McQuellon et al. also studied long term survivor ship in 17 patients (40). They were interviewed from 3.1 to 8.0 years after treatment. Sixty-two percent described their health as excellent or very

good. No limitations on moderate activity were reported in 94% of cases. Functional well-being, physical well-being and FACT total were significantly www.selleckchem.com/products/Vorinostat-saha.html improved and demonstrated that long-term survivors of peritoneal carcinomas after CRS and HIPEC can return to a good life of quality. Appendiceal Inhibitors,research,lifescience,medical selleck chemical cancer is also research interest for investigators. QoL for patients with disseminated peritoneal cancer of appendiceal cancer were studied by McQuellon et al. Fifty-eight patients with a mean age 52.4 years were assessed before surgery. Overall survival at 1 year was 78.7%. Emotional well-being improved over the study period, while physical well-being and physical functioning declined at 3 months and then improved to near baseline Inhibitors,research,lifescience,medical levels at 6 and 12 months. Depressive symptoms and some physical limitations remain in surviving patients. Percentage of patients with depressive symptoms ranges from 24% to 33% in baseline, 3, 6, and 12 months (41). The authors conclude survival in appendix cancer Inhibitors,research,lifescience,medical patients with peritoneal cancer is good, although complications may affect short-form recovery. However, half of

patients dropped out of the study. In Hill et al.’s recently published paper a total 62 patients who underwent HIPEC Inhibitors,research,lifescience,medical for peritoneal carcinomatosis of colonic origin were studied (42). Questionnaires were completed preoperatively and after surgery at 3, 6, and 12 months. The authors used FACT-C, Brief Pain Inventory (BPI), SF-36, CES-D, and the ECOG Performance

Status Rating to estimate their QoL. Median overall survival Inhibitors,research,lifescience,medical was 18 months, with 71.3% survival at 1 year. Emotional well-being scores significantly improved after HIPEC. Social/family wellbeing and the colon subscale of the FACT worsened at 3 months, but recovered at 6 months. CES-D scores showed 33%-50% of patients reported depressive symptom. Pain scores increased above base line at 3 AV-951 months, but decreased below base line at 6 and 12 months. 47% of patients reported normal activity according to their performance status. Long-term functioning in patients following CRS and HIPEC has also been studied by Schmidt et al. who evaluated QoL in 67 patients using the EORTC QLQ-C30 questionnaire with an average post-treatment time of 4 years (range 1-8 years) (43). The mean score for global health status of long-term survivors was 62.6, which was significantly decreased when compared with the general Norwegian population (73.3). The authors showed functional status, particularly the role and the social functioning, were impaired because of presence of ostomies, fatigue, insomnia, or pain. These data indicated that QoL may be adversely affected following CRS and HIPEC. Per Jess et al.

Other in vivo studies in this field include the investigations carried out by Shen et al. [109], which focused on the codelivery of paclitaxel and survivin short hairpin RNA (shRNA) for circumventing chemoresistance in lung cancer. The investigators utilized the pluronic block co-polymer P85 combined

with D-α-Tocopheryl polyethylene glycol 1000 succinate (P85-PEI/TPGS) for developing the nanoparticles to be implemented in this study [109]. Inhibitors,research,lifescience,medical These nanoparticles were based upon triblock structural formation of hydrophilic poly(ethylene oxide) (PEO) blocks and hydrophobic poly(propylene oxide) (PPO) blocks, which also gives enhanced capacity to revert chemoresistance due to drug efflux pump inhibition properties, downregulation Inhibitors,research,lifescience,medical of ATPase activity and P85-induced inhibition of the gluthathione S-transferase compound detoxification enzyme at the subcellular level [109]. Paclitaxel and surviving shRNA were selected as the ideal drugs for nanoparticle delivery due to the former having poor efficacy due to chemoresistance

within the tumour, and survivin was identified as highly expressed within chemoresistant tumours [109]. The in vivo activity of such nanoparticle systems (with/without paclitaxel and survivin Inhibitors,research,lifescience,medical shRNA) was sellekchem evaluated on BALB/c nude mice injected with viable, paclitaxel-resistant, A549/T lung adenocarcinoma epithelial cells [109]. The results of this study demonstrated that deployment of the nanoparticle-based chemotherapeutic drug proved to have distinct enhancement Inhibitors,research,lifescience,medical of antitumour efficacy, when compared to deployment of the drug/s alone [109]. Chemoresistance to the aromatase inhibitor www.selleckchem.com/products/CP-690550.html letrozole in postmenopausal breast cancer is another major therapeutic hurdle which was investigated in vivo [110]. Biodegradable PLGA-polyethylene glycol copolymer nanoparticles were developed by nanoprecipitation and designed to

