Pharmacological inhibition of N-Acylethanolamine acid amidase (NAAA) mitigates intestinal fibrosis through modulation of macrophage activity.

BACKGROUND AND AIMS: Intestinal fibrosis, a frequent complication of inflammatory bowel disease, is characterized by stricture formation with no pharmacological treatment to date. N-acylethanolamine acid amidase (NAAA) is responsible of acylethanolamides (AEs, e.g., palmitoylethanolamide and oleoylethanolamide) hydrolysis. Here, we investigated NAAA and AEs signalling in gut fibrosis. METHODS: NAAA and AEs signalling were evaluated in human intestinal specimens from stenotic Crohn's diseases (CD) patients. Gut fibrosis was induced by TNBS, monitored by colonoscopy and unascertained by qRT-PCR, histological analyses, and confocal microscopy. Immune cells were analysed in mesenteric lymph nodes by FACS. Colonic fibroblasts were cultured in conditioned media derived from polarized or not bone marrow-derived macrophages (BMDM). IL-23 signalling was evaluated by qRT-PCR, ELISA, FACS, and western blot in BMDM and in lamina propria CX3CR1+ cells. RESULTS: In ileocolonic human CD strictures, increased transcript expression of NAAA was observed with a decrease of its substrates OEA and PEA. NAAA inhibition reduced intestinal fibrosis in vivo, as revealed by decrease in inflammatory parameters, collagen deposition and fibrosis genes, including epithelial to mesenchymal transition. More in-depth studies revealed modulation of the immune response related to IL-23 following NAAA inhibition. The antifibrotic actions of NAAA inhibition are mediated by Mφ and M2 macrophages that indirectly affect fibroblast collagenogenesis. NAAA inhibitor AM9053 normalized IL-23 signalling in BMDM and in lamina propria CX3CR1+ cells. CONCLUSIONS: Our findings provide new insights into the pathophysiological mechanism of intestinal fibrosis and identify NAAA as a promising target for the development of therapeutic treatments to alleviate CD fibrosis.

Protocol for a pilot and feasibility study evaluating a complex nurse-led patient education intervention to promote cancer patient engagement in healthy lifestyle (O-PHE programme).

INTRODUCTION: Literature suggests that patient engagement in healthy lifestyle is of crucial importance in ensuring a more effective management of side effects of cancer therapies and better quality of life for patients. While many studies describe educational interventions to promote healthy lifestyles, few are focused on promoting active patient engagement in this field. This protocol paper outlines a study to determine the feasibility of a complex nurse-led patient education intervention aimed to promote cancer patient engagement in a healthy lifestyle. METHOD AND ANALYSIS: This is a randomised pilot and feasibility study. Research nurses will recruit 40 adult patients newly diagnosed with cancer. Consenting participants will be randomised to undergo the patient engagement in healthy lifestyle intervention or the control group by means of a four-block randomisation procedure. The intervention will be delivered by a clinical nurse trained in patient engagement strategies. The primary outcome will be a description of study feasibility (recruitment and retention rates, protocol adherence and stakeholder acceptability). Secondary outcomes include changes between and within groups in healthy lifestyle behaviours (ie, increase in healthy diet, smoke cessation or reduction, increase in physical activity), in quality-of-life rates after the intervention, in patient engagement levels, in the perception of the quality of care, in nutritional status; the number of recurrences or the onset of new cancer diagnosis; the number of hospitalization. ETHICS AND DISSEMINATION: The study protocol has been approved by the Canton Ticino Ethical Committee (Protocol ID: 2020-02477 TI). The results will be published in peer-reviewed journals and will be presented at national and international congresses. Finally, patients' organisations, such as the Swiss Cancer League, will be involved in the dissemination process. This study will inform the decision to proceed with a randomised controlled trial to assess the effect of this intervention.

Expression study of candidate miRNAs and evaluation of their potential use as biomarkers of diabetic neuropathy.

