Association of ALOX12 gene polymorphism with all-cause and cardiovascular mortality in diabetic nephropathy

Purpose

Cardiovascular (CV) events are the first cause of death in patients with chronic renal disease (CKD) and in patients with type 2 diabetes mellitus (DM2). The combination of CKD and DM2 elevates the risk of both cardiovascular disease (CVD) and death in this high-risk population. Besides traditional risk factors, such as dyslipidemia, smoking, obesity, and carotid atherosclerosis, novel factors are under investigation such as genetic polymorphisms. Lipoxygenases (LOXs) and their genes are of critical importance in oxidative stress, inflammation, and atherosclerosis. The aim of the study is to clarify a potential ALOX12 role in CVD presence and progress of diabetic patients in different stages of nephropathy.

Methods

We studied 145 patients with a documented history of DM2 for at least 10 years and diabetic nephropathy (DN), mean age 68 ± 9 years, body mass index 31 ± 5 kg/m², and different stages of renal disease, depending on glomerular filtration rate. The sample population consisted of two groups: 108 DM2 patients with DN in all five stages of CKD and 37 DM2 patients as controls. Anthropometric and clinical characteristics, interview for history of previous CV event, and assessment of carotid intima-media thickness (cIMT) were recorded at baseline. All patients were genotyped for ALOX12 polymorphisms with focus on rs14309. Genotypes (AA, AG, and GG) were evaluated for any possible role in CVD, and grouping was performed on A genotype, which is the dominant model. All participants were followed over a period of 7 years, and the end points studied were all-cause mortality, CV mortality, and CV events. CV events were defined as myocardial infarction (MI), stroke, or peripheral artery disease.

Results

The GG genotype has been significantly associated with cIMT levels above 0.86 mm and with history of MI. Regarding the presence of an atherosclerotic plaque in either carotid artery, no significant association was found when the genotypes were assessed on their own. After grouping, though, GG genotype revealed a significant association between carotid plaque formation and atheromatosis. Kaplan–Meier analysis revealed that ALOX12 gene GG genotype predicted all-cause mortality, CV mortality, and CV events. Similarly, when AA and AG genotypes were grouped, Kaplan–Meier analysis showed that patients with GG genotype presented an even more significant higher all-cause mortality, CV mortality, and CV events compared with AA and AG genotypes combined. After adjustment for several traditional risk factors, multivariate Cox proportional hazard analysis showed that patients with the GG genotype had a significant higher risk of all-cause mortality, a threefold increase in CV mortality, and a twofold increased risk for CV events compared to patients with the AA or the AG genotype.

Conclusion

ALOX12 rs14309 GG genotype expression was found to be significantly associated with MI, higher cIMT, increased CV events, CV, and overall mortality. This phenomenon could be partially explained by the increased platelet proaggregatory activity of AA products and the control they exert in thrombotic occurrence and plaque formation.

     

Tonic Pain Abolishes Cortical Habituation of Visual Evoked Potentials in Healthy Subjects

We investigated changes in visual cortex excitability by analyzing visual evoked potential (VEP) habituation in healthy subjects during tonic pain evoked by the cold-pressor test (CPT). We tested VEP amplitude habituation (slope of the linear regression line for N1-P1 amplitude from the 1st to 6th block of 100 sweeps) in 19 healthy volunteers during 4 experimental conditions: baseline; no-pain (hand held in warm water, 25°C); pain (hand held in cold water, 2–4°C); and the after-effects of tonic pain. During baseline and no-pain sessions, VEPs habituated normally across the 6 consecutive blocks (mean slope –.28 and –.18%), whereas during pain and its after-effects they failed to decrease (0%, and –.11%). Tonic pain induced by the CPT abolishes normal VEP habituation and the lack of habituation persists after the CPT is stopped. Tonic pain probably abolishes VEP habituation by acting on brainstem neural structures which modulate thalamo-cortical activation thereby changing visual cortex excitability.PerspectiveThis study shows that tonic pain alters visual cortex excitability, a brain region unrelated to pain processing. These changes probably reflect defensive strategies against pain. Extending the study from healthy volunteers to patients with migraine between attacks would offer the opportunity to investigate visual cortical excitability under conditions when baseline habituation is absent.     

