The effect of greater occipital nerve block on amplification of somatic symptoms and anxiety and depression levels in chronic migraine.

OBJECTIVES: It is known that chronic migraine (CM) is often accompanied by anxiety, depression, and psychosomatic complaints. We designed this study with the assumption that greater occipital nerve (GON) block treatment could potentially improve not only pain symptoms but also psychosomatic complaints. This study aimed to evaluate the changes in the visual analog scale (VAS), somatosensory amplification scale (SSAS), beck depression inventory (BDI), and beck anxiety inventory (BAI) with GON block treatment in patients with CM. METHODS: This study was conducted retrospectively on 164 patients with CM between December 2018 and January 2023. Patients underwent six sessions of GON block treatment at weeks 0, 1, 2, 3, 5, and 7. VAS, SSAS, BAI, and BDI scores; number of attacks per month (NAM); attack pain duration (APD); and monthly use of analgesics (UA) were compared before the start and at week 8 of GON block treatment. RESULTS: The mean age of the subjects was 38 ± 9 years. Statistical analysis revealed that VAS, SSAS, BAI, and BDI scores; NAM; APD; and monthly UA were statistically significantly lower following GON block treatment than before GON block treatment (p < 0.001 each). CONCLUSION: GON block treatment was effective for pain and somatic complaints (amplification of physical symptoms), anxiety, and depressive symptoms accompanying CM in patients with CM.

Investigation of the effects of upper extremity home exercises on grip strength, range of motion, activity performance, and functionality in individuals with systemic sclerosis: a randomized controlled trial.

OBJECTIVE: This study aimed to investigate the effects of upper extremity home exercises on grip strength, range of motion, activity performance, and functionality in individuals with systemic sclerosis and to compare with patient education. METHODS: A total of 46 individuals with systemic sclerosis (55.52±11.54 years) were included. Individuals were randomly assigned into intervention (n=23) and control (n=23) groups. Dynamometer, goniometer, Canadian Occupational Performance Measurement, Disabilities of the Arm, Shoulder, and Hand, Score for Assessment and Quantification of Chronic Rheumatic Affections of the Hands, and Duruoz Hand Index were used for evaluation. RESULTS: Post-treatment, in terms of delta (Δ) values, hand grip and pinch strengths (p: 0.000-0.016), active (p: 0.000-0.032) and passive (p: 0.000-0.043) total range of motions, Canadian Occupational Performance Measurement performance and satisfaction, Disabilities of the Arm, Shoulder, Score for Assessment and Quantification of Chronic Rheumatic Affections of the Hands, and Duruoz Hand Index (p: 0.000) were in favor of the intervention group. CONCLUSION: Upper extremity home exercises increase grip strength, range of motion, activity performance, and functionality in patients with systemic sclerosis. We recommend that rehabilitation programs include not only hand exercises but also upper extremity exercises.

Investigation of the effects of upper extremity home exercises on grip strength, range of motion, activity performance, and functionality in individuals with systemic sclerosis: a randomized controlled trial

SUMMARY OBJECTIVE: This study aimed to investigate the effects of upper extremity home exercises on grip strength, range of motion, activity performance, and functionality in individuals with systemic sclerosis and to compare with patient education. METHODS: A total of 46 individuals with systemic sclerosis (55.52±11.54 years) were included. Individuals were randomly assigned into intervention (n=23) and control (n=23) groups. Dynamometer, goniometer, Canadian Occupational Performance Measurement, Disabilities of the Arm, Shoulder, and Hand, Score for Assessment and Quantification of Chronic Rheumatic Affections of the Hands, and Duruoz Hand Index were used for evaluation. RESULTS: Post-treatment, in terms of delta (Δ) values, hand grip and pinch strengths (p: 0.000-0.016), active (p: 0.000-0.032) and passive (p: 0.000-0.043) total range of motions, Canadian Occupational Performance Measurement performance and satisfaction, Disabilities of the Arm, Shoulder, Score for Assessment and Quantification of Chronic Rheumatic Affections of the Hands, and Duruoz Hand Index (p: 0.000) were in favor of the intervention group. CONCLUSION: Upper extremity home exercises increase grip strength, range of motion, activity performance, and functionality in patients with systemic sclerosis. We recommend that rehabilitation programs include not only hand exercises but also upper extremity exercises.

