The antidotal potency of pyridinium oximes is as a result of reactivation of the phosphorylated cholinesterases.96,97 Oximes can reactivate phosphorylated cholinesterases via replacing the phosphoryl moiety from the enzyme. Phosphorylated oximes are produced during this reaction and some of them seem to be potent inhibitors of AChE.98 The choice of oximes is based on the data presently available and may also be dependent on factors other than Inhibitors,research,lifescience,medical protection against lethality, such as cost and availability of the oximes and their side effects. Obidoxime (Toxogonin) is likely to cause more toxic effects than

pralidoxime and HI6. asoxime is the least toxic, but is less unstable in solution and is not commercially available in many parts of the

world.18 In soman-intoxicated guinea pigs, HI6 was therapeutically slightly more effective than HLo7, but was less effective than HLo7 against tabun intoxication.99 Pyridinium oximes are mostly used against OP-inhibited AChE in Inhibitors,research,lifescience,medical the peripheral nervous system and not as much in CNS. This is due to a limited penetration across the blood–brain Inhibitors,research,lifescience,medical barrier (BBB). However, it appears that the oximes penetrate BBB more than expected, since in soman poisoning oxime concentration in the brain was high.100 Recent studies in rats have shown that modulation of the BBB by a drug like tariquidar is of great value in enhancing the efficacy of oximes.101 The induction of local inflammatory processes and increase of brain–blood flow may also have some roles in enhancing the penetration of oximes through BBB. Sakurada et al have determined the amount of PAM-2 passing across the BBB at approximately 10% of the given dose. This amount may be effective in the reactivation of OP-inhibited AChE in

the brain. Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical A new class of amidine-oxime HA1077 reactivators of organophosphate (OP)-inhibited cholinesterases (ChE) have been reported to have increased BBB penetration with greater reactivation rates for OP-BuChE than pralidoxime (2-PAM) and monoisonitrosoacetone, but lower rates for OP-AChE reactivation compared to 2-PAM.102 In another study, the authors demonstrated that purified human and rabbit serum paraoxonase1 significantly protected against sarin and soman exposure in guinea pigs.103 Newly developed oximes (K206, K269) are relatively effective in reducing nearly cyclosarin-induced lethal toxic effects in mice. Their therapeutic efficacies exceed the therapeutic potency of obidoxime but not HI-6.104 Relative therapeutic effects of oximes in different OPs are presented in table 3. Table 3: Relative therapeutic effects of different oximes in organophosphate nerve agents poisoning Pralidoxime should be administered intravenously at 30 mg/kg initially over 30 min, followed by constant infusion of 8 mg/kg/hr in dextrose 5% solution.105 It could be continued until the full recovery or until atropine is required.

85.6%, P=0.304) survival rates, suggesting that RFA is an acceptable alternative treatment in patients with solitary CRHM smaller than 3 cm who are not candidates for resection. In another study, Otto et al. (63) showed that there is no difference in overall 3-year survival between resection and RFA for early CRHM, even though RFA was associated with higher local tumor recurrence rates and shorter time to progression. In yet another recent study, Kim et al. (52)

suggest that RFA may be a safe alternative treatment for solitary CRHM <3 cm, with equivalent outcomes Inhibitors,research,lifescience,medical (overall and disease-free survival) compared to resection. These data suggest that RFA represents an effective local treatment for patients who are unsuitable for conventional surgical treatment. However, caution is warranted in using CI-1033 datasheet ablation Inhibitors,research,lifescience,medical in lieu of resection for patients who are suitable candidates for surgical treatment. Ablation should NOT be seen as a replacement for hepatic resection and does not preclude the need of systemic chemotherapy. Furthermore, the candidates for this specific approach are likely to be few. Important clinical and technical considerations for thermal tumor ablation

