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Background: Several modifiable risk factors, including dietary habits, are linked to cardiovascular disease (CVD) progression. However, lifestyle changes remain notoriously challenging, perhaps due to psychosocial factors. This pilot study aims to investigate the relationship between adherence to a healthy diet, CVD risk factors, psychological factors and sociodemographic variables among middle-aged adults in Sweden., Methods: Data were collected from March to December 2012 in the SCAPIS diet sub-study, where a total of 200 participants aged 50-64 years were enrolled. Dietary intake was assessed using the MiniMeal-Q food frequency questionnaire, and adherence to healthy eating patterns was evaluated using the Diet Quality Index-Swedish Nutrition Recommendations (DQI-SNR). Psychological factors, stress and sleep patterns were assessed through a comprehensive questionnaire. Statistical analyses included t-tests, analysis of variance, X 2 tests and logistic regression to identify predictors of unfavourable apolipoprotein (Apo) B/Apo A1 ratios., Results: Out of 200 participants, 182 had complete and reliable dietary data. The majority exhibited intermediate adherence to a healthy diet, with women showing better adherence to dietary fibre intake compared with men. Women with high dietary quality had better cardiovascular profiles, including higher levels of Apo A1 and high-density lipoprotein cholesterol, lower Apo B/Apo A1 ratios and higher plasma carotenoids. Significant predictors of unfavourable Apo B/Apo A1 ratios included low socioeconomic status (SES), higher body mass index, larger waist circumference and smoking. Stratified adjusted analyses revealed distinct predictors based on SES, with depression increasing the OR of an unfavourable lipid profile by 6.41 times (p=0.019) in low SES areas., Conclusions: This study highlights the potential of tailored recommendations considering socioeconomic and psychological factors. Addressing mental health and promoting physical activity may be crucial for CVD risk reduction, particularly in low SES areas. Further research is needed to confirm these findings in larger cohorts and to develop targeted interventions for diverse population groups., Competing Interests: None declared., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Dysregulated branched-chain amino acid (BCAA) metabolism has emerged as a key metabolic feature associated with the obese insulin-resistant state, and adipose BCAA catabolism is decreased in this context. BCAA catabolism is upregulated early in adipogenesis, but the impact of suppressing this pathway on the broader metabolic functions of the resultant adipocyte remains unclear. Here, we use CRISPR/Cas9 to decrease BCKDHA in 3T3-L1 and human pre-adipocytes, and ACAD8 in 3T3-L1 pre-adipocytes to induce a deficiency in BCAA catabolism through differentiation. We characterize the transcriptional and metabolic phenotype of 3T1-L1 cells using RNAseq and 13 C metabolic flux analysis within a network spanning glycolysis, tricarboxylic acid (TCA) metabolism, BCAA catabolism, and fatty acid synthesis. While lipid droplet accumulation is maintained in Bckdha-deficient adipocytes, they display a more fibroblast-like transcriptional signature. In contrast, Acad8 deficiency minimally impacts gene expression. Decreased glycolytic flux emerges as the most distinct metabolic feature of 3T3-L1 Bckdha-deficient cells, accompanied by a ∼40% decrease in lactate secretion, yet pyruvate oxidation and utilization for de novo lipogenesis is increased to compensate for the loss of BCAA carbon. Deletion of BCKDHA in human adipocyte progenitors also led to a decrease in glucose uptake and lactate secretion; however, these cells did not upregulate pyruvate utilization, and lipid droplet accumulation and expression of adipocyte differentiation markers was decreased in BCKDH knockout cells. Overall our data suggest that human adipocyte differentiation may be more sensitive to the impact of decreased BCKDH activity than 3T3-L1 cells and that both metabolic and regulatory cross-talk exist between BCAA catabolism and glycolysis in adipocytes. Suppression of BCAA catabolism associated with metabolic syndrome may result in a metabolically compromised adipocyte., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Study Objectives: Napping is a common habit in many countries. Nevertheless, studies about the chronic effects of napping on obesity are contradictory, and the molecular link between napping and metabolic alterations has yet to be studied. We aim to identify molecular mechanisms in adipose tissue (AT) that may connect napping and abdominal obesity., Methods: In this cross-sectional study, we extracted the RNA repeatedly across 24 hours from cultured AT explants and performed RNA sequencing. Circadian rhythms were analyzed using six consecutive time points across 24 hours. We also assessed global gene expression in each group (nappers vs. non-nappers)., Results: With napping, there was an 88% decrease in the number of rhythmic genes compared to that in non-nappers, a reduction in rhythm amplitudes of 29%, and significant phase changes from a coherent unimodal acrophase in non-nappers, towards a scattered and bimodal acrophase in nappers. Those genes that lost rhythmicity with napping were mainly involved in pathways of glucose and lipid metabolism, and of the circadian clock. Additionally, we found differential global gene expression between nappers and non-nappers with 34 genes down- and 32 genes upregulated in nappers. The top upregulated gene (IER3) and top down-regulated pseudogene (VDAC2P2) in nappers have been previously shown to be involved in inflammation., Conclusions: These new findings have implications for our understanding of napping's relationship with obesity and metabolic disorders., (Published by Oxford University Press on behalf of Sleep Research Society (SRS) 2024.)

