Neuropathic pain in ankylosing spondylitis: a meta-analysis.

AIM: The aim of this study was to compare demographic characteristics, disease activity, functional status, and quality of life between ankylosing spondylitis (AS) with neuropatic pain (NP) and AS without NP (Non-NP). METHODS: The MEDLINE via PubMed, Cochrane, Scopus, and Embase database, from the earliest available date of indexing through December 20, 2018, were searched for comparative studies evaluating NP in AS patients. Two authors performed the data extraction independently. Any discrepancies were resolved by consensus. RESULTS: Four comparative studies were identified. There was no statistically significant difference in terms of age, body mass index, symptom duration, and inflammatory markers, such as erythrocyte sedimentation rate and C­reactive protein between NP and Non-NP. The sex ratios (F/M) were approximately 1/1 in NP and 1/2 in Non-NP and the proportion of human leukocyte antigen (HLA) B27-positive patients in NP and Non-NP was 65.7% and 83.0%, respectively. NP patients had significantly higher visual analogue scale pain scores, higher Bath Ankylosing Spondylitis Disease Activity Index, higher Bath Ankylosing Spondylitis Functional Index, and lower SF-Item Short Form physical component scores compare to Non-NP patients. CONCLUSION: The current meta-analysis showed that NP patients had significantly higher pain severity, higher disease activity and lower quality of life than Non-NP patients. The sex ratio (F/M) and proportion of HLA-B27 positive patients were different between the two groups. Further well-designed studies are needed to substantiate our results.

Efficacy and safety of glimepiride/metformin sustained release once daily vs. glimepiride/metformin twice daily in patients with type 2 diabetes.

AIMS: The study investigated the clinical equivalence in reducing haemoglobin A1c (A1C) between glimepiride/metformin sustained release (GM-SR) 2/500 mg, a fixed-dose combination, once daily and glimepiride/metformin (GM) 1/250 mg, a fixed-dose combination, twice daily in patients with type 2 diabetes (T2D). METHODS: A multicentre, randomised, double-blind, double-dummy study was conducted in 14 hospitals in Korea. Inclusion criteria were age 30-75 years, T2D diagnosis no longer than 10 years previously, A1C between 7% and 10%, and body mass index <40 kg/m(2) . A total of 207 subjects were randomised into the GM-SR group (n=101) or the GM group (n=106). Participants were assessed at baseline, 8 weeks and 16 weeks after treatment. RESULTS: After 16 weeks treatment, no difference in baseline-adjusted changes of A1C (primary efficacy variable) was observed between the two groups (-0.59% for GM-SR group vs. -0.61% for GM group, 95% CI: -0.17 to 0.21; p=0.84). In addition, there were no significant differences in secondary efficacy parameters between the two groups, including changes in A1C up to week 8, changes in fasting plasma glucose (FPG) and 2-h-postprandial plasma glucose up to week 8 and week 16, response rate, drug compliance and hypoglycaemic events. However, there was a difference in baseline-adjusted changes of FPG between the two groups (-1.01 mmol/l for GM-SR group vs. -1.52 mmol/l for GM group, p=0.01 in the intention to treat set). CONCLUSIONS: GM-SR 2/500 mg once daily was as effective as GM 1/250 mg twice daily in lowering A1C. In addition, no difference was noted in hypoglycaemic events between the two groups.

RAGE regulates BACE1 and Abeta generation via NFAT1 activation in Alzheimer's disease animal model.

The receptor for advanced glycation end products (RAGE) is a multiligand cell surface receptor, and amyloid beta peptide (Abeta) is one of the ligands for RAGE. Because RAGE is a transporter of Abeta from the blood to the brain, RAGE is believed to play an important role in Alzheimer's disease (AD) pathogenesis. In the present study, the role of RAGE in Abeta production was examined in the brain tissue of an AD animal model, Tg2576 mice, as well as cultured cells. Because beta-site APP-cleaving enzyme 1 (BACE1), an essential protease for Abeta production, is up-regulated in cells overexpressing RAGE and in RAGE-injected brains of Tg2576 mice, the molecular mechanisms underlying RAGE, BACE1 expression, and Abeta production were examined. Because RAGE stimulates intracellular calcium, nuclear factor of activated T-cells 1 (NFAT1) was examined. NFAT1 was activated following RAGE-induced BACE1 expression followed by Abeta generation. Injection of soluble RAGE (sRAGE), which acts as a competitor with full-length RAGE (fRAGE), into aged Tg2576 mouse brains reduced the levels of plaques, Abeta, BACE1, and the active form of NFAT1 compared with fRAGE-injected Tg2576 mice. Taken together, RAGE stimulates functional BACE1 expression through NFAT1 activation, resulting in more Abeta production and deposition in the brain.

CR6-interacting factor 1 is a key regulator in Aß-induced mitochondrial disruption and pathogenesis of Alzheimer's disease.