Investigation of the relationship between sexual and pelvic floor dysfunction in female patients with fibromyalgia syndrome.

The aim of the study was to examine the relationship between pelvic floor functions and sexual functions in women with fibromyalgia. The study included 204 women with fibromyalgia, mean aged 43.43 ± 8.61 years. All patients who met the inclusion criteria and applied to the rheumatology outpatient clinic were included in the study. The study was conducted between September 2020 and June 2022. The Female Sexual Function Scale (FSFI) was used to evaluate sexual function, Pelvic Floor Distress Scale-20 (PFDI-20), Pelvic Floor Impact Questionnaire (PFIQ-7) and Pelvic Organ Prolapse/Incontinence Sexual Function Assessment (PSIQ-12) were used to evaluate pelvic floor problems. The relationship between sexual dysfunction and other parameters was analyzed using Spearman correlation analysis. There was a weak negative correlation between many sub-parameters of FSFI and scores of PFDI-20, PFIQ-7, PSIQ-12 (r:-0.165--0.377 p: 0.02-0.00). According to the results of this study, sexual dysfunction was negatively affected by pelvic floor dysfunction and symptoms related to bladder, bowel, and pelvic organs in women with fibromyalgia. These results may suggest that sexual function and pelvic floor problems in women with fibromyalgia should be considered together and an approach should be planned for such problems in treatment programs.

Design and synthesis of new heterocyclic compounds containing 5-[(1H-1,2,4-triazol-1-yl)methyl]-3H-1,2,4-triazole-3-thione structure as potent hEGFR inhibitors.

EGFR is one of the important mediators of the signaling cascade that determines key roles in various biological processes such as growth, differentiation, metabolism and apoptosis in the cell in response to external and internal stimuli. In recent years, it has been proven that although this enzyme activity is tightly regulated in normal cells, if the enzyme activity cannot be controlled, it can lead to malignancy. EGFR is also considered a prominent macromolecule in targeted cancer chemotherapy. For this purpose, a comprehensive modeling studies were conducted against EGFR protein and novel molecules containing 5-[(1H-1,2,4-triazol-1-yl)methyl]-3H-1,2,4-triazole-3-thione structure were suggested to be synthesized. Among the synthesized molecules, compounds 7c, 8c, 8f and 8g were determined to have significant IC50 values. Compound 8g was found to have the IC50 value closest to the very well-known EGFR inhibitor Gefitinib with its noncompetitive inhibition form. Ki value of compound 8g was calculated as 0.00232 µM.Communicated by Ramaswamy H. Sarma.

Comparison of Dementia Patients Admission Rates and Dementia Characteristics Before and During the COVID-19 Pandemic.

Background The coronavirus disease 2019 (COVID-19) epidemic was recognized as a pandemic by the World Health Organization on March 2020. There have been significant changes in our lives due to the measures used to prevent the spread of the COVID-19 pandemic. Dementia patients are one of the most vulnerable groups who have difficulties in adapting to this situation. Our study aimed to compare the admission rate to the hospital and dementia characteristics of dementia patients in the COVID-19 pandemic and pre-pandemic periods. Methods Dementia patients admitted to the neurology outpatient clinic during the pandemic and pre-pandemic periods were included in the study. In these two periods, age, gender, dementia type, stage, age of onset, mini-mental state examination, reason for admission, vitamin B12, vitamin D, folic acid levels, brain imaging, electroencephalogram results were analysed retrospectively. Dementia characteristics and vitamin levels were compared. Results Two hundred and two dementia patients were included in the study. When the reasons for admission to the hospital were examined, the number of applications with the complaint of forgetfulness was highest in the pre-COVID period (53.1%); this rate was 37.8% in the COVID period. Also, 9.5% of patients were admitted for a drug prescription or medication report during the COVID period, while this rate was 1.6% in the pre-COVID period. Brain imaging was performed on 91 patients in the pre-COVID period, while 42 patients underwent imaging in the COVID period. Conclusions Although this study was performed with a limited population, it indicates that the COVID-19 pandemic indirectly affects the clinical conditions of people living with dementia.