Background and Purpose: Napping is a widespread practice worldwide and has in recent years been linked to increased abdominal adiposity. Lipase E or LIPE encodes the protein hormone-sensitive lipase (HSL), an enzyme that plays an important role in lipid mobilization and exhibits a circadian expression rhythm in human adipose tissue. We hypothesized that habitual napping may impact the circadian expression pattern of LIPE , which in turn may attenuate lipid mobilization and induce abdominal fat accumulation., Methods: Abdominal adipose tissue explants from participants with obesity (n = 17) were cultured for a 24-h duration and analyzed every 4 h. Habitual nappers (n = 8) were selected to match non-nappers (n = 9) in age, sex, BMI, adiposity, and metabolic syndrome traits. Circadian LIPE expression rhythmicity was analyzed using the cosinor method., Results: Adipose tissue explants exhibited robust circadian rhythms in LIPE expression in non-nappers. In contrast, nappers had a flattened rhythm. LIPE amplitude was decreased in nappers as compared with non-nappers (71% lower). The decrease in amplitude among nappers was related to the frequency of napping (times per week) where a lower rhythm amplitude was associated with a higher napping frequency (r = -0.80; P = 0.018). Confirmatory analyses in the activity of LIPE 's protein (i.e., HSL) also showed a significant rhythm in non-nappers, whereas significance in the activity of HSL was lost among nappers., Conclusion: Our results suggest that nappers display dysregulated circadian LIPE expression as well as dysregulated circadian HSL activity, which may alter lipid mobilization and contribute to increased abdominal obesity in habitual nappers., Competing Interests: FS served on the Board of Directors for the Sleep Research Society and has received consulting fees from the University of Alabama at Birmingham and Morehouse School of Medicine. FS’ interests were reviewed and managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. FS’ consultancies are not related to the current work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zambrano, Kulyté, Luján, Rivero-Gutierrez, Sánchez de Medina, Martínez-Augustin, Ryden, Scheer and Garaulet.)

Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance, and fatty liver disease. Here we report that mitochondria undergo fragmentation and reduced oxidative capacity specifically in inguinal white adipose tissue after feeding mice high fat diet (HFD) by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes from mice fed HFD. Targeted deletion of Rala in white adipocytes prevents the obesity-induced fragmentation of mitochondria and produces mice resistant to HFD-induced weight gain via increased fatty acid oxidation. As a result, these mice also exhibit improved glucose tolerance and liver function. In vitro mechanistic studies revealed that RalA suppresses mitochondrial oxidative function in adipocytes by increasing fission through reversing the protein kinase A-catalyzed inhibitory Ser 637 phosphorylation of the mitochondrial fission protein Drp1. Active RalA recruits protein phosphatase 2A (PP2Aa) to specifically dephosphorylate this inhibitory site on Drp1, activating the protein, thus increasing mitochondrial fission. Adipose tissue expression of the human homolog of Drp1, DNML1, is positively correlated with obesity and insulin resistance in patients. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics towards excessive fission, contributing to weight gain and related metabolic dysfunction., Competing Interests: Competing interests The authors declare no competing interests.

Background: Due to an ageing demographic and rapid increase of cognitive impairment and dementia, combined with potential disease-modifying drugs and other interventions in the pipeline, there is a need for the development of accurate, accessible and efficient cognitive screening instruments, focused on early-stage detection of neurodegenerative disorders., Objective: In this proof of concept report, we examine the validity of a newly developed digital cognitive test, the Geras Solutions Cognitive Test (GCST) and compare its accuracy against the Montreal Cognitive Assessment (MoCA)., Methods: 106 patients, referred to the memory clinic, Karolinska University Hospital, due to memory complaints were included. All patients were assessed for presence of neurodegenerative disorder in accordance with standard investigative procedures. 66% were diagnosed with subjective cognitive impairment (SCI), 25% with mild cognitive impairment (MCI) and 9% fulfilled criteria for dementia. All patients were administered both MoCA and GSCT. Descriptive statistics and specificity, sensitivity and ROC curves were established for both test., Results: Mean score differed significantly between all diagnostic subgroups for both GSCT and MoCA (p<0.05). GSCT total test time differed significantly between all diagnostic subgroups (p<0.05). Overall, MoCA showed a sensitivity of 0.88 and specificity of 0.54 at a cut-off of <=26 while GSCT displayed 0.91 and 0.55 in sensitivity and specificity respectively at a cut-off of <=45., Conclusion: This report suggests that GSCT is a viable cognitive screening instrument for both MCI and dementia., Competing Interests: MK: Advisory board: Combinostics, Roche; GH: Advisory board: Gears Solutions; VB: Consultant for Geras Solutions.

