Geriatric chronic recurrent multifocal osteomyelitis (CRMO) mimicking multifocal multiple myeloma: a first in an octogenarian.

Chronic recurrent multifocal osteomyelitis (CRMO), an autoinflammatory bone disorder characterized by non-bacterial osteomyelitis causing recurrent multifocal bone lesions, is a well-known, yet uncommon pediatric condition that rarely affects adults; to date, it has never been diagnosed over the age of 75. The following report will discuss the first octogenarian diagnosed with CRMO and therefore represents an exceptionally rare presentation of a rare disease. An 83-year-old woman presented with progressive right shoulder, forearm, and hip pain, with associated weight loss and global weakness, requiring a wheelchair for mobility. Imaging revealed a pathologic right ulna fracture in addition to lytic lesions of the right proximal humerus and proximal femur. The clinical picture was thus that of a patient with probable multiple myeloma versus metastatic disease. After an extensive workup, however, the lesions were not malignant; histologic findings were instead suggestive of chronic osteomyelitis with negative cultures. Given the multifocal nature of this condition, combined with a lack of clinical symptoms of infection, a diagnosis of CRMO was rendered. The patient underwent intramedullary nailing of the right femur and splinting of the ulna, with a subsequent remarkable recovery to painless ambulation, complete union of the right ulna fracture, and resolution of the lytic lesions without receiving any targeted medical treatment. This case highlights the importance of maintaining CRMO on the differential for multifocal skeletal lesions, regardless of age. Performing a thorough workup with necessary imaging, biopsy, and culture are critical to establishing this diagnosis, which can only made as a diagnosis of exclusion.

Lipid Droplet Protein PLIN1 Regulates Inflammatory Polarity in Human Macrophages and is Involved in Atherosclerotic Plaque Development by Promoting Stable Lipid Storage.

AIM: Perilipins (PLINs), peripheral lipid droplet (LD) proteins, play important roles in lipid accumulation and maturation in adipocytes. The relationship between PLIN family proteins and macrophage polarization in atherosclerosis has not been elucidated. METHODS: The experiments used tissues from human arteries of 65 patients who had undergone a carotid endarterectomy, and cultured macrophages generated from healthy human peripheral blood mononuclear cells. RESULTS: Plaque immunohistochemistry demonstrated co-expression of PLIN1 and PLIN2 in both symptomatic (n=31) and asymptomatic patients (n=34). PLIN2 mRNA expression increased 3.38-fold in the symptomatic group compared with those from asymptomatic. PLIN1 was not expressed on small LDs at a shorter incubation but was on large LDs at longer incubation with oxidized LDL and VLDL, while PLIN2 was observed after 24 h and increased with a longer incubation in cultured M1 macrophage. In M2 macrophages, PLIN1 was seen as early as 24 h following incubation with VLDL, and LD size increased with longer incubation. PLIN1 overexpression increased the size of LDs in M1 macrophages, even after a short incubation, and reduced the RNA expression of TNFA, MMP2, ABCA1, and ABCG1 versus the M1 control. Conversely, silencing of PLIN1 in M2 macrophages had the opposite effects on LD size and RNA expression. CONCLUSION: There was a relationship between macrophage polarity, cytosolic LD size, and PLIN1/PLIN2 expression levels. PLIN2 was mainly expressed in arterial plaques in symptomatic stroke patients, and associated with the inflammatory phenotype of human macrophages, while PLIN1 expression is closely associated with plaque stability and the anti-inflammatory phenotype.

Ferroptosis of tumour neutrophils causes immune suppression in cancer.

Ferroptosis is a non-apoptotic form of regulated cell death that is triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Ferroptosis inducers have shown considerable effectiveness in killing tumour cells in vitro, yet there has been no obvious success in experimental animal models, with the notable exception of immunodeficient mice1,2. This suggests that the effect of ferroptosis on immune cells remains poorly understood. Pathologically activated neutrophils (PMNs), termed myeloid-derived suppressor cells (PMN-MDSCs), are major negative regulators of anti-tumour immunity3-5. Here we found that PMN-MDSCs in the tumour microenvironment spontaneously die by ferroptosis. Although decreasing the presence of PMN-MDSCs, ferroptosis induces the release of oxygenated lipids and limits the activity of human and mouse T cells. In immunocompetent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSCs, reduces tumour progression and synergizes with immune checkpoint blockade to suppress the tumour growth. By contrast, induction of ferroptosis in immunocompetent mice promotes tumour growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSCs in the tumour microenvironment that can be pharmacologically modulated to limit tumour progression.

