Potent relaxant effect of a Celastrus paniculatus extract in the rat and human ileum

Ethnopharmacological importance

Celastrus paniculatus Willd. (Celastraceae) is an Ayurvedic remedy used for the treatment of a number of diseases, including bowel spasms.

Aim of the study

To investigate the mode of the relaxing action of a methanolic extract prepared from the seeds of Celastrus paniculatus (CPE, 0.0001–10 μg/mL) in the rat ileum and to try to confirm on human tissues the intestinal pharmacological activity of the extract.

Materials and methods

The relaxant effect of CPE was studied in vitro by evaluating its effect on the spontaneous contractions of the isolated ileum.

Results

CPE exerted a tetrodotoxin- and ω-conotoxin-resistant inhibitory effect on rat ileum motility (IC₅₀: 0.24 ± 0.02 μg/mL; E_max: 99.0 ± 0.60%). The inhibitory effect was reduced by nifedipine but not by cyclopiazonic acid. Experiments with specific antagonists enabled us to exclude the involvement of the main endogenous spasmogenic (i.e. acetylcholine and tachykinins) and relaxing (noradrenaline, nitric oxide, ATP) compounds. CPE also relaxed the isolated human ileum (IC₅₀: 0.26 ± 0.02 μg/mL; E_max: 99.1 ± 0.46%).

Conclusion

It is concluded that (i) CPE exerted a powerful myogenic and L-type Ca²⁺-dependent relaxing effect in the isolated rat ileum and that (ii) the human ileum is sensitive to the inhibitory effect of CPE. If confirmed in vivo, our data could explain the traditional use of this herb in the treatment of intestinal spasms.     

Untersuchungen über die Veränderungen der Blutgefässe bei der Entzündung

Ohne Zusammenfassung     

Prognostic value of persistent thallium-201 defects that become reversible after reinjection in patients with chronic myocardial infarction

Background

The presence of defects at stress-redistribution thallium-201 scintigraphy is related to a higher risk of cardiac events. However, the prognostic value of defects that become reversible after reinjection is not known. In this study we evaluated the prognostic contribution of stress-redistribution-reinjection with special regard to 3-hour fixed defects that become reversible after reinjection.

Methods and Results

We studied 122 patients with chronic myocardial infarction (>2 months) and suspected or known residual ischemia, with stress-redistribution-reinjection planar scintigraphy. Thallium scans were analyzed by three observers (three segments per view, 5-point score) and classified as normal, fixed, and reversible. The lung/heart ratio was also calculated. At a median follow-up of 47 months, 10 patients had hard events (four deaths and six myocardial infarctions) (group I), 12 patients had unstable angina (group II), 12 patients underwent planned coronary artery bypass grafting or percutaneous transluminal coronary angioplasty (group III), and 86 patients had no events (group IV). The presence of fixed defects that became reversible after reinjection did not identify patients at higher risk. The number of reversible defects at 3 hours was significantly higher only in patients who underwent revascularization. Unstable angina was not predicted by any scintigraphic pattern. The variables that were statistically related to hard events by univariate analysis were increased lung uptake, reversible cavity dilation, and the number of fixed defects that remained fixed after reinjection. By Cox multivariate analysis, the strongest predictor of hard events was the presence of more than three fixed defects that remained fixed after reinjection as a marker of irreversible myocardial damage.

Conclusions

²⁰¹TI reinjection is a useful approach for not only detecting viable myocardium but also risk stratification in patients with chronic myocardial infarction.     

Melanoma risk alleles are associated with downregulation of the MTAP gene and hypermethylation of a CpG island upstream of the gene in dermal fibroblasts

Several association studies and GWAS on melanoma skin cancer risk have reported statistically significant signals on 9p21.3 region, where MTAP gene maps. None of the associated SNPs identified in these studies lie in the coding region of the gene and the causative relation of risk alleles with melanoma predisposition has not been elucidated. MTAP has a tumor suppressor activity and epigenetic silencing has been described in melanoma cell lines. In the present study, we show that melanoma risk alleles correlate with a MTAP allele‐specific hyper‐methylation and down‐regulation of gene expression.     

