Do we have predictors of therapy responsiveness for a multimodal therapy concept and aerobic training in breast cancer survivors with chronic cancer-related fatigue?

Cancer-related fatigue (CRF) is a burdensome symptom for breast cancer (BC) patients. In this pilot study, we tested several questionnaires as predictors for treatment responsiveness, along with the implementation of a multimodal therapy concept consisting of sleep, psycho-education, eurythmy, painting therapy and standard aerobic training. At the Community Hospital Havelhöhe and the Hannover Medical School, 31 BC patients suffering from CRF could be evaluated in a 10-week intervention study. CRF was assessed by the Cancer Fatigue Scale (CFS-D). Further questionnaires were the Pittsburgh Sleep Quality Index, the autonomic regulation scale, Self-Regulation Scale (SRS), the Internal Coherence Scale (ICS) and the European Organization of Research and Treatment Health-Related Quality of Life Core Questionnaire scale. We estimated the regression coefficients of all scales on CFS-D by simple and multiple linear regression analyses and compared regression slopes and variances between the different questionnaires on CFS-D at the end of treatment. We found a significant impact of SRS and ICS at baseline on CFS-D at the end of the intervention [absolute standardised multiple regression coefficient values ranging from 0.319 (SRS) to 0.269 (ICS)] but not for the other questionnaires. In conclusion, this study supports the hypothesis that the SRS or ICS measuring adaptive capacities could be more appropriate as outcome predictors than classical questionnaire measures in complex interventions studies.

Four-year follow-up on fatigue and sleep quality of a three-armed partly randomized controlled study in breast cancer survivors with cancer-related fatigue.

Cancer-related fatigue (CRF) is a frequent long-term symptom in non-metastasized breast cancer patients (BC). This 4-year follow-up intended to compare the long-term effects of a 10-week multimodal therapy (MT: sleep education, psychoeducation, eurythmy- and painting therapy) and combination therapy [CT: MT plus aerobic training (AT)] to AT-control. BC-patients were randomized or allocated by preference to three arms in a comprehensive cohort study. Primary outcome was a composite score including Pittsburgh Sleep Quality Index (PSQI) and Cancer Fatigue Scale (CFS-D), captured at baseline, after 10 weeks of intervention (T1), 6 months later (T2), and after 4 years (T3). We exploratively tested for superiority of MT and CT versus AT after 4 years (T3) based on the statistical model of the main analysis. Of 126 (65 randomized) BC-patients included, 105 started treatments and 79 were re-assessed for long-term effects (T3). MT and CT were superior over AT after 4 years regarding PSQI/CFS-D and PSQI sum-score, respectively (all p < 0.05), but not for CFS-D. The multimodal and combination treatment for breast cancer patients with CRF indicates sustainable long-term superiority over aerobic training for the outcomes sleep quality and combined sleep quality/fatigue. A confirmative randomized controlled trial is warranted.

The Anthroposophic Artistic Movement Assessment for Eurythmy Therapy (AART-ASSESS-EuMove). A validation study.

OBJECTIVE: Eurythmy Therapy (ET) is a mindfulness oriented therapy developed in the context of anthroposophic medicine. Despite commonly used in practice, it remains unclear whether active participation (Inner Correspondence) during ET can be observed in eurythmy gestures (EGest). So far, no validated peer-report instrument to evaluate EGest exists. METHOD: To validate an 83-item ET peer-report scale, a nested study on a sample of n = 82 breast cancer survivors with cancer-related fatigue was conducted. EGest were evaluated twice, at baseline and at 10-week follow-up, by peer-reports from two separate therapists. Interrater-reliability (IRR) was estimated by Cohen's weighted kappa (κw) across all items. Additionally, reliability-(RA) and principal component analyses (PCA) were conducted. Patients completed two self-report scales: Satisfaction with ET (SET) and Inner Correspondence with the Movement Therapy (ICPH). RESULTS: IRR was greater than or equal (κw ≥ 0.25) for 41 items (49.3%) with a mean weighted kappa of κ̅w = 0.40 (SD = 0.17, range = 0.25-0.85). RA resulted in the exclusion of 25 items with insufficient item-total correlations < 0.40. A PCA with 16 items revealed 3 subscales: 1. Mindfulness in Movement (8 items), 2. Motor Skills (5 items), 3. Walking Pattern (3items) explaining 63.86% of total variance. Internal consistency (Cronbach's alpha) was high for the sum score with α = 0.89 and for the subscales with α = 0.88, 0.86 and 0.84 respectively. Significant small to moderate subscale correlations were found ranging from r = 0.29-0.63 (all p < 0.01). Mindfulness in Movement correlated with Inner Correspondence (r = 0.32) and with Satisfaction with ET (r = - 0.25, both p < 0.05). CONCLUSIONS: The new AART-ASSESS-EuMove is the first consistent and reliable peer-report instrument to evaluate EGest. It shows associations between peer-reported Mindful Movement and patients' self-reported ICPH and SET.

Calling 911 in response to stroke: no change following a four-year educational campaign.

BACKGROUND: Public awareness campaigns are conducted to increase stroke awareness, yet evidence of their long-term effectiveness is limited. Since 2006, the Czech Stroke Society has conducted an educational campaign throughout the Czech Republic (CR) to increase awareness about stroke. This report evaluates the effectiveness of this campaign by comparing the results of a nationwide survey on stroke awareness in 2009 with the results from 2005. METHODS: In 2009, a nationwide survey was conducted throughout the CR using the same methodology as in 2005 and employing a 3-stage random sampling method (area, household, and household member sampling). Participants >40 years of age were personally interviewed via a structured questionnaire concerning their knowledge and ability to correctly respond to stroke as assessed by the validated Stroke Action Test (STAT). The primary outcome measure was the difference in a STAT score >50% (i.e. respondents chose to call 911 for >50% of stroke symptoms) between 2005 and 2009. Campaign intensity was characterized by a systematic search for media messages about stroke in the CR. RESULTS: A total of 601 interviews were obtained (90% response rate) in 2009 (592 people were interviewed in 2005). A STAT score >50% was achieved by 18% of the respondents both in 2005 and 2009 (p = 0.89). There was no increase in the knowledge of risk factors or warning signs between 2005 and 2009. Respondents who noticed the campaign (19%) had better STAT scores than respondents who did not (25 vs. 17%; p = 0.038). A systematic search revealed that the campaign had reasonable intensity because there were 978 media reports about stroke between 2006 and 2008. CONCLUSIONS: A medium-intensity educational campaign, based on donated advertising media, failed to increase stroke awareness. However, if the campaign had reached more people, it might have been effective. Therefore, in the future, paid advertising media should accompany free media, although such approach would require a substantially larger budget. Awareness campaigns should be constantly evaluated for their effectiveness to develop more successful strategies.

Validation of the State Version Questionnaire on Autonomic Regulation (State-aR) for cancer patients.

OBJECTIVES: Current quality of life inventories used in oncology mainly measure the effects of chemo- or radiotherapy alongside functional and role scales. A new approach is to measure the autonomic state of regulation with the trait-inventory of autonomic regulation (Trait-aR). Loss of Trait-aR has been shown in different medical conditions such as breast cancer (BC) but not in colorectal cancer patients (CRC). In this paper we report the validation of a new state autonomic regulation scale (State-aR) of the last week. METHODS: Study 1 included 114 participants: (41 women/16 men with cancer and 57 age- and gender-matched healthy people) to conduct a reliability-, factor- and validity-analysis. Concurrent and convergent validity was evaluated with Trait-aR, Fatigue-Numerical-Scale, Hospital Anxiety and Depression Scale (HADS-D) and the self-regulation scale, 65 participants were retested. Study 2 completed 42 participants: 17 with BC and 25 with CRC receiving chemotherapy. The State-aR was administered prior, during and after chemotherapy for measuring responsiveness. RESULTS: The factor analysis loaded to four subscales of State-aR (rest-activity, orthostatic-circulatory, thermo-sweating and digestive regulation) with a: Cronbach-α r(α) = 0.77?0.83 and a test-retest-reliability r(rt) = 0.60?0.80. The sum- and subscales correlated with their concurrent subscales in the Trait-aR (0.48?0.74) and with the sum-scale moderately with all convergent criteria (r = 0.41?-0.44; p <0.001). During chemotherapy the State-aR-sum and rest-activity-scale decreased significantly compared to the change in the Trait-aR (p <0.05). CONCLUSIONS: These findings support that the state autonomic regulation scale has satisfactory to good reliability, good validity and acceptable responsiveness in the context of chemotherapy treatment.

