. The aims of this study were to determine (1) whether superoxide mediates the hypercholesterolemia-induced inflammatory response and (2) whether leukocyte and/or vessel wall NAD(P)H oxidase contributes to this response. Intravital videomicroscopy was used to quantify leukocyte-endothelial cell adhesion in cremasteric postcapillary venules of wild-type (WT) mice, CuZn-superoxide dismutase transgenic (SOD TgN) mice, and mice heterozygous (p47(phox)+/-) or homozygous (p47(phox)-/-) for NAD(P)H oxidase placed on either a normal diet or high-cholesterol diet (HCD) for 2 weeks. The number of adherent and emigrated leukocytes in postcapillary venules of WT HCD mice was significantly higher than that detected in venules of their normal-diet counterparts. However, the HCD-induced recruitment of adherent and emigrated leukocytes was not observed in SOD TgN mice. Whereas hypercholesterolemic p47(phox)+/- and WT mice exhibited similar inflammatory responses, p47(phox)-/- mice did not. Bone marrow chimeras were developed to selectively delete p47(phox) from either the vessel wall or circulating leukocytes. Whereas WT marrow transplanted into WT mice produced a normal inflammatory response of venules to HCD, chimeric mice with p47(phox) deficiency in either the vessel wall or leukocytes exhibited an attenuated inflammatory response to HCD that was comparable with that observed in p47(phox)-/- HCD mice. Our findings indicate that enhanced superoxide production is a critical event that initiates the leukocyte-endothelial cell adhesion in postcapillary venules of HCD mice. NAD(P)H oxidase appears to be an important source of this superoxide.

Ground-based assessment of the bias and long-term stability of fourteen limb and occultation ozone profile data records.

The ozone profile records of a large number of limb and occultation satellite instruments are widely used to address several key questions in ozone research. Further progress in some domains depends on a more detailed understanding of these data sets, especially of their long-term stability and their mutual consistency. To this end, we made a systematic assessment of fourteen limb and occultation sounders that, together, provide more than three decades of global ozone profile measurements. In particular, we considered the latest operational Level-2 records by SAGE II, SAGE III, HALOE, UARS MLS, Aura MLS, POAM II, POAM III, OSIRIS, SMR, GOMOS, MIPAS, SCIAMACHY, ACE-FTS and MAESTRO. Central to our work is a consistent and robust analysis of the comparisons against the ground-based ozonesonde and stratospheric ozone lidar networks. It allowed us to investigate, from the troposphere up to the stratopause, the following main aspects of satellite data quality: long-term stability, overall bias, and short-term variability, together with their dependence on geophysical parameters and profile representation. In addition, it permitted us to quantify the overall consistency between the ozone profilers. Generally, we found that between 20-40 km the satellite ozone measurement biases are smaller than ±5 %, the short-term variabilities are less than 5-12% and the drifts are at most ±5% decade-1 (or even ±3 % decade-1 for a few records). The agreement with ground-based data degrades somewhat towards the stratopause and especially towards the tropopause where natural variability and low ozone abundances impede a more precise analysis. In part of the stratosphere a few records deviate from the preceding general conclusions; we identified biases of 10% and more (POAM II and SCIAMACHY), markedly higher single-profile variability (SMR and SCIAMACHY), and significant long-term drifts (SCIAMACHY, OSIRIS, HALOE, and possibly GOMOS and SMR as well). Furthermore, we reflected on the repercussions of our findings for the construction, analysis and interpretation of merged data records. Most notably, the discrepancies between several recent ozone profile trend assessments can be mostly explained by instrumental drift. This clearly demonstrates the need for systematic comprehensive multi-instrument comparison analyses.

Intracellular Ca2+ does not activate the SITS-sensitive anion transporter in barnacle muscle.

By means of the intracellular dialysis technique, we have measured 36Cl efflux from single barnacle muscle fibers and compared the effects of raising intracellular ionized calcium concentration [( Ca2+]i) to the effects of lowering intracellular pH (pHi). Lowering pHi by 1 unit or less resulted in a 20-fold stimulation of 36Cl efflux which occurred relatively rapidly and which could be inhibited by 90-95% by 4-acetamido-4'-isothio-cyanostilbene-2,2'-disulfonic acid (SITS). In contrast, raising [Ca2+]i as much as 250-fold resulted in a relatively small increase of 36Cl efflux. The small increase occurred after a long latency, developed slowly and could not be blocked or prevented by treatment with SITS. We conclude that the increase of the SITS-sensitive 36Cl efflux caused by a fall of pHi is not mediated by a rise of [Ca2+]i.

Activation of Na+,K+,Cl- cotransport in squid giant axon by extracellular ions: evidence for ordered binding.

Activation of the influx mode of the Na+,K+,Cl- cotransporter (NKCC) by extracellular Na+, K+ and Cl- was studied using the internally dialyzed squid giant axon. Cooperative interactions among the three transported ions were assessed using ion activation of NKCC-mediated 36Cl influx under two sets of experimental conditions. The first, or control condition, used high, non-limiting concentrations of two of the cotransported ions (the co-ions) while activating cotransport with the third ion. Under this non-limiting co-ion condition the calculated Vmax of the cotransporter was between 57 and 60 pmol/cm2/s. The apparent activation (KApp, or half-saturation) constants were: K+, 9 mM; Na+, 52 mM; and Cl-, 146 mM. The second condition used limiting co-ion concentration conditions. In this case, activation by each ion was determined when one of the other two co-ions was present at or near its apparent half-saturation concentration as determined above. Under these limiting conditions, the KApp values for all three co-ions were significantly increased regardless of which co-ion was present at a limiting concentration. The effects on the apparent Vmax were more complicated. When K+ was the limiting co-ion, there was little effect on the Vmax for Na+ or Cl- activation. In contrast, limiting concentrations of Na+ or Cl- both resulted in a large reduction of the apparent Vmax when activating with the other two co-ions. These results are consistent with an ordered binding mechanism for the NKCC in which K+ binds before Na+ or Cl-. Physiological implications for these results are discussed.

Optimal planning target volume for stage I testicular seminoma: A Medical Research Council randomized trial. Medical Research Council Testicular Tumor Working Group.

PURPOSE: To compare relapse rates and toxicity associated with para-aortic (PA) strip or PA and ipsilateral iliac lymph node irradiation (dogleg [DL] field) (30 Gy/15 fractions/3 weeks) for stage I testicular seminoma. PATIENTS AND METHODS: Between July 1989 and May 1993, 478 men with testicular seminoma stage I (T1 to T3; no ipsilateral inguinoscrotal operation before orchiectomy) were randomized (PA, 236 patients; DL, 242 patients). RESULTS: Median follow-up time is 4.5 years. Eighteen relapses, nine in each treatment group, have occurred 4 to 35 months after radiotherapy; among these, four were pelvic relapses, all occurring after PA radiotherapy. However, the 95% confidence interval (CI) for the difference in pelvic relapse rates excludes differences of more than 4%. The 3-year relapse-free survival was 96% (95% CI, 94% to 99%) after PA radiotherapy and 96.6% (95% CI, 94% to 99%) after DL (difference, 0.6%; 95% confidence limits, -3.4%, +4.6%). One patient (PA field) has died from seminoma. Survival at 3 years was 99.3% for PA and 100% for DL radiotherapy. Acute toxicity (nausea, vomiting, leukopenia) was less frequent and less pronounced in patients in the PA arm. Within the first 18 months of follow-up, the sperm counts were significantly higher after PA than after DL irradiation. CONCLUSION: In patients with testicular seminoma stage I (T1 to T3) and with undisturbed lymphatic drainage, adjuvant radiotherapy confined to the PA lymph nodes is associated with reduced hematologic, gastrointestinal, and gonadal toxicity, but with a higher risk of pelvic recurrence, compared with DL radiotherapy. The recurrence rate is low with either treatment. PA radiotherapy is recommended as standard treatment in these patients.