Single Incision Modified Tension Slide Technique in Distal Biceps Repair: Improved Load to Failure While Reducing Surgical Pitfalls.

Historically, distal biceps tendon repair through the tension slide technique (TST) using a cortical button has yielded the strongest published repair measured by observed gap formation in both cyclic and maximal load to failure. The modified tension slide technique (MTST) was developed in order to provide the surgeon with a technically simpler and biomechanically more effective way to reduce gap formation and consistently seat/bottom-out the tendon within the bone tunnel through a more direct line of pull. In order to compare the biomechanics of the MTST to the TST, we used 24 matched bovine extensor tendons, and conducted maximal load to failure and cyclical load to failure testing using an Instron 5566 machine. The mean maximal load to failure for the MTST was 444 N versus 229 N for the TST ( P <0.004) while no gap formation was observed in either group after cyclic load testing. These findings indicate that the MTST has a statistically significant increased load to gap formation of ∼2-fold in comparison to TST. In the MTST both limbs of suture are passed back through the tendon, before button implantation, eliminating the "operating in a hole" effect required in the TST, and making for a simpler surgical procedure.

The good and bad of adipose tissue macrophage exosomes in obesity.

Adipose tissue macrophages regulate adipose tissue inflammation and systemic insulin-glucose homeostasis. In a recent study by Ying et al. (2021), M2 polarized bone marrow-derived macrophages secreted exosomes containing miR-690 that, when administered to obese mice, improved glucose-insulin homeostasis. miR-690 reduced expression of Nadk, which decreased inflammation and improved insulin signaling.

Decellularized extracellular matrix scaffolds identify full-length collagen VI as a driver of breast cancer cell invasion in obesity and metastasis.

The extracellular matrix (ECM), a major component of the tumor microenvironment, promotes local invasion to drive metastasis. Here, we describe a method to study whole-tissue ECM effects from disease states associated with metastasis on tumor cell phenotypes and identify the individual ECM proteins and signaling pathways that are driving these effects. We show that decellularized ECM from tumor-bearing and obese mammary glands drives TNBC cell invasion. Proteomics of the ECM from the obese mammary gland led us to identify full-length collagen VI as a novel driver of TNBC cell invasion whose abundance in tumor stroma increases with body mass index in human TNBC patients. Last, we describe the mechanism by which collagen VI contributes to TNBC cell invasion via NG2-EGFR cross-talk and MAPK signaling. Overall, these studies demonstrate the value of decellularized ECM scaffolds obtained from tissues to identify novel functions of the ECM.

Dorsal Plating for Intra-articular Middle Phalangeal Base Fractures With Volar Instability.

Background: Intra-articular middle phalangeal base fractures with volar instability are rare injuries with scant literature on optimal management. Our purpose is to describe our method of dorsal plating and report postoperative outcomes. Methods: This study is a retrospective case review of 5 patients with intra-articular middle phalangeal base fractures with volar proximal interphalangeal joint instability, measuring subjective, clinical, and radiographic outcomes. Results: Patient age averaged 38.2 years (range, 23-56 years), and 80% were male. Sporting injuries were the most common mechanism (80%). Time to surgery averaged 7 days, and postoperative follow-up duration averaged 19.6 months (median 8 months). All fractures were intra-articular at the proximal interphalangeal joint with volar instability. There were no complications and no patients required secondary surgery. Grip strength was maintained and range of motion was good, based on the American Society for Surgery of the Hand Total Active Motion score. Average Quick Disability of the Arm, Shoulder and Hand was 0.5 (range, 0-2.3), 100% of patients were satisfied, and average visual analog pain score was 1.2. Patients returned to work at a median of 4 days. There was radiographic union at an average of 6.6 weeks (range, 6-7 weeks) in all fractures. Conclusions: Dorsal plating using a 1.5-mm modular hand plate is a viable option for rigid fixation of intra-articular middle phalangeal base fractures with volar instability. This fixation method allows for early range of motion without complications in this case series. All fractures united, and patients had minimal functional deficits and were able to maintain good range of motion.