Aim: To evaluate the expression of candidate miRNAs in relation to diabetic polyneuropathy (DPN) and cardiovascular autonomic neuropathy (CAN). Materials & methods: The expression of six candidate miRNAs has been evaluated in 49 Type 2 diabetes patients with neurological evaluation. Results: A higher expression of miR-128a was seen in patients with DPN compared with those without DPN (p = 0.015). miR-155 and miR-499a seemed to be down-expressed in patients with DPN (p = 0.04 and p = 0.05, respectively). A lower expression of miR-155 (p = 0.05) was observed even in patients with CAN with respect to CAN-negative. A higher expression of miR-155 was associated with the rs767649 polymorphism variant allele compared with the wild-type allele (p = 0.03). Conclusion: miR-128a, miR-155 and miR-499a might be involved in diabetic neuropathies development.

Utilidad de diferentes puntajes de riesgo de mortalidad en pacientes con insuficiencia cardíaca. Estudio observacional retrospectivo / Usefulness of Different Mortality Risk Scores in Patients with Heart Failure. A Retrospective and Observational Study

RESUMEN Introducción: El Cardiac and Comorbid Conditions - Heart Failure (3C-HF) y el Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) son dos sistemas de puntaje desarrollados para predecir la mortalidad en pacientes con insuficiencia cardíaca (IC). El desempeño de estos puntajes ha sido poco estudiado en nuestro medio. Objetivo: Evaluar el desempeño del 3C-HF y del MAGGIC para predecir la mortalidad al año en una población de pacientes con IC. Material y métodos: Se incluyeron pacientes con diagnóstico de IC ambulatorios y dados de alta luego de una internación por IC aguda atendidos en dos centros. Se calcularon los puntajes 3C-HF y MAGGIC. Se evaluó como punto final la mortalidad global al año. La capacidad de discriminación de estos puntajes se analizó a partir del cálculo del área bajo la curva (ABC) ROC, y la calidad de su calibración, aplicando el test de Hosmer-Lemeshow. Se compararon ambas ABC mediante el test de Hanley-Mc Neil. Resultados: Se incluyeron 704 pacientes con una edad promedio de 73 ± 11 años, el 39,6% eran mujeres. La mortalidad al año fue del 12,4% (n = 87). Ambos puntajes fueron predictores independientes de mortalidad, con HR de 1,03 (IC95% 1,008-1,06; p = 0,02) y 1,08 (IC95% 1,02-1,13; p = 0,004) para el puntaje 3C-HF y el MAGGIC, respectivamente. El 3C-HF presentó un ABC de 0,70 (IC95% 0,64-0,75) y el MAGGIC de 0,67 (IC95% 0,61-0,73), sin diferencias entre las ABC (p = 0,41). Ambos presentaron adecuada calibración (p = 0,06 y p = 0,32, respectivamente). Conclusión: Los puntajes 3C-HF y MAGGIC fueron predictores de mortalidad a un año, con una moderada capacidad de discriminar eventos y una adecuada calibración. No hubo diferencias en la capacidad de discriminación entre ambos puntajes.

ABSTRACT Background: The Cardiac and Comorbid Conditions - Heart Failure (3C-HF) and the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) are two score models developed to predict mortality in patients with heart failure (HF). The performance of these scores has been little studied in our setting. Objective: The aim of this study was to assess the performance of the 3C-HF and the MAGGIC scores to predict one-year mortality in a population of patients with H F. Methods: Ambulatory HF patients discharged after hospitalization due to acute HF in two centers were included in the study. The 3C-HF and MAGGIC scores were calculated and one-year mortality was the study endpoint. The discrimination ability of the scores was analyzed from the calculated area under the ROC curve and their calibration quality was assessed applying the Hosmer-Lemeshow test. Both areas under the ROC curve were compared using the Hanley-Mc Neil test. Results: A total of 704 patients with mean age of 73±11 years and 39.6% women were included in the study. One-year mortal-ity was 12.4% (n=87). Both scores were independent predictors of mortality, with HR of 1.03 (95% CI 1.008-1.06; p=0.02) and 1.08 (95% CI 1.02-1.13; p=0.004) for the 3C-HF and MAGGIC scores, respectively. The area under the ROC curve for the 3C-HF score was 0.70 (95% CI 0.64-0.75) and for the MAGGIC score 0.67 (95% CI 0.61-0.73), without significant differences between them (p=0.41). Both scores presented adequate calibration (p=0.06 and p=0.32, respectively). Conclusion: The 3C-HF and MAGGIC scores were predictors of one-year mortality, with a moderate ability to discriminate events and adequate calibration. The discrimination ability between both scores was not significant.

