Phase Ib Safety, Two-Dose Study of MultiGeneAngio in Patients with Chronic Critical Limb Ischemia.

Critical limb ischemia (CLI) is the most severe presentation of peripheral arterial disease. We developed cell-based therapy entailing intra-arterial injection of autologous venous endothelial cells (ECs) modified to express angiopoietin 1, combined with autologous venous smooth muscle cells (SMCs) modified to express vascular endothelial growth factor. This combination promoted arteriogenesis in animal models and was safe in patients with limiting claudication. In an open-label, phase Ib study, we assessed the safety and efficacy of this therapy in CLI patients who failed or were unsuitable for surgery or intravascular intervention. Of 23 patients enrolled, 18 with rest pain or non-healing ulcers (Rutherford categories 4 and 5) were treated according to protocol, and 5 with significant tissue loss (Rutherford 6) were treated under compassionate treatment. Patients were assigned randomly to receive 1 × 107 or 5 × 107 (EC-to-SMC ratio, 1:1) of the cell combination. One-year amputation-free survival rate was 72% (13/18) for Rutherford 4 and 5 patients; all 5 patients with Rutherford 6 underwent amputation. Of the 12 with unhealing ulcers at dosing, 6 had complete healing and 2 others had >66% reduction in ulcer size. Outcomes did not differ between the dose groups. No severe adverse events were observed related to the therapy.

Daclatasvir plus asunaprevir for HCV genotype 1b infection in patients with or without compensated cirrhosis: a pooled analysis.

BACKGROUND & AIMS: We compared outcomes by cirrhosis status across studies of the all-oral combination of daclatasvir (DCV) plus asunaprevir (ASV). METHODS: Outcomes from global and Japanese phase 2 and 3 clinical studies of DCV+ASV in patients with genotype (GT) 1b infection were assessed by cirrhosis status. Sustained virological response (SVR) was assessed in individual phase 3 studies; a pooled analysis was carried out for safety outcomes. RESULTS: In the Japanese phase 3 study, SVR12 was achieved by 91% of patients with cirrhosis (n = 22) and 84% of patients without cirrhosis (n = 200); in the global phase 3 study, SVR12 was achieved by 84% of patients with cirrhosis (n = 206) and by 85% of patients without cirrhosis (n = 437). The frequency of serious adverse events, adverse events leading to treatment discontinuation and treatment-emergent grade 3/4 laboratory abnormalities was low (<10%) and similar among patients with (n = 229) or without (n = 689) compensated cirrhosis receiving DCV+ASV. Grade 3/4 reductions in platelets and neutrophils were more common among patients with cirrhosis (1.3 and 2.2%, respectively) compared with those without cirrhosis (both 0.6%). Grade 3/4 liver function test abnormalities were less common among patients with cirrhosis (1.8%) compared with those without cirrhosis (3.5-4.7%). Alanine aminotransferase elevations were not associated with hepatic decompensation. CONCLUSIONS: The safety and efficacy of DCV+ASV were similar in patients with or without compensated cirrhosis. This all-oral, interferon- and ribavirin-free combination is an effective and well-tolerated treatment option for patients with HCV GT1b infection and cirrhosis. Trial registrations numbers: Clinicaltrials.gov identifiers: NCT01012895; NCT01051414; NCT01581203; NCT01497834.

[SINGLE-INCISION TECHNIQUE FOR RIGHT HEMICOLECTOMY].

AIMS: The single incision laparoscopic technique is an emerging modality. The aim of our study was to compare the intra-operative and short term post-operative outcomes of single incision versus multi-incision laparoscopy for right hemicolectomy. METHODS: We retrospectively reviewed the charts of all patients who underwent right hemicolectomy from October 2010 till December 2012. RESULTS: Thirty six patients underwent laparoscopic right hemicolectomy, of which, twenty five were performed with the traditional multi-incision technique and eleven were conducted with a single incision. From the parameters that were evaluated, we found that in the single incision technique there was a statistical trend [p=0.08] of better oncological results with a higher mean lymph node extraction. In addition, there was a statistically significant [p=0.05] advantage of decreased length of hospitalization. CONCLUSIONS: The single incision technique is feasible and safe for right hemicolectomy. Given our findings, we believe that it can be an effective alternative to the traditional multi-port technique.