incorporate hyaluronic acid-bound letrozole (HA-Letr-NPs) [110]. The addition of hyaluronic Inhibitors,research,lifescience,medical acid served to enhance letrozole binding specificity to CD44 on the target tumour cell surface, with the expected consequences of enhanced drug accumulation within the target tumour cell cytoplasm and resultant re-sensitization of the target tumour cells to letrozole Brefeldin_A activity [110]. Such HA-Letr-NPs, once produced at a size of less than 100nm diameter, were deployed within a letrozole-resistant murine xenograft tumour model [110]. The results of this study demonstrated a highly efficient nanoparticle-based drug delivery system, with the IC(50) for HA-Letr-NPs within the murine xenograft model being only 5μM when compared to the control groups, thus enhancing the in vivo aromatase enzyme activity within the xenograft and ultimately inducing a prolonged resensitising of the breast cancer tumour to letrozole activity [110].

Table 1 The 5 (five) scale groups from A to E used at Peijas and Jorvi ED The impact of introducing

the ABCDE-triage tool in emergency services was enhanced by increasing simultaneously the education of the staff in EDs and the publicity about the issue. A discussion was also raised in the media around these services and information #http://www.selleckchem.com/products/MLN8237.html keyword# was delivered both to professionals and the public outside EDs. The main message to the public was that those who require immediate medical help should come to EDs but EDs are not overflow services of office-hour services. Guidelines were written for the staff about triage. The staff also got training and encouragement by the project workers and leaders. The training was arranged for public health care inside EDs and in office-hour services. Inhibitors,research,lifescience,medical Altogether 60 nurses were trained in four 4-hour seminars in primary care EDs to perform the triage. The general public was informed of the project through the media, and all the information focused on the transparency of the system. Necessary data was also available via Internet, and both the public and staff had access to the internet pages of the campaign http://www.hus.fi/default.asp?path=1,32,660,546,570,4384,6950,6956,11437. All related material

was, and is still, available at this page. Local print media, radio and bulletins were also used. About thirty articles were published in both Inhibitors,research,lifescience,medical national and local newspapers. Posters and leaflets about the project were delivered to the patients in EDs and Inhibitors,research,lifescience,medical in office-hour services. The aim of the project group was to publish as much information as possible related to the changes to keep

the population, all organizations associated with the project and the staff fully informed. The objective of this information campaign was to guide non-acute patients (group E) directly to appropriate daytime services. There was also lively public and political debate about emergency services going on at the same time. Feedback was actively gathered both from Inhibitors,research,lifescience,medical patients and the staff with questionnaires and interviews. The Numbers of visits to doctors and nurses and assessed patients were frequently measured. Similarly, patients assessed in triage groups, waiting times and diagnoses in different triage groups were irregularly measured. In order to discuss the implementation process and problematic patient cases, follow-up GSK-3 meetings were organized every month. Statistical analysis The triage system was introduced at the beginning of March 2007. The frequencies of monthly patient visits in the three previous years were third compared to the number of patient visits in the respective months of the next year (March 2007-February 2008), e.g. after the triage was applied. One-way ANOVA of repeated measurements followed by t-test with the Bonferroni Correction was chosen as the method for statistical analysis. [16].

Figure 7. The connectome as an example of an intermediate phenotype. This schematic diagram illustrates a hierarchy of brain phenotypes, ranging from molecular to behavioral scales. Variations along these scales are influences by genetic HTC variation and environmental … Outlook The study of brain

networks is still in its infancy. The development of new analytic techniques and modeling approaches, in parallel with continued methodological refinements in the area of human neuroimaging, continue Inhibitors,research,lifescience,medical to allow ever more detailed analyses of human structural and functional networks. Graph methods have proven useful for capturing how networks vary across individuals, how they change with experience, how they evolve across the human life span, and why they fail in a variety of brain and mental disorders. In the immediate

