Prognosis of Patients With Severe Aortic Stenosis After the Decision to Perform an Intervention

Introduction and objectives

Current therapeutic options for severe aortic stenosis (AS) include transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR). Our aim was to describe the prognosis of patients with severe AS after the decision to perform an intervention, to study the variables influencing their prognosis, and to describe the determinants of waiting time > 2 months.

Involvement of SNAP-23 and syntaxin 6 in human neutrophil exocytosis

To understand the molecular basis of exocytosis in human neutrophils, the role of syntaxin 6 and SNAP-23 in neutrophil degranulation was examined. Human syntaxin 6 was cloned and identified as a 255-amino acid protein with a carboxy-terminal transmembrane region and two coiled-coil domains. Syntaxin 6 was localized mainly in the plasma membrane of human resting neutrophils, whereas SNAP-23 was located primarily in the mobilizable tertiary and specific granules. SNAP-23 was translocated to the cell surface, colocalizing with syntaxin 6, on neutrophil activation. In vitro binding studies established that SNAP-23 binds to syntaxin 6. Coimmunoprecipitation assays indicated that SNAP-23 interacts with syntaxin 6 in vivo, and this interaction was dramatically increased on neutrophil activation. Antibodies against SNAP-23 inhibited Ca(++) and GTP-gamma-S-induced exocytosis of CD67-enriched specific granules, but they hardly affected exocytosis of the CD63-enriched azurophilic granules, when introduced into electropermeabilized neutrophils. Anti-syntaxin 6 antibodies prevented exocytosis of both CD67- and CD63-enriched granules in electropermeabilized neutrophils. These data show that syntaxin 6 and SNAP-23 are involved in human neutrophil exocytosis, demonstrating that vesicle SNAP receptor-target SNAP receptor (v-SNARE- t-SNARE) interactions modulate neutrophil secretion. Syntaxin 6 acts as a target for secretion of specific and azurophilic granules, whereas SNAP-23 mediates specific granule secretion.     

Fatal upper and lower gastrointestinal cytomegalovirus disease following autologous peripheral blood stem cell transplantation

Although the life-threatening cytomegalovirus (CMV) disease is a well known complication following allogeneic hematopoietic stem cell transplantation (HSCT), it has been considered infrequent after autologous peripheral blood stem cell transplantation (PBSCT). On the other hand, the massive involvement of the gastrointestinal (GI) tract as the primary site of fatal CMV disease is particularly rare after autologous PBSCT. We present the case of a woman who suffered from CMV disease after high-dose busulphan/melphalan/thiotepa (BuMelTT) and autologous PBSCT. The primary site of infection was the GI tract, which was extensively affected. During the fifth week post-transplant the patient started with epigastralgia, diarrhea, fever, GI bleeding, and thrombocytopenia, and she died on day +52. Another case of fatal CMV disease among the few patients treated with BuMelTT has been recently reported, which suggests that the immunodeficiency associated with that regimen can be as intense as that occurring after allogeneic BMT.     

Increased bile lithogenicity after simultaneous total parenteral nutrition and octrotide. A model of calcium palmitate Gallstones

Gallbladder stasis and gallstone formation are well-known complications of both fasting-associated total parenteral nutrition (TPN) and long-term treatment with octreotide. Additive noxious effects to hepatobiliary function may develop when both therapies are given together as treatment of enteric fistulae. The aim of this study was to assess the risk of gallstone formation during treatment with TPN and octreotide separately and in combination. We studied four groups of New Zealand rabbits (n = 32) during a 2-week intervention period: 14 chow-fed controls; 6 fasted and TPN-fed; 6 chow-fed and administered octreotide, and 6 fasted and treated with both TPN and octreotide. After treatment, the bile duct was cannulated and the gallbladder and liver tissue were obtained for histological analysis. Hepatic and gallbladder bile were retrieved for microscopic examination and measurement of biliary lipids, bilirubin, calcium, total protein, and cholesterol nucleation time. The chemical composition of gallstones was also analyzed. The results of the study suggest that simultaneous administration of these two therapies in rabbits has additive effects on gallbladder stasis and bile lithogenicity. The administration of both treatments can play an important role in the formation of calcium palmitate gallstones in these animals.     

Calcitriol-Mediated Hypercalcaemia and Increased Interleukins in a Patient with Sarcoid Myopathy

In this report we describe a patient with Sjo¨gren’s syndrome (SS) and calcitriol-mediated hypercalcaemia. Initially, there was no clinical evidence of sarcoidosis. The patient had hypercalcaemia associated with increased calcitriol serum levels; circulating interleukin-6 and tumour necrosis factor alpha levels were also elevated. At the beginning, therapy with clodronate was effective in decreasing the serum calcium levels. However, the serum calcitriol decreased only after chloroquine treatment was added. After 2 years of therapy, the patient developed progressive and extensive muscle weakness. A muscle biopsy revealed a very prominent non-caseating granulomatous myopathy. Corticosteroid therapy was then instituted. Although both chloroquine and corticosteroid therapy were associated with decreased serum interleukin and calcitriol levels, only corticosteroid therapy was effective in treating the sarcoid myopathy. The role of cytokines in calcitriol mediated hypercalcaemia is discussed. Received: 1 February 1999 / Accepted: 2 June 1999     

Autologous blood stem cell transplantation for acute myeloblastic leukemia in first complete remission. Intensification therapy before transplantation does not prolong disease-free survival

BACKGROUND AND OBJECTIVE: To compare the clinical results of two consecutive therapeutic protocols including autologous blood stem cell transplantation (ABSCT) for patients with de novo acute myeloblastic leukemia (AML) in first complete remission (CR1). DESIGