3). Figure 3 Bar chart illustrating left and right hippocampal volumes computed from MRI for intact hippocampi, AD without HS, bilateral HS, left-only HS, and right-only HS. Analysis of variance showed Romidepsin purchase significant group differences in hippocampal MRI volumes (P < 0.001). Post hoc comparisons showed 32% greater atrophy in bilateral HS compared with AD (P < 0.001). There were also statistically significant differences Inhibitors,research,lifescience,medical between intact versus AD and intact versus HS for both right and left hippocampi

(P < 0.001). On average, volumes for HS hippocampus were 52% and AD volumes were 30% less than intact hippocampi. As one might expect, for left-only HS, the left HV was smaller than the right (P = 0.002), and for right-only HS, the right volume was smaller than the left (P = 0.04). Inhibitors,research,lifescience,medical As noted previously in the literature (Wang et al. 2003; Lye et al. 2004), in the cases with intact hippocampi, the right hippocampus was significantly larger than the left hippocampus (P = 0.009). The right HV for right-only HS was 31.3% larger than the left HV for left-only

Inhibitors,research,lifescience,medical HS (P = 0.01), which may reflect underlying hemispheric asymmetries found in normal controls. Of interest, in right- or left-only HS cases, the MRI volumes in the contralateral and apparently uninvolved hippocampus were smaller than normal. For left-only HS cases, the right HV was significantly less than for normal controls (P = 0.0002). For right-only HS cases, there was a trend showing smaller volume of the left hippocampus compared with controls (P = 0.07). No statistically significant Inhibitors,research,lifescience,medical right versus left differences was found for either bilateral HS or AD. Discussion HS may be a dramatic finding at autopsy that often escaped clinical recognition and diagnosis during a given subject’s lifetime. In Inhibitors,research,lifescience,medical this convenience sample enriched for SIVD, AD, and normal aging, we found HS in 24.5% of autopsy cases. In our 31 cases, the laterality of HS showed significant variability: 45% were

bilateral, 32% left-sided, and 23% right-sided. The frequency of HS in our study was nearly isothipendyl double the 12% previously reported in a community-based dementia autopsy series (Leverenz et al. 2002). Compared with the literature, our sample was intentionally enriched for SIVD, however, HS was found in roughly equal proportions in AD and SIVD (24% and 29%, respectively). More likely, the higher frequency of HS in our sample reflects the systematic examination of both hippocampi throughout their rostral–caudal extent in the majority of our cases. Indeed, based on our findings, the prevalence of HS will be underestimated by at least 25% if only one cerebral hemisphere is examined. We initially defined complete HS as involvement across multiple coronal sections.

The location of these carcinoid tumors can be divided based on their embryologic derivation into find more carcinoids of the foregut (esophagus, stomach and duodenum), midgut (jejunum, ileum, appendix and ascending colon) and hindgut (transverse colon, descending colon, sigmoid and rectum) (71). Tumors from each different region of the gastrointestinal tract may secrete different hormones as

well. Foregut and midgut carcinoid often produce serotonin and substance P while hindgut carcinoids may produce glucagon like peptide, pancreatic polypeptide, and polypeptide YY (72-78). In spite of these differences, these tumors share similar morphologic features such as clusters/sheets/nests of neuroendocrine cells with round to Inhibitors,research,lifescience,medical ovoid nuclei, “salt and pepper” chromatin Inhibitors,research,lifescience,medical and moderate amounts of clear cytoplasm. All gastrointestinal neuroendocrine tumors are positive for the generic markers of neuroendocrine differentiation such as chromogranin A, synaptophysin and NSE, as well as PGP 9.5, and CD56 (79). Determining

the origin of the tumor may be challenging; however, immunohistochemical stains can be very helpful. Carcinoids Inhibitors,research,lifescience,medical from the foregut and midgut are generally positive for chromogranin A and CD56, while those from the hindgut are usually negative (73,80,81). Hindgut carcinoids on the other hand often express prostatic acid phosphatase (82). A less helpful marker is CDX-2, which although positive for most colorectal carcinomas has an immunoreactivity of about 40% in well differentiated carcinoids (83-87) but has a reported 80% expression rate in poorly differentiated carcinoids (80). Carcinoid tumors make up about a third of the neoplasms in the small intestine. They most often occur in the ileum and rarely in the duodenum and can be separated by their Inhibitors,research,lifescience,medical location:

duodenal and jejunoilieal carcinoids. Duodenal carcinoids, similar to any carcinoid in the gastrointestinal tract can be further divided by the type of cells which make up the tumor into gastrinomas (G-cell tumors), somatostatinomas (D-cell tumors) and a small percentage Inhibitors,research,lifescience,medical of the undefined type (88). Classification of neuroendocrine tumors is based on the degree of differentiation. Most carcinoids are well-differentiated carcinoid (50-75%), well-differentiated neuroendocrine Terminal deoxynucleotidyl transferase carcinoma and poorly differentiated neuroendocrine carcinoma (<1-3%) (88). Carcinoid tumors usually show a monotonous proliferation of small bland polygonal cells with round nuclei, “salt and pepper” chromatin and moderate amounts of cytoplasm in either a nested (type A), trabecular (type B) or acinar (type C) pattern. Distinction between benign and malignant carcinoid is based on the presence or absence of metastasis rather than just on histology. Colon and rectum Colorectal cancer (CRC) CRC is the third most common cancer diagnosed in the United States and third most common cause of cancer deaths. Risk for development of colorectal carcinoma increases significantly after the age of 40.

Bleuler’s approach was also notable for other reasons. First, his reformulation of dementia praecox as “the group of schizophrenias” foreshadowed the modern view that schizophrenia is a heterogeneous group of disorders with similar clinical presentations. Second, Bleuler included defects in affect as a core feature of the disorder. Third, his view of schizophrenia allowed for the possibility

of remission or recovery. Kraepelin’s and Bleuler’s observations provided the foundation for contemporary systems Inhibitors,research,lifescience,medical of psychiatric classification, including the International Classification of Disease and Death (ICD) and the American Psychiatric Association’s DSM. These systems have thus benefited from incisive clinical observations of, and conceptualizations about, schizophrenic illness. They also, however, inherited the limitations of Kraepelin and Bleuler’s efforts at classification and diagnosis. The first DSM definition of schizophrenia was vague, unreliable,

and allowed for too much discretion on the part of clinicians. As a result, apparent geographical differences Inhibitors,research,lifescience,medical arose in the rates of schizophrenia. In the United States, schizophrenia became the diagnosis of choice for psychotic conditions that lacked a clear “organic” etiology, and thus appeared to occur more frequently than it did in the United Kingdom.3 DSM-II continued’the DSM-I Inhibitors,research,lifescience,medical tradition of unreliable diagnoses, although it did incorporate the issue of differential diagnoses. Inhibitors,research,lifescience,medical Both of these early systems viewed psychosis as a key feature of the disorder (we use the term psychosis to encompass hallucinations, delusions, and gross disorganization of thought or behavior). Interestingly, however, and despite its emphasis on psychosis, DSM-II did contain a nonpsychotic subtype of schizophrenia, called latent schizophrenia, which Inhibitors,research,lifescience,medical included a heterogeneous group of FK228 cell line patients who in DSM-I were diagnosed with “incipient” or “borderline” schizophrenia, among other conditions. As the term “latent” implies, however, the category was intended to encompass individuals with underlying or occult psychotic conditions, instead

of identifying individuals who had schizophrenia in the absence of psychosis. Nevertheless, the category did represent an important crotamiton attempt to delineate the role of psychosis in schizophrenia. DSM-III resulted largely from the efforts of the “neo Kraepelinian” movement of the 1960s and 1970s,4 and from the efforts of other investigators in psychiatry and clinical psychology who argued for empirical, psychometric validation of psychiatric syndromes (eg, reference 5). DSM-III represented a marked shift from previous DSM.s, and contained a number of innovations, like field tests of diagnostic reliability, specific inclusion and exclusion criteria for diagnoses, multiaxial diagnosis, and a focus on the description of syndromes and course of disorders rather than inferences about their etiology.

As a result, they need product, labeling that differentiates their drug from those already marketed. Marketing has to selleck compound provide creative concepts for the prescribing physician, the patient, and the company’s senior management. They also have to make sure that, budget goals arc met. It is not uncommon for the marketing group to have differences of opinion from both the clinical and regulatory groups within their own company, as well as with the FDA.

Legal In order for a drug to be financially successful, patent protection Inhibitors,research,lifescience,medical is a key element. The legal group must submit patents at the appropriate time and do all in its power to avoid lawsuits from potential competitors. The legal group also ensures that neither the FDA nor the Federal Trade Commission (FTC) will challenge advertising and promotional materials. Food and Drug Administration Inhibitors,research,lifescience,medical Hie FDA’s primary mission is to protect public health by regulating the food supply, drugs, devices, and cosmetics. The FDA regulates through the FDCA, Title 21 of the Code of Federal Regulations

(CFR)2 and publications in the Federal Register,3 and by issuing guidance and other regulatory documents. Development philosophy Don’t waste time: time is money Time is a key factor in drug development. With finite patent lives, the quicker a drug gets to the market, the longer the revenue stream will be free of generic competition. Therefore, in order to minimize the development time, the team should: Plan carefully. Inhibitors,research,lifescience,medical Execute meticulously. Replan when necessary. Do only what is needed. Hire people who want to get the job done. Have pride in their Inhibitors,research,lifescience,medical product. Working with the FDA Structure of the FDA There are four FDA centers that have the potential to interact, in drug development. These are the Center for Drug Evaluation and Research

(CDER), Center for Biologies Evaluation and Research (CBER), Center for Devices and Radiological Health (CDRH), and Center for Food Safety and Applied Nutrition (CFSAN). With the advent of drug-delivery devices and dietary Inhibitors,research,lifescience,medical supplements that, can sometimes appear to be drugs, the boundaries between the centers can at times be unclear. As a result, it, is always a good idea to know which center will review a particular product. Sources of information MRIP There are several sources from which information can be obtained about the FDA. Through the Freedom of Information Act,4 the United States government has established a mechanism to obtain information directly from the FDA, which is otherwise not easily accessible through publicly available information. The FDA can be contacted via letter or fax. The FDA also has research services and can provide, on a fee-for-service basis, specific information located within their archives. Commercial companies also provide information services. With the creation of the Internet, public information is more readily available than ever before. The FDA has a web site for each of its divisions with a sophisticated search engine and document services (http://www.

The subcortical structure borders were plotted by freeview visualization tools (part of FreeSurfer package) and compared against the brain regions. In case of discrepancy, they were corrected manually. A separate mask was generated for each and every segmented subcortical region and parcellated cortical region. These masks were transferred to the T1 native space

using nearest-neighbor interpolation. The transformation matrix was obtained by registering Inhibitors,research,lifescience,medical the subject’s head from FreeSurfer space to native space by FMRIB software library (FSL) linear registration tool (http://fsl.fmrib.ox.ac.uk/fsl/flirt/) with 6 degree of freedom (df), rigid-body, 256 bins normalized mutual information cost function, and trilinear interpolation. Quality check was performed by overlaying the masks on top of the T1 image in the subject’s native space. No discrepancy was found at this stage. Resting BOLD fMRI preprocessing Inhibitors,research,lifescience,medical The 6:1 slice interleaving of Philips scanner was corrected using Sinc selleck chemicals llc interpolation using SPM8 software package. Our MRI protocol did not include bias field map acquisition, thus we could not correct for B0 field inhomogeneity correction. However, correlations in temporal signals are not altered with the mean of the signals, therefore the effect of B0 field inhomogeneity Inhibitors,research,lifescience,medical in the Inhibitors,research,lifescience,medical absence of spatial smoothing is negligible.

It should be emphasized that spatial smoothing is not required in fMRI data analysis in native space. However, this does not rule out the effect of B0 field inhomogeneity in the intermodal registration of fMRI and T1 scans. This will be discussed next in the next section. There have been many reports of motion-induced correlation between ROIs in resting-state BOLD fMRI data (Birn et al. 2006; Power et al. 2012; Van Dijk et al. 2012; Carp 2013), so extra caution was taken in this study to deal with this issue (see Fig. 3). We used mcflirt

(motion correction tools Inhibitors,research,lifescience,medical in the FSL package [Jenkinson et al. 2012]) to DNA ligase register all the volumes to a reference image (Jenkinson et al. 2002). The reference image was generated by registering (6 df, 256 bins mutual information, and Sinc interpolation) all volumes to the middle volume and averaging them. We made sure that the selected middle volume was free of artifacts and motion by examining the derivative of the transformation parameters around that volume. We then used the method described in Power et al. (2012) to calculate frame-wise displacement (FD) from the six motion parameters and root mean square difference (RMSD) of the bold percentage signal in the consecutive volumes for every subject. To be more conservative, we lowered the threshold of our RMSD to 0.3%. (It was originally suggested to be 0.5%.

Conversely, to the extent that the PROSPECT intervention is successful, the study will have sufficient data to develop and then test hypotheses about the most critical components. Primary care

sites To evaluate the this website impact of its intervention on patient outcomes, PROSPECT is collecting data from 18 separate primary care practices from 3 geographic areas (metropolitan and Inhibitors,research,lifescience,medical outlying New York, Philadelphia, and Pittsburgh). Practices were selected in pairs sharing similar characteristics in terms of academic affiliation, location (urban, suburban, or rural), size (number of physicians), and the racc/cthnicity of the patients. All practices serve both managed-care and fee-for-service patients. As seen in Table I, the 9 pairs of practices Inhibitors,research,lifescience,medical represent

considerable diversity including both academic and nonacademic urban practices, a wide range in patient racial/ethnic composition, including both academic and nonacademic practices with greater than 50% minority patients, and solo as well as large group practices. Table I. Characteristics of PROSPECT physician practices (n=18). The generalizability of PROSPECT Inhibitors,research,lifescience,medical findings to primary care throughout the United States is limited to some extent by the fact that practices were not randomly selected and are all located in the northeast. On the other hand, the heterogeneous characteristics of the recruited practices and their patients do extend the representative of PROSPECT findings beyond much previous research that was limited to academic-affiliated settings, predominately white patients, or single locations. In the Inhibitors,research,lifescience,medical United States, the vast majority (74%) of elderly adults live in a metropolitan area (1990 Census),51 lending further generalizability

to findings from the study. Within each pair, practices were randomly selected Inhibitors,research,lifescience,medical to receive the guideline management intervention or “enhanced care,” a less intense intervention consisting primarily of physician education and depression identification. Although acknowledging that identification of depression is an important part of clinical care, PROSPECT is not designed to evaluate different methods of identifying depression in primary care, for several reasons. First, previous research has shown that identification of depression in primary care alone has little effect on patient outcomes. ADP ribosylation factor Second, in order to evaluate the effect of the proposed intervention on patient outcomes, comparable assessment is needed in both intervention and usual care patients, necessitating integrating assessment into the research protocol. And third, for ethical reasons, physicians in both groups need to be informed of the results of these assessments, making a test of identification of depression by physicians nonfeasible in the context of the current study.

Conclusions In unipolar depressed patients, beneficial rTMS treatment has immediate and prolonged neurobiological effects. Neurobiological data support the choice of the left DLPFC as a valid rTMS target site

to intervene with the neuronal pathways deregulated in major depression. The observed changes in a depressionrelated neurocircuitry seem to agree with other successful treatment modalities, such as pharmacological antidepressant treatment and ECT. Although further research is required, biological data indicate that depressed patients with some kind of “preserved” cortico- subcortical neurocircuitries could Inhibitors,research,lifescience,medical be susceptible to rTMS treatment. Displaying a metabolically more active fronto-cingulate network at baseline indicates a possible better clinical outcome. This observation is consistent with the Inhibitors,research,lifescience,medical hypothesis that the synchronized modulation of “dysfunctional fronto-cingulate pathways” is critical for illness remission.23 In short, successful rTMS treatment seems to result in a cascade of neurobiological changes in brain Inhibitors,research,lifescience,medical areas linked with the stimulated area, supporting the integrative model of action depicted in Figures 1 and 2. Whether the rTMS effects are modulated by NT systems or neurotrophic factors remains to be clarified. Selected abbreviations and acronyms ACC anterior cingulate cortex BDNF brain-derived neurotrophic factor DLPFC dorsolateral prefrontal

cortex HF high-frequency HPA hypothalamic-pituitary-adrenal Inhibitors,research,lifescience,medical LF low-frequency rTMS repetitive transcranial magnetic stimulation
Clinical