future, some important areas of research will likely focus on structure function relationships, leading to a better Inhibitors,research,lifescience,medical understanding of how structural networks give rise to rich and flexible neural dynamics. Another promising area involves the analysis of network dynamics, the ever-changing topology of brain networks that are endogenously generated and modulated by Inhibitors,research,lifescience,medical stimuli and the http://www.selleckchem.com/products/XL184.html environment. Studies of how networks change in the course of early development will likely stimulate new approaches towards mapping Inhibitors,research,lifescience,medical individual cognitive and behavioral developmental trajectories. Studies

of networks may also prove important in the context of neurodegenerative disorders such as Alzheimer’s disease, contributing to the as-yet elusive goal of developing better diagnoses and treatment options. Whatever the future may bring the convergence of new technologies for observing the structure and function of the human brain with new analysis and modeling methods for the study of complex networks will almost certainly continue Inhibitors,research,lifescience,medical to bring change to the field. The new science of networks may provide a much needed theoretical framework for uniting empirical and computational studies of the nervous systems at all scales, from neurons to systems. Along the way, we may Entinostat finally uncover the principles of network organization that account for the human brain’s astonishing computational power, flexibility, and robustness. Acknowledgments The author’s research was supported by the JS McDonnell Foundation.
Various theoretical orientations have converged upon the conceptualization of borderline personality disorder (BPD) as a disturbance in mental representations of self and other, contributing to core difficulties in identity, intimacy, empathy, and self-directed motivation.

The field of obsessive-compulsive disorder (OCD) owes much to French physicians. Pinel (1745-1826) coined the term folie raisonnante; Esquirol (1772-1840) identified monomanie and folie du doute et du toucher. Morel (1886) gave a good semiological description, and Luys (1883) was the first to use the word “obsession” in an article entitled “Des obsessions pathologiques.” Pierre Janet1 (1903)

defined “psychasthenia” and viewed obsessions as the result of diminishing psychic energy #selleckchem keyword# and as a degradation product of higher mental activity. He was also one of the first to describe a pediatric case. For a child psychiatrist trained 30 years ago, OCD in children was an infrequent encounter. Most clinical discussions revolved around the Freudian theory of neurotic anal regression secondary to an unresolved (Edipal conflict (although Freud postulated a certain predisposition), as outlined in the famous Rat Man case (S. Freud2) and specific defense mechanisms, such as affect isolation, Inhibitors,research,lifescience,medical reaction

formation, retroactive annulation, pathological doubts, and rituals (A. Freud3). Much was said, and taught, about the psychodynamic treatment of this disorder in younger patients, and accounts of such therapies were published, even if the results were equivocal in the long run. For older adolescents, clinicians debated the role of obsessive-compulsive Inhibitors,research,lifescience,medical manifestations as a prodromal symptom of schizophrenia, and there were anecdotal accounts of much older Inhibitors,research,lifescience,medical adults with 17-DMAG IC50 severe obsessions, resistant

to all known treatments, who in the 1940s and 1950s had neurosurgical procedures such as frontal lobotomy. The late 1960s and early 1970s saw the introduction of the first specific drug therapies for adults such as phenelzine and, most importantly, clomipramine. Inhibitors,research,lifescience,medical At the same time, the first behavioral treatments appeared, and were developed and studied in later years. In the late 1980s, fluoxetine was released and quickly recognized as a powerful antiobsessional drug. It is worthy of note that in 1942, Berman,4 in an article on obsessive-compulsive neurosis in children, reviewed the psychodynamic theories on the subject, giving an account of few cases; a prevalence of 0.02% was Entinostat found in 2800 children admitted between 1935 and 1939, at the Bellevue Hospital in New York. It is with the pioneering work of Judith Rapoport5 at the National Institute of Mental Health (USA) in the early 1970s, trying the thenunreleased drug clomipramine on adolescents with severe OCD, that serious research began. As related in the introduction of her book, The Boy Who Couldn’t Stop Washing,5 the fact that over 50% of adults with OCD had the first manifestations of their illness during childhood and adolescence emphasized the great importance of such work.

