Translation and cross-cultural adaptation of Polish version of Neuropathic Pain Questionnaire (NPQ-PL) and its comparisons with different questionnaires.

AIM OF THE STUDY: The aim of this study was to assess the validity and reliability of the Polish version of the Neuropathic Pain Questionnaire (NPQ-PL), and to compare it to other diagnostic tools. CLINICAL RATIONALE FOR THE STUDY: Neuropathic pain is a burdensome condition, of which the exact prevalence is difficult to estimate. During initial screening, pain questionnaires are helpful in alerting clinicians about the need for further evaluation. MATERIAL AND METHODS: The NPQ-PL has been developed following the guidelines for translation and cultural adaptation. A total of 140 patients with chronic pain (ChP), 90 with neuropathic pain (NP), and 50 with nociceptive pain (NoP), were enrolled into this study. RESULTS: The study group consisted of 60.71% women and 39.29% men; the mean age of patients (standard deviation, SD) was 53.22 years (15.81), and the average NPQ-PL score (SD) was 0.49 (1.27). Statistically significant relationships were found between higher age distribution and greater pain intensity in the NP group compared to the NoP group. There were also significant differences in pain levels between people of different ages, with the predominance in the elderly. Cronbach's alpha coefficient of the whole questionnaire was 0.85 and the intraclass correlation coefficient (ICC) for test-retest reliability was 0.635. Using receiver-operating characteristic (ROC) curve analysis, the area under the curve (AUC) was 0.97 and the best cut-off value was 0.002, which resulted in the highest sensitivity (93.3%) and specificity (96.0%). CONCLUSIONS AND CLINICAL IMPLICATIONS: The NPQ-PL is a valid tool for discriminating between neuropathic and nociceptive pain. It can be used by physicians of various disciplines when assessing patients with ChP of various origins.

Analysis of seroconversion following COVID-19 vaccination among multiple sclerosis patients treated with disease-modifying therapies in Poland.

CLINICAL RATIONALE FOR THE STUDY: The rapid spread of SARS-CoV-2 throughout the world has highlighted the importance of vaccinations to control the pandemic and to protect people at risk for severe disease courses. Disease-modifying therapies (DMT) in multiple sclerosis (MS), whether immunomodulatory or immunosuppressive, may affect the immune response. Therefore, the question arose as to whether these vaccinations would be effective. AIM OF THE STUDY: We planned a study to assess the immune response to SARS-CoV-2 vaccines by type of therapy. MATERIAL AND METHODS: Participants were recruited from 14 Polish MS centres. The data was obtained by neurologists using a questionnaire. We collected data on 353 MS patients (269 females, 84 males) who received complete primary SARS-CoV-2 vaccination. All persons with MS (PwMS) were treated with disease-modifying therapies. RESULTS: 305 out of 353 PwMS (86.4%) were positive for IgG Abs against SARS-CoV-2 S domain S1 Ag after vaccination. A strong immune response was noted in 129 PwMS (36.5%). The rate of seroconversion after SARS-CoV-2 vaccination in PwMS who received immunomodulatory DMTs (interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate, natalizumab) was 91.5%, in PwMS receiving immune reconstruction therapy (alemtuzumab, cladribine) was 92%, and in immunosuppressive DMTs (fingolimod, ocrelizumab), the seroconversion rate was 59%. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our study shows that, in PwMS receiving immunomodulatory therapy, the immune response to vaccination is generally excellent. Even in immunosuppressive patients, seroconversion is satisfactory.

Cladribine tablets for highly active relapsing-remitting multiple sclerosis in Poland: a real-world, multi-centre, retrospective, cohort study during the COVID-19 pandemic.

