Unraveling the parahormetic mechanism underlying the health-protecting effects of grapeseed procyanidins.

Proanthocyanidins (PACs), the predominant constituents within Grape Seed Extract (GSE), are intricate compounds composed of interconnected flavan-3-ol units. Renowned for their health-affirming properties, PACs offer a shield against a spectrum of inflammation associated diseases, such as diabetes, obesity, degenerations and possibly cancer. While monomeric and dimeric PACs undergo some absorption within the gastrointestinal tract, their larger oligomeric and polymeric counterparts are not bioavailable. However, higher molecular weight PACs engage with the colonic microbiota, fostering the production of bioavailable metabolites that undergo metabolic processes, culminating in the emergence of bioactive agents capable of modulating physiological processes. Within this investigation, a GSE enriched with polymeric PACs was employed to explore in detail their impact. Through comprehensive analysis, the present study unequivocally verified the gastrointestinal-mediated transformation of medium to high molecular weight polymeric PACs, thereby establishing the bioaccessibility of a principal catabolite termed 5-(3',4'-dihydroxyphenyl)-γ-valerolactone (VL). Notably, our findings, encompassing cell biology, chemistry and proteomics, converge to the proposal of the notion of the capacity of VL to activate, upon oxidation to the corresponding quinone, the nuclear factor E2-related factor 2 (Nrf2) pathway-an intricate process that incites cellular defenses and mitigates stress-induced responses, such as a challenge brought by TNFα. This mechanistic paradigm seamlessly aligns with the concept of para-hormesis, ultimately orchestrating the resilience to stress and the preservation of cellular redox equilibrium and homeostasis as benchmarks of health.

An unusual case of melanoma metastasis in the buccal space: learning by mistakes to distinguish it from salivary neoplasms.

BACKGROUND: The buccal space is an unusual location of malignancies. We report here the case of a woman with a melanoma metastasis in buccal fat pad, to evaluate the imaging features which might lead to the correct, although uncommon, diagnosis. CASE PRESENTATION: A 71-year-old woman presented with a painless visible swelling of the left cheek. MRI revealed the presence of a solid lesion located in the buccal fat pad with features suggestive of malignancy. It showed T1 hyperintensity and T2 hypointensity, and restriction of diffusion. Histological examination showed neoplastic cells compatible with melanoma. DISCUSSION: The lesion features (T1 hyperintensity and T2 hypointensity) initially lead our team to believe that there was a hemorrhagic component, possibly a residue of the biopsy. However, when associated with other malignancy features, such as low apparent diffusion coefficient (ADC) values and contrast enhancement, they should evoke the suspect of melanoma, provided that no biopsy was performed and no trauma occurred in the 3-7 days before.

The importance of subcapsular anesthesia in the anesthesiological management for thyroid radiofrequency ablation.

Radiofrequency ablation is a minimally invasive procedure alternative to surgery to treat benign thyroid nodules causing compressive symptoms. Tolerability of this procedure, aimed at treatment of benign conditions, is fundamental. In this study, we evaluated if local anesthesia should be enough to reduce both hospital costs and sedation-related risks for the patient, avoiding deep sedation and presence of the anesthesiologist. From July 2017 to August 2018, 14 consecutive patients (mean age 60.1 years) were treated and divided in two groups: Group A (7 patients) underwent systemic sedoanalgesia (intravenous remifentanil/fentanyl ± intravenous midazolam ± intravenous acetaminophen/nonsteroidal anti-inflammatory drugs) + subcutaneous anesthesia (lidocaine), with anesthesiologist. Group B (7 patients) underwent mild systemic sedoanalgesia (oral solution morphine sulfate + intravenous midazolam + intravenous acetaminophen) + both subcutaneous and subcapsular anesthesia (mepivacaine + bupivacaine), without anesthesiologist. Tolerability, sedation grade (Ramsay scale), total opioid dose, complications, and results at 12 months were analyzed and compared. Mean tolerability was 9.4 in group A and 8.9 in group B (p: 0.786). Mean sedation grade was 3.86 in group A and 2.71 in group B (p: 0.016). Mean total opioid dose was 70.9 mg in group A and 10 mg in group B (p:0.00015). No complications were observed. At 12 months, mean volume reduction was 56.1% in the group A and 60% in the group B. In thyroid radiofrequency ablation, subcapsular anesthesia can decrease both total opioid dose and level of patient's sedation without significant differences in tolerability, allowing to perform ablation without the anesthesiologist.

