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Primary responses in sepsis-mediated inflammation are regulated by pro-inflammatory cytokines. Variations in the cytokine genes might modify their transcription or expression, plasma cytokines levels and response to sepsis. Activation protein-1 (AP-1) and NF-κB regulate cytokines gene expression in sepsis. A total of 90 severely septic and 91 non-infected patients were prospectively studied. IL-1α ( –889 C/T), IL-1β ( +3954 C/T), IL-6 ( –174 G/C), TNF-α ( –238 G/A), TNF-α ( –308G/A), IL-8 ( –251A/T) and IL-10 ( –1082 G/A) SNPs, plasma IL-1β, IL-4, IL-6, IL-8, IL-10, IL-13, IFN-γ, TNF-α and monocyte chemoattractant protein 1 (MCP-1) levels, and AP-1 and NF-κB gene expression by neutrophils were assessed. A allele carriers of TNF-α ( –238 G/A) SNP were less frequent among septic patients. IL-6, IL-8, IL-10, TNF-α and MCP-1 levels were higher, and AP-1 and NF-κB gene expressions lower in septic patients. Sepsis was independently associated with higher fibrinogen, neutrophils counts and IL-8 levels, lower prothrombin, absence of the variant A allele of the TNF-α (–238 G/A) SNP, and haemodynamic failure. Death was independently associated with a higher APACHE II score, higher IL-8 levels, and the diagnosis of sepsis. TNF-a ( –238 G/A) SNP could protect against sepsis development. Higher IL-8 levels are predictive of sepsis and mortality.

Background The “diagnose-and-leave-in” policy has been established to reduce the risks and costs related to unnecessary polypectomies in the average-risk population. In individuals with Lynch syndrome, owing to accelerated carcinogenesis, the general recommendation is to remove all polyps, irrespective of size, location, and appearance. We evaluated the feasibility and safety of the diagnose-and-leave-in strategy in individuals with Lynch syndrome. Methods We performed a post hoc analysis based on per-polyp data from a randomized, clinical trial conducted by 24 dedicated colonoscopists at 14 academic centers, in which 256 patients with confirmed Lynch syndrome underwent surveillance colonoscopy from July 2016 to January 2018. In vivo optical diagnosis with confidence level for all detected lesions was obtained before polypectomy using virtual chromoendoscopy alone or with dye-based chromoendoscopy. Primary outcome was the negative predictive value (NPV) for neoplasia of high-confidence optical diagnosis among diminutive (≤ 5 mm) rectosigmoid lesions. Histology was the reference standard. Results Of 147 rectosigmoid lesions, 128 were diminutive. In 103 of the 128 lesions (81 %), the optical diagnostic confidence was high and showed an NPV of 96.0 % (95 % confidence interval [CI] 88.9 %–98.6 %) and accuracy of 89.3 % (95 %CI 81.9 %–93.9 %). By following the diagnose-and-leave-in policy, we would have avoided 59 % (75/128) of polypectomies at the expense of two diminutive low grade dysplastic adenomas and one diminutive sessile serrated lesion that would have been left in situ. Conclusion In patients with Lynch syndrome, the diagnose-and-leave-in strategy for diminutive rectosigmoid polyps would be feasible and safe.

Minimally processed fruits are an alternative to dairy products to deliver probiotics. Bio-protection against several factors that affect their viability has been proposed in the food industry. In this study, probiotic Lactobacillus rhamnosus CECT 8361 was added to alginate-based coatings enriched with inulin and oligofructose and applied on fresh-blueberries. Probiotic viability, microbiological, physicochemical and sensory quality parameters of blueberries were monitored during 21 days of refrigerated storage. Also, L. rhamnosus CECT 8361 was tested for its antagonistic effect against inoculated Listeria innocua and E. coli O157:H7. Advantageously, prebiotic compounds allowed improving probiotic viability with counts above 6.2 log CFU/g for the entire period. Native microbiota counts remained under safe levels. Overall visual quality, odor and flavor were acceptable up to day 14 of storage. Regarding antimicrobial activity, L. rhamnosus CECT 8361 was able to reduce L. innocua counts by 1.7 log in inoculated blueberries. These results encourage further implementation of new fruit-based foods with multifunctional properties. Fil: Bambace, María Florencia. Universidad Nacional de Mar del Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina Fil: Alvarez, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Moreira, María del Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

The detection rates of whole-body combined [18 F]NaF/[18 F]FDG positron emission tomography combined with computed tomography (PET/CT), CT alone, whole-body magnetic resonance imaging (WB-MRI), and X-ray were prospectively studied in patients with treatment-requiring plasma cell disorders The detection rates of imaging techniques were compared, and focal lesions were classified according to their anatomic location. Twenty-six out of 30 initially included patients were assessable. The number of focal lesions detected in newly diagnosed patients (n = 13) and in relapsed patients (n = 13) were 296 and 234, respectively. The detection rate of PET/CT was significantly higher than those of WB-MRI (P < 0.05) and CT (P < 0.0001) both in patients with newly diagnosed and in those with relapsed multiple myeloma (MM). The X-ray detection rate was significantly lower than those of all other techniques, while CT detected more lesions compared with WB-MRI at diagnosis (P = 0.025). With regard to the infiltration patters, relapsed patients presented more diffuse patterns, and more focal lesions located in the limbs compared with newly diagnosed patients. In conclusion, the detection rate of [18 F]NaF/[18 F]FDG PET/CT was significantly higher than those of CT, MRI, and X-ray, while the detection rate of X-rays was significantly lower than those of all other imaging techniques except for focal lesions located in the skull.

Background: Many evidences suggest a pathological link between neurodegenerative diseases and cancer. In fact, several epidemiologic studies indicate a decreased incidence of most cancer types in Parkinson’s disease (PD) patients and some PD genes are involved in cancer networks. Objective: The aim of this study is to assess the influence of several factors in the risk of cancer in a cohort of 753 PD patients and to study how these variables interact with each other. Methods: We analyzed the effect of gender, tobacco, alcohol, type of PD (genetic or idiopathic PD), and two genetic variants, previously associated with cancer, rs5848-GRN and rs1042522-TP53. Results: A higher age at PD onset was observed in patients who develop cancer before PD (p < 0.001). Alcohol consumption was a risk factor to develop cancer in PD patients (p = 0.011), while smoking was not a cancer risk factor in our cohort (p = 0.098). Among the genetic factors, the genotype TT GRN-rs5848 was statistically more frequent in PD patients without cancer (p = 0.05). Conclusions: Our study identified several factors, genetic and nongenetic, which contribute to the risk for cancer in PD.

Background and aims The interferon-induced transmembrane proteins play an important antiviral role by preventing viruses from traversing the cellular lipid bilayer. IFITM3 gene variants have been associated with the clinical response to influenza and other viruses. Our aim was to determine whether the IFITM3 rs12252 polymorphism was associated with the risk of developing severe symptoms of COVID-19 in our population. Methods A total of 288 COVID-19 patients who required hospitalization (81 in the intensive care unit) and 440 age matched controls were genotyped with a Taqman assay. Linear regression models were used to compare allele and genotype frequencies between the groups, correcting for age and sex. Results Carriers of the minor allele frequency (rs12252 C) were significantly more frequent in the patients compared to controls after correcting by age and sex (p = 0.01, OR = 2.02, 95%CI = 1.19–3.42). This genotype was non-significantly more common among patients who required ICU. Conclusions The IFITM3 rs12252 C allele was a risk factor for COVID-19 hospitalization in our Caucasian population. The extent of the association was lower than the reported among Chinese, a population with a much higher frequency of the risk allele.

