Chronic elevation of IL-1ß induces diuresis via a cyclooxygenase 2-mediated mechanism.

Chronic renal inflammation is an increasingly recognized phenomenon in multiple disease states, but the impact of specific cytokines on renal function is unclear. Previously, we found that 14-day interleukin-1ß (IL-1ß) infusion increased urine flow in mice. To determine the mechanism by which this occurs, the current study tested the possible involvement of three classical prodiuretic pathways. Chronic IL-1ß infusion significantly increased urine flow (6.5 ± 1 ml/day at day 14 vs. 2.3 ± 0.3 ml/day in vehicle group; P < 0.05) and expression of cyclooxygenase (COX)-2, all three nitric oxide synthase (NOS) isoforms, and endothelin (ET)-1 in the kidney (P < 0.05 in all cases). Urinary prostaglandin E metabolite (PGEM) excretion was also significantly increased at day 14 of IL-1ß infusion (1.21 ± 0.26 vs. 0.29 ± 0.06 ng/day in vehicle-infused mice; P = 0.001). The selective COX-2 inhibitor celecoxib markedly attenuated urinary PGEM excretion and abolished the diuretic response to chronic IL-1ß infusion. In contrast, deletion of NOS3, or inhibition of NOS1 with L-VNIO, did not blunt the diuretic effect of IL-1ß, nor did pharmacological blockade of endothelin ETA and ETB receptors with A-182086. Consistent with a primary effect on water transport, IL-1ß infusion markedly reduced inner medullary aquaporin-2 expression (P < 0.05) and did not alter urinary Na⁺ or K⁺ excretion. These data indicate a critical role for COX-2 in mediating the effects of chronic IL-1ß elevation on the kidney.

Incidence of cutaneous malignant melanoma in Denmark, 1978-2007.

BACKGROUND: Incidence rates of cutaneous malignant melanoma (CMM) have been increasing markedly worldwide. The ongoing debate about possible overdiagnosis remains unresolved. OBJECTIVES: To determine the population-based incidence of CMM in Denmark between 1978 and 2007 and to analyse sex-, site- and extent of disease-specific changes in incidence rates of CMM over time. METHODS: We used the virtually complete nationwide Danish Cancer Register in this population-based study, which contains data on 25,851 cases reported in Denmark between 1978 and 2007. We calculated age-standardized (world standard population) incidence rates per 100,000 person-years and age-specific rates. RESULTS: The age-standardized incidence rates increased from 6·5 to 14·4 among men and from 8·6 to 18·9 among women. During the last 5 years of the study period, a sudden marked increase was seen in women of all ages and in men aged 65 years or older. The most marked site-specific change was in the incidence of melanoma on the trunk in both men and women. An increase in the rates of disease with regional spread was seen during the last 10 years of observation. CONCLUSIONS: The incidence rate of CMM more than doubled in Denmark between 1978 and 2007. The increases in both site-specific incidence rates and CMM with regional spread suggest an association with risk behaviour, such as intermittent sun exposure, although possible overdiagnosis must be taken into account in evaluating the implications of the increase.

Endothelin receptor A-specific stimulation of glomerular inflammation and injury in a streptozotocin-induced rat model of diabetes.

AIMS/HYPOTHESIS: Activation of endothelin receptor-A (ET(A)) increases glomerular permeability to albumin (P(alb)) and elevates pro-inflammatory markers in hyperglycaemic rats. METHODS: Male Sprague-Dawley rats were given streptozotocin (n = 32) or saline (sham; n = 32). Half of the animals in each group received the ET(A)-selective antagonist, ABT-627 (atrasentan; orally), beginning immediately after hyperglycaemia was confirmed. Glomeruli were isolated by sieving techniques and P(alb) determined from the change in glomerular volume induced by oncotic gradients of albumin. Glomerular nephrin levels were assessed by immunofluorescence, whereas urinary nephrin was measured by immunoassay. RESULTS: At 3 and 6 weeks after streptozotocin injection, proteinuria was significantly increased compared with sham controls and significantly reduced by ABT-627 treatment. P(alb) was also increased at 3 and 6 weeks post-streptozotocin. ABT-627 had no effect on P(alb) or protein excretion in sham control rats. In glomeruli isolated from hyperglycaemic rats, incubation with BQ-123, a selective ET(A) antagonist, reduced P(alb), whereas BQ-788, a selective endothelin receptor-B antagonist had no effect (n = 6 rats per group, 5-8 glomeruli per rat). Glomerular and plasma content of soluble intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 were significantly increased 6 weeks after streptozotocin (ELISA). ABT-627 attenuated these increases. After 6 weeks of hyperglycaemia, glomerular nephrin content was decreased with a concurrent increase in urinary nephrin excretion. ABT-627 prevented glomerular nephrin loss in hyperglycaemic rats (n = 5-8 rats per group; eight groups). CONCLUSIONS/INTERPRETATION: These observations support the hypothesis that endothelin-1, via the ET(A) receptor, directly increases P(alb), possibly via nephrin loss, as well as early inflammation in the hyperglycaemic rat.