In the present study, MPO activity was assessed for the index of tissue oxidative load, which is considered

as one of the hallmark indicator of necrotic cell death (Erman et al. 2005). We observed that hypoxic spinal cord showed increase in MPO activity. Neutrophil and microglia activation have been shown responsible for increased MPO activity (Taoka and Okajima 1998; Erman et al. 2005; Fleming et al. 2006) during CNS injuries. In this in vitro model, since there is no blood infusion, Inhibitors,research,lifescience,medical so the probable source of MPO is microglia alone. We used two neuroimmunophilins (FK-506 and CsA) to understand their effects on spinal cord hypoxic injury induced secondary neuronal damage in spinal cord. It was observed that both FK-506 and CsA significantly Inhibitors,research,lifescience,medical reduced the level of LPO and MPO activity in the hypoxic group. This could be due to the ability of FK-506 and CsA to inhibit microglia activation by inhibiting calcineurin, which activates transcription factor NF-AT and thereby eventually decreasing MPO and LPO level in the hypoxic spinal cord (Taoka and Okajima 1998; Erman et al. 2005). However, study by Mun and Ha (2010) has shown that CsA treatment of glioma leads to increase ROS production and neurological side effects. FK-506 has been reported to protect the spinal cord by targeting microglia cells (Guzmán–Lenis et al. 2008) after excitotoxicity. CsA and FK-506 have been used as an immunosuppressant in traumatic or ischemic Inhibitors,research,lifescience,medical CNS damage and

it was shown that these neuroprotectants inhibit microglia cells activation (Hailer 2008). FK-506 is also reported to block NF-κB, turning

off the gene of ICAM-I, thereby limiting the inflammatory damage and infarct size during ischemia/reperfusion (Squadrito et al. 2000). Nishinaka et al. (1993) reported that FK-506 Inhibitors,research,lifescience,medical exerted a protection on ischemia/reperfusion-induced damage Inhibitors,research,lifescience,medical in canine heart, which was suggested due to the ability of FK-506 to reduce superoxide radical formation. It was observed that FK-506 and CsA treatment significantly restored GSH content in the hypoxic groups. There is a correlation between the level of LPO and GSH content; both are Crenolanib molecular weight inversely proportional to each other. The inversely proportional LPO and GSH content could help explain the mechanism by which FK-506 and CsA reduced Carfilzomib Rucaparib peroxidative membrane damage by inhibiting microglia activation and thereby maintaining GSH content. FK-506 and CsA treatment markedly decreased mitochondrial swelling in hypoxic mitochondria. ATP content was also found to be increased with FK-506 and CsA treatment. It has been reported that ROS generation plays a central role in altering mitochondrial membrane integrity, which leads to opening of MPTP and increased ion influx, that is, calcium (Peng and Jou 2004). MPTP opening results in uncoupling respiration from ATP synthesis, organelle swelling, disruption of the outer membrane, and release of different apoptogenic factors into the cytosol (Green and Reed 1998; Kroemer et al.

Inflammation Induced By Glycated Proteins, Interferon Gamma and Lipopolysaccharide It has been reported that glycated proteins trigger the inflammation. The pathophysiology of inflammation includes the recruitment of white blood

cells and production of http://www.selleckchem.com/products/U0126.html cytokines which are the messenger among the cells.84 In addition, lipopolysaccharide (LPS), which is the outer membrane of gram negative bacteria, elicits the production of a number of cytokines.85 Cytokines can bind to specific receptors and trigger the complex Inhibitors,research,lifescience,medical cytokine network signalling. An excessively elevated level of cytokines was observed in AD patients. Among those, INF-γ, which was originally called macrophage-activating factor, is of potential interest.86 Macrophages are sensitive to INF-γ. Inhibitors,research,lifescience,medical In addition, the non lethal dose of LPS was shown to be toxic in combination with INF-γ in mice. The involvement of cytokines with LPS in Shwartzman-like lethal inflammatory response was observed in rabbits and mice.87,88 There is evidence that this protein modification results in the elevated level of cytokines.89 Inhibition of Inhibitors,research,lifescience,medical Glycated Protein Induced-Inflammation

by Different Antioxidants Inflammation is known as a potential cause of neurodegenerative diseases such as AD and Parkinson’s. Several inhibitor order us studies have shown that neuronal cell death is regulated by inflammation. Microglia, the resident macrophages in the brain, can produce Inhibitors,research,lifescience,medical inflammation markers such as NO and TNF-α. The inflammation, which results in neurodegenerative diseases, has a deleterious effect on neurons.90 Reduction of inflammation might help to decrease the level of induced damages. Polyphenols are a group of compounds with defined structures and are abundant in fruit and vegetables. They are well known as antioxidants and antiinflammatory compounds.91

