Thirty-day hospital readmission predictors in older patients receiving hospital-at-home: a 3-year retrospective study in France.

OBJECTIVE: This study described older patients receiving hospitalisation-at-home (HaH) services and identified factors associated with 30-day hospital readmission. DESIGN: 3-year retrospective study in 2017-2019 in France. PARTICIPANTS: 75 108 patients aged 75 years and older who were discharged from hospital medical wards (internal medicine and geriatric units) and admitted to HaH. PRIMARY OUTCOME MEASURE: 30-day hospital readmission. RESULTS: The mean age of patients was 83.4 years (SD 5.7), 52.3% were male and 88.4% lived in a private household. Patients were primarily discharged from the internal medicine unit (85.3%). The top four areas of care in the HaH were palliative care, complex dressing, intravenous therapy and complex nursing care. Overall, 23.5% of patients died during their HaH stay and 27.8% were readmitted to the hospital at 30 days. In the multivariate model, male (OR 1.19, 95% CI 1.16 to 1.23), supportive cancer HaH care (OR 1.78, 95% CI 1.51 to 2.11) and very high intensity care during the previous in-person hospitalisation (OR 1.45, 95% CI 1.34 to 1.57) increased the risk of hospital readmission at 30 days. Older age (OR 0.97, 95% CI 0.97 to 0.98), living in a nursing home (OR 0.51, 95% CI 0.48 to 0.54), postsurgery HaH care (OR 0.49, 95% CI 0.41 to 0.58) and having been previously hospitalised in a geriatric unit (OR 0.81, 95% CI 0.77 to 0.85) decreased the risk of hospital readmission at 30 days. CONCLUSIONS: HaH provides complex care to very old patients, which is associated with high mortality. Several factors are associated with rehospitalisation within 30 days that could be avoided with better integration of different services with higher geriatric skills. TRIAL REGISTRATION NUMBER: CNIL:2228861.

[Hypophosphatemia after injectable iron treatments in adults: Comparison between ferric carboxymaltose and iron sucrose]. / Hypophosphorémie après traitement par fer injectable chez l'adulte : comparaison entre le carboxymaltose ferrique et l'hydroxyde ferrique-saccharose.

Hypophosphatemia is a recognized side effect of treatment of iron deficiency anemias with injectable iron. We analyzed 35 clinical trials that used ferric carboxymaltose (FCM) or iron sucrose (IS). Hypophosphatemia prevalence ranged from 0 to 91.7%. FCM-induced a significant (P<0.001) greater hypophosphatemia prevalence and phosphatemia decrease than IS (52.0% [95% CI: 42.2-61.8%] vs. 7.7% [95% CI: -2.8 to 18.2%] and -1.12mmol/L [95% CI: -1.36 to -0.89mmol/L] vs. -0.13mmol/L [95% CI: -0.59 to 0.32mmol/L]). FCM-induced hypophosphatemia was dose-dependent. The nadir of hypophosphatemia was reached in almost all studies after 7 and 14days. Hypophosphatemia persisted at the end of the study in 53.8% of the reported studies that used FCM and lasted up to 6months. FCM-induced an increase in intact circulating fibroblast growth factor 23 and in renal phosphorus excretion while serum 1-25 dihydroxyvitamin D was decreased. Risk factors for hypophosphatemia after FCM therapy were low basal circulating phosphate or ferritin, low body weight, high glomerular filtration rate, serum parathyroid hormone or hemoglobin and age, whereas renal insufficiency was associated with a lower risk. In conclusion, hypophosphatemia is common after treatment with injectable iron, FCM being associated with a higher risk than IS and with disorders of phosphocalcium metabolism. Monitoring of blood phosphate and 1-25 dihydroxyvitamin D could be considered during FCM therapy.

Hypnotherapy in Treatment of Mastocytosis: A Prospective Study.

Mastocytosis is an orphan disease associated with many systemic symptoms, chronic handicap, and potentially marked social consequences despite improved therapies. In this study, the authors aimed to measure the effect of 2 hypnosis sessions on mastocytosis symptoms in a clinical setting. Questionnaires (pain, flushes, energy, digestive symptoms, quality of life, perceived symptom severity, and global impression of change) were completed pre- and posthypnosis intervention. Data from 20 patients were analyzed (mean age: 53.3 years, 75% female). Compared to baseline assessment, patients exhibited a significant improvement immediately after the first and second hypnosis sessions with regard to the number of days with abdominal pain, abdominal pain intensity and fatigue (p = .03 and p = .005; p = .05 and p = .02; p = .034, and p = .039, respectively). Perceived severity of symptoms was significantly improved throughout the study (p = .0075). Long-term improvement in global impression of change was observed in half the responders (8/16). Patients with mastocytosis had an improvement in disabling symptoms with the impact of hypnotic intervention persisting at 1 month. Several patients experienced long-term improvement.

