Examination of PACAP Expression and Function in the Inflammatory Gastrointestinal Diseases and in their Models

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide belonging to the secretin/glucagon/vasoactive intestinal peptide family. It was first identified in ovine hypothalamus based on the efficacy on influencing adenylate cyclase activity. PACAP has a widespread distribution in the body and exerts a wide range of physiological effects also in the gastrointestinal system. The occurrence and functions of PACAP and its receptors can be well demonstrated in neuroendocrine and interstitial cells, in the myenteric and submucosal plexus in the entire length of the gastrointestinal tract and also pancreas, gall bladder and liver. PACAP exerts a variety of functions in the intestine. PACAP influences motility of the intestinal wall, inhibits pacemaker activity of interstitial cells of Cajal, regulates sphincter function, affects on secretion of various glands and gastric acid. PACAP exerts relaxant activity in the body and fundus of the stomach and PACAP-immunoreactive fibers are often observed around and in the walls of blood vessels. The general vasodilatory action of PACAP is well established in several species and experimental models. This was also described for the stomach wall. Several in vivo and in vitro studies confirmed the general cytoprotective, antiapoptotic, antioxidant, and anti-inflammatory effects of PACAP. These effects are exerted mainly through G protein-coupled receptors, the specific PAC1 and the VPAC1/2 receptors, which are shared with VIP. In the intestinal system, PACAP has been shown to be protective in various models of intestinal injuries, such as ischemia-reperfusion, transplantation and inflammatory disorders. In small intestinal ischemia, both endogenous and exogenous PACAP have been shown to have protective effects. The anti-inflammatory activity of PACAP can be ascribed to inhibition of immune and inflammatory cells. PACAP decreases the release of inflammatory chemokines and cytokines such as TNF- and IL-6, inhibits chemotaxis and phagocytosis. Hence, it is an important endogenous immunomodulatory peptide in many different models of inflammatory diseases. In humans, several studies have previously shown PACAP level changes in colon diseases. An earlier study found significantly lower levels of PACAP in sigmoid colon and rectum tumors compared to normal healthy tissue. Another study described significantly higher PACAP levels in patients with symptomatic diverticular disease. On the contrary, investigations of colon mucosa of children with ulcerative colitis found decreases in nerve fibers containing PACAP. In case of acute ileitis caused by experimental Toxoplasma gondii infection in mice, PACAP prophylaxis improved survival and anti-inflammatory cytokine response. A recent study has revealed direct antimicrobial effect of PACAP38 against Gram-positive and Gram-negative bacteria. All these results indicate that PACAP influences directly and indirectly the intestinal flora and bacterial colonization, which might be a link with increased susceptibility of PACAP deficient mice to intestinal inflammatory diseases and tumors. PACAP deficient mice have been shown to be more vulnerable to harmful stimuli to the central nervous system, but also peripheral organs including peripheral nerves, kidney, and the intestinal tract. For instance, applying the acute dextran sodium sulfate (DSS)-induced colitis model, PACAP deficient mice displayed 50% higher mortality rates as compared to wildtype mice. In addition, PACAP deficient mice were suffering from more severe chronic DSS-induced colitis, whereas 60% of diseased animals additionally developed colorectal tumors with aggressive phenotypes. Interestingly, naive PACAP deficient mice did not display histopathological changes in their intestinal mucosa. Hence, lack of endogeneous PACAP resulted in increased susceptibility of the murine host to intestinal inflammation and inflammation-induced colonic cancer development. There is compelling evidence that the host microbiota constitutes a key factor in health and disease of vertebrates. In fact, it has been shown that the gut microbiota is essentially involved in a multitude of physiological processes including food digestion, fat metabolism, vitamin synthesis, intestinal angiogenesis, enteric nerve function, and protection from pathogens as well as immune cell development. Conversely, pertubations of this complex intestinal ecosystem termed dysbiosis are associated with increased susceptibility of the host to distinct intestinal (e.g., inflammatory bowel disease, irritable bowel syndrome, coeliac disease) as well as to extra-intestinal immunopathological conditions (e.g., multiple sclerosis, autism, depression, allergy, asthma, cardiovascular morbidities)

Immunotoxicological investigation of subacute combined exposure with low doses of pb, hg and cd in rats

Detectable interactions between NOEL (No Observed Effect Level) doses of Pb, Hg and Cd in general toxicological, hematological, and immune function parameters were investigated. The metals (Pb-acetate, 20 mg/kg; HgCl 2, 0.40 mg/kg; CdCl2, 1.61 mg/kg) were combined. First, the rats received the combination Pb + Hg + Cd for 4 weeks per os. Significant difference vs. control was found only in the weight of lung and popliteal lymph node (PLN). The Pb + Hg and Pb + Cd combinations significantly decreased the PLN to 100 g body weight and PLN to brain weight ratio, and Pb+Hg also decreased the relative adrenal weight. After 12 weeks treatment with the same doses, effects on the thymus, kidney, and adrenal weights in the Pb + Hg, and thymus weight in the Pb + Cd, combination were seen. Pb + Cd also affected the white and red blood cell count and hematocrit. Combined with Hg or Cd, NOEL dose Pb showed toxicity, indicating that exposure limits may be inefficient in combined exposure situations. Š 2006 AkadÊmiai Kiadó

Egy diagnosztikus kihívás: paraduodenalis pancreatitis. Két eset bemutatása = A diagnostic challenge: paraduodenal pancreatitis. Two case reports

Absztrakt: A paraduodenalis, vagy groove pancreatitis egy kevéssé ismert krónikus hasnyálmirigygyulladás-típus, mely malignitást utánozva sokszor differenciáldiagnosztikai nehézségeket okoz. Közleményünkben két esetet mutatunk be: mindkét esetben műtéti reszekcióra volt szükség a biztos diagnózishoz, az inadekvát preoperatív szövettani mintavétel és a klinikai kép miatt. A képalkotó vizsgálatok az első esetben malignitás gyanúját vetették fel, a második esetben gyomorürülési zavar indikálta a reszekciót. Irodalmi áttekintést adunk az elváltozás klinikopatológiájáról, beleértve annak epidemiológiáját, klinikai megjelenését és az alkalmazható diagnosztikus módszereket, a betegség makroszkópos és mikroszkópos patomorfológiáját. Kialakulásának háttere összetett: az alkohol patogenetikai szerepe mellett a pancreaticus ductalis rendszer anatómiai variációi, a dorsalis pancreas inkomplett involúciójából származó duodenumfali pancreasszigetek vagy az elváltozás részeként gyakran megfigyelt Brunner-mirigy-hyperplasia is szerepet játszhat a minor papilla területén jelentkező pancreasnedv-elfolyási zavarban, mely a jellegzetes lokalizációjú gyulladáshoz vezet. A legfrissebb kutatások génpolimorfizmusok hajlamosító szerepét is kimutatták a hasnyálmirigy gyulladásos folyamataiban. A paraduodenalis pancreatitis differenciáldiagnosztikájának kérdése mellett a terápiás lehetőségekről is szót ejtünk, kiemelve a sikeres elkülönítés esetén jó hatásfokkal alkalmazható konzervatív kezelés lehetőségét. Orv Hetil. 2019; 160(22): 873–879. | Abstract: The paraduodenal, or groove pancreatitis is a lesser-known type of chronic pancreatitis, often mimicking malignancy, hence resulting in serious differential diagnostic challenges. Herein we report two cases of this entity. Both required analysis of the surgical specimen in order to ensure the diagnosis due to inadequate preoperative histological sampling and a vague clinical presentation. In the first case, strong suspicion of malignancy following imaging, while in the second, severe gastric outlet stenosis indicated the resection. In our report, we give a clinicopathological summary from the literature of this entity, including its epidemiology, clinical presentation and applicable diagnostic methods as well as macroscopic and microscopic pathomorphology. The pathogenesis of this disease is complex. Beside the role of alcohol, anatomic variations of the pancreatic ductal system, pancreatic islets in duodenal wall resulting from incomplete involution of dorsal pancreas, or Brunner gland hyperplasia (often observed as part of the lesion) can all play a role in the disturbance of pancreatic fluid discharge in the minor papilla area, eventually leading to this specific localised inflammation. In addition, recent investigations revealed a susceptible role of genetic polymorphism in the persistent inflammatory disorders of the pancreas. Besides summarizing the differential diagnostic aspects, we also discuss therapeutic possibilities, underlining the conservative methods, which can be used with good efficacy after a successful identification of this entity. Orv Hetil. 2019; 160(22): 873–879

Serum L-arginine and Dimethylarginine Levels in Migraine Patients with Brain White Matter Lesions

Background/Aim Migraine is a risk factor for the formation of silent brain white matter lesions (WMLs) that are possibly ischemic in nature. Although dysfunction of the L-arginine/nitric oxide (NO) pathway has been associated with oxidative stress and endothelial dysfunction in migraine, its role in WML development has not been specifically investigated. Thus, this prospective study aimed to measure the serum concentrations of the NO substrate L-arginine, the NO synthase inhibitor asymmetric dimethylarginine (ADMA), and the L-arginine transport regulator symmetric dimethylarginine (SDMA) in migraine patients in a headache-free period. Methods All participants underwent MR imaging to assess for the presence of WMLs on fluid-attenuated inversion recovery imaging. Altogether 109 migraine patients (43 with lesions, 66 without lesions) and 46 control individuals were studied. High-performance liquid chromatography was used to quantify L-arginine, ADMA and SDMA serum concentrations. Migraine characteristics were investigated, and participants were screened for risk factors that can lead to elevated serum ADMA levels independent of migraine. Results Migraine patients and controls did not differ in regard to vascular risk factors. Migraineurs with WMLs had a longer disease duration ( p &lt; 0.001) and a higher number of lifetime headache attacks ( p = 0.005) than lesion-free patients. Higher L-arginine serum levels were found in both migraine subgroups compared to controls ( p &lt; 0.001). Migraine patients with WMLs showed higher ADMA concentrations than lesion-free patients and controls ( p &lt; 0.001, for both). In migraineurs, the presence of WMLs, aura and increasing age proved to be significant predictors of increased ADMA levels ( p = 0.008, 0.047 and 0.012, respectively). SDMA serum levels of lesional migraineurs were higher than in nonlesional patients ( p &lt; 0.001). The presence of lesions and increasing age indicated an increased SDMA level ( p = 0.017 and 0.001, respectively). Binary logistic regression analysis showed that ADMA level ( p = 0.006), increasing age ( p = 0.017) and the total number of lifetime migraine attacks ( p = 0.026) were associated with an increased likelihood of exhibiting WMLs. There was no significant effect of age on ADMA and SDMA concentrations in controls. Conclusions Elevated ADMA levels may impact the pathogenesis of migraine-related WMLs by influencing cerebrovascular autoregulation and vasomotor reactivity. Higher SDMA concentrations may indirectly influence NO synthesis by reducing substrate availability. Elevated L-arginine serum levels might reflect an increased demand for NO synthesis. </jats:sec

Meta-Analysis of Early Nutrition: The Benefits of Enteral Feeding Compared to a Nil Per Os Diet Not Only in Severe, but Also in Mild and Moderate Acute Pancreatitis.

The recently published guidelines for acute pancreatitis (AP) suggest that enteral nutrition (EN) should be the primary therapy in patients suffering from severe acute pancreatitis (SAP); however, none of the guidelines have recommendations on mild and moderate AP (MAP). A meta-analysis was performed using the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P). The following PICO (problem, intervention, comparison, outcome) was applied: P: nutrition in AP; I: enteral nutrition (EN); C: nil per os diet (NPO); and O: outcome. There were 717 articles found in Embase, 831 in PubMed, and 10 in the Cochrane database. Altogether, seven SAP and six MAP articles were suitable for analyses. In SAP, forest plots were used to illustrate three primary endpoints (mortality, multiorgan failure, and intervention). In MAP, 14 additional secondary endpoints were analyzed (such as CRP (C-reactive protein), WCC (white cell count), complications, etc.). After pooling the data, the Mann-Whitney U test was used to detect significant differences. Funnel plots were created for testing heterogeneity. All of the primary endpoints investigated showed that EN is beneficial vs. NPO in SAP. In MAP, all of the six articles found merit in EN. Analyses of the primary endpoints did not show significant differences between the groups; however, analyzing the 17 endpoints together showed a significant difference in favor of EN vs. NPO. EN is beneficial compared to a nil per os diet not only in severe, but also in mild and moderate AP

Országos Táplálkozás és Tápláltsági Állapot Vizsgálat – OTÁP2014. II. A magyar lakosság energia- és makrotápanyag-bevitele | Hungarian Diet and Nutritional Status Survey – OTÁP2014 II. Energy and macronutrient intake of the Hungarian population

Absztrakt: Bevezetés és célkitűzés: A vizsgálat célja a magyar felnőtt lakosság táplálkozási szokásainak, tápanyagbevitelének és ezek időbeli változásainak monitorozása. Módszer: A táplálkozási adatfelvétel háromnapos táplálkozási naplóval történt. A minta a 18 éves és a 18 évesnél idősebb lakosságot reprezentálja nem és életkor szerint. Eredmények: A magyar lakosság táplálkozásában kimutatható a túlzott zsírbevitel (38 E% férfiak, 37 E% nők), ezzel szemben a szénhidrátok energiaaránya túl kevés (45 E% férfiak, 47 E% nők), míg a fehérjebevitel megfelelő. Következtetés: Kedvezőtlen változás a 2009-es táplálkozási vizsgálathoz képest a nők zsír és telített zsírsavak energiaarányának növekedése, és mindkét nem esetén a zöldség-, gyümölcsfogyasztás csökkenése, amely utóbbi magyarázza a rostbevitel csökkenését. A hozzáadott cukor energiaaránya a 2009-es vizsgálathoz képest mindkét nem minden korosztályában növekedést mutat. Így a zöldség- és gyümölcsfogyasztás növelésére, a hozzáadott cukor és telített zsírsavak energiaarányának csökkentésére fókuszáló beavatkozások szükségesek a lakosság egészségi állapotának javítása érdekében. Orv. Hetil., 2017, 158(15), 587–597. | Abstract: Introduction and aim: The aim of the study was to assess and monitor the dietary habits and nutrient intake of Hungarian adults. Method: Three-day dietary records were used for dietary assessment, the sample was representative for the Hungarian population aged ≥18ys by gender and age. Results: The mean proportion of energy from fat was higher (men: 38 energy%, women: 37 energy%), that from carbohydrates was lower (men: 45 energy%, women: 47 energy%) than recommended, the protein intake is adequate. Conclusion: Unfavorable change compared to the previous survey in 2009 was the increase of fat and saturated fatty acid energy percent in women, the decrease in fruit and vegetable consumption, which explains the decreased fiber intake. An increasing trend in added sugar energy percent in each age groups of both genders was observed compared to 2009. Interventions focusing on the promotion of fruit and vegetable consumption and decreasing of saturated fat and added sugar intake are needed. Orv. Hetil., 2017, 158(15), 587–597

Evaluation of Retinal Blood Flow in Patients with Monoclonal Gammopathy Using OCT Angiography

Background: Monoclonal gammopathy (MG) is characterized by monoclonal protein overproduction, potentially leading to the development of hyperviscosity syndrome. Objective: To assess retinal circulation using optical coherence tomography angiography (OCTA) parameters in patients with monoclonal gammopathy. Methods: OCTA measurements were performed using the Optovue AngioVue system by examining 44 eyes of 27 patients with MG and 62 eyes of 36 control subjects. Superficial and deep retinal capillary vessel density (VD SVP and DVP) in the whole 3 × 3 mm macular and parafoveal area, foveal avascular zone (FAZ) area, and central retinal thickness (CRT) were measured using the AngioAnalytics software. The OCTA parameters were evaluated in both groups using a multivariate regression model, after controlling for the effect of imaging quality (SQ). Results: There was no significant difference in age between the subjects with monoclonal gammopathy and the controls (63.59 ± 9.33 vs. 58.01 ± 11.46 years; p > 0.05). Taking into account the effect of image quality, the VD SVP was significantly lower in the MG group compared to the control group (44.54 ± 3.22% vs. 46.62 ± 2.84%; p < 0.05). No significant differences were found between the two groups regarding the other OCTA parameters (p > 0.05). Conclusions: A decreased superficial retinal capillary vessel density measured using OCTA in patients with MG suggests a slow blood flow, reduced capillary circulation, and consequent tissue hypoperfusion. An evaluation of retinal circulation using OCTA in cases of monoclonal gammopathy may be a sensitive method for the non-invasive detection and follow-up of early microcirculatory dysfunction caused by increased viscosity

Gender difference in the effects of interleukin-6 on grip strength - a systematic review and meta-analysis

BACKGROUND: Aging sarcopenia characterized by low muscle mass with low muscle strength affects men and women differently. The contribution of interleukin-6 (IL-6) to sarcopenia has been suggested based on a negative correlation between plasma IL-6 and muscle function described by some studies. However, no consensus regarding clinically relevant cut-off criteria has been reached. Another question arises whether pooling male and female data is an accurate way to determine the predictive value of IL-6 in sarcopenia. The present meta-analysis was designed to assess: (1) whether plasma IL-6 in aged populations in fact correlates negatively to muscle strength; (2) whether such a correlation exists both in men and in women; and (3) whether plasma IL-6 shows a gender difference in old age. METHODS: We applied the preferred reporting items for systematic review and meta-analysis protocols (PRISMA). We searched PubMed and Embase for papers that reported data on individuals over 65 without inflammatory diseases. We extracted either separate male and female data on plasma IL-6 along with at least one muscle parameter or correlation coefficient between plasma IL-6 and these parameters. Random effect models calculated with DerSimonian and Laird weighting methods were applied to analyze correlation coefficients and gender difference in plasma IL-6. Egger's test was used to assess the small study effect. RESULTS: Twenty articles out of 468 records identified were suitable for analyses. Plasma IL-6 correlates negatively with grip strength in mixed populations and also separately in men [- 0.25 with 95% confidence interval (CI): - 0.48, - 0.02] and in women (- 0.14 with 95% CI: - 0.24, - 0.03). However, contrary to expectations, men with better muscle condition have higher plasma IL-6 than women of similar age with worse muscle condition (plasma IL-6 male-female difference: 0.25 pg/mL with 95% CI: 0.15, 0.35). CONCLUSION: This is the first study to demonstrate that a higher predictive IL-6 cut-off level should be determined for aging sarcopenia in men than in women

Treatment of relapsing multiple sclerosis in Hungary – consensus recommendation from the Hungarian neuroimmunology society

Multiple sclerosis (MS) may impact quality of life, careers and family plans of the affected individuals. The current treatments with disease modifying therapies aim to prevent people with MS (pwMS) from disability accumulation and progression. Different countries have different reimbursement policies resulting in inequalities in patient care among geographical regions. Access to anti-CD20 therapies for relapsing MS is restricted in Hungary because therapy of individual cases only is reimbursed. In the light of the latest research and national guidelines, 17 Hungarian MS experts agreed on 8 recommendations regarding relapsing pwMS using the Delphi round method. Strong agreement (> 80%) was achieved in all except one recommendation after three rounds, which generated a fourth Delphi round. The experts agreed on treatment initiation, switch, follow-up and discontinuation, as well as on special issues such as pregnancy, lactation, elderly population, and vaccination. Well-defined national consensus protocols may facilitate dialogue between policymakers and healthcare professionals and thus contribute to better patient care in the long run