Mitochondrial dysfunction, often characterized by massive fission and other morphological abnormalities, is a well-known risk factor for Alzheimer's disease (AD). One causative mechanism underlying AD-associated mitochondrial dysfunction is thought to be amyloid-ß (Aß), yet the pathways between Aß and mitochondrial dysfunction remain elusive. In this study, we report that CR6-interacting factor 1 (Crif1), a mitochondrial inner membrane protein, is a key player in Aß-induced mitochondrial dysfunction. Specifically, we found that Crif1 levels were downregulated in the pathological regions of Tg6799 mice brains, wherein overexpressed Aß undergoes self-aggregation. Downregulation of Crif1 was similarly observed in human AD brains as well as in SH-SY5Y cells treated with Aß. In addition, knockdown of Crif1, using RNA interference, induced mitochondrial dysfunction with phenotypes similar to those observed in Aß-treated cells. Conversely, Crif1 overexpression prevented Aß-induced mitochondrial dysfunction and cell death. Finally, we show that Aß-induced downregulation of Crif1 is mediated by enhanced reactive oxygen species (ROS) and ROS-dependent sumoylation of the transcription factor specificity protein 1 (Sp1). These results identify the ROS-Sp1-Crif1 pathway to be a new mechanism underlying Aß-induced mitochondrial dysfunction and suggest that ROS-mediated downregulation of Crif1 is a crucial event in AD pathology. We propose that Crif1 may serve as a novel therapeutic target in the treatment of AD.

Kinetic study of oxalic acid inhibition on enzymatic browning.

Oxalic acid has a strong antibrowning activity. The inhibitory pattern on catechol-PPO model system appeared to be competitive, with a K(i) value of 2.0 mM. When the PPO was incubated with oxalic acid, the activity was not recovered via dialysis, but the inactivated enzyme partially recovered its activity when cupric ion was added. Comparing the relative antibrowning effectiveness of oxalic acid with other common antibrowning agents, oxalic acid with I(50) value of 1.1 mM is as effective as kojic acid and more potent than cysteine and glutathione.

Reduced IRE1α mediates apoptotic cell death by disrupting calcium homeostasis via the InsP3 receptor.

The endoplasmic reticulum (ER) is not only a home for folding and posttranslational modifications of secretory proteins but also a reservoir for intracellular Ca(2+). Perturbation of ER homeostasis contributes to the pathogenesis of various neurodegenerative diseases, such as Alzheimer's and Parkinson diseases. One key regulator that underlies cell survival and Ca(2+) homeostasis during ER stress responses is inositol-requiring enzyme 1α (IRE1α). Despite extensive studies on this ER membrane-associated protein, little is known about the molecular mechanisms by which excessive ER stress triggers cell death and Ca(2+) dysregulation via the IRE1α-dependent signaling pathway. In this study, we show that inactivation of IRE1α by RNA interference increases cytosolic Ca(2+) concentration in SH-SY5Y cells, leading to cell death. This dysregulation is caused by an accelerated ER-to-cytosolic efflux of Ca(2+) through the InsP3 receptor (InsP3R). The Ca(2+) efflux in IRE1α-deficient cells correlates with dissociation of the Ca(2+)-binding InsP3R inhibitor CIB1 and increased complex formation of CIB1 with the pro-apoptotic kinase ASK1, which otherwise remains inactivated in the IRE1α-TRAF2-ASK1 complex. The increased cytosolic concentration of Ca(2+) induces mitochondrial production of reactive oxygen species (ROS), in particular superoxide, resulting in severe mitochondrial abnormalities, such as fragmentation and depolarization of membrane potential. These Ca(2+) dysregulation-induced mitochondrial abnormalities and cell death in IRE1α-deficient cells can be blocked by depleting ROS or inhibiting Ca(2+) influx into the mitochondria. These results demonstrate the importance of IRE1α in Ca(2+) homeostasis and cell survival during ER stress and reveal a previously unknown Ca(2+)-mediated cell death signaling between the IRE1α-InsP3R pathway in the ER and the redox-dependent apoptotic pathway in the mitochondrion.

Crucial role of calbindin-D28k in the pathogenesis of Alzheimer's disease mouse model.