A polymorphism in the LZTFL1 gene located in the chemokine-receptor gene cluster (chromosome 3p) has been associated with the risk of developing COVID-19. The chemokine receptor-5 (CCR5) maps to this region, and the common 32 bp deletion variant (Δ32) has been associated with the extent of inflammatory disease and the outcome in several viral diseases. Several studies have also suggested that the pharmacological targeting of CCR5 could reduce the impact of SARS-CoV-2 infection and the severity of COVID-19. We sought to investigate whether this polymorphism was associated with the risk of moderate-severe COVID-19.We genotyped 294 patients who required hospitalization due to COVID-19 (85 were severe cases) and 460 controls. We found a significantly lower frequency of CCR5-Δ32 among the COVID-19 patients (0.10 vs 0.18 in controls; p=0.002, OR=0.48, 95%CI=0.29-0.76). The difference was mainly due to the reduced frequency of CCR5-Δ32 carriers in the severe, significantly lower than in the non-severe patients (p=0.036). Of note, we did not find deletion-homozygotes among the patients compared to 1% among controls. We also confirmed the association between a LZTFL1 variant and COVID-19. Our study points to CCR5 as a promising target for treatment of COVID-19, but requires validation in additional large cohorts. In confirmed by others, the genetic analysis of CCR5-variants (such as Δ32) might help to identify patients with a higher susceptibility to severe COVID-19.

Pancreatic cystic lesions (PCLs) are increasingly being identified because of the widespread use of high-resolution abdominal imaging. These cysts encompass a spectrum from malignant disease to benign lesions, and therefore, accurate diagnosis is crucial to determine the best management strategy, either surgical resection or surveillance. However, the current standard of diagnosis is not accurate enough due to limitations of imaging and tissue sampling techniques, which entail the risk of unnecessary burdensome surgery for benign lesions or missed opportunities of prophylactic surgery for potentially malignant PCLs. In the last decade, endoscopic innovations based on endoscopic ultrasonography (EUS) imaging have emerged, aiming to overcome the present limitations. These new EUS-based technologies are contrast harmonic EUS, needle-based confocal endomicroscopy, through-the-needle cystoscopy and through-the needle intracystic biopsy. Here, we present a comprehensive and critical review of these emerging endoscopic tools for the diagnosis of PCLs, with a special emphasis on feasibility, safety and diagnostic performance.

It has been suggested that EUS-BD may be a feasible and safer alternative to percutaneous transhepatic biliary drainage (PTBD) after failed ERCP in patients with ascites. To date, no study has specifically evaluated the performance of EUS-BD in this context. Retrospective analysis was done for patients with and without ascites who underwent EUS-BD for malignant biliary obstruction after failed ERCP between July 2010 and September 2014. Complications and technical and clinical successes between the two groups were compared. A total of 31 patients were included: 20 patients without ascites (group 1) and 11 with ascites (group 2). Nineteen patients underwent EUS-hepaticogastrostomy (six in group 2), and 12 underwent EUS-choledochoduodenostomy (five in group 2). Technical success was achieved in all patients. Clinical success was observed in 95% (n = 19) in group 1 and 64% (n = 7) in group 2 (p = 0.042). In three out of four patients without clinical success in group 2, the follow-up period was not long enough to observe the clinical response because of early death within the 2 weeks after EUS-BD secondary to disease progression or preprocedural unresponsive sepsis. No significant differences were observed between groups 1 and 2 either in the overall rates of procedural-related complications (20 and 9%, respectively, p = 0.63) or in the rates of major complications (15 vs 9%, respectively, p = 0.639). Stent migration occurred in one patient in each group, intra- or post-procedural bleeding occurred in two patients in group 1, which was conservatively managed, and one patient in group 1 presented biliary leakage. Stent patency and the number of re-interventions were not significantly different. EUS-BD is technically feasible in patients with ascites. Our results suggest that EUS-BD may be a clinically effective and safe alternative after failed ERCP in patients with ascites.

The chemokine receptor CCR5 has been implicated in COVID-19. CCR5 and its ligands are overexpressed in patients. The pharmacological targeting of CCR5 would improve the COVID-19 severity. We sought to investigate the role of the CCR5-Δ32 variant (rs333) in COVID-19. The CCR5-Δ32 was genotyped in 801 patients (353 in the intensive care unit, ICU) and 660 healthy controls, and the deletion was significantly less frequent in hospitalysed COVID-19 than in healthy controls (p = 0.01, OR = 0.66, 95%CI = 0.49-0.88). Of note, we did not find homozygotes among the patients, compared to 1% of the controls. The CCR5 transcript was measured in leukocytes from 85 patients and 40 controls. We found a significantly higher expression of the CCR5 transcript among the patients, with significant difference when comparing the non-deletion carriers (controls = 35; patients = 81; p = 0.01). ICU-patients showed non-significantly higher expression than no-ICU cases. Our study points to CCR5 as a genetic marker for COVID-19. The pharmacological targeting of CCR5 should be a promising treatment for COVID-19.

BACKGROUNDDisentangling the genetic constellation underlying Alzheimer’s disease (AD) is important. Doing so allows us to identify biological pathways underlying AD, point towards novel drug targets and use the variants for individualised risk predictions in disease modifying or prevention trials. In the present work we report on the largest genome-wide association study (GWAS) for AD risk to date and show the combined utility of proven AD loci for precision medicine using polygenic risk scores (PRS).METHODSThree sets of summary statistics were included in our meta-GWAS of AD: an Spanish case-control study (GR@ACE/DEGESCO study, n = 12,386), the case-control study of International Genomics of Alzheimer project (IGAP, n = 82,771) and the UK Biobank (UKB) AD-by-proxy case-control study (n=314,278). Using these resources, we performed a fixed-effects inverse-variance-weighted meta-analysis. Detected loci were confirmed in a replication study of 19,089 AD cases and 39,101 controls from 16 European-ancestry cohorts not previously used. We constructed a weighted PRS based on the 39 AD variants. PRS were generated by multiplying the genotype dosage of each risk allele for each variant by its respective weight, and then summing across all variants. We first validated it for AD in independent data (assessing effects of sub-threshold signal, diagnostic certainty, age at onset and sex) and tested its effect on risk (odds for disease) and age at onset in the GR@ACE/DEGESCO study.FINDINGSUsing our meta-GWAS approach and follow-up analysis, we identified novel genome-wide significant associations of six genetic variants with AD risk (rs72835061-CHRNE, rs2154481-APP, rs876461-PRKD3/NDUFAF7, rs3935877-PLCG2 and two missense variants: rs34173062/rs34674752 in SHARPIN gene) and confirmed a stop codon mutation in the IL34 gene increasing the risk of AD (IL34-Tyr213Ter), and two other variants in PLCG2 and HS3ST1 regions. This brings the total number of genetic variants associated with AD to 39 (excluding APOE). The PRS based on these variants was associated with AD in an independent clinical AD-case control dataset (OR=1.30, per 1-SD increase in the PRS, 95%CI 1.18-1.44, p = 1.1×10−7), a similar effect to that in the GR@ACE/DEGESCO (OR=1.27, 95%CI 1.23-1.32, p = 7.4×10−39). We then explored the combined effects of these 39 variants in a PRS for AD risk and age-at-onset stratification in GR@ACE/DEGESCO. Excluding APOE, we observed a gradual risk increase over the 2% tiles; when comparing the extremes, those with the 2% highest risk had a 2.98-fold (95% CI 2.12–4.18, p = 3.2×10−10) increased risk compared to those with the 2% lowest risk (p = 5.9×10−10). Using the PRS we identified APOE ε33 carriers with a similar risk as APOE ε4 heterozygotes carriers, as well as APOE ε4 heterozygote carriers with a similar risk as APOE ε4 homozygote. Considering age at onset; there was a 9-year difference between median onset of AD the lowest risk group and the highest risk group (82 vs 73 years; p = 1.6×10−6); a 4-year median onset difference (81 vs 77 years; p = 6.9×10−5) within APOE ε4 heterozygotes and a 5.5-year median onset difference (78.5 vs 73 years; p = 4.6×10−5) within APOE ε4 carriers.INTERPRETATIONWe identified six novel genetic variants associated with AD-risk, among which one common APP variant. A PRS of all genetic loci reported to date could be a robust tool to predict the risk and age at onset of AD, beyond APOE alone. These properties make PRS instrumental in selecting individuals at risk in order to apply preventative strategies and might have potential use in diagnostic work-up.

Category: Bunion Introduction/Purpose: Surgical correction of hallux valgus rebalances the first ray, correcting the various features of the deformity. While several surgical methods are available, consensus regarding the best management has yet to be established. In the last decades, there was an increasing interest in mini-invasive procedures. In this scenario the Bosch technique appears to be a reproducible DMO to achieve proper correction. Theoretically, it allows for fast and safe correction of the deformity, however it was criticized for its unstable nature. We describe a new distal metatarsal osteotomy (DMO) that it is a combination of the (traditional) chevron and the (mini-invasive) Bosch-SERI techniques. The purpose of this investigation is to describe the surgical technique and report the results of this modified procedure at a minimum 2-year follow-up. Methods: Between January 2016 and June 2018, 63 consecutive patients, with mild to moderate hallux valgus deformity underwent corrective surgery using the BC technique. Preoperatively, each patient’s data was recorded and all patients underwent an assessment of functional limitation and pain level as well as a physical examination that included measurement of the passive range of motion of the first metatarsophalangeal joint. At final follow up, the patients were assessed using the American Orthopaedic Foot & Ankle Society’s (AOFAS) hallux- metatarsophalangeal and interphalangeal scale. Additionally, patients were asked to rate their satisfaction with regard to the overall result of the operation according to the Coughlin overall satisfaction scale. Anteroposterior and lateral weight-bearing radiographs were made preoperatively as well as at the short-term and intermediate-term follow-up evaluations. The HVA, the first IMA, and the congruency of the first metatarsophalangeal joint were measured with the technique recommended by the AOFAS. Results: BC osteotomy was performed in 62 patients, including 33 right feet and 29 left feet, with no bilateral procedures. The patient population consisted of 50 females (79%), with an average age of 50.4 years (range 19 to 75) years. The mean follow-up time was 36.5 months (range 23 to 59). The mean AOFAS score improved from 69.3 preoperatively to 88 postoperatively (pConclusion: We believe this osteotomy has a number of advantages: (1) one mini-invasive approach is used; (2) a large correction can be obtained in all directions including the frontal and sagittal planes; (3) blood supply to the metatarsal head is preserved; and (4) intrinsically stable OT, allowing immediate full weight bearing. The merge, of percutaneous techniques and classic stable fixed approach may seems to offer a stable, effective and reproducible correction of hallux valgus deformity with the advantages of a minimally-invasive technique

Category: Midfoot/Forefoot Introduction/Purpose: Limited ankle dorsiflexion associated with an isolated gastrocnemius contracture is one of the key impairments present in some chronic foot and ankle pathologies. The Baumann procedure consists of a gastrocnemius recession through an incision along the proximal medial calf performed in the interval between the gastrocnemius and soleus fascia. The advantages of the technique is that isolates the lengthening to the gastrocnemius muscle and preserves muscle strength. It is performed in supine decubitus, making unnecessary to switch position of the patient. We performed it in a minimally invasive fashion through a 4 cm approach. Our purpose was to evaluate the functional results and satisfaction of patients after performing a release of the gastrocnemius through the Baumann minimally invasive procedure in different foot and ankle pathologies. Methods: 34 patients (37 procedures) whom presented with forefoot or midfoot or rearfoot pathologies that were suspected to be associated with gastrocnemius contracture between 2015 and 2017 were retrospectively evaluated (Table 1). All patient demographic information; such as age, sex, diagnosis and date of surgical, was retrieved from clinical charts. Patients included were to have an isolated gastrocnemius contracture as determined by a positive Silfverskiold test. Patients underwent Bauman gastrocnemius recession alone or in combination with other procedures according to each patient´s primary diagnosis. A supervised physical therapy program that consisted on stretching and flexibility of the posterior chain, was started as soon as possible depending on the underlying pathology, when possible, during the first postoperative week. Results: Thirty-seven procedures belonging to thirty-four patients were included in this investigation. The mean age of the patients was 47.13 years (range 26-78 years). The mean follow-up was 21.6 months (range 7-42 months). The average initial amount of ankle dorsiflexion measured was 108 (range 95 to 120) degrees. After gastrocnemius muscle recession, the average ankle dorsiflexion measured was 91 (range 84 to 95) degrees. Therefore, an overall improvement of 17 degrees was obtained. There were significant differences in the dorsiflexion angle measured pre and post-surgery (p < 0.05). 88.9% of the patients were satisfied and would undergo the same surgery if necessary. 91.7% would recommend the procedure to a friend or family member. Conclusion: There exists reasonably convincing evidence to support the use of gastrocnemius recession as a therapeutic intervention for isolated foot pain associated with an overload syndrome, justifying a grade of recommendation B. It is our perspective that the Bauman procedure offers a chance to lengthen the musculotendinous unit in a predictable manner, through a small incision avoiding the potential risks of over lengthening the gastrocnemius-soleus complex.

Background & Aims Dye-based pancolonic chromoendoscopy is recommended for colorectal cancer surveillance in patients with Lynch syndrome. However, there is scarce evidence to support its superiority to high-definition white-light endoscopy. We performed a prospective study assess whether in the hands of high detecting colonoscopists, high-definition, white-light endoscopy is noninferior to pancolonic chromoendoscopy for detection of adenomas in patients with Lynch syndrome. Methods We conducted a parallel controlled study, from July 2016 through January 2018 at 14 centers in Spain of adults with pathogenic germline variants in mismatch repair genes (60% women; mean age, 47 ± 14 years) under surveillance. Patients were randomly assigned to groups that underwent high-definition white-light endoscopy (n = 128) or pancolonic chromoendoscopy (n = 128) evaluations by 24 colonoscopists who specialized in detection of colorectal lesions in high-risk patients for colorectal cancer. Adenoma detection rates (defined as the proportion of patients with at least 1 adenoma) were compared between groups, with a noninferiority margin (relative difference) of 15%. Results We found an important overlap of confidence intervals (CIs) and no significant difference in adenoma detection rates by pancolonic chromoendoscopy (34.4%; 95% CI 26.4%–43.3%) vs white-light endoscopy (28.1%; 95% CI 21.1%–36.4%; P = .28). However, pancolonic chromoendoscopy detected serrated lesions in a significantly higher proportion of patients (37.5%; 95% CI 29.5–46.1) than white-light endoscopy (23.4%; 95% CI 16.9–31.4; P = .01). However, there were no significant differences between groups in proportions of patients found to have serrated lesions of 5 mm or larger (9.4% vs 7.0%; P = .49), of proximal location (11.7% vs 10.2%; P = .68), or sessile serrated lesions (3.9% vs 5.5%; P = .55), respectively. Total procedure and withdrawal times with pancolonic chromoendoscopy (30.7 ± 12.8 minutes and 18.3 ± 7.6 minutes, respectively) were significantly longer than with white-light endoscopy (22.4 ± 8.7 minutes and 13.5 ± 5.6 minutes; P Conclusions In a randomized parallel trial, we found that for Lynch syndrome surveillance, high-definition white-light endoscopy is not inferior to pancolonic chromoendoscopy if performed by experienced and dedicated endoscopists. ClinicalTrials.gov no: NCT02951390.

We analyzed the frequency of intermediate alleles (IAs) in the ATXN1, ATXN2, and HTT genes in several neurodegenerative diseases. The study included 1126 patients with Alzheimer's disease (AD), 440 patients with frontotemporal dementia (FTD), and 610 patients with Parkinson's disease. In all cohorts, we genotyped ATXN1 and ATXN2 CAG repeats. In addition, in the FTD cohort, we determined the number of HIT CAG repeats. The frequency of HIT IAs was higher in patients with FTD (6.9%) versus controls (2.9%) and in the C9orf72 expansion noncarriers (7.2%) versus controls (2.9%), although the difference was nonsignificant after correction for multiple testing. Compared with controls, progressive nonfluent aphasia (PNFA) groups showed a significantly higher frequency of HTT IAs (13.6% vs. 2.9% controls). For the ATXN2 gene, we observed an increase in IA frequency in AD cases (AD 4.1% vs. controls 1.8%) and in the behavioral FTD group (4.8% vs. 1.8%). For the ATXN1 gene, we found a significant increase of IAs in patients with PNFA (18.6%) versus controls (6.7%). In conclusion, our work suggests that the HTT and ATXN1 IAS may contribute to PNFA pathogenesis and point to a link between ATXN2 IAS and AD. (C) 2019 Elsevier Inc. All rights reserved.