Effect of infusion and withdrawl of glucose and insulin on gas exchange in injured ventilated patients

To evaluate the effect induced on gas exchange and on urea excretion by glucose and insulin infusion in injured patients. The magnitude and time necessary for the full development of the metabolic effect were investigated. Six injured patients were investigated. During the first 24 hours, the fasting period, patients received 1 mg/kg^*min of glucose; during the second 24 hours, the treatment period, infusion was increased to about the 95% of the energy production rate; during the last 8 hours, (stop period) the infusion rate was again set to 1 mg/kg^*min. Gas exchange was determined in two consecutive 12-hour series, for 30 minutes every hour, either during a stabilized treatment or after its variation. Urea excretion was determinated on 4-hour samples. With respect to the fasting period, during the last 4 hours of the treatment period, the energy production rate did not vary; urea excretion (−25%) and oxygen consumption (−9%) decreased significantly. Carbon dioxide production (+16%), total respiratory quotient, and minute ventilation (+5%) increased significantly. Carbon dioxide production varied linearly with time (glucose infusion ⁺1.74 mL/min^*m2^*h, P <.05; glucose withdrawal −1.89 mL/min^*m2^*h, P < .01). Minute ventilation decreased only during the withdrawal period by 65 mL/ min^*m2^*h (P < .05). The infusion of glucose and insulin, in an amount slightly lower than the metabolic expenditure, leads to a consistently reduced amino acid catabolism and to a decreased oxygen consumption, without affecting energy requirements. Although it leads to an increase of carbon dioxide production, the measured change is so small and slow that it is not harmful unless there is severe respiratory insufficiency.     

Emergency laparoscopic surgery

The laparoscopic approach has represented a major step forward in general and emergency surgery. Its application in the emergency setting still raises a number of concerns that limit its more widespread use. To assess the true scope of laparoscopic surgery in the acute abdominal setting, we retrospectively evaluated our experience. From February 2003 to June 2007, 314 patients underwent an emergency laparoscopic operation, for low abdominal pain (193 patients), acute cholecystitis (78 patients), bowel obstruction (18 patients), diffuse peritonitis (16 patients), blunt abdominal trauma (6 patients), and acute pancreatitis (3 patients). Laparoscopy yielded a good diagnostic definition in all cases. The conversion rate was 16.6% (52 patients). Mean operative time was 63 +/- 29 minutes. The general major morbidity rate was 1.5% (4 patients) and the mortality rate was 0.4% (1 pt.). The laparoscopic approach in patients with abdominal emergencies is a useful tool that yields a reliable diagnostic definition in uncertain cases and allows minimal access treatment of the causative disease in the majority of cases.     

Adenocarcinoma of the Ampulla of Vater: T-Stage,Chromosome 17p Allelic Loss,and Extended Pancreaticoduodenectomy are Relevant Prognostic Factors

Objective To evaluate the prognostic significance of different clinico-pathological and molecular factors, and to compare survival after standard and extended pancreaticoduodenectomy (PD) in ampulla of Vater adenocarcinoma (AVAC). Summary Background Data There are discordant data on factors affecting prognosis, and hence therapeutic choices, in AVAC. Patients and Methods Clinical-pathological factors were evaluated in 59 patients, subjected to PD for AVAC; in 42 subjects information on chromosome 17p and 18q allelic losses (LOH) and microsatellite instability (MSI) was also available. The association between survival and type of PD was investigated in the 25 patients operated between 1990 and 2001 (16 standard and nine extended). Results The overall 5- and 10-year tumor-related survival rates were 46% and 33%, respectively. Sixteen patients had T-stages 1–2, 14 T-stage 3, and 29 T-stage 4 cancers. Chromosome 17p and 18q LOH were detected in 23 (55%) and 15 cases (36%), respectively, and in 12 cases (29%) coexisted. Five cases were MSI-positive (12%). At univariate analysis, poor survival was associated with cancer ulceration (P = 0.051), poor differentiation (P = 0.008), T-stage 4 (P < 0.001), nodal metastases (P = 0.004), chromosome 17p (P < 0.001) and 18q LOH (P = 0.002), and absence of MSI (P = 0.009). At multivariate analysis, only T-stage (P = 0.002) and 17p LOH (P = 0.001) were independent predictors of survival. All patients with MSI-positive cancers were long-survivors (>12 yrs), whereas only 30% of MSI-negative cancer patients survived at 5 years. Extended pancreaticoduodenectomy was associated with a 3-year disease-related survival higher than standard resection (83% vs 31%; P = 0.018). Conclusion MSI and chromosome 17p status allow to better define prognosis within ampullary cancers at the same stage. Surgery alone resulted curative in MSI-positive cancer patients, whereas it was inadequate in patients showing allelic losses, who might benefit from adjuvant therapy. In this observational study, extended PD was associated with increased survival compared to standard procedures. Presented at the 2006 Annual Meeting of the American Hepato-Pancreato-Biliary Association, Miami Beach, Florida, March 9–12, 2006     