Alkaloids and biological activity of beribá (Annona hypoglauca)

ABSTRACT Annona hypoglauca Mart., Annonaceae, popularly known as “beribá”, was collected in flooded areas of the Amazonian Rain Forest. The crude extract obtained from this species was found to be cytotoxic against human cancer cells. Chemical information on A. hypoglauca is scarce. So, the present work aimed the isolation and identification of its alkaloids and to test their cytotoxic activity. Alkaloids were obtained from stem by acid–base partitioning and the remaining alkaloid-free extract was partitioned with organic solvents. Gas chromatography–mass spectrometry GC/MS analysis of total alkaloids allowed the identification of four aporphine alkaloids: actinodaphnine, anonaine, isoboldine and nornuciferine. Total alkaloids were fractionated by column chromatography and were purified by preparative thin-layer-chromatography, which allowed the isolation of two aporphine alkaloids, actinodaphnine and isoboldine, characterized by NMR and CG–MS analyses. This is the first report for the occurrence of actinodaphnine in Annona species. All the samples were tested in cytotoxic and antibacterial assays. Total alkaloid extract and its fractions showed antimicrobial activity against Staphylococcus aureus and Enterococcus faecalis. In the cytotoxicity assay, the crude extract showed a lethal effect against breast and colon cancer cells. Isoboldine-containing FA5 and actinodaphnine-containing FA6 showed activity against breast cancer cell line, while the alkaloid-free fractions did not show significant activity against cancer cell lines.

Severe hypoglycemia in patients with known diabetes requiring emergency department care: A report from an Italian multicenter study.

AIMS: To describe the characteristics and associated risk factors of patients with established diabetes who required Emergency Department (ED) care for severe hypoglycemia. METHODS: We performed an observational retrospective study to identify all cases of severe hypoglycemia among attendees at the EDs of three Italian University hospitals from January 2010 to December 2014. RESULTS: Overall, 520 patients with established diabetes were identified. Mean out-of-hospital blood glucose concentrations at the time of the hypoglycemic event were 2.2 ± 1.3 mmol/L. Most of these patients were frail and had multiple comorbidities. They were treated with oral hypoglycemic drugs (43.6%), insulin (42.8%), or both (13.6%). Among the oral hypoglycemic drugs, glibenclamide (54.5%) and repaglinide (25.7%) were the two most frequently used drugs, followed by glimepiride (11.3%) and gliclazide (7.5%). Hospitalization rates and in-hospital deaths occurred in 35.4% and in 2.3% of patients, respectively. Cirrhosis (odds ratio [OR] 6.76, 95% confidence interval [CI] 1.24-36.8, p < 0.05), chronic kidney disease (OR 2.42, 95% CI 1.11-8.69, p < 0.05) and center (Sapienza University OR 3.70, 95% CI 1.57-8.69, p < 0.05) were the strongest predictors of increased rates of hospital admission. CONCLUSIONS: Severe hypoglycemia is a remarkable burden for patients with established diabetes and increases the risk of adverse clinical outcomes (in-hospital death and hospitalization), mainly in elderly and frail patients. This study further reinforces the notion that careful attention should be taken by health care providers when they prescribe drug therapy in elderly patients with serious comorbidities.

Peanut allergy diagnoses among children residing in Olmsted County, Minnesota.

