Mitogen induction of murine C-type viruses. IV. Effects of lipoprotein E. coli, pokeweed mitogen and dextran sulphate.

Lipoprotein E. coli, a B-cell mitogen, is identified as a new agent inducing the release of endogenous C-type virus from mouse spleen cells. Like lipopolysaccharide, a previously identified inducer, this compound has a synergistic effect with 5-bromo-2'-deoxyuridine. Induced virus has the characteristic density as well as morphology of C-type viruses. Budding viruses are detected on cultured BALB/c cells by electron microscopy 2 to 4 days following culturing in the presence of lipoprotein. Pokeweed mitogen, a compound mitogenic for T- and B-cells was negative when tested for virus induction, both alone and in combination with 5-bromo-2'-deoxyuridine. Dextran sulphate, another B-cell mitogen, was negative for induction as well. However, when, combined with lipopolysaccharide, it enhanced the virus release induced by this mitogen. In contrast, no additive effects were observed either by combining dextran sulphate with other virus amplifying mitogens or by combinations of mitogens which both have virus-inducing ability. This finding is discussed with respect to B-cell differentiation.     

TUBB3 E410K syndrome: Case report and review of the clinical spectrum of TUBB3 mutations

The tubulinopathies refer to a wide range of brain malformations caused by mutations in one of the seven genes encoding different tubulin's isotypes. The β‐tubulin isotype III (TUBB3) gene has a primary function in nervous system development and axon generation and maintenance, due to its neuron‐specific expression pattern. A recurrent heterozygous mutation, c.1228G > A; p.E410K, in TUBB3 gene is responsible of a rare disorder clinically characterized by congenital fibrosis of the extraocular muscle type 3 (CFEOM3), intellectual disability and a wide range of neurological and endocrine abnormalities. Other mutations have been described spanning the entire gene and genotype–phenotype correlations have been proposed. We report on a 3‐year‐old boy in whom clinical exome sequencing allowed to identify a de novo TUBB3 E410K mutation as the molecular cause underlying a complex phenotype characterized by a severe bilateral palpebral ptosis refractory to eye surgery, psychomotor delay, absent speech, hypogonadism, celiac disease, and cyclic vomiting. Brain MRI revealed thinning of the corpus callosum with no evidence of malformation cortical dysplasia. We reviewed available records of patients with TUBB3 E410K mutation and compared their phenotype with the clinical outcome of patients with other mutations in TUBB3 gene. The present study confirms that TUBB3 E410K results in a clinically recognizable phenotype, unassociated to the distinct cortical dysplasia caused by other mutations in the same gene. Early molecular characterization of TUBB3 E410K syndrome is critical for targeted genetic counseling and prompt prospective care in term of neurological, ophthalmological, endocrine, and gastrointestinal follow‐up.     

IgM and IgG antibodies to human T cell lymphotropic retrovirus (HTLV-III) in lymphadenopathy syndrome and subjects at risk for AIDS in Italy

A study was performed to assess the prevalence of specific antibodies to human T cell lymphotropic retrovirus (HTLV-III) in patients with lymphadenopathy syndrome, patients with the acquired immune deficiency syndrome (AIDS), and those at risk of AIDS. Serum samples were obtained from these groups and from healthy controls in selected cities in Italy, and antibodies to HTLV-III were measured by immunofluorescence assay and, in a few patients, by Western blotting. In addition, IgM antibody values were measured in 82 of those positive for HTLV-III. Altogether, 235 out of 320 patients with lymphadenopathy syndrome had antibodies to HTLV-III, the proportions being highest in haemophiliacs, homosexuals, and drug addicts from Rome; 11 out of 12 patients with AIDS had antibodies; 78 out of 439 subjects at risk for AIDS had antibodies; and six out of 30 patients with lymphadenopathy syndrome and positive for HTLV-III antibodies and nine of 52 patients at risk of AIDS had a detectable titre of IgM. HTLV-III is widespread in groups at risk of AIDS in Italy, and antibodies to HTLV-III are highly prevalent in patients with lymphadenopathy syndrome. A higher proportion of drug abusers were positive for antibodies than in previous studies. HTLV-III "infection" would appear to be spread mainly in compromised hosts, as none of the controls were positive for antibodies.     

Is choledochoduodenostomy in the treatment of stones in the common bile duct an obsolete technique?

The complex pathogenesis of bile duct stones, the anatomical properties of the biliary tree, the patient's age, associated diseases, as well as the technical devices available, may explain the great variety of procedures and preferences of different groups in the treatment of choledocholithiasis. Since no technique is infallible or free of complications, it seems unfair to argue that procedures whose efficacy has been proven by many authors are obsolete. This is the case of choledochoduodenostomy (CDS) in the treatment of common bile duct (CBD) stones. The complications associated with CDS, (ascending cholangitis, and sump syndrome) have been overemphasized and have led CDS to be rejected by many surgeons. Our experience with this technique is good and concurs with that of Madden and others.Data on 125 patients with CBD stones treated with CDS between 1968 and 1982 are analyzed. Sixty-eight of them were female and the mean age was 61.4 years; 73.6% were more than 50 years old. There were frequent accompanying diseases, especially cardiovascular ones. More than half of the patients had a previous operation on the biliary tree. The duct diameter was always greater than 20 mm and it was frequently associated with stenosis of the distal choledochus. Floercken's technique of CDS was the most frequently used, after Kocher's maneuver had been performed. There was no intraoperative mortality. Postoperative mortality was 3.2% and is analyzed in detail. The incidence of postoperative complications was 42.4%. Most were septic complications or those ascribed to accompanying diseases. Late operative cholangitis was present in 1.6% of patients, comparable with reports of other authors. We encourage the use of CDS in the treatment of CBD stones provided that: (a) careful attention is paid to its clinical indications, considering that the patient may benefit from alternative techniques, for example, duodenoscopic papillotomy; and (b) choledochal dilatation is greater than 20 mm in diameter and the choledochal and duodenal walls are normal. We specifically recommend CDS as the primary operation for patients with choledochal funnel syndrome. The operation is simple, restores normal digestive function, and almost always resolves the problems of CBD stones in high-risk patients.

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Resumen La compleja patogenia de los cálculos del colédoco, las propiedades anatómicas del árbol biliar, la edad del paciente, las patologías asociadas y otros factores, junto con la disponibilidad de diversos elementos técnicos, explican la gran variedad de procedimientos y de preferencias por parte de los cirujanos en el tratamiento y de preferencias por parte de los cirujanos en el tratamiento de la litiasis biliar. Puesto que ninguna técnica operatoria es infalible ni totalmente libre de complicaciones, parece injusto argumentar que procedimientos cuya eficacia ha sido comprobada por muchos autores sean calificados como obsoletos. Tal es el caso de la coledocoduodenostomía (CDS) en el tratamiento de los cálculos del colédoco. Las complicaciones asociadas con la CDS (colangitis ascendente y el sindrome del segmento distal ciego) han sido exageradas, lo cual ha llevado a muchos cirujanos a rechazar la CDS. Nuestra experiencia con esta técnica es buena y está de acuerdo con la de Madden y de otros. Se analizaron los datos en 125 pacientes con cálculos del colédoco tratados con CDS entre 1968 y 1982. Sesenta y ocho eran mujeres y la edad promedio fué de 61.4 años; 73.6% eran mayores de cincuenta años. Otras enfermedades asociadas fueron halladas con frecuencia, especialmente las cardiovasculares. Más de la mitad de los pacientes tenían historia de una operación previa sobre el árbol biliar. El diámetro del colédoco fué superior a 20 mm en todos los casos y con frecuencia se encontró estenosis árbol de la porción distal. La técnica de Floercken fué la más frecuentemente utilizada, una vez realizada la maniobra de Kocher. No hubo mortalidad intraoperatoria. La mortalidad postoperatoria fué de 3.2% y se analiza en detalle. La tasa de complicaciones postoperatorias fué de 42.4%, incluyendo las sistematicas y las locales, leves y severas, habiéndose observado predominancia de las complicaciones sépticas y de aquellas relativas a patologiás asociadas. La colangitis operatoria tardía ocurrió en el 1.6% de los pacientes, tasa comparable a la informada por otros autores. Nosotros preconizamos el uso de la CDS en el tratamiento de los cálculos del colédoco siempre que: (a) se preste atención cuidadosa a sus indicaciones clínicas, considerando que el paciente puede beneficiarse con otras alternativas, por ejemplo la papilotomía duodenoscópica; y (b) la dilatación del colédoco sea de un diámetro superior a 20 mm y que las paredes tanto del colédoco como del duodeno sean normales. Específicamente recomendamos la CDS como la operación primaria para pacientes con el síndrome del embudo coledociano (estenosis distal con dilatación proximal). La operación es sencilla, restaura la función digestiva normal y en forma casi uniforme resuelve los problemas que producen los cálculos del colédoco en pacientes de alto riesgo.

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Résumé La pathogénie complexe de la lithiase biliaire, les caractères anatomiques des voies biliaires ainsi que l'âge des malades, les affections associées et la grande variété des méthodes techniques expliquent la grande diversité des procédés de traitement de la lithiase choledocienne employés par les différentes équipes chirurgicales. Aucune technique n'étant infaillible ou exempte de complications, il paraît inconsidéré d'abandonner toute méthode qui a fait ses preuves. Il en est ainsi de la choledocoduodénostomie. Les complications attribuées à ce type d'intervention comme l'angiocholite ascendante, et le syndrome du moignon sous-anastomotique ont été exagérées conduisant de nombreux chirurgiens à l'écarter de leur pratique. Notre expérience de la choledocoduodénostomie est bonne et coincide avec celle de Madden et d'autres auteurs. Les données recueillies chez 125 malades qui présentaient des calculs de la V.B.P. et qui furent traités par la choledocoduodénostomile de 1968 à 1982 ont été étudiées. Soixante-huit étaient des femmes. La moyenne d'âge était de 61.4 ans, 73.6% étaient âgés de plus de 50 ans. Les affections associées étaient fréquentes en particulier les affections cardiovasculaires. Plus de la moitié de nos opérés avaient déjà subi une intervention sur la voie biliaire. Le diamètre de la voie biliaire a toujours été supérieur à 20 mm et la dilatation se trouvait souvent au dessus d'un rétrécissement du bas cholédoque. La technique de Floercken fut le plus souvent employée après le décollement du bloc duodénopancréatique. Il n'y eu aucun décès peropératoire. La mortalité postopératoire s'est élevée à 3.2% et a été étudiée avec précision. Le taux des complications postopératoires a atteint 42.4%, dont les infections et les désordres secondaires aux affections associées occupent la première place. Le taux de l'angiocholite postopératoire tardive s'est élevé à 1.6%, identique à celui rapporté par d'autres auteurs. Notre expérience nous permet de recommander la choledocoduodénostomie à condition (a) d'apporter une attention particulière aux indications après avoir pris en considération la possibilité de traiter la lithiase par une autre méthode, la sphinctérotomie endoscopique par exemple; et (b) de la réserver aux cas où le diamètre de la V.B.P. est supérieur à 20 et ou les parois de la voie biliaire et du duodénum sont normales. Nous considérons qu'elle est particulièrement indiquée en présence du syndrome du cholédoque en entonnoir. L'intervention est simple, restaure la fonction digestive normale et résoud le problème des calculs de la V.B.P. chez les malades de haut risque.

     

Drop attack as the only symptom of type 1 Chiari malformation. Illustration by a case

An unusual case of Chiari type I malformation is presented. The only symptom was a "drop attack" during sneezing or coughing. The possible pathogenetic mechanisms are briefly reviewed and the good results of the surgical therapy are stressed.     

Polyphenols and Human Health: The Role of Bioavailability

Polyphenols are a group of phytochemicals with potential health-promoting effects. They are classified as flavonoid (flavonols, flavanols, flavones, flavanones, isoflavones, and anthocyanins) and non-flavonoid molecules (phenolic acids, hydroxycinnamic acids, lignans, stilbenes, and tannins). Although an increasing number of trials have shown a correlation among polyphenol consumption and a reduction in risk factors for chronic diseases, discrepancies in explaining their positive effects have been found in terms of the bioavailability. In fact, polyphenols show a low bioavailability due to several factors: interaction with the food matrix, the metabolic processes mediated by the liver (phase I and II metabolism), intestine and microbiota. On the other hand, the biological activities of phenol compounds may be mediated by their metabolites, which are produced in vivo, and recent studies have confirmed that these molecules may have antioxidant and anti-phlogistic properties. This review discusses the studies performed in vivo, which consider the polyphenol bioavailability and their different food sources. Factors influencing the biological effects of the main classes of polyphenols are also considered.     

Gestation Food Restriction and Refeeding Compensate Maternal Energy Status and Alleviate Metabolic Consequences in Juvenile Offspring in a Rabbit Model

Nutritional status during gestation can influence mother and offspring metabolism. Undernutrition in pregnancy affects women in both western and developing countries, and it is associated with a high prevalence of chronic diseases in later life. The present work was conducted in the rabbit model, as a longitudinal study, to examine the effect of food restriction during early and mid-gestation, and re-feeding ad libitum until the end of pregnancy on metabolic status and body reserves of mother and, its association with development and metabolism of fetuses and female offspring to the juvenile stage. Little changes in live body weight (LBW), compensatory feed intake, similar body reserves, and metabolism were observed in dams. Placenta biometry and efficiency were slightly affected, but fetal BW and phenotype were not modified. However, hyperinsulinemia, insulin resistance, and hypertriglyceridemia were demonstrated in pre-term fetuses. In the juvenile period, these changes were not evidenced, and a similar pattern of growth and serum metabolic parameters in offspring of food-restricted mothers were found, except in serum aminotransferases levels, which increased. These were associated with higher liver fibrosis. Maternal food restriction in the early and mid-pregnancy followed by re-feeding in our rabbit model established a compensatory energy status in dams and alleviated potential long-term consequences in growth and metabolism in the offspring, even if fetal metabolism was altered.     

Colonic In Vitro Model Assessment of the Prebiotic Potential of Bread Fortified with Polyphenols Rich Olive Fiber

The use of olive pomace could represent an innovative and low-cost strategy to formulate healthier and value-added foods, and bakery products are good candidates for enrichment. In this work, we explored the prebiotic potential of bread enriched with Polyphenol Rich Fiber (PRF), a defatted olive pomace byproduct previously studied in the European Project H2020 EcoProlive. To this aim, after in vitro digestion, the PRF-enriched bread, its standard control, and fructo-oligosaccharides (FOS) underwent distal colonic fermentation using the in vitro colon model MICODE (multi-unit colon gut model). Sampling was done prior, over and after 24 h of fermentation, then metabolomic analysis by Solid Phase Micro Extraction Gas Chromatography Mass Spectrometry (SPME GCMS), 16S-rDNA genomic sequencing of colonic microbiota by MiSeq, and absolute quantification of main bacterial species by qPCR were performed. The results indicated that PRF-enriched bread generated positive effects on the host gut model: (i) surge in eubiosis; (ii) increased abundance of beneficial bacterial groups, such as Bifidobacteriaceae and Lactobacillales; (iii) production of certain bioactive metabolites, such as low organic fatty acids; (iv) reduction in detrimental compounds, such as skatole. Our study not only evidenced the prebiotic role of PRF-enriched bread, thereby paving the road for further use of olive by-products, but also highlighted the potential of the in vitro gut model MICODE in the critical evaluation of functionality of food prototypes as modulators of the gut microbiota.     

Vascular Effects of the Polyphenolic Nutraceutical Supplement Taurisolo®: Focus on the Protection of the Endothelial Function

Preservation of vascular endothelium integrity and functionality represents an unmet medical need. Indeed, endothelial dysfunction leads to decreased nitric oxide biosynthesis, which is prodromic of hypertension and hypercoagulability. In this panorama, the nutraceutical supplement Taurisolo^®, a polyphenolic extract from Aglianico cultivar grape, rich in catechin and procyanidins, was evaluated as a vasoprotective, vasorelaxing, anti-hypertensive and anti-coagulant agent in: cell lines, isolated vessels, in vivo models of chronic hypertension and hypercoagulability, and in clinical tests of endothelial reactivity. Taurisolo^® demonstrated to fully protect vascular cell viability from oxidative stimulus at 100 µg/mL and evoke vasorelaxing effects (Emax = 80.6% ± 1.9 and pEC50 = 1.19 ± 0.03) by activation of the Sirtuins-AMPK-pathway. Moreover, Taurisolo^®, chronically administered at 20 mg/Kg/die in in vivo experiments, inhibited the onset of cardiac hypertrophy (heart weight/rat weight = 3.96 ± 0.09 vs. 4.30 ± 0.03), hypercoagulability (decrease of fibrinogen vs. control: p < 0.01) and hypertension (mean of Psys: 200 ± 2 vs. control 234 ± 2 mmHg) and improved endothelial function (Emax = 88.9% ± 1.5 vs. control 59.6% ± 3.6; flow-mediated dilation in healthy volunteers after 400 mg twice daily for 8 weeks vs. baseline: p = 0.019). In conclusion, Taurisolo^® preserves the vascular function against ox-inflamm-ageing process and the consequent cardiovascular accidents.