Identification and quantification of oxo-bile acids in human faeces with liquid chromatography-mass spectrometry: A potent tool for human gut acidic sterolbiome studies.

Bile acids (BAs) are endogenous steroids involved in the transport of lipids in bile, acting also as molecular signaling hormones. Primary BAs synthesized in the liver undergo several metabolic pathways in the intestine by gut microbiota to produce secondary BAs. Together with secondary BAs, other metabolites have been recovered from human faeces, including many oxo-BA analogues produced in the colon through oxidation of BA hydroxy groups. However, the complete oxo-BA characterization in biospecimens (particularly intestinal content and faeces) has not been reported yet, hampering the assessment of their potential physiological role. Herein, we have developed and validated a new RP-HPLC-ESI-MS/MS method in negative ionization mode for the simultaneous analysis of 21 oxo-BAs and their 7 metabolic BAs precursors in human faeces. The elution was performed in gradient mode and 28 compounds, including primary, secondary BAs, and their oxo-derivatives, were separated within 50 min at 40 °C column temperature. The method is accurate (bias% <13%), precise (CV% <10%), with limits of quantification (LOQ <30 ng/mLextract samples), similar for all the studied compounds. The matrix effect does not significantly affect the analysis accuracy, allowing the use of standard solutions for the quantifications, without matrix-matched protocols. Thanks to the high detectability and the relatively high concentration of oxo-BAs (about µg/gwet faeces), the method does not require a pre-analytical clean-up step. This method was used to identify and quantify oxo-BAs in human faecal samples from healthy subjects, serving as a proof of concept for application in patients with hepatobiliary disease and bacteria overgrowth.

Nutrición enteral en el paciente hemodinámicamente inestable. ¿Qué nos dice la evidencia actual? / Enteral nutrition in the patient hemodynamically unstable What the evidence tells us current?

Los beneficios de la nutrición enteral, especialmente de la nutrición enteral precoz, están documentados. Sin embargo, aún existen controversias al momento de decidir el inicio del soporte nutricional por esta vía en pacientes críticos hemodinámicamente inestables, que están recibiendo agentes vasopresores o inotrópicos. La experiencia clínica en seres humanos sugiere que la provisión de nutrición enteral después de un período de hipotensión puede reducir la lesión o el grado de isquemia del intestino delgado. Sobre la base de la evidencia, el inicio cauteloso de la nutrición enteral con sustancias vasoactivas es posible y seguro. No obstante, se necesitan más estudios para poder profundizar en los aspectos relativos al inicio y la implementación del soporte nutricional.(AU)

Benefits of enteral nutrition, especially early enteral nutrition, have been well documented. However, there are still controversies when deciding the initiation of nutritional support by this route in critical hemodynamically unstable patients who are receiving vasopressor or inotropic drugs. Clinical experience in humans suggests that provision of enteral nutrition after a period of hypotension may reduce injury or the extent of small bowel ischemia. Based on the evidence, cautious onset of enteral nutrition with vasoactive substances is possible and safe. However, more studies are needed to know the aspects related to the initiation and implementation of nutritional support. (AU)

Systematic review with meta-analysis: proximal disease extension in limited ulcerative colitis.

BACKGROUND: Disease extent in ulcerative colitis is one of the major factors determining prognosis over the long-term. Disease extent is dynamic and a proportion of patients presenting with limited disease progress to more extensive forms of disease over time. AIM: To perform a systematic review and meta-analysis of epidemiological studies reporting on extension of ulcerative colitis to determine frequency of disease extension in patients with limited ulcerative colitis at diagnosis. METHODS: We performed a systematic literature search to identify studies on disease extension of ulcerative colitis (UC) and predictors of disease progression. RESULTS: Overall, 41 studies were eligible for systematic review but only 30 for meta-analysis. The overall pooled frequency of UC extension was 22.8% with colonic extension being 17.8% at 5 years and 31% at 10 years. Extension was 17.8% (95% CI 11.2-27.3) from E1 to E3, 27.5% (95% CI 7.6-45.6) from E2 to E3 and 20.8% (95% CI 11.4-26.8) from E1 to E2. Rate of extension was significantly higher in patients younger than 18 years (29.2% (CI 6.4-71.3) compared to older patients (20.2% (CI 13.0-30.1) (P<.0001). Risk of extension was significantly higher in patients from North America (37.8%) than from Europe (19.6%) (P<.0001). CONCLUSIONS: In this meta-analysis, approximately one quarter of patients with limited UC extend over time with most extension occurring during the first 10 years. Rate of extension depends on age at diagnosis and geographic origin. Predicting those at high risk of disease extension from diagnosis could lead to personalised therapeutic strategies.

Review article: non-malignant oral manifestations in inflammatory bowel diseases.

BACKGROUND: Patients with inflammatory bowel diseases (IBD) may present with lesions in their oral cavity. Lesions may be associated with the disease itself representing an extraintestinal manifestation, with nutritional deficiencies or with complications from therapy. AIM: To review and describe the spectrum of oral nonmalignant manifestations in patients with inflammatory bowel diseases [ulcerative colitis (UC), Crohn's disease (CD)] and to critically review all relevant data. METHODS: A literature search using the terms and variants of all nonmalignant oral manifestations of inflammatory bowel diseases (UC, CD) was performed in November 2014 within Pubmed, Embase and Scopus and restricted to human studies. RESULTS: Oral lesions in IBD can be divided into three categories: (i) lesions highly specific for IBD, (ii) lesions highly suspicious of IBD and (iii) nonspecific lesions. Oral lesions are more common in CD compared to UC, and more prevalent in children. In adult CD patients, the prevalence rate of oral lesions is higher in CD patients with proximal gastrointestinal tract and/or perianal involvement, and estimated to range between 20% and 50%. Oral lesions can also occur in UC, with aphthous ulcers being the most frequent type. Oral manifestations in paediatric UC may be present in up to one-third of patients and are usually nonspecific. CONCLUSIONS: Oral manifestations in IBD can be a diagnostic challenge. Treatment generally involves managing the underlying intestinal disease. In cases presenting with local disabling symptoms and impaired quality of life, local and systemic medical therapy must be considered and/or oral surgery may be required.

Cannabinoid-free Cannabis sativa L. grown in the Po valley: evaluation of fatty acid profile, antioxidant capacity and metabolic content.

Within a project aimed to reintroduce non-drug hemp cultivars in the Italian Po valley, for fibre but also high added-value nutraceutical production, investigation on locally grown plants has been performed, in order to assess their oil and metabolic content. This study provides useful information regarding three different hemp cultivars, from two sites, in view of their potential industrial application. The oil was characterised by a high unsaturated/saturated fatty acid ratio and by an almost perfect balance of ω-3 and ω-6 fatty acids, as requested for healthy foods. The alcoholic extracts, for which a high content of amino acids and phenolic compounds has been highlighted, could provide dietary supplements to help in preventing oxidative stress. By investigating the Carmagnola cultivar, six known and four new lignanamides have been identified, confirming and assessing the general metabolic pattern in the seeds of these locally grown plants.

Mouse and human Notch-1 regulate mucosal immune responses.

The Notch-1 signaling pathway is responsible for homeostatic tight junction expression in vitro, and promotes barrier function in vivo in the RAG1-adoptive transfer model of colitis. In this study, we sought to determine the role of colonic Notch-1 in the lymphoepithelial crosstalk in health and disease. We utilized in vivo and in vitro knockdown to target the expression of Notch-1. We identified that epithelial Notch-1 is required for appropriate activation of intestinal epithelial cells at steady state and upon inflammatory stimulus. Notch-1 expression modulates mucosal chemokine and cytokine secretion, and FoxP3 and effector T-cell responses. We showed that epithelial Notch-1 controls the immune function of the epithelium through crosstalk with the nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) pathways that, in turn, elicits T-cell responses. Overall, epithelial Notch-1 bridges innate and adaptive immunity in the gut. Our findings highlight an indispensable role for Notch-1-mediated signaling in the intricate epithelial-immune crosstalk, and validate that epithelial Notch-1 is necessary and sufficient to support protective epithelial proinflammatory responses.

Characterizing CEACAM5 interaction with CD8α and CD1d in intestinal homeostasis.

Normal intestinal epithelial cells (IECs) could act as non-professional antigen-presenting cells, selectively activating CD8(+)-suppressor T cells. An epithelial cell surface glycoprotein, gp180, recognized by monoclonal antibodies B9 and L12 was determined to be critical in this process. Purification and sequence analysis of mAb B9 reactive material revealed amino-acid sequence homology with CEACAM5. We demonstrate that CEACAM5 has properties attributed to gp180, such as CD8α binding and activation of CD8-associated Lck. CEACAM5 is the only CEACAM member interacting with CD1d through the B3 domain. Its N domain (recognized by B9) is required for CD8α binding. Removal of the N-domain glycosylated residues reduces B9 recognition, CD8α binding affinity, and activation of LcK. Therefore, conformational changes in CEACAM5 glycosylation site are critical for its interaction with CD8α. CEACAM5-activated CD8(+) T cells acquire the ability to suppress the proliferation of CD4(+) T cells in vitro in the presence of interleukin (IL)-15 or IL-7. We provide new insights into the role of CEACAM5 and define its specific immunoregulatory properties among the CEACAMs expressed on IECs. We suggest that unique set of interactions between CEACAM5, CD1d, and CD8 render CD1d more class I-like molecule, facilitating antigen presentation and activation of CD8(+)-suppressor regulatory T cells.

Combination of ozonation and photocatalysis for purification of aqueous effluents containing formic acid as probe pollutant and bromide ion.

The treatment by advanced oxidation processes (AOPs) of waters contaminated by organic pollutants and containing also innocuous bromide ions may generate bromate ions as a co-product. In the present work heterogeneous photocatalysis and ozonation have individually been applied and in combination (integrated process) to degrade the organic compounds in water containing also bromide anions. The results show that: i) the sole photocatalysis does not produce bromate ions and in the case of its presence, it is able to reduce bromate to innocuous bromide ions; ii) the integration of photocatalysis and ozonation synergistically enhances the oxidation capabilities; and iii) in the integrated process bromate ions are not produced as long as some oxidizable organics are present.

Update on Crohn's disease: a polymorphic entity.

Crohn's disease is a chronic transmural inflammatory disease that most commonly affects the intestinal wall, but may also occur in any part of the gastrointestinal tract; its incidence is higher in industrialized countries, urban areas and upper socioeconomic classes. Various environmental risk factors have been associated with the pathogenesis of Crohn's disease and possible infectious agents (viruses, bacteria, yeasts) have also been considered. However, none of these factors alone leads to the development of the disease, which may occur only when there is a genetic predisposition and/or an abnormal function of the intestinal immune system. Histopathology demonstrates mucosal hyperemia, with small superficial ulcers in mild forms of the disease; in moderate-to-severe forms, serpiginous ulcerations demarcating areas of edematous mucosa produce the characteristic "cobblestone" appearance. The earliest microscopic lesions appear as neutrophil-mediated cryptic damage, with the formation of focal cryptic abscesses and granulomas throughout the layers of the intestinal wall. In addition to weight loss, patients mainly refer chronic diarrhea and recurrent right iliac fossa abdominal pain. Extraintestinal manifestations include ocular or articular complications. There are several drugs classes available for treating Crohn's disease, but the therapeutic approach depends on the clinical picture and differs from patient to patient. The broad clinical and the histopathological features of Crohn's disease make it a highly polymorphic entity. Diagnostic tests and a thorough knowledge of its various aspects are essential for guiding diagnosis and treatment.