So far, the use of polyphenols as antiinflammatories has been studied extensively.92 The flavone structure is known as the antiinflammatory structure in a wide range of plant extracts. Resveratrol; however, Inhibitors,research,lifescience,medical belongs to a different structural family of plant extracts, and has stilbene structure (figure 4).93 The chemical structures of apigenin and resveratrol, their core structures, and related chemical groups are shown Cilengitide in figure 4.94 Inhibition of AGE-Induced Inflammation by Compounds Acting on the Receptors Protein glycation is a protein modification, and is observed in ageing. Glycated proteins can be up taken via the RAGE receptor.49 There are various ways to intervene at the receptor level in AGE-RAGE signalling pathway such as the blockade of the receptor by antagonist and antibody.95 The RAGE was implicated to be involved in AD and diabetic vascular diseases.96 Blockade of RAGE-ligand interaction by soluble RAGE, RAGE antibody and RAGE antagonist were considered in the reduction of plaque formation.97 The RAGE-ligand interaction triggers the AGE-RAGE signalling pathway.

Drugs of abuse are thought to produce this aberrant and maladaptive behavioral state by hijacking normal neuronal processes involved in motivated behavior, reinforcement, and plasticity.79 From the perspective of multiple memory systems, there may be multiple pathways to the addicted state. Maladaptive drug-associated

patterns of behavior may derive, for example, Inhibitors,research,lifescience,medical from enhanced motivational power of the drug or reduced motivational power of other, naturalistic rewards, or from an increased reliance on inflexible habitual patterns of learned behavior or a reduced capacity of more flexible control systems. This view has recently been developed at length in an enumeration Inhibitors,research,lifescience,medical of 10 major vulnerabilities in the mechanisms underlying normal decision-making, exploitation of any one of which by a drug may lead to an addicted state.6 Addiction is characterized by enhanced use of rigid habit-like patterns of drug-associated behavior. One can envision such a pattern NSC-737664 deriving from enhancement of the habit learning system

described above, through repeated drug exposure and reinforcement of acquisition and consumption-related behaviors.80 However, in light of the multiple memory systems model, one can also envision over-reliance Inhibitors,research,lifescience,medical on habitual modes of learned behavior deriving from impairment or inhibition of potentially competing learning systems and behaviors. A shift from habits to more flexible forms of behavior is thought to require top-down reference regulation of action selection by prefrontal cortex (eg, Inhibitors,research,lifescience,medical ref 81). Inhibition or dysfunction of this cortical capacity may inappropriately leave

behavior in a habit-guided mode, predisposing towards the inflexible behavior patterns that characterize the addicted state.6 There is evidence that alcohol, amphetamine, and cocaine can all induce such a bias towards habitual control of behavior and a reduced capacity to recruit the prefrontal cortex to regulate it.82,83 OCD is also characterized Inhibitors,research,lifescience,medical by maladaptive inflexible patterns of behavior.84 Increased activation of the basal ganglia circuitry is well established in this condition, as is pathology of the prefrontal cortex.85 This raises the question of whether dysregulation of striatum-dependent habit learning, Entinostat or the balance between habit learning and more flexible forms of behavioral regulation, may contribute to OCD, as well as to drug addiction. Recent work suggests just such a dysregulation. Subjects were trained in behavioral paradigms in which their choices could be guided by an outcome-dependent strategy or a more automatic, habitual strategy. With overtraining, individuals with OCD showed a greater tendency to rely on inflexible habit-like behavioral routines.

Instead, several studies report a differential gene expression in cases versus controls in target areas of the brain for NRG1 and DTNBP1; given that associated alleles/haplotypes are located in introns, it can be suggested that the pathogenic mutations induce a regulatory dysfunction. The meaning of the variation of haplotypes across studies is currently not appropriately understood. Two Inhibitors,research,lifescience,medical putative interpretations are possible: Different “causal” mutations in the same gene contribute to the emergence of schizophrenia; these mutations are not yet known; different “causal” mutations