INTRODUCTION: Treatment with cladribine tablets is indicated in highly active relapsing-remitting multiple sclerosis (RRMS). Cladribine tablets proved safe and effective in the pivotal CLARITY trial, but that trial included primarily treatment-naïve patients. In clinical practice however, cladribine tablets are often given to patients who have failed other treatments. Therefore, this study investigated the real-world safety and efficacy of cladribine tablets. MATERIAL AND METHODS: We gathered data from nine MS clinical centres across Poland for patients with RRMS who started treatment with cladribine tablets from December 2019 to June 2022. RESULTS: We enrolled 140 patients, with follow-up data available for 136 in year 1 and for 66 in year 2. At baseline, the mean age was 35.6 years, mean disease duration was 7.3 years, median EDSS score was 2.5, and 94% of patients were treatment- -experienced. Thirty-nine patients (27.9%) had undergone COVID-19, and 94 (67.1%) were vaccinated against COVID-19. The annualised relapse rate (ARR) decreased from 1.49 at baseline to 0.33 in year 1 (p < 0.001) and to 0.25 in year 2 (p < 0.001). The percentage of relapse-free patients increased from 11.5% at baseline to 70.2% in year 1 and 82.1% in year 2. The percentage of patients with active lesions decreased from 91.4% at baseline to 36.2% in year 1 and 18.2% in year 2. EDSS score remained stable or improved in 83.7% of patients in year 1 and 89.6% in year 2. No evidence of disease activity (NEDA-3) was achieved in 42.7% of patients in year 1 and 66.7% in year 2. Only one patient (0.72%) had grade 4 lymphopenia and 21 (15.1%) had grade 3 lymphopenia. Varicella zoster virus infections occurred in three patients. Eight patients discontinued treatment with cladribine: five due to inefficacy, one due to lymphopenia, and two due to a personal decision. CONCLUSIONS: Cladribine tablets proved safe and effective in a real-world cohort of treatment-experienced patients. However, the efficacy measures improved to a lesser extent in our cohort than in the pivotal clinical trial, which is probably due to a higher proportion of treatment-experienced patients in our cohort.

Analysis of Side Effects Following Vaccination Against COVID-19 Among Individuals With Multiple Sclerosis Treated With DMTs in Poland.

Background and Objectives: Since vaccination against COVID-19 is available for over a year and the population of immunized individuals with autoimmune disorders is higher than several months before, an evaluation of safety and registered adverse events can be made. We conducted a large study of side effects following the COVID-19 vaccine among patients with multiple (MS) sclerosis treated with disease-modifying therapies (DMTs) and analyzed factors predisposing for particular adverse events. Methods: We gathered data of individuals with MS treated with DMTs from 19 Polish MS Centers, who reported at least one adverse event following COVID-19 vaccination. The information was obtained by neurologists using a questionnaire. The same questionnaire was used at all MS Centers. To assess the relevance of reported adverse events, we used Fisher's exact test, t-test, and U-Menn-Whutney test. Results: A total of 1,668 patients with MS and reports of adverse events after COVID-19 vaccination were finally included in the study. Besides one case marked as "red flag", all adverse events were classified as mild. Pain at the injection site was the most common adverse event, with a greater frequency after the first dose. Pain at the injection site was significantly more frequent after the first dose among individuals with a lower disability (EDSS ≤2). The reported adverse events following immunization did not differ over sex. According to age, pain at the injection site was more common among individuals between 30 and 40 years old, only after the first vaccination dose. None of the DMTs predisposed for particular side effects. Conclusions: According to our findings, vaccination against COVID-19 among patients with MS treated with DMTs is safe. Our study can contribute to reducing hesitancy toward vaccination among patients with MS.

Novel Drugs in a Pipeline for Progressive Multiple Sclerosis.

Multiple sclerosis (MS) is a widely known inflammatory, demyelinating disease of the central nervous system. The pathogenesis of progressive multiple sclerosis (PMS) is a complex, multi-level process that causes therapeutic difficulties. Along with variables such as age and duration of the disease, pathogenetic mechanisms change from inflammatory to neurodegenerative processes. Therefore, the efficacy of available anti-inflammatory drugs approved for the treatment of PMS, such as ocrelizumab or siponimod, is limited in time. In search of innovative solutions, several research studies have been conducted to evaluate the effectiveness of drugs with neuroprotective or remyelinating effects in PMS, including biotin, ibudilast, simvastatin, alpha-lipoic acid, clemastine, amiloride, fluoxetine, riluzole, masitinib, opicinumab, and lamotrigine. The current review includes those compounds, which have entered the clinical phase of assessment, and the authors discuss future prospects for successful PMS treatment.

Safety of Vaccines against SARS-CoV-2 among Polish Patients with Multiple Sclerosis Treated with Disease-Modifying Therapies.