The Anthroposophic Art Therapy Assessment Paint (AART-ASSESS-P): A peer-report instrument to assess patients' pictorial expression during Anthroposophic Painting Therapy.

OBJECTIVE: Anthroposophic painting therapy (APT) is a specific form of art therapy that aims to activate self-healing capacities through painting aquarelles. METHODS: The Anthroposophic Art Therapy Assessment-Paint' (AART-ASSESS-P) was developed to measure pictorial expression and validated in the framework of a comprehensive cohort design study. The validation study examined 68 breast cancer patients with fatigue. Art therapists made pre- and post-assessments of spontaneously drawn water-color paintings with a preliminary version of the AART-ASSESS-P (58 items). Inter-rater reliability (IRR) for the items was examined with Cohen's weighted Kappa (κw). Additionally, a reliability- and factor analysis (FA) were conducted. Convergence criteria were patients' self-report measures: the Satisfaction with Painting Therapy, Inner Correspondence with Painting Therapy and the Self-Regulation Questionnaire. RESULTS: IRR for the items was heterogeneous (κw= 0.09-0.89, Mean κw= 0.40, SD = 0.17). Thirty-six items were excluded due to insufficient IRR and item-total correlation (κw= < 0.30, ρitem-total< 0.30). A FA with 22 items revealed 5 subscales: Shape Development (6 items), Shape Arrangement (6 items), Order and Symmetry (5 items), Color Application (3 items), and Color Quality (2 items) explaining 61% of total variance. Psychometric properties for the AART-ASSESS-P were satisfying with Cronbach's alpha coefficients (rα = 0.60-0.81) across subscales. Due to weak inter-subscale correlations (r = 0.18-0.48, p < 0.05) and the ambiguity of face validity a sum-score was not formed. Correlations between subscales and self-reports were small (all p < 0.05). CONCLUSION: The AART-ASSESS-P is the first reliable instrument to measure pictorial expression during APT.

Safety of performing CT angiography in stroke patients treated with intravenous thrombolysis.

OBJECTIVE: Exposure to contrast agents may cause nephrotoxicity. The safety of performing CT angiography without having knowledge of the baseline creatinine level in stroke patients treated with tissue plasminogen activator (tPA) has not been established. METHODS: This is an observational cohort study, with a historical control group to evaluate the safety of CT angiography performed before tPA treatment given within 3 h of symptom onset. The CT angiography group represents all patients treated with tPA between September/2003 and November/2007 who had CT angiography. The control group consists of all patients treated with tPA between January 1999 and August 2003 when CT angiography was not performed. The primary outcome was a creatinine increase in 24-72 h compared with baseline; the secondary outcome was a creatinine increase by > or = 44 micromol/l in 24-72 h and the incidence of symptomatic intracerebral haemorrhage (sICH). RESULTS: Baseline parameters between the CT angiography group (164 patients, age 70+/-11; 91 male) and the control group (77 patients, age 67+/-11; 45 male) were similar. In the CT angiography group, the mean creatinine increase was -0.89 mmol/l and in the control group 2.2 mmol/l (p=0.42). A creatinine increase of > or = 44 micromol/l occurred in five patients (3%) in the CT angiography group and in three patients (4%) in the control group (p=0.50). Also, in the CT angiography group, eight patients (5%) had sICH as compared with three patients (4%) in the control group (p=0.73). CONCLUSION: Contrast agents given for CT angiography, performed in patients with normal and abnormal creatinine level, neither caused renal injury nor interfered with the safety of tPA treatment.

Reliability and first validity of the inner correspondence questionnaire for painting therapy (ICPTh) in a sample of breast cancer patients.