Membrane-Initiated Estrogen Receptor Signaling Mediates Metabolic Homeostasis via Central Activation of Protein Phosphatase 2A.

Women gain weight and their diabetes risk increases as they transition through menopause; these changes can be partly reversed by hormone therapy. However, the underlying molecular mechanisms mediating these effects are unknown. A novel knock-in mouse line with the selective blockade of the membrane-initiated estrogen receptor (ER) pathway was used, and we found that the lack of this pathway precipitated excessive weight gain and glucose intolerance independent of food intake and that this was accompanied by impaired adaptive thermogenesis and reduced physical activity. Notably, the central activation of protein phosphatase (PP) 2A improved metabolic disorders induced by the lack of membrane-initiated ER signaling. Furthermore, the antiobesity effect of estrogen replacement in a murine menopause model was abolished by central PP2A inactivation. These findings define a critical role for membrane-initiated ER signaling in metabolic homeostasis via the central action of PP2A.

TPL2 Is a Key Regulator of Intestinal Inflammation in Clostridium difficile Infection.

Tumor progression locus 2 (TPL2), a serine/threonine protein kinase, is a major inflammatory mediator in immune cells. The predominant inflammatory actions of TPL2 depend on the activation of mitogen-activated protein kinases (MAPK) and the upregulated production of the cytokines tumor necrosis factor alpha (TNF-α) and interleukin 1ß (IL-1ß) in macrophages and dendritic cells in response to lipopolysaccharide (LPS). Significant increases in TNF-α, IL-6, IL-ß, and IL-8 levels in patients with Clostridium difficile infection (CDI) have been reported. Both TNF-α and IL-6 have been postulated to play key roles in the systemic inflammatory response in CDI, and IL-8 is essential for the development of local intestinal inflammatory responses in CDI. The objective of this study was to elucidate the role of TPL2 in the pathogenesis of CDI. We found that TPL2 was significantly activated in human and mouse intestinal tissues upon C. difficile toxin exposure or CDI. We further demonstrated that TPL2 knockout (TPL2-KO) mice were significantly more resistant to CDI than wild-type mice, with significantly reduced production of TNF-α, IL-6, IL-1ß, KC (a mouse homologue of IL-8), and myeloperoxidase (MPO) in the ceca and colons of TPL2-KO mice. Finally, we found that TPL2 inhibition by a specific inhibitor or TPL2 gene ablation significantly reduced TcdB-induced production of TNF-α, IL-6, IL-ß, and KC by inhibiting the activation of p38, extracellular signal-regulated kinase (ERK), and c-Jun NH2-terminal kinase (JNK). Taken together, our data suggest that TPL2 represents a potential therapeutic target for CDI treatment.

CDK6 inhibits white to beige fat transition by suppressing RUNX1.

Whereas white adipose tissue depots contribute to the development of metabolic diseases, brown and beige adipose tissue has beneficial metabolic effects. Here we show that CDK6 regulates beige adipocyte formation. We demonstrate that mice lacking the CDK6 protein or its kinase domain (K43M) exhibit significant increases beige cell formation, enhanced energy expenditure, better glucose tolerance, and improved insulin sensitivity, and are more resistant to high-fat diet-induced obesity. Re-expression of CDK6 in Cdk6 -/- mature or precursor cells, or ablation of RUNX1 in K43M mature or precursor cells, reverses these phenotypes. Furthermore, RUNX1 positively regulates the expression of Ucp-1 and Pgc1α by binding to proximal promoter regions. Our findings indicate that CDK6 kinase activity negatively regulates the conversion of fat-storing cells into fat-burning cells by suppressing RUNX1, and suggest that CDK6 may be a therapeutic target for the treatment of obesity and related metabolic diseases.

