A perspective on risk factors for esophageal adenocarcinoma: emphasis on Helicobacter pylori infection.

Gastroesophageal reflux disease (GERD) and the increasing rate of its associated complications, including esophageal adenocarcinoma (EAC), has stimulated a plethora of studies attempting to evaluate provocative and protective factors. Helicobacter pylori (Hp) infection (Hp-I) was initially considered as a beneficial condition in GERD management based on rather limited data. Large-scale regional studies revealed an alternative approach, by suggesting a positive relationship between Hp-I and EAC development. Regarding pathophysiology, Hp-I induces gastric microbiota disturbances through hypochlorhydria and chronic inflammation, with a subsequent possible effect on the GERD-Barrett's esophagus (BE)-EAC cascade. Additionally, both direct effects on esophageal mucosa and indirect effects on known mechanisms of GERD, such as acid pocket and transient lower esophageal sphincter relaxation, remain to be elucidated. Hp contribution to carcinogenesis is related to oncogenic gastrin, cyclooxygenase-2, and prostaglandins; Ki-67 is also expressed and represents an index of BE-related malignancy. Moreover, Hp-I is vigorously suggested as a risk factor for metabolic syndrome, which may be the link between Hp-I and EAC. Although further studies are necessary to establish a pathophysiologic risk between Hp-I and the GERD-BE-EAC sequence, the theory of Hp protection against GERD seems outdated.

Effect of integrin AV and B8 gene polymorphisms in patients with traumatic brain injury.

Background: Α few genetic variants are associated with the outcome after traumatic brain injury (TBI). Integrins are glycoprotein receptors that play an important role in the integrity of microvasculature of the brain. Objective: To examine the role of integrin-AV (ITGAV) and integrin-B8 (ITGB8) tag single nucleotide polymorphisms (SNPs) on the outcome of patients with TBI. Methods: 363 participants were included and genotyped for 11 SNPs for ITGAV and 11 for ITGB8 gene. SNPs were tested for associations with the 6-month outcome after TBI, the presence of a hemorrhagic event after TBI, and the initial TBI severity after adjustment for TBI's main predictors. Results: The ITGAV rs3911239 CC and rs7596996 GG genotypes were associated with an unfavorable outcome after TBI, compared to the TT and AA genotypes, respectively. The ITGB8 rs10239099 CC and rs3757727 CC genotypes were associated with increased risk of any cerebral hemorrhagic event after TBI compared to GG and TT respectively. The ITGAV rs7589470 and rs7565633 were associated with the TBI's initial severity. Conclusions: ITGAV gene SNPs may be implicated in the outcome after TBI, as well as in the initial TBI severity, and also of ITGB8 gene SNPs in the risk of hemorrhagic event after a TBI.

Hypertension in hematologic malignancies and hematopoietic cell transplantation: An emerging issue with the introduction of novel treatments.

Blood pressure levels are directly associated with cardiovascular and cerebrovascular morbidity and mortality, rendering arterial hypertension a major public health problem affecting almost 1 billion people worldwide. Several models have been used for cardiovascular risk prediction based on traditional cardiovascular risk factors. Among them, hypertension represents a factor that may be triggered by distinct pathogenetic mechanisms in specific disease populations. Accumulating evidence points towards an increased incidence of hypertension in patients with hematologic malignancies and recipients of hematopoietic cell transplantation. However, the role of hypertension in these entities remains under-reported in the relevant literature. In the complex setting of life-threatening conditions that need immediate and aggressive treatment, conditions that are common and easy to diagnose such as hypertension, may be neglected by treating physicians. However, hypertension may represent a key diagnostic and prognostic clinical finding in acute syndromes, such as thrombotic microangiopathy. Furthermore, hypertension may arise as a late effect of long-term survivors leading to increased morbidity and mortality across all age groups. Our concise review focuses on incidence, pathophysiology and management of hypertension in patients following hematopoietic cell transplantation and treatment for hematologic malignancies.

AQP4 tag SNPs in patients with intracerebral hemorrhage in Greek and Polish population.

BACKROUND: A relatively small number of genetic variants are implicated to pathophysiology of intracerebral hemorrhage (ICH). Aquaporin-4 (AQP4) has been reported to be implicated in the pathophysiological processes of ICH development. OBJECTIVE: To examine the role of AQP4 gene region polymorphisms on the ICH risk. METHODS: A total of 250 Greek and 193 Polish patients with primary ICH and 250 and 322 respective controls were enrolled, forming two independent cohorts in order to validate any significant effect. With logistic regression analyses, 7 AQP4 tag single nucleotide polymorphisms (SNPs) were examined for association with ICH risk, lobar/non-lobar ICH risk, and 6-month disability after ICH. Cox regression analysis was applied in order to the effect of AQP4 SNPs on ICH age of onset be tested. Correction for multiple comparisons was applied. RESULTS: Multivariate logistic regression analysis showed that rs3875089 in the Greek cohort and rs3763043, rs335931 in the Polish cohort had a significant influence on the risk of ICH, lobar and non-lobar ICH. Regarding the age of onset, rs3875089 in the Greek cohort and rs3763043, rs11661256 in the Polish cohort were found to significantly alter the age of onset of ICH and its subtypes. However, all of the above associations did not survive the Bonferroni correction (p-value >0.007). Finally, AQP4 tag SNPs were not found to have any significant effect on long-term disability after ICH. CONCLUSIONS: In conclusion, the present study provides an indication that AQP4 gene variants may affect susceptibility to primary ICH and may influence the ICH age of onset.

Integrins AV and B8 Gene Polymorphisms and Risk for Intracerebral Hemorrhage in Greek and Polish Populations.

Α limited number of genetic variants have been linked to the development of intracerebral hemorrhage (ICH). Ιntegrin AV and/or B8-deficient mice were found to develop ICH. The present candidate gene association study was designed to investigate possible influence of integrin AV (ITGAV) and integrin B8 (ITGB8) gene region polymorphisms on the risk of ICH. 1015 participants (250 Greek and 193 Polish patients with primary ICH and 250 Greek and 322 Polish controls) were included in the study. Using logistic regression analyses, 11 tag single nucleotide polymorphisms (SNPs) for ITGAV and 11 for ITGB8 gene were tested for associations with ICH risk, lobar ICH risk and non-lobar ICH after adjustment for age, gender, history of hypertension and country of origin. Linear regression models were used to test the effect of tag SNPs on the ICH age of onset. Correction for multiple comparisons was carried out. The rs7565633 tag SNP of the ITGAV gene was independently associated with the risk of lobar ICH in the codominant model of inheritance [odds ratio (95 % confidence interval (CI)) 0.56 (0.36-0.86), p = 0.0013]. Furthermore, heterozygous individuals of the rs10251386 and the rs10239099 of the ITGB8 gene had significantly lower age of ICH onset compared to the wild-type genotypes [regression coefficient (b) -3.884 (95 % CI -6.519, -1.249), p = 0.0039 and b = -4.502 (95 % CI -7.159, -1.845), p = 0.0009, respectively]. The present study provides preliminary indication for an influence of ITGAV gene tag SNP in the development of lobar ICH and of ITGB8 gene variants in the age of ICH onset.

A Comparison of Prognostic Value of the Levels of ProBNP and Troponin T in Patients with Acute Coronary Syndrome (ACS).