Predicting Chemotherapy Toxicity and Death in Older Adults with Colon Cancer: Results of MOST Study.

PURPOSE: Older patients with colon cancer (CC) are vulnerable to chemotherapy toxicity and death. Establishing simple scores specific for patients with CC to predict severe chemotoxicity or early death is needed to select the best treatment strategy. SUBJECTS, MATERIALS, AND METHODS: This prospective multicenter study included patients aged ≥70 years with CC receiving adjuvant or first-line metastatic chemotherapy. Frailty markers (nutrition, physical activity, energy, mobility, strength), comprehensive geriatric assessment (functional status, comorbidities, falls, nutrition, cognition, and depression), and usual laboratory parameters were collected. Logistic or Cox regression was used to examine at 500 days the association between frailty markers, comprehensive geriatric assessment, laboratory parameters, and grade 3-4 toxicity or death. RESULTS: A total of 97 patients (median age, 79.0 years) received adjuvant (37.1%) or metastatic (62.9%) chemotherapy. During the first 500 days, grade 3-4 toxicity occurred in 49.5%, and 30% died. The predictive model for grade 3-4 toxicity combined (polychemotherapy × 3) + (hypoalbuminemia <32 g/L × 2) + (abnormal grip strength × 1.5) + C-reactive protein >11 mg/L + Eastern Cooperative Oncology Group performance status (ECOG-PS), cutoff score >3. The predictive model for death combined (metastasis × 5) + (age × 2) + alkaline phosphatase >100 IU/mL + sex (female) + abnormal grip strength + ECOG-PS, cutoff score >6. For chemotoxicity prediction, sensitivity was 81.6% and specificity 71.4%. For death prediction, sensitivity was 89.7% and specificity was 83.6%. CONCLUSION: These simple and efficient "ColonPrediscores" will help to better identify older patients with CC with increased risk of chemotherapy-related toxicity and/or death. IMPLICATIONS FOR PRACTICE: The two scores assessed in this study, called "ColonPrediscores", offer a major advantage in that they do not need a previous complete geriatric assessment, which makes them an easy-to-use tool in oncologic settings.

Platelet CD40 ligand and bleeding during P2Y12 inhibitor treatment in acute coronary syndrome.

Antiplatelet therapy through inhibition of the adenosine diphosphate (ADP)/P2Y12 pathway is commonly used in the treatment of acute coronary syndrome (ACS). Although efficient in preventing platelet activation and thrombus formation, it increases the risk of bleeding complications. In patients with ACS receiving platelet aggregation inhibitors, that is, P2Y12 blockers (n = 923), we investigated the relationship between plasma and platelet-associated CD40L levels and bleeding events (n = 71). Treatment with P2Y12 inhibitors in patients with ACS did not affect plasma-soluble CD40L levels, but decreased platelet CD40L surface expression (pCD40L) and platelet-released CD40L (rCD40L) levels in response to stimulation as compared to healthy controls. In vitro inhibition of the ADP pathway in healthy control platelets reduced both pCD40L and rCD40L levels. In a multivariable analysis, the reduced pCD40L level observed in ACS patients was significantly associated with the risk of bleeding occurrence (adjusted odds ratio = 0.15; 95% confidence interval = 0.034-0.67). P2Y12 inhibitor-treated (ticagrelor) mice exhibited a 2.5-fold increase in tail bleeding duration compared with controls. A significant reduction in bleeding duration was observed on CD40L+/+ but not CD40L-/- platelet infusion. In addition, CD40L blockade in P2Y12 inhibitor-treated blood samples from a healthy human reduced thrombus growth over immobilized collagen under arterial flow. In conclusion, measurement of pCD40L may offer a novel approach to assessing bleeding risk in patients with ACS who are being treated with P2Y12 inhibitors.

Increased levels of the megakaryocyte and platelet expressed cysteine proteases stefin A and cystatin A prevent thrombosis.