Gender Disparity in the Relationship between Prevalence of Thyroid Nodules and Metabolic Syndrome Components: The SHDC-CDPC Community-Based Study.

The study is aimed to investigate the pathogenesis underlying the increased prevalence of thyroid nodule (TN) in different levels of metabolic syndrome (MetS) components and analyze the relationships between TN and MetS components. A total of 6,798 subjects, including 2201 patients with TN, were enrolled in this study. Anthropometric, biochemical, thyroid ultrasonographic, and other metabolic parameters were all measured. There was obviously sexual difference in the prevalence of TN (males 26.0%, females 38.5%, resp.). The prevalence of TN in hyperuricemia (45.7% versus 37.4%, P = 0.001), NAFLD (41.2% versus 36.4%, P < 0.05), and MetS (41.4% versus 35.4%, P < 0.001) groups was significantly increased only in females. Insulin resistance [OR = 1.31 (1.15, 1.49)], MetS [OR = 1.18 (1.03, 1.35)], and diabetes [OR = 1.25 (1.06, 1.48)] were all independent risk factors for TN in total subjects, whereas, after stratified analysis of gender, MetS [OR = 1.29, (1.09, 1.53)] and diabetes [OR = 1.47, (1.17, 1.84)] are still strongly and independently associated with the higher risks of TN in female subjects, but not in males. Our results suggest that the components of MetS might associate with the higher risks of TN in women than in men, but further cohort study of this gender disparity in the association between TN and MetS is required.

Association of betatrophin with metabolic characteristics in overweight/obese and lean women with PCOS.

As a new hormone, betatrophin has gained attention as a potential new target to combat insulin resistance (IR) and diabetes. Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder among women of the reproductive age with long term sequelae which include IR and metabolic syndrome. The aim of this study is to evaluate the circulating plasma betatrophin levels in overweight/obese or lean women with or without PCOS and also to elucidate possible correlations with anthropometric and metabolic parameters. Thirty-two patients with PCOS as well as fifty-three control subjects were enrolled after obtaining informed written consent. Clinical and biochemical parameters of all subjects were determined. Plasma adiponectin, GLP-1 and betatrophin levels were measured by ELISA. Plasma betatrophin levels were significantly increased in lean patients with PCOS compared with lean and obese controls. Moreover, in PCOS group, betatrophin levels were significantly negatively correlated with waist hip ratio (WHR), fasting insulin level (FINS) and HOMA-IR, whereas, significantly positively correlated with adiponectin level. Multiple regression analysis showed that HOMA-IR was an independent factor influencing serum betatrophin levels. Further follow-up studies are needed to highlight whether and how increased betatrophin secretion play an important role in IR and carbohydrates metabolism in patients with PCOS.

Deletion of tumor progression locus 2 attenuates alcohol-induced hepatic inflammation.

BACKGROUND: The pathogenesis of alcoholic liver disease (ALD) involves the interaction of several inflammatory signaling pathways. Tumor progression locus 2 (TPL2), also known as Cancer Osaka Thyroid (COT) and MAP3K8, is a serine-threonine kinase that functions as a critical regulator of inflammatory pathways by up-regulating production of inflammatory cytokines. The present study aims to fill the gap in knowledge regarding the involvement of TPL2 in the mechanism of alcohol-induced hepatic inflammation. METHODS: Male TPL2(-/-) knockout (TPL2KO) mice and TPL2(+/+) wild-type (WT) mice were group pair-fed with Lieber-DeCarli liquid ethanol diet (EtOH diet, 27% energy from EtOH) or control diet (ctrl diet) for 4 weeks. Both histological and molecular biomarkers involved in the induction of hepatic inflammation by alcohol consumption were examined. RESULTS: Consumption of the EtOH diet in WT mice lead to a significant induction of TPL2 mRNA expression as compared with WT mice fed ctrl diet. A significant induction in inflammatory foci and steatosis was also observed in WT mice fed EtOH diet. The deletion of TPL2 significantly reduced inflammatory foci in the liver of mice consuming both ctrl and EtOH diets as compared to their respective WT controls. This reduction was associated with suppression of hepatic inflammatory gene expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) and macrophage marker F4/80. In addition, histological analysis of livers revealed that TPL2 deletion resulted in reduced steatosis in both ctrl (significant) and EtOH (non-significant) diet-fed mice as compared to their respective WT controls. CONCLUSIONS: The demonstration that TPL2 deletion attenuates alcohol-induced hepatic inflammation provides evidence of a novel role for TPL2 in the pathogenesis of ALD.