Novel complication of Flakka: Stevens-Johnson syndrome/Toxic epidermal necrolysis overlap.

Flakka, as the newest member of the synthetic cathinone group, is a substance with serious cardiovascular, neurological, psychiatric, infectious effects and addictive potential. There are only a few case reports and laboratory studies in the literature and there is no dermatological side effects reported yet. We present the first Stevens-Johnson syndrome/Toxic epidermal necrolysis (SJS/TEN) overlap case after Flakka use.

Mitochondrial DNA variants of Podolian cattle breeds testify for a dual maternal origin.

BACKGROUND: Over the past 15 years, 300 out of 6000 breeds of all farm animal species identified by the Food and Agriculture Organization of the United Nations (FAO) have gone extinct. Among cattle, many Podolian breeds are seriously endangered in various European areas. Podolian cattle include a group of very ancient European breeds, phenotypically close to the aurochs ancestors (Bos primigenius). The aim of the present study was to assess the genetic diversity of Podolian breeds and to reconstruct their origin. METHODOLOGY: The mitochondrial DNA (mtDNA) control-regions of 18 Podolian breeds have been phylogenetically assessed. Nine non-Podolian breeds have been also included for comparison. CONCLUSION: The overall analysis clearly highlights some peculiarities in the mtDNA gene pool of some Podolian breeds. In particular, a principal component analysis point to a genetic proximity between five breeds (Chianina, Marchigiana, Maremmana, Podolica Italiana and Romagnola) reared in Central Italy and the Turkish Grey. We here propose the suggestive hypothesis of a dual ancestral contribution to the present gene pool of Podolian breeds, one deriving from Eastern European cattle; the other arising from the arrival of Middle Eastern cattle into Central Italy through a different route, perhaps by sea, ferried by Etruscan boats. The historical migration of Podolian cattle from North Eastern Europe towards Italy has not cancelled the mtDNA footprints of this previous ancient migration.

FGF5 is expressed in melanoma and enhances malignancy in vitro and in vivo.

Although FGF5 mRNA was previously found expressed in some melanoma cell lines in contrast to normal human melanocytes, neither its contribution to melanoma growth nor its expression in melanoma tissue has been investigated. Here we demonstrate that ectopic overexpression of FGF5 in human melanoma cells with low endogenous FGF5 expression increased clonogenicity and invasion but not short-term growth in vitro. Silencing of FGF5 in melanoma cells with high endogenous FGF5 expression had the opposite effect on clonogenicity. FGF overexpression led to increased signaling along the MAPK and NFAT axis but had no effect on STAT3 signaling. In an in vivo experiment in immunocompromised mice, human melanoma xenografts overexpressing FGF5 showed enhanced tumor growth, a higher Ki-67 proliferation index, decreased apoptosis and enhanced angiogenesis. Immunohistochemistry performed on a tissue microarray demonstrated FGF5 protein expression in more than 50% of samples of melanoma and benign nevi. These data suggest that FGF5 has oncogenic potential in melanoma cells and contributes to melanoma growth in a subset of patients. This highlights the importance of further evaluating FGF5 as potential biomarker and therapy target in melanoma.

MicroRNA-146a governs fibroblast activation and joint pathology in arthritis.

Synovial fibroblasts are key cells orchestrating the inflammatory response in arthritis. Here we demonstrate that loss of miR-146a, a key epigenetic regulator of the innate immune response, leads to increased joint destruction in a TNF-driven model of arthritis by specifically regulating the behavior of synovial fibroblasts. Absence of miR-146a in synovial fibroblasts display a highly deregulated gene expression pattern and enhanced proliferation in vitro and in vivo. Deficiency of miR-146a induces deregulation of tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) in synovial fibroblasts, leading to increased proliferation. In addition, loss of miR-146a shifts the metabolic state of fibroblasts towards glycolysis and augments the ability of synovial fibroblasts to support the generation of osteoclasts by controlling the balance of osteoclastogenic regulatory factors receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG). Bone marrow transplantation experiments confirmed the importance of miR-146a in the radioresistant mesenchymal compartment for the control of arthritis severity, in particular for inflammatory joint destruction. This study therefore identifies microRNA-146a as an important local epigenetic regulator of the inflammatory response in arthritis. It is a central element of an anti-inflammatory feedback loop in resident synovial fibroblasts, who are orchestrating the inflammatory response in chronic arthritis. MiR-146a restricts their activation, thereby preventing excessive tissue damage during arthritis.

