Increased expression of markers of early atherosclerosis in patients with inflammatory bowel disease

Recent studies documented an increased cardiovascular risk in patients with inflammatory bowel disease (IBD). Our study aimed at investigating the prevalence of intima-media thickness (IMT) of the carotid arteries and the arterial stiffness indices as markers of early atherosclerosis in young IBD patients

Early high-dosage atorvastatin treatment improved serum immune-inflammatory markers and functional outcome in acute ischemic strokes classified as large artery atherosclerotic stroke: A randomized trial

Statins have beneficial effects on cerebral circulation and brain parenchyma during ischemic stroke and reperfusion. The primary hypothesis of this randomized parallel trial was that treatment with 80 mg/day of atorvastatin administered early at admission after acute atherosclerotic ischemic stroke could reduce serum levels of markers of immune-inflammatory activation of the acute phase and that this immune-inflammatory modulation could have a possible effect on prognosis of ischemic stroke evaluated by some outcome indicators. We enrolled 42 patients with acute ischemic stroke classified as large arteries atherosclerosis stroke (LAAS) randomly assigned in a randomized parallel trial to the following groups: Group A, 22 patients treated with atorvastatin 80mg (once-daily) from admission day until discharge; Group B, 20 patients not treated with atorvastatin 80mg until discharge, and after discharge, treatment with atorvastatin has been started. At 72 hours and at 7 days after acute ischemic stroke, subjects of group A showed significantly lower plasma levels of tumor necrosis factor-a, interleukin (IL)-6, vascular cell adhesion molecule-1, whereas no significant difference with regard to plasma levels of IL-10, E-Selectin, and P-Selectin was observed between the 2 groups. At 72 hours and 7 days after admission, stroke patients treated with atorvastatin 80mg in comparison with stroke subjects not treated with atorvastatin showed a significantly lower mean National Institutes of Health Stroke Scale and modified Rankin scores. Our findings provide the first evidence that atorvastatin acutely administered immediately after an atherosclerotic ischemic stroke exerts a lowering effect on immune-inflammatory activation of the acute phase of stroke and that its early use is associated to a better functional and prognostic profile

Arterial stiffness, endothelial and cognitive function in subjects with type 2 diabetes in accordance with absence or presence of diabetic foot syndrome

Abstract Background Endothelial dysfunction is an early marker of cardiovascular disease so endothelial and arterial stiffness indexes are good indicators of vascular health. We aimed to assess whether the presence of diabetic foot is associated with arterial stiffness and endothelial function impairment. Methods We studied 50 subjects with type 2 diabetes mellitus and diabetic foot syndrome (DFS) compared to 50 diabetic subjects without diabetic foot, and 53 patients without diabetes mellitus, by means of the mini mental state examination (MMSE) administered to evaluate cognitive performance. Carotid-femoral pulse wave velocity (PWV) and augmentation index (Aix) were also evaluated by Applanation tonometry (SphygmoCor version 7.1), and the RH-PAT data were digitally analyzed online by Endo-PAT2000 using reactive hyperemia index (RHI) values. Results In comparison to diabetic subjects without diabetic foot the subjects with diabetic foot had higher mean values of PWV, lower mean values of RHI, and lower mean MMSE. At multinomial logistic regression PWV and RHI were significantly associated with diabetic foot presence, whereas ROC curve analysis had good sensitivity and specificity in arterial PWV and RHI for diabetic foot presence. Conclusions Pulse wave velocity and augmentation index, mean RHI values, and mean MMSE were effective indicators of diabetic foot. Future research could address these issues by means of longitudinal studies to evaluate cardiovascular event incidence in relation to arterial stiffness, endothelial and cognitive markers

HLA and killer cell immunoglobulin-like receptor (KIRs) genotyping in patients with acute viral encephalitis