Pulsed light (PL) treatments stand as an alternative for the shelf-life extension of fresh-cut products. The antimicrobial effects of PL are well known; however, its influence on quality attributes needs to be assessed. This study was aimed at evaluating the application of PL treatments in combination with pectin-based edible coatings enriched with dietary fiber for the preservation of fresh-cut apples. RESULTS Dipping of fresh-cut apples in ascorbic acid/calcium chloride solution prior to pectin coating and PL treatments was effective to minimize browning and softening of apple surfaces. Incorporation of fiber in the pectin coating did not cause any change in microbial loads and sensory acceptability of apple cubes. Pectin-coated PL-treated apple pieces exhibited significantly higher antioxidant activity values than fresh and PL control samples. At the end of storage, the combination of both treatments resulted in an almost 2 log CFU g?1 reduction of microbial counts. Sensory attribute scores did not fall below the rejection limit throughout 14 days, although the presence of off-odors limited the acceptability of the pectin-coated samples. CONCLUSION The results demonstrate that PL treatments applied to pectin-coated fresh-cut apples may be used to maintain quality attributes, thus conferring prebiotic potential and extending the shelf-life of the product. ? 2016 Society of Chemical Industry

Author(s): Perez-Is, Laura; Ocana, Marcos G; Montes, A Hugo; Carton, Jose A; Alvarez, Victoria; Meana, Alvaro; Fierer, Joshua; Valle-Garay, Eulalia; Asensi, Victor | Abstract: BACKGROUND:Osteomyelitis is a bone infection, most often caused by Staphylococcus aureus, in which neutrophils play a key role. Cathepsin G (CTSG) is a bactericidal serine protease stored in the neutrophil azurophilic granules. CTSG regulates inflammation, activating matrix metalloproteinases (MMPs), and coagulation. Lactoferrin (LF), a neutrophil glycoprotein, increases CTSG catalytic activity and induces inflammation. The aim of this study was to analyze a potential association between a CTSG gene polymorphism (Asn125Ser or N125S, rs45567233), that modifies CTSG activity, and could affect susceptibility to, or outcome of, bacterial osteomyelitis. METHODS:CTSG N125S polymorphism was genotyped in 329 osteomyelitis patients and 415 controls), Blood coagulation parameters, serum CTSG activity, LF, MMP-1, MMP-13, and soluble receptor activator for nuclear factor κ B ligand (sRANKL) levels were assessed in carriers of the different CTSG genotypes. RESULTS:CTSG N125S (AG) genotype was significantly more frequent among osteomyelitis patients than controls (15.5% vs. 9.4%, p = 0.014). CTSG N125S variant G allele (AG +GG) was also more frequent among osteomyelitis patients (8.1% vs. 4.7%, p = 0.01). Serum CTSG activity and LF levels were significantly higher in osteomyelitis patients carrying the G allele compared to those with the AA genotype, (pl0.04). Serum MMP-1 was lower in the G allele carriers (p = 0.01). There was no association between these genotypes and clinical characteristics of osteomyelitis, or coagulation parameters, MMP-13, and sRANKL serum levels. CONCLUSIONS:Differences in the CTSG gene might enhance osteomyelitis susceptibility by increasing CTSG activity and LF levels.

Huntington's disease (HD) is an autosomal progressive neurodegenerative disorder caused by the expansion of CAG repeats in the HTT gene. Intermediate alleles (IAs) are in the range of 27–35 repeats and have been associated to a normal phenotype. The aim of this work was to analyze the association between intermediate huntingtin CAG-repeat alleles (IAs) and neurodegenerative diseases, other than HD. We screened the HTT CAG repeats in patients with Alzheimer's disease (AD) (n = 1126), Parkinson's disease (PD) (n = 610), and frontotemporal lobar degeneration (FTLD) (n = 225). We also studied 509 healthy controls (HCs). The relative frequency of IAs for each group was 6.03% in AD, 5.3% in FTLD, 3.5% in PD, and 2.9% in HCs. The frequency of IA was significantly higher among patients with AD when compared to HCs (p = 0.011, OR = 2.11, 95% CI = 1.19–3.74); no significant difference was observed in FTLD (p = 0.17; OR = 1.88, 95% CI = 0.85–4.03) and PD (p = 0.69; OR = 1.21; 95% CI (0.61–2.37) versus HCs. No atypical symptoms or clinical features distinctive of HD were found among carriers of IAs. We found 3 cases with CAG expansions within the pathological range, one diagnosed with AD, one with PD, and one with FTD. Results suggest that IAs might have a role in the pathogenesis of AD. In addition, HD patients might be misdiagnosed with other neurodegenerative diseases, particularly when CAG repeats are in the lower pathological range.

With the widespread use of endoscopy, gastrointestinal submucosal lesions are now more commonly discovered. Although endoscopic ultrasound (EUS) is superior to all other imaging techniques for the diagnosis of submucosal tumors (SMTs), it is still suboptimal for differentiating hypoechoic lesions arising from the fourth sonographic gastrointestinal wall layer, which encompass tumors with very different prognosis. EUS tissue acquisition has provided with the unique opportunity to obtain histological confirmation, but it is not accurate enough to evaluate the malignant potential of gastrointestinal stromal tumors (GISTs). In the last years, contrast-enhanced harmonic EUS (CH-EUS) emerged as a powerful imaging modality to assess the microperfusion patterns of pancreatic tumors. Based on the distinct microvascularity of malignant SMTs, it was hypothesized that CH-EUS might also assist in the differential diagnosis of SMTs. Preliminary experience in this field is now available and suggests CH-EUS as a performant modality to distinguish between benign SMTs and GISTs and to evaluate the malignant potential of GISTs. High expectations are also relied on CH-EUS for the monitoring of antiangiogenic treatments of GISTs and the evaluation of gastrointestinal neuroendocrine tumors (NETs).

This work reports on musculoskeletal uptake of 18F-FPRGD2, targeting the integrin αvβ3, in patients who had undergone 18F-FPRGD2 positron emission tomography combined with computed tomography (PET/CT) for oncologic purposes. Whole-body 18F-FPRGD2 PET/CT images of 62 cancer patients were retrospectively reviewed to detect foci of musculoskeletal 18F-FPRGD2 uptake. For 37 patients, a FDG PET/CT performed in clinical settings was available. In each joint with an abnormal uptake, the maximum standardized uptake value (SUVmax) was estimated. A total of 260 musculoskeletal foci of 18F-FPRGD2 uptake were detected. Most common sites of uptake were joints and discs (n = 160; 61.5 %), entheses (osteotendinous and osteoligamentous junctions; n = 55; 21.2 %) and recent fractures (n = 18; 6.9 %). In addition, 27 (10.4 %) miscellaneous foci were detected. Out of the 146 lesions for which a FDG PET was available, 63 % showed both 18F-FPRGD2 and FDG uptake, 33.6 % did not show FDG avidity and 3.4 % showed only FDG uptake. The uptake intensity of the 92 lesions positive with 18F-FPRGD2 and FDG was similar with both radiopharmaceuticals, but the target-to-background (blood pool or muscle) ratios were significantly higher with 18F-FPRGD2 than with FDG (p

Background: Hindfoot coronal alignment is an important factor in the assessment of patients with many different foot and ankle complaints. A number of clinical and radiographic techniques have been described to measure hindfoot coronal alignment, but none of them are widely accepted. The purpose of the present study was to assess the correlation between clinical and radiographic hindfoot alignment measures and to evaluate the reproducibility of each. Methods: We evaluated 85 patients with foot and/or ankle symptoms. Hindfoot clinical alignment was measured from photographs. Each patient was placed at a distance of 1 m from the observer, with both feet placed parallel. Four photographs were taken, at a height of 40 cm: a posterior view of both lower limbs including knees, a posterior view focalized on the studied hindfoot, an anterior view of the foot, and the last view of the medial aspect of the foot. Radiographic alignment was quantified on long axial view radiographs. Patients were lying over the film cassette with a focus distance of 1 m and the beam pointed to the ankle joint. The inclination angle of the beam was 45 degrees to the floor. Measurements were independently made by 2 observers, who were asked to classify pictures into 3 categories: varus, neutral, and valgus. Radiographic measurements were made using the angle measurement tool on the radiograph viewer. The intraclass correlation coefficients (ICCs) and the 95% confidence interval (CI) of the ICC were used to quantify the inter- and intraobserver reliability for clinical assessment. Radiographic parameters were correlated by calculating the Pearson correlation coefficient (r). Results: The intraobserver ICC for clinical analysis was good for both observers, while the interobserver ICC was moderate for both measurements. Regarding radiographic assessment, there was significant intra- and interobserver reliability. The correlation between both methods was weak for both observers. Conclusions: We found only weak intra- and interobserver correlations between the clinical and radiographic assessment of hindfoot coronal alignment. It is therefore necessary to complement the clinical evaluation of hindfoot alignment with an objective measurement method such as a long axial view radiograph. Further studies comparing different measurement methods need to be performed to establish the most objective evaluation. Level of Evidence: Level III, diagnostic study.

Background Urinary tract infections (UTIs) are among the most common causes for antibiotic prescription. The use of clinical scoring models in predicting infection with extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (E. coli) may help select an adequate empiric treatment. Methods This retrospective case–control study included all urine cultures with E. coli from symptomatic patients 18 years of age or more admitted to Medica Sur Hospital from December 2014 to 2016. Cases were ESBL producing cultures and controls non-ESBL. Demographic and clinical information was drawn from electronic file. Sensitivities and specificities were performed at various cutoffs and area under the receiver curve (ROC AUC) was determined for each of the two models studied. Results A total of 171 cases and 294 controls were included. Table 1 displays the statistically significant variables associated with ESBL in a multivariate regression model. ROC AUC in Figure 1 was 0.691 for Tumbarello and 0.670 for Duke. With a 2-point cutoff, sensitivity for Tumbarello was 71% and specificity 61%, for Duke 58% and 75%, increasing cutoff to 4 points increases specificity to 87 and 93%, decreasing sensibility to 35 and 20%, respectively. Table 2 classifies by type of UTI, shows the percentage of adequate initial antibiotic for ESBL, and the number of cases predicted by each model. Tumbarello’s model predicts all cases, while Duke’s model predicts most cases of cystitis and pyelonephritis and all cases of complicated UTI and urosepsis. Figure 1 Table 1 Variable β-Coefficient P Confidence Interval 95% Recent antibiotic therapy 0.23

Category: Midfoot/Forefoot Introduction/Purpose: Hallux rigidus treatment by the means of decompressive osteotomy would theoretically be able to alleviate pain and improve function. The Youngswick osteotomy is a procedure conceived for relatively long first metatarsals, a characteristic that has been associated with the pathogenesis of hallux rigidus. Nevertheless, studies of this procedure that assessed the overall results and further need of a first metatarsal arthrodesis over the years are lacking. After using the Youngswick first metatarsal decompressive osteotomy for many years, we decided to review a retrospective series of patients. The purpose of this study was to evaluate the need for first metatarsophalangeal joint arthrodesis or any other secondary procedures in the long term follow up in patients with stage II and III hallux rigidus. Methods: A retrospective review of 61 consecutive patients (61 feet) who had undergone decompressive osteotomy by the same surgical team during a period of 156 months was performed. The candidates for inclusion into the present study underwent a clinical evaluation preoperatively, and the clinical data recorded in the patients’ medical records were reviewed retrospectively. All clinical measurements were taken at the initial preoperative examination and at the final follow-up visit. Patients underwent Youngswick first metatarsal osteotomy as described in previous publication. The clinical examination included the the Foot and Ankle Outcome Score (FAOS), total range of motion of the first MTPJ. Radiographic examinations (AP and lateral weightbearing) were performed preoperatively, immediately postoperatively, and at each patient’s last follow-up visit by another member who was unaware of the clinical results. The need of any secondary procedure of the first metatarsal or subsequent need of first MTPJ arthrodesis was also recorded. Results: Decompressive osteotomy was performed in 61 patients, including 41 right feet and 20 left feet, with no bilateral procedures. The patient population consisted of 45 females (78%), with an average age of 53.8 years (range 29 to 72) years. The mean follow-up time was 54.8 months (range 12 to 150). 74% (45 patients) were classified as grade II and 16 patients (26%) as grade III. All patients who underwent this procedure had improvement their visual analog scale foot and ankle score, with all achieving postoperative scores >75 points. Evaluation at the last follow-up visit showed that 91% of patients would recommend the same procedure to a family member. In our group of patients there were no further needs of first MTPJ arthrodesis. Conclusion: We found significant visual analog scale foot and ankle score, providing evidence that good outcomes and high levels of patient satisfaction can be achieved, and that this results would maintain over time. Secondary procedures mainly hardware removal were somewhat usual, however no first MTPJ arthrodesis was needed in the medium term.

This study presents an innovative blast analysis tool that can be used in assessing blast performance of concrete masonry walls. The analysis tool proposes a structural model of unreinforced masonry (URM) walls, and a simplified procedure to generate load histories on structures subjected to blast loading. This study focuses on hollow concrete masonry units (CMU) walls. Three-dimensional masonry walls are modeled using discrete rigid bodies connected by nonlinear springs. Connections between two masonry blocks attached by mortar joint are modeled by treating adjoining springs as springs in series. The blast load histories are calculated using UFC 3-340-02. The proposed tool generates individual load-time histories for each discrete elements of a wall. The individual load-time histories, and the peak pressure distribution on a wall surface, are compared to experimental measurements to validate the blast-load-generating algorithm. The two modules (blast-load, and numerical model generator) are then used to simulate an actual experiment on URM wall for validation. For this study, experiments on URM wall arching is simulated. The proposed tool is able to approximate the wall response, particularly, the maximum positive and negative displacements. The good agreement proved the applicability of the proposed analysis tool to the analysis of URM walls.

We sought to optimize the kilovoltage, tube current, and the radiation dose of computed tomographic arthrography of the hip joint using in vitro methods. A phantom was prepared using a left femoral head harvested from a patient undergoing total hip arthroplasty and packed in a condom filled with iodinated contrast. The right hip joint of a cadaver was also injected with iodinated contrast. The phantom and the cadaver were scanned using different values of peak kilovoltage (kVp) and tube current (milliamp seconds, mAs). Three different regions of interest (ROI) were drawn in the cartilage, subchondral bone plate, and intraarticular contrast. The attenuation values, contrast/noise ratio (CNR), and effective dose were calculated. Two independent observers classified the quality of the contrast-cartilage interface and the cartilage-subchondral bone plate interface as (1) diagnostic quality or (2) nondiagnostic quality. Contrast, cartilage, and subchondral bone plate attenuation values decreased at higher kVp. CNR increased with both kVp and mAs. The qualitative analysis showed that in both phantom and cadaver, at 120 kVp and 50 mAs, the contrast-cartilage and cartilage-subchondral bone plate interfaces were of diagnostic quality, with an effective dose decreased to 0.5 MSv. The absolute effective dose is not directly related to the quality of images but to the specific combination of kVp and mAs used for image acquisition. The combination of 120 kVp and 50 mAs can be suggested to decrease the dose without adversely affect the visibility of cartilage and subchondral bone plate.

To assess the intraobserver, interobserver, and test-retest reproducibility of minimum joint space width (mJSW) measurement of medial and lateral patellofemoral joints on standing "skyline" radiographs and to compare the mJSW of the patellofemoral joint to the mean cartilage thickness calculated by quantitative magnetic resonance imaging (qMRI).A couple of standing "skyline" radiographs of the patellofemoral joints and MRI of 55 knees of 28 volunteers (18 females, ten males, mean age, 48.5 ± 16.2 years) were obtained on the same day. The mJSW of the patellofemoral joint was manually measured and Kellgren and Lawrence grade (KLG) was independently assessed by two observers. The mJSW was compared to the mean cartilage thickness of patellofemoral joint calculated by qMRI.mJSW of the medial and lateral patellofemoral joint showed an excellent intraobserver agreement (interclass correlation (ICC) = 0.94 and 0.96), interobserver agreement (ICC = 0.90 and 0.95) and test-retest agreement (ICC = 0.92 and 0.96). The mJSW measured on radiographs was correlated to mean cartilage thickness calculated by qMRI (r = 0.71, p 0.0001 for the medial PFJ and r = 0.81, p 0.0001 for the lateral PFJ). However, there was a lack of concordance between radiographs and qMRI for extreme values of joint width and KLG. Radiographs yielded higher joint space measures than qMRI in knees with a normal joint space, while qMRI yielded higher joint space measures than radiographs in knees with joint space narrowing and higher KLG.Standing "skyline" radiographs are a reproducible tool for measuring the mJSW of the patellofemoral joint. The mJSW of the patellofemoral joint on radiographs are correlated with, but not concordant with, qMRI measurements.

Objective:APOE gene variants may contribute to the risk of chronic kidney disease. Our aim was to determine whether the common APOE-ε2/ε3/ε4 polymorphism is associated with a reduced estimated glomerular filtration rate (eGFR) in the RENASTUR population, a cohort of elderly individuals from the region Asturias (northern Spain). Methods: A total of 743 Spanish Caucasians aged 55-85 years were genotyped for the APOE-ε2/ε3/ε4 polymorphism. Individuals with a previous diagnosis of renal disease were not eligible for the study. Participants with a documented history of type 2 diabetes mellitus (T2DM) or hypertension or who were receiving antidiabetic or antihypertensive drugs were classified as diabetics and hypertensives. The eGFR was calculated using the Modification of Diet in Renal Disease formula, and those with an eGFR 2 (n = 91) were considered as having impaired renal function. The effect of alleles and genotypes on clinical (hypertension, T2DM) and analytical findings was statistically determined. Results: In addition to age and T2DM, APOE-ε2 was significantly associated with an eGFR 2 (p = 0.002; OR = 2.30). This association remained statistically significant after correction for multiple variables. Although the effect of the APOE-ε2 allele on the eGFR was observed both among diabetics and nondiabetics, the significance was stronger in the T2DM group. Conclusion: The APOE-ε2 allele is a genetic risk factor for impaired renal function among healthy elderly Spanish individuals.

Most pancreatic cancers and extrahepatic cholangiocarcinomas are unresectable at the time of diagnosis, and even in case of a resectable cancer, for elderly or patients with coexistent comorbidities, surgery is not an option. Current treatment alternatives in these scenarios are very limited. Biliary stenting with self-expanding metal stents (SEMS) is the mainstay palliative treatment of biliary obstruction due to unresectable pancreatic cancer or cholangiocarcinoma. Nevertheless, more than 50% of SEMS become occluded after 6 mo due to tumour over- and ingrowth, leading to hospital readmissions and reinterventions that significantly impair quality of life. Regimes of chemotherapy or chemoradiotherapy also provide minimal survival benefits. Therefore, novel therapies are eagerly awaited. Radiofrequency (RF) energy causes coagulative necrosis leading to local destruction of the accessed malignant tissue and has an established role in the treatment of malignancies in several solid organs, especially liver cancers. However, pancreatic and extrahepatic biliary cancers are not easily accessed by a percutaneous route, making the procedure dangerous. Over the past five years, the development of dedicated devices compatible with endoscopic instruments has offered a minimally invasive option for RF energy delivery in biliopancreatic cancers. Emerging experience with endoscopic RF ablation (RFA) in this setting has been reported in the literature, but little is known about its feasibility, efficacy and safety. A literature review makes it clear that RFA in biliopancreatic tumours is feasible with high rates of technical success and acceptable safety profile. Although available data suggest a benefit of survival with RFA, there is not enough evidence to draw a firm conclusion about its efficacy. For this reason, prospective randomized trials comparing RFA with standard palliative treatments with quality-of-life and survival endpoints are required. Anecdotal reports have also highlighted a potential curative role of RFA in small pancreatic tumours and benign conditions, such as ductal extension of ampullomas, intrahepatic adenomas or non-tumoural biliary strictures. These newest indications also deserve further examination in larger series of studies.

Network virtualization is an emerging technique that enables multiple tenants to share an underlying physical infrastructure, isolating the traffic running over different virtual infrastructures/tenants. This technique aims to improve network utilization, while reducing the complexities in terms of network management for operators. Applied to this context, software defined networking (SDN) paradigm can ease network configurations by enabling network programmability and automation, which reduces the amount of operations required from both service and infrastructure providers. SDN techniques are decreasing vendor lock-in issues due to specific configuration methods or protocols. Application-based Network Operations (ABNO) is a toolbox of key network functional components with the goal of offering application-driven network management. Service provisioning using ABNO may involve direct configuration of data plane elements or delegate it to several control plane modules. We validate the applicability of ABNO to multi-tenant virtual networks in multi-technology optical domains based on two scenarios, in which multiple control plane instances are orchestrated by the architecture. Congestion Detection and Failure Recovery, are chosen to demonstrate fast recalculation and reconfiguration, while hiding the configurations in the physical layer from the upper layer.

The therapeutic role of endoscopic papillectomy (EP) for early ampullary cancer (AC) is still controversial. The aim of the present study was to evaluate the curative potential of EP for early AC and to identify predictors of lymph node metastases (LNMs). We retrospectively reviewed 173 patients who were prospectively included in a database and who underwent EP between 1999 and 2013. Adenocarcinoma was present in 28 resected specimens. An additional surgery was proposed in cases of duodenal submucosal infiltration, duct ingrowth, R1 resection or lymphovascular invasion. Clinicopathological information and outcomes were collected, and predictors of LNMs were evaluated. Duodenal submucosal invasion was present in 16/28 cases and LNMs, in 9/28 cases. ACs of the biliopancreatic subtype were smaller (NS); 100 % had submucosal invasion, and 71 % had LNMs. Smaller tumour size, biliopancreatic subtype and submucosal invasion were significantly correlated with LNMs (p

Tacrolimus (Tac) exhibits an interindividual pharmacokinetic variability that affects the dose required to reach the target concentration in blood. Tac is metabolized by two enzymes of the cytochrome P450 family, CYP3A5 and CYP3A4. The effect of the CYP3A5 genotype on Tac bioavailability has been demonstrated, and the main determinant of this pharmacogenetic effect is a single-nucleotide polymorphism (SNP) in intron 3 of CYP3A5 (6986 A>G; SNP rs776746; also known as CYP3A5*3). The mean dose-adjusted blood Tac concentration was significantly higher among CYP3A5*3 homozygotes than that of carriers of the wild-type allele (CYP3A5*1). In a recent prospective study, a group of kidney transplant patients received a Tac dose either according to the CYP3A5 genotype (the adapted group) or according to the standard regimen (the control group). All patients received induction therapy with mycophenolate mofetil, corticosteroids, and either basiliximab or intravenous anti-thymocyte globulin. Patients in the adapted-dose group required 3–8 days (median 6 days) to reach the target range compared with 3–25 days (median 7 days) in the control group (P=0.001). The total number of dose modifications was also lower in the adapted-dose group. This study also suggested that the CYP3A5 genotype might contribute minimally to the reduction of early acute rejection. However, additional studies are necessary to determine whether the pharmacogenetic approach could help reduce the necessity for induction therapy and co-immunosuppressors.

Recent genome-wide association studies identified single-nucleotide polymorphisms (SNPs) in the gene encoding the pore-forming subunit of the voltage-gated K+ channel (KCNQ1) as a risk factor for type 2 diabetes. Tacrolimus (Tac) increased the risk of new-onset diabetes after transplantation (NODAT). The aim of this study was to analyze the association between KCNQ1 variants and the risk for NODAT in kidney-transplanted patients who received Tac as primary immunosuppressor. We genotyped three common KCNQ1 SNPs in 145 Spanish patients who received a cadaveric kidney graft and developed NODAT in the first-year post-transplant (the NODAT group), and 260 patients who remained non-diabetics (non-NODAT). In addition, we searched for DNA variants in the whole KCNQ1 coding exons in these patients. SNP rs2237895 (genotype CC) was associated with an increased risk for NODAT in our population (p = 0.008; OR = 1.83, 95% CI = 1.14-2.93), independently of other risk factors as body mass index, recipient age, or tacrolimus dosage. Other KCNQ1 variants were not associated with NODAT in our patients. Our work supported a role for KCNQ1 gene variants as determinants of the risk of developing NODAT among Tac-treated patients.

El sindrome de Brugada se caracteriza por un bloqueo de la rama derecha y elevacion del segmento ST en las derivaciones precordiales derechas del electrocardiograma. Con frecuencia se observa una transmision familiar, y en aproximadamente el 25% de los casos se han hallado mutaciones en el gen SCN5A. Hemos analizado la secuencia de este gen en 25 pacientes espanoles con sindrome de Brugada. En 4 de ellos (16%) hallamos mutaciones que no habian sido descritas previamente: 3 eran cambios de aminoacidos (Ala2>Tre, Ala735>Tre y Val1340>Ile) y 1 era intronica y afectaria al procesamiento del ARNm (intron 18 IVS18-1G>A). En los 4 habia familiares portadores, y varios de ellos tenian electrocardiogramas normales, incluso tras induccion con flecainida. Nuestro estudio indica que el analisis genetico seria util para el diagnostico presintomatico, pero de utilidad limitada para estratificar el riesgo de eventos adversos.

Background. Gitelman syndrome is a primary tubular disorder causing hypokalaemic metabolic alkalosis with hypocalciuria. Its prevalence is high in Gypsies, who harbour an identical mutation, intron 9 + 1 G>T, in the SLC12A3 gene. Methods. To better define the Gitelman syndrome in Gypsies, the clinical and biochemical features of 34 Spanish paediatric Gypsy patients were analysed. At diagnosis, symptoms, height and weight as well as serum and urinary biochemical data were collected. During a follow-up of 4.5 ± 2.4 years [X ± standard deviation (SD)], therapy, treatment compliance, symptoms, frequency of hospital admissions and, at the last visit, growth and biochemical work-up of 29 patients followed for at least 6 months were analysed. Quality of life items were also assessed by a questionnaire. Results. Muscle cramps (41%) and asthenia (35%) were the most frequent presenting symptoms. Biochemical data at diagnosis were serum K 2.76 ± 0.46 mEq/L, serum Mg 1.32 ± 0.28 mg/dL, blood pH 7.45 ± 0.06, serum bicarbonate 28.2 ± 2.9 mEq/L, urinary calcium/creatinine ratio 0.03 ± 0.04 mg/mg, fractional K excretion 24.4 ± 17.1% and fractional Mg excretion 8.9 ± 8.3%. During followup, Mg and K supplements were prescribed to 79 and 86% of patients, respectively; compliance with treatment was good in 35%. Hospital admission rate was 0.03/patient/ month. Muscle cramps were the symptom most often referred by the patients (45%) during the follow-up, and 71% of patients considered their health status as excellent or good. Twenty-one patients stated that their disease did not adversely interfere with their mood or social relationships. Height and weight of patients at diagnosis were −0.60 ± 1.17 and −0.49 ± 1.32 SD, respectively, and improved to −0.44 ± 1.28 (P < 0.05) and 0.18 ± 1.79 SD (P < 0.01) at the last visit. Conclusions. Gypsy children with Gitelman syndrome mostly exhibit muscle symptoms and asthenia although the disease is not particularly severe in this ethnic group. Body growth improves with treatment and close follow-up.

Brugada syndrome is characterized by right bundle branch block and ST-segment elevation in the right precordial ECG leads. Familial transmission is frequent and approximately 25% of cases exhibit mutations in the SCN5A gene. We analyzed the sequence of this gene in 25 Spanish patients with Brugada syndrome. In 4 (16%), we found mutations that had not previously been described: three were amino acid changes (i.e. Ala2>Thr, Ala735>Thr and Val1340>Ile) and one was an intron mutation that affected messenger RNA processing (i.e. IVS18-1G>A). These four patients had relatives who were also mutation carriers, several of whom had normal ECGs, even on flecainide challenge. Our study suggests that genetic analysis could be helpful in the presymptomatic diagnosis of Brugada syndrome, but may be less useful for stratifying the risk of adverse events.

Data on the potential influence of the angiotensin-converting enzyme (ACE) insertion/ deletion (I/D) genotype on psoriasis are contradictory. Our aim was to investigate the relationship between the ACE gene I/D polymorphism and psoriasis/psoriatic arthritis. To investigate this, a genetic association study was conducted among 268 unrelated patients with psoriasis and 272 controls. The distribution of DD, ID, and II genotypes did not significantly differ between psoriatic patients and controls (DD: 39.6% vs. 34.2%; ID: 46.3% vs. 53.3%; II: 14.1% vs. 12.5%). In conclusion, the ACE polymorphism is not likely to be associated with either psoriasis or psoriatic arthritis in this study.

A deficit in bone formation is a major factor in diabetes-related osteopenia. We examined here whether diabetes-associated changes in osteoblast phenotype might in part result from a decrease in PTH-related protein (PTHrP). We used a bone marrow ablation model in diabetic mice by multiple streptozotocin injections. PTHrP (1–36) (100 μg/kg, every other day) or vehicle was administered to mice for 13 d starting 1 wk before marrow ablation. Diabetic mice showed bone loss in both the intact femur and the regenerating tibia on d 6 after ablation; in the latter, this was related to decreased bone-forming cells, osteoid surface, and blood vessels, and increased marrow adiposity. Moreover, a decrease in matrix mineralization occurred in ex vivo bone marrow cultures from the unablated tibia from diabetic mice. These skeletal alterations were associated with decreased gene expression (by real-time PCR) of Runx2, osterix, osteocalcin, PTHrP, the PTH type 1 receptor, vascular endothelial growth factor and its receptors, and osteoprotegerin to receptor activator of nuclear factor-κB ligand mRNA ratio, and increased peroxisome proliferator-activated receptor-γ2 mRNA levels. Similar changes were induced by hyperosmotic (high glucose or mannitol) medium in osteoblastic MC3T3-E1 cells, which were mimicked by adding a neutralizing anti-PTHrP antibody or PTH type 1 receptor antagonists to these cells in normal glucose medium. PTHrP (1–36) administration reversed these changes in both intact and regenerating bones from diabetic mice in vivo, and in MC3T3-E1 cells exposed to high glucose. These findings strongly suggest that PTHrP has an important role in the altered osteoblastic function related to diabetes.

Background: Gitelman’s syndrome (GS) is caused by mutations in the SLC12A3. Most of the mutations are rare, making it difficult to establish a genotype-phenotype correlation. Although GS is a recessive disorder, some patients also have an affected parent, suggesting a dominant inheritance. Methods: We sequenced the 26 coding exons of SLC12A3 in a family in which the proband and her father had a late onset GS. We obtained cDNA of the 2 patients and analyzed the effect of a mutation on pre-mRNA splicing. Results: The 2 patients were homozygous for a nucleotide change in the last nucleotide of exon 15: c.1925 G>A. The mother was a heterozygous carrier for this putative mutation. Amplification of cDNA with primers for exons 14–17 was negative, suggesting that this mutation affected the splicing and promoted mRNA degradation through nonsense-mediated decay. Conclusions: We report a family with 2 patients with late onset GS and homozygous for a mutation in the last nucleotide of exon 15. Our study shows that homozygosity for this mutation resulted in a significant loss of normal SLC12A3 transcript.

Introduccion y objetivos. Las mutaciones en los genes sarcomericos son la causa mas frecuente de miocardiopatia hipertrofica. Para cada gen, la frecuencia de mutaciones varia entre los estudios, y las manifestaciones clinicas son muy heterogeneas, lo que dificulta el empleo de la informacion genetica en la practica clinica. Nuestro objetivo es determinar la frecuencia de mutaciones en los genes sarcomericos MYH7, MYBPC3, TNNT2, TNNI3 y TPM1 en una serie de pacientes con miocardiopatia hipertrofica. Metodos. Se analizaron las regiones codificantes de estos cinco genes mediante secuenciacion en 120 pacientes (el 29% con antecedentes familiares), comparando el fenotipo segun el gen mutado. Resultados. Se hallaron mutaciones en 32 pacientes; 10 y 20 tenian mutaciones en MYH7 (8%) y MYBPC3 (16%). Se hallaron mutaciones de TNNT2 y TPM1 en 2 y 1 pacientes, y ninguna de TNNI3. Dos pacientes tenian dos mutaciones (dobles mutantes). El 61% de las mutaciones no habian sido descritas previamente. No hallamos diferencias en la media de edad al diagnostico o el tamano de la hipertrofia entre los portadores de mutaciones en MYH7 y los de MYBPC3. Conclusiones. El 26% de los pacientes tenian mutaciones en alguno de los cinco genes estudiados. Mas de la mitad de las mutaciones no habian sido descritas. El gen MYBPC3 fue el mas mutado, seguido de MYH7. No se hallaron diferencias fenotipicas entre los pacientes segun el gen mutado, lo que dificultaria el empleo de la informacion genetica para estratificar el riesgo en estos pacientes.

Background: The cyclophilin A (CypA) - cyclosporine (CsA) complex promotes immune response. The variation at the CypA gene could explain CsA-pharmacokinetics and clinical outcomes among CsA-treated patients. Methods: The study included 290 kidney transplanted patients (65% male; mean age 51 ± 15 yr), treated with CsA. The five CypA- exons and the promoter region were analysed through single-strand conformation analysis, denaturing high performance liquid chromatography, and direct sequencing. The effect of a promoter polymorphism (−11 G/C) on gene expression was analysed in cell-cultures. Results: We found two polymorphisms in the promoter (−11 G/C) and exon 1 (+36 G/A). Genotype frequencies did not differ between patients according to their pharmacokinetics status. In vitro studies showed that −11 G/C affected gene expression. The −11 G allele was significantly associated with clinical nephrotoxicity (p = 0.006). The strongest predictors for nephrotoxicity were a donor age ≥55 yr, and the promoter GG + GC genotypes. Conclusions: Our work suggests that a CypA-promoter polymorphism (−11 G/C) could be associated with clinical nephrotoxicity. Replication of this study in other populations is necessary to define the role of CypA-variants in the main clinical outcomes among CsA-treated kidney-transplanted patients.

To investigate the association between four functional polymorphisms in interleukin-1 (IL-1) [IL-1 alpha -889 C/T, IL-1 beta +3953 C/T, IL-1RA (86 bp)n] and tumor necrosis factor alpha (TNFalpha) (-308A/G) genes and suicide attempts. Distribution of the aforesaid polymorphisms was analyzed in 193 suicide attempters compared with 420 unrelated healthy controls from Asturias (Northern Spain). Genotypes were determined using standard methods. No significant differences were found in genotype or in allelic distribution of IL-1 alpha, IL-1 beta, IL-1RA, or TNFalpha gene polymorphisms. No relationship was found between genotypes and the impulsivity of the suicide attempt. Estimated IL-1 haplotype frequencies were similar in both groups (likelihood ratio test=13.26, df=14, P=0.506). Our data do not suggest that genetically determined changes in the IL-1 or TNFalpha genes confer increased susceptibility to suicidal behavior. Language: en

Purpose: To evaluate the impact of acquired and inherited factors on the development of lipodystrophic syndrome in patients on highly active antiretroviral therapy. Methods: Two hundred forty-three human immunodeficiency virus-infected Caucasians on highly active antiretroviral therapy were prospectively followed-up for 3 years. Eleven were naIve and 232 were on antiretrovirals (mean, 93.0 months ± 43.8 months). Lipodystrophic syndrome was diagnosed clinically with a lipodystrophy severity grading scale. Polymorphisms of cytokines (IL-1β, IL-6, TNF-α), TLR4, and NOS genes were genotyped. Results: Ninety (37%) patients developed lipodystrophic syndrome. The polymorphic T allele of the (+3954C/T) polymorphism of IL-1β was less frequent in patients with lipodystrophic syndrome compared with those without (17.8% vs. 27.0%, P = 0.03). Factors significantly associated with lipodystrophic syndrome were time on stavudine (P < 0.001), use of stavudine (P = 0.001), absence of the T allele of the (+3954C/T) IL-1β polymorphism (P = 0.02), acquired immune deficiency syndrome diagnosis (P = 0.005), nadir levels of CD4 (P = 0.003), and time on highly active antiretroviral therapy (P = 0.003). Of these factors, only the time on stavudine (hazard ratio [95% confidence intervals] 1.007 [1.001–1.013]), use of stavudine (1.678 [1.048–2.68]), and absence of the T allele of the IL-1β (+3954C/T) polymorphism (0.569 [0.347–0.931]) were significantly associated with lipodystrophic syndrome by Cox regression. Conclusions: Genotyping of the (+3954C/T) polymorphism of IL-1β could be useful in patients starting highly active antiretroviral therapy, especially in potential users of stavudine, to predict their risk of developing lipodystrophic syndrome.

Objective: To investigate the association between four polymorphisms of the 5-HT2A receptor and 5-HT transporter genes and heroin dependence. Methods: 113 heroin- dependent patients (DSM-IV criteria) and 420 unrelated healthy controls from Asturias (Northern Spain) were genotyped using standard methods. Results: There was an apparent difference in the distribution of genotypes for A-1438G polymorphisms (p = 0.024, not significant after Bonferroni correction). The 5-HT2A -1438A allele was significantly more common in patients than controls [0.55 and 0.45, respectively; corrected p = 0.042, OR = 1.51 (95% CI = 1.13–2.03)]. An interaction was observed between A-1438G of 5-HT2A and 5-HTT polymorphisms. The association between the -1438AA vs. AG/GG genotypes and heroin dependence was enhanced in the presence of 12-repeat 5-HTT VNTR and short 5-HTTLPR alleles [24.8% in heroin-dependent patients vs. 12.6% in controls; corrected p = 0.045, OR = 2.28 (95% CI = 1.36–3.82)]. Conclusions: Our findings support a contribution of the 5-HT2A gene to susceptibility to heroin dependence, as well as a possible synergistic effect of 5-HT2A and 5-HTT genes on susceptibility to heroin dependence.

A minor proportion of patients with achalasia eventually have a neoplasm and, as a consequence, pseudoachalasia is diagnosed. A neoplasm may either involve gastrointestinal junction or present a paraneoplastic effect. Over the global diagnoses of achalasia issued in 5 years of experience in our motility unit, we have found 13% (3/23 cases) of pseudoachalasia (2-4% in previous series, probably due to the fact that the population assisted was mainly composed of elderly patients). The origin of the neoplasm was bladder, prostate and metastases from epidermoid carcinoma of vocal chord. Treatment of primary neoplasm, besides classical approach (with dilatation of botulinum injection) may help in the resolution of this clinical disorder.