Acyclovir-induced bullous reaction in a patient with metastatic breast cancer.

Acyclovir is a synthetic guanosine analog, which is a potent and highly selective inhibitor of the DNA polymerases of several herpes viruses. Acyclovir is known as a relatively safe drug with few significant adverse effects, of which nephrotoxicity seems to be the most dreaded one. On the other hand, inflammation and phlebitis at the injection site have been reported to be the most frequent side effects of intravenous acyclovir administration. Although exceptionally rare, there have been case reports of bullous eruption occurring after intravenous acyclovir therapy, a similar of which we have also observed. Here, we present a case of localized bullous eruption and phlebitis associated with intravenous acyclovir treatment in a patient with metastatic breast cancer. Our case distinctively demonstrated two consequential juxtaposing vesiculobullous lesions and phlebitis manifesting as erythema along the course of a vein after intravenous acyclovir injection. We emphasize this hardly known side effect and importance of early recognition and appropriate management of unpredictable side effects of widely used medications.

Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis.

Multiple sclerosis (MS) is the most common autoimmune disease affecting the central nervous system. It is characterized by auto-reactive T cells that induce demyelination and neuronal degradation. Treatment options are still limited and several MS medications need to be administered by parenteral application but are modestly effective. Oral active drugs such as fingolimod have been weighed down by safety concerns. Consequently, there is a demand for novel, especially orally active therapeutics. Nature offers an abundance of compounds for drug discovery. Recently, the circular plant peptide kalata B1 was shown to silence T-cell proliferation in vitro in an IL-2-dependent mechanism. Owing to this promising effect, we aimed to determine in vivo activity of the cyclotide [T20K]kalata B1 using the MS mouse model experimental autoimmune encephalomyelitis (EAE). Treatment of mice with the cyclotide resulted in a significant delay and diminished symptoms of EAE by oral administration. Cyclotide application substantially impeded disease progression and did not exhibit adverse effects. Inhibition of lymphocyte proliferation and the reduction of proinflammatory cytokines, in particular IL-2, distinguish the cyclotide from other marketed drugs. Considering their stable structural topology and oral activity, cyclotides are candidates as peptide therapeutics for pharmaceutical drug development for treatment of T-cell-mediated disorders.

Sustained PI3K Activation exacerbates BLM-induced Lung Fibrosis via activation of pro-inflammatory and pro-fibrotic pathways.

Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease with limited treatment options. Additionally, the lack of a complete understanding of underlying immunological mechanisms underscores the importance of discovering novel options for therapeutic intervention. Since the PI3K/PTEN pathway in myeloid cells influences their effector functions, we wanted to elucidate how sustained PI3K activity induced by cell-type specific genetic deficiency of its antagonist PTEN modulates IPF, in a murine model of bleomycin-induced pulmonary fibrosis (BIPF). We found that myeloid PTEN deficient mice (PTEN(MyKO)), after induction of BIPF, exhibit increased TGF-ß1 activation, mRNA expression of pro-collagens and lysyl oxidase as well as augmented collagen deposition compared to wild-type littermates, leading to enhanced morbidity and decreased survival. Analysis of alveolar lavage and lung cell composition revealed that PTEN(MyKO) mice exhibit reduced numbers of macrophages and T-cells in response to bleomycin, indicating an impaired recruitment function. Interestingly, we found dysregulated macrophage polarization as well as elevated expression and release of the pro-fibrotic cytokines IL-6 and TNF-α in PTEN(MyKO) mice during BIPF. This might point to an uncontrolled wound healing response in which the inflammatory as well as tissue repair mechanisms proceed in parallel, thereby preventing resolution and at the same time promoting extensive fibrosis.

Phosphatase and tensin homolog (PTEN) in antigen-presenting cells controls Th17-mediated autoimmune arthritis.