Introduction: The HLA genes, as well as the innate immune KIR genes, are considered relevant determinants of viral outcomes but no study, to our knowledge, has evaluated their role in the clinical setting of acute viral encephalitis. Results: Subjects with acute viral encephalitis in comparison to subjects without acute viral encephalitis showed a significantly higher frequency of 2DL1 KIR gene and AA KIR haplotypes and of HLA-C2 and HLA-A-Bw4 alleles. Subjects without acute viral encephalitis showed a higher frequency of interaction between KIR2DL2 and HLAC1. Multiple logistic regression analysis showed the detrimental effect of HLA-A haplotype and HLA-C1, HLA-A-BW4 HLA-B-BW4T alleles, whereas multiple logistic regression showed a protective effect of AB+BB KIR haplotype and a detrimental effect of interaction between KIR3DL1 and HLA-A-Bw4. Discussion: Our findings of a lower frequency of activating receptors in patients with acute encephalitis compared to controls could result in a less efficient response of NK cells. This finding could represent a possible pathogenetic explanation of susceptibility to acute symptomatic encephalitis in patients with viral infection from potentially responsible viruses such as Herpes virus. Materials and Methods: 30 Consecutive patients with symptomatic acute viral encephalitis and as controls, 36 consecutive subjects without acute encephalitis were analyzed. The following KIR genes were analyzed, KIR2DL1, 2DL2, 2DL3, 2DL5, 3DL1, 3DL2, 3DL3, 2DL4, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DS1, 2 pseudogenes (2DP1 and 3DP1) and the common variants of KIR2DL5 (KIR2DL5A, KIR2DL5B)

HLA and killer cell immunoglobulin-like receptor (KIRs) genotyping in patients with acute ischemic stroke

Introduction: In humans, a major component of natural killer (NK) and T cell target recognition depends on the surveillance of human leukocyte antigen (HLA) class I molecules by killer immunoglobulin-like receptors (KIRs). Aims: To implement the knowledge about the immunological genetic background of acute ischemic stroke susceptibility in relation to the frequency of the KIR genes and HLA alleles. Methods: Subjects with acute ischemic stroke and subjects without stroke were genotyped for the presence of KIR genes and of the three major KIR ligand groups, HLA-C1, HLA-C2, and HLA-Bw4, both HLA-B and HLA-A loci. Results: Between November 2013 and February 2016, consecutive patients with acute ischemic stroke were recruited. As healthy controls, we enrolled subjects without acute ischemic stroke. Subjects with acute ischemic stroke in comparison with controls showed a higher frequency of 2DL3, 2DL5B, 2DS2, and 2DS4 KIR genes and a lower frequency of HLA-B-Bw4 I alleles. Subjects without acute ischemic stroke showed a higher frequency of interaction between KIR 2DS2 and HLAC2. We also observed a higher frequency of 2DL3 and 2 DL4 KIR genes in subjects with atherosclerotic (LAAS) subtype. Multiple logistic regression analysis showed a protective effect towards stroke of HLA-B-Bw4 I and interaction between KIR 2DL2 and HLAC1 and 2DS2-HLAC2 and a detrimental effect of 2DL2-HLA-C1-A interactions. Conclusion: Our findings of a higher frequency of activating KIR genes seem to be consistent with findings previously reported patients with coronary syndrome. This higher frequency of "proinflammatory" genes in subjects with ischemic stroke could also explain the immunoinflammatory activation of the acute phase of stroke