Tumor progression locus 2 ablation suppressed hepatocellular carcinoma development by inhibiting hepatic inflammation and steatosis in mice.

BACKGROUND: Tumor progression locus 2 (TPL2), a serine-threonine kinase, functions as a critical regulator of inflammatory pathways and mediates oncogenic events. The potential role of Tpl2 in nonalcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC) development remains unknown. METHODS: Both wild-type and Tpl2 knockout male mice were initiated by a hepatic carcinogen (diethylnitrosamine, i.p. with a single dose of 25 mg.kg(-1))at 2 weeks of age, and then were given the high carbohydrate diet feeding to induce hepatic steatosis, inflammation, adenoma and HCC for 24 weeks. RESULTS: Tpl2 knockout mice had significantly lower incidences of liver tumor and developed hepatocellular adenoma only, which is contrast to wild-type mice where they all developed HCC. Tpl2 knockout mice had significantly down-regulated phosphorylation of JNK and ERK, and levels of mRNA expression of pro-inflammatory cytokines (Il-1ß, Il-18, Mcp-1 and Nalp3), which correlated with the reduced incidence and number of hepatic inflammatory foci. Furthermore, Tpl2 ablation resulted in decreased hepatic steatosis and expression of de novo lipogenesis related markers (ACC, SCD1, SREBP1C and AKT phosphorylation), as well as reduction of endoplasmic reticulum stress biomarkers PERK and eIF-2a. CONCLUSION: The study revealed for the first time that Tpl2 plays a significant role in promoting HCC development by its pro-inflammatory effect, which suggested that Tpl2 could be a molecular target for HCC prevention.

Diet- and Genetically-Induced Obesity Differentially Affect the Fecal Microbiome and Metabolome in Apc1638N Mice.

Obesity is a risk factor for colorectal cancer (CRC), and alterations in the colonic microbiome and metabolome may be mechanistically involved in this relationship. The relative contribution of diet and obesity per se are unclear. We compared the effect of diet- and genetically-induced obesity on the intestinal microbiome and metabolome in a mouse model of CRC. Apc1638N mice were made obese by either high fat (HF) feeding or the presence of the Leprdb/db (DbDb) mutation. Intestinal tumors were quantified and stool microbiome and metabolome were profiled. Genetic obesity, and to a lesser extent HF feeding, promoted intestinal tumorigenesis. Each induced distinct microbial patterns: taxa enriched in HF were mostly Firmicutes (6 of 8) while those enriched in DbDb were split between Firmicutes (7 of 12) and Proteobacteria (5 of 12). Parabecteroides distasonis was lower in tumor-bearing mice and its abundance was inversely associated with colonic Il1b production (p<0.05). HF and genetic obesity altered the abundance of 49 and 40 fecal metabolites respectively, with 5 in common. Of these 5, adenosine was also lower in obese and in tumor-bearing mice (p<0.05) and its concentration was inversely associated with colonic Il1b and Tnf production (p<0.05). HF and genetic obesity differentially alter the intestinal microbiome and metabolome. A depletion of adenosine and P.distasonis in tumor-bearing mice could play a mechanistic role in tumor formation. Adenosine and P. distasonis have previously been shown to be anti-inflammatory in the colon and we postulate their reduction could promote tumorigenesis by de-repressing inflammation.

Inhibition of diethylnitrosamine-initiated alcohol-promoted hepatic inflammation and precancerous lesions by flavonoid luteolin is associated with increased sirtuin 1 activity in mice.

