A Drosophila model targets Eiger/TNFα to alleviate obesity-related insulin resistance and macrophage infiltration.

Obesity is associated with various metabolic disorders, such as insulin resistance and adipose tissue inflammation (ATM), characterized by macrophage infiltration into adipose cells. This study presents a new Drosophila model to investigate the mechanisms underlying these obesity-related pathologies. We employed genetic manipulation to reduce ecdysone levels to prolong the larval stage. These animals are hyperphagic and exhibit features resembling obesity in mammals, including increased lipid storage, adipocyte hypertrophy and high circulating glucose levels. Moreover, we observed significant infiltration of immune cells (hemocytes) into the fat bodies, accompanied by insulin resistance. We found that attenuation of Eiger/TNFα signaling reduced ATM and improved insulin sensitivity. Furthermore, using metformin and the antioxidants anthocyanins, we ameliorated both phenotypes. Our data highlight evolutionarily conserved mechanisms allowing the development of Drosophila models for discovering therapeutic pathways in adipose tissue immune cell infiltration and insulin resistance. Our model can also provide a platform to perform genetic screens or test the efficacy of therapeutic interventions for diseases such as obesity, type 2 diabetes and non-alcoholic fatty liver disease.

A Novel Drosophila Model to Investigate Adipose Tissue Macrophage Infiltration (ATM) and Obesity highlights the Therapeutic Potential of Attenuating Eiger/TNFα Signaling to Ameliorate Insulin Resistance and ATM.

Obesity is a global health concern associated with various metabolic disorders including insulin resistance and adipose tissue inflammation characterized by adipose tissue macrophage (ATM) infiltration. In this study, we present a novel Drosophila model to investigate the mechanisms underlying ATM infiltration and its association with obesity-related pathologies. Furthermore, we demonstrate the therapeutic potential of attenuating Eiger/TNFα signaling to ameliorate insulin resistance and ATM. To study ATM infiltration and its consequences, we established a novel Drosophila model (OBL) that mimics key aspects of human adipose tissue and allows for investigating ATM infiltration and other related metabolic disorders in a controlled experimental system. We employed genetic manipulation to reduce ecdysone levels to prolong the larval stage. These animals are hyperphagic, and exhibit features resembling obesity in mammals, including increased lipid storage, adipocyte hypertrophy, and high levels of circulating glucose. Moreover, we observed a significant infiltration of immune cells (hemocytes) in the fat bodies accompanied by insulin resistance and systemic metabolic dysregulation. Furthermore, we found that attenuation of Eiger/TNFα signaling and using metformin and anti-oxidant bio-products like anthocyanins led to a reduction in ATM infiltration and improved insulin sensitivity. Our data suggest that the key mechanisms that trigger immune cell infiltration into adipose tissue are evolutionarily conserved and may provide the opportunity to develop Drosophila models to better understand pathways critical for immune cell recruitment into adipose tissue, in relation to the development of insulin resistance in metabolic diseases such as obesity and type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). We believe that our OBL model can also be a valuable tool and provide a platform either to perform genetic screens or to test the efficacy and safety of novel therapeutic interventions for these diseases.

Can Calprotectin Show Subclinical Inflammation in Familial Mediterranean Fever Patients?