Tongue strength,dysphagia questionnaire,pharyngeal secretions and FEES findings in dysphagia management in amyotrophic lateral sclerosis

ObjectiveDysphagia is common in Amyotrophic lateral sclerosis (ALS). ALS shows significant phenotypic variability. It is characterized by progressive weakness and/or spasticity of muscles. Dysphagia symptoms vary. Aspiration is often silent and cognitive dysfunction is common. The purpose of the study was to evaluate tongue strength measurements, dysphagia questionnaire, the presence of pharyngeal secretions, and FEES findings in dysphagia management in ALS.MethodsTwenty-five patients completed the Eating Assessment Tool-10 (EAT-10), had their Maximum Isometric Tongue Pressure (MITP), and endurance measured and underwent Flexible Endoscopic Evaluation of Swallowing (FEES) providing 31 examinations.ResultsOut of 25 patients, 76% were self-reported as dysphagic (EAT-10≥3) with a mean EAT-10 at 14.95 (±7.96). ALS patients had significantly decreased tongue strength (mean MITPanterior: 31.69 ± 17.32kPa). Comparing examinations of dysphagic and non-dysphagic status the mean MITPa of non-dysphagic was significantly greater (52.33 ± 10.97 kPa versus 20.6 ± 12.67 kPa), p<0.001. FEES detected aspiration in 10 out of 31 examinations [Penetration Aspiration Scale(PAS) ≥6]. Aspirator status examinations showed statistically significantly worse cough (p = 0.001), tongue strength (p = 0.001) and endurance (p = 0.003), pharyngeal secretions (p<0.001), velopharyngeal sufficiency (p = 0.006), pharyngeal squeeze (p = 0.009), vocal cords’ movements (p = 0.001), pharyngeal pooling (p<0.001), EAT-10 (p = 0.001) and bulbar subscale of ALS Functioning Rating Scale-Revised (b-ALSFRS-R) scores (p = 0.014) compared to non-aspirator status. Correlation analysis indicated that the feeding status had strong statistically significant correlations with the EAT-10 score (rho = ?0.816), anterior tongue strength (rho = 0.735), secretions (rho = ?0.811), pharyngeal pooling (rho = ?0.712) and PAS (rho = ?0.676) at FEES, and b-ALSFRS-R score (rho = 0.791), all p<0.001. The EAT-10 had strong statistically significant correlations with the MITPa (r = ?0.794, p<0.001), secretions (rho = 0.668, p<0.001), and b-ALSFRS-R score (rho = -0.766, p = 0.001). The FEES findings had strong statistically significant correlations with the anterior tongue strength (pooling: rho = ?0.784), and secretions (PAS: rho = 0.723; pooling: rho = 0.671), all p<0.001. For the questionnaire, tongue strength and pharyngeal secretions, ROC analysis assessed cut-off points and discriminating ability to predict aspiration status (Area Under the Curve: 0.838; 0.845 and 0.93, respectively). EAT-10 with a cut-off at 8 was able to predict aspirator status with a sensitivity of 100% and a specificity of 42.9% (negative predictive value-NPV = 100%). A cut-off value of 22KPa for the MITPa discriminated aspirator status (sensitivity = 80%, specificity = 89.5%, NPV = 89.5%). The quantity of secretions observed upon endoscopy with a cut-off value at 1 was able to predict aspirator status (sensitivity = 90%, specificity = 80%, NPV = 94.1%).ConclusionReduced tongue strength, questionnaire-reported symptoms, pharyngeal secretions, and FESS findings can guide identification of patients with ALS at risk of inefficient and unsafe swallowing.     

Active Computerized Pharmacovigilance Using Natural Language Processing, Statistics, and Electronic Health Records: A Feasibility Study

Objective

It is vital to detect the full safety profile of a drug throughout its market life. Current pharmacovigilance systems still have substantial limitations, however. The objective of our work is to demonstrate the feasibility of using natural language processing (NLP), the comprehensive Electronic Health Record (EHR), and association statistics for pharmacovigilance purposes.