BACKGROUND: Chronic and excessive alcohol consumption is an established risk for hepatic inflammation and carcinogenesis. Luteolin is one of the most common flavonoids present in plants and has potential beneficial effects against cancer. In this study, we examined the effect and potential mechanisms of luteolin supplementation in a carcinogen initiated alcohol-promoted pre-neoplastic liver lesion mouse model. METHODS: C57BL/6 mice were injected with diethylnitrosamine (DEN) [i.p. 25 mg/kg of body weight (BW)] at 14 days of age. At 8 weeks of age mice were group pair-fed with Lieber-DeCarli liquid control diet or alcoholic diet [ethanol (EtOH) diet, 27% total energy from ethanol] and supplemented with a dose of 30 mg luteolin/kg BW per day for 21 days. RESULTS: DEN-injected mice fed EtOH diet displayed a significant induction of pre-neoplastic lesions, a marker associated with presence of steatosis and inflammation. Dietary luteolin significantly reduced the severity and incidence of hepatic inflammatory foci and steatosis in DEN-injected mice fed EtOH diet, as well the presence of preneoplastic lesions. There was no difference on hepatic protein levels of sirtuin 1 (SIRT1) among all groups; however, luteolin supplementation significantly reversed alcohol-reduced SIRT1 activity assessed by the ratio of acetylated and total forkhead box protein O1 (FoXO1) and SIRT1 target proliferator-activated receptor gamma, coactivator 1 alpha (PGC1α). CONCLUSIONS: Dietary intake of luteolin prevents alcohol promoted pre-neoplastic lesions, potentially mediated by SIRT1 signaling pathway.

Dietary tomato powder inhibits alcohol-induced hepatic injury by suppressing cytochrome p450 2E1 induction in rodent models.

Chronic and excessive alcohol consumption leads to the development of alcoholic liver disease (ALD) and greatly increases the risk of liver cancer. Induction of the cytochrome p450 2E1 (CYP2E1) enzyme by chronic and excessive alcohol intake is known to play a role in the pathogenesis of ALD. High intake of tomatoes, rich in the carotenoid lycopene, is associated with a decreased risk of chronic disease. We investigated the effects of whole tomato (tomato powder, TP), partial tomato (tomato extract, TE), and purified lycopene (LYC) against ALD development in rats. Of the three supplements, only TP reduced the severity of alcohol-induced steatosis, hepatic inflammatory foci, and CYP2E1 protein levels. TE had no effect on these outcomes and LYC greatly increased inflammatory foci in alcohol-fed rats. To further support the protective effect of TP against ALD, TP was supplemented in a carcinogen (diethylnitrosamine, DEN)-initiated alcohol-promoted mouse model. In addition to reduced steatosis and inflammatory foci, TP abolished the presence of preneoplastic foci of altered hepatocytes in DEN-injected mice fed alcohol. These reductions were associated with decreased hepatic CYP2E1 protein levels, restored levels of peroxisome proliferator-activated receptor-α and downstream gene expression, decreased inflammatory gene expression, and reduced endoplasmic reticulum stress markers. These data provide strong evidence for TP as an effective whole food prevention strategy against ALD.

Fatty acid elongase-5 (Elovl5) regulates hepatic triglyceride catabolism in obese C57BL/6J mice.

Nonalcoholic fatty liver disease is a major public health concern in the obese and type 2 diabetic populations. The high-fat lard diet induces obesity and fatty liver in C57BL/6J mice and suppresses expression of the PPAR-target gene, FA elongase 5 (Elovl5). Elovl5 plays a key role in MUFA and PUFA synthesis. Increasing hepatic Elovl5 activity in obese mice lowered hepatic TGs and endoplasmic reticulum stress markers (X-box binding protein 1 and cAMP-dependent transcription factor 6α) and increased TG catabolism and fatty acyl carnitines. Increased hepatic Elovl5 activity did not increase hepatic capacity for ß-oxidation. Elovl5 effects on hepatic TG catabolism were linked to increased protein levels of adipocyte TG lipase (ATGL) and comparative gene identification 58 (CGI58). Elevated hepatic Elovl5 activity also induced the expression of some (pyruvate dehydrogenase kinase 4 and fibroblast growth factor 21), but not other cytochrome P450 4A10 (CYP4A10), PPAR-target genes. FA products of Elovl5 activity increased ATGL, but not CGI58, mRNA through PPARß-dependent mechanisms in human HepG2 cells. Treatment of mouse AML12 hepatocytes with the PPARß agonist (GW0742) decreased (14)C-18:2,n-6 in TGs but did not affect ß-oxidation. These studies establish that Elovl5 activity regulates hepatic levels of FAs controlling PPARß activity, ATGL expression, and TG catabolism, but not FA oxidation.