might predominate in different samples due to “genetic heterogeneity” of schizophrenia; significant associations Inhibitors,research,lifescience,medical to different haplotypes may be a consequence. Linkage disequilibrium between positional markers is variable across populations and samples; thus, the positional markers in linkage disequilibrium with the same “causal” mutations are different between populations and samples. It is currently not possible to decide which of both options Inhibitors,research,lifescience,medical is true. In any case, it is very unlikely that

the disparity between associated haplotypes of the gene reflects a “false positive” finding. Alternative successful strategies Two alternative strategies have also turned out to be successful: Cytogenic analyses in isolated families highly loaded with schizophrenia: A translocation was detected Inhibitors,research,lifescience,medical to cosegregate with the condition status in the family.6 A specific gene (not previously known) on chromosome 1 was regularly disrupted, and was named DISC1. Surprisingly, common mutations in this gene were also found to be associated Inhibitors,research,lifescience,medical with schizophrenia in outbred populations.7 Gene expression might guide to susceptibility genes: Given the plethora of differentially expressed genes in postmortem brains of patients with schizophrenia, specific hypotheses are required to sharpen the focus to differentially expressed

genes for further study. Assuming that synaptic and postsynaptic transmission is a crucial feature of schizophrenia, phosphokinases present as a our website family of candidate proteins; polymorphic genes coding for these units of intracellular signal transmission thus Oligomycin A msds became “hot” candidate genes. These DNA-sequence Batimastat variants in the differentially expressed protein kinase B (AKT1) were found to be associated with schizophrenia.8 Several replications of the original finding have now been published.9 The detected susceptibility genes throw light on the etiology and the pathophysiology of schizophrenia. None of the abovementioned detected candidate genes has been implicated in the development of schizophrenia before.

At none of the doses used Urtica dioica extract changed serum ALP relative to that of the fructose group. However, at 100 and 200 mg/kg/day, the extract increased serum AST relative to that of the fructose group (table 1). Effect of Extract on Leptin The fructose-treated group had a significantly (P<0.05) higher serum leptin compared to that of the control group. Urtica dioica extract at 50 and 100 mg/kg/day, but not 200 mg/kg/day, reduced serum leptin compared to that of the fructose group

Inhibitors,research,lifescience,medical (table 1). Discussion Type 2 diabetes is a multi-factorial disease, frequently associated with a cluster of pathologies including obesity, hypertriglyceridemia, impaired glucose tolerance, and insulin resistance. Fructose intake Inhibitors,research,lifescience,medical may be associated with increased risk of type 2 diabetes through several biological mechanisms.12 A higher fructose intake may play a role in an increase in body weight due to the positive energy balance. Positive energy balance leads to obesity that is associated with a higher concentration of nonesterified fatty acids, which may reduce insulin sensitivity, increase hepatic

glucose production, and have a deleterious effect Inhibitors,research,lifescience,medical on the beta cell function.13 Golalipour et al showed that the protective administration of hydroalcholic extract of Urtica dioica had hypoglycemic effect as well as protective activity on pancreatic beta cells in hyperglycemic Inhibitors,research,lifescience,medical rats.14 Our findings are agreement with those of Ahangarpour,11 and Jalal’s,15 studies that higher intake of fructose increased glucose, insulin, and FIRI. Therefore fructose may increase the risk of type 2 diabetes. The

increase of serum glucose by fructose in our study is similar to that of Magno et al.16 who showed that glucose namely concentrations increased to 145-150 mg/dl in animals drinking 10% fructose solutions. This shows that animals in the present study were diabetic. Urtica dioica is known in Iran’s folk medicine to have hypotensive and antidiabetic activities.4 Domola Inhibitors,research,lifescience,medical et al showed that Urtica Brefeldin_A dioica reduced blood glucose levels upon oral ingestion.17 Moreover, it was shown that a http://www.selleckchem.com/products/Trichostatin-A.html preparation containing various plants with Urtica dioica extract had antidiabetic activity.18 However, other studies reported no hypoglycemic action of this plant.19 The results of this study showed that hydroalcoholic extract of Urtica dioica leaves could decrease the blood glucose and insulin in hyperglycemic rats, which may be caused in part by the reduction of insulin resistance. Cholesterol is one of the body fats and is an important building block in the structure of biological membranes, and used in the biosynthesis of steroid hormones, bile acids and vitamin D. Moreover, the high cholesterol concentration in the blood increases the risk of developing atherosclerosis and related cardiovascular diseases.