Increased platelet activity occurs in type 2 diabetes mellitus (T2DM) and such platelet dysregulation likely originates from altered megakaryopoiesis. We initiated identification of dysregulated pathways in megakaryocytes in the setting of T2DM. We evaluated through transcriptomic analysis, differential gene expressions in megakaryocytes from leptin receptor-deficient mice (db/db), exhibiting features of human T2DM, and control mice (db/+). Functional gene analysis revealed an upregulation of transcripts related to calcium signaling, coagulation cascade and platelet receptors in diabetic mouse megakaryocytes. We also evidenced an upregulation (7- to 9.7-fold) of genes encoding stefin A (StfA), the human ortholog of Cystatin A (CSTA), inhibitor of cathepsin B, H and L. StfA/CSTA was present in megakaryocytes and platelets and its expression increased during obesity and diabetes in rats and humans. StfA/CSTA was primarily localized at platelet membranes and granules and was released upon agonist stimulation and clot formation through a metalloprotease-dependent mechanism. StfA/CSTA did not affect platelet aggregation, but reduced platelet accumulation on immobilized collagen from flowing whole blood (1200 s-1). In-vivo, upon laser-induced vascular injury, platelet recruitment and thrombus formation were markedly reduced in StfA1-overexpressing mice without affecting bleeding time. The presence of CA-074Me, a cathepsin B specific inhibitor significantly reduced thrombus formation in-vitro and in-vivo in human and mouse, respectively. Our study identifies StfA/CSTA as a key contributor of platelet-dependent thrombus formation in both rodents and humans.

The beta secretase BACE1 regulates the expression of insulin receptor in the liver.

Insulin receptor (IR) plays a key role in the control of glucose homeostasis; however, the regulation of its cellular expression remains poorly understood. Here we show that the amount of biologically active IR is regulated by the cleavage of its ectodomain, by the ß-site amyloid precursor protein cleaving enzyme 1 (BACE1), in a glucose concentration-dependent manner. In vivo studies demonstrate that BACE1 regulates the amount of IR and insulin signaling in the liver. During diabetes, BACE1-dependent cleavage of IR is increased and the amount of IR in the liver is reduced, whereas infusion of a BACE1 inhibitor partially restores liver IR. We suggest the potential use of BACE1 inhibitors to enhance insulin signaling during diabetes. Additionally, we show that plasma levels of cleaved IR reflect IR isoform A expression levels in liver tumors, which prompts us to propose that the measurement of circulating cleaved IR may assist hepatic cancer detection and management.

Diagnostic value of conventional chest radiography in intrathoracic goiters-retrospective analysis of 2570 patients.

PURPOSE: Since intrathoracic goiters (IG), either cervico-mediastinal goiters (CMGs) or mediastinal nodules (MNs), can lead to sternotomies and/or evitable reoperations, their detection is mandatory before thyroid surgery. A systematic screening by CT scan or MRI is not conceivable because of their expensiveness. We tested if conventional chest radiography (CCR) could remain a good screening tool for IG before thyroid surgery. METHODS: In this retrospective study (2554 patients), CCR usefulness was evaluated in relation with patients' complaints, clinical examination, neck US, and anatomical and surgical findings. RESULTS: CMGs (n = 67) and MNs (n = 42) were symptomatic in 10 and 5 patients, respectively. Clinical examination or neck US suspected their existence in 25 and 13 and 45 and 17 patients, respectively. Among the 50 IG detected by CCR (42 CMGs and 8 MNs), 4 CMGs and 2 MNs were missed by clinical examination or neck US. CCR failed to detect IG in 59 patients (54%): 25 CMGs (37%) and 34 MNs (80%). Twenty-eight IG (9 CMGs and 19 MNs) were discovered during surgery. CCR resulted in false positive in 88 out of 2445 patients (3.5%). CCR potentially avoided reoperation in two patients (a maximum saving of 6160 €, whereas the total cost of CCR was 54,895 €). CONCLUSIONS: CCR should not be used routinely for the preoperative detection of IG. Surgeons should preferably use clinical examination or neck US and directly perform CT scan when a mediastinal extension is suspected.

Surgical management of primary hyperparathyroidism in older adults.