(1) Background: The present study aims to report the side effects of vaccination against coronavirus disease 2019 (COVID-19) among patients with multiple sclerosis (MS) who were being treated with disease-modifying therapies (DMTs) in Poland. (2) Methods: The study included 2261 patients with MS who were being treated with DMTs, and who were vaccinated against COVID-19 in 16 Polish MS centers. The data collected were demographic information, specific MS characteristics, current DMTs, type of vaccine, side effects after vaccination, time of side-effect symptom onset and resolution, applied treatment, relapse occurrence, and incidence of COVID-19 after vaccination. The results were presented using maximum likelihood estimates of the odds ratio, t-test, Pearson's chi-squared test, Fisher's exact p, and logistic regression. The statistical analyses were performed using STATA 15 software. (3) Of the 2261 sampled patients, 1862 (82.4%) were vaccinated with nucleoside-modified messenger RNA (mRNA) vaccines. Mild symptoms after immunization, often after the first dose, were reported in 70.6% of individuals. Symptoms included arm pain (47.5% after the first dose and 38.7% after the second dose), fever/chills/flu-like symptoms (17.1% after the first dose and 20.5% after the second dose), and fatigue (10.3% after the first dose and 11.3% after the second dose). Only one individual presented with severe side effects (pro-thrombotic complications) after vaccination. None of the DMTs in the presented cohort were predisposed to the development of side effects. Nine patients (0.4%) had a SARS-CoV-2 infection confirmed despite vaccination. (4) Conclusions: Vaccination against SARS-CoV-2 is safe for people with MS who are being treated with DMTs. Most adverse events following vaccination are mild and the acute relapse incidence is low.

Susac syndrome as a multidisciplinary diagnostic challenge.

INTRODUCTION: Susac syndrome (SuS) is a disease manifested as the clinical triad of encephalopathy, branch retinal artery occlusion, and loss of sensory neural hearing. CASE REPORT: The case is presented of a 28-year-old patient hospitalized due to visual impairment of the left eye, and whose hearing and neuropsychiatric disorders had appeared two years earlier. Magnetic resonance imaging demonstrated lesions located in the white matter and along the corpus callosum. An audiogram showed bilateral sensory neural hearing loss. Fluorescein angiography examination revealed branch retinal artery occlusion of the left eye. Based on the clinical picture and results of tests, the diagnosis of SuS was made. Despite the use of steroid and immunosuppression therapy the disease progressed. CONCLUSIONS: The prognosis for SuS depends on the early diagnosis and implementation of treatment. It should be underlined that in case of hearing loss or encephalopathy of unknown cause, SuS should always be excluded.

Neuropathic pain and chronic pain as an underestimated interdisciplinary problem.

Neuropathic pain and chronic pain constitute an interdisciplinary problem on the border of medicine, psychology, sociology and economics. While it seems to be underestimated, the scale of this problem will continue to increase due to the population aging and the growing incidence of lifestyle disorders. People employed in various occupational sectors may also wrestle with these disease units, which affect the quality of their life, mental health and work productivity. A narrative review provided an overview of neuropathic pain and chronic pain, and their relationship to such factors as job type, work absenteeism and productivity decline, as well mental well-being. A systematic literature search was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines to identify appropriate literature by searching the electronic databases: PubMed/MEDLINE, Pain Journal and the Cochrane Database of Systematic Reviews. Studies were published in Polish, English and French. Research shows an increasing number of musculoskeletal diseases in professionally active people, which lead to disability or provoke work absences. However, sickness presenteeism and/or absenteeism caused by pain not only leads to economic burdens, but also to burnout, fatigue and depression syndromes in employees. These disorders may require specialized effective interventions to support the return to work or maintaining employment despite experiencing pain. Every patient with chronic or neuropathic pain should be correctly assessed to determine the best method of treatment and its effectiveness. Int J Occup Med Environ Health. 2022;35(3):249-64.

Possible Neuropathic Pain in Clinical Practice-Review on Selected Diagnostic Tools and Its Further Challenges.