Objectives Art therapy (ArT) such as mindfulness-oriented painting therapy is increasingly used in psychosomatic, oncological integrative and rehabilitative medicine. Though it remains unknown how ArT works, we hypothesize that an engaged participation with painting ('Inner-Correspondence') contributes to improved symptom scores. In the context of a comprehensive cohort study for breast cancer survivors with cancer-related fatigue, we developed a patient-reported outcome measure to assess 'Inner Correspondence' with painting therapy and conducted a first validation study. Design A 24-item questionnaire on 'Inner Correspondence' (ICPTh) was administered after ten weeks of intervention and at six month followup together with concurrent scales (Inner Correspondence and Peaceful Harmony, Cancer Fatigue Scale, Hospital Anxiety and Depression Scale, Internal Coherence Scale). Statistical assessment included reliability- and factor analyses. Results A total of n = 68 BC (mean age, 58.2 years, SD = 8.7) participated in the preliminary validation study. Exploratory factor analysis revealed a robust 22-item scale with an unambiguous four-factor solution explaining 78% of total variance and the following subsales: 1) therapy congruence and relaxation (11 items), 2) inner development and mood (6 items), 3) artistic skill (3 items) and 4) task congruence (2 items). The 22-item ICPTh yielded high reliability (Cronbach's alpha = .966, item-total correlation = .497 - .883, test-retest reliability = .888). Conclusions We present a reliable instrument to measure 'Inner Correspondence' with painting therapy. Due to the small sample size and sample selection further validation studies are indicated.

Validation of a questionnaire measuring the regulation of autonomic function.

BACKGROUND: To broaden the range of outcomes that we can measure for patients undergoing treatment for oncological and other chronic conditions, we aimed to validate a questionnaire measuring self-reported autonomic regulation (aR), i.e. to characterise a subject's autonomic functioning by questions on sleeping and waking, vertigo, morningness-eveningness, thermoregulation, perspiration, bowel movements and digestion. METHODS: We administered the questionnaire to 440 participants (female symbol: N = 316, male symbol: N = 124): 95 patients with breast cancer, 49 with colorectal cancer, 60 with diabetes mellitus, 39 with coronary heart disease, 28 with rheumatological conditions, 32 with Hashimoto's disease, 22 with multiple morbidities and 115 healthy people. We administered the questionnaire a second time to 50.2% of the participants. External convergence criteria included the German version of the Hospital Anxiety and Depression Scale (HADS-D), a short questionnaire on morningness-eveningness, the Herdecke Quality of Life Questionnaire (HLQ) and a short version questionnaire on self-regulation. RESULTS: A principal component analysis yielded a three dimensional 18-item inventory of aR. The subscales orthostatic-circulatory, rest/activity and digestive regulation had internal consistency (Cronbach-alpha: ralpha = 0.65 - 0.75) and test-retest reliability (rrt = 0.70 - 85). AR was negatively associated with anxiety, depression, and dysmenorrhoea but positively correlated to HLQ, self-regulation and in part to morningness (except digestive aR) (0.49 - 0.13, all p < 0.05). CONCLUSION: An internal validation of the long-version scale of aR yielded consistent relationships with health versus illness, quality of life and personality. Further studies are required to clarify the issues of external validity, clinical and physiological relevance.

Sodium transport by rat cortical collecting tubule. Effects of vasopressin and desoxycorticosterone.

We have used rat cortical collecting tubules perfused in vitro to study the effects of antidiuretic hormone (ADH) and desoxycorticosterone (DOCA) on the unidirectional fluxes of sodium. We found that in the basal state, lumen-to-bath flux (Jlb) and bath-to-lumen flux (Jbl) of 22Na were approximately equal, 39.5 +/- 3.9 and 41.8 +/- 11.0 pmol X min-1 X min-1, respectively, resulting in no net flux. Addition of 100 microU/ml ADH to the bath produced a stable increase in Jlb to 58.3 +/- 4.7 pmol X min-1 X mm-1. Pretreatment of the animal with DOCA for 4 to 7 d (20 mg/kg per d) increased baseline Jlb to 81.6 +/- 8.7 pmol X min-1 X mm-1. Addition of ADH to a tubule from a DOCA-pretreated rat caused an increase in Jlb to 144.1 +/- 12.0 pmol X min-1 X mm-1 X Neither hormone had an effect on Jbl X Thus ADH produced a greater absolute and fractional increase in Jlb when the animal was pretreated with DOCA, and the ADH-induced increase over baseline was greater than the DOCA-induced increase. Both the ADH-and DOCA-induced stimulation of Jlb were completely abolished by 10(-5) M luminal amiloride, suggesting that the route of sodium transport stimulated by both hormones involves apical sodium channels. However, ADH and DOCA have very different time courses of action; ADH acted within minutes, while aldosterone and DOCA are known to require 90-180 min. The facilitating action of ADH on DOCA-induced stimulation of sodium transport may be important for maximal sodium reabsorption and for the ability to achieve a maximally concentrated urine.

Caregivers' perception of HIV-infected Dominican children's behaviour.

Caregivers (mothers and non-mothers) of HIV children face many challenges related to both physical demands and emotional well-being. The perception of caregivers in the Dominican Republic, a country greatly impacted by HIV/AIDS, in regard to their children's behaviour, has not been investigated to date. To extend understanding of the potential behavioural issues involved in providing care to children without access to antiretroviral therapy, the Child Behaviour Checklist was administered to 52 caregivers of HIV Dominican children (2-8 years old). Both mothers and non-mothers perceived significant pathological internalizing behavioural symptoms in immunosuppressed children, compared to children with less disease progression. Analyses of gender comparisons revealed that older female children were perceived as withdrawn/depressed by their caregivers. These findings suggest that children's disease status may be an important contributor to caregiver perception in mothers, as well as non-mothers and indicate that gender-specific relationships warrant further study.

Behavioural symptoms of children with HIV infection living in the Dominican Republic.

OBJECTIVE: The purpose of this report is to describe behavioural problems encountered in a group of Dominican children living with Human Immunodeficency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) in the Dominican Republic. They were not receiving antiretroviral treatment. METHOD: The participants were 43 children with HIV infection (2 to 8 years of age) who were attending an immunology clinic in the largest paediatric hospital in the Dominican Republic. All of the participants were vertically infected with the HIV virus (mother-to-child transmission) and had a very low socio-economic status. The children's caregivers were administered the Child Behavioural Checklist (CBCL) by trained psychologists to determine the caregivers 'perception of the children's behavioural problems. Behavioural findings were examined according to the CBCL age format: younger children (under 5 years of age) and older children (over 6 years of age). RESULTS: Descriptive statistics revealed a high proportion of the children, both younger (approximately 40%) and older (46%) scored in the borderline/clinical ranges for internalizing problems, including anxiety, withdrawn-depressed and somatic complaints. In addition, 46% of the older children were perceived as having externalizing problems (rule breaking and aggressive behaviour). CONCLUSION: These findings suggest that a high incidence of behavioural and mood problems may be prevalent among Dominican children with HIV Thefindings are discussed in terms of future research to examine other risk factors that might contribute to the high rate of maladaptive behaviours observed in the present report, including the contribution of socio-economic status, caregiver illness, caregiver education and parental loss.

A pilot study on systemic thrombolysis followed by low molecular weight heparin in ischemic stroke.

Low molecular weight heparin (LMWH) administered immediately after intravenous thrombolysis (IT) may reduce the risk of arterial re-occlusion. Its benefit, however, may not outweigh the risk of intracranial hemorrhage (ICH). We sought preliminary data regarding safety of this combined therapy in an open-label, non-randomized study. The patients received either a standard anticoagulation (AC) starting 24 h after IT (the standard AC group) or AC with 2850 IU of nadroparin, given every 12 h immediately after IT (the early AC group). Sixty patients received IT treatment: 25 in the standard AC group [mean age 66, median National Institutes of Health Stroke Scale (NIHSS) 13, 64% men] and 35 in the early AC group (mean age 68, median NIHSS 13, 69% men). Symptomatic ICH occurred in one patient (4%) in the standard AC group and three patients (8.6%) in the early AC group [odds ratio (OR) 1.8; 95%CI 0.2-12.8]. At 3 months, nine patients in the standard AC group (36%) and 16 patients in the early AC group (45.7%) achieved a modified Rankin scale 0 or 1 (OR 1.2; 95%CI 0.5-3.2). Our study suggests that treatment with LMWH could be associated with higher odds of ICH, although it may not necessarily lead to a worse outcome. This justifies larger clinical trials.

Stimulation of sodium transport by aldosterone and arginine vasotocin in A6 cells.