Pilot study: the use of sulfasalazine for the treatment of acute pouchitis.

BACKGROUND: Acute pouchitis, an idiopathic inflammatory condition of the ileal pouch anal anastomosis, is the most frequent complication after proctocolectomy for ulcerative colitis. AIM: To test the hypothesis that sulfasalazine (SASP) might have a synergistic beneficial effect in acute pouchitis, by combining the anti-inflammatory activity of 5-aminosalicylic Acid and the bacteriostatic effect of sulphapyridine. METHODS: Twenty two patients were investigated for acute pouchitis; the Pouchitis Disease Activity Index (PDAI) was calculated and 11 patients with acute pouchitis (PDAI >7) were included in an open study, after obtaining their informed consent. Patients were treated with SASP 500 mg tablets, two tablets three times per day (3000 mg daily), for 2 months. Pouch endoscopy with biopsies was performed at the entry and at the end of the study. RESULTS: According to the PDAI score, 8/11 patients (73%) improved their clinical condition and 7/11 (63%) were in remission at the end of the treatment. At 8 weeks, the median PDAI index decreased from 11.2 +/- 2.3 to 6.6 +/- 4.7 P < 0.01. No adverse events or toxicity were reported and all patients completed the study. CONCLUSIONS: Despite the limitations of the current study, sulfasalazine seems to be a potential treatment for acute pouchitis.

Intra-operative assessment of technical defects after carotid endarterectomy: a comparison between angiography and colour duplex scan.

We compared the intra-operative diagnostic value of CDS vs IA-DSA in identifying major and minor technical defects after CEA. Between August 1997 and December 1998, 138 consecutive patients undergoing 141 carotid endarterectomies were intra-operatively investigated with colour duplex scan and intra-arterial digital subtraction angiography. Thirty-six (25.5%) technical defects were identified. Four (11.1%) major defects were detected by both methods and they were immediately corrected. Fifteen (41.6%) minor defects were detected by both methods, thirteen (36.1%) minor defects were detected by colour duplex but ignored by angiography. Angiography detected four (11.1%) kinkings missed with the colour duplex. The overall sensitivity of both methods for major defect was 100%. The sensitivity of colour duplex for minor defects was 87% vs 59% for angiography. On the basis of our study, colour duplex could be considered the choice method for quality control after carotid endarterectomy.

Echo-controlled endomyocardial biopsy.

Endomyocardial biopsy is an essential procedure for the diagnosis and grading of rejection in heart transplant patients. Direct control of the bioptome positioning has classically been obtained by fluoroscopy. Starting in June 1988, at our institution an alternative approach involving the use of two-dimensional echocardiography was introduced in clinical practice. In 125 patients 1591 biopsies have been performed: 445 under echographic control and 1146 under fluoroscopic control with 3.6 and 4.5 samples/biopsy, respectively. The percentages of inadequate samples caused by biopsy site sampling were 0.4% and 1.3%, respectively, in the two groups. Cardiac perforation has occurred twice in the fluoroscopic group; it has not been observed in the echographic group. One case of iatrogenic tricuspid regurgitation was detected in each group. We now consider echocardiography the method of choice to guide the bioptome. We prefer it to fluoroscopy because it eliminates the risks of x-ray exposure, increases the number of sampling sites in cases of echocardiographic evidence of rejection, can be easily performed as a bedside procedure, allows choice and variation of sampling sites, and permits monitoring of cardiac complications during and after the procedure. A randomized clinical trial is probably needed to assess with statistical significance the superiority of the echographic-controlled biopsy.

[Doppler evaluation of the Sorin and Medtronic-Hall prostheses in the aortic position]. / Valutazione Doppler delle protesi Sorin e Medtronic-Hall in posizione aortica.