INTRODUCTION: Autoreactive T cells are a central element in many systemic autoimmune diseases. The generation of these pathogenic T cells is instructed by antigen-presenting cells (APCs). However, signaling pathways in APCs that drive autoimmune diseases, such as rheumatoid arthritis, are not understood. METHODS: We measured phenotypic maturation, cytokine production and induction of T cell proliferation of APCs derived from wt mice and mice with a myeloid-specific deletion of PTEN (myeloid PTEN(-/-)) in vitro and in vivo. We induced collagen-induced arthritis (CIA) and K/BxN serum transfer arthritis in wt and myeloid-specific PTEN(-/-) mice. We measured the cellular composition of lymph nodes by flow cytometry and cytokines in serum and after ex vivo stimulation of T cells. RESULTS: We show that myeloid-specific PTEN(-/-) mice are almost protected from CIA. Myeloid-specific deletion of PTEN leads to a significant reduction of cytokine expression pivotal for the induction of systemic autoimmunity such as interleukin (IL)-23 and IL-6, leading to a significant reduction of a Th17 type of immune response characterized by reduced production of IL-17 and IL-22. In contrast, myeloid-specific PTEN deficiency did not affect K/BxN serum transfer arthritis, which is independent of the adaptive immune system and solely depends on innate effector functions. CONCLUSIONS: These data demonstrate that the presence of PTEN in myeloid cells is required for the development of CIA. Deletion of PTEN in myeloid cells inhibits the development of autoimmune arthritis by preventing the generation of a pathogenic Th17 type of immune response.

Loss of Phosphatase and Tensin Homolog in APCs Impedes Th17-Mediated Autoimmune Encephalomyelitis.

The PI3K signaling cascade in APCs has been recognized as an essential pathway to initiate, maintain, and resolve immune responses. In this study, we demonstrate that a cell type-specific loss of the PI3K antagonist phosphatase and tensin homolog (PTEN) in myeloid cells renders APCs toward a regulatory phenotype. APCs deficient for PTEN exhibit reduced activation of p38 MAPK and reduced expression of T cell-polarizing cytokines. Furthermore, PTEN deficiency leads to upregulation of markers for alternative activation, such as Arginase 1, with concomitant downregulation of inducible NO synthase in APCs in vitro and in vivo. As a result, T cell polarization was dysfunctional in PTEN(-/-) APCs, in particular affecting the Th17 cell subset. Intriguingly, mice with cell type-specific deletions of PTEN-targeting APCs were protected from experimental autoimmune encephalomyelitis, which was accompanied by a pronounced reduction of IL-17- and IL-22-producing autoreactive T cells and reduced CNS influx of classically activated monocytes/macrophages. These observations support the notion that activation of the PI3K signaling cascade promotes regulatory APC properties and suppresses pathogenic T cell polarization, thereby reducing the clinical symptoms and pathology of experimental autoimmune encephalomyelitis.

The MAPK-Activated Kinase MK2 Attenuates Dendritic Cell-Mediated Th1 Differentiation and Autoimmune Encephalomyelitis.

Dendritic cell (DC)-mediated inflammation induced via TLRs is promoted by MAPK-activated protein kinase (MK)-2, a substrate of p38 MAPK. In this study we show an opposing role of MK2, by which it consolidates immune regulatory functions in DCs through modulation of p38, ERK1/2-MAPK, and STAT3 signaling. During primary TLR/p38 signaling, MK2 mediates the inhibition of p38 activation and positively cross-regulates ERK1/2 activity, leading to a reduction of IL-12 and IL-1α/ß secretion. Consequently, MK2 impairs secondary autocrine IL-1α signaling in DCs, which further decreases the IL-1α/p38 but increases the anti-inflammatory IL-10/STAT3 signaling route. Therefore, the blockade of MK2 activity enables human and murine DCs to strengthen proinflammatory effector mechanisms by promoting IL-1α-mediated Th1 effector functions in vitro. Furthermore, MK2-deficient DCs trigger Th1 differentiation and Ag-specific cytotoxicity in vivo. Finally, wild-type mice immunized with LPS in the presence of an MK2 inhibitor strongly accumulate Th1 cells in their lymph nodes. These observations correlate with a severe clinical course in DC-specific MK2 knockout mice compared with wild-type littermates upon induction of experimental autoimmune encephalitis. Our data suggest that MK2 exerts a profound anti-inflammatory effect that prevents DCs from prolonging excessive Th1 effector T cell functions and autoimmunity.