The effects of aldosterone and arginine vasotocin (AVT) on transepithelial Na+ transport of cultured A6 cells were investigated. All experiments were performed with cells grown on Millicell TM culture-plate inserts for a period of 2-4 weeks in defined, serum-free medium. Omitting fetal bovine serum 2 days after seeding the cells on filters did not influence potential difference (PD) development or the hormonal responses tested. The cell layers were placed in an Ussing chamber for short-circuit current (ISC) and transepithelial conductance (G) measurements. Base-line values were (n = 93): PD, 51.0 +/- 0.2 mV (apical side negative); ISC, 14.55 +/- 0.06 microA/cm2; G, 0.306 +/- 0.001 mS/cm2. ISC and G were higher in cells pretreated with 10(-7) M aldosterone for 24 h in the incubator, when compared to controls (ISC, 28 +/- 2 vs. 16 +/- 2 microA/cm2, G, 0.41 +/- 0.04 vs. 0.26 +/- 0.01 mS/cm2, n = 5) and both remained stable for at least 6 h. In cells not treated with aldosterone, 10(-7) M AVT increased ISC within 1 min after addition, producing a maximum ISC within 15 min which then declined to baseline levels over the next 5 h. Addition of AVT to aldosterone-pretreated cells resulted in a significantly greater peak increase in ISC than in non-pretreated cells (change in ISC compared to controls: 8.1 +/- 0.4 vs. 4.9 +/- 0.4 microA/cm2, n = 5, P less than 0.001), indicating a synergistic effect. A dose-response curve for amiloride obtained in the presence of AVT showed that amiloride completely inhibits ISC. Pretreatment of the A6 cells with aldosterone for 24 h shifted the amiloride dose-response curve to the right, as expressed in a doubling of the apparent Ki value (from 0.17 +/- 0.02 to 0.33 +/- 0.04 microM). In conclusion, A6 cells grown in defined, serum-free medium express a greater than additive synergism between aldosterone and AVT in stimulating transepithelial Na+ transport.

A nuclear mutation that post-transcriptionally blocks accumulation of a yeast mitochondrial gene product can be suppressed by a mitochondrial gene rearrangement.

The nuclear amber mutation, pet494-1, specifically blocks the accumulation of the product of the mitochondrial gene oxi2, cytochrome oxidase subunit III. The pet494-1 mutation does not prevent transcription of the mitochondrial gene since RNA--gel blot hybridizations showed that mutant cells contain normal amounts of an oxi2 transcript, indistinguishable in size from wild-type. A mitochondrial mutation that partially suppresses the nuclear mutation was isolated. The "mitochondrial revertant" behaved as though it contained two different mitochondrial DNAs: one rho+, the other rho-. The suppressor mutation is carried on the rho- mitochondrial DNA and is apparently the result of a gene fusion between oxi2 and another mitochondrial gene, oxi3. This gene rearrangement replaced the normal 5'-non-translated sequence of oxi2 with a portion of the open reading frame of the second intron of oxi3. Novel transcripts of the rearranged gene, containing oxi3 sequences upstream from oxi2 were detected in the mitochondrial revertant. The strain accumulated an electrophoretically variant form of cytochrome oxidase subunit III, probably translated from a new initiation codon. The data are consistent with models in which the PET494 protein acts within the mitochondria to specifically promote the translation of the oxi2 messenger RNA.

Genetic markers at the leptin (OB) locus are not significantly linked to hypertension in African Americans.

Increased body mass index (BMI) has been correlated with increased blood pressure in human populations. To examine the role of the leptin gene (OB) in essential hypertension in African Americans, we performed affected sib pair analysis on a set of 103 hypertensive African American sibships using four highly polymorphic markers at the human leptin locus. No evidence of linkage was detected between these markers and the phenotype of essential hypertension either in these sibships or in a severely obese subset of 46 sibships in which each sibling had a BMI > or = 85th percentile for the US population. Using BMI rather than hypertension as a quantitative trait, we found significant linkage for the marker D7S504 (P=0.029) but not for the other markers. Significance strengthened in the overweight subset of sibships for this marker (P=0.001), and there was a trend of lower P values for the other three markers. However, multipoint analysis with the use of all four markers simultaneously to estimate linkage between BMI and the leptin locus did not demonstrate a statistically significant relationship. Analysis of the coding region of the leptin gene (exons 2 and 3) by single-strand conformational polymorphism revealed a rare Ile-Val polymorphism at amino acid 45 but revealed no other alterations. These results suggest that the OB gene is not a major contributor to the phenotype of essential hypertension in African Americans, although a minor contribution to the phenotype of extreme obesity in this group cannot be ruled out.