BACKGROUND: Neuropathic pain (NeP) is a wide group of conditions provoked by many different causes and with different patterns. The creation of a grading system was intended to determine the level of certainty that the pain is of neuropathic nature. METHODS: The aim of this review is to update previously published data on some NeP questionnaires and their measurement properties. The selection of articles is based on the basic neurological units. To assess the usefulness and credibility of the questionnaires, the authors searched for a commonly used measure of reliability, as well as sensitivity and specificity. RESULTS: Studies regarding the usefulness and credibility of questionnaires used in NeP were realized. Different patient cohorts, etiologies and sample sizes, do not allow for an unambiguous comparison of the presented scales; however, all of these studies found good measures of reliability, specificity and sensitivity. CONCLUSIONS: NeP tools seem to be beneficial screening instruments that should be utilized by specialists and general practitioners to improve the recognition of "possible" NeP and to determine the epidemiology of this disorder. They have been developed to distinguish perceived pain into neuropathic and non-neuropathic, and, therefore, patients with a mixed pain can still present a diagnostic challenge. Clinical examination and interview play an essential role in the diagnostic process and monitoring, and cannot be neglected.

The Impact of Study Mode (Online vs. Hybrid) on Early Symptoms of Depression and Coping Strategies among University Students in Poland in Time of COVID-19 Pandemic-Preliminary Study.

INTRODUCTION: mental health has been one of the most important issues surrounding the COVID-19 pandemic; mental disorders can be exacerbated by isolation during lockdowns or online learning. The aim of this study was to analyze the relationship between non-clinical (early) symptoms of depressed moods, personality traits, and coping strategies, as well as whether the learning mode (online versus hybrid) differentiates the experiences of these early symptoms and coping strategies. METHODS: 114 university students aged 19 to 34, whose education model was changed from stationary to hybrid or online due to COVID-19 restrictions, participated in the study. The participants completed the online questionnaire, which consisted of two sections: (1) demographic questions to characterize the subjects and 44 questions based on the literature review. (2) Mini-COPE Inventory. RESULTS: the study showed that the fully online study mode has a negative impact on the mental health of students; hybrid students are more likely to use active and positive coping strategies, which effectively help to control negative thoughts and/or reduce negative mental states. CONCLUSIONS: the COVID-19 pandemic has had significant psychological effects that will extend to coming years; therefore, implementing systemic psychological care is of utmost importance.

Facial Diplegia-Complication or Manifestation of SARS-CoV-2 Infection? A Case Report and Systemic Literature Review.

Since the outbreak of the new coronavirus, healthcare systems around the world have witnessed not only COVID-19 symptoms but also long-term complications of the aforementioned, including neurological problems. We report a clinical case of an adult patient with bilateral facial nerve palsy and progressive ascending paresis of the limbs after contracting the novel coronavirus (COVID-19). Additionally, the systematic review aimed to identify and summarize specific clinical features, outcomes and complications of the studies focusing on bilateral facial diplegia as a sequela of COVID-19 infection. The total number of analyzed patients was 15. Only one patient was diagnosed with isolated bilateral palsy; the rest had Guillain-Barré Syndrome (GBS). With one exception, all the presented cases had favorable outcomes, with facial palsy recovery from slight to almost complete. In patients with a confirmed COVID-19 diagnosis, bilateral facial palsy may be an isolated symptom as well as a variant of GBS. Symptoms of cranial nerve damage during a COVID-19 infection may explain the appearance of facial nerve damage. In order to clarify the spectrum of neurological manifestations and a causal relation between SARS-CoV-2, COVID-19 vaccination and neurological symptoms, direct attention towards the study of this virus is crucial. It seems reasonable to recognize human coronavirus as another potential GBS trigger.

A Retrospective Analysis of Pain Etiology in Middle-Aged Patients with Peripheral Neuropathy.

Background and Objectives: Correct assessment and a multidisciplinary approach appear to be extremely important in preventing peripheral neuropathy and its complications. The purpose of this study was to find the correlations and dissimilarities between different types of peripheral neuropathy, the occurrence of pain, and laboratory results. Materials and Methods: This retrospective study assessed 124 patients who were hospitalized in our neurology department due to various types of sensory or motor disturbances. The patients were eventually diagnosed with peripheral neuropathy, based on the electrophysiological study, anamnesis, physical examination, and laboratory results. The whole group was subjected to statistical analysis. Results: The mean age of patients was over 56 years, with a slight woman predominance. A statistically significant (p < 0.05) relationship between the place of residence and gender was seen, where more men than women live in the rural area, while more women than men live in the urban area. Most often we observed symmetric, sensorimotor, demyelinating, inflammatory, and chronic neuropathy. More than 40% of patients reported pain. A statistically significant correlation between the evolution/severity and the occurrence of pain was seen in subacute type (p < 0.05) and small fibre neuropathy (p < 0.01). Conclusions: A higher incidence of peripheral neuropathy in middle-aged people will become essential in the aging society with lifestyle and chronic disorders. Peripheral neuropathy is slightly more common in women than men and its occurrence may be influenced by work performed or internal and external factors. In the study group, more than 40% of patients reported pain, therefore the pain measurement for each patient should be implemented and repeated at every visit. An assessment of sodium level and, in women, markers of neuroinflammation level in the various types of peripheral neuropathy may be an interesting direction for the future.