OBJECTIVES: To compare the feasibility, safety, and outcome of parathyroidectomy in the management of primary hyperparathyroidism (PHPT) in individuals aged 75 and older with that of those younger than 50. DESIGN: Retrospective chart review. SETTING: Department of Endocrine Surgery, Hospital Paul Desbief (Marseille, France). PARTICIPANTS: Individuals who underwent surgery from June 2005 to February 2013 (N = 526) had a clinical examination and laboratory and imaging assessments to diagnose PHPT. MEASUREMENTS: The clinical and biochemical characteristics and surgery outcomes of individuals younger than 50 (n = 80) were compared with the characteristics and outcomes of those aged 75 and older (n = 89). RESULTS: Most of the participants did not have any specific signs of PHPT, and the diagnosis of PHPT was established in some participants during routine clinical and laboratory examination. Nephrolithiasis and osteitis fibrosa cystica were observed only in the younger group. Urinary calcium decreased with age. Nine participants aged 75 and older did not undergo surgery (four declined, five had medical contraindications). Conventional surgery through transverse cervicotomy was used in the majority of participants. Cure rate was excellent (158/160), with few and reversible minor complications. The coexistence of thyroid lesions was significantly higher in the older (47.5%) than in the younger group (32.3%). Nodules and multinodular goiters were removed in the majority of participants during the parathyroidectomy procedure. CONCLUSION: With the exception of a few cases with severe associated comorbidities, parathyroidectomy is safe and curative and should be considered as first-line choice for older adult with PHPT.

Inflammatory phenotyping identifies CD11d as a gene markedly induced in white adipose tissue in obese rodents and women.

In severe obesity, white adipose tissue (WAT) inflammation and macrophage infiltration are thought to contribute to WAT and whole-body insulin resistance. Specific players involved in triggering and maintaining inflammation (i.e. those regulating adipokine release and WAT macrophage recruitment, retention, or function) remain to be fully elaborated, and the degree to which moderate obesity promotes WAT inflammation remains to be clarified further. Therefore, we characterized adiposity and metabolic phenotypes in adult male C57BL/6J mice fed differing levels of dietary fat (10, 45, and 60% of energy) for 12 wk, concurrent with determinations of WAT inflammation markers and mRNA expression of leukocyte-derived integrins (CD11b, CD11c, CD11d) involved in macrophage extravasation and tissue macrophage homing/retention. As expected, a lard-based, very high-fat diet (60% energy) significantly increased adiposity and glucose intolerance compared with 10% fat-fed controls, coincident with higher retroperitoneal (RP) WAT transcript levels for proinflammatory factors and macrophage markers, including TNFα and CD68 mRNA, which were ~3- and ~15-fold of control levels, respectively (P < 0.001). Mice fed the 45% fat diet had more moderate obesity, less glucose intolerance, and lower WAT macrophage/inflammatory marker mRNA abundances compared with 60% fat-fed mice; TNFα and CD68 mRNA levels were ~2- and ~5-fold of control levels (P < 0.01). Relative WAT expression of CD11d was massively induced by obesity to an extent greater than any other inflammatory marker (to >300-fold of controls in the 45 and 60% fat groups) (P < 0.0001) and this induction was WAT specific. Because we found that CD11d expression also increased in RP-WAT of Zucker obese rats and in the subcutaneous WAT of obese adult women, this appears to be a common feature of obesity. Observed correlations of WAT macrophage transcript marker abundances with body weight in lean to modestly obese mice raises an interesting possibility that the activities of at least some WAT macrophages are closely linked to the normal adipose remodeling that is a requisite for changes in WAT energy storage capacity.

Molecular Characterization of the Tumor Suppressor Candidate 5 Gene: Regulation by PPARgamma and Identification of TUSC5 Coding Variants in Lean and Obese Humans.

Tumor suppressor candidate 5 (TUSC5) is a gene expressed abundantly in white adipose tissue (WAT), brown adipose tissue (BAT), and peripheral afferent neurons. Strong adipocyte expression and increased expression following peroxisome proliferator activated receptor gamma (PPARgamma) agonist treatment of 3T3-L1 adipocytes suggested a role for Tusc5 in fat cell proliferation and/or metabolism. However, the regulation of Tusc5 in WAT and its potential association with obesity phenotypes remain unclear. We tested the hypothesis that the TUSC5 gene is a bona fide PPARgamma target and evaluated whether its WAT expression or single-nucleotide polymorphisms (SNPs) in the TUSC5 coding region are associated with human obesity. Induction of Tusc5 mRNA levels in 3T3-L1 adipocytes by troglitazone and GW1929 followed a dose-response consistent with these agents' binding affinities for PPARgamma. Chromatin immunoprecipitation (ChIP) experiments confirmed that PPARgamma protein binds a approximately -1.1 kb promotor sequence of murine TUSC5 transiently during 3T3-L1 adipogenesis, concurrent with histone H3 acetylation. No change in Tusc5 mRNA or protein levels was evident in type 2 diabetic patients treated with pioglitazone. Tusc5 expression was not induced appreciably in liver preparations overexpressing PPARs, suggesting that tissue-specific factors regulate PPARgamma responsiveness of the TUSC5 gene. Finally, we observed no differences in Tusc5 WAT expression or prevalence of coding region SNPs in lean versus obese human subjects. These studies firmly establish the murine TUSC5 gene locus as a PPARgamma target, but the significance of Tusc5 in obesity phenotypes or in the pharmacologic actions of PPARgamma agonists in humans remains equivocal.