Use of a porcine dermal collagen implant for contaminated abdominal wall reconstruction in a 105-year-old woman: a case report and review of the literature.

INTRODUCTION: Repair of contaminated abdominal wall defect in a geriatric patient is a challenge for the surgeon. We present the case of the oldest patient (105-years old) to successfully undergo a single-stage repair of a contaminated abdominal wall defect with a Permacol™ implant. CASE PRESENTATION: A 105-year-old Caucasian woman presented to our emergency room with a clinical and radiological diagnosis of small bowel obstruction due to prior operative adhesions. She underwent laparotomy with small bowel resection and primary closure of her abdomen. There was total eventration of her bowel through the suture line 9 days after surgery. She underwent a second laparotomy that revealed no signs of peritonitis or turbid fluid. Her abdomen was closed with a 15 × 10 cm Permacol™ implant sutured sublay with prolene sutures. Her postoperative period was unremarkable. After a follow-up period of 3 years and 2 months, there was no sign of recurrent hernia or wound contamination. CONCLUSION: We suggest that Permacol™ mesh can be considered an efficient alternative to primary closure or synthetic mesh in geriatric patients with contaminated abdominal wall defects.

All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study.

BACKGROUND: An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. METHODS: We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. FINDINGS: This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and intolerant patients. Daclatasvir plus asunaprevir provided sustained virological response in 182 (90%, 95% CI 85-94) patients in the treatment-naive cohort, 168 (82%, 77-87) in the non-responder cohort, and 192 (82%, 77-87) in the ineligible, intolerant, or ineligible and intolerant cohort. Serious adverse events occurred in 12 (6%) patients in the treatment-naive group; 11 (5%) non-responders, and 16 (7%) ineligible, intolerant, or ineligible and intolerant patients; adverse events leading to discontinuation (most commonly reversible increases in alanine or aspartate aminotransferase) occurred in six (3%), two (1%), and two (1%) patients, respectively, with no deaths recorded. Grade 3 or 4 laboratory abnormalities were uncommon, with low incidences of aminotransferase increases during the first 12 weeks with daclatasvir plus asunaprevir and placebo in treatment-naive patients (≤2% each). INTERPRETATION: Daclatasvir plus asunaprevir provided high sustained virological response rates in treatment-naive, non-responder, and ineligible, intolerant, or ineligible and intolerant patients, and was well tolerated in patients with HCV genotype 1b infection. These results support the use of daclatasvir plus asunaprevir as an all-oral, interferon-free and ribavirin-free treatment option for patients with HCV genotype 1b infection, including those with cirrhosis. FUNDING: Bristol-Myers Squibb.

Evaluation of a porcine dermal collagen (permacol) implant for abdominal wall reconstruction in a pediatric multitrauma patient.

The presence of a contaminated surgical field in abdominal wall defects caused by trauma presents a challenge for surgeons. Both primary suture and synthetic meshes are strongly discouraged as surgical treatments in such cases. We describe the use of a porcine dermal collagen (Permacol) implant in an eight-year-old patient with multiple injuries. Three months after discharge, the child remains well with good cosmetic results. He is free of pain and has returned to full activity levels with complete wound closure and without any evidence of residual hernia. In conclusion, our experience indicates that the use of Permacol can be considered an efficient technique for reconstructing an infected abdominal wall defect of a pediatric multitrauma patient.

[Intraoperative margin evaluation in breast-conservation surgery using margin probe technique].

BACKGROUND: The most important prognostic factor after breast conservation surgery is surgical margin involvement. In cases where surgical margins are involved, the patient must return to the OR for a second operation. Therefore, there is a need for an intra-operative tool to assess the surgical margins. The Margin Probe technique was developed for this need. In this article we present our experience at the "Barzilai" Medical Center using the Margin Probe during breast conservation surgery. METHODS: The Margin Probe technique is added to routine standard of care at "Barzilai" Medical Center. The device sends radiofrequency signals to the resected tissue and spectroscopy analysis provides data to the surgeon about the involvement of the surgical margins. In cases where the device signals for positive margins, the surgeon expands the resection, in order to avoid a second surgery in the future. RESULTS: From sixty four patients who underwent breast conservative surgery, twenty four (37.5%) underwent intraoperative additional re-excision due to positive margin signals from the Margin Probe device. From those patients, nine patients (37.5%) indeed had surgical margins involvement in the pathology analysis. From all patients, four (6.25%) underwent a second surgery, while only one patient had a false negative measurement from the device. CONCLUSIONS: According to our experience, using the Margin Probe technique is feasible, safe and reduces the rate of repeated operation.

