Thus, the erratic pattern of microtubule tortuosity and

disarray together with apparent efforts at microtubule regeneration may reflect abnormal hyperactivity of this M3-linked second messenger system and consequent disruption of its protein phosphorylation functions. Since other unknown second messenger systems are also hyperactivated simultaneously in the same neuron, these systems may also contribute to the cytoskeletal disruption pattern. Neurofibrillary tangles and psychosis could be associated through NRHypo We are beginning to study the possible relationship between this cytoskeletal disruption process in the NRHypo model and NFTs, its potential counterpart Inhibitors,research,lifescience,medical in the AD brain. Thus far, we have not detected ultrastructural evidence of paired helical filaments. Even if such evidence cannot be found, this might signify species specificity of this particular abnormality without disqualifying the NRHypo degenerative process as a valid model of the mechanism giving rise to NFT in the human AD Inhibitors,research,lifescience,medical brain. Thus, our findings in the rat are consistent with the conclusion that NRHypo alone can produce many of the neuropathological

features of AD. The observations that NRHypo can produce psychotic Inhibitors,research,lifescience,medical symptoms, as well as potentially contribute to NFT formation, suggest that psychosis could be associated with NFT burden in AD patients. We recently tested this hypothesis in a postmortem sample of AD Inhibitors,research,lifescience,medical patients and found that, after controlling for the severity of dementia, neocortical NFT EPZ-6438 in vivo counts

were increased in patients with AD who experienced psychotic symptoms in comparison to patients who did not.151 Amyloidopathy and NRHypo Most investigators of amyloidosis have tended to focus exclusively on the potential of beta-amyloid to kill neurons by itself Inhibitors,research,lifescience,medical without, reference to its potential pathological interaction with NMDA receptors. We think the focus should be redirected. Beta-amyloid alone is not. toxic except at very high concentrations, whereas at substantially lower concentrations beta-amyloid causes cultured neurons to become hypersensitive to Glu until or NMDA excitotoxicity.152-154 We propose, therefore, that predisposing factors (eg, apoE4 genotype in sporadic AD, amyloidogenic mutations in familial AD) promote amyloidosis which, in turn, increases the sensitivity of NMDA receptors so that even normal concentrations of Glu can trigger abnormal currents, which on a chronic low-grade excitotoxic basis can destroy NMDA receptor-bearing neurons. Loss of these neurons and their NMDA receptors increases the NRHypo burden in the aging brain. Other factors such as oxidative stress and disturbances in energy metabolism may also contribute to beta-amyloid’s augmentation of neuronal sensitivity to Glu.

In SPDs, plasma homovanillic acid (HVA)

was found to be higher in patients with SPD compared with normal controls83 and the plasma HVA concentrations were correlated with degree of psychotic-like symptomatology.83 In this study, group differences were abolished after covarying for psychotic-like symptoms. An identical configuration of results was found in another Inhibitors,research,lifescience,medical partially overlapping cohort of patients using cerebrospinal fluid (CSF) HVA.83 Another potential index of subcortical dopaminergic responsivity can be assessed by measuring plasma HVA responses to the glycopyruvic stressor, 2-deoxyglucose (2-DG). By blocking glucose absorption into brain cells of frontal lobe, 2-DG induces stress responses including plasma Cortisol and HVA increases following 2-DG administration. Patients with schizophrenia demonstrate elevated HVA responses to 2-DG compared to controls; schizotypal patients have normal responses and, compared with normal controls, Inhibitors,research,lifescience,medical reduced Cortisol responses. Functional and structural imaging studies of striatum point

to the possibility of increased dopaminergic activity. Thus, patients with Inhibitors,research,lifescience,medical SPD show increased striatal volume, particularly in ventral putamen, which may reflect dendritic proliferation secondary to increased dopaminergic activity. Increased metabolic Inhibitors,research,lifescience,medical activation

