PKD1 protein is involved in reactive oxygen species-mediated mitochondrial depolarization in cooperation with protein kinase Cδ (PKCδ).

In this study, we used gene targeting in mice to identify the in vivo functions of PKD1. In addition to phenotypically characterizing the resulting knock-out animals, we also used mouse embryonic fibroblasts to investigate the associated signaling pathways in detail. This study is the first to use genetic deletion to reveal that PKD1 is a key regulator involved in determining the threshold of mitochondrial depolarization that leads to the production of reactive oxygen species. In addition, we also provide clear evidence that PKCδ is upstream of PKD1 in this process and acts as the activating kinase of PKD1. Therefore, our in vivo data indicate that PKD1 functions not only in the context of aging but also during nutrient deprivation, which occurs during specific phases of tumor growth.

Use of a values inventory as a discussion aid about end-of-life care: A pilot randomized controlled trial.

OBJECTIVE: We examined the utility of a brief values inventory as a discussion aid to elicit patients' values and goals for end-of-life (EoL) care during audiotaped outpatient physician-patient encounters. METHOD: Participants were seriously ill male outpatients (n = 120) at a large urban Veterans Affairs medical center. We conducted a pilot randomized controlled trial, randomizing 60 patients to either the intervention (with the values inventory) or usual care. We used descriptive statistics and qualitative methods to analyze the data. We coded any EoL discussions and recorded the length of such discussions. RESULTS: A total of 8 patients (13%) in the control group and 13 (23%) in the intervention group had EoL discussions with a physician (p = 0.77). All EoL discussions in the control group were initiated by the physician, compared with only five (38%) in the intervention group. Because most EoL discussions took place toward the end of the encounter, discussions were usually brief. SIGNIFICANCE OF RESULTS: The outpatient setting has been promoted as a better place for discussing EoL care than a hospital during an acute hospitalization for a chronic serious illness. However, the low effectiveness of our intervention calls into question the feasibility of discussing EoL care during a single outpatient visit. Allowing extra time or an extra visit for EoL discussions might increase the efficacy of advance care planning.

A Review of Olanzapine in the Treatment of Cancer Anorexia-Cachexia Syndrome.

BACKGROUND: Cancer anorexia-cachexia syndrome (CAS) is a multifactorial condition that is highly prevalent in advanced cancer patients and associated with significant reduction in functional performance, reduction in quality of life, and increased mortality. Currently, no medications are approved for this indication. Recently, the American Society of Clinical Oncology (ASCO) released a rapid recommendation suggesting that low-dose olanzapine once daily may be used to treat cancer cachexia. Many questions still exist on how to use olanzapine for this indication in clinical practice. The objective of this review is to identify existing knowledge on the use of olanzapine for CAS. METHODS: A comprehensive search was conducted to identify the primary literature that involved olanzapine for anorexia and cachexia in cancer patients between 2000 and 2023. RESULTS: Seven articles were identified and are discussed here, including two randomized double-blinded placebo-controlled studies, one randomized comparative study, two prospective open-label studies, one retrospective chart review, and one case report. CONCLUSIONS: Low dose olanzapine (2.5-5 mg once daily) may be useful in the treatment of CAS for increasing appetite, reducing nausea and vomiting, and promoting weight gain. Further large-scale multi-center randomized placebo-controlled studies will be needed to investigate the impact of olanzapine on weight change in CAS patients.

Rational Prescribing of Pancreatic Enzymes for Patients with Pancreatic Cancer.

Most patients with pancreatic cancer at some point present with symptoms related to exocrine pancreatic insufficiency (EPI). These include diarrhea, abdominal bloating, indigestion, steatorrhea, weight loss, and anorexia. Even though up to 80% of pancreatic cancer patients eventually present with symptoms related to exocrine pancreatic insufficiency, only 21% are prescribed pancreatic enzyme replacement therapy (PERT). Its effectiveness is also highly dependent on its proper timing of administration, and patients must be thoroughly educated about this. The impact of symptoms of EPI can lead to poorer overall well-being. Pharmacists play a crucial role in properly educating patients on the correct use of pancreatic enzyme replacement therapy. PERT is a key strategy in managing the symptoms of EPI and can improve quality of life, which is a central focus in palliative care. This treatment is profoundly underutilized in the palliative care of these patients. The objective of this review is to discuss the pharmacology, pharmacokinetics, side effects, available evidence of the effectiveness of pancreatic enzyme use for patients with pancreatic cancer, and challenges, along with proposed solutions regarding its use.

A Systematic Review of Naldemedine and Naloxegol for the Treatment of Opioid-Induced Constipation in Cancer Patients.

BACKGROUND: Opioid-induced constipation (OIC) is a pervasive and distressing side effect of chronic opioid therapy in patients with cancer pain, significantly impacting their quality of life. Peripherally acting µ-opioid receptor antagonists (PAMORAS) were developed for treatment-resistant OIC but most studies were conducted with non-cancer patients. OBJECTIVE: to discuss two oral formulations of PAMORAs, naldemedine and naloxegol, and to review available evidence of the effectiveness of these drugs for OIC in cancer patients. METHODS: a comprehensive search to identify primary literature for either naldemedine or naloxegol for OIC in cancer patients. RESULTS: Only three prospective randomized, double-blind, placebo-controlled clinical trials for naldemedine enrolling cancer patients were identified; the results of a subgroup analysis of two of those studies and two non-interventional post marketing surveillance studies of these trials are also reported here. For naloxegol, only two randomized controlled trials were identified; both were unsuccessful in enrolling sufficient patients. An additional four prospective non-interventional observational studies with naloxegol were found that enrolled cancer patients. There were significantly higher rates of responders in the PAMORA groups than in the placebo groups. The most common side effect for both PAMORAs was diarrhea. LIMITATIONS: All studies were industry-funded, and given that only three trials were randomized controlled studies, the overall quality of the studies was lacking. CONCLUSION: Naldemedine or naloxegol appeared safe and useful in the treatment of OIC in cancer patients and may improve their quality of life. Larger-scale randomized placebo-controlled studies of PAMORAs in cancer patients would strengthen existing evidence.

Evolution of Telehealth-Its Impact on Palliative Care and Medication Management.

Palliative care plays a crucial role in enhancing the quality of life for individuals facing serious illnesses, aiming to alleviate suffering and provide holistic support. With the advent of telehealth, there is a growing interest in leveraging technology to extend the reach and effectiveness of palliative care services. This article provides a comprehensive review of the evolution of telehealth, the current state of telemedicine in palliative care, and the role of telepharmacy and medication management. Herein we highlight the potential benefits, challenges, and future directions of palliative telemedicine. As the field continues to advance, the article proposes key considerations for future research, policy development, and clinical implementation, aiming to maximize the advantages of telehealth in assisting individuals and their families throughout the palliative care journey. The comprehensive analysis presented herein contributes to a deeper understanding of the role of telehealth in palliative care and serves as a guide for shaping its future trajectory.

Buprenorphine Use for Analgesia in Palliative Care.

Buprenorphine is a semi-synthetic long-acting partial µ-opioid receptor (MOR) agonist that can be used for chronic pain as a sublingual tablet, transdermal patch (Butrans®), or a buccal film (Belbuca®). Buprenorphine's unique high receptor binding affinity and slow dissociation at the MOR allow for effective analgesia while offering less adverse effects compared to a full agonist opioid, in particular, less concern for respiratory depression and constipation. It is underused in chronic pain and palliative care due to misconceptions and stigma from its use in opioid use disorder (OUD). This case report discusses the unique pharmacology of buprenorphine, including its advantages, disadvantages, available formulations, drug-drug interactions, initiation and conversion strategies, and identifies ideal populations for use, especially within the palliative care patient population.

Expression pattern of protein kinase Cδ during mouse embryogenesis.

BACKGROUND: The members of the protein kinase C (PKC) family consist of serine/threonine kinases classified according to their regulatory domain. Those that belong to the novel PKC subfamily, such as PKCδ, are dependent on diacylglycerol but not Calcium when considering their catalytic activity. Although several studies have shown the importance of PKCδ in different cellular events in health and disease, the overall in vivo distribution of this PKC isoform during development is still lacking. Through Lac Z and antibody staining procedures, we show here the in vivo expression of PKCδ during mouse embryogenesis. RESULTS: Ganglia were the domains with most prominent expression of PKCδ in most of the stages analysed, although PKCδ could also be detected in heart and somites at earlier stages, and cartilage primordium and skin among other sites in older embryos. CONCLUSIONS: The strong expression of PKCδ in ganglia during murine development shown in this study suggests a significant role of this isoform as well as redundancy with other PKCs within the nervous system, since PKCδ deficient mice develop normally.