Doppler characteristics of normally functioning tilting disk prostheses in aortic position were studied in 55 patients (30 Medtronic-Hall and 25 Sorin) whose valvular function was considered normal using clinical and echocardiographic evaluation. Peak gradients, mean gradients and effective orifice area were estimated for different sizes of prostheses. The peak gradient calculated from maximal aortic velocity was 27.3 +/- 11.1 mmHg in Sorin and 21.1 +/- 9.7 mmHg in Medtronic-Hall valves; the mean gradients were 12.9 +/- 6.2 mmHg and 10.8 +/- 5.7 mmHg in Sorin and Medtronic-Hall valves respectively. The effective orifice area calculated by the continuity equation was 1.4 +/- 0.5 cm2 in Sorin and 1.5 +/- 0.57 cm2 in Medtronic-Hall prostheses; the performance index calculated as the ratio between functional area and manufactured area was 0.4-0.6 for Medtronic-Hall and 0.45-0.52 for Sorin prostheses. Prosthetic regurgitation was found in 64% of Sorin valves and 80% of Medtronic-Hall valves; prosthetic regurgitation was mild in 81% and moderate in 19% of cases. Doppler echocardiography is a reliable method for the characterization of the normal function of prosthetic aortic valves and provides information similar to cardiac catheterization.

Craniomandibular bone density in the primate as assessed by computed tomography.

Ten normal rhesus monkeys, five juvenile and five adult animals, were analyzed for symmetry in bone density across the cranioskeleton with computed tomography (CT). Fifty contiguous axial CT scans were done using 1.5-mm thick scans between the lower mandibular border and inferior orbital ridge, and 3-mm thick scans from the inferior orbital ridge to the rostral level of insertion of the temporalis muscle. Eleven regions comprising areas of the lower mandibular border, lower ramus, upper ramus with condyle, the coronoid process, the zygomatic arch, and cranial bone were analyzed for symmetry using small regions of interest. Only one region, the condyle, demonstrated a statistically significant difference between the two sides with all other measured sites demonstrating the same bone mineral density bilaterally. Large area analysis of five regions--the lower mandibular border, upper ramus with condyle, the coronoid process, the zygomatic arch, and upper cranium--demonstrated no significant difference in the distribution of CT numbers. This analysis of bilateral distribution of bone density in the primate craniofacial skeleton demonstrates a basic symmetry that can be used to study altered patterns of neuromuscular function and their effects on bone density.

The subunit structure of bovine brain 14-3-2.

Two aspects of the subunit structure of the bovine brain specific protein 14-3-2 have been examined. On the one hand, native 14-3-2 has been separated into two fractions by hydroxylapatite chromatography. One eluted at the same position when chromatographed on the same column, while the other redistributed into the same two fractions again. Amino acid analysis of these two forms of 14-3-2 gave results that were not significantly different under the condition of analysis. Furthermore, when each peak was subjected to cyanogen bromide cleavage, very similar elution profiles of the resultant fragments were obtained. The two pools also cross-reacted with antiserum to 14-3-2. Reaction of purified 14-3-2 with dimethylsuberimidate caused the formation of covalently bound protein units of 100,000 molecular weight when measured by sodium dodecyl sulfate polyacrylamide gel electrophoresis, as opposed to the 50,000 minimal molecular weight normally detected. On the other hand, analysis of the soluble tryptic peptides of S-[14C]carboxymethyl 14-3-2 yielded only three distinct radioactive peptides, each with one residue of S-carboxymethylcysteine whereas 8 are expected on the basis of the amino acid composition of the 50,000 molecular weight polypeptide chains. Thermolysin digestion of a similarly modified 14-3-2 preparation yielded all of the radioactivity in 5 S-carboxymethylcysteine-containing peptides. The partial amino acid sequence of these peptides indicates that they represent 4 unique areas of the polypeptide chain. Since 8 such peptides were expected, that is, double the number found, the minimum structural unit of the protein must be of 25,000 molecular weight. The results of these experiments do not permit distinction between a duplication of the structure within a single polypeptide chain or the alternate possibility of two polypeptide chains bound by unusually strong non-covalent bonds. These results suggest that 14-3-2 is a covalently linked dimer of 25,000 mol.wt. units that can aggregate to form larger species of 100,000 mol.wt. and higher.