Background: Fat mobilization in adipose tissue (AT) has a specific timing. However, circadian rhythms in the activity of the major enzyme responsible for fat mobilization, hormone-sensitive lipase (HSL), have not been demonstrated in humans., Objective: To analyze in a cross-sectional study whether there is an endogenous circadian rhythm in HSL activity in human AT ex vivo and whether rhythm characteristics are related to food timing or fasting duration., Methods: Abdominal AT biopsies were obtained from 18 severely obese participants (age: 46 ± 11 years; body mass index 42 ± 6 kg/m2) who underwent laparoscopic gastric bypass. Twenty-four-hour rhythms of HSL activity and LIPE (HSL transcript in humans) expression in subcutaneous AT were analyzed together with habitual food timing and night fasting duration., Results: HSL activity exhibited a circadian rhythm (P = .023) and reached the maximum value at circadian time 16 (CT) that corresponded to around midnight (relative local clock time. Similarly, LIPE displayed a circadian rhythm with acrophase also at night (P = .0002). Participants with longer night fasting duration >11.20 hours displayed almost double the amplitude (1.91 times) in HSL activity rhythm than those with short duration (P = .013); while habitual early diners (before 21:52 hours) had 1.60 times higher amplitude than late diners (P = .035)., Conclusions: Our results demonstrate circadian rhythms in HSL activity and may lead to a better understanding of the intricate relationships between food timing, fasting duration and body fat regulation., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims/hypothesis: By genome-wide association meta-analysis, 17 genetic loci associated with fasting serum insulin (FSI), a marker of systemic insulin resistance, have been identified. To define potential culprit genes in these loci, in a cross-sectional study we analysed white adipose tissue (WAT) expression of 120 genes in these loci in relation to systemic and adipose tissue variables, and functionally evaluated genes demonstrating genotype-specific expression in WAT (eQTLs)., Methods: Abdominal subcutaneous adipose tissue biopsies were obtained from 114 women. Basal lipolytic activity was measured as glycerol release from adipose tissue explants. Adipocytes were isolated and insulin-stimulated incorporation of radiolabelled glucose into lipids was used to quantify adipocyte insulin sensitivity. Small interfering RNA-mediated knockout in human mesenchymal stem cells was used for functional evaluation of genes., Results: Adipose expression of 48 of the studied candidate genes associated significantly with FSI, whereas expression of 24, 17 and 2 genes, respectively, associated with adipocyte insulin sensitivity, lipolysis and/or WAT morphology (i.e. fat cell size relative to total body fat mass). Four genetic loci contained eQTLs. In one chromosome 4 locus (rs3822072), the FSI-increasing allele associated with lower FAM13A expression and FAM13A expression associated with a beneficial metabolic profile including decreased WAT lipolysis (regression coefficient, R = -0.50, p = 5.6 × 10 -7 ). Knockdown of FAM13A increased lipolysis by ~1.5-fold and the expression of LIPE (encoding hormone-sensitive lipase, a rate-limiting enzyme in lipolysis). At the chromosome 7 locus (rs1167800), the FSI-increasing allele associated with lower POM121C expression. Consistent with an insulin-sensitising function, POM121C expression associated with systemic insulin sensitivity (R = -0.22, p = 2.0 × 10 -2 ), adipocyte insulin sensitivity (R = 0.28, p = 3.4 × 10 -3 ) and adipose hyperplasia (R = -0.29, p = 2.6 × 10 -2 ). POM121C knockdown decreased expression of all adipocyte-specific markers by 25-50%, suggesting that POM121C is necessary for adipogenesis., Conclusions/interpretation: Gene expression and adipocyte functional studies support the notion that FAM13A and POM121C control adipocyte lipolysis and adipogenesis, respectively, and might thereby be involved in genetic control of systemic insulin sensitivity.

Aims: Type 2 diabetes is associated with insulin resistance, adipose hypertrophy and increased lipolysis. The heritability of these traits has been determined by associating them with a family history of diabetes., Methods: Abdominal subcutaneous fat biopsies were obtained from 581 subjects in a cross-sectional study. Fat cells were isolated, and the difference between measured and expected fat-cell volume was used to determine adipose morphology (degree of hypertrophy or hyperplasia). Spontaneous lipolytic activity was determined in explants of adipose tissue by measuring glycerol release. Insulin-stimulated lipogenesis was assessed by measuring the incorporation of radiolabelled glucose into fat-cell lipids. Information on parental history of diabetes was gathered by a questionnaire., Results: Adipose morphology correlated positively with lipolysis (P<0.0001) and inversely with insulin-stimulated lipogenesis (P<0.008). Also, 24% of probands had a family history of diabetes, which was associated with higher body mass index (BMI) scores, and more insulin resistance (HOMA IR ) and adipose hypertrophy. Lipolytic activity was increased, and insulin-stimulated lipogenesis decreased, in probands with a parental history of diabetes. The results for HOMA IR , lipolysis and adipose morphology remained significant after adjusting for proband BMI. A maternal history of diabetes was associated with increased adipose lipolytic activity in probands., Conclusion: A family history of diabetes is independent of proband BMI, but associated with adipocyte hypertrophy and enhanced lipolysis, which suggests that these factors are genetically linked to diabetes. Moreover, the influence on lipolysis was only observed in probands with a maternal history of diabetes, thereby supporting an epigenetic impact., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Most studies of human adipose tissue (AT) metabolism and functionality have been performed in vitro on isolated mature adipocyte or in situ using the microdialysis technique (Lafontan, 2012). However, these approaches have several limitations. The use of mature isolated adipocytes is limiting as adipocytes are not in their physiological environment and the collagenase digestion process could affect both adipocyte survival and functionality. While metabolic studies using microdialysis have brought the advantage of studying the lipolytic response of the adipose tissue in situ , it provides only qualitative measures but does not give any information on the contribution of different adipose tissue cell components. Moreover, the number of microdialysis probes that can be used concomitantly in one subject is limited and can be influenced by local blood flow changes and by the molecular size cut-off of the microdialysis probe. Here we present a protocol to assess adipose tissue functionality ex vivo in AT explants allowing the studies of adipose tissue in its whole context, for several hours. In addition, the isolation of the different cell components to evaluate the cell-specific impact of lipolysis can be performed. We recently used the present protocol and demonstrated that fatty acid release during lipolysis impacts directly on a specific cell subset present in the adipose tissue stroma-vascular compartment. This assay can be adapted to address other research questions such as the effects of hormones or drugs treatment on the phenotype of the various cell types present in adipose tissue ( Gao et al. , 2016 )., (Copyright © 2018 The Authors; exclusive licensee Bio-protocol LLC.)