BACKGROUND: Peanut allergy is a major health concern, particularly in developed countries. Research indicates that as many as 2% of children are allergic to peanuts, which represents a 3-fold increase in diagnoses over the past 2 decades. OBJECTIVE: This population-based descriptive study used the Rochester Epidemiology Project to estimate the prevalence in 2007 and annual incidence rates of peanut allergy diagnoses from 1999 to 2007 among children residing in Olmsted County, Minnesota. METHODS: Residents of Olmsted County from January 1, 1999, through December 31, 2007, who received medical care at a Rochester Epidemiology Project facility and provided research authorization were eligible for the study. A medical chart review of 547 potential diagnoses resulted in 244 prevalent and 170 incident cases. Annual rates, crude and adjusted for age and sex, were standardized with the use of the indirect method to the Olmsted County population data in 1999. Incidence rate ratios were estimated with Poisson regression. RESULTS: The prevalence in 2007 was 0.65%. Female children were less likely to be diagnosed than male children (incidence rate ratio = 0.18; 95% CI, 0.07-0.48). Children aged birth to 2 years were significantly more likely to be diagnosed than older children aged 3-17 years (incidence rate ratio = 0.001; 95% CI, 0.0004-0.004). A significant 3-fold increasing trend was observed in diagnoses over time from 2.05 cases per 10,000 children in 1999 to 6.88 cases per 10,000 in 2007. CONCLUSIONS: Peanut allergies are an increasing concern in Olmsted County, Minnesota, as indicated by a 3-fold increase in diagnoses from 2.05 per 10,000 children in 1999 to 6.88 per 10,000 children in 2007.

Incidental vertebral compression fractures in imaging studies: Lessons not learned by radiologists.

AIM: To assess radiologists reporting rates of incidental vertebral compression fractures in imaging studies. METHODS: We performed a review of the current literature on the prevalence and reporting rates of incidental vertebral compression fractures in radiologic examinations. RESULTS: The bibliographic search revealed 12 studies: 7 studies using conventional radiology and 5 using multidetector computed tomography (MDCT). The loss of height cut-off to define a vertebral fracture varied from 15% to 25%. Fracture prevalence was high (mean 21.1%; range 9.5%-35%) in both radiographic and MDCT studies (mean 21.6% and 20.2%, respectively). Reporting rates were low with a mean value of 27.4% (range 0%-66.3%) and were significantly lower in MDCT than in radiographic studies (mean 8.1% vs 41.1%). Notably, recent studies showed lower reporting rates than older studies. CONCLUSION: Many scientific studies have confirmed a high prevalence of vertebral compression fractures as incidental findings on imaging studies. However, the underreporting of these fractures, as determined in our study, may negatively affect patient care.

High-molecular weight hyaluronan reduced renal PKC activation in genetically diabetic mice.

The cluster determinant (CD44) seems to play a key role in tissues injured by diabetes type 2. CD44 stimulation activates the protein kinase C (PKC) family which in turn activates the transcriptional nuclear factor kappa B (NF-κB) responsible for the expression of the inflammation mediators such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-18 (IL-18), inducible nitric oxide synthase (iNOS), and matrix metalloproteinases (MMPs). Regulation of CD44 interaction with its ligands depends greatly upon PKC. We investigated the effect of the treatment with high-molecular weight hyaluronan (HA) on diabetic nephropathy in genetically diabetic mice. BKS.Cg-m+/+Lepr(db) mice had elevated plasma insulin from 15 days of age and high blood sugar levels at 4 weeks. The severe nephropathy that developed was characterized by a marked increased in CD44 receptors, protein kinase C betaI, betaII, and epsilon (PKC(ßI), PKC(ßII), and PKCε) mRNA expression and the related protein products in kidney tissue. High levels of mRNA and related protein levels were also detected in the damaged kidney for NF-κB, TNF-α, IL-6, IL-18, MMP-7, and iNOS. Chronic daily administration of high-molecular mass HA for 2 weeks significantly reduced CD44, PKC(ßI), PKC(ßII), and PKCα gene expression and the related protein production in kidney tissue and TNF-α, IL-6, IL-18, MMP-7, and iNOS expression and levels also decreased. Histological analysis confirmed the biochemical data. However, blood parameters of diabetes were unchanged. These results suggest that the CD44 and PKC play an important role in diabetes and interaction of high-molecular weight HA with these proteins may reduce inflammation and secondary pathologies due to this disease.

Lack of awareness for spatial and verbal constructive apraxia.

It is still a matter of debate whether constructive apraxia (CA) should be considered a form of apraxia or, rather, the motor expression of a more pervasive impairment in visuo-spatial processing. Constructive disorders were linked to visuo-spatial disorders and to deficits in appreciating spatial relations among component sub-parts or problems in reproducing three-dimensionality. We screened a large population of brain-damaged patients for CA. Only patients with constructive disorders and no signs of neglect and/or aphasia were selected. Five apractic subjects were tested with both visuo-spatial and verbal tasks requiring constructive abilities. The former ones were tests such as design copying, while the latter were experimental tasks built to transpose into the linguistic domain the constructive process as phrasing by arranging paper scraps into a sentence. A first result showed a constructive impairment in both the visuo-spatial and the linguistic domain; this finding challenges the idea that CA is confined to the visuo-spatial domain. A second result showed a systematic association between CA and unawareness for constructive disorders. Third, lack of awareness was always associated with a lesion in the right dorsolateral prefrontal cortex, a region deemed as involved in managing a conflict between intentions and sensory feed-back. Anosognosia for constructive disorders and the potential role of the right prefrontal cortex in generating the impairment, are discussed in the light of current models of action control. The core of CA could be the inability to detect any inconsistency between intended and executed action rather than a deficit in reproducing spatial relationship.

Asthma and behavior in homeless 4- to 7-year-olds.

OBJECTIVE: Low-income, urban, ethnic minority children have higher rates of asthma, more severe symptoms, and more management issues, as well as high risk for academic and behavior problems. This study focused on asthma reported in young children who resided in a family emergency homeless shelter. Asthma rates were considered along with their relation to hospitalization and emergency department use and behavior that is important for school success, including cognitive function, conduct, and academic functioning. METHODS: A total of 104 children (age 4.0-7.5 years) and parents were recruited while residing in an urban emergency homeless shelter for families. Children had no previously identified developmental delays and spoke English proficiently. Parents reported whether the child experienced asthma, as well as emergency department use and hospitalization. Parents and teachers completed measures of child inattention/hyperactivity and behavior problems. Cognitive function of children was directly assessed. RESULTS: Asthma was reported for 27.9% of children, approximately 3 times the national average. Children with asthma had been hospitalized more often, showed higher levels of inattention/hyperactivity and behavior problems, and evidenced lower academic functioning. CONCLUSIONS: Young children in homeless family emergency shelters have high rates of asthma and related problems that could lead to higher hospitalization rates, more behavioral problems, and lower academic functioning at school. Screening and treatment of children who stay in emergency family shelters may be particularly important for reducing risks associated with asthma in highly mobile, low-income families.

Incidental lung nodules on CT examinations of the abdomen: prevalence and reporting rates in the PACS era.

OBJECTIVES: To retrospectively evaluate prevalence, reporting rates and clinical implications of incidental pulmonary nodules detected in multidetector computed tomography (MDCT) abdominal studies. MATERIALS AND METHODS: Abdominal MDCT studies of 243 consecutive patients, 94 of whom had a history of cancer, were evaluated. Lung bases included in the scan were reviewed on a PACS workstation with different window settings and post-processing techniques. Nodules were classified according to their density (calcified, solid noncalcified, non-solid, part-solid) and size (<4mm; 4-6mm; 6-8mm; >8mm). The study findings were compared with the corresponding radiologic reports. Previous of following CT studies, when available from the PACS, were also reviewed to evaluate changes in number and size of the detected nodules. RESULTS: An average of 8.2 cm of lung parenchyma was imaged in each patient. 213 noncalcified nodules (NCNs) were identified in 95 patients (39.1%) but only 8 patients (8.4%) had it mentioned in the final report. Comparison CT studies were available for 44 out of the 95 positive patients showing disappearance of the nodules in 2 cases, no interval change in 26 and progression in size and/or number in 16 patients, in whom a final diagnosis of metastasis or primary lung cancers was achieved. CONCLUSION: Radiologists tend to overlook lung portions on abdominal CT studies. Underreporting may affect patient care and have medico-legal implications since images are permanently stored in digital format on PACS and CD-ROMs. Management of the discovered nodules should be tailored to the clinical situation of the patient, and particular care should be reserved to patients with oncologic history.

Hourglass cystic schwannoma of the trochlear nerve.

