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.

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.

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.

Chronic liver injury by thioacetamide and promotion of hepatic carcinogenesis.

To verify whether a mild, but prolonged liver injury by chemicals needing bioactivation causes both hepatic cirrhosis and the appearance of hepatocyte nodules and tumors (providing the liver has been exposed previously to initiating stimuli), diethylnitrosamine-initiated and uninitiated rats were administered thioacetamide at low dose (250 mg/l drinking water) for 6 months. Hepatocyte nodule incidence as well as changes in the drug-metabolizing system were followed at monthly intervals. In the uninitiated rats a micronodular liver cirrhosis slowly developed upon thioacetamide chronic administration; a few hepatocyte focal lesions of small size were seen from the 3rd month onward. By contrast in the diethylnitrosamine-initiated thioacetamide-treated rats the liver was macronodular because of the appearance and growth of many hepatocyte nodules; some hepatomas were also seen. During thioacetamide administration both uninitiated and diethylnitrosamine-initiated rats underwent a progressive decrease of the cytochrome P-450 liver content as well as of the activity of aminopyrine N-demethylase, ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase. On the other hand, most components of the phase II of the drug-metabolizing system were markedly enhanced. In conclusion, chronic administration of thioacetamide at low doses provided strong promoting stimuli for previously initiated hepatocytes.

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.

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.

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.

Fine needle aspiration cytologic diagnosis of focal intrahepatic extramedullary hematopoiesis.

A computed tomographic scan in an 80-year-old man with a urinary obstruction demonstrated a solitary space-occupying liver lesion, which was clinically suspected to be a metastatic carcinoma. Fine needle aspiration (FNA) of the mass produced a smear containing atypical, possibly malignant, cells. Correlation of the FNA findings with the patient's history resulted in a cytologic diagnosis of an intrahepatic focus of extramedullary hematopoiesis (EMH). This case shows FNA biopsy to be a reliable method of diagnosing foci of EMH, but also demonstrates the potential pitfall of diagnosing atypical megakaryocytes as malignant in FNA smears. EMH should be considered in the differential diagnosis of patients with bone marrow disorders and mass lesions in extramedullary sites.

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.

[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.

[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.

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.

[Ultrasonography in abdominal emergencies]. / L'ultrasonografia nelle urgenze addominali.

From February 1986 to March 1988 113 abdominal US exams were performed in emergency situation to evaluate the accuracy of this methodology: 13 were blunt traumas, 18 postoperative complications. A real-time scanner with a linear probe of 5 MHz was employed. The results were confirmed by surgical and/or clinical and instrumental evaluation. In 81% of the examinations, ultrasonography allowed a diagnosis to be made. Gallbladder and biliary pathologies were the most common findings. The results (sensibility 96%, specificity 88%, accuracy 95%) confirm the reliability of ultrasonography in abdominal emergencies, as shown in literature.

Multifocal leiomyosarcoma of the gastrointestinal tract requiring emergency surgical treatment for small bowel intussusception.

A case of multifocal leiomyosarcoma of the stomach, duodenum and jejunum presenting as an intestinal occlusion for small bowel intussusception is reported. Complete surgical excision of the tumour was not possible due to the wide dissemination. The patient died two months later for haemorrhage from an ulcerated gastric localization. Surgical and prognostic implications of disseminated gastrointestinal leiomyosarcoma are briefly discussed through a literature review.

Altered cardiac repolarization during exercise in congenital aortic stenosis.

The incidence of sudden death in children with congenital aortic stenosis (CAS) varies between 4 and 20%. In several syndromes sudden death is associated with a long QT interval in the electrocardiogram (ECG). The aim of the study was to evaluate the cardiac repolarization in CAS during stress. We included 40 children and young persons, 20 with CAS and 20 healthy controls. All underwent echocardiographic study and treadmill stress test. The QT and relative RR intervals were measured in leads II and V6 at rest and during exercise at preselected heart rates. Mean values of QT were compared by analysis of variance, Student's t-test, and linear regression method. No statistically significant differences in the resting ECG were found between the two groups, whereas during exercise the mean QT of the CAS group was significantly longer than in the controls (p < 0.05), except at a heart rate of 140 +/- 5. Our study demonstrates that patients with CAS have transiently altered cardiac repolarization when there are sudden variations in heart rate. Such a defect could predispose patients with CAS to fatal arrhythmias and sudden death.

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.