endocrine Forskolin price disorders have long been recognized to have psychiatric symptoms as a prominent feature of their clinical presentation. Both hyper- and hypofunction of the various endocrine glands have led to a wide range of psychiatric symptoms and syndromes, most commonly depression. Moreover, treatment of the endocrine condition frequently results in resolution Inhibitors,research,lifescience,medical of the psychiatric sequelae. These observations in endocrine patients led to a comprehensive search for a hormonal etiology for many psychiatric disorders, particularly major depression and bipolar disorder. While this research effort was largely unsuccessful, with the possible exception of perturbations of the adrenal axis in major depression (see below), it did lead to substantial Adenylyl cyclase enquiry into whether various hormones may have clinically useful antidepressant efficacy in primary major depression and, to a lesser extent, bipolar disorder. While there are a number of case reports and small case series documenting the antidepressant effects of a large number of hormones of various endocrine systems, there is a limited database on just a few endocrine systems, which include large open trials or randomized controlled trials. This review will focus on these hormones which include: Hormones of the thyroid axis Gonadal steroids, which include testosterone in men and gonadal steroids in women Melatonin Adrenal cortex hormones.

Strengths and weaknesses of the study The main strength of our study is the large register of data collected, where we were able to prospectively collect a complete material of more than 5 000 red responses during the three month period, based on a population close to 820 000 inhabitants, about 20% of the Norwegian population. Limitations include NACA-scores in most of the cases being assessed retrospectively based on medical records, which might give a lower accuracy when registering the severity of the illness. Inhibitors,research,lifescience,medical Severity assessment in patients with chest pain can be difficult from medical records alone, but the records included the patients’ symptoms and clinical findings, making it possible

to achieve reliable registrations. Ideally the study would have included on-going clinical evaluation by the physicians on-site, in IOX1 mw addition to results and diagnoses

from the investigations for the patients admitted to the hospital. Our results are based solely Inhibitors,research,lifescience,medical on patients in an emergency situation defined by the EMCCs using the Index (red response), and thus Inhibitors,research,lifescience,medical undertriaged patients would not be included. Patients with chest pain assigned with a yellow response might be at risk of being undertriaged (“false negatives”), supporting the need for further studies on all patients with chest pain outside hospitals. The degree of urgency was set by trained nurses using the Norwegian Medical Index of Emergencies, but little is known about the validity of the Index and how the Index is used in the different EMCCs. A throughout evaluation and validation of the Index is needed. Previous studies The rate of acutely ill patients with chest pain in our study is similar to the findings in two other studies Inhibitors,research,lifescience,medical from Norway, reporting rates of 4.8 [7] and 5.4 [8]. The Inhibitors,research,lifescience,medical difference in median age between the genders, with the males being significantly younger, is in accordance with previous studies [14]. Recent studies from the UK [2,3] and the US [15] have shown that around 10% of calls to emergency

medical dispatch systems involve acute chest pain. A Norwegian publication from 2009 [16] showed that 22% of all the calls to the emergency number 113 ended in a red response, and it is intended that most of the chest pain incidents will be classified as a red response. In our study this would indicate that approximately 5% of all calls to the EMCCs involved not chest pain as the main complaint, given that all incidents with chest pain were classified as a red response. Meaning of study A substantial number of the patients were not in a life threatening medical situation. This sheds light on the challenges for the EMCCs in deciding the appropriate level of response in patients with acute chest pain. Overtriage is to some extent both expected and desirable to intercept all patients in need of immediate help, but it is also well known that overtriage is resource demanding.

There were no group differences in demographic characteristics, except for the PCI-32765 solubility dmso cognitive score. Our finding of a higher cognitive score at 2002 and 2005 in the E4- group is consistent with previous studies.15 Table I Demographic characteristics in the

analysis of the effect of lipids/lipoproteins. a P value was calculated by unpaired two-tailed t test. b P value was calculated by Pearson χ2 two-tailed test. c P value was calculated by analysis of covariance … Figure 1 and 2 show the median plasma concentrations of lipids for the three strata according to the tertiles of plasma levels of lipids/apoE, and the mean cognitive scores of the E4- and E4+ groups at 2002 and 2005 according Inhibitors,research,lifescience,medical to the three strata of plasma concentrations of lipids/apoE. Figure 1. Mean cognitive test score of each tertile groups of lipid levels in ApoE4+ group. a, data Inhibitors,research,lifescience,medical are mean after adjustment for age, sex, years of education, Geriatric Depression Scale score, cigarette smoking, and medical history of cardiovascular disease, diabetes … ANCOVA analysis evaluating the influence of lipids level on cognitive function