Cranial nerves' schwannomas most commonly arise from the vestibular nerve. Involvement of other cranial nerves, in absence of neurofibromatosis, is extremely rare. A case of a pathology proven trochlear nerve schwannoma, with internal cystic components, in a patient with isolated right superior oblique muscle palsy, is described. Only 67 cases of such entity have been previously reported in the literature.

DISH of the cervical spine causing epiglottis impingement.

Diffuse idiopathic skeletal hyperostosis (DISH) is a condition characterized by calcification and ossification of ligaments and entheses; it mainly affects the vertebral column. We report the case of a patient with pharyngeal dysphagia and episodic aspiration secondary to DISH involvement of the cervical spine, which had caused alteration in the epiglottic tilt mechanism during deglutition.

Tract metastasis from previously unknown malignant pleural mesothelioma: a case report.

A case of malignant pleural mesothelioma discovered because of a chest wall metastasis which developed over a previous pleural drainage site is presented. Imaging findings at sonography, contrast enhanced computed tomography and fluorodeoxyglucose - positron emission tomography are shown.

Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome.

Genomic imprinting is an epigenetic phenomenon restricting gene expression in a manner dependent on parent of origin. Imprinted gene products are critical regulators of growth and development, and imprinting disorders are associated with both genetic and epigenetic mutations, including disruption of DNA methylation within the imprinting control regions (ICRs) of these genes. It was recently reported that some patients with imprinting disorders have a more generalised imprinting defect, with hypomethylation at a range of maternally methylated ICRs. We report a cohort of 149 patients with a clinical diagnosis of Beckwith-Wiedemann syndrome (BWS), including 81 with maternal hypomethylation of the KCNQ1OT1 ICR. Methylation analysis of 11 ICRs in these patients showed that hypomethylation affecting multiple imprinted loci was restricted to 17 patients with hypomethylation of the KCNQ1OT1 ICR, and involved only maternally methylated loci. Both partial and complete hypomethylation was demonstrated in these cases, suggesting a possible postzygotic origin of a mosaic imprinting error. Some ICRs, including the PLAGL1 and GNAS/NESPAS ICRs implicated in the aetiology of transient neonatal diabetes and pseudohypoparathyroidism type 1b, respectively, were more frequently affected than others. Although we did not find any evidence for mutation of the candidate gene DNMT3L, these results support the hypotheses that trans-acting factors affect the somatic maintenance of imprinting at multiple maternally methylated loci and that the clinical presentation of these complex cases may reflect the loci and tissues affected with the epigenetic abnormalities.

Prevalence of thoracolumbar vertebral fractures on multidetector CT: underreporting by radiologists.

OBJECTIVE: To evaluate the prevalence of osteoporotic vertebral fractures in patients undergoing multidetector computed tomography (MDCT) of the chest and/or abdomen. MATERIALS AND METHODS: 323 consecutive patients (196 males, 127 females) with a mean age of 62.6 years (range 20-88) who had undergone chest and/or abdominal MDCT were evaluated. Sagittal reformats of the spine obtained from thin section datasets were reviewed by two radiologists and assessed for vertebral fractures. Morphometric analysis using electronic calipers was performed on vertebral bodies which appeared abnormal upon visual inspection. A vertebral body height loss of 15% or more was considered a fracture and graded as mild (15-24%), moderate (25-49%) or severe (more than 50%). Official radiology reports were reviewed and whether the vertebral fractures had been reported or not was noted. RESULTS: 31 out of 323 patients (9.5%) had at least 1 vertebral fracture and 7 of those patients had multiple fractures for a total of 41 fractures. Morphometric grading revealed 10 mild, 16 moderate and 15 severe fractures. Prevalence was higher in women (14.1%) than men (6.6%) and increased with patients age with a 17.1% prevalence in post-menopausal women. Only 6 out 41 vertebral fractures (14.6%) had been noted in the radiology final report while the remaining 35 (85.45) had not. CONCLUSION: although vertebral fractures represent frequent incidental findings on multidetector CT studies and may be easily identified on sagittal reformats, they are often underreported by radiologists, most likely because of unawareness of their clinical importance.