Modified Rio Score with Platform Therapy Predicts Treatment Success with Fingolimod and Natalizumab in Relapsing-Remitting Multiple Sclerosis Patients.

BACKGROUND: Reliable markers of disease outcomes in multiple sclerosis (MS) would help to predict the response to treatment in patients treated with high efficacy drugs. No evidence of disease activity (NEDA) has become a treatment goal whereas the modified Rio score (MRS) predicts future suboptimal responders to treatment. The aim of our study was to identify factors that would predict poor response to treatment with natalizumab and fingolimod. METHODS: In the multicenter prospective trial, 336 subjects were enrolled, initiating therapy with natalizumab (n = 135) or fingolimod (n = 201). Data on relapse rate, the expanded disability status scale, and MRI results were collected, and MRS was estimated. RESULTS: NEDA-3 after the first year of therapy was 73.9% for natalizumab and 54.8% for fingolimod (p < 0.0001). Patients with MRS = 0 in the last year on platform therapy had the best NEDA-3 (71%) and patients with MRS = 3 had the worst NEDA-3 (41%) in the first year of treatment with the second-line therapy. CONCLUSION: We conclude that switching to the second-line therapy should occur earlier to enable better results for patients treated with natalizumab or fingolimod. The outcome on both drugs is better with better neurological conditions and lower MRS of the patient on the platform therapy.

Biomarkers in Multiple Sclerosis: a review of diagnostic and prognostic factors.

INTRODUCTION: Multiple Sclerosis (MS) is a chronic, demyelinating disease of the central nervous system which affects mostly young people. Because it leads to disability and cognitive impairment, it is crucial to recognise MS at an early stage. STATE OF THE ART: Magnetic resonance imaging is the golden standard in MS diagnosis. However, it is not an infallible diagnostic tool, especially at the stage of clinically isolated syndrome. The incorporation of oligoclonal bands in the diagnostic process of MS is a step towards the extension of diagnostic methods. Recently, a lot of research has been carried out on potential biomarkers in blood serum and cerebrospinal fluid that may be useful in the diagnosis of MS. CLINICAL IMPLICATIONS: This article summarises current knowledge on the use of new prognostic factors such as neurofilament light chain, chitinase 3-like 1 and 2, heat shock proteins, and tubulins in MS. FUTURE DIRECTIONS: Despite numerous studies on the use of biomarkers in the diagnosis of MS, more extensive research is needed to determine the clinical usefulness of these molecules and to develop diagnostic tests applicable in everyday practice. This in turn may result in earlier MS detection, faster implementation of treatment, and better therapeutic effects.

Cladribine Treatment Improved Homocysteine Metabolism and Increased Total Serum Antioxidant Activity in Secondary Progressive Multiple Sclerosis Patients.

