The Kir1.1 (ROMK) subtypes of inward rectifier K ؉ channels mediate potassium secretion and regulate sodium chloride reabsorption in the kidney. The density of ROMK channels on the cortical collecting duct apical membrane is exquisitely regulated in concert with physiological demands. Although protein kinase A-dependent phosphorylation of one of the three phospho-acceptors in Kir1.1, Ser-44, also a canonical serum-glucocorticoid-regulated kinase (SGK-1) phosphorylation site, controls the number of active channels, it is unknown whether this involves activating dormant channels already residing on the plasma membrane or recruiting new channels to the cell surface. Here we explore the mechanism and test whether SGK-1 phosphorylation of ROMK regulates cell surface expression. Removal of the phosphorylation site by point mutation (Kir1.1, S44A) dramatically attenuated the macroscopic current density in Xenopus oocytes. As measured by antibody binding of external epitope-tagged forms of Kir1.1, surface expression of Kir1.1 S44A was inhibited, paralleling the reduction in macroscopic current. In contrast, surface expression and macroscopic current density was augmented by a phosphorylation mimic mutation, Kir1.1 S44D. In vitro phosphorylation assays revealed that Ser-44 is a substrate of SGK-1 phosphorylation, and expression of SGK-1 with the wild type channel increased channel density to the same level as the phosphorylation mimic mutation. Moreover, the stimulatory effect of SGK-1 was completely abrogated by mutation of the phosphorylation site. In conclusion, SGK-1 phosphorylation of Kir1.1 drives expression on the plasmalemma. Because SGK-1 is an early aldosterone-induced gene, our results suggest a possible molecular mechanism for aldosterone-dependent regulation of the secretory potassium channel in the kidney.Extracellular potassium homeostasis, maintained by the regulation of renal potassium excretion, is dependent on the activity of weakly inward rectifying ''small conductance'' potassium channels (SK) 1 that are expressed on the apical membrane of epithelial cells in the distal nephron (1, 2). Encoded by the ROMK (Kir 1.1 or KCNJ1) gene (3, 4), these Kir channels are thought to be the major, but not exclusive (5, 6), route for potassium transport into the tubule lumen and constitute a final regulated component of the potassium secretory machinery of the kidney (7,8). Indeed, aldosterone, vasopressin, and other factors precisely regulate SK activity, controlling potassium excretion in accord with the demands of potassium balance. Because ROMK channels normally exhibit a very high open probability, near unity, physiologic augmentation of channel activity, as controlled by hormones and dietary potassium (9), is achieved largely by regulated changes in the number of active channels on the plasmalemma.Although the precise molecular mechanisms responsible for physiological augmentation of ROMK channel surface density have remained unclear, a growing body of evidence has pointed to an important role of protein kina...
Objective Patients with comorbid cancer and dementia have poorer outcomes than those without dementia. We observe oncology teams managing patients with dementia and memory loss and explore these patients' needs and experiences of out-patient cancer services. MethodsA single site investigation of case study design to examine practices in four clinics using multi-methods of data collection; retrospective note review, observation, interviews and recorded consultations. A framework analytic approach identifies themes within and across cases. ResultsThirty-three clinical encounters with patients with memory loss were observed. Ten consultations were audio-recorded and 16 individuals interviewed (n=6 patients-carer dyads, n=1 lone patient, n=5 staff). Medical records were reviewed for 338 cases. Cancer referrals did not document memory health, so clinicians rely on patient/carer disclosure to identify patients with memory problems. In practice the problem often remains hidden. Treating teams who do become aware of memory difficulties are unsure how to support patients, but marked memory loss can limit treatment options and preclude radical intent. Carers are key facilitators of successful cancer consultations and management. Their support needs are largely unrecognised. ConclusionsTraining that educates cancer teams on how to identify and support individuals with memory problems before and during treatment and recognise the carer role may facilitate complex cancer care and help reduce inequalities of outcomes.
Objective: The objective of the study is to report a systematic review of what is currently known about the experience of cancer treatment and cancer treatment in adults with dementia.Methods: The analytic plan and inclusion/exclusion criteria were specified in advance of the search process in a protocol.Searches were conducted in MEDLINE, CINAHL, PsycINFO and the Cochrane Library for publications about people with cancer and a pre-existing dementia. Limits were English language; 2000 to 12/2015; adults; >18 years old.The search identified 5214 titles and abstracts that were assessed against eligibility criteria and 101 were selected for full-text examination by two researchers who agreed inclusion of nine papers, extracted data independently then conducted a content analysis and narrative synthesis.Results: Nine studies conducted in four resource rich countries were included in the review. These studies evidence that when compared with other cancer patients, those with dementia are diagnosed at a later stage, receive less treatment, are more likely to experience complications from treatment and have poorer survival.The experience of supportive care and preferences of people with dementia receiving cancer services and cancer treatment have not been investigated. Research into how the cancer team manage the particular needs of people with dementia and their family members has been limited to one study that reported how a cancer team managed the particular needs of seven people with dementia.Conclusion: Further work is needed to establish practice guidelines for the management of cancer in people with dementia.
BackgroundMore research on sustainment of interventions is needed, especially return on investment (ROI) studies to determine cost-benefit trade-offs for effort required to sustain and how much is gained when effective programs are sustained. The ROSE sustainment (ROSES) study uses a sequential multiple assignment randomized (SMART) design to evaluate the effectiveness and cost-effectiveness of a stepwise approach to sustainment of the ROSE postpartum depression prevention program in 90 outpatient clinics providing prenatal care to pregnant women on public assistance. Postpartum depression (PPD) is common and can have lasting consequences. Outpatient clinics offering prenatal care are an opportune place to provide PPD prevention because most women visit while pregnant. The ROSE (Reach Out, Stay Strong, Essentials for mothers of newborns) program is a group educational intervention to prevent PPD, delivered during pregnancy. ROSE has been found to reduce cases of PPD in community prenatal settings serving low-income pregnant women.MethodsAll 90 prenatal clinics will receive enhanced implementation as usual (EIAU; initial training + tools for sustainment). At the first time at which a clinic is determined to be at risk for failure to sustain (i.e., at 3, 6, 9, 12, and 15 months), that clinic will be randomized to receive either (1) no additional implementation support (i.e., EIAU only), or (2) low-intensity coaching and feedback (LICF). If clinics receiving LICF are still at risk at subsequent assessments, they will be randomized to either (1) EIAU + LICF only, or (2) high-intensity coaching and feedback (HICF). Additional follow-up interviews will occur at 18, 24, and 30 months, but no implementation intervention will occur after 18 months. Outcomes include (1) percent sustainment of core program elements at each time point, (2) health impact (PPD rates over time at each clinic) and reach, and (3) ROI (costs and cost-effectiveness) of each sustainment step. Hypothesized mechanisms include sustainment of capacity to deliver core elements and engagement/ownership.DiscussionThis study is the first randomized trial evaluating the ROI of a stepped approach to sustainment, a critical unanswered question in implementation science. It will also advance knowledge of implementation mechanisms and clinical care for an at-risk population.Trial registrationClinicaltrials.gov, NCT03267563. Registered June 14, 2018.
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