Growth of cultured human cerebral meningiomas is inhibited by dopaminergic agents. Presence of high affinity dopamine-D1 receptors.

We have found that microM concentrations of the dopamine agonist bromocriptine significantly decrease the proliferation rate of human meningioma cells in culture (25-56% inhibition). This effect was also seen with direct application of dopamine, as well as the dopamine-D1 agonist (+)-SKF-38393 (both applied in microM concentrations) to meningioma cell cultures. Receptor studies with the dopamine-D1 ligand (125I)SCH-23982 (dopamine-D1 antagonist) indicated that dopamine-D1 binding sites were present in the membranes of meningioma tissue. The mean dissociation constant (Kd) was 325 ( +/- 74.5 SEM) pM and the receptor density (Bmax) was 25.4 ( +/- 1.5 SEM) fmol/mg pellet protein in 5 human meningiomas. The pharmacological specificity was proven by (+)-SKF-38393, ( +/-SKF-83566 or (+)-butaclamol and their inactive isomers (-)-SKF-38393 and (-)-butaclamol in a 1000 fold excess. These results provide evidence that human meningiomas possess high affinity dopamine-D1 receptors and that dopamine agonists have an antiproliferative effect on these tumors in culture. We conclude that the proliferation of cerebral meningiomas may be under dopaminergic control and that dopamine agonists may have a role in the medical treatment of patients with meningiomas.

Safety, tolerability, and efficacy of orally administered cannabinoids in MS.

The authors conducted a randomized, double-blind, placebo-controlled, twofold crossover study in 16 patients with MS who presented with severe spasticity to investigate safety, tolerability, and efficacy of oral Delta(9)-Tetrahydrocannabinol (THC) and Cannabis sativa plant extract. Both drugs were safe, but adverse events were more common with plant-extract treatment. Compared with placebo, neither THC nor plant-extract treatment reduced spasticity. Both THC and plant-extract treatment worsened the participant's global impression.

Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis.

Cannabinoids can modulate the function of immune cells. We here present the first human in vivo study measuring immune function in 16 MS patients treated with oral cannabinoids. A modest increase of TNF-alpha in LPS-stimulated whole blood was found during cannabis plant-extract treatment (p=0.037), with no change in other cytokines. In the subgroup of patients with high adverse event scores, we found an increase in plasma IL-12p40 (p=0.002). The results suggest pro-inflammatory disease-modifying potential of cannabinoids in MS.

Effects of candesartan cilexetil in patients with systemic hypertension. Candesartan Cilexetil Study Investigators.

The objectives of this double-blind, multicenter, randomized, parallel-arm, placebo-controlled study were to evaluate the dose-related efficacy, tolerability, and safety of candesartan cilexetil, a potent, AT1 selective, long-acting angiotensin II receptor blocker, in 365 adult patients with systemic hypertension and mean sitting diastolic blood pressure (BP) of 95 to 114 mm Hg. Patients received either placebo or candesartan cilexetil 2, 4, 8, 16, or 32 mg once daily for 8 weeks. All doses of candesartan cilexetil reduced trough (24 hours after treatment) sitting diastolic and systolic BP significantly compared with placebo (p < 0.005). A significant (p < or = 0.0001) dose response was evident, with greater decreases in BP at higher doses. Mean changes in BP were -10.7/-7.8 mm Hg and -12.6/-10.2 mm Hg in the 16- and 32-mg groups, respectively, versus -0.3/-2.6 mm Hg in the placebo group. The 16- and 32-mg doses were consistently significantly superior to placebo in antihypertensive effect with regard to all BP measurements, including peak (6 hours after treatment), trough, sitting, and standing measurements of diastolic and systolic BP. Responder rates (trough sitting diastolic BP < 90 or > or = 10 mm Hg BP decrease) were 54% and 64% for the 16- and 32-mg groups, respectively. Tolerability and safety profiles were similar to placebo at all doses. In conclusion, candesartan cilexetil administered once daily effectively reduces BP in a dose-related manner while maintaining safety and tolerability; doses of 16 and 32 mg are most effective for treatment of hypertension.