Farnesoid X receptor activation by the novel agonist TC-100 (3α, 7α, 11ß-Trihydroxy-6α-ethyl-5ß-cholan-24-oic Acid) preserves the intestinal barrier integrity and promotes intestinal microbial reshaping in a mouse model of obstructed bile acid flow.

The intestinal tract hosts the gut microbiota (GM), actively shaping health. Bile acids(BAs) are both digestive and signaling molecules acting as hormones via the activation of farnesoid X receptor (FXR). Obstruction of bile flow initiates a cascade of pathological events ultimately leading to intestinal mucosal injury. Administration of BAs in models of obstructed bile flow counteracts these detrimental effects. Objective of this study was to investigate the effects of the novel FXR agonist 3α, 7α, 11ß-Trihydroxy-6α-ethyl-5ß-cholan-24-oic Acid (TC-100) on intestinal mucosa integrity and cecal microbiome composition after surgical bile duct ligation (BDL), a rodent model causing bile flow obstruction. Pharmacological FXR activation was accomplished by daily oral gavage with TC-100 for 5 days. 2 days after treatment initiation, BDL was performed. BAs measurement was carried out and the 16S rDNA (V5-V6 hyper-variable regions) extracted from the cecal content was sequenced. TC-100 activates Fxr in the gut-liver axis and this translated into a significant reduction of serum and bile BA pool size with a shift to a more hydrophilic composition, while signs of intestinal mucosal damage were prevented. Firmicutes:Bacteroidota ratio progressively increased from Sham Operated (SO) mice to TC-100-treated mice. LEfSe analysis showed that Verrucomicrobia, and particularly Akkermansia muciniphila (Amuc) increasingly recognized for improving gut homeostasis and immune functions, were strongly associated to TC-100-treated mice. Intriguingly, Amuc abundance was also negatively associated to cholic acid levels. Collectively, these data indicate that intestinal FXR activation by TC-100 prevents early signs of intestinal mucosal damage by modulating BA homeostasis and GM composition.

Anti-HIV activity of new higher order G-quadruplex aptamers obtained from tetra-end-linked oligonucleotides.

By combining the ability of short G-rich oligodeoxyribonucleotides (ODNs) containing the sequence 5'CGGA3' to form higher order G-quadruplex (G4) complexes with the tetra-end-linked (TEL) concept to produce aptamers targeting the HIV envelope glycoprotein 120 (gp120), three new TEL-ODNs (1-3) having the sequence 5'CGGAGG3' were synthesized with the aim of studying the effect of G4 dimerization on their anti-HIV activity. Furthermore, in order to investigate the effect of the groups at the 5' position, the 5' ends of 1-3 were left uncapped (1) or capped with either the lipophilic dimethoxytrityl (DMT) (2) or the hydrophilic glucosyl-4-phosphate (3) moieties. The here reported results demonstrate that only the DMT-substituted TEL-ODN 2 is effective in protecting human MT-4 cell cultures from HIV infection (76% max protection), notwithstanding all the three new aptamers proved to be capable of forming stable higher order dimeric G4s when annealed in K+-containing buffer, thus suggesting that the recognition of a hydrophobic pocket on the target glycoprotein by the aptamers represents a main structural feature for triggering their anti-HIV activity.

[Experience of a peripheral center in the surgical treatment of hepatic metastasis from colorectal cancer]. / Esperienza di un centro periferico nel trattamento chirurgico delle metastasi epatiche da cancro colorettale.

Surgical resection is still the first therapeutic option in patients with resectable colorectal cancer metastatic to the liver. Application of radiofrequency energy has been used in patients who did not meet the criteria for resectability and yet were candidates for a liver-directed procedure based upon the presence of liver-only disease. Hepatic resection has evolved in the last two or three decades from a procedure with associated mortality rate of up to 20% in the early 80s to usually less than 5% in patients undergoing liver resection thereafter. This improvement in morbidity and mortality is multifactorial; despite the increased safety of liver operations, hepatic resection still remains a complex surgical procedure with serious potential morbidity. The experience with liver resections and/or radiofrequency ablations, for colorectal cancer metastatic to the liver, performed at a medium-volume center (15 cases in 4 years) is presented. Some features of the metastatic disease, including the number, size and location of metastases are identified. The perioperative mortality is 0, morbidity for non surgical complications is 40%. In this series the reported overall 1-yr survival is 80%, 2-yr is 67%. This paper reviews the experienced factors that have defined the morbidity and mortality associated with liver surgery.