INTRODUCTION: The propeptide of brain natriuretic peptide (ProBNP) is used for the diagnosis of left ventricle dysfunction and heart failure. In patients with an Acute Coronary Syndrome (ACS) it can contribute to both short and long term prognosis of cardiovascular events that could be very important for management and therapy of these patients. AIM: The aim of this study was to evaluate the prognostic value of ProBNP for the clinical course after an acute coronary syndrome, compared with that of cardiac troponine T (cTnT) and the risk stratification of patients with acute coronary syndrome, both during hospitalization and six months later. METHODS: We studied 390 patients (256 men, 134 women, mean age 66.04+12.38) with an acute coronary syndrome who were hospitalized in the Coronary Unit of our cardiology clinic. We studied epidemiological and clinical data and biochemical markers were examined as prognostic factors for clinical course intrahospital and during six months follow-up. RESULTS: In the majority of patients, a myocardial infarction without ST elevation was diagnosed (NSTEMI) (193 patients 49.49%) while 167 patients (42.82%) had a myocardial infarction with ST elevation (STEMI) and the remaining 30 patients (7.69%) had unstable angina. Patients had multiple risk factors for coronary heart disease. The levels of ProBNP were significantly elevated in patients with STEMI (p=0.003) and NSTEMI (p=0.002) who died or experienced an adverse event (angina, myocardial infarction, cardiogenic shock, congestive heart failure, arrhythmias) during hospitalization. After six months of follow-up, patients who had an adverse event had higher levels of ProBNP. There was no difference in troponine T levels in patients with STEMI and NSTEMI who had adverse events compared with the others, either during hospitalization or after six months. CONCLUSION: The level of ProBNP is an important predictor of cardiovascular events in patients with acute coronary syndrome. This study showed that it provides better predictive power than the troponine T.

Effect of angiotensin-converting enzyme tag single nucleotide polymorphisms on the outcome of patients with traumatic brain injury.

BACKGROUND: Genetic variants appear to influence, at least to some degree, the extent of brain injury and the clinical outcome of patients who have sustained a traumatic brain injury (TBI). Angiotensin-converting enzyme (ACE) is a zinc metallopeptidase that is implicated in the regulation of blood pressure and cerebral circulation. ACE gene polymorphisms were found to regulate serum ACE enzyme activity. OBJECTIVE: The present study aimed to investigate possible influence of ACE gene region variants on patients' outcome after TBI. PATIENTS AND METHODS: In total, 363 TBI patients prospectively enrolled in the study were genotyped for five tag single nucleotide polymorphisms (SNPs) across the ACE gene. Using logistic regression analyses, tag SNPs and their constructed haplotypes were tested for associations with 6-month Glasgow Outcome Scale scores, after adjustment for age, sex, Glasgow Coma Scale scores at admission, and the presence of a hemorrhagic event in the initial computed tomography scan. RESULTS: Significant effects on TBI outcome were found for three neighboring tag SNPs in the codominant (genotypic) model of inheritance [rs4461142: odds ratio (OR) 0.26, 95% confidence interval (CI) 0.12-0.57, P = 0.0001; rs7221780: OR 2.67, 95% CI 1.25-5.72, P = 0.0003; and rs8066276: OR 3.82, 95% CI 1.80-8.13, P = 0.0002; for the heterozygous variants compared with the common alleles]. None of the constructed common tag SNPs haplotypes was associated with TBI outcome. CONCLUSION: The present study provides evidence of the possible influence of genetic variations in a specific region of the ACE gene on the outcome of TBI patients. This association may have pharmacogenetic implications in identifying those TBI patients who may benefit from ACE inhibition.

AQP4 tag single nucleotide polymorphisms in patients with traumatic brain injury.

Accumulating evidence suggests that the extent of brain injury and the clinical outcome after traumatic brain injury (TBI) are modulated, to some degree, by genetic variants. Aquaporin-4 (AQP4) is the predominant water channel in the central nervous system and plays a critical role in controlling the water content of brain cells and the development of brain edema after TBI. We sought to investigate the influence of the AQP4 gene region on patient outcome after TBI by genotyping tag single nucleotide polymorphisms (SNPs) along AQP4 gene. A total of 363 patients with TBI (19.6% female) were prospectively evaluated. Data including the Glasgow Coma Scale (GCS) scores at admission, the presence of intracranial hemorrhage, and the 6-month Glasgow Outcome Scale (GOS) scores were collected. Seven tag SNPs across the AQP4 gene were identified based on the HapMap data. Using logistic regression analyses, SNPs and haplotypes were tested for associations with 6-month GOS after adjusting for age, GCS score, and sex. Significant associations with TBI outcome were detected for rs3763043 (OR [95% confidence interval (CI)]: 5.15 [1.60-16.5], p=0.006, for recessive model), rs3875089 (OR [95% CI]: 0.18 [0.07-0.50] p=0.0009, for allele difference model), and a common haplotype of AQP4 tag SNPs (OR [95% CI]: 2.94, [1.34-6.36], p=0.0065). AQP4 tag SNPs were not found to influence the initial severity of TBI or the presence of intracranial hemorrhages. In conclusion, the present study provides evidence for possible involvement of genetic variations in AQP4 gene in the functional outcome of patients with TBI.