A randomized trial on the effect of a multimodal intervention on physical capacity, functional performance and quality of life in adult patients undergoing allogeneic SCT.

The aim of this randomized controlled trial was to investigate the effect of a 4- to 6-week multimodal program of exercise, relaxation and psychoeducation on physical capacity, functional performance and quality of life (QOL) in allogeneic hematopoietic cell transplantation (allo-HSCT) adult recipients. In all, 42 patients were randomized to a supervised multimodal intervention or to a control group receiving usual care. The primary end point was on aerobic capacity measured in VO(2) max. Secondary end points were muscle strength, functional performance, physical activity level, QOL, fatigue, psychological well-being and clinical outcomes. The multimodal intervention had a significant effect on physical capacity: VO(2) max (P<0.0001) and muscle strength: chest press (P<0.0001), leg extension (P=0.0003), right elbow flexor (P=0.0009), right knee extensor (P<0.0001) and functional performance (stair test) (0.0008). Moreover, the intervention group showed significantly better results for the severity of diarrhea (P=0.014) and fewer days of total parenteral nutrition (P=0.019). Longitudinal changes in QOL, fatigue and psychological well-being favored the intervention group, but did not reach statistical significance. Assignment of a multimodal intervention during allo-HSCT did not cause untoward events, sustained aerobic capacity and muscle strength and reduced loss of functional performance during hospitalization.

Pilot study of a multimodal intervention: mixed-type exercise and psychoeducation in patients undergoing allogeneic stem cell transplantation.

Substantial physical and functional deconditioning and diminished psychological wellbeing are all potential adverse effects of allogeneic stem cell transplantation (allo-HSCT). The aim of this study was to evaluate the feasibility, safety and benefits (physical and functional capacity) of a 4-6 week supervised and structured mixed-type exercise, progressive relaxation and psychoeducation programme in patients undergoing allo-HSCT. Nineteen patients were randomized to an intervention or a conventional care group (CC) and were tested for physical and functional capacity before admission and upon hospital discharge. In all, 14 patients completed all study requirements (74%) and no adverse reactions that could be attributed to the intervention were observed. At the time of discharge, the intervention group showed significant improvements in several muscle strength scores as compared to the CC group; chest press (P=0.023), leg extension (P=0.007) and isometric right knee flexor (P=0.033). The intervention proved feasible, safe and well tolerated in this small sample of patients undergoing allo-HSCT. An intervention of this type may be a useful strategy for maintaining or improving muscle strength, and minimizing loss of physical and functional capacity in patients undergoing allo-HSCT.

Acute pressure-natriuresis relationship following withdrawal of chronic noradrenaline infusion.

1. Pathological changes to the kidney, such as vascular remodelling, have been found in several models of hypertension and may contribute to the maintenance of hypertension or confer susceptibility to redeveloping hypertension after the original prohypertensive stimulus is withdrawn. 2. To investigate whether noradrenaline-induced hypertension induces persistent, functionally important changes to the kidney, the acute pressure-natriuresis relationship was characterized in anaesthetized rats under controlled neural and hormonal conditions following chronic (14 days) intravenous infusion of noradrenaline (48 microg/kg per h) or vehicle (0.04 mg/mL ascorbic acid and 0.156 mg/mL NaH2PO4 2 H2O in 10 IU/mL heparinized saline). 3. Conscious mean arterial pressure was significantly elevated by infusion of noradrenaline at 48 microg/kg per h (+10 +/- 2 mmHg at Day 14; P < 0.01 vs vehicle group). The acute relationships between arterial pressure and renal blood flow, glomerular filtration rate, Na+ excretion and urine flow were not significantly different between the noradrenaline- and vehicle-infused rats immediately after termination of noradrenaline infusion. 4. In summary, chronic intravenous noradrenaline infusion did not cause persistent changes in renal function, indicating that, in contrast with many models of hypertension, this model does not induce underlying prohypertensive changes to the kidney.

Mind and cancer: does psychosocial intervention improve survival and psychological well-being?

The aim of this review was to evaluate the scientific evidence for an effect of psychosocial intervention on survival from cancer and well-being and in particular on anxiety and depression. A literature search yielded 43 randomised studies of psychosocial intervention. Four of the eight studies in which survival was assessed showed a significant effect, and the effect on anxiety and depression was also inconsistent, indicating three possible explanations: (i) only some of the intervention strategies affect prognosis and/or well-being and in only certain patient groups; (ii) the effect was weak, so that inconsistent results were found in the generally small study populations; or (iii) the effect was diluted by the inclusion of unselected patient groups rather than being restricted to patients in need of psychosocial support. Thus, large-scale studies with sound methods are needed in which eligible patients are screened for distress. Meanwhile, the question of whether psychosocial intervention among cancer patients has a beneficial effect remains unresolved.

Mind and cancer. do psychological factors cause cancer?

We have reviewed the evidence for an association between major life events, depression and personality factors and the risk for cancer. We identified and included only those prospective or retrospective studies in which the psychological variable was collected independently of the outcome. The evidence failed to support the hypothesis that major life events are a risk factor for cancer. The evidence was inconsistent for both depression and personality factors. Chance, bias or confounding may explain this result, as many of the studies had methodological weaknesses. The generally weak associations found, the inconsistency of the results, the unresolved underlying biological mechanism and equivocal findings of dose-response relationships prevent a conclusion that psychological factors are established risk factors. However, certain intriguing findings warrant further studies, which must, however, be well conducted and large and include detailed information on confounders.

Tropisetron alone or in combination with dexamethasone for the prevention and treatment of emesis induced by non-cisplatin chemotherapy: a randomized trial.

This study compared the efficacy and tolerability of tropisetron (Navoban, Novaban) alone or in combination with dexamethasone for the treatment of emesis induced by moderately emetogenic non-cisplatin chemotherapy. In total, 126 patients with cancer, who had never received chemotherapy and who required at least two courses of moderately emetogenic non-cisplatin chemotherapy each lasting for a minimum of 5 days, were recruited into the study. Patients were randomized to receive tropisetron, 5 mg o.d., plus either dexamethasone, 12 mg i.v. on day 1 followed by 4 mg orally b.i.d. on days 2-5, or placebo. Greater control of acute and delayed vomiting and nausea was achieved in patients given the tropisetron-dexamethasone combination than in those who received the tropisetron-placebo treatment. The majority of adverse events were mild and could be attributed to the chemotherapeutic regimen used or to the underlying disease. Patients and investigators both rated tropisetron alone or in combination with dexamethasone as a highly effective and well-tolerated antiemetic treatment. The results of this study show that tropisetron, 5 mg o.d., is an effective, well-tolerated and simple to use antiemetic treatment for patients receiving moderately emetogenic non-cisplatin chemotherapy. The addition of dexamethasone increases the efficacy of tropisetron without significantly decreasing its tolerability.

Plasma soluble interleukin 2 receptor levels in patients with malignant lymphoma are correlated with disease activity but not cellular immunosuppression.

Studies of peripheral blood lymphocytes (PBL) and plasma from patients with malignant lymphoma [Hodgkin's disease (HD) and non Hodgkin's lymphoma (NHL)] show that plasma soluble interleukin 2 receptor (sIL2R) levels are closely linked with disease status [normal volunteers (n = 15) 402 +/- 158 u/ml; patients with Hodgkin's disease in remission (n = 4) 525 +/- 195 u/ml or with active disease (n = 11) 3026 +/- 1602 u/ml (p < 0.001); patients with non Hodgkin's lymphoma in remission (n = 6) 462 +/- 202 u/ml, active disease (n = 15) 2713 +/- 1755 u/ml, (p < 0.001)] but no correlation between sIL2R and the inhibition of interleukin 2 (IL2) generated cytotoxicity for the cell line K562. In only 1 of 15 patient plasma samples studied was there a dose dependent inhibition of IL2 generated cell killing. In a further patient, IL2 generated K562 killing was inhibited at all doses (500-3000 brmp units/ml); treatment of this plasma with anti-Interleukin 4 (alpha IL4) had no effect on the potent inhibitory activity of the plasma. Plasma sIL2R levels were markedly elevated in patients receiving IL2 in vivo (pre treatment 520 +/- 170 IU/ml, during treatment 5578 +/- 2564 IU/ml, p = 0.05). The aetiology of immunosuppression in patients with lymphoma appears to be multi-factorial; although sIL2R correlates with disease activity it does not appear to directly mediate immunosuppression in most patients with malignant lymphoma.