of ventral putamen in SPD compared with schizophrenia is also consistent with reduced dopaminergic inhibitory tone and may also be a promising imaging endophenotype for candidate gene studies. Finally, amphetamine, by releasing dopamine, will displace radiotracers that bind the D2 receptor, which can be evaluated using IBZM ([123I]iodobenzamide) as a radioligand in single-photon emission computed tomography (SPECT) studies or in PET studies using raclopride as Inhibitors,research,lifescience,medical a radioligand. A SPECT study utilizing IBZM as a ligand indicated that SPD subjects have displacement of IBZM following Methisazone amphetamine, which is intermediate between the markedly increased displacement values found in acute selleck screening library schizophrenic patients and normal controls. Raclopride displacement studies using PET scanning following amphetamine also suggest significant increases in raclopride displacement in schizophrenic patients88 and such studies are underway in SPD patients. These studies suggest that dopaminergic activity in subcortex is normal to modestly increased, but consistently less than that observed in acutely schizophrenic patients. Thus, the dopamine system may be better buffered in schizotypal patients, and dopaminergic indices may provide promising endophenotypes for a dimension of psychosis in schizophrenia.

Gold nanoparticles were also exploited in the study high throughput screening compounds conducted by Tomuleasa et al. [103] for the purpose of reducing MDR hepatocellular carcinoma-derived cancer cells. The gold nanoparticles were loaded with doxorubicin, capecitabine, and cisplatin, followed by nanoparticle stabilization by L-aspartate [103]. The resultant cellular proliferation rates of the hepatocellular carcinoma cells treated with this nanoparticle-based therapy were found to be lowered drastically [103]. In the study carried out by Punfa et al. [104], the cytotoxic properties of curcumin on multidrug resistant

cervical tumours were maximized through the development of a nanoparticle-curcumin drug delivery system. Curcumin Inhibitors,research,lifescience,medical was successfully entrapped within poly (DL-lactide-co-glycolide) (PLGA) nanoparticles, followed by the incorporation of the amino-terminal of anti-P-gp [104]. Consequently, the curcumin-nanoparticle conjugates were Inhibitors,research,lifescience,medical deployed onto the KB-V1 cervical cancer cell line, having upregulated P-gp expression, together with the KB-3-1 cell line that has a reduced P-gp expression level [104]. The results of this study demonstrated that nanoparticle conjugates bearing anti-P-gp

surface markers were highly efficient in binding to the MDR-inducing surface protein, allowing enhanced cellular uptake and ultimately aid in the cytotoxic efficacy of curcumin Inhibitors,research,lifescience,medical due to increased accumulation of the drug, particularly within the KB-V1 cell line due to its exacerbated P-gp expression status [104]. Curcumin/doxorubicin-laden composite polymer nanoparticles were also developed in other studies [105] as a means of enhancing the pharmacokinetic and pharmacodynamics properties of curcumin, thus enhancing its MDR-modulating effect Inhibitors,research,lifescience,medical in the target tumour cells. The resultant nanoparticle complex was deployed onto several MDR tumour models such as acute leukaemia, multiple myeloma, and ovarian Inhibitors,research,lifescience,medical cancers, both in vitro and in vivo

[105]. The results of this study highlighted the possibility of administration of lower doses of doxorubicin due to the circumvention of tumour MDR by efficient curcumin activity, thus enhancing the toxicity profile for to doxorubicin in clinical use stemming from the reduction in cardiotoxicity and haematological toxicity dose-dependent adverse effects [105]. Retinoblastoma therapeutic avenues have also been increased due to the introduction of nanoparticle drug delivery technology. The study by Das and Sahoo demonstrated the effectiveness of utilising a nanoparticle delivery system which was dual loaded with curcumin together with nutlin-3a (which has been proven to stimulate the activity of the tumour suppressor protein p53) [106]. The results of this particular investigation highlighted an enhanced level of therapeutic efficacy on utilizing the nanoparticle-curcumin-nutlin-3a conjugates on the target retinoblastoma Y79 cell lines [106].

As shown in Figure 2a, whereas Syn-wt Luminespib order formed amyloid fibrils after an 80-h incubation, all C-terminal truncated mutants formed fibrils much more quickly (~10–20 h), suggesting that deletion of negative charges from the C-terminal region caused a significant change