Type I interferons in the treatment of pancreatic cancer: mechanisms of action and role of related receptors

OBJECTIVE: We evaluated the role of type I interferons (IFNs) and IFN receptors in the regulation of cell growth in 3 human pancreatic adenocarcinoma cell lines (BxPC-3, MiaPaCa-2, and Panc-1). BACKGROUND: Chemotherapy and radiotherapy have a marginal role in the management of pancreatic adenocarcinoma. The addition of IFN-alpha showed promising results in early clinical trials. METHODS: Cell proliferation and apoptosis were evaluated by DNA measurement and DNA fragmentation, respectively. Type I IFN receptor (IFNAR-1 and IFNAR-2 subunits) was determined by quantitative RT-PCR and immunocytochemistry. Cell cycle distribution was evaluated by propidium iodide staining and flow-cytometric analysis. RESULTS: The incubation with IFN-beta for 6 days showed a potent inhibitory effect on the proliferation of BxPC-3 (IC(50), 14 IU/mL) and MiaPaCa-2 (IC(50), 64 IU/mL). The inhibitory effect of IFN-beta was stronger than IFN-alpha in all 3 cell lines and mainly modulated by the stimulation of apoptosis, although cell cycle arrest was induced as well. The expression of the type I IFN receptors was significantly higher in BxPC-3 (the most sensitive cell line to IFN) and mainly localized on the membrane, whereas in Panc-1 (the most resistant cell line) about 60% to 70% of cells were negative for IFNAR-2c with a mainly cytoplasmic staining for IFNAR-2c. CONCLUSION: The antitumor activity of IFN-beta is more potent than IFN-alpha in pancreatic cancer cell lines through the induction of apoptosis. Further studies should investigate in vivo whether the intensity and distribution of IFNAR-1 and IFNAR-2c may predict the response to therapy with IFN-alpha and IFN-beta in pancreatic cancer.     

The ALPPS Procedure: A Surgical Option for Hepatocellular Carcinoma with Major Vascular Invasion

Background

Hepatocellular carcinoma (HCC) tends to have a particular invasiveness toward the portal vein (PV) branches and hepatic veins. This situation can hamper major surgical resection with a risk of postoperative liver failure due to the small future liver remnant (FLR) in cirrhotic livers. These patients are then usually directed to palliative treatments with poor results. The associating liver partition and PV ligation (PVL) in staged hepatectomy (ALPPS) strategy is one of the main surgical innovations in recent years in the field of liver surgical oncology. The ALPPS approach could allow surgical resection in patients with HCC and associated major vascular invasion.

Methods

Among 1,143 liver resection performed in our center, the ALPPS approach was employed in order to induce rapid hypertrophy of the left FLR in patients with HCC and associated major vascular invasion. This strategy consists of combining the in situ splitting of the liver along the main portal scissura or on the right side of the falciform ligament and PVL in a strategy of staged hepatectomy.

Results

In our experience the ALPPS approach allowed us to achieve a sufficient FLR in two cases of HCC with major vascular invasion, in which the classic two-stage strategy could not be applied. In both cases the patients could undergo major hepatectomies without mortality.

Conclusions

This novel strategy could expand the number of patients undergoing major liver resections that were previously considered non-resectable because of the risk of liver decompensation for an insufficient FLR.