Intravenous treosulfan versus intravenous treosulfan plus cisplatinum in advanced ovarian carcinoma.

In a prospective, multicentre, randomized trial, the efficacy and tolerance of treosulfan alone was compared with that of treosulfan plus cisplatinum in 135 women with advanced ovarian carcinoma. No statistically significant difference was found between the two treatments in terms of median survival. Combined treatment was associated with significantly greater side-effects and haematological toxicity. Optimal survival with minimal toxicity can be achieved by using treosulfan alone in patients (mainly stages Ic or II) with minimal postoperative residual disease. Patients (likely to be stage III or IV) with greater residual disease should receive treosulfan plus cisplatinum.

EMOP/CA chemotherapy for the treatment of aggressive non-Hodgkin's lymphomas.

From October 1983 to June 1987, 32 patients with aggressive non-Hodgkin's lymphomas (diffuse centroblastic, lymphoblastic and Burkitt type) were treated with the weekly alternating EMOP/CA schedule, total duration 12 weeks. There were six bulky stage II, nine stage III and 17 stage IV patients, median age 54 years (range 19-75). The complete remission rate was 59% (95% confidence limits 40-76%) and the partial remission rate 28% providing an overall response rate of 87%. With a median follow up time of 33 months (range 18-56) the relapse-free survival of those patients achieving a complete remission is 52% and the overall survival for the 32 patients treated is 27%. The CR rate for patients with stage IV disease was 47% and for those with stage II and III disease was 73% of whom 81% remain in remission. EMOP/CA chemotherapy produces acceptable results in stage II and III aggressive non-Hodgkin's lymphomas but is inadequate therapy for stage IV disease.

Disappearance of antibodies to Factor VIII in a patient with acquired haemophilia and carcinoma of the pancreas during cytotoxic therapy with fluorouracil and CCNU.

An inhibitor to clotting factor VIII (anti-VIII:C) developed in a 70 year old woman with carcinoma of the pancreas three months after palliative by-pass surgery. A life-threatening sublingual haemorrhage was controlled by infusion of human factor VIII concentrate in high dosage. With the objective of reducing pancreatic tumour size, combination cytotoxic therapy with fluorouracil and CCNU was given. Reduction in the size of the tumour was associated with disappearance of anti-VIII:C, reappearance of normal quantities of clotting factor VIII (VIII:C) in the plasma and resolution of the bleeding tendency. The anti-VIII:C was characterised as being predominantly of the IgG4 sub-class with k light chains. In vitro and in vivo studies showed the inactivation of VIII:C by anti-VIII:C was markedly non-linear. Normal quantities of factor VIII coagulant antigen (VIII:CAg) were detected in the patient's plasma when VIII:C levels were negligible.

High-dose melphalan with autologous bone marrow transplant. Treatment of poor prognosis tumors.

Seventeen patients were treated with high-dose melphalan with autologous bone marrow transplant (ABMT) and cyclophosphamide pretreatment. All of the patients had marrow reconstitution. Although there was one death caused by infection, high-dose melphalan with ABMT causes toxicity that is generally acceptable, and can achieve a high-response rate, but with responses of short duration in tumors resistant to standard-dose combination chemotherapy. In other poor-prognosis tumors that are sensitive to chemotherapy, or can be debulked surgically, or locally irradiated, high-dose melphalan with ABMT given as late intensification therapy may significantly prolong time to relapse, and ultimately prolong survival.

[The contraceptive habits of women applying for termination of pregnancy]. / Abortsøgende kvinders kontraceptionsvaner.