in the fibril formation rate under these conditions; a significant acceleration in fibril formation was observed even for Syn129, which had only four acidic amino acid residues deleted from the C-terminus. Figure 2 Fibril formation characteristics of the C-terminal truncated mutants. (a) and (b) Amyloid fibril formation monitored by ThioT binding assay. Conditions were 1 mg/mL protein in 25 mmol/L Tris–HCl buffer, pH 7.5, containing 0 mol/L (a) and 150 mmol/L … Inhibitors,research,lifescience,medical To observe in more detail differences caused by deleting some or all of the acidic amino acid residues from the α-syn Inhibitors,research,lifescience,medical C-terminus, fibril formation experiments were performed in buffer containing 150 mmol/L NaCl, a salt concentration that more closely resembles physiological conditions. At 150 mmol/L NaCl, as shown in Figure 2b, Syn103 formed fibrils most quickly, and Syn-wt was the slowest, although a large acceleration was observed for Syn-wt when compared to the reaction in 0 mol/L NaCl (from 80 to 25 h). In the presence of 150 mmol/L NaCl (Fig. 2b), the degree of acceleration correlated very well with the number of negative residues

Inhibitors,research,lifescience,medical deleted from the C-terminus. A similar correlation has been reported by Hoyer et al. (2004). Notably, as the rate of fibril extension (as monitored by the slope of ThioT fluorescence increase seen after the initial lag Inhibitors,research,lifescience,medical stage) was similar for all of the mutants and Syn-wt (Fig. 2b), it is likely that the removal of negative charges from the C-terminal region of α-syn mainly affects fibril nucleus formation. This correlation was also reported by Levitan et al. (2011) very recently. In Figure 2c, CD spectra and TEM images of Syn-wt and all mutant proteins after formation Inhibitors,research,lifescience,medical of fibrils are shown. In CD spectra, β-sheet-like structural characteristics were observed for all

proteins. In TEM images, although minute differences in morphology were observed depending on the mutant protein, linear fibers with similar dimensions (~20 nm in width) were observed. through In order to clarify the notion that the acceleration of nucleus formation is due only to changes in negative charge, rather than overall polypeptide length, we next prepared two charge-neutralized full-length α-syn mutants, Syn130-140CF and Syn119-140CF. Syn130-140CF is a full-length (140 AA) α-syn polypeptide in which four Glu residues and one Asp residue located between positions 130 and 140 have been replaced by the noncharged amino acid residue asparagine. In Syn119-140CF, six Glu and three Asp residues between positions 119 and 140 have been changed to Asn (Fig. 1 and Table 1). Fibril formation of these mutants were examined and compared with Syn-wt.

Fewer than half of patients respond to treatment under this paradigm, and fewer than one third recover. This paradigm leads to prolonged suffering and increased health care costs. If we were successful in identifying response endophenotypes for patients with MDD, medications would be prescribed under

an entirely Inhibitors,research,lifescience,medical new paradigm that relied upon an early response profile of each patient. The concept of the response endophenotype shifts from the examination of endophenotypes and genotypes, which have not proved highly productive, to the study of dynamic treatmentemergent characteristics. In this paper we have suggested early changes in symptoms, brain neurophysiology, and patterns Inhibitors,research,lifescience,medical of changes in gene expression as potential REs. The RE concept need not be limited, however, to these few measures. Any early treatment-emergent measures that could be Doxorubicin datasheet examined within the individual patient could be incorporated in this paradigm. We posit that this paradigm could optimize response and remission rates with medication and prove superior to the current approach, leading to earlier symptom improvement, recovery from the illness, and ultimately profound health and economic benefits in terms. Acknowledgments Financial support

Inhibitors,research,lifescience,medical of this project was provided by a grant from the National Institute on Mental Health (R01 MH 085925) and by an endowment in depression research from Joanne and George Miller and Family (Dr Cook), and by NIH Training

Grant T32 MH017140 (Mr Inhibitors,research,lifescience,medical Korb). Andrew Leuchter, MD, has provided scientific consultation or served on advisory boards for Aspect Medical Systems, Eli Lilly and Company, Novartis Pharmaceuticals, MEDACorp, AstraZeneca, Takeda Pharmaceuticals, and Merck & Co. He has served on a speaker’s bureau for Eli Lilly and Company and Wyeth-Ayerst Inhibitors,research,lifescience,medical Pharmaceuticals. He has received research/grant support from the National Institute of Mental Health, the National Center for Complementary STK38 and Alternative Medicine, Aspect Medical Systems, Eli Lilly and Company, Novartis Pharmaceuticals, Wyeth-Ayerst Pharmaceuticals, Merck & Co, Pfizer, Vivometrics, and MedAvante. Ian A. Cook, MD, has served as an advisor and consultant for Ascend Media, Bristol-Meyers Squibb, Cyberonics Inc, and Janssen. He has served on the Speaker’s Bureau for Bristol-Meyers Squibb, Medical Education Speakers Network, Pfizer Pharmaceuticals Inc, and Wyeth Pharmaceuticals. Dr Cook receives Research Support from Aspect Medical Systems, Cyberonics Inc, Eli Lilly & Company, Novartis Pharmaceuticals, Pfizer, Inc, and Sepracor. Dr Hunter and Mr Korb have nothing to disclose.