RENAL SALT WASTING: UNA SINDROME DA INAPPROPRIATA SECREZIONE DI URODILATINA? UNO STUDIO PILOTA

La Renal Salt Wasting Syndrome (RSW) è una sindrome clinica con caratteristiche di laboratorio che si sovrappongono completamente alla sindrome da secrezione inappropriata di ADH (SIADH). La differenza fondamentale tra le due sindromi risiede nel volume extracellulare (ECV), ridotto nella RSW e normale o leggermente aumentato nella SIADH. Le difficoltà nella diagnosi differenziale di questa sindrome e nella comprensione del preciso meccanismo patogenetico hanno contribuito a mettere in discussione l'esistenza stessa di RSW. Considerando le caratteristiche della RSW, è stato studiato il possibile ruolo dei peptidi natriuretici per spiegare la sua patogenesi come ANP e BNP, con risultati insoddisfacenti. Tuttavia, nessuno studio ha ancora indagato il possibile ruolo dell'urodilatina, un peptide appartenente alla famiglia dei peptidi natriuretici, che sembra avere un ruolo cruciale nella regolazione della sodiemia e del sodio urinario anche più dell'ANP. Abbiamo eseguito uno studio osservazionale retrospettivo, i pazienti sono stati divisi in 3 gruppi: un gruppo di pazienti senza iponatriemia e due gruppi di pazienti con iponatriemia, uno costituito da pazienti con RSW e l'altro costituito da pazienti con iponatriemia da altre cause. I pazienti con RSW mostrano livelli medi di urodilatina significativamente più elevati rispetto a entrambi i pazienti con (mediana 5,46 vs 0,57 ng/mL, p=0,006) o senza iponatriemia (mediana 5,46 vs 0,27 ng/mL, p<0,001). Livelli medi più elevati statisticamente significativi di urodilatina sono stati osservati anche quando i pazienti con RSW sono stati confrontati con gli altri due gruppi di pazienti considerati insieme (5,46 vs 0,32 ng/mL, test MW p<0,001). Al contrario, i livelli di proANP non erano statisticamente differenti tra i 3 sottogruppi (test KS complessivo p=0,266) o tra pazienti con RSW e pazienti con/senza iponatriemia (4,9 vs 9,7 nM, test MW p=0,122). Le prestazioni diagnostiche dei livelli medi di urodilatina per la diagnosi di RSW sono state valutate mediante la curva ROC. L'area sotto la curva (AUC) era 0,94 (IC 95% 0,86-1,00). Il miglior cut-off per i livelli medi di urodilatina, secondo l'indice di Youden, era di 2,87 ng/mL. A questo cut-off sensibilità, specificità, valore predittivo positivo e valore predittivo negativo erano, rispettivamente, 1,00, 0,88, 0,60 e 1,00. In conclusione, questo studio pilota ha mostrato risultati interessanti per quanto riguarda il dosaggio di urodilatina urinaria in pazienti con RSW, con implicazioni potenzialmente chiarificatrici e di utilità pratica sia per quanto riguarda la patogenesi di questa sindrome, sia per quanto riguarda i suoi criteri diagnostici e quindi sulla gestione clinica dei pazienti. Ci auguriamo che ulteriori studi futuri possano continuare a fare luce su questo interessante argomento.Renal Salt Wasting Syndrome (RSW) is a clinical syndrome with laboratory characteristics completely overlapping with the syndrome of inappropriate ADH secretion (SIADH). The fundamental difference between the two syndromes lies in the extracellular volume (ECV), reduced in RSW and normal or slightly increased in SIADH. The difficulties in the differential diagnosis of this syndrome and in understanding the precise pathogenetic mechanism have contributed some authors to question the very existence of RSW. Considering the characteristics of RSW, natriuretic peptides were investigated to explain its onset such as ANP and BNP, with unsatisfactory results. However, no studies have yet investigated the possible role of urodilatin, a peptide belonging to the natriuretic peptide family, which seems to have a crucial role in regulating blood sodium and urinary sodium even more than ANP. We performed a retrospective observational study, the patients were divided into 3 groups: a group of patients without hyponatremia and two groups of patients with hyponatremia, one consisting of patients with RSW and the other consisting of patients with hyponatremia from other causes. patients with RSW display significantly higher mean urodilatin levels than both patients with (median 5.46 vs 0.57 ng/mL, p=0.006) or without hyponatremia (median 5.46 vs 0.27 ng/mL, p<0.001). Statistically significant higher mean levels of urodilatin were also observed when patients with RSW were compared with the other two groups of patients considered together (5.46 vs 0.32 ng/mL, MW test p<0.001). Conversely, proANP levels were not statistically different among the 3 subgroups (overall KS test p=0.266) or between patients with RSW and patients with/without hyponatremia (4.9 vs 9.7 nM, MW test p=0.122). Diagnostics performances of mean urodilatin levels for RSW diagnosis were evaluated by ROC curve. Area under the curve (AUC) was 0.94 (95%CI 0.86-1.00). Best cut-off for mean urodilatin levels, according to Youden’s index, was 2.87 ng/mL. At this cut-off sensitivity, specificity, positive predictive value and negative predictive value were, respectively, 1.00, 0.88, 0.60 and 1.00. In conclusion, this pilot study has shown interesting results regarding the dosage of urinary urodilatin in patients with RSW, with potentially clarifying implications and of practical utility both regarding the pathogenesis of this syndrome and regarding its diagnostic criteria and therefore on the clinical management of patients. We hope that further future studies can continue to shed light on this interesting topic

Molecular Mechanisms of Inflammasome in Ischemic Stroke Pathogenesis

Abstract: Ischemic stroke (also called cerebral ischemia) is one of the leading causes of death and severe disability worldwide. NLR inflammasomes play a crucial role in sensing cell damage in response to a harmful stimuli and modulating the inflammatory response, promoting the release of pro-inflammatory cytokines such as IL-18 and IL-1β following ischemic injury. Therefore, a neuroprotective effect is achieved by inhibiting the expression, assembly, and secretion of inflammasomes, thus limiting the extent of brain detriment and neurological sequelae. This review aims to illustrate the molecular characteristics, expression levels, and assembly of NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin-domain-containing 3) inflammasome, the most studied in the literature, in order to discover promising therapeutic implications. In addition, we provide some information regarding the contribution of NLRP1, NLRP2, and NLRC4 inflammasomes to ischemic stroke pathogenesis, highlighting potential therapeutic strategies that require further study