BACKGROUND: Familial Mediterranean fever (FMF) is an autoinflammatory disease that has self-limiting inflammatory attacks during polyserositis. Hepcidin is a protein, and interleukin-6 stimulation increases hepcidin levels. Calprotectin (CLP) is a recently defined cytokine released from monocytes and neutrophils in response to tissue trauma and inflammation. There are studies in the literature showing that it can be used as a biomarker in rheumatic diseases such as ankylosing spondylitis and rheumatoid arthritis. Here, we compared the levels of hepcidin and CLP in healthy individuals and FMF patients during an attack-free period and show its relation to genetic mutations. METHODS: This is a cross-sectional study. Between July 2017 and December 2017, 60 patients diagnosed with FMF an admitted to the Cumhuriyet University Faculty of Medicine Department of Internal Medicine Rheumatology as well as 60 healthy volunteers without any rheumatic, systemic, or metabolic diseases were enrolled in this study. Blood was collected from a peripheral vein to measure serum CLP and hepcidin levels. Blood tests were examined by ELISA; the study protocol was approved by the local ethics committee. RESULTS: Median serum hepcidin level was 468.1 (210.3-807.8) pg/mL in FMF group and 890.0 (495.0-1,716.9) pg/mL in the healthy control (HC) group. There was a statistically significant difference between the two groups (P < 0.001). The median serum levels of CLP in the FMF group were measured as 1,331.4 (969.3-1,584.6 pg/mL and 73.8(45.0-147.9) pg/mL in the HC group. There was a statistically significant difference between the two groups (P < 0.001). Receiver operating characteristic analysis showed that the sensitivity was 66.7% and the specificity was 71.7% at serum hepcidin < 581.25 pg/mL (P < 0.05); the sensitivity was 96.7% and specificity was 100% at CLP > 238 pg/mL (P < 0.05). There was no significant difference between serum hepcidin and CLP levels in FMF patients with M694V homozygous and M694V heterozygous (P > 0.05). There was no significant difference in serum hepcidin levels between FMF patients with and without arthritis, proteinuria, and amyloidosis (P < 0.05). There was no significant correlation between laboratory findings, gender, age, and serum CLP and hepcidin levels (P > 0.05, r < 0.25). CONCLUSION: Serum CLP levels in FMF patients during an attack-free period are significantly higher than in the HC groups. Serum hepcidin levels in FMF patients are significantly lower than in the HC group. Low levels of hepcidin may be explained by including FMF patients during an attack-free period in the study. CLP may be an important biomarker in FMF. A better understanding of the role of these biomarkers in the diagnosis of FMF is needed to evaluate the results in a more comprehensive way.

High prolidase levels in patients with Familial Mediterranean Fever (FMF).

INTRODUCTION: Familial Mediterranean Fever (FMF) is an autoinflammatory disease. Prolidase is a specific imidodipeptidase that plays a role in collagen degradation, and an important role in inflammation and wound healing. Hypoxia-inducible factor-1α (HIF-1) is an important protein in the regulation of immunological response, hemostasis, vascularization. The aim of the study was to compare serum prolidase and HIF-1α levels in patients with FMF in attack-free period and healthy control group. METHODS: Between August 2017 and December 2017, sixty patients diagnosed with FMF according to the criteria of the Tel-hashomer and admitted to Sivas Cumhuriyet University Medical Faculty, Internal Medicine Rheumatology Department and sixty healthy volunteers were enrolled in the study. RESULTS: Median serum prolidase levels were 72.1 (25.1-114.9) ng/ml in FMF group and 30.7 (21.3-86.2) ng/mL in healthy control (HC) group (p = 0.018). ROC analysis showed that the sensitivity was 65% and the specificity was 68.3% at serum prolidase levels 54.03 ng/mL (p < 0.05). The median serum levels of HIF-1α in the FMF group was 482.0 (292.0-3967.0) pg/mL and 632.0 (362.0-927.0) pg/mL in the HC group (p > 0.05). There was no significant correlation between laboratory findings, sex, age, and prolidase (p > 0.05). CONCLUSION: Serum prolidase enzyme levels in FMF patients with attack-free period were significantly higher than in the HC group. However, the role of prolidase and HIF1-α in the FMF disease needs to be clarified with more extensive and comprehensive studies.

The Effects of Tofacitinib-Mediated Janus Kinase/Signal Transducers and Activators of the Transcription Signal Pathway Inhibition on Collagen Biosynthesis in Hepatic and Skin Fibroblast Cell Culture.

OBJECTIVES: This study aims to investigate the effects of Janus kinase/signal transducers and activators of the transcription (JAK/STAT) pathway inhibition on collagen biosynthesis in fibroblast cell culture by tofacitinib. MATERIALS AND METHODS: BJ-CRL-1474® (skin) and BRL3A® (hepatic) fibroblast cell cultures were proliferated in a suitable medium. Tofacitinib was administered to fibroblast cells proliferating in 96-well flasks at concentrations of 25, 50, 100, 200, 400, and 800 nM. Tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-3 (MMP-3), transforming growth factor beta 1 (TGF-ß1), and hydroxyproline levels were measured using the enzyme-linked immunosorbent assay method. RESULTS: Tofacitinib showed cytotoxic effect on skin and liver cell culture. The cytotoxic effect of tofacitinib started at 100 nM (p<0.05). The highest effect was obtained at 800 nM. The time-dependent cytotoxic effect of tofacitinib was significantly higher at all concentrations after 72 hours than at 24 and 48 hours (p<0.05). The level of TGF-ß1 was significantly lower even at a tofacitinib concentration of 25 nM (p<0.05). There were significant decreases in MMP-3, TIMP-1, and hydroxyproline levels after tofacitinib administration (p<0.05). CONCLUSION: Tofacitinib inhibited fibroblast cell proliferation in a concentration-dependent manner in a fibroblast cell culture. However, further extensive animal and human studies are necessary to determine the clinical significance of this effect.

Low levels of pannexin-1 in Behçet's syndrome.

OBJECTIVE: Behçet's syndrome (BS) is a chronic, multisystemic and inflammatory syndrome. In our study, we aimed to compare the initiator, effector and inflammatory caspases and pannexin channel protein, which is thought to have an activity in inflammation, in the inflammatory process of BS, with healthy subjects, to investigate their level in patients and their relationship with the clinical findings. METHOD: Forty-six patients who were under follow-up for BS in the Sivas Cumhuriyet University Medical Faculty Department of Internal Diseases, Rheumatology Unit, between January 2017 and June 2017 and 44 healthy controls (HC) who did not have any rheumatic, systemic or metabolic diseases, were enrolled in this study. RESULTS: The mean serum pannexin-1 level was 6.36 (4.21-527.2) pg/mL in the BS group and 255.8 (5.38-2000) pg/mL in the HC group. Serum pannexin-1 levels were statistically significantly lower in the BS group (P < 0.0001). The measured mean serum caspase-3 level was 12.04 (11.25-43.69) pg/mL in the group with BS and 12.1 (11.19-484.3) pg/mL in the HC group (P = 0.143), mean serum caspase-9 level was 22 (5.14-29.33) pg/mL in the BS group and 22.01 (11.23-850) pg/mL in the HC group (P = 0.593), mean serum caspase-14 level was 6 (5.2-8.21) pg/mL in the BS group and 6.15 (5.7-353) pg/mL in the HC group (P = 0.053). CONCLUSION: Comparison of serum caspase-3, caspase-9 and caspase-14 levels in subjects with BS and in the HC group did not reveal any statistically significant differences. On the other hand, serum pannexin-1 levels were statistically significantly lower in the BS group.

A Multicenter Pilot Study of Burden Among Caregivers of Geriatric Rehabilitation Patients With Neuromusculoskeletal Diseases.