A direct comparison of 0.5- and 100-Hz activation patterns revealed no significant differences between frequencies. The block-by-block analysis, performed to understand

the pattern of deactivation for each stimulation time period over the experimental run, revealed that the majority of the blocks for both 0.5 and 100 Hz demonstrated a reliable pattern of deactivation Inhibitors,research,lifescience,medical during “on” and relative activation during baseline (Fig. 3). Figure 3 Time course of activation/deactivation block-by-block, averaged for regions for which there was overlap from all 11 participants’ leave-one-subject-out group activation maps (see Fig. S1). ROI analysis We found no differences in mean thalamic activity when the device was “on” versus baseline for either the 0.5- or 100-Hz CES. Current BGJ398 intensity regression Inhibitors,research,lifescience,medical A voxel-wise analysis using current as a regressor revealed positive associations between current and activation for 100-Hz but not 0.5-Hz stimulation. Regions included right/left posterior cingulate cortex, left superior parietal lobule, left angular gyrus, left supramarginal gyrus, and left lateral occipital cortex (Table S2). There were no significant associations with brain deactivation in any region. Inhibitors,research,lifescience,medical This pattern for current intensity therefore differed from what was found in the “on” versus baseline analyses, suggesting that cortical deactivation may depend more on frequency than intensity of stimulation.

PPI analysis (Fig. 4 and Table 2) Figure 4 Regions of altered connectivity with the posterior cingulate seed

within the default mode network associated with 100-Hz stimulation. Regions of increased connectivity are depicted in yellow–orange and decreased connectivity Inhibitors,research,lifescience,medical are depicted in blue–light … Table 2 Regions of altered functional connectivity associated with CES stimulation at 100 Hz between the bilateral posterior cingulate gyrus (seed region) and other regions within the default mode network. Inhibitors,research,lifescience,medical Z scores and MNI coordinates for local maxima (x, y, … For the DMN analysis, 100 Hz was associated with increased connectivity between the posterior cingulate Urease cortex seed and the left planum temporale, bilateral postcentral gyrus, and bilateral anterior supramarginal gyrus (Fig. 4 and Table 2). A total of 100 Hz was also associated with decreased connectivity between the posterior cingulate cortex seed and the left posterior supramarginal gyrus, the left angular gyrus, and the left superior lateral occipital cortex. A total of 0.5 Hz was not associated with any significant changes in connectivity. For the SMN, neither 100-Hz nor 0.5-Hz stimulation was associated with any significant changes in connectivity. For the FPN, there were no significant alterations of connectivity detected for either frequency. Discussion Results from this study suggest that 0.5- and 100-Hz CES causes cortical brain deactivation in midline prefrontal and parietal regions.

Background: The touch preparation technique is an accurate and rapid method, and when used as intraoperative consultation examination technique it preserves a good amount of tissue for paraffin embedded sections. This study aimed at examining the accuracy of the touch preparation technique by comparing its www.selleckchem.com/products/pd-0332991-palbociclib-isethionate.html diagnosis Inhibitors,research,lifescience,medical with that of final pathological diagnosis made by microscopic examinations. Methods: The diagnoses of 139 central nervous system lesions by touch preparation technique and paraffin-embedded sections were compared. Results: Touch preparation technique diagnosed correctly 118 (84%) of the lesions. However,

the technique failed to correctly diagnose 12% of the cases. The highest rate of accurate diagnosis (100%) was observed in five types out of 11 types of tumor Inhibitors,research,lifescience,medical examined. However, the technique was not able to diagnose hydatid cysts correctly. Conclusion: The findings indicate that touch preparation technique may be useful in diagnosing tumor type during surgical operations. Touch preparation Inhibitors,research,lifescience,medical technique is very accurate for intraoperative diagnosis. However, adequate clinical history, neuroimaging details, and the intraoperative impressions of the neurosurgeons, if