Aims/hypothesis: Insulin resistance (IR) links obesity to type 2 diabetes. The aim of this study was to explore whether white adipose tissue (WAT) epigenetic dysregulation is associated with systemic IR by genome-wide CG dinucleotide (CpG) methylation and gene expression profiling in WAT from insulin-resistant and insulin-sensitive women. A secondary aim was to determine whether the DNA methylation signature in peripheral blood mononuclear cells (PBMCs) reflects WAT methylation and, if so, can be used as a marker for systemic IR., Methods: From 220 obese women, we selected a total of 80 individuals from either of the extreme ends of the distribution curve of HOMA-IR, an indirect measure of systemic insulin sensitivity. Genome-wide transcriptome and DNA CpG methylation profiling by array was performed on subcutaneous (SAT) and visceral (omental) adipose tissue (VAT). CpG methylation in PBMCs was assayed in the same cohort., Results: There were 647 differentially expressed genes (false discovery rate [FDR] 10%) in SAT, all of which displayed directionally consistent associations in VAT. This suggests that IR is associated with dysregulated expression of a common set of genes in SAT and VAT. The average degree of DNA methylation did not differ between the insulin-resistant and insulin-sensitive group in any of the analysed tissues/cells. There were 223 IR-associated genes in SAT containing a total of 336 nominally significant differentially methylated sites (DMS). The 223 IR-associated genes were over-represented in pathways related to integrin cell surface interactions and insulin signalling and included COL5A1, GAB1, IRS2, PFKFB3 and PTPRJ. In VAT there were a total of 51 differentially expressed genes (FDR 10%); 18 IR-associated genes contained a total of 29 DMS., Conclusions/interpretation: In individuals discordant for insulin sensitivity, the average DNA CpG methylation in SAT and VAT is similar, although specific genes, particularly in SAT, display significantly altered expression and DMS in IR, possibly indicating that epigenetic regulation of these genes influences metabolism.

Cachexia represents a fatal energy-wasting syndrome in a large number of patients with cancer that mostly results in a pathological loss of skeletal muscle and adipose tissue. Here we show that tumor cell exposure and tumor growth in mice triggered a futile energy-wasting cycle in cultured white adipocytes and white adipose tissue (WAT), respectively. Although uncoupling protein 1 (Ucp1)-dependent thermogenesis was dispensable for tumor-induced body wasting, WAT from cachectic mice and tumor-cell-supernatant-treated adipocytes were consistently characterized by the simultaneous induction of both lipolytic and lipogenic pathways. Paradoxically, this was accompanied by an inactivated AMP-activated protein kinase (Ampk), which is normally activated in peripheral tissues during states of low cellular energy. Ampk inactivation correlated with its degradation and with upregulation of the Ampk-interacting protein Cidea. Therefore, we developed an Ampk-stabilizing peptide, ACIP, which was able to ameliorate WAT wasting in vitro and in vivo by shielding the Cidea-targeted interaction surface on Ampk. Thus, our data establish the Ucp1-independent remodeling of adipocyte lipid homeostasis as a key event in tumor-induced WAT wasting, and we propose the ACIP-dependent preservation of Ampk integrity in the WAT as a concept in future therapies for cachexia.

Objective: Comprehensive proteomic profiling of the human adipocyte secretome identified dipeptidyl peptidase 4 (DPP4) as a novel adipokine. This study assessed the functional implications of the adipokine DPP4 and its association to the metabolic syndrome., Research Design and Methods: Human adipocytes and skeletal and smooth muscle cells were used to monitor DPP4 release and assess the effects of soluble DPP4 on insulin signaling. In lean and obese subjects, depot-specific expression of DPP4 and its release from adipose tissue explants were determined and correlated to parameters of the metabolic syndrome., Results: Fully differentiated adipocytes exhibit a substantially higher release of DPP4 compared with preadipocytes or macrophages. Direct addition of DPP4 to fat and skeletal and smooth muscle cells impairs insulin signaling. A fivefold higher level of DPP4 protein expression was seen in visceral compared with subcutaneous fat of obese patients, with no regional difference in lean subjects. DPP4 serum concentrations significantly correlated with adipocyte size. By using adipose tissue explants from lean and obese subjects, we observed a twofold increase in DPP4 release that strongly correlated with adipocyte volume and parameters of the metabolic syndrome and was decreased to the lean level after weight reduction. DPP4 released from adipose tissue correlated positively with an increasing risk score for the metabolic syndrome., Conclusions: DPP4 is a novel adipokine that may impair insulin sensitivity in an autocrine and paracrine fashion. Furthermore, DPP4 release strongly correlates with adipocyte size, potentially representing an important source of DPP4 in obesity. Therefore, we suggest that DPP4 may be involved in linking adipose tissue and the metabolic syndrome., (© 2011 by the American Diabetes Association.)