Efficacy of dulaglutide on vascular health indexes in subjects with type 2 diabetes: a randomized trial

Recent cardiovascular outcome trials have shown significant reductions in major cardiovascular (CV) events with glucagon-like peptide (GLP)-1 receptor agonists. Additionally, adjunctive surrogates for cardiovascular risk validated by some studies include arterial stiffness and endothelial function indexes. To date, no randomized trial has addressed the possible effects of antidiabetic interventional drugs such as GLP1 agonists on endothelial and arterial stiffness indexes as surrogate markers of vascular damage. Aims We aimed to evaluate metabolic efficacy and surrogate vascular efficacy endpoints of once-weekly dulaglutide (1.5 mg) plus traditional antidiabetic treatment compared with traditional antidiabetic treatment alone in subjects with type 2 diabetes. Methods Men and women (aged ≥ 50 years) with established or newly detected type 2 diabetes whose HbA1c level was 9.5% or less on stable doses of up to two oral glucose­ lowering drugs with or without basal insulin therapy were eligible for randomization. Subcutaneous dulaglutide was initiated at the full dose (1.5 mg/day weekly). Arterial stiffness (PWV: pulse wave velocity and augmentation index) and endothelial function (RHI: reactive hyperaemia index) were evaluated at baseline and at three-month and nine-month examination visits. At each visit (at 3 and 9 months), the subjects were also evaluated for glycaemic variables such as fasting plasma glucose (FPG) and HbA1c and lipid variables such as total cholesterol, LDL cholesterol, HDL cholesterol and triglyceride levels. Results At the three-month follow-up, the subjects treated with dulaglutide showed significantly lower serum levels of FPG and HbA1c than control subjects treated with conventional therapy. At the 9-month follow-up, subjects treated with dulaglutide showed significant lower values of the mean diastolic blood pressure, BMI, total serum cholesterol, LDL cholesterol, FPG, HbA1c and PWV and higher mean RHI values than control subjects treated with conventional therapy. Conclusions Our randomized trial showed that subjects with type 2 diabetes treated with conventional therapy plus 1.5 mg/day of subcutaneous dulaglutide compared with subjects treated with conventional therapy alone showed favourable metabolic effects associated with positive effects on vascular health markers such as arterial stiffness and endothelial function markers. These findings are consistent with previous study findings indicating the strict relationship between cardiovascular risk factors such as systolic blood pressure, total serum cholesterol and LDL levels and cardiovascular events and vascular health surrogate markers

A family with various symptomatology suggestive of Anderson-Fabry disease and a genetic polymorphism of alpha galactosidase A gene

Background: Anderson/Fabry disease expresses a wide range of clinical variability in patients that it is possible to explain referring to a genetic variability with numerous mutations described in the literature (more than 600). Methods: We report some clinical cases of some members of a Sicilian family to express phenotypical variability of this disease in subjects with the same genetic mutation. Results: The first case was a 59-year-old female. Brain MRI revealed right frontal periventricular white matter of likely vascular-degenerative origin. The proband's alpha galactosidase A activity was 3.7. nmol/mL/h. Molecular genetics revealed a polymorphism: - 10 C. &gt;. T; IVS 2-76_80del5; IVS4-16 A. &gt;. G; IVS6-22 C. &gt;. T. The second case was a 30. year-old male affected by acroparesthesias and hypoidrosis since he was an adolescent. Renal impairment was first detected at age 29; it began with high plasma levels of creatinine and microalbuminuria date. The third case was a 41. year-old daughter that presented with acroparesthesias, hypoidrosis since she was very young. The patient's alpha galactosidase A activity was 4.1. nmol/mL/h, in whole blood, which is compatible with heterozygote subject for Fabry's disease or healthy control. The fourth case was a male grandson of the proband, 9. year-old child. He had a classic gastrointestinal involvement. He complained of recurrent abdominal pain, post prandial bloating and pain. This child's enzyme activity was 1.65. nmol/mL/h. In cases 2, 3, and 4, molecular genetics revealed a polymorphism: - 10 C. &gt;. T; IVS 2-76_80del5; IVS4-16 A. &gt;. G; IVS6-22 C. &lt;. T. Discussion: A recent study reported that IVS4. +. 68 A. &gt;. G, IVS6-22C. &gt;. T polymorphisms occurred in 8.9% and 3.7% of the subjects respectively, and the significance of this haplotype in FD pathology remains unknown but possibly suggestive of Anderson/Fabry disease