Case of Myhre syndrome with autism and peculiar skin histological findings.

Myhre syndrome (MS) (MIM 139210) is a rare disorder characterized by short stature, mental retardation, muscular build, blepharophimosis, and decreased joint mobility. We report on a 14-year-old boy with clinical findings consistent with a diagnosis of Myhre syndrome, associated with autism and peculiar skin histological findings.

Fractions of chemically oversulphated galactosaminoglycan sulphates inhibit three enveloped viruses: human immunodeficiency virus type 1, herpes simplex virus type 1 and human cytomegalovirus.

A series of chemically oversulphated galactosaminoglycans (SO3H:COOH ratio > or = 2) were tested in vitro as antiviral agents against human immunodeficiency virus type 1 (HIV-1), the aetiological agent of AIDS, and against herpes simplex virus type 1 and human cytomegalovirus, two agents responsible for opportunistic infections in HIV-infected people. The oversulphated derivatives displayed an increase in activity ranging from one to four orders of magnitude against the three viruses, as compared to the natural parent compounds (SO3H:COOH, ratio approx. 1). The antiviral activity of these polyanions appears to be favoured by a high degree of sulphation and a high molecular mass. An oversulphated dermatan, with a SO3H:COOH ratio of 2.86 and molecular mass of 23.2 kDa, was the most potent anti-HIV-1 compound (EC50 0.04 microgram/ml). A second oversulphated dermatan, with a SO3H:COOH ratio of 2.40 and molecular mass of 25 kDa, displayed the highest activity against HSV-1 (EC50 0.01 microgram/ml). An oversulphated chondroitin, with a SO3H:COOH ratio of 2.80 and molecular mass of 17.3 kDa, was the strongest anti-HCMV agent (EC50 0.4 microgram/ml). In view of the absence of the side-effects typical of heparin-like compounds, a combination of these derivatives could have therapeutic potential.

Hydrolysis of peripheral leucine enkephalin in allergic asthma.

Plasma hydrolysis of leucine enkephalin was studied in a group of patients affected by seasonal allergic asthma in acute and quiescent stage; data were compared with those obtained from a control group of healthy volunteers. Results obtained indicate a statistically significant reduction of leu-enkephalin hydrolysis in allergic subjects. In the quiescent stage, substrate degradation is reduced, and the pattern of the hydrolysis by-products is modified with respect to normal controls. In the acute stage, hydrolysis is further reduced, and the pattern of the hydrolysis by-products is further modified with respect to the quiescent stage. The variations of leu-enkephalin hydrolysis appear to be controlled by decreased activity of proteolytic enzymes and by increased activity of the low-molecular-weight plasma inhibitors active on these enzymes. The sum of these processes is conducive to a distribution of enkephalin-hydrolyzing enzymes, as well as a hydrolysis pattern, that appears to be specific for the allergic subjects and distinct from that seen in the controls.

Age increases leucine enkephalin hydrolysis in human plasma.

BACKGROUND: The existence of age-associated alterations in immune functions and neuropeptides capable of modulating these functions prompted us to advance the hypothesis that the degradation of plasma neuropeptides, specifically opioid peptides, may be altered by aging. OBJECTIVE: To verify the possible existence of age-induced variations in neuropeptide hydrolysis in human plasma, using leucine enkephalin as the model substrate. METHODS: The hydrolysis of leucine enkephalin and the formation of its hydrolysis byproducts in the presence of plasma enzymes were studied by kinetic and chromatographic techniques in a group of elderly individuals and a control group. RESULTS: The results obtained indicate that in elderly individuals the activity of enkephalin-degrading plasma enzymes is greater than in controls. ANOVA analysis of these data indicates that the dependency of the variation of hydrolysis upon the 2 age groups is statistically significant. Increased substrate hydrolysis, and a modified hydrolysis pattern, appear to be associated with increased activity of the enzymes involved, and with different distribution of the individual enzymes within each class, as well as with severely reduced activity of the low molecular weight plasma inhibitors. CONCLUSION: The combination of the above-mentioned factors appears to define a characteristic hydrolysis pattern for elderly individuals which is different from that found in controls.

Early renal involvement in diabetes mellitus: comparison of renal Doppler US and radioisotope evaluation of glomerular hyperfiltration.

PURPOSE: To evaluate the usefulness of Doppler ultrasonography (US) in the diagnosis of hyperfiltration in patients with insulin-dependent diabetes mellitus (IDDM). MATERIALS AND METHODS: Eighty-one consecutive patients with IDDM were studied. All patients were normotensive and had normal creatinine and blood urea nitrogen levels. The glomerular filtration rate (GFR) was evaluated by means of plasma clearance of chromium-51 ethylenediaminetetraacetic acid, urinary albumin excretion, US evaluation of renal volume, and Doppler evaluation of resistance index (RI) in the renal interlobar arteries. The patients were divided according to GFR into the following groups: those with hyperfiltering kidneys (group 1, n = 40) and those with normofiltering kidneys (group 2, n = 41). RESULTS: The median renal volume was 351 mL (95% CI = 337 mL, 379 mL) in group 1 and 318 mL (95% CI = 300 mL, 335 mL) in group 2 (P = .005). The number of patients with microalbuminuria was significantly lower in group 1 than in group 2 (P = .02). The median RI was significantly lower in group 1 (0.55; 95% CI = 0.53, 0.57) than in group 2 (0.57; 95% CI = 0.56, 0.59) (P = .04). An RI of less than 0.5, a renal volume greater than 410 mL/m2, and the absence of microalbuminuria were independent predictors of hyperfiltration. An RI of less than 0.5 and a renal volume greater than 410 mL/m2 showed high specificity (98% and 95%, respectively) and poor sensitivity (25% and 23%, respectively) in the diagnosis of hyperfiltration in IDDM patients. CONCLUSION: Both RI and renal volume showed correlation with GFR, but neither parameter is sufficiently sensitive in screening for hyperfiltration in IDDM patients.

Age-induced increase of leucine enkephalin enzyme degradation in human plasma.

Possible age-induced variations of the hydrolysis of leucine enkephalin in the presence of plasma enzymes were studied by kinetic and chromatographic techniques in a group of elderly individuals. Results obtained indicate that in elderly individuals the activity of enkephalin-degrading plasma enzymes is greater than in the controls; ANOVA analysis of these data indicates that the dependency of the variation of hydrolysis upon the two age groups is statistically significant. Increased substrate hydrolysis, and a modified hydrolysis pattern, appear to be associated with increased activity of the enzymes involved, and with different distribution of the individual enzymes within each class, as well as with severely reduced activity of the low molecular weight plasma inhibitors. The combination of these factors defines a characteristic hydrolysis pattern for the elderly individuals, different from that found in the controls.

Leucine enkephalin degradation in allergopathic versus normal human plasma.

The enzyme hydrolysis of labelled leu-enkephalin in the presence of plasma enzymes was studied by kinetic and chromatographic techniques in a group of allergopathic patients in the acute and quiescent stage; data obtained have been compared with those obtained with normal controls. Results shown indicate that in the quiescent stage substrate degradation is reduced, and that the pattern of the hydrolysis by-products is modified with respect to the controls. In the acute as compared to the quiescent stage, enkephalin hydrolysis is further reduced, and the pattern of hydrolysis by-products is further modified. ANOVA analysis of these data indicates that the dependency of hydrolysis reduction upon the grouping of subjects (i.e., controls, quiescent and acute stage) is statistically very significant. Reduced substrate hydrolysis, and modified hydrolysis pattern, appears to be associated with decreased activity of the enzymes involved and more significantly with increased activity of the low molecular weight plasma inhibitors. The combination of these two factors appears to define a hydrolysis pattern characteristic of the allergopathic subjects, similar in the quiescent and acute phase, and different from that observed in the controls.

Doppler ultrasound evaluation of acute effects of cigarette smoking on portal blood flow in man.

The acute systemic haemodynamic effects of cigarette smoking are well known, but there are no studies dealing with the possible smoke-related acute changes of splanchnic circulation in man. In the present study we evaluated the acute effects of cigarette smoking on portal blood flow (PBF) in normal subjects by the use of Doppler ultrasound. Twenty-three normal volunteers were asked to smoke two cigarettes with a known total nicotine content (1.1 mg each) in a supine position. Each cigarette was smoked during a 5 min period and a 5 min interval between the two cigarettes was allowed. Both mean PBF velocity and volume were evaluated at time 0 (basal values) and 8, 15, 30, 45 and 60 min after the first inhalation of the first cigarette. The basal mean PBF velocity (22 cm/s; 95% CI 20.9-24.2) was significantly decreased at 8 min (19 cm/s; 95% CI 17.9-20.8; P < 0.0007) and 15 min (20 cm/s; 95% CI 17.8-21.3; P < 0.005). Similarly, the PBF volumes at 8 min (710 mL/min; 95% CI 660-876; P < 0.002) and 15 min (750 mL/min; 95% CI 650-862; P < 0.005) were significantly lower than those measured at time 0 (850 mL/min; 95% CI 766-987). Both mean PBF velocity and volume measured at successive times did not differ significantly from basal values. The present study shows that cigarette smoking causes acute and transient reduction of PBF velocity and volume in normal subjects.