Lipolysis is the catabolic pathway by which triglycerides are hydrolyzed into fatty acids. Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) have the capacity to hydrolyze in vitro the first ester bond of triglycerides, but their respective contributions to whole cell lipolysis in human adipocytes is unclear. Here, we have investigated the roles of HSL, ATGL, and its coactivator CGI-58 in basal and forskolin-stimulated lipolysis in a human white adipocyte model, the hMADS cells. The hMADS adipocytes express the various components of fatty acid metabolism and show lipolytic capacity similar to primary cultured adipocytes. We show that lipolysis and fatty acid esterification are tightly coupled except in conditions of stimulated lipolysis. Immunocytochemistry experiments revealed that acute forskolin treatment promotes HSL translocation from the cytosol to small lipid droplets and redistribution of ATGL from the cytosol and large lipid droplets to small lipid droplets, resulting in enriched colocalization of the two lipases. HSL or ATGL overexpression resulted in increased triglyceride-specific hydrolase capacity, but only ATGL overexpression increased whole cell lipolysis. HSL silencing had no effect on basal lipolysis and only partially reduced forskolin-stimulated lipolysis. Conversely, silencing of ATGL or CGI-58 significantly reduced basal lipolysis and essentially abolished forskolin-stimulated lipolysis. Altogether, these results suggest that ATGL/CGI-58 acts independently of HSL and precedes its action in the sequential hydrolysis of triglycerides in human hMADS adipocytes.

Context: Six transmembrane protein of prostate 2 (STAMP2) is a counterregulator of adipose inflammation and insulin resistance in mice. Our hypothesis was that STAMP2 could be involved in human obesity and insulin resistance., Objective: The objective of the study was to elucidate the role of adipose STAMP2 expression in human obesity and insulin resistance., Design: The design was to quantify STAMP2 in human abdominal sc and omental white adipose tissue (WAT), isolated adipocytes, and stroma and in vitro differentiated preadipocytes and relate levels of STAMP2 in sc WAT to clinical and adipocyte phenotypes involved in insulin resistance., Participants: Nonobese and obese women and men (n = 236) recruited from an obesity clinic or through local advertisement., Main Outcome Measurement: Clinical measures included body mass index, body fat, total adiponectin, and homeostasis model assessment as measure of overall insulin resistance. In adipocytes we determined cell size, sensitivity of lipolysis and lipogenesis to insulin, adiponectin secretion, and inflammatory gene expression., Results: STAMP2 levels in sc and visceral WAT and adipocytes were increased in obesity (P = 0.0008-0.05) but not influenced by weight loss. Increased WAT STAMP2 levels associated with a high amount of body fat (P = 0.04), high homeostasis model assessment (P = 0.01), and large adipocytes (P = 0.02). Subjects with high STAMP2 levels displayed reduced sensitivity of adipocyte lipogenesis (P = 0.04) and lipolysis (P = 0.03) to insulin but had normal adiponectin levels. WAT STAMP2 levels correlated with expression of the macrophage marker CD68 (P = 0.0006)., Conclusion: Human WAT STAMP2 associates with obesity and insulin resistance independently of adiponectin, but the role of STAMP2 in obesity and its complications seems different from that in mice.

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine with a proposed role in obesity-related insulin resistance. This could be mediated by increased lipolysis in adipose tissue resulting in elevated free fatty acid levels. The early intracellular signals entailed in TNF-alpha-mediated lipolysis are unknown but may involve members of the mitogen-activated protein kinase (MAPK) family. We investigated the possible contribution of MAPK in TNF-alpha-induced lipolysis in human preadipocytes. TNF-alpha activated the three mammalian MAPK, p44/42, JNK, and p38, in a distinct time- and concentration-dependent manner. TNF-alpha also induced a concentration-dependent stimulation of lipolysis with a more than 3-fold increase at the maximal dose. Lipolysis was completely inhibited by blockers specific for p44/42 (PD98059) and JNK (dimetylaminopurine) but was not affected by the p38 blocker SB203580. Use of receptor-specific TNF-alpha mutants showed that activation of MAPK is entirely mediated by the TNFR1 receptor. The results in human preadipocytes differed from those obtained in murine 3T3-L1 adipocytes in which all three MAPK were constitutively active. Thus, studies of intracellular signaling pathways obtained in different cellular contexts should be interpreted with caution. In conclusion, although TNF-alpha activates all three known MAPK in human preadipocytes, only p44/42 and JNK appear to be involved in the regulation of lipolysis.

The purpose of this study was to determine the effect on clinical outcomes for newly admitted nursing home residents when advanced practice gerontological nurses (APNs) worked with staff to implement scientifically based protocols for incontinence, pressure ulcers, depression, and aggressive behavior. Use of APNs in this manner differs from the usual way APNs have been used in nursing homes, in which their primary focus has been to augment the physician's role. The APN treatment was randomly assigned to two nursing homes and usual care was assigned to a third. Trajectories from admission to 6 months revealed that residents with APN input into their care (n = 86) experienced significantly greater improvement or less decline in incontinence, pressure ulcers, and aggressive behavior, and they had higher mean composite trajectory scores compared with residents receiving usual care (n = 111). Significantly less deterioration in affect was noted in cognitively impaired residents in the treatment group. Findings suggest that APNs can be effective links between current scientific knowledge about clinical problems and nursing home staff.