Hyperhomocysteinemia plays a crucial role in the pathogenesis of many diseases of the central nervous system (CNS). The nervous system is particularly sensitive to high homocysteine (Hcy) level mainly due to its prooxidative and cytotoxic effects. Cladribine, a drug recently registered for the treatment of multiple sclerosis (MS), possesses additionally neuroprotective effects which are independent of its peripheral immunosuppressant action. Accumulating evidence suggests that oxidative stress and homocysteine thiolactone-mediated protein homocysteinylation play a causal role in MS. Both of these processes may be attenuated by paraoxonase 1 (PON1). Therefore, in the present study, we aimed to examine whether the beneficial effects of the drug in MS patients with a secondary progressive (SP) clinical course, treated with cladribine subcutaneously (s.c.), may be related to its ability to modify serum PON1 activity, Hcy concentration, and protein homocysteinylation, as well as to correct total antioxidant status. A total of 118 subjects were enrolled into the study: (1) patients with a SP type of MS, SP-MS (n = 40); (2) patients with a relapsing-remitting (RR) type of MS, RR-MS (n = 30); and (3) healthy people (n = 48). Patients with SP-MS were treated with cladribine. The drug was given in SP-SM patients s.c. six times every 6 weeks up to a total mean cumulative dose of 1.8 mg/kg. PON1 activity was assessed spectrophotometrically. The level of Hcy, homocysteine thiolactone (HTL) attached to plasma proteins (N-Hcy-protein), and antibodies against homocysteinylated proteins was assessed with an enzyme immunoassay. The total antioxidant activity of the serum was assessed with the ferric-reducing activity of plasma (FRAP) method. Basically, there was no difference in PON1 activity between untreated SP-MS, RR-MS, and control subjects. Serum Hcy was significantly higher in RR-MS patients (p < 0.001) and in SP-MS patients (p < 0.01) compared to the control group. The N-Hcy protein level was higher in RR-MS patients (p < 0.05) in comparison to the control group. Moreover, the elevated level of antibodies against homocysteinylated proteins was observed in the serum of patients with SP-MS. The total antioxidant capacity of serum was lower in MS patients vs. the control group (p < 0.001). After cladribine treatment, the activity of PON1 did not change in SP-MS patients, whereas cladribine treatment decreased the level of total Hcy (p < 0.05). Treatment with cladribine increased the total serum antioxidant activity in SP-MS patients (p < 0.01). The Expanded Disability Status Scale (EDSS) score did not change in SP-MS patients. Cladribine treatment in the SP-MS group attenuates hyperhomocysteinemia-induced protein homocysteinylation (n.s.). It also stabilises the neurological condition of SP-MS patients. The stabilisation of a neurological condition observed in SP-MS patients after cladribine treatment may be partially related to its ability to reduce elevated Hcy level and to improve serum antioxidant potential.

The effect of exenatide (a GLP-1 analog) and sitagliptin (a DPP-4 inhibitor) on plasma platelet-activating factor acetylhydrolase (PAF-AH) activity and concentration in normal and fructose-fed rats.

Inflammation and oxidative stress are the two processes crucial in atherogenesis. Platelet-activating factor acetylhydrolase (PAF-AH), a plasma lipoprotein-associated enzyme, degrades pro-inflammatory lipids generated within oxidatively modified lipoproteins. Extensive evidence shows that incretin-based drugs, a new class of anti-diabetic agents, can provide cardiovascular protection that cannot be attributed to their glucose-lowering effects. The present study was undertaken to determine whether the antiatherogenic effects of the GLP-1(glucagon-like peptide-1) receptor agonist (exenatide) and DPP-4(dipeptidyl peptidase-4) inhibitors (sitagliptin) may occur via the regulation of platelet-activating factor acetylhydrolase (PAF-AH) activity/mass and inhibition of low-density lipoprotein (LDL) oxidation in the fructose-fed rats. Normal and fructose-fed rats (8 wk) were treated (4 wk) with sitagliptin (5 and 10 mg/kg p.o.) or with exenatide (5 and 10 µg/kg, s.c.). Plasma PAF-AH activity and phosphatidylcholine (PC) concentration were measured colorimetrically. Plasma PAF-AH concentration, oxidized LDL (oxLDL), hexanoyl-Lys adduct (HEL), lyso-PC, apolipoprotein A-I (apoA-I), apoB, platelet-activating factor (PAF), monocyte chemoattractant protein-1 (MCP-1) and endothelin-1 (ET-1) were measured by ELISA. The four-week exenatide (5 µg/kg, sc.) treatment of fructose fed-rats significantly increased plasma PAF-AH activity (+33%, P < 0.001) and decreased the level of circulating oxLDL (-42%, P < 0.05) and MCP-1 (-23%, P < 0.01). These changes were accompanied by the decrease in plasma PC/lyso-PC (-47%, P < 0.001) and apoB/apoA-I ratio (-75%, P < 0.001). The effect of exenatide on enzyme activity was associated with only a minor effect on metabolic parameters and was independent of weight reduction. Exenatide but not sitagliptin inhibits oxidative modification of LDL probably due to favorable effect on plasma PAF-AH activity.

Hydrogen sulfide in the regulation of insulin secretion and insulin sensitivity: Implications for the pathogenesis and treatment of diabetes mellitus.