PURPOSE: In this study, we aimed to describe the sociodemographic characteristics of caregivers of patients in a geriatric unit and to clarify the relationship between caregiver burden and specific clinical variables in the patients and the characteristics of the caregivers. DESIGN: Cross-sectional multicenter study. METHODS: One hundred twenty-three patients and 123 caregiver dyads, with mean ages of 72.5 ± 7.7 years and 51 ± 14.7 years, respectively, were included. The functional, psychological, and cognitive statuses of the patients were determined, and the sociodemographic characteristics of the caregivers as well as the type and duration of caregiving were recorded. Caregivers completed the Caregiver Burden Inventory (CBI) to measure the perceived burden of care. Most patients were female and generally lived with their family. FINDINGS: Most of the caregivers were family members (90%), female (73.2%), primary school graduates (52.8%), and first-degree relatives (73.1%). The average CBI score was 33, and the highest CBI subscores were for time, developmental, and physical burdens. Caregiver burden correlated with the patient's ambulatory, psychological, and cognitive status and with the caregiver's age, gender, income level, and duration of caregiving. CONCLUSIONS: We have highlighted the relationship between caregiver and patient characteristics in a cohort of elderly Turkish patients with neurological and musculoskeletal disorders. In particular, we have highlighted the heavy caregiver burden in a developing country. CLINICAL RELEVANCE: Our results may guide the nurses to understand the requirements of caregivers and to help them find suitable resources that would meet their needs to cope with their burden.

The effect of hip and knee exercises on pain, function, and strength in patientswith patellofemoral pain syndrome: a randomized controlled trial.

BACKGROUND/AIM: The role of hip muscles in the rehabilitation of patellofemoral pain syndrome has recently received interest. The aim of this study was to compare the efficiencies of hip exercises alongside knee exercises versus only knee exercises on pain, function, and isokinetic muscle strength in patients with this syndrome. MATERIALS AND METHODS: Fifty-five young female patients (mean age: 34.1 ± 6.2 years; mean BMI: 25.9 ± 3.9 kg/m2) with patellofemoral pain syndrome were included. The patients were randomized into groups of hip-and-knee exercises and knee-only exercise programs for 6 weeks with a total of 30 sessions at the clinic. Both groups were evaluated before therapy, after 6 weeks of a supervised exercise program, and after 6 weeks of an at-home exercise program. The outcome measures were muscle strength, pain, and both subjective and objective function. RESULTS: The improvements of the patients in the hip-and-knee exercise group were better than in patients of the knee-only exercise group in terms of scores of pain relief (P < 0.001) and functional gain (P = 0.002) after 12 weeks. CONCLUSION: We suggest additional hip-strengthening exercises to patients with patellofemoral pain syndrome in order to decrease pain and increase functional status.

Antioxidant and Anti-quorum Sensing Potential of Acer monspessulanum subsp. monspessulanum Extracts.

In this study, anti-quorum sensing, and antioxidant activities, and chemical composition of Acer monspessulanum subsp. monspessulanum extracts were evaluated. Determination of the antioxidant activity was revealed by DPPH radical scavenging activity, the total phenolic content assay, and the ß-carotene/linoleic acid assay. The detection of phenolic compounds was determined using RP-HPLC. Anti-quorum sensing activity and violacein inhibition activity were determined using Chromobacterium violaceum CV026 and C. violaceum ATCC 112 472, respectively. The determination of anti-swarming activity was carried out with Pseudomonas aeruginosa PA01. In DPPH and total phenolic content assays, the water extract exhibited good antioxidant activity. In the ß-carotene-linoleic acid assay, ethyl acetate and ethanol extracts exhibited good lipid peroxidation inhibition activity, demonstrating 96.95 ± 0.03 % and 95.35 ± 0.00 % at 2.5 mg/mL concentrations, respectively. The predominant phenolic compounds of the extracts were determined as rutin, naringin, catechin hydrate, quercetin, and protocatechuic acid. Ethyl acetate and ethanol extracts were found to contain a high level of violacein inhibition and anti-quorum sensing activity. The ethanol extract also showed weak anti-swarming activity. In this first study that used Acer monspessulanum subsp. monspessulanum extracts, it was revealed that the water extract has antioxidant activity and the ethanol and ethyl acetate extracts have anti-quorum sensing activity depending on the phenolic compounds that it contained.

Presepsin Levels of Patients with Crimean-Congo Hemorrhagic Fever.

Levels of presepsin (a soluble cluster of differentiation subtype 14 [CD14]) are thought to increase in cases of bacterial infection. CD14 has also been found to play a role in the pathogenesis of various viral diseases. Crimean-Congo hemorrhagic fever (CCHF) is a zoonotic arboviral infection. Our study focuses on presepsin levels as a biomarker for CCHF. Serum presepsin levels in a CCHF group (n = 59) and control group (n = 28) were compared. Patients with CCHF were classified according to severity grading score as having mild, moderate, or severe infection and were allocated to corresponding subgroups (groups 1, 2, and 3, respectively). Presepsin levels were measured in serum samples by using a commercial enzyme-linked immunosorbent assay kit. The mean presepsin levels in the CCHF group as a whole and the healthy group were found to be significantly different (1,499.46 ± 411.96 pg/ml and 430.68 ± 61.21 pg/ml, respectively). The mean presepsin levels of the CCHF subgroups (1, 2 and 3) and the healthy group were also found to be significantly different (1,204.53 ± 371.18, 1,464.21 ± 338.37, 2,007.36 ± 82.18, and 430.68 ± 61.21 pg/ml, respectively) (p < 0.05). We also found that as the severity of the disease increased, the presepsin level also increased. We postulate that the presepsin levels could be used as a supportive biomarker for diagnosis and follow-up of the disease.

Rheumatoid Arthritis and Familial Mediterranean Fever or Sacroiliitis Accompanied by FMF.

The coexistence of rheumatoid arthritis (RA) and familial Mediterranean fever (FMF) has been rarely seen in case reports in the literature. Herein, we wanted to present a patient who had been followed up and treated as RA, but on investigation we concluded that he really had FMF and its joint complaints associated with sacroiliitis. Recovery was achieved by etanercept administered as if he was an RA patient.

Foot problems in a group of patients with rheumatoid arthritis: an unmet need for foot care.

OBJECTIVES: The aim of this study was to evaluate the foot involvement in a group of RA patients in regard to symptoms, type and frequency of deformities, location, radiological changes, and foot care. PATIENTS AND METHODS: A randomized selected 100 rheumatoid arthritis (RA) patients were recruited to the study. Data about foot symptoms, duration and location of foot pain, pain intensity, access to services related to foot, treatment, orthoses and assistive devices, and usefulness of therapies were determined by the questionnaire. Radiological changes were assessed according to modified Larsen scoring system. The scores of disease activity scale of 28 joints and Health Assessment Questionnaire indicating the functional status of RA patients were collected from patient files. RESULTS: A total of 100 RA patients (90 female, 10 male) with a mean age of 52.5 ±10.9 years were enrolled to the study. Eighty-nine of the 100 patients had experienced foot complaints/symptoms in the past or currently. Foot pain and foot symptoms were reported as the first site of involvement in 14 patients. Thirty-six patients had ankle pain and the most common sites of the foot symptoms were ankle (36%) and forefoot (30%) followed by hindfoot (17%) and midfoot (7%) currently. Forty-nine of the patients described that they had difficulty in performing their foot care. Insoles and orthopedic shoes were prescribed in 39 patients, but only 14 of them continued to use them. The main reasons for not wearing them were; 17 not helpful (43%), 5 made foot pain worse (12.8%), and 3 did not fit (7.6%). Foot symptoms were reported to be decreased in 24 % of the subjects after the medical treatment and 6 patients indicated that they had underwent foot surgery. Current foot pain was significantly associated with higher body mass index and longer disease duration, and duration of morning stiffness. The radiological scores did not correlate with duration of foot symptoms and current foot pain (p>0.05) but the total number of foot deformities was found to be correlated with Larsen scores (p<0.05). CONCLUSION: In our study, foot involvement and foot symptoms were seen frequently in RA but there is an unmet need for provision and monitoring of foot care in patients suffering from this chronic disease.