provided, help the pathologists to improve the diagnostic accuracy of the technique. Key Words: Intraoperative, central nervous system, frozen sections Introduction Tissue specimens Inhibitors,research,lifescience,medical taken from patients during operations or biopsies are usually assessed by the pathologists one or two days after the

surgery. However, sometimes pathological results are needed urgently during the operation, while the patient is still on the operation table. In neurosurgical operations the need of a rapid diagnosis during the operation can be met by intraoperative consultation examinations. During surgeries, surgeons want to particularly know whether or Inhibitors,research,lifescience,medical not a lesion is malignant. The use of touch preparation technique, known as touch preparation as an intraoperative consultation examination technique is now well established.1-3 A Suplatast tosilate good intraoperative consultation examination technique should preserve good amount of tissue for paraffin embedded sections, and should be accurate and rapid. Frozen section is another intraoperative consultation examination technique that needs more tissue and has some freezing artifacts. The architecture of tissues in frozen section closely approximates permanent histology sections, and enables a degree of comfort. Touch preparation provides a better and crisp cellular details and even some tissue architecture.

Comparison between the different muscles in each stage of the four-point kneeling exercise showed that muscle activation was significantly different in all the exercises (P<0.001). The post-hoc test with Bonferroni correction revealed that in each exercise, the right

TrA had the highest activation of all the muscles, whereas right and left multifidus muscles exhibited the lowest activation pattern (table 1). Table 1 Comparison of mean muscle activation between the different levels of the four-point kneeling exercise According Inhibitors,research,lifescience,medical to the results, statistically significant differences (P<0.05) were found in the activation of all the muscles, except for

the right IO. On the other hand, the amplitudes of these muscles for the bird-dog position Inhibitors,research,lifescience,medical were significantly higher than those recorded for right arm extension. Furthermore, a statistically significant difference was found between left leg extension and bird-dog position (P<0.05) in as much as the left multifidus was activated at a significantly higher level than the other muscles in the bird-dog stage. Discussion The current study aimed to compare the EMG amplitudes of trunk and lumbar muscles during the performance of the three stages of the four-point kneeling position. The results showed that the mean activation of abdominal and lumbar Inhibitors,research,lifescience,medical muscles was different in the three stages of the four-point kneeling exercise. Overall, the right TrA had the highest activation of all the muscles, while right and left multifidus muscles showed the lowest activation pattern. This finding is related to the

role of the TrA in every Inhibitors,research,lifescience,medical trunk and limb movement. In order to provide spinal stability, the central nervous system (CNS) estimates the amount of disturbance produced by the motion of the limbs and sends the inputs to the TrA proprioceptive receptors, which trigger coordinated Inhibitors,research,lifescience,medical muscle activation. Therefore, the feed-forward mechanism is performed by the CNS in two ways: Methisazone (1) non-directional for the Palbociclib nmr excitation of intrinsic muscles and (2) direction-specific for the control of spinal situations.4 The TrA is a primary trunk stabilizer via the modulation of intra-abdominal pressure, tension through the thoracolumbar fascia, and compression of sacroiliac joints. Richardson et al.4 demonstrated that a voluntary contraction of the TrA reduced the laxity of the sacroiliac joint. Another study showed different levels of the feed-forward contraction of the TrA during rapid arm movements.22 The findings of the present study revealed that the activation of left IO and right and left mulitifudus muscles in the bird-dog position was higher than that in the other two exercises.

Also, other categories

of metabolic reactions derived from large FBA screens can be topologically assessed, for example reactions that are active only in a very small number of environmental conditions (rarely active reactions). We expect that the topological implementation of such rarely active reactions can shed light on the robustness of metabolic systems against environmental variations. Lastly, further validating the results with gene expression data can be an interesting line of investigation, starting from our previous work on effective networks Inhibitors,research,lifescience,medical derived from gene expression patterns [35] and a www.selleckchem.com/products/MK-2206.html network interpretation of reactions contributing to metabolic inconsistency (i.e., to mismatches between gene expression data and predicted metabolic Inhibitors,research,lifescience,medical flux patterns; see [36]). Acknowledgments The authors thank ZebaWunderlich for providing additional information on the synthetic accessibility approach. Furthermore, the authors would like to thank Areejit Samal for discussions about topological implications of reaction essentiality and Moritz Beber for providing his python wrapper for mfinder. MH acknowledges Inhibitors,research,lifescience,medical support from Volkswagen Foundation (grant I/82717) and Deutsche Forschungsgemeinschaft (grant HU 937/6). NS acknowledges support by Jacobs University Bremen in form of a PhD scholarship. CM acknowledges support from the Helmholtz Alliance on Systems Biology (project “CoReNe”). Supplementary