Just as the vast majority of patients with CRHM are not candidates for potentially curative resection, most will also Inhibitors,research,lifescience,medical not be candidates for evolving strategies that includes staged hepatic resection with or without tumor ablation, regional infusion therapies, and the preceding approaches in the context of systemic regimens. The evolving field of regional hepatic therapies lacks mature data to guide the Inhibitors,research,lifescience,medical approach, such as the

optimal sequence of therapies and defining the target patient population that may be most likely to benefit. As such, we put forth a few caveats, which are critical in the treatment planning process for these complex patients. The most important determinant of outcome for patients with CRHM is the biology or extent of disease. Regardless of the treatment efficacy of any one modality at the local level (liver), the presence of progressive, persistent, or chemotherapy-refractory systemic disease should in most instances preclude the use of resection or thermal Inhibitors,research,lifescience,medical tumor ablation. heptaminol Assuming the conditions described in the previous paragraph are met, the limitations of thermal tumor ablation are straightforward, and by no means complete in the listing that follows: (I) At any given time, there must be sufficient hepatic reserve to ensure adequate function. (II) The use of ablation as a prelude to resection should encompass the principles of known treatment failures, such as heat sinks. Basing a future liver remnant on a portion of liver at high risk for persistent or recurrent tumor in the ablation zone should be avoided. (III) The potential for inadvertent for injury to vital hepatic structures needs to be carefully considered utilizing TTA for CRHM, particularly in the context of a staged approach to ensure adequate inflow and outflow for the liver remnant.

Imaging results MS-275 cell line Consistent groups The first comparison of interest was activation to all DD task trials versus SMC trials. In the within-group results, consistent HC qualitatively showed more widespread activation, such as in putative executive function areas (the inferior and middle

frontal gyri, dorsal anterior cingulate cortex or dACC, and inferior parietal lobule), attention-related areas (precuneus), and midbrain, to the task than did consistent SZ (Table S2, Fig. S1). In the consistent between-group analysis (Table ​(Table2,2, Fig. ​Fig.6),6), significantly enhanced activation in DD over SMC trials in the HC (Fig. ​(Fig.6,6, red) occurred in regions including the inferior frontal gyrus; Inhibitors,research,lifescience,medical medial wall locations such as dACC extending into supplementary motor area (SMA) Inhibitors,research,lifescience,medical and pre-SMA motor areas; posterior parietal cortex extending into occipital cortex; and subcortically, in the ventral striatum, thalamus, and midbrain. By contrast, greater activation in the SZ group (Fig. ​(Fig.6,6, blue) was found in the insula, with the cluster extending Inhibitors,research,lifescience,medical into the frontal operculum and superior temporal gyrus, and in a more posterior medial wall cluster that included the precuneus and posterior and middle cingulate gyrus. Table 2 Consistent patients and consistent

controls: between-group fMRI results for DD task>SMC trials1 Figure 6 Between-group results for activation to task>SMC trials revealed more activation in controls (red) in frontoparietal areas, including inferior frontal gyrus and medial areas of the prefrontal cortex, and subcortically in the striatum and thalamus; … Additional contrasts of interest

were related to DD trial difficulty. Although the within-group analyses of activation to hard>easy trials were not significant Inhibitors,research,lifescience,medical in HC or in Inhibitors,research,lifescience,medical SZ, the reverse contrast of easy>hard trials revealed significant results in both groups (Table S3). HC exhibited activation in areas including the middle cingulate gyrus, superior parietal cortex, insula, and middle temporal cortex. SZ showed activation in the superior and middle frontal gyri, middle and posterior cingulate gyrus, inferior parietal Bay 11-7085 cortex, and middle temporal cortex. Comparing groups for the difference in activation to easy versus hard trials (Fig. ​(Fig.7,7, Table ​Table3)3) showed an interaction between group and difficulty in one large cluster that included lateral frontal regions such as the superior and middle frontal gyri, medial wall regions such as the dACC extending into the SMA/pre-SMA areas, and parietal locations such as inferior parietal lobule. Table 3 Consistent patients and consistent controls: between-group fMRI results for trial difficulty1 Figure 7 Between-group results for activation to hard>easy trials revealed an interaction between difficulty and group. For controls>consistent patients, the contrast is hard>easy; for consistent patients>controls, the contrast …

In keeping with the hypothesis of a common pathogenetic pathway, allelic mutations of any of these genes results in conditions of variable severity broadly correlated with the degree of ADG hypoglycosylation. Molecular genetic PH-797804 supplier analysis of patients with a dystroglycanopathy therefore should include all these 6 genes; however, approximately 35% of patients have no identifiable mutations, Inhibitors,research,lifescience,medical strongly pointing towards further genetic heterogeneity. Genetic analysis suggests that the possibility of a single major locus accounting for the remaining dystroglycanopathies

is unlikely and we must be prepared to search for multiple genes associated with the glycosylation of ADG. Acknowledgement

The authors wish to thank the ENMC CMD consortium Inhibitors,research,lifescience,medical for the ongoing collaboration. The financial support of the Muscular Dystrophy Campaign and of the Department of Health (NCG) is gratefully acknowledged. The group at Guy’s Hospital Trust London involved in the NCG diagnostic work (Dr Stephen Abbs; Mrs Rachael Mein; Miss Judith Pagan) is also gratefully acknowledged.