Linoleic acid suppresses cholesterol efflux and ATP-binding cassette transporters in murine bone marrow-derived macrophages.

Individuals with type 2 diabetes mellitus (T2DM) are at increased risk of developing cardiovascular disease (CVD), possibly associated with elevated plasma free fatty acid concentrations. Paradoxically, evidence suggests that unsaturated, compared to saturated fatty acids, suppress macrophage cholesterol efflux, favoring cholesterol accumulation in the artery wall. Murine bone marrow-derived macrophages (BMDM) were used to further explore the relationship between saturated and unsaturated fatty acids, and cholesterol efflux mediated by ATP-binding cassette transporters (ABCA1 and ABCG1) through transcription factors liver-x-receptor-alpha (LXR-α) and sterol receptor element binding protein (SREBP)-1. BMDM isolated from C57BL/6 mice were exposed to 100 µM linoleic acid (18:2) or palmitic acid (16:0) for 16 h, and 25 µg/mL oxidized low density lipoprotein for an additional 24 h. ABCA1 and ABCG1 mRNA expression was suppressed to a greater extent by 18:2 (60 % and 54 %, respectively) than 16:0 (30 % and 29 %, respectively) relative to the control (all p < 0.01). 18:2 decreased ABCA1 protein levels by 94 % and high density lipoprotein (HDL) mediated cholesterol efflux by 53 % (both p < 0.05), and had no significant effect on ABCG1, LXR-α or SREBP-1 protein levels. 16:0 had no effect on ABCA1, ABCG1, LXR-α or SREBP-1 protein expression or HDL-mediated cholesterol efflux. These results suggest that 18:2, relative to 16:0, attenuated macrophage HDL-mediated cholesterol efflux through down regulation of ABCA1 mRNA and protein levels but not through changes in LXR-α or SREBP-1 expression. The effect of 18:2 relative to 16:0 on macrophages cholesterol homeostasis may exacerbate the predisposition of individuals with T2DM to increased CVD risk.

Early motion following 4-corner arthrodesis using cannulated compression screws: a biomechanical study.

PURPOSE: To assess the ability of headless compression screws to maintain immobile bony contact throughout wrist cycling following simulated 4-corner arthrodesis. Our hypothesis was that the screw constructs would not permit displacement of the carpal bones and, therefore, could tolerate early postoperative range of motion in vivo. METHODS: Using 6 matched-paired cadaveric arms, 4-corner arthrodesis was performed using an all-cannulated compression screw construct (capitolunate, lunotriquetral, and triquetrohamate screws) or a partial compression screw combined with partial K-wire construct (2 crossing capitolunate screws with the lunotriquetral and triquetrohamate interfaces immobilized with 2 K-wires). Wrists were mounted and cycled 5,000 times. Intercarpal distances were measured at 0, 100, 1,000, and 5,000 cycles at fixed points of passive flexion. Because previously published studies considered intercarpal distances of greater than 1 mm as significant, we defined fixation failure as greater than 0.5 mm gapping. RESULTS: Neither screw construct showed any significant intercarpal gapping at any point during the experimental cycling (largest average intercarpal gapping was 0.2 mm). There were no significant differences between the constructs regarding gapping at any point. CONCLUSIONS: In this biomechanical model, cannulated compression screws effectively resist significant intercarpal gapping during early motion after 4-corner arthrodesis. This may allow for immediate postoperative range of motion. CLINICAL RELEVANCE: Early gentle range of motion may be possible immediately following 4-corner arthrodesis using a construct consisting of headless compression screws.