Insulin secretion and sensitivity play an essential role in maintaining normal glucose level and their abnormalities result in diabetes mellitus. H2S-synthesizing enzymes, CBS and/or CSE, are expressed in insulin-secreting pancreatic ß cells and H2S inhibits insulin secretion by activating ATP-sensitive K+ channels. In addition, H2S has been reported to have either pro- or antiapoptotic effects on ß cells. Studies in the animal models suggest that excess of H2S in pancreatic islets may contribute to both type 1 and type 2 diabetes. H2S has also been demonstrated to regulate insulin sensitivity. In the liver, H2S stimulates gluconeogenesis and glycogenolysis and inhibits glucose utilization and glycogen storage. Its effect on insulin-stimulated glucose uptake in the adipose tissue is controversial; both stimulation and inhibition have been reported. H2S may also regulate adipose tissue lipolysis, adipokine production and inflammation; the processes important for local and systemic insulin sensitivity. Little is known about the effect of H2S on skeletal muscle metabolism. High fat diet, obesity and insulin resistance affect CBS/CSE/H2S system in the liver and adipose tissue, although the effect depends on diet composition, animals species and time of high-fat feeding. Most studies indicate that blood H2S concentration decreases in animal models of diabetes and in diabetic humans.

The paraoxonase 1 (PON1), platelet-activating factor acetylohydrolase (PAF-AH) and dimethylarginine dimethylaminohydrolase (DDAH) activity in the metformin treated normal and diabetic rats.

Antidiabetic agents per se, apart from their glucose-lowering effect, can have an important impact on modifying the cardiovascular risk. The present study was undertaken to determine whether the known cardio-protective effects of metformin are linked to its potential ability to affect activities of HDL's paraoxonase (PON1) and platelet activating factor acetylohydrolase (PAF-AH) or via its interaction with the asymmetric dimethylarginine (ADMA)- dimethylarginine dimethylaminohydrolase (DDAH) axis. Normal and streptozotocin (STZ)-induced diabetic rats were treated with metformin (300mg/kg; 4 weeks). The activity of PON1, PAF-AH and DDAH were measured spectrophotometrically. The plasma ADMA level was determined by ELISA method. In STZ-induced diabetic rats the long-term administration of metformin normalized reduced PON1 activity assayed toward paraoxon (+42.5%, P<0.05), phenyl acetate (+22.35%, P<0.05) and γ-decanolactone (+108.0%, P<0.01), without affecting elevated PAF-AH activity in the plasma. Moreover, metformin increased DDAH activity in the renal cortex (+38.24%, P<0.01). Additionally metformin administration caused the increase in PON1 activity in the liver (+29.2%, P<0.01) accompanied by the reduction in the lipid peroxidation (-59.8%, P<0.001). Similarly, in non-diabetic treated rats the increase in liver PON1 activity was observed toward both paraoxon (+80.19%, P<0.001) and phenyl acetate (+29.3%, P<0.05), respectively. The present study has demonstrated that insulin-sensitizer metformin is important for preserving antioxidant HDL function in diabetes. Metformin might also exert its effect against diabetic complications by improving DDAH activity in the kidney and increasing PON1 activity in the liver.

Hydrogen Sulfide in the Adipose Tissue-Physiology, Pathology and a Target for Pharmacotherapy.

Hydrogen sulfide (H2S) is synthesized in the adipose tissue mainly by cystathionine γ-lyase (CSE). Several studies have demonstrated that H2S is involved in adipogenesis, that is the differentiation of preadipocytes to adipocytes, most likely by inhibiting phosphodiesterases and increasing cyclic AMP concentration. The effect of H2S on adipose tissue insulin sensitivity and glucose uptake is controversial. Some studies suggest that H2S inhibits insulin-induced glucose uptake and that excess of H2S contributes to adipose tissue insulin resistance in metabolic syndrome. In contrast, other studies have demonstrated that H2S stimulates glucose uptake and its deficiency contributes to insulin resistance. Similarly, the effect of H2S on adipose tissue lipolysis is controversial. H2S produced by perivascular adipose tissue decreases vascular tone by activating ATP-sensitive and/or voltage-gated potassium channels in smooth muscle cells. Experimental obesity induced by high calorie diet has a time dependent effect on H2S in perivascular adipose tissue; short and long-term obesity increase and decrease H2S production, respectively. Hyperglycemia has been consistently demonstrated to suppress CSE-H2S pathway in various adipose tissue depots. Finally, H2S deficiency may contribute to adipose tissue inflammation associated with obesity/metabolic syndrome.