Gamma-synuclein is an adipocyte-neuron gene coordinately expressed with leptin and increased in human obesity.

Recently, we characterized tumor suppressor candidate 5 (Tusc5) as an adipocyte-neuron PPARgamma target gene. Our objective herein was to identify additional genes that display distinctly high expression in fat and neurons, because such a pattern could signal previously uncharacterized functional pathways shared in these disparate tissues. gamma-Synuclein, a marker of peripheral and select central nervous system neurons, was strongly expressed in white adipose tissue (WAT) and peripheral nervous system ganglia using bioinformatics and quantitative PCR approaches. Gamma-synuclein expression was determined during adipogenesis and in subcutaneous (SC) and visceral adipose tissue (VAT) from obese and nonobese humans. Gamma-synuclein mRNA increased from trace levels in preadipocytes to high levels in mature 3T3-L1 adipocytes and decreased approximately 50% following treatment with the PPARgamma agonist GW1929 (P < 0.01). Because gamma-synuclein limits growth arrest and is implicated in cancer progression in nonadipocytes, we suspected that expression would be increased in situations where WAT plasticity/adipocyte turnover are engaged. Consistent with this postulate, human WAT gamma-synuclein mRNA levels consistently increased in obesity and were higher in SC than in VAT; i.e. they increased approximately 1.7-fold in obese Pima Indian adipocytes (P = 0.003) and approximately 2-fold in SC and VAT of other obese cohorts relative to nonobese subjects. Expression correlated with leptin transcript levels in human SC and VAT (r = 0.887; P < 0.0001; n = 44). Gamma-synuclein protein was observed in rodent and human WAT but not in negative control liver. These results are consistent with the hypothesis that gamma-synuclein plays an important role in adipocyte physiology.

Postnatal programming of glucocorticoid metabolism in rats modulates high-fat diet-induced regulation of visceral adipose tissue glucocorticoid exposure and sensitivity and adiponectin and proinflammatory adipokines gene expression in adulthood.

OBJECTIVE: Alterations of the perinatal environment, which lead to increased prevalence of the metabolic syndrome in adulthood, program an upregulation of systemic and/or adipose tissue glucocorticoid metabolism (11 beta-hydroxysteroid dehydrogenase type 1 [11 beta-HSD-1]-induced corticosterone reactivation). We hypothesized that postnatal programming could modulate high-fat diet-induced adipose tissue dysregulation in adulthood. RESEARCH DESIGN AND METHODS: We compared the effects of chronic (since weaning) high- or low-fat diet in postnatally normofed (control) or overfed (programmed) rats. RESULTS: Postnatal programming accentuated high-fat diet-induced overweight, insulin resistance, glucose intolerance, and decrease in circulating and epididymal adipose tissue adiponectin. Neither manipulation altered liver function. Postnatal programming or high-fat diet increased systemic corticosterone production, which was not further modified when both manipulations were associated. Postnatal programming suppressed high-fat diet-induced decrease in mesenteric adipose tissue (MAT) glucocorticoid sensitivity and triggered high-fat diet-induced increase in MAT glucocorticoid exposure, subsequent to enhanced MAT 11 beta-HSD-1 gene expression. MAT tumor necrosis factor (TNF)-alpha, TNF-receptor 1, interleukin (IL)-6, resistin, and plasminogen activator inhibitor-1 mRNAs were not changed by high-fat feeding in control rats and showed a large increase in programmed animals, with this effect further enhanced by high-fat diet for TNF-alpha and IL-6. CONCLUSIONS: Our data show for the first time that postnatal manipulation programs high-fat diet-induced upregulation of MAT glucocorticoid exposure, sensitivity, and inflammatory status and therefore reveal the pivotal role of the environment during the perinatal period on the development of diet-induced adipose tissue dysregulation in adulthood. They also urge the need for clinical trials with specific 11 beta-HSD-1 inhibitors.

Expression of adrenomedullin in human epicardial adipose tissue: role of coronary status.