This very rare disease has a frequency estimated at 1 in 8 million births. This, however, seems to be underestimated due to misdiagnosed or non-recognized cases and could Inhibitors,research,lifescience,medical be 1 in 4 million. The disease affects mainly Caucasians, slightly more boys (M:F = 1.5:1). HGPS is a multisystem disorder affecting

various organs – muscles, bones, skin, subcutaneous Inhibitors,research,lifescience,medical tissue, heart, etc. The classic symptoms are: short stature, bird-like faces, cranio-facial disproportion, baked beak nose, micrognathia, graying sparse hair, wrinkled tight skin with pigmentation and prominent vessels, in some cases scleroderma-like indurations, pear-shaped thorax, coxa valga, short clavicles, joint contractures, osteolysis of distal phalanges Inhibitors,research,lifescience,medical of fingers, delayed dentition, cataract (Fig. ​(Fig.1).1). Early atherosclerosis, leading to heart infarction or stroke is the main cause of death. Very characteristic is low weight and delayed growth. IQ is usually normal, no brain changes have been described (3–7). Figure 1 Hutchinson-Gilford progeria (from CYTH4 collection of prof. S. Jablońska). Most of these symptoms mentioned appear between 6 and 18 months of life, at birth the child is usually considered to be normal. The mean life-span in typical cases is estimated at about 11 years, but single older cases (even > 20 years old) with confirmed diagnosis have been reported (9). Most of the cases reported so far (no more than ± 110) were sporadic, products of consanguineous parents. The mode of transmission, according to most authors, is autosomal dominant (AD). In a few cases, the mode of transmission was autosomal recessive (10, 11). The risk of recurrence is estimated as lower than 3%.

Brown et al. performed a study

yielding these data (39). From their work, it is possible to estimate the average number of lymph nodes present per centimeter of resected colon (three) as well as the average number of positive nodes present in surgical cases that have become metastatic (nine). While these numbers seem high, it should be kept in mind that these were collected in an exhaustive search utilizing fat-clearing methods. Utilizing these numbers, we have plotted the Negative Predictive Value (NPV) versus number of lymph nodes sampled and conclude Inhibitors,research,lifescience,medical that sampling 12-15 lymph nodes produces an NPV of 78-83% (Figure 2). Figure 2 Negative Predictive Value vs. Number of Negative Lymph Nodes Sampled. Plot demonstrates the theoretical negative predictive value (NPV) for lymph node metastatic disease based upon Inhibitors,research,lifescience,medical the number of lymph nodes sampled, assuming each node sampled is negative … Difficulties in staging Current surgical guidelines (41) recommend excising the primary feeder arterial vessel supplying the involved section of colon, along with the corresponding mesocolon, lymph nodes and lymphatics. These guidelines recommend 5 cm of normal bowel surrounding the primary lesion. The resected material is then sent for pathology evaluation. There Inhibitors,research,lifescience,medical are many factors involved in staging colon cancer, of which the most prognostically significant is the lymph node

status (2-4). The College of American Pathologists currently recommends examination of 12 lymph nodes as a benchmark Inhibitors,research,lifescience,medical for proper staging (14); this is supported by numerous studies including the analysis above, although some even advocate

a higher number (5,27). All specimens (like all patients) are not equal, however. Many times the standard approach to both surgery and staging must be modified. From the pathologist’s perspective, no guidelines exist to standardize the process involved in lymph node search. Inhibitors,research,lifescience,medical Some institutions occasionally use fat-clearing methods, such as soaking the mesenteric tissue in a chemical soup that dissolves away the fat leaving behind the Dipeptidyl peptidase lymph nodes and other non-fatty tissue. However, most institutions do not routinely use fat clearing methods, and some use fat-clearing methods only when 12 nodes cannot be found. Brown et al. (39), as well as Scott (40), reported significantly Crenolanib supplier increased lymph node harvests utilizing fat clearing techniques. They showed an average of 20.9 lymph nodes harvested using the traditional manual method. They were able to additionally examine 68.6 lymph nodes after clearance of mesenteric fat and submission of all remaining tissue. Of these additional nodes, 82% were smaller than 2 mm. Unarguably, while these techniques are useful, they are also time consuming, labor intensive, and utilize chemicals that are both toxic and expensive.