showed a significant Inhibitors,research,lifescience,medical influence of the HDL level on composite cognitive scores at both 2002 and 2005 in the E4- group (F2,498=9.3, P<0.001 for 2002, F2,498=9.3, P<0.001 for 2005). Subjects with higher HDL concentrations had higher cognitive scores. The effect Inhibitors,research,lifescience,medical size of the influence of the plasma HDL level on cognitive score was more than 0.01(η2=0.04 for 2002, η2=0.04 for 2005). No such significant association was observed in the E4+ group (Figure 2). Figure 2. Mean cognitive test score of each tertile groups of lipid levels in the ApoE4- group. a, data are mean after adjustment for age, Inhibitors,research,lifescience,medical sex, years of education; Geriatric Depression Scale score, cigarette smoking, and medical history of cardiovascular disease, ... A significant main effect of the apoE level was found by ANCOVA on composite cognitive scores at 2002 and 2005 in both of the E4- and E4+ group (F2,498=11.3, P<0.001 for 2002, F2,498=7.3, P=0.001 for 2005

in the E4-, and F2,102=7.0, P=0.001 for 2002, F2,102=4.0, Casein kinase 1 P=0.02 for 2005 in the E4+ ). Subjects with higher plasma apoE concentration had higher cognitive scores in both groups. The effect size of the association of the plasma apoE level on these cognitive scores was more than 0.01(η2=0.04 for 2002, η2=0.03 for 2005 in the E4-,and η2=0.12 for 2002, η2=0.07 for 2005 in the E4+). Why are cognitive scores associated with plasma apoE and HDL levels? Each of the analyses using the data from the baseline and 3-year follow-up examinations revealed that cognitive scores were associated with the plasma apoE level in both E4- and E4+, and the HDL level in E4-. We will discuss these findings. ApoE plays a significant role in response to neuronal injury by reducing inflammation, endothelial dysfunction, and lipid oxidation.

In addition, the nurses recognized that the practice of ACP could be time consuming; a challenge in the context of an already unpredictable workload [19]. Among the greatest challenges that nurses Rapamycin concentration perceived to be associated with ACP were their own and colleagues’

knowledge and skills about communication practice, recording and follow up. A need for careful clinical supervision was perceived, since ACP can raise issues which have the potential to engage with fears and emotions within Inhibitors,research,lifescience,medical nurses’ biographical lives [33]. The inclusion of ACP issues into communications skills training is important if nurses can fulfill their potential as key players in raising and discussing ACP issues with their patients but must be accompanied at the level of practice by appropriate mechanisms of ongoing support and

supervision so that nurses can reflect upon but not be disabled by concerns about illness and death that inevitably surface in ACP work. Not affording formal recognition of the emotional toll of palliative focused work Inhibitors,research,lifescience,medical on district nurses has been Inhibitors,research,lifescience,medical reported as a barrier to the implementation of palliative care [19]. Conclusions Community nurses have a key role in providing palliative care to patients in the community and are well placed to facilitate a process of ACP which has the potential to improve the quality of end-of-life care that patients receive. This paper has highlighted some critical areas of concern if this potential is to be fully realized. Competing interests The

authors declare that they have no competing interests. Authors’ contributions JS conceived and led the study, participated in data analysis and wrote the first draft of this paper. KA and SK assisted Inhibitors,research,lifescience,medical in the conduct of the study, participated in data analysis and edited the paper. All authors read and approved the final manuscript. Pre-publication Inhibitors,research,lifescience,medical history The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1472-684X/9/4/prepub Acknowledgements We gratefully acknowledge funding from the Burdett Trust for Nursing Cytidine deaminase and from Help the Aged (now Aged UK). The funders played no part in the study design, or collection, analysis or interpretation of data or in the decision to submit the manuscript for publication. We also thank our colleagues in the Peer Education Project Group for their role in the wider study which this paper draws upon.
One of the main objectives of a culture is re-orienting death towards life[1]: each person’s death threatens society’s cohesion by casting a shadow on the feelings of safety and continuity on which every human being bases his/her life and finds support and consolation. For ages the “good death” reflected the community’s religious beliefs, and the suffering of the dying person was considered mostly as an unavoidable aspect of the dying process.