Objective. This article reviews the potential physical and psychological consequences of chronic pain and the importance of implementing effective therapeutic strategies to mitigate the harms ...associated with inadequate treatment.
Results. A review of recent literature examining the neurobiology and pathophysiology of chronic pain reveals that this highly prevalent condition negatively impacts multiple aspects of patient health, including sleep, cognitive processes and brain function, mood/mental health, cardiovascular health, sexual function, and overall quality of life. Furthermore, chronic pain has the capacity to become increasingly complex in its pathophysiology, and thus potentially more difficult to treat over time. The various health complications related to chronic pain can also incur significant economic consequences for patients.
Conclusions. Like other chronic conditions, it is important that chronic pain is managed with the objective of minimizing or avoiding its associated long‐term sequelae. In line with this approach, early and effective multimodal treatment strategies, including analgesic therapy that controls pain intensity, are essential to improving outcomes and returning patients to normal levels of function.
After three and a half decades of experience with the Medicare hospice benefit in the U.S., despite excellent quality outcomes in symptom management, patient and family satisfaction, and reduction in ...health care costs, only 12%–15% of beneficiaries' days during the last year of life are spent being cared for within the highly cost-effective interdisciplinary coordinated advanced illness care model known as hospice. Although there are many reasons for this, including difficulties in acknowledging mortality among patients, their families, and physicians, a significant cause of low overall hospice utilization and intractably low median lengths of stay, reflective of late admissions, can be attributed to increasingly difficult and highly variable prognostic determinations for most of the leading causes of death among Medicare beneficiaries.
Medicare is the payer for most hospice care in the U.S. and requires certification of a prognosis of six months or less for a beneficiary to access hospice support. At the time of admission to hospice, two physicians must predict that a patient is more likely to die in the next six months than survive, based on clinical status. In addition to prognostic uncertainty constituting a barrier to timely hospice referral, the Centers for Medicare and Medicaid Services and its payer contractors have developed a robust and expensive retrospective review process that penalizes hospices when patients outlive their expected prognosis. The administratively burdensome and financially punitive review practices further delay or limit access to care for eligible patients as certifying physicians and agencies, fearful of the financial and legal repercussions of reviews and audits, are hesitant to take patients under care unless they are clearly in the dying process. This article will review pertinent history and address the core problem of access to a health care benefit built on a policy that requires far greater prognostic certainty than any clinician can reasonably ascertain and fails to take into consideration the favorable impact hospice care has on terminally ill patients in improving prognosis. This clinical conundrum that limits access of seriously ill people to high-value quality care is of profound importance to the U.S. Medicare population and also one with potential relevance to all complex and regulated health systems and to other models of care whose eligibility criteria are based on prognostication.
Understanding the function of social networks can make a critical contribution to achieving desirable environmental outcomes. Social-ecological systems are complex, adaptive systems in which ...environmental decision makers adapt to a changing social and ecological context. However, it remains unclear how multiple social influences interact with environmental feedbacks to generate environmental outcomes. Based on national-scale survey data and a social-ecological agent-based model in the context of voluntary private land conservation, our results suggest that social influences can operate synergistically or antagonistically, thereby enabling behaviors to spread by two or more mechanisms that amplify each other's effects. Furthermore, information through social networks may indirectly affect and respond to isolated individuals through environmental change. The interplay of social influences can, therefore, explain the success or failure of conservation outcomes emerging from collective behavior. To understand the capacity of social influence to generate environmental outcomes, social networks must not be seen as 'closed systems'; rather, the outcomes of environmental interventions depend on feedbacks between the environment and different components of the social system.
Alzheimer's disease (AD) is a complex disorder influenced by environmental and genetic factors. Recent work has identified 11 AD markers in 10 loci. We used Genome-wide Complex Trait Analysis to ...analyze >2 million SNPs for 10,922 individuals from the Alzheimer's Disease Genetics Consortium to assess the phenotypic variance explained first by known late-onset AD loci, and then by all SNPs in the Alzheimer's Disease Genetics Consortium dataset. In all, 33% of total phenotypic variance is explained by all common SNPs. APOE alone explained 6% and other known markers 2%, meaning more than 25% of phenotypic variance remains unexplained by known markers, but is tagged by common SNPs included on genotyping arrays or imputed with HapMap genotypes. Novel AD markers that explain large amounts of phenotypic variance are likely to be rare and unidentifiable using genome-wide association studies. Based on our findings and the current direction of human genetics research, we suggest specific study designs for future studies to identify the remaining heritability of Alzheimer's disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Puberty is defined as when ovulation is accompanied by visual signs of estrus and subsequent normal luteal function. Age at puberty is an important trait in relation to reproductive success, ...productive life span, and profitability in beef operations. Although puberty and initiation of normal estrous cycles are complex events that require maturation of the hypothalamic-pituitary-ovarian axis, it has been well documented that nutrition, age, and genetics are regulators of age at puberty. However, their role is mainly as regulators of the endocrine maturation that must occur for sustained ovarian cyclicity to be initiated. Increased growth rate between 4 and 7 months of age is apparently sufficient to induce early puberty, and this increased growth rate decreased the negative feedback of estradiol on LH secretion during the prepubertal period. As puberty approaches, a progressive decrease in the negative feedback of estradiol on GnRH secretion allows increased pulse frequency of LH, thus stimulating follicular growth and increased estradiol production. In addition, expression of estrogen receptors in the anterior hypothalamus and ventromedial nucleus is negatively correlated with LH pulse frequency. Although a significant number of genes and pathways are involved in neuromaturation for the initiation of normal estrous cycles, the inhibitory effects of neuropeptide Y on GnRH/LH release appear to decrease, and the stimulatory effect of melanocyte-stimulating hormone alpha on GnRH appears to increase as puberty approaches. Thus, a thorough understanding of the metabolic and neuroendocrine changes that occur to initiate normal estrous cycles is needed to facilitate management of the important reproductive event.
Selenium is an essential trace element in mammals due to its presence in proteins in the form of selenocysteine (Sec). Human genome codes for 25 Sec-containing protein genes, and mouse and rat ...genomes for 24.
We characterized the selenoproteomes of 44 sequenced vertebrates by applying gene prediction and phylogenetic reconstruction methods, supplemented with the analyses of gene structures, alternative splicing isoforms, untranslated regions, SECIS elements, and pseudogenes. In total, we detected 45 selenoprotein subfamilies. 28 of them were found in mammals, and 41 in bony fishes. We define the ancestral vertebrate (28 proteins) and mammalian (25 proteins) selenoproteomes, and describe how they evolved along lineages through gene duplication (20 events), gene loss (10 events) and replacement of Sec with cysteine (12 events). We show that an intronless selenophosphate synthetase 2 gene evolved in early mammals and replaced functionally the original multiexon gene in placental mammals, whereas both genes remain in marsupials. Mammalian thioredoxin reductase 1 and thioredoxin-glutathione reductase evolved from an ancestral glutaredoxin-domain containing enzyme, still present in fish. Selenoprotein V and GPx6 evolved specifically in placental mammals from duplications of SelW and GPx3, respectively, and GPx6 lost Sec several times independently. Bony fishes were characterized by duplications of several selenoprotein families (GPx1, GPx3, GPx4, Dio3, MsrB1, SelJ, SelO, SelT, SelU1, and SelW2). Finally, we report identification of new isoforms for several selenoproteins and describe unusually conserved selenoprotein pseudogenes.
This analysis represents the first comprehensive survey of the vertebrate and mammal selenoproteomes, and depicts their evolution along lineages. It also provides a wealth of information on these selenoproteins and their forms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We report the results from a haloscope search for axion dark matter in the 3.3-4.2 μeV mass range. This search excludes the axion-photon coupling predicted by one of the benchmark models of ..."invisible" axion dark matter, the Kim-Shifman-Vainshtein-Zakharov model. This sensitivity is achieved using a large-volume cavity, a superconducting magnet, an ultra low noise Josephson parametric amplifier, and sub-Kelvin temperatures. The validity of our detection procedure is ensured by injecting and detecting blind synthetic axion signals.
Exercise training induces mitochondrial biogenesis, but the time course of molecular sequelae that accompany repetitive training stimuli remains to be determined in human skeletal muscle. Therefore, ...throughout a seven‐session, high‐intensity interval training period that increased (12%), we examined the time course of responses of (a) mitochondrial biogenesis and fusion and fission proteins, and (b) selected transcriptional and mitochondrial mRNAs and proteins in human muscle. Muscle biopsies were obtained 4 and 24 h after the 1st, 3rd, 5th and 7th training session. PGC‐1α mRNA was increased >10‐fold 4 h after the 1st session and returned to control within 24 h. This ‘saw‐tooth’ pattern continued until the 7th bout, with smaller increases after each bout. In contrast, PGC‐1α protein was increased 24 h after the 1st bout (23%) and plateaued at +30–40% between the 3rd and 7th bout. Increases in PGC‐1β mRNA and protein were more delayed and smaller, and did not persist. Distinct patterns of increases were observed in peroxisome proliferator‐activated receptor (PPAR) α and γ protein (1 session), PPAR β/δ mRNA and protein (5 sessions) and nuclear respiratory factor‐2 protein (3 sessions) while no changes occurred in mitochondrial transcription factor A protein. Citrate synthase (CS) and β‐HAD mRNA were rapidly increased (1 session), followed 2 sessions later (session 3) by increases in CS and β‐HAD activities, and mitochondrial DNA. Changes in COX‐IV mRNA (session 3) and protein (session 5) were more delayed. Training also increased mitochondrial fission proteins (fission protein‐1, >2‐fold; dynamin‐related protein‐1, 47%) and the fusion protein mitofusin‐1 (35%) but not mitofusin‐2. This study has provided the following novel information: (a) the training‐induced increases in transcriptional and mitochondrial proteins appear to result from the cumulative effects of transient bursts in their mRNAs, (b) training‐induced mitochondrial biogenesis appears to involve re‐modelling in addition to increased mitochondrial content, and (c) the ‘transcriptional capacity’ of human muscle is extremely sensitive, being activated by one training bout.
It is believed that exercise training stimulates mitochondrial biogenesis by repeatedly increasing mRNA contents for mitochondrial proteins via activation of specific nuclear transcription proteins. These transcription proteins may also increase early during training. The timing of these responses may be important and occur in unique patterns but this has not been determined in human muscle. We show that mitochondrial biogenesis occurs very rapidly (3 exercise sessions) with steady increases thereafter. Furthermore, only one session increased the content of two important transcription factors (PGC‐1α and PPARα) with others increasing after 3–5 sessions. Numerous mitochondrial and transcription protein increases appeared to result from repeated short bursts in their mRNA contents which occurred in very distinct patterns. These results show that mitochondrial biogenesis occurs rapidly and suggests the contribution of specific transcription proteins to this process may be time‐dependent. This information may help our understanding of how exercise improves muscle metabolic capacities.
Abstract Abnormal oxidative stress is an established feature of Alzheimer's disease, but clinical trials aiming to reduce oxidative stress have not yet proven an effective therapy for dementia ...patients. The purpose of this review is to systematically analyze available data describing markers of oxidative stress and antioxidants in blood from subjects with Alzheimer's disease or those with mild cognitive impairment to highlight potential interactions between peripheral redox changes and central nervous system pathology and contribute to the design of future clinical study. PubMed, SCOPUS and Web of Science were systematically queried to collect studies which have evaluated markers of oxidative stress, levels of antioxidants, copper, transferrin and ceruloplasmin levels in blood from subjects with Alzheimer's disease and matched controls. After application of quality measures, results were aggregated in a random effects analysis. We found that markers of lipid peroxidation are elevated in blood in Alzheimer's disease and in mild cognitive impairment, copper metabolism is dysregulated and total antioxidant capacity is decreased. While surprisingly none of the major antioxidative enzymes are significantly decreased, non-enzymatic antioxidants in blood (particularly uric acid, vitamins A, E and C, α- and β-carotene) are significantly decreased. There is significant oxidative damage in peripheral blood early in the process of neurodegeneration. We propose that clinical studies assessing cognitive outcomes after antioxidant therapy tailor interventions to individual patients' deficiencies and confirm an improvement in an appropriate serological marker of oxidative stress. This strategy may be most effectively applied in a clinical trial of primary prevention.
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