A satisfaction instrument specifically designed for use with nursing home residents, the Satisfaction with the Nursing Home Instrument (SNHI), was developed and tested with a sample of 110 nursing home residents from three proprietary facilities in Minnesota. As hypothesized, significant relationships were found between SNHI scores and measures of affect (negatively associated with depression and positively associated with morale), providing support for the construct validity of the scale. The lack of a significant relationship between SNHI scores and both age and mental status confirmed the predicted divergent validity of the instrument. The alpha coefficient for the 29-item scale was 0.81., (Copyright 2000 John Wiley & Sons, Inc.)

This study examined relationships between aggressive behavior in cognitively impaired nursing home residents and physical restraints, psychoactive drugs, and placement on a secured unit. Data were obtained from 116 residents who were consistently aggressive as measured by the Ryden Aggression Scale 2. Subjects averaged 9.5 aggressive behaviors per day. Forty-seven percent of subjects were restrained, and 62% were regularly receiving psychoactive drugs. Use of restraints, antipsychotics, and placement on a secured unit were all significantly related to increased physical aggression scores. Four variables accounted for 23% of the variance in physical aggression scores: location on a secured unit, not receiving an antidepressant, being restrained, and number of psychotropic and/or anxiolytic medications administered. Significantly lower physical aggression scores were noted for subjects receiving antidepressants.

The purpose of this study was to explore the policies and practices of nursing homes with respect to the resuscitation of residents who do not have a do-not-resuscitate (DNR) order. Responses from a survey of 36 facilities revealed that most residents had DNR orders and most facilities were capable of providing basic cardiopulmonary resuscitation (CPR). Less than 30% had performed CPR in the past 6 months, and 22.8% had no written CPR policies. More facilities required CPR in witnessed arrests of non-DNR residents (79.3%) than in unwitnessed arrests (24%). Methods for identifying CPR status need improvement to enable accurate identification and prompt resuscitation of residents who want CPR.

Few studies have explored the phenomenon of pain in people with severe cognitive impairment. Pain assessment, which depends primarily on people's ability to describe dimensions of pain, becomes problematic when clients' cognitive impairment is so severe they cannot respond to pain assessment tools. The purpose of this study was to describe the phenomenon of pain for a subgroup of aggressive cognitively impaired nursing home residents who were enrolled in a larger study of aggressive behavior. To determine if pain was a possible factor influencing aggression, information was sought from five sources: family members, nursing assistant (NA) caregivers, medical record listings of pain-related diagnoses, use of analgesics, and observations of aggressive behaviors. Families reported pain in 44% of subjects, while NAs reported pain in 66% of subjects. Seventy-six percent of subjects had one or more pain-causing diagnoses. Sixty-four percent of subjects whose family members thought they may have pain were being treated with analgesics, compared to 44% of subjects whose NA reported they may be experiencing pain. Aggression scores were significantly higher in subjects who had two or more pain-related diagnoses and in subjects with arthritis. Nurses who are aware of a history of pain, reports of pain by families and caregivers, presence of pain-related medical diagnoses, and who realize pain may be a trigger for aggressive behavior may be more likely to recognize pain in cognitively impaired older adults. Better pain assessment should lead to improved treatment of pain in this population.

Objective: To compare the experience of pain and treatment of pain in cognitively impaired and cognitively intact older adults after surgical repair of a hip fracture., Design: Prospective comparative survey design., Participants: A convenience sample of 88 hip fracture patients (53 cognitively impaired, 35 cognitively intact) from three Midwestern urban hospital orthopedic units was interviewed between days 2 and 5 postoperatively. Subjects whose Folstein Mini-Mental State Exam (MMSE) score was less than or equal to 23 were categorized as impaired., Results: Pain report and intensity did not differ significantly between the two groups. One-third of the subjects in both groups rated pain as severe or worse. Cognitively impaired subjects scored significantly higher on the Checklist of Nonverbal Pain Indicators observed with movement (CNPI-m) than did cognitively intact subjects. Cognitively impaired subjects received significantly less opioid analgesics than cognitively intact subjects in the first and second 48 hours postoperatively. Both groups received less than 25% of the mean prescribed amount of opioid analgesics. Age, MMSE, and CNPI-m score accounted for 27% of the variance in the amount of opioid analgesic administered in the first 48 hours postoperatively., Conclusions: Pain is treated poorly in older postoperative patients. Cognitive impairment and age strongly influence the amount of analgesic nurses administer to older patients after surgical repair of hip fracture. Provision for patient comfort is a fundamental ethical obligation of healthcare providers. Clinicians need to pursue this goal more aggressively, especially for cognitively impaired, postoperative older adults.

Urinary incontinence is a major care problem in nursing homes. Despite legislation aimed at decreasing its incidence, minimal progress has been made to achieve this goal. Obtaining an accurate assessment about the level and pattern of incontinence will assist caregivers in developing plans to reduce it. This article identifies barriers the authors have encountered in obtaining accurate records in a research project and strategies implemented to overcome these barriers.