99 In animal experiments, BDNF ameliorated learned helplessness, an effect that is normally observed with antidepressant treatment.100 Further studies underlined these interrelations and it was shown that treatment with antidepressants, including specific inhibitors of 5-HT or NE uptake as well as MAOIs, elevates BDNF mRNA levels in the rat hippocampus via the 5-HT2A and the β-adrenoceptor subtypes, and prevents the stress-induced decreases in BDNF mRNA.101 Interestingly, this effect became evident after 3 weeks of Inhibitors,research,lifescience,medical treatment, but not after a single dose, thus being reminiscent of the delay in treatment

response. The results of these animal experiments were confirmed by a recent postmortem finding of increased BDNF expression in patients being treated with antidepressants.102 Understanding the mechanism of how these drugs elevate BDNF mRNA could be Inhibitors,research,lifescience,medical particularly important, since BDNF concentration cannot be increased by exogenous neurotrophins, which Inhibitors,research,lifescience,medical are relatively

large lipophobic proteins that do not cross the blood-brain barrier. However, small molecules that pass through the blood-brain barrier and subsequently boost endogenous neurotrophin levels could represent a new generation of antidepressants.103 Interaction between monoamines and other neurotransmitters and neuropeptides Inhibitors,research,lifescience,medical Three decades after its formulation, the monoamine hypothesis of depression underwent various adaptations. Although it has contributed to our understanding of the regulation of neuronal function in general, there is no doubt that a dysfunction in one of the monoaminergic systems alone does not provide an adequate explanation for the pathophysiology

of depression or the mechanism of drug action. One of the intriguing problems of therapy is the fact that it takes several days to weeks before the antidepressant effect becomes apparent, although the neurotransmitter concentrations are increased within hours of a single dose of reuptake inhibitor. The results Inhibitors,research,lifescience,medical of depletion studies further support the hypothesis that a simple change in the level of one of the monoamines or their receptor affinity is sufficient to induce or alleviate depression.104 It is now well established that there are considerable interactions of monoaminergic neurones with each other and with other systems in the brain, and Ketanserin there are many behavioral overlaps that reflect interactions among these neurotransmitters. Although NE.controls vigilance, like 5-HT, it also influences anxiety and irritability. In addition, impulsive behavior appears to be controlled by 5-HT, and yet it shares with DA an LY2835219 mw influence on appetite, sex, and aggression. Moreover, DA and NE. appear to affect euphoria and pleasure, thus influencing motivation and energy.

26, P < 0.001; statistical significance not shown on graph). Post hoc comparisons using the Bonferroni adjustment for comparisons to Day 1 indicate that after 9 days, are all significantly faster than Day 1 (family-wise P < 0.02 after Bonferroni adjustments, individual P all ≤0.00115). The time to complete the task decreased from an average of 13 min to approximately 3 min overall (standard deviation among crayfish Inhibitors,research,lifescience,medical 4.55, estimated from the repeated measures ANOVA). Figure 3 Graphical representation of species and environmental factor comparison in a motor task. Graphs show both sighted and blind crayfish in white and red light. Sighted

(white light, N = 16; red light, Inhibitors,research,lifescience,medical N = 8) and blind crayfish (white light, N = 16; red light, … In contrast, blind crayfish in white light showed no such observed trend on a daily basis (only 1 day had a t-statistic less than [−2], which is not significant after accounting for the multiple comparisons). However, there was an overall learning difference between the first and last days of the experiment (df Inhibitors,research,lifescience,medical = 30, t = 3.78, P < 0.001; Fig. 3). Thus, blind crayfish in white light did not show a significant daily trend in increasing task efficiency due to the variation across days, but did show an overall decreased time to complete the task by the end

of the experiment, to the point of not being significantly different from the other groups (Fig. 3). Further detailed analysis examining only the environmental interference factor of white (visible) light versus red (invisible) light in the learning capability between the two species showed similar overall learning trends. Specifically, a statistical Inhibitors,research,lifescience,medical comparison of both sighted crayfish Inhibitors,research,lifescience,medical conditions (white and red light) to that of blind crayfish conditions (white and red light) showed