Epicardial white adipose tissue (eWAT) is in close contact with coronary vessels and therefore could alter coronary homeostasis. Adrenomedullin (AM) is a potent vasodilatator and antioxidative peptide which has been shown to play a cytoprotective role in experimental models of acute myocardial infarction. We studied, using immunohistochemistry and qRT-PCR, the expression of AM and its receptors calcitonin receptor-like receptor (CRLR), and receptor activity-modifying protein (RAMP)2 and -3 in paired biopsies of subcutaneous WAT (sWAT) and eWAT obtained from patients with coronary artery disease (CAD) or without CAD (NCAD). In eWAT obtained from NCAD or CAD patients, immunoreactivity for AM, CRLR, and RAMP2 and -3 was detected in blood vessel walls and isolated stromal cells close to adipocytes. Some of the AM positive stromal cells colocalized CD68 immunoreactivity. eWAT from CAD patients showed increased AM immunoreactivity and AM gene expression. CRLR mRNA levels were comparable in sWAT of both groups and decreased by 40-50% in eWAT, irrespectively of the coronary status. RAMP2 mRNA concentrations did not change while RAMP3 mRNA levels increased in sWAT from CAD patients. There was a positive linear relationship between eWAT 11beta-hydroxysteroid dehydrogenase type 1 mRNA (11beta-HSD-1, the enzyme that converts inactive to active glucocorticoids) and AM mRNA. In conclusion, we demonstrate that AM and its receptors are expressed in eWAT. Our data suggest that eWAT AM, which could originate from macrophages, is related to 11beta-HSD-1 expression. AM synthesis, which is increased in eWAT during chronic CAD in humans, can play a cardioprotective role.

Differential regulation of proopiomelanocortin and pituitary-restricted transcription factor (TPIT), a new marker of normal and adenomatous human corticotrophs.

Since the identification of the pituitary-restricted transcription factor Tpit, a novel T-box factor that is only present in mouse in the two pituitary proopiomelanocortin (POMC)-expressing lineages, no information was available on its pattern of expression in human pituitary. We investigated by immunohistochemistry and in situ hybridization the expression of TPIT in normal human anterior pituitary tissue and in several types of human pituitary adenomas (n = 52). TPIT expression was restricted to the nucleus of normal or adenomatous human corticotroph cells. No specific TPIT immunostaining was detectable in all prolactin (PRL)-, GH-, or gonadotropin-secreting adenomas. In situ hybridization studies demonstrated that TPIT transcripts were coexpressed with POMC mRNA in both secreting and silent corticotroph adenomas, and in normal corticotrophs, whereas TPIT mRNA was not detectable in other types of pituitary adenomas. Unlike POMC, TPIT was not up-regulated by adrenalectomy in rats and did not seem down-regulated in the normal pituitary adjacent to human corticotroph microadenomas. TPIT is the only currently known transcription factor selectively expressed in human normal and adenomatous corticotrophs. In human and experimental models, TPIT and its target gene POMC were thus differentially regulated by glucocorticoids. Moreover, TPIT represents a new marker of POMC-expressing pituitary cells.

Plasma PAI-1 levels are more strongly related to liver steatosis than to adipose tissue accumulation.

OBJECTIVE: Because obesity and insulin resistance (IR) are strongly associated with liver steatosis (LS), we investigated the relation between the degree of LS and plasminogen activator inhibitor-1 (PAI-1) in ob/ob mice, in C57/BL6 mice with alcoholic LS, and in severely obese humans. METHODS AND RESULTS: In both mouse models, plasma PAI-1 levels were associated with PAI-1 expression in the liver and with the degree of LS. Liver PAI-1 antigen was associated with the tumor necrosis factor receptor-II (TNFRII) antigen, whereas association with TNF antigen content was found in ob/ob mice only. No significant correlation between plasma PAI-1 and PAI-1 expression in adipose tissue of ob/ob mice was observed. Furthermore, the relation between plasma PAI-1 levels and body weight was positive in ob/ob mice but negative in C57/BL6 mice (both P<0.001). In humans, PAI-1 levels were correlated with the degree of LS, and 26% of plasma PAI-1 activity was independently explained by LS and serum insulin levels. CONCLUSIONS: Plasma PAI-1 levels are more closely related to fat accumulation and PAI-1 expression in the liver than in adipose tissue. In steatotic liver, PAI-1 antigen content is associated with those of TNF and TNFRII. Therefore, we suggest that TNF pathway dysregulation in LS could be involved in increased plasma PAI-1 in obesity with IR.