24-nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic schistosomiasis.

BACKGROUND & AIMS: Intrahepatic granuloma formation and fibrosis characterize the pathological features of Schistosoma mansoni infection. Based on previously observed substantial anti-fibrotic effects of 24-nor-ursodeoxycholic acid (norUDCA) in Abcb4/Mdr2(-/-) mice with cholestatic liver injury and biliary fibrosis, we hypothesized that norUDCA improves inflammation-driven liver fibrosis in S. mansoni infection. METHODS: Adult NMRI mice were infected with 50 S. mansoni cercariae and after 12 weeks received either norUDCA- or ursodeoxycholic acid (UDCA)-enriched diet (0.5% wt/wt) for 4 weeks. Bile acid effects on liver histology, serum biochemistry, key regulatory cytokines, hepatic hydroxyproline content as well as granuloma formation were compared to naive mice and infected controls. In addition, effects of norUDCA on primary T-cell activation/proliferation and maturation of the antigen-presenting-cells (dendritic cells, macrophages) were determined in vitro. RESULTS: UDCA as well as norUDCA attenuated the inflammatory response in livers of S. mansoni infected mice, but exclusively norUDCA changed cellular composition and reduced size of hepatic granulomas as well as TH2-mediated hepatic fibrosis in vivo. Moreover, norUDCA affected surface expression level of major histocompatibility complex (MHC) class II of macrophages and dendritic cells as well as activation/proliferation of T-lymphocytes in vitro, whereas UDCA had no effect. CONCLUSIONS: This study demonstrates pronounced anti-inflammatory and anti-fibrotic effects of norUDCA compared to UDCA in S. mansoni induced liver injury, and indicates that norUDCA directly represses antigen presentation of antigen presenting cells and subsequent T-cell activation in vitro. Therefore, norUDCA represents a promising drug for the treatment of this important cause of liver fibrosis.

Loss of phosphatase and tensin homolog (PTEN) in myeloid cells controls inflammatory bone destruction by regulating the osteoclastogenic potential of myeloid cells.

OBJECTIVE: Local bone destruction in rheumatic diseases, which often leads to disability and severely reduced quality of life, is almost exclusively mediated by osteoclasts. Therefore, it is important to understand pathways regulating the generation of osteoclasts. Here, we analysed the impact of the Phosphoinositide-3-Kinase (PI3K)/Phosphatase and tensin homolog (PTEN) axis on osteoclast generation and bone biology under basal and inflammatory conditions. METHODS: We analysed osteoclastogenesis of wildtype (wt) and PTEN(-/-) cells in vitro and in vivo, pit resorption and qPCR of osteoclasts in vitro. Mice with a myeloid cell-specific deletion of PTEN and wt littermate mice were investigated by bone histomorphometry and clinical and histological assessment in the human tumour necrosis factor (TNF)-transgenic (hTNFtg) arthritis model. RESULTS: We show that myeloid-specific PTEN(-/-) mice display increased osteoclastogenesis in vitro and in vivo compared to wt mice. Loss of PTEN did not affect the generation or survival of osteoclast precursor cells. However, PTEN deficiency greatly enhanced receptor activator of nuclear factor κ-B ligand (RANKL)-induced expression of the master transcription factor of osteoclastogenesis, nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), resulting in markedly increased terminal differentiation of osteoclasts in vitro. We also observed increased osteoclastogenesis under inflammatory conditions in the hTNFtg mouse model of arthritis, where hTNFtg/myeloid-specific PTEN(-/-) mice displayed enhanced local bone destruction as well as osteoclast formation in the inflamed joints. The extent of synovial inflammation, however, as well as recruitment of osteoclast precursor cells was not different between wt and myeloid-specific PTEN(-/-) mice. CONCLUSIONS: These data demonstrate that loss of PTEN and, therefore, sustained PI3-Kinase signalling in myeloid cells especially, elevates the osteoclastogenic potential of myeloid cells, leading to enhanced inflammatory local bone destruction. Therefore, although our study allows no direct translational conclusion since we used a conditional knockout approach, the therapeutic targeting of the PI3-Kinase pathway may be of benefit in preventing structural joint damage.