PIP: During the period 1977-78, interviews were conducted with 431 women who applied for termination of pregnancy, 441 pregnant women, and 485 women selected at random and aged 15-49 from the catchment region of Herlev Hospital. The object of this investigation was to illustrate the contraceptive habits prior to, during and after conception and the intervention of women applying for pregnancy termination. Follow-up investigations were undertaken for 231 of those applying. At the time of conception, 42% of the women applying for termination stated that they had not used contraception. The method last employed depended on the circumstances of the coitus (condom, pessary, and chemical methods) in 69%. Approximately 6 months after pregnancy termination, 19% used methods dependent on the circumstances of coitus while 73% used the most effective means (IUD, pill, minipill, or sterilization). The contraceptive pattern in women applying for termination was in keeping with plans mentioned at the original interview with regard to the pregnancy termination. In the control group of fertile women chosen at random from the same geographical region, 39% employed contraceptive methods depending on circumstances of coitus and 47% employed the more effective methods. Women ages 20-34 applying for termination who had used the condom, pessary, or chemical methods as their last method prior to termination had previously used 1 of the more effective methods (OCs, minipill, or IUD). In addition, women applying for termination had employed more than 14 different methods of contraception somewhat more frequently than the control group. It is concluded that research concerning better methods of contraception should be intensified, and that information concerning contraception should be given to all and not only to special risk groups.^ieng

[Choice of termination of pregnancy. The significance of demographic and social factors]. / Valg af abort. Demografiske og sociale forholds betydning.

PIP: This investigation illustrated the causes and reasons for women's choice of pregnancy termination and various aspects of that decision making process. During a 1-year period (1977-78), 431 women applying for pregnancy termination were interviewed. Simultaneously, 441 pregnant women and 485 representatively chosen women ages 15-49 from the district served by Herlev Hospital were also questioned. Follow-up investigation was undertaken on 231 women applying for the procedure. During the investigation period, 36% of the pregnancies registered (terminations and deliveries) were interrupted by abortion. The proportion of pregnancies interrupted varied greatly depending on demographic characteristics of the women. Most of the women (81.9%) applying for pregnancy termination were either under age 20 or over 34, either unmarried or with no consort or had already had 2 or more children. Only 18.1% of the women applying for pregnancy termination were in situations which statistically fulfilled the necessary conditions for a positive attitude toward the birth of an infant; i.e., to be married or have a partner, to have fewer than 2 children, and to be between 20-35 years. 77.1% of the pregnant women who wanted to carry to term were characterized thus. Women's reasons for selecting termination reflect this pattern accurately. Consideration for profession or education and housing and economic conditions play a lesser role in the choice than the demographic factors already mentioned. The predictive value of the combination of demographic variables is reflected in the assessment of the aspects of the decision making process and the reaction to the intervention. The decision concerning pregnancy termination was most difficult to make by women who are presumed not to be past childbearing. Similarly, they more frequently developed negative reactions to the intervention than did women who are presumed to be past childbearing. (author's modified)^ieng

Prednimustine in combination with methotrexate and 5-fluorouracil in advanced breast cancer: a phase I-II study.

Forty-seven patients with advanced breast cancer were treated with a combination of prednimustine (P), methotrexate (M), 5-fluorouracil (F), and tamoxifen (TAM). Twenty-six patients received P, 80 mg/m2 day 1-5 (series I) and 21 patients received P, 100 mg/m2 day 1-5 (series II). Both series of patients received M, 40 mg/m2 day 1 and 8 and F, 600 mg/m2 day 1 and 8 with a cycle duration of 4 weeks. All patients received TAM 20 mg twice daily. As concerns the haematologic toxicity, WBC were depressed significantly more often than platelet counts, and during the first 3 cycles 70% of the patients had a WBC nadir corresponding to toxicity grade II or more. No signs of cumulative haematologic toxicity were observed. Nausea and vomiting were registered in 40 out of 47 patients but in 35 of these only of grade I-II. Only one patient developed alopecia requiring a wig. The response to treatment could be evaluated in 28 patients, 21 of whom experienced response (CR or PR) of a median duration of 13 months. In conclusion, it seems that prednimustine can be safely used in combination with methotrexate and 5-fluorouracil. The frequency of alopecia is definitely lower than with CMF. Whether this relates also to subjective side effects will require a randomized study, as will a final conclusion concerning the efficacy compared to that of CMF.

Prednimustine in combination with methotrexate and 5-FU (PMF): a pilot study.

A group of 47 patients with advanced breast cancer were treated with a combination of prednimustine, methotrexate, 5-FU, and tamoxifen. In this combination, with methotrexate and 5-FU administered at standard doses, hematologic toxicity of prednimustine at a dose of 100 mg/m2 orally on Days 1-5 repeated every 4 weeks was acceptable. Nausea and vomiting occurred in 40 of the 47 patients but was only grade 1-2 in 35 of these patients. Only one patient had alopecia to the extent of requiring a wig. Response to treatment could be evaluated in 28 patients; 21 achieved a response (complete or partial lasting a median of 13 months.