Depression in newly admitted nursing home residents is a frequently overlooked area of nursing concern. Educating staff to systematically use a standardized depression assessment protocol with all newly admitted residents would facilitate efforts to enhance the quality of residents' lives by identifying depression so that prompt treatment is possible. Other previously admitted residents who appear to be particularly vulnerable to depression would also benefit from this assessment. The use of this protocol for the assessment of depression offers the possibility of providing more accurate and more comprehensive information regarding mood states than that currently being documented in the Minimum Data Set.

Changes in moral reasoning between entry into and exit from a baccalaureate nursing program and the relationship between student characteristics and moral reasoning at entry and exit were explored in this descriptive study. The moral reasoning of four cohorts of students was measured using the Defining Issues Test (DIT). Admission grade point average, prior college credits, and gender accounted for 10% of the variance in DIT P% scores at entry and 14% of the variance at exit from the program. Female students had significantly higher moral reasoning scores than men. Age did not contribute significantly to explaining DIT score variance. DIT P% scores at entry for all four cohorts were within the range of reported norms for college students. Exit scores for all four cohorts were between the normative means for undergraduate students and graduate students. DIT P% score gains between entry and exit were significant for all four cohorts. Students whose entry scores were in the lowest categories had the greatest mean gains.

Nursing facility staff may not be properly trained to deal with behavioral symptoms of Alzheimer's disease. We collected data about specialized dementia training and turnover among licensed nurses and nursing assistants in 400 nursing units in 124 Minnesota nursing facilities. Staff training may affect the retention of paraprofessional and professional nursing staff. A diversity of training methods, including workshops or seminars, films or videos, outside consultants, reading materials, training manuals, in-house experts, role playing techniques, or an orientation program for new staff, might be used to develop more effective training programs and reduce rates of nursing assistant turnover.

This article describes an approach to the evaluation of students' clinical performance. Specifically, the paper describes: (a) the history of the evaluation of clinical performance in nursing education; (b) the development of the Clinical Evaluation Tool (CET), an instrument designed to measure the clinical performance of nursing students across settings; and (c) the relationships between basic baccalaureate nursing students' scores on the CET and the following variables: age, college credits earned prior to entry to the program, grade point average at entry, college aptitude, and moral reasoning.

1. Aggressive behavior in elders with dementia occurs most often during personal care. It is often a response to invasion of private space and may be prevented or reduced by interpersonal approaches that reflect a set of individualized goals for the resident. 2. Five resident goals for preventing or reducing aggressive behavior are to feel safe, to feel physically comfortable, to experience a sense of control, to experience optimal stress, and to experience pleasure. 3. These goals provide a framework for humane care that respects the personhood of the individual and minimizes the need for psychotropic medications and physical restraints.

Discussions in the nursing literature about the usefulness of Kohlberg's theory of moral reasoning for women and nurses, and assertions about the level of moral reasoning scores of nurses have been clouded by inaccuracies and misperceptions. In this article, theoretical and measurement issues related to moral reasoning are clarified and a critical review of the literature is provided about the moral reasoning of nursing students and nurses as measured by the Defining Issues Test (DIT). The review indicates the need for greater rigor in studies of moral reasoning among nurses and the need for accuracy in interpreting and reporting moral reasoning scores. The data show that the moral reasoning of nurses, like that of other groups, tends to increase with formal education. Nurses' scores are usually comparable to, and sometimes higher than, scores of their academic peers.

An assessment was made of 129 faculty who teach nursing students about the care of aged clients to determine their level of interest and expertise in 21 content areas related to gerontology. Faculty rated their expertise consistently lower than the relevance of, and their interest in, each of the content areas. Areas identified as most important for their professional growth tended to be areas where faculty ranked their expertise as already being high. The mean self-rated expertise of faculty who taught a course in gerontological nursing was significantly higher than those who did not. Most respondents lacked formal education in gerontology: 9% of respondents had gerontology in their undergraduate program; 27% in their graduate program. Only 4% were certified as gerontological nurses or gerontological nurse practitioners.

Caring for cognitively impaired aggressive residents presents a challenge to nursing assistants in long-term care facilities. Nursing assistants participated in an educational program that included content about cognitive losses, precipitants of aggression, communication techniques, strategies for preventing aggressive behavior, and managing personal feelings. Following the educational intervention in this study, nursing assistants reported that caring for cognitively impaired residents was significantly more rewarding and less frustrating. The use of the clinical nurse specialist to teach and assist in role modeling direct care of residents was effective in improving nursing assistant skill in working with aggressive cognitively impaired residents.

Helping styles of nursing students were compared with those of subjects in a prior study (17 psychotherapists, 12 crisis interveners, and 15 untrained people). Subjects were 30 junior-year college students in the second part of a two-course sequence in interpersonal relations. The subjects were videotaped in a 3-minute interaction with a simulated client. An experienced psychotherapist who was trained in the use of the Helping Skills Verbal Response System instrument rated each student. The helping behaviors of nursing students were found to resemble those of trained mental health practitioners; their behavior was significantly different from those of untrained individuals, who were highly verbose, directive, and used minimal reflection of affect or content.