Inferior vena cava involvement by a left side adrenocortical carcinoma: operative and prognostic considerations.

We report the fifth case of neoplastic involvement of the infrahepatic portion of the inferior vena cava, observed in a young woman affected by a left adrenal cortical carcinoma. The intracaval extension of a neoplastic thrombus from an adrenal tumor is a rare complication that should not be considered a dismal prognostic factor and does not contraindicate tumor resection with curative intent. Caval invasion must be preoperatively investigated to plan the correct surgical access and avoid the risk of neoplastic embolization.

Structure-activity relationships in open ansa-chain rifamycin S derivatives as inhibitors of HIV-1 reverse transcriptase.

Three types of open ansa-chain rifamycin S derivatives have been prepared: derivatives with the ansa-chain open at C(29) and the original dihydrofuranone ring; derivatives with the ansa-chain open at C(29) and a furane ring; derivatives with the ansa-chain at open NH-C(15). Only derivatives of the first type are weak inhibitors of HIV-1 reverse transcriptase (IC50 ca.300 microM) while derivatives of the two other types are inactive. It has been hypothesized that the active derivatives inhibit the viral enzyme interacting through the groups C(14)H3, C(13)H3, and C(1)O at the same site as the well-known inhibitors TIBO and Nevirapine. In particular C(13)H3 must be unhindered and in an appropriate position out of the plane containing the chromophore-rings. The open ansa-chain seems to play the role of a lipophylic substituent.

Emergency transjugular intrahepatic portosystemic shunt in patients with active variceal bleeding and hepatocarcinoma.

Variceal hemorrhage is a leading cause of death in patients with hepatic cirrhosis. We report the case of two cirrhotic patients with hepatocarcinoma in whom oesophageal varices bled repeatedly. Because the bleeding was not controlled by sclerotherapy, vasopressin or Blakemore balloon, the patients were evaluated for emergency transjugular intrahepatic portosystemic shunt. After the procedure, portal vein pressure decreased from 45.5 mmHg to 18 mmHg and from 44 mmHg to 19 mmHg respectively and no filling of varices was evident at venogram or endoscopy. After 16 and 8 months respectively, bleeding had not recurred, and no episodes of encephalopathy were referred. Transjugular intrahepatic portosystemic shunt should always be considered an effective emergency therapeutic alternative to shunt surgery in patients with active variceal bleeding when traditional management fails.

Fatal bleeding after fine-needle aspiration biopsy of the liver.

Ultrasonographic-guided fine-needle aspiration (FNA) biopsy has become a routine diagnostic procedure in the histological evaluation of both focal and chronic liver diseases. It is a safe and low-cost procedure that may be quickly and easily performed by radiologists and gastroenterologists. Severe and unexpected complications, of FNA biopsy, are rarely observed, haemorrhage being the most frequent and often fatal (1,2). This report presents the case of a patient with chronic liver disease who died of massive hemorrhage due to a FNA biopsy complication.

Lipohyperplasia of the ileocaecal valve as a cause of intestinal haemorrhage: an ultrasound Doppler study.

We present a case of lipohyperplasia of the ileocaecal valve causing intermittent intestinal bleeding visualized by Doppler ultrasound of the lower abdominal quadrant as an intestinal mass with intralesional arteriovenous fistula. These findings, never described before, are suggestive of highly vascularized lesions of the ileocaecal region and their recognition may avoid the need to perform an angiographic study of the superior mesenteric artery.

[Duplication of the gastrointestinal tract: a report of a rare case of mediastinal cyst]. / Duplicazione del tratto gastrointestinale: descrizione di un raro caso di cisti mediastinica.

An unusual case of alimentary tract duplication located in the left anterior mediastinum and observed in a 37-year-old woman is reported. Resection of the lesion through a left thoracotomy approach was resolutive and followed by an excellent long term outcome. Etiology, diagnosis and therapeutic problems as well as differential diagnosis with benign and malignant chest lesions of adult population are briefly discussed.