A new role of vemurafenib as a neoadjuvant treatment of axillary and brain melanoma metastases.

Vemurafenib is approved by the FDA for the management of unresectable or metastatic melanoma. However, its role as a neoadjuvant therapy has not been determined. We present the first documented case in which vemurafenib induced complete tumor necrosis of both lymph node and brain metastases within one month or less, an outcome that indicated that the patient was a good candidate for excisional surgery.

Identification of components of grape powder with anti-apoptotic effects.

This study is to investigate the mechanism underlying the anti-apoptotic effects of freeze-dried grape powder (FDGP) and identify the polyphenolic compounds involved. We examined apoptotic signaling pathways affected by FDGP and by its active components, including epicatechin, cyanidin, quercetin, and resveratrol, in human Huh7 hepatoma cells by assaying cell viability assays, the activities of caspase 3 and caspase 7, and the expression of endoplasmic reticulum stress-associated proteins. FDGP dramatically decreased taurodeoxycholic acid (TDCA)-induced production of reactive oxygen species (ROS). Assessment of individual active components revealed that at concentrations corresponding to 300 µg/mL FDGP, only quercetin demonstrated cytoprotective effects against mitochondrial-mediated apoptosis. In contrast, increased concentrations of other individual polyphenolic compounds were required to produce measurable cytoprotective effect. Only combinations of all four polyphenolic compounds (epicatechin, cyanidin, quercetin, and resveratrol) restored a degree of the anti-apoptotic effects seen with FDGP. The pretreatment of FDGP at 30 µg/mL concentration could reverse the thapsigargin-induced effects on the expression of endoplasmic reticulum stress-associated proteins. In conclusion, FDGP reduced oxidative stress, endoplasmic reticulum stress, and apoptosis. The mechanisms involved in the anti-apoptotic effects of FDGP included reduced generation of ROS, and reduced processing of certain caspases. We demonstrated that quercetin, epicatechin, and cyanidin are active compounds within FDGP that attenuate apoptosis. These findings contribute to our understanding of the molecular mechanisms of anti-apoptotic and anti-oxidant effects of grape and are expected to assist in developing clinical protocols to treat a variety of stress-mediated conditions.

Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection.

UNLABELLED: Interferon lambda 1 (IFN-lambda1) is a type III IFN that produces intracellular responses similar to those of IFN-alpha but in fewer cell types because of differences in the receptor distribution pattern, and this could potentially result in an improved safety profile. This was an open-label three-part study of patients with chronic hepatitis C virus (HCV) genotype 1 infection. Part 1 evaluated single-agent pegylated interferon lambda (PEG-IFN-lambda) at 1.5 or 3.0 microg/kg administered every 2 weeks or weekly for 4 weeks in patients who had relapsed after previous IFN-alpha-based treatment. Part 2 evaluated weekly doses of PEG-IFN-lambda ranging from 0.5 to 2.25 microg/kg in combination with ribavirin (RBV) for 4 weeks in treatment-relapse patients. Part 3 evaluated weekly PEG-IFN-lambda at 1.5 microg/kg in combination with RBV for 4 weeks in treatment-naive patients. Fifty-six patients were enrolled: 24 patients in part 1, 25 patients in part 2, and 7 patients in part 3. Antiviral activity was observed at all PEG-IFN-lambda dose levels (from 0.5 to 3.0 microg/kg). Two of seven treatment-naive patients (29%) achieved rapid virological response. Treatment was well tolerated with minimal flu-like symptoms and no significant hematologic changes other than RBV-associated decreases in hemoglobin. The most common adverse events were fatigue (29%), nausea (12%), and myalgia (11%). Six patients experienced increases in aminotransferases that met protocol-defined criteria for dose-limiting toxicity (DLT) or temporarily holding therapy with PEG-IFN-lambda. Most DLT occurred in patients with high PEG-IFN-lambda exposure. CONCLUSION: Weekly PEG-IFN-lambda with or without daily RBV for 4 weeks is well tolerated with minimal adverse events and hematologic effects and is associated with clear antiviral activity across a broad range of doses in patients with chronic HCV.

Freeze-dried grape powder attenuates mitochondria- and oxidative stress-mediated apoptosis in liver cells.

The beneficial effects of grape consumption have been attributed to the antioxidant activity of its polyphenols. This study was conducted to investigate the cytoprotective effects of a freeze-dried grape powder (FDGP) on liver cells. FDGP treatment of primary hepatocytes and hepatoma cells revealed increased metabolic activity of cells and phosphorylation of Akt and IkappaBalpha, as well as up-regulation of proliferating cell nuclear antigen (PCNA) level. To study the molecular mechanisms of FDGP effects, cells were treated with TNF-related apoptosis-inducing ligand (TRAIL); taurodeoxycholic acid (TDCA); thapsigargin (TG), to induce cell apoptosis through death receptor-, mitochondria-, or ER-mediated pathway; and H(2)O(2), to induce oxidative stress, respectively. TDCA-induced activation of caspase-3, caspase-7, caspase-9, and Bax was dramatically decreased with cotreatment of FDGP. Furthermore, FDGP reduced levels of annexin V positive cells by 4-fold. Also, FDGP pretreatment restored cellular glutathione content by 71% in cells treated with H(2)O(2). However, FDGP did not inhibit ER-mediated apoptosis. In conclusion, FDGP increased the viability and metabolic activity of liver cells and attenuated oxidative stress- and mitochondria-mediated apoptosis. These data may contribute to the understanding of the mechanisms involved in protective effects of grape in a variety of liver conditions associated with cellular stress.

[Epicatechin abolished TDCA-induced apoptosis in Huh7 cell by inhibiting Bax, p38 MAPK and ROS production].

OBJECTIVE: To investigate the molecular mechanisms involved in anti-apoptotic effects of epicathechin in liver cells. METHOD: Human hepatoma cell line (Huh7) was treated with 400 miromol x L(-1) taurodeoxycholic acid (TDCA) for 48 hours to induce apoptosis. Intracellular generation of reactive oxygen species (ROS) was detected with DCFH-DA assay. Caspase-3/7 activity was analyzed with EnzoLyte Homogeneous AMC kit. Cell proliferation was measured by MTT assay. The expression of Bax, Phospho-p38 MAPK and the levels of cytochrome C were assessed by Western-blot analysis. RESULT: TDCA-dependent intracellular ROS production was 8-fold higher as compared to untreated cells, consequently resulting in 45% reduction of cell viability. Interestingly, pretreatment of cells with epicatechin resulted in a dose-dependent inhibition of TDCA-induced ROS generation and reduced cell apoptosis by threefold as compared to TDCA treatment alone. In addition epicatechin reduced Bax expression with consequential inhibition of cytochrome C release from mitochondria, inhibition of caspase 3/7 activation and p38 MAPK phosphorylation. CONCLUSION: Epicatechin protects Huh7 cells from oxidative stress and mitochondria-induced apoptosis. The molecular mechanisms of anti-apoptotic effects of epicatechin were associated with inhibition of p38 MAPK phosphorylation and Bax expression, and reduction of ROS production. These findings implicate epicathechin might have potential as protective agent against a variety of oxidative stress-mediated liver conditions.

Concurrent primary biliary cirrhosis and autoimmune hepatitis presenting as subfulminant hepatic failure.

Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) overlap syndrome may be found in a significant percentage of patients with either PBC or AIH. However, it is conceivable that most cases of PBC-AIH overlap syndrome are a concurrent manifestation of both diseases which therefore requires treatment of both disease entities. While most cases are found in asymptomatic patients or in patients who have been previously diagnosed with PBC, our patient presented with concurrent PBC and AIH resulting in subfulminant liver failure that responded to treatment with prednisone and ursodeoxycholic acid (UDCA). Extended 4-year follow-up and treatment with UDCA confirmed the diagnosis of PBC and demonstrated serological resolution of AIH.

Disturbance of apoptosis and DNA synthesis by Helicobacter pylori infection of hepatocytes.

We evaluated the effects of infection of hepatocytes with the well-characterized Helicobacter species, H. pylori. Cell number doubled during each 24 h period in mock cultures or following infection with H. pylori 401C (CagA-, VacA-, BabA-, OipA-) (P < 0.05). In contrast, infection with the more virulent H. pylori NCTC11637 (CagA+, VacA+, BabA+, OipA+) resulted in cell arrest (P < 0.05). Furthermore, NCTC11637 activated caspase-3 and increased DNA fragmentation 6.1 +/- 1.2 fold (P < 0.01) and the number of apoptotic bodies 9.4 +/- 3.5 fold (P < 0.01) compared to controls. The effect was greater than with the less virulent strain 401C (3.8 +/- 0.6 fold and 3.9 +/- 1.7, respectively, P < 0.05). Strain NCTC11637 at low concentrations increased cellular DNA synthesis 139 +/- 6% (P < 0.05) but decreased it to 16 +/- 7% (P < 0.01) at high concentrations. In contrast, strain 401C increased DNA synthesis 155 +/- 14% of controls (P < 0.05) at high concentrations. The presence of intracellular NCTC11637 within hepatocytes increased DNA fragmentation 3.0 +/- 0.4 fold (P < 0.01) greater than in controls. H. pylori infection resulted in strain-species-dependent effects on hepatocytes, and virulent strain caused cell arrest and apoptosis of infected hepatocytes.

Role of the long cytoplasmic domain of the SIV Env glycoprotein in early and late stages of infection.

BACKGROUND: The Env glycoproteins of retroviruses play an important role in the initial steps of infection involving the binding to cell surface receptors and entry by membrane fusion. The Env glycoprotein also plays an important role in viral assembly at a late step of infection. Although the Env glycoprotein interacts with viral matrix proteins and cellular proteins associated with lipid rafts, its possible role during the early replication events remains unclear. Truncation of the cytoplasmic tail (CT) of the Env glycoprotein is acquired by SIV in the course of adaptation to human cells, and is known to be a determinant of SIV pathogenicity. RESULTS: We compared SIV viruses with full length or truncated (T) Env glycoproteins to analyze possible differences in entry and post-entry events, and assembly of virions. We observed that early steps in replication of SIV with full length or T Env were similar in dividing and non-dividing cells. However, the proviral DNA of the pathogenic virus clone SIVmac239 with full length Env was imported to the nucleus about 20-fold more efficiently than proviral DNA of SIVmac239T with T Env, and 100-fold more efficiently than an SIVmac18T variant with a single mutation A239T in the SU subunit and with a truncated cytoplasmic tail (CT). In contrast, proviral DNA of SIVmac18 with a full length CT and with a single mutation A239T in the SU subunit was imported to the nucleus about 50-fold more efficiently than SIVmac18T. SIV particles with full length Env were released from rhesus monkey PBMC, whereas a restriction of release of virus particles was observed from human 293T, CEMx174, HUT78 or macrophages. In contrast, SIV with T Envs were able to overcome the inhibition of release in human HUT78, CEMx174, 293T or growth-arrested CEMx174 cells and macrophages resulting in production of infectious particles. We found that the long CT of the Env glycoprotein was required for association of Env with lipid rafts. An Env mutant C787S which eliminated palmitoylation did not abolish Env incorporation into lipid rafts, but prevented virus assembly. CONCLUSION: The results indicate that the long cytoplasmic tail of the SIV Env glycoprotein may govern post-entry replication events and plays a role in the assembly process.

Efficacy of interferon alpha-2b induction therapy before retreatment for chronic hepatitis C.

BACKGROUND/AIMS: Chronic hepatitis C (HCV) patients who have failed previous treatment have low sustained viral response (SVR) rates with repeat treatment. We evaluated whether interferon (IFN) induction during retreatment improves response rates. METHODS: Two randomized, controlled trials were conducted in chronic HCV patients who failed IFN. In Study 1, patients received IFN 3 MU daily plus ribavirin (RBV) 1000 mg/day for 4 weeks, followed by IFN 3 MU TIW plus RBV 1000 mg/day for 44 weeks (induction; n=232), or IFN 3 MU TIW plus RBV 1000 mg/day for 48 weeks (non-induction; n=237). In Study 2, patients received IFN 5 MU B.I.D. plus RBV 1000-1200 mg/day for 2 weeks, followed by pegylated IFN (PEG-IFN) 75-150 mug weekly plus RBV 1000-1200 mg/day for 46 weeks (induction; n=201), or PEG-IFN 75-150 mug weekly plus RBV 1000-1200 mg/day for 48 weeks (non-induction; n=206). The primary end point for both trials was SVR. RESULTS: Induction did not increase SVR compared with non-induction, but did increase the on-treatment response among genotype non-1 patients in Study 2. By intention-to-treat (ITT) analysis, SVR in Study 1 was 13% for induction vs. 9% for non-induction (P=NS). In Study 2 (ITT), SVR was 20% for induction vs. 24% for non-induction (P=NS). However, by non-ITT analysis of Study 2, genotype non-1-previous non-responders showed significantly higher response rates with induction than non-induction. CONCLUSION: For chronic HCV patients who have failed IFN, induction with retreatment does not improve SVR, but may be beneficial for patients with genotype non-1 HCV.

Endoscopic intraoral plating of orbital floor fractures.

PURPOSE: This article describes a new endoscopic approach for orbital floor fractures, reduction, and fixation and reports the clinical results. PATIENTS AND METHODS: Ten patients who sustained either a comminuted or trap door orbital floor fracture were treated in 2 medical centers following the same surgical protocol. The indications for orbital reconstruction were limited eye movement, diplopia, and significant enophthalmos. The new approach is discussed in detail. RESULTS: All patients healed uneventfully. No major complications were noted in the postoperative period, and good functional and esthetic results were obtained. CONCLUSIONS: Our results demonstrate that endoscopic intraoral plating is a safe and effective procedure for treating orbital floor fractures.

The ductal stretching technique: an endoscopic-assisted technique for removal of submandibular stones.

OBJECTIVE: The purpose of this study was to describe an innovative surgical technique for the removal of posterior and hilar stones of the submandibular salivary duct. METHODS: Between 1999 and 2005, 172 patients who had sialolithiasis of the submandibular duct were treated primarily by transoral incision and marsupialization of the duct and salivary gland. The ductal stretching technique involved endoscopic location of the stone, incision of the oral mucosa above the duct, isolation of the duct from the surrounding tissues, stretching of the duct, ductal incision above the calculus, sialolithotomy, and insertion of a drain. RESULTS: Forty-one patients with stones located in the posterior aspect of the duct were symptom-free and stone free after the procedure. One hundred and five patients with stones located in the hilum were treated with a success rate of 98%. Twenty-six patients with multiple stones in the hilar region were treated with a success rate of 81%. The overall success rate of the procedure was 96%. In 48 patients (28%), an additional undetected stone was diagnosed by endoscopy after the removal of the stone in the hilum. In 62 patients (36%), strictures were diagnosed endoscopically posterior to the stone. Lingual nerve paresthesia occurred in one patient, who recovered completely. CONCLUSION: The ductal stretching technique is recommended as the procedure of choice in cases with posterior and hilar stones more than 5 mm in diameter to avoid surgical removal of the salivary gland.

Intra-arterial infusion of nitric oxide (NO) - first animal trial.

OBJECTIVE: Nitric oxide (NO) is an important signaling molecule that acts in many tissues to regulate a diverse range of physiological processes. NO has been implicated in a number of cardiovascular diseases. Reduced basal NO synthesis or function may lead to: vasoconstriction, elevated blood pressure and thrombus formation. By contrast, overproduction of NO results in vasodilatation, hypotension, vascular leakage, and disruption of cell metabolism. The purpose of this study was to determine the effects of NO gas directly infused into the arteries. METHODS: The study was performed on 28 rabbits and 10 pigs. We developed a device that enables quantitatively controlled infusion of NO gas, directly into the arteries. RESULTS: We found that administration of NO gas via arteries caused widening of the blood vessels as well as increasing blood flow in the extremity. It emerges that. These effects persist up to 2-3 h after the NO infusion ceased. Although the NO breaks down when diffused in blood, its influence commences rapidly and continues for a relatively long time. CONCLUSIONS: Our findings indicate that, administration of NO into blood vessels causes a long lasting vasodilatation and enhanced blood flow. Despite the fact that NO is broken down rapidly.