Aggressive behavior was documented in a sample of 124 residents on units for the cognitively impaired in four nursing homes over a period of 7 days using the Ryden Aggression Scale. Some form of aggression was found in 86.3% of the residents, with no differences among facility, gender or diagnostic group. Neither mental status nor physical dependency was associated with aggression. The 68.5% who received psychotropic drugs had significantly higher aggression scores. Most incidents of aggression involved response to invasion of personal space and occurred during the day shift.

This article describes the use of structured controversy as an educational strategy for helping students learn content and skills needed for dealing with difficult ethical situations that arise during the practice of nursing. Structured controversy, an innovative technique that encourages learners to deal with conflict constructively, is described, and research validating its benefits is reviewed. A comprehensive description of how structured controversy was operationalized, using the issue of whether or not to give nutrition and hydration to a dying patient, is included to provide other nursing educators with an illustration of how this strategy can be applied.

The morale of cognitively impaired elderly has not been systematically studied as this group has been excluded in most studies of well-being. This study showed that most cognitively impaired persons who retain verbal skills were able to respond to a verbally administered assessment using the Philadelphia Geriatric Center Morale Scale. Support for the reliability and validity of measurement of morale in cognitively impaired elderly using the Philadelphia Geriatric Center Morale Scale was reported. Ratings of the morale of cognitively impaired persons by family members were significantly associated with self-report by elders, but tended to be lower.

Developing cases for the clinical teaching of ethics can be extremely time-consuming. Often, the cases that are developed either represent unrealistic situations or mere technical puzzles rather than genuine ethical problems. This article describes how faculty at the University of Minnesota modified a simple, quick and inexpensive think tank technique, the Crawford Slip Method, for use with nursing educators to generate an extensive list of ethical issues within each clinical specialty. Selecting from these lists, faculty in each specialty developed one realistic nursing case situation to illustrate selected ethical issues. Faculty were asked to use the Alverno College criteria for designing a moral dilemma when writing their cases. Suggestions for adapting the cases for multiple uses are presented.

Aggressive behavior in persons with dementia who are living in the community was explored in a pilot study using a newly developed instrument, the Ryden Aggression Scale. Factors affecting this kind of research are addressed, including reliability and validity of the instrument, sample bias, diagnostic workup, and control groups. Results of a pilot survey of caregivers revealed aggressive behavior in 65% of a sample of 183 subjects, occurring weekly or more often in 31% and daily in 16%. Verbal and physical aggression were most prevalent (50% and 46%, respectively), while sexual aggression appeared less frequently (18%). Aggression was significantly related to degree of cognitive impairment and prior history of aggressive behavior, but not to diagnosis nor administration of psychotropic medications. Men showed significantly more sexual aggression. Further research to verify these findings is needed.

The climate for autonomy in four urban proprietary nursing homes was investigated as part of a larger study of the relationship between perceived control and morale. Data from 113 residents, 137 caregivers, and 10 administrative personnel revealed that caregivers see themselves as the predominant decision makers. Although they prefer a slightly higher level of self-determination for residents, only in one-to-one and solitary activities do they prefer giving residents the primary decision making role, possibly because they see most residents as not capable of making decisions. Residents saw themselves as having more control than did staff. Grooming and eating were identified by both groups as areas where residents had the least control. A substantial proportion of caregivers and administrative staff did not emphasize the availability of options to residents.

Carefully constructed policies or guidelines for the limitation of treatment in long-term care facilities are necessary to ensure that such limitation is consistent with ethical and legal principles. These protocols can be useful in protecting the rights of the residents, improving service, assuring the accountability of health care professionals, educating staff, and preventing legal controversies. Even the best protocol cannot eliminate controversy regarding decisions about limitation of treatment, but a clearly articulated policy can provide a process for addressing these concerns in a manner that takes into account the rights and responsibilities of all involved.

Two-thirds of the long-term care facilities in Minnesota accept do-not-resuscitate (DNR) orders and 73% accept care plans to limit medical treatment. The major objectives for limited-treatment plans cited by the 16.3% of facilities with administrative protocols for such plans was to provide for the resident's physical and emotional comfort and dignity. Nearly half of the protocols said limited treatment plans were intended to limit emergency care or hospitalization or to allow death to occur. Protocols advocated the alleviation of physical discomfort, anxiety, and social isolation. Tube feedings were not recommended when oral feeding became impossible. Airway suctioning, oxygen, or antibiotic treatment was suggested only as needed to alleviate suffering. Only a fourth of the protocols described a primary role for the resident in these decisions. This study demonstrates that nursing homes are developing administrative protocols for the formulation of limited-treatment plans and suggests that model policy statements describing key decision-making principles, issues, and procedural safeguards could play a constructive role in this process.

This article provides an account of the use of a model-building process as an educational strategy for the teaching of ethics. Designed to integrate students' growing knowledge and skill in nursing with their intellectual and professional development, this model-building process has its theoretical foundations in cognitive moral development theory, and in an integrative approach to nursing education called Multi-Course Sequential Learning (MCSL).

The practice of screening applicants for nursing home admission to determine whether less restrictive residential settings are possible is growing as states attempt to limit costs of Medicaid expenditures for long-term care. Preadmission screening (PAS) is a repetitive task conducted under conditions of complexity and uncertainty. Extensive knowledge and skills are required to make recommendations concerning appropriate residences for elderly persons that match their needs with available services while assuring their autonomy, as well as that of their families. We used task analysis to explicate the specific task characteristics and the knowledge and skill requirements for successful PAS.