Splenic infarction as a rare complication of infectious mononucleosis due to Epstein-Barr virus infection in a patient with no significant comorbidity: case report and review of the literature.

We report the case of a 17-y-old boy diagnosed with infectious mononucleosis due to Epstein-Barr virus infection who complained of left upper quadrant pain. A magnetic resonance imaging scan showed a splenic infarct in the enlarged spleen. Other causes of splenic infarction were excluded. Thus, infectious mononucleosis may cause splenic infarction in patients without other comorbidities.

Genetic factors influencing outcome from neurotrauma.

PURPOSE OF REVIEW: Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors. There is converging evidence from genetic research that a number of genetic variants may contribute to this variability. This review provides recent data from human studies, published in the previous year, on genetic factors influencing outcome after neurotrauma. The bibliographic databases MEDLINE, EMBASE and PsycINFO were searched to identify relevant studies. RECENT FINDINGS: Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies. Genetic loci investigated include polymorphisms in APOE, MAO-A, BDNF, NOS3, IL-6, NEFH, SLC6A4, COMT, PPP3CC and KIBRA genes. The importance of these findings and future directions are discussed. SUMMARY: Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity. A better understanding of the underlying biological pathways and molecular mechanisms of an individual's response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome.

Neuroinflammation in multiple sclerosis: evidence for autoimmune dysregulation, not simple autoimmune reaction.

Both inflammatory and neurodegenerative components may contribute to the clinical profile of multiple sclerosis (MS) leading to irreversible deficits when they exceed the threshold of compensation. The mechanisms leading to tissue injury in MS are complex. Inflammation appears to be caused by overactive pro-inflammatory T-helper 1 cells, initiating an inflammatory cascade with several cellular and molecular immune components participating in the pathogenetic mechanism. Current treatments are most effective in the inflammatory phase of the disease since they may interfere with various stages of the immune cascade. Recent evidence has emerged that inflammation may not only be destructive, but may also play a part in tissue repair. This has opened up a new aspect of our knowledge of the role of the inflammatory process in MS. Data regarding the role of regulatory cells in particular, imply that specific immunomodulatory strategies that support the function of these particular cellular subpopulations may participate in the downregulation of autoimmune responses in MS.

Neuroprotection in multiple sclerosis.

In chronic inflammatory diseases like multiple sclerosis (MS), neuroprotection refers to strategies aimed at prevention of the irreversible damage of various neuronal and glial cell populations, and promoting regeneration. It is increasingly recognized that MS progression, in addition to demyelination, leads to substantial irreversible damage to, and loss of neurons, resulting in brain atrophy and cumulative disability. One of the most promising neuroprotective strategies involves the use of bone marrow derived stem cells. Both hematopoietic and non-hematopoietic (stromal) cells can, under certain circumstances, differentiate into cells of various neuronal and glial lineages. Neuronal stem cells have also been reported to suppress EAE by exerting direct in situ immunomodulating effects, in addition to their ability to provide a potential source for remyelination and neuroregeneration. Preliminary results from our laboratory indicate that intravenous or intracerebral/intraventricular injection of bone marrow derived stromal cells could differentiate in neuronal/glial cells and suppress the clinical signs of chronic EAE. Both bone marrow and neuronal stem cells may therefore have a therapeutic potential in MS. It seems that future treatment strategies for MS should combine immunomodulation with neuroprotective modalities to achieve maximal clinical benefit.