Calbindin-D28k (CB), one of the major calcium-binding and buffering proteins, has a critical role in preventing a neuronal death as well as maintaining calcium homeostasis. Although marked reductions of CB expression have been observed in the brains of mice and humans with Alzheimer disease (AD), it is unknown whether these changes contribute to AD-related dysfunction. To determine the pathogenic importance of CB depletions in AD models, we crossed 5 familial AD mutations (5XFAD; Tg) mice with CB knock-out (CBKO) mice and generated a novel line CBKO·5XFAD (CBKOTg) mice. We first identified the change of signaling pathways and differentially expressed proteins globally by removing CB in Tg mice using mass spectrometry and antibody microarray. Immunohistochemistry showed that CBKOTg mice had significant neuronal loss in the subiculum area without changing the magnitude (number) of amyloid ß-peptide (Aß) plaques deposition and elicited significant apoptotic features and mitochondrial dysfunction compared with Tg mice. Moreover, CBKOTg mice reduced levels of phosphorylated mitogen-activated protein kinase (extracellular signal-regulated kinase) 1/2 and cAMP response element-binding protein at Ser-133 and synaptic molecules such as N-methyl-D-aspartate receptor 1 (NMDA receptor 1), NMDA receptor 2A, PSD-95 and synaptophysin in the subiculum compared with Tg mice. Importantly, this is the first experimental evidence that removal of CB from amyloid precursor protein/presenilin transgenic mice aggravates AD pathogenesis, suggesting that CB has a critical role in AD pathogenesis.

Diffusion tensor imaging-demonstrated differences between hemiplegic and diplegic cerebral palsy with symmetric periventricular leukomalacia.

BACKGROUND AND PURPOSE: Patients with cerebral palsy have variable clinical presentations such as hemiplegic, diplegic, or quadriplegic patterns though they have PVL on conventional MR images. The authors investigated whether DTT can differentiate between hemiplegic and diplegic CP in patients presenting with symmetric PVL on conventional MR images. MATERIALS AND METHODS: One hundred thirteen consecutive pediatric patients with definite hemiplegic (59 patients; 30 boys, 29 girls; mean age, 34.19 months; range, 24-52 months) or diplegic (54 patients; 27 boys, 27 girls; mean age, 31.07 months; range, 24-48 months) symptoms and bilateral symmetric PVL on conventional brain MR imaging were recruited. The states of CSTs were examined by using DTT, and the asymmetries of right and left CSTs in the hemiplegic and diplegic groups were compared by using asymmetric anisotropy indexes and asymmetric mean diffusivity indexes. RESULTS: All patients in the hemiplegic group with asymmetric results exhibited disrupted integrities of more affected CSTs and sparing of less affected CSTs. However, diplegic patients revealed symmetric disrupted findings of the right and left CSTs at the upper periventricular level. Asymmetric anisotropy index and asymmetric mean diffusivity index values were significantly higher in the hemiplegic group than in the diplegic group (P < .05), and these results of DTT significantly corresponded with their typical clinical manifestation. CONCLUSIONS: DTT may be very useful for the detailed estimation of the CST state in patients with bilateral symmetric PVL.

The effects of the overexpression of recombinant uncoupling protein 2 on proliferation, migration and plasminogen activator inhibitor 1 expression in human vascular smooth muscle cells.

AIMS/HYPOTHESIS: Increased oxidative stress in vascular smooth muscle cells (VSMCs) has been implicated in the pathogenesis of accelerated atherosclerosis in patients with diabetes mellitus. Uncoupling protein 2 (UCP-2) is an important regulator of intracellular reactive oxygen species (ROS) production. We hypothesised that UCP-2 functions as an inhibitor of the atherosclerotic process in VSMCs. METHODS: Overexpression of human UCP-2 was performed in primary cultured human VSMCs (HVSMCs) via adenovirus-mediated gene transfer. Its effects on ROS production, AP-1 activity, plasminogen activator inhibitor 1 (PAI-1) gene expression, and cellular proliferation and migration were measured in response to high glucose and angiotensin II (Ang II) concentrations, two major factors in the pathogenesis of atherosclerosis in patients with diabetes and hypertension. Mitochondrial membrane potential and NAD(P)H oxidase activity were also measured. RESULTS: High glucose and Ang II caused transient mitochondrial membrane hyperpolarisation. They also significantly stimulated ROS production, NAD(P)H oxidase activity, mitochondrial membrane potential, AP-1 activity, PAI-1 mRNA expression, and proliferation and migration of HVSMCs. Adenovirus-mediated transfer of the UCP-2 gene reversed all of these effects. CONCLUSIONS/INTERPRETATION: The present study demonstrates that UCP-2 can modify atherosclerotic processes in HVSMCs in response to high glucose and Ang II. Our data suggest that agents increasing UCP-2 expression in vascular cells may help prevent the development and progression of atherosclerosis in patients with diabetes and hypertension.

[Transformation of human corneal endothelial cells by micro- injection of oncogenes]. / Transformatsiia kletok rogovichnogo éndoteliia cheloveka mikroin''ektsirovannymi onkogenami.

Human corneal endothelial cells (HCEC) were transfected with some cloned oncogenes. The direct microinjection of either early region (E1) genes of monkey (SA7) and human (Ad5) adenoviruses or Ha-ras oncogen in conjunction with the Ad5 Ela-gene into embryonic HCEC nuclei was shown to result in immortalization of these cells. 3 independent immortalized HCEC lines were established in their growth and morphological properties were studied. These properties were very similar to those of primary HCEC, but unlike primary HCEC the immortalized cells didn't need the endothelial cell growth factor.