no significant differences in overall learning between the two groups. The environmental factor of white light versus red light was investigated by fitting a repeated measures ANOVA that also included fixed terms for Light and the interaction of Light with Day (significance in the interaction term would indicate differing rates of learning). Using a Selleck ABT 263 backward elimination method, neither Rolziracetam the interaction term nor the Light variable itself was significant for sighted and blind crayfish (F14,224 = 1.35, P = 0.18 for the interaction and F1,224 = 0.24, P = 0.62 for the main effect of Light). The performance index for blind crayfish in white light (Fig. 3) appears to oscillate, but there is no phased locked cycle that we could quantify. To understand the time difference between when the crayfish found the spatial access point and when they completed the motor task, further analysis of the performance index divided the total task time into orientation and manipulation index.

13 The majority of fMRI studies in ASDs indicate FG hypoactivity to faces14-22 and to facial expressions.15,20,23-25 However, other reports suggest no differences in FG activation to familiar faces,26-29 stranger faces

in the presence of an attentional cue,30 or when matching upright with inverted faces.31 These apparently inconsistent findings may be reconciled in a number of ways.32,33 The degree of visual attention to faces appears to be a critical factor moderating FG activation to faces in ASDs, with tasks Inhibitors,research,lifescience,medical that guide visual attention to faces or analytic approaches that account for point-of-regard resulting in relatively less FG hypoactivation in ASDs.21,30 This conclusion is supported by research indicating that face familiarity moderates FG responses to faces in ASDs28 and that impaired social cognition in ASDs may be mediated, Inhibitors,research,lifescience,medical at least in part, by attention to social cues, rather than by deficits in social cue processing per se.31,35 Similarly, lifelong amotivation to interact with faces may result in reduced perceptual skill when processing faces,

and, Inhibitors,research,lifescience,medical in turn, cause FG hypoactivation to faces in ASDs that is perhaps a downstream consequence of reduced social experience rather than pathognomonic to ASDs.36 Moreover, the FG encodes not only face percepts, but social check details knowledge as well,37 suggesting that the FG may mediate: (i) the attribution of social meaning to stimuli: (ii) the retrieval of social semantic information; and (iii) self-referential experiences.28 Thus, the disparate results of the face processing literature in ASDs likely reflect the diverse and subtle social processes mediated by the FG and recruited by diverse fMRI tasks. Amygdala response to faces Inhibitors,research,lifescience,medical in ASDs has also been extensively studied, and results in this area are decidedly mixed. There is evidence of no differences in amygdala activation to faces,18 of amygdala hypoactivation during face viewing15,16,26,31,38 and face matching,16

as well as evidence of amygdala hyperactivation to faces39,40 in ASDs, particularly Inhibitors,research,lifescience,medical when accounting for gaze time to faces21 (but see ref 41 for an exception). One study reported decreased amygdala habituation to the repeated MTMR9 presentation of faces, suggesting that social deficits in ASDs may be influenced by hyperarousal to faces due to protracted amygdala activation.42 Theory of mind Theory of mind and mental inferences have been examine in ASDs via fMRI studies that address the ability to infer feeling states and/or intentions (Table II), skills that typically develop during the first 4 or 5 years of life and that are critical for the development of social skills and for successful navigation of the social world.43 Such tasks include images, stories, and animations designed to elicit the attribution of mental states.

The tumor cell nuclei usually show a quite high Ki-67 nuclear proliferative

index (Figure 5, bottom right). However, the tumor cells are usually negative for CD4. Similarly, the intraepithelial lymphocytes in close proximity may express the same aberrant phenotypes (8,10,61). Figure 4 Type II EATL showing monomorphous, neoplastic lymphoid infiltrate (H&E, 500×). The inset image (upper left, H&E, 20×) Inhibitors,research,lifescience,medical demonstrates involvement of surface epithelium Figure 5 The CD3/CD20 stain, a polymer cocktail consisting of anti-mouse/alkaline phosphatase and anti-rabbit/horseradish peroxidase demonstrates diffuse infiltration of CD3 positive neoplastic T cells (red), whereas, only rare CD20 positive B cells (brown) are … Molecular abnormalities Rearrangements of TCRβ and TCRγ are present in both type I and II EATLs. Approximately 58-70% of the cases show Inhibitors,research,lifescience,medical complex chromosomal aberrations including gains at 9q31.3-qter or deletions in 16q12.1. Moreover, type I EATL demonstrates gains at 5q, or gains or partial trisomy of 1q22-q44, while amplification of the MYC locus at 8q24 is more commonly expressed in type Inhibitors,research,lifescience,medical II EATL (8,61). The HLA-DQA1*0501, DQB1*0201 genotype is identified in greater than 90% of patients with celiac disease. This genotype is also noted in patients with EATL (61) see more further supporting the association between the two diseases.

Prognosis Both type I and type II EATL have poor clinical outcomes (61) with a reported 5-year survival of 8-20% (64). Death often results from malabsorption and other abdominal

or clinical complications. Extranodal NK/T cell lymphoma, nasal type (ENKTL) This aggressive entity primarily Inhibitors,research,lifescience,medical occurs in the nasal cavity, nasopharynx and paranasal sinuses but also involves a number of extranasal locations including the GI tract where it may present as ulceration (65) or perforation. Inhibitors,research,lifescience,medical The disease is more commonly seen in Asians, Mexicans and natives of Central and South America, and more frequently affects males than females. Virtually all cases of ENKTL are associated with EBV infection (8,9). Pathogenesis Although evolution of this entity remains uncertain, studies attribute to the probable role of EBV which presents in a clonal episomal form resulting in the production of cytokines such as IL-9 and IL-10 inducing oncogenicity. This clonal EBV harbored of by the tumor cells typically shows type II latency pattern with Epstein-Barr nuclear antigen 1 (EBNA-1) and LMP1 positivity and non-reactivity for EBNA-2 (8,9,66). Morphology and immunophenotype The infiltrate often effaces the mucosal architecture and consists of varying sizes of pleomorphic neoplastic lymphoid cells with irregular, convoluted nuclear contour with indistinct nucleoli. The larger lymphoid cells show irregular nuclei with vesicular chromatin. The moderate to abundant cytoplasm is usually clear or faint.

The questionnaire will be completed by the patient, a member of

the palliative consultation team and the GP following the first two teleconsultations. The NCQ is developed and validated by the Radboud University Nijmegen Medical Centre (Department of Primary and Community Care). The questionnaire measures the patients’ experienced continuity of care across primary and secondary care settings and consists of 3 subscales: ‘Personal or relational continuity: care provider knows me’ (5 items), ‘Personal continuity: care provider shows commitment’ (3 items) and ‘Team/cross-boundary Inhibitors,research,lifescience,medical continuity’ (4 items). Items are scored on a 5-point Tasocitinib Likert scale, with Inhibitors,research,lifescience,medical an additional option to choose ‘?’ (‘do not know’). The NCQ was tested on 268 patients with a chronic disease and proved to be a reliable and valid instrument with good discriminant abilities [Uijen AA, Schellevis FG, Mokkink HGA, van Weel C, van den Bosch WJHM, Schers HJ: Measuring continuity from the patient perspective: psychometric properties of the Nijmegen Continuity Questionnaire (NCQ), submitted]. In this study, only the domains on the experienced quality of the relation between GP and

specialist and the confidence in the GP and in the specialist are being used. Publications on the development Inhibitors,research,lifescience,medical of the questionnaire and the examination of the reliability and validity have been submitted to a journal and are available Inhibitors,research,lifescience,medical on request. The EDIZ is a 5-point Likert scale screening questionnaire with 9 subjects to measure the self-perceived burden from informal care. This burden is expressed in thoughts (e.g. ‘the situation of my…. is constantly on my mind’) as well as in his/her interaction with the social environment (e.g. ‘it’s not easy to combine Inhibitors,research,lifescience,medical the responsibility for my … with the responsibility for my work/family’). The EDIZ is a validated instrument [42]. Sample size calculation The null hypothesis of this cluster randomized trial is that there are no significant differences in symptom distress between palliative patients at home with and without

a telemedicine-computer for videoconference. Symptom distress will be measured by the Edmonton Symptom Assessment Scale (ESAS). The ESAS is a 0 to 10 numeric Rutecarpine scale (0 = best, 10 = worst) to rate severity of 10 symptoms. The sum of all 10 scales makes the Total Distress score (max.100). Based on a study of Follwell et al. [43] we determined a Total Distress score of 8 as the minimum clinically important difference for the power calculation. Without a cluster-effect and without repeated measures, we would need 80 patients per condition, assuming an α of .05 and a power of 80% (calculated with nQuery advisor 4.0). However, there is a cluster-effect and there are repeated measures that we corrected for.