Expression pattern of protein kinase C ϵ during mouse embryogenesis.

BACKGROUND: Protein kinase C epsilon (PKCϵ) belongs to the novel PKC subfamily, which consists of diacylglycerol dependent- and calcium independent-PKCs. Previous studies have shown that PKCϵ is important in different contexts, such as wound healing or cancer. In this study, we contribute to expand the knowledge on PKCϵ by reporting its expression pattern during murine midgestation using the LacZ reporter gene and immunostaining procedures. RESULTS: Sites showing highest PKCϵ expression were heart at ealier stages, and ganglia in older embryos. Other stained domains included somites, bone, stomach, kidney, and blood vessels. CONCLUSIONS: The seemingly strong expression of PKCϵ in heart and ganglia shown in this study suggests a important role of this isoform in the vascular and nervous systems during mouse development. However, functional redundancy with other PKCs during midgestation within these domains and others reported here possibly exists since PKCϵ deficient mice do not display obvious embryonic developmental defects.

Update in palliative care--2011.

INTRODUCTION: The aim of this update is to summarize scientifically rigorous articles published in 2010 that serve to advance the field of palliative medicine and have an impact on clinical practice. METHOD: We conducted two separate literature searches for articles published between January 1, 2010 and December 31, 2010. We reviewed title pages from the Annals of Internal Medicine, British Medical Journal, Journal of the American Geriatrics Society, JAMA, Journal of Clinical Oncology, JGIM, Journal of Pain and Symptom Management, Journal of Palliative Medicine, Lancet, New England Journal of Medicine, PC-FACS (Fast Article Critical Summaries for Clinicians in Palliative Care). We also conducted a Medline search with the key words "palliative," "hospice," and "terminal" care. Each author presented approximately 20 abstracts to the group. All authors reviewed these abstracts, and when needed, full text publications. We focused on articles relevant to general internists. We rated the articles individually, eliminating by consensus those that were not deemed of highest priority, and discussed the final choices as a group. RESULTS: We first identified 126 articles with potential relevance. We presented 20 at the annual SGIM update session, and discuss 11 in this paper.

ERK1-independent α-secretase cut of ß-amyloid precursor protein via M1 muscarinic receptors and PKCα/ε.

The amyloid precursor protein (ßAPP) undergoes several proteolytic cleavages. While ß- and γ-secretases are responsible for the production of the 40-43 amino-acid long amyloid ß peptide (Aß), the α-secretase cut performed by the disintegrins ADAM10 and ADAM17, occurs in the middle of the Aß sequence, thereby preventing its formation and leading to the secretion of the large sAPPα neuroprotective fragment. Here we showed that a series of M1 muscarinic receptor agonists dose-dependently stimulated sAPPα secretion without interfering with ßAPP subcellular distribution. Carbachol- and PDBu-induced sAPPα secretions were blocked by the general PKC inhibitor GF109203X. We established that HEK293 and rhabdhomyosarcoma cells overexpressing constitutively active (CA) PKCα or PKCε secrete increased amounts of sAPPα while those expressing PKCδ were unable to modify sAPPα recovery. Conversely, the overexpression of PKCα or PKCε dominant negative (DN) constructs abolished PDBU-stimulated sAPPα secretion, whereas DN-PKCδ remained inert. In agreement, PKCα knockout lowered sAPPα recovery in primary cultured fibroblasts. We also demonstrated that the regulated α-secretase processing of ßAPP is not controlled by the Extracellular-Regulated Kinase-1/MAP-ERK Kinase (ERK1/MEK) cascade and likely does not require ADAM17 phosphorylation on its threonine735 residue. Because the muscarinic-dependent α-secretase-like processing of PrP(c) is fully dependent on ADAM17 phosphorylation on its threonine735 residue by ERK1, these results indicate that a single extracellular signal triggers ADAM17-dependent regulated cleavages of ßAPP and PrP(c) through distinct signalling cascades. This opens new potential therapeutic strategies aimed, in the context of Alzheimer's disease, at selectively activating ADAM17 towards ßAPP without affecting the cleavages of its numerous other substrates.

The Role of an Inpatient Hospice and Palliative Clinical Pharmacist in the Interdisciplinary Team.

Palliative care is a specialized health care service for individuals with serious illness at any stage and can be provided in any setting. Current national consensus developed by palliative care experts recommends the inclusion of pharmacists in an interdisciplinary team (IDT) to provide quality palliative care. However, national registry data report that less than 10% of inpatient palliative teams in the U.S. have a clinical pharmacist. Clinical pharmacists have an impactful role in palliative patients' quality of life by optimizing symptom management, deprescribing, and providing education to the palliative care team as well as patients and their families. In this report, we review the current literature on the role of a palliative pharmacist in an inpatient palliative care setting and compare and contrast this with our own clinical practice, providing case examples about the role of a palliative clinical pharmacist in an interdisciplinary inpatient palliative care setting. Future strategies are needed to increase post-graduate specialized pharmacy residency training in palliative care as well as education on palliative and hospice care in pharmacy schools to support the role of clinical pharmacists in palliative care.

Preventing life-sustaining treatment by default.

Many physicians will at some point care for patients who will receive life-sustaining treatment by default, because there are no instructions available from the patient as to what kind of care is preferred, and because surrogates are likely to ask for everything to be done when they do not know a patient's preferences. We use the methods of ethics informed by qualitative focus group research to identify 5 pathways to life-sustaining treatment by default originating with the patient's preferred decision-making style: deciding for oneself or letting others decide. We emphasize preventing the ethically unwelcome outcome of life-sustaining treatment by default by increasing the frequency with which patients make clear decisions or clearly express their values and goals that they then communicate to physicians or surrogates.

Muscle-specific knockout of PKC-lambda impairs glucose transport and induces metabolic and diabetic syndromes.

Obesity, the metabolic syndrome, and type 2 diabetes mellitus (T2DM) are major global health problems. Insulin resistance is frequently present in these disorders, but the causes and effects of such resistance are unknown. Here, we generated mice with muscle-specific knockout of the major murine atypical PKC (aPKC), PKC-lambda, a postulated mediator for insulin-stimulated glucose transport. Glucose transport and translocation of glucose transporter 4 (GLUT4) to the plasma membrane were diminished in muscles of both homozygous and heterozygous PKC-lambda knockout mice and were accompanied by systemic insulin resistance; impaired glucose tolerance or diabetes; islet beta cell hyperplasia; abdominal adiposity; hepatosteatosis; elevated serum triglycerides, FFAs, and LDL-cholesterol; and diminished HDL-cholesterol. In contrast to the defective activation of muscle aPKC, insulin signaling and actions were intact in muscle, liver, and adipocytes. These findings demonstrate the importance of aPKC in insulin-stimulated glucose transport in muscles of intact mice and show that insulin resistance and resultant hyperinsulinemia owing to a specific defect in muscle aPKC is sufficient to induce abdominal obesity and other lipid abnormalities of the metabolic syndrome and T2DM. These findings are particularly relevant because humans who have obesity, impaired glucose tolerance, and T2DM reportedly have defective activation and/or diminished levels of muscle aPKC.

Racial/ethnic differences in blood pressure control and medication utilization in a cohort of older veterans with dementia.

Hypertension and dementia are common illnesses in geriatric patients, resulting in significant morbidity and mortality. The objective of this study was to investigate racial and ethnic differences in blood pressure control and medication utilization in veterans aged 65 years or older with a diagnosis of both hypertension and dementia. We conducted a retrospective chart review for such veterans who attended the Michael E. DeBakey VA Medical Center outpatient clinics in Houston, Texas, during the period of October 1, 2003, to September 30, 2004. A total of 304 patients (190 Caucasians and 114 African-Americans) were included in the study. The mean number of concurrent antihypertensive medications for African-Americans was higher than for Caucasians (3.2 and 2.8, respectively; P = 0.02). African-American ethnicity was associated with higher use of thiazide diuretics (P = 0.02), dihydropyridine calcium channel blockers (P = 0.04), and clonidine (P = 0.01) than was Caucasian ethnicity. Forty-eight percent of African-Americans achieved adequate blood pressure control, compared with 59% of Caucasians. Mini-mental state exam scores were lower for African-Americans than for Caucasians (17.8 and 21.6, respectively; P = 0.01). The utilization of dementia medications was not found to be different between African-Americans and Caucasians. Veterans in this cohort achieved better blood pressure control than previously reported in other studies consisting of older patients. Physicians might have considered patients' race when prescribing antihypertensive medications reflected by the higher use of thiazide diuretics and calcium channel blockers for African-Americans.

Results From a Survey of American Geriatrics Society Members' Views on Physician-Assisted Suicide.

BACKGROUND: Physician-assisted suicide (PAS) is a controversial practice, currently legal in nine states and the District of Columbia. No prior study explores the views of the American Geriatrics Society (AGS) membership on PAS. DESIGN: We surveyed 1488 randomly selected AGS members via email. PARTICIPANTS: A total of 369 AGS members completed the survey (24.8% response rate). ANALYSIS: We conducted bivariate correlation analyses of beliefs related to support for PAS. We also conducted qualitative analysis of open-ended responses. RESULTS: There was no consensus regarding the acceptability of PAS, with 47% supporting and 52% opposing this practice. PAS being legal in the respondent's state, belief that respect for autonomy alone is sufficient to justify PAS, and intent to prescribe or support requests for PAS if legal in state of practice all correlated with support for PAS. There was no consensus on whether the AGS should oppose, support, or adopt a neutral stance on PAS. Most respondents believed that PAS is more complex among patients with low health literacy, low English proficiency, disability, dependency, or frailty. Most respondents supported mandatory palliative care consultation and independent assessments from two physicians. Themes identified from qualitative analysis include role of the medical profession, uncertainty of the role of professional organizations, potential unintended consequences, autonomy, and ethical and moral considerations. CONCLUSION: There was no consensus among respondents regarding the acceptability of PAS. Respondents expressed concern about vulnerable older populations and the need for safeguards when responding to requests for PAS. Ethical, legal, and policy discussions regarding PAS should consider vulnerable populations. J Am Geriatr Soc 68:23-30, 2019.

AGS Position Statement: Resource Allocation Strategies and Age-Related Considerations in the COVID-19 Era and Beyond.

Coronavirus disease 2019 (COVID-19) continues to impact older adults disproportionately, from severe illness and hospitalization to increased mortality risk. Concurrently, concerns about potential shortages of healthcare professionals and health supplies to address these needs have focused attention on how resources are ultimately allocated and used. Some strategies misguidedly use age as an arbitrary criterion, inappropriately disfavoring older adults. This statement represents the official policy position of the American Geriatrics Society (AGS). It is intended to inform stakeholders including hospitals, health systems, and policymakers about ethical considerations to consider when developing strategies for allocating scarce resources during an emergency involving older adults. Members of the AGS Ethics Committee collaborated with interprofessional experts in ethics, law, nursing, and medicine (including geriatrics, palliative care, emergency medicine, and pulmonology/critical care) to conduct a structured literature review and examine relevant reports. The resulting recommendations defend a particular view of distributive justice that maximizes relevant clinical factors and deemphasizes or eliminates factors placing arbitrary, disproportionate weight on advanced age. The AGS positions include (1) avoiding age per se as a means for excluding anyone from care; (2) assessing comorbidities and considering the disparate impact of social determinants of health; (3) encouraging decision makers to focus primarily on potential short-term (not long-term) outcomes; (4) avoiding ancillary criteria such as "life-years saved" and "long-term predicted life expectancy" that might disadvantage older people; (5) forming and staffing triage committees tasked with allocating scarce resources; (6) developing institutional resource allocation strategies that are transparent and applied uniformly; and (7) facilitating appropriate advance care planning. The statement includes recommendations that should be immediately implemented to address resource allocation strategies during COVID-19, aligning with AGS positions. The statement also includes recommendations for post-pandemic review. Such review would support revised strategies to ensure that governments and institutions have equitable emergency resource allocation strategies, avoid future discriminatory language and practice, and have appropriate guidance to develop national frameworks for emergent resource allocation decisions. J Am Geriatr Soc 68:1136-1142, 2020.