Files Supplementary File 1 PDF-Document (PDF, Inhibitors,research,lifescience,medical 758 KB) Click here for additional data file.(758K, pdf)
Minimal cut sets (MCSs) have been developed from elementary

modes (EMs) [1,2,3,4], a metabolic pathway analysis (MPA) [5,6,7] method that uses convex analysis [8,9] to identify all possible and feasible metabolic routes for a given network at steady state. A review of the history of EMs can be seen in [10]. This review focuses on MCSs which, together with EMs, form dual representations of metabolic networks with both being able to Inhibitors,research,lifescience,medical be converted into each other [11]. The MCSs approach identifies target genes for eliminating a certain objective function; it adds to the increasing importance of MPA methods Rolziracetam [5,6,7], and the capacity to employ metabolic engineering and biological systems to produce industrially relevant compounds from renewable resources, by providing a means of finding suitable targets for repressing undesirable metabolic functions. MCSs can be considered the smallest “failure modes” in a system; they were first introduced in 2004 by S. Klamt and Gilles [12], motivated by their desire to gain deeper insight into the functionality and capability of an organism by further analyzing the structure of its metabolic network. In particular, they looked at how potential failure modes in a metabolic network could render the network structurally incapable of performing certain functions.

Possibly the increased expression of these epidermal growth factor (EGF) ligands is responsible for driving the growth of these tumours. Recent reviews (146) and a pooled analysis (147) showed that both on univariate and multivariate analysis, there is a significantly lower tumour regression grade and a non significant trend towards a lower pCR rate (9% vs. 16%) when Cetuximab was added to a combination of 5-FU/ Capecitabine and Oxaliplatin. Recent work on the same data set has evaluated functional germline polymorphisms of EGF and TS (148), and biomarkers such as Kras status in combination with TS, VEGFR1 and VEGFR2d expression

Inhibitors,research,lifescience,medical (149) which appear to predict for histopathological response. Other potential markers Inhibitors,research,lifescience,medical of response include the TP53 mutation

(150). In an Italian study the EGFR gene copy number was found to correlate significantly with tumour regression and response to cetuximab (108) but is not prognostic in standard chemoradiotherapy (114). Even though in rectal cancer there will be no concern that expression in the primary tumour and metastatic Inhibitors,research,lifescience,medical sites will be different, rectal and colon cancers do have different gene expression profiles, different cytokeratin profiles, different levels of MSI-H, and different levels of mutations in Kras and BRAF (151-154). Thus PI3K inhibitor extrapolating results from colon cancer trials to the treatment in rectal cancer might not demonstrate the same outcome. Pre-clinical data suggests that the sequencing of chemotherapy, EGFR inhibition and radiation may be clinically significant and that the sequence of oxaliplatin followed by cetuximab may be more effective than cetuximab

prior to Inhibitors,research,lifescience,medical oxaliplatin [Morelli 2005 (155)]. Better efficacy might Inhibitors,research,lifescience,medical be achieved by integrating cetuximab in the latter portion of the radiotherapy, or following chemoradiation. This strategy has already been proposed when integrating anti-metabolites such as gemcitabine with EGFR inhibitors and radiation [Shewach 2007 (156)]. Finally, better selection for the potential efficacy of EGFR inhibition by molecular markers could be appropriate in the future (140). A recent study in rectal cancer examining a combined analysis of VEGF and EGFR identified a subgroup of EGFR-negative and VEGF-positive patients who appeared resistant to radiotherapy, of whom only 2/34 (6%) achieved a pCR (95). Early endpoints in terms of efficacy only at the level of the primary tumor (e.g., pCR), may not in themselves be coupled to longer-term endpoints such as DFS and OS. Phase III randomised studies are the best way to define the advantages of a novel treatment. It should be borne in mind that 50% of patients are in their 70s and more than 70% of patients with colorectal cancer are over 65. Many of these patients have extensive other co-morbidity including cardiac problems.