Design

Narrative discharge summaries were collected from the Clinical Information System at New York Presbyterian Hospital (NYPH). MedLEE, an NLP system, was applied to the collection to identify medication events and entities which could be potential adverse drug events (ADEs). Co-occurrence statistics with adjusted volume tests were used to detect associations between the two types of entities, to calculate the strengths of the associations, and to determine their cutoff thresholds. Seven drugs/drug classes (ibuprofen, morphine, warfarin, bupropion, paroxetine, rosiglitazone, ACE inhibitors) with known ADEs were selected to evaluate the system.

Results

One hundred thirty-two potential ADEs were found to be associated with the 7 drugs. Overall recall and precision were 0.75 and 0.31 for known ADEs respectively. Importantly, qualitative evaluation using historic roll back design suggested that novel ADEs could be detected using our system.

Conclusions

This study provides a framework for the development of active, high-throughput and prospective systems which could potentially unveil drug safety profiles throughout their entire market life. Our results demonstrate that the framework is feasible although there are some challenging issues. To the best of our knowledge, this is the first study using comprehensive unstructured data from the EHR for pharmacovigilance.     

Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations

Pituitary adenomas are common neoplasms of the anterior pituitary gland. Germ-line mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene cause pituitary adenoma predisposition (PAP), a recent discovery based on genetic studies in Northern Finland. In this population, a founder mutation explained a significant proportion of all acromegaly cases. Typically, PAP patients were of a young age at diagnosis but did not display a strong family history of pituitary adenomas. To evaluate the role of AIP in pituitary adenoma susceptibility in other populations and to gain insight into patient selection for molecular screening of the condition, we investigated the possible contribution of AIP mutations in pituitary tumorigenesis in patients from Europe and the United States. A total of 460 patients were investigated by AIP sequencing: young acromegaly patients, unselected acromegaly patients, unselected pituitary adenoma patients, and endocrine neoplasia-predisposition patients who were negative for MEN1 mutations. Nine AIP mutations were identified. Because many of the patients displayed no family history of pituitary adenomas, detection of the condition appears challenging. Feasibility of AIP immunohistochemistry (IHC) as a prescreening tool was tested in 50 adenomas: 12 AIP mutation-positive versus 38 mutation-negative pituitary tumors. AIP IHC staining levels proved to be a useful predictor of AIP status, with 75% sensitivity and 95% specificity for germ-line mutations. AIP contributes to PAP in all studied populations. AIP IHC, followed by genetic counseling and possible AIP mutation analysis in IHC-negative cases, a procedure similar to the diagnostics of the Lynch syndrome, appears feasible in identification of PAP.     

EMT as the ultimate survival mechanism of cancer cells

Epithelial cancers make up the vast majority of cancer types and, during the transition from benign adenoma to malignant carcinoma and metastasis, epithelial tumor cells acquire a de-differentiated, migratory and invasive behavior. This process of epithelial-mesenchymal transition (EMT) goes along with dramatic changes in cellular morphology, the loss and remodeling of cell-cell and cell-matrix adhesions, and the gain of migratory and invasive capabilities. EMT itself is a multistage process, involving a high degree of cellular plasticity and a large number of distinct genetic and epigenetic alterations, as fully differentiated epithelial cells convert into poorly differentiated, migratory and invasive mesenchymal cells. In the past years, a plethora of genes have been identified that are critical for EMT and metastasis formation. Notably, the EMT process not only induces increased cancer cell motility and invasiveness but also allows cancer cells to avoid apoptosis, anoikis, oncogene addiction, cellular, senescence and general immune defense. Notably, EMT seems to play a critical role in the generation and maintenance of cancer stem cells, highly consistent with the notion that metastatic cells carry the ability to initiate new tumors.     

Health care access and prevalence of the metabolic syndrome among elders living in high-altitude areas of the Mediterranean islands: the MEDIS study

AIM: The aim of the present work was to evaluate the relationships between sociodemographic, clinical, and lifestyle characteristics and the presence of metabolic syndrome, among high and low altitude living elderly individuals without known CVD. METHODS: During 2005-2011, 1959 elderly (aged 65 to 100 years) individuals from 13 Mediterranean islands were enrolled. Sociodemographic, clinical, and lifestyle factors were assessed using standard procedures. Metabolic syndrome was defined according to the (Adult Treatment Panel) ATP III criteria. Mountainous areas were defined those more than 400 meters in height. RESULTS: For the present analysis 713 men and 596 women were studied; the prevalence of the metabolic syndrome was 29% (24% in men, 35% in women, p < 0.001). Furthermore, the prevalence of metabolic syndrome was 55% in the elders living in mountainous areas, as compared with 26% among those living at sea-level (p = 0.01). Similarly, the prevalence of hypertension, hypercholesterolemia, and obesity were higher in high altitude as compared with low altitude areas (all p-values < 0.01). After adjusting for various confounders, elders living in high altitude areas were 3.06-times more likely to have the metabolic syndrome than those living at sea-level (OR = 3.06, 95%CI 2.02-4.65). However, when the annual number of visits to health care centers was taken into account, the effect of altitude of living was not associated with the presence of the syndrome. CONCLUSIONS: A considerable proportion of mountainous living elderly had the metabolic syndrome. Public health actions need to be taken to reduce the burden of cardiometabolic disorders by enabling better access to health care, especially in remote mountainous rural areas.     

Ischemic Preconditioning Attenuates Lactate Release by the Liver During Hepatectomies Under Vascular Control: A Case–Control Study

Background  

We have previously demonstrated lactate release by the liver itself in hepatectomies performed under selective hepatic vascular exclusion. We hypothesized that ischemic preconditioning applied in this setting might lead to a reduction of hepatic lactate production.     

Molecular interactions between dimethoxycurcumin and Pamam dendrimer carriers

Dimethoxycurcumin, a lipophilic analog of curcumin found as a major pigment in the Indian species turmeric (Curcuma longa Linn.), is known to possess significant activity against various cancer cell lines, but its use as an anticancer drug is hindered by its poor water solubility. The conjugation of dimethoxycurcumin to water-soluble PAMAM dendrimers (generations 3.5 and 4) is demonstrated. The maximum drug-dendrimer incorporation efficiency is 4.3 and 5.0 molar for G3.5 and G4, respectively. The FTIR-ATR investigation of the neat compounds and the drug-dendrimer systems indicate that dimethoxycurcumin is in the enolic form, while its interaction with the integer generation dendrimer involves the major conformational change of the terminal ethylene amine groups.     

Concurrent administration of liposomal doxorubicin improves the survival of patients with invasive bladder cancer undergoing hypofractionated accelerated radiotherapy (HypoARC)

Cisplatin-based radio-chemotherapy is an effective alternative to cystectomy. The position of cisplatin has been challenged by novel drugs, while altered radiotherapy fractionation is also tested against conventional radiotherapy (RT). This study focuses on liposomal doxorubicin (LDox) in combination with an aggressive radiotherapy scheme (HypoARC). Eighty-two bladder cancer patients were treated with hypofractionated/accelerated RT (14 × 2.7 Gy to the pelvis and 15 × 3.4 Gy to the bladder, within 19 days), supported with amifostine (0–1,000 mg sc.). Forty-one out of 82 patients received concurrently LDox (20 mg/m2 for 3 bi-weekly cycles). LDox was free of haematological toxicity, erythordysestesia grade 1 being the only side effect noted in 5/41 patients. Although the incidence of early toxicities did not increase with LDox, delays of radiotherapy were increased (P = 0.16). Amifostine significantly protected patients against toxicities and delays. There were no severe late complications recorded. Complete response rate was similar in both groups (85.4 vs. 87.8%). The 3-year local relapse-free survival was better in patients receiving LDox, but at a non-statistical level (64 vs. 47%; P = 0.59). The 3-year survival rate was significantly improved in T2-4 stage patients receiving LDox (72.1 vs. 58.7%; P = 0.04). Multivariate analysis did not identify any independent prognostic variables of relapse or death events. LDox is a well-tolerated drug during pelvic radiotherapy. Although its efficacy in terms of bladder tumour control rates could not be substantiated due to the high efficacy of the HypoARC regimen applied, survival was improved suggesting either a spatial co-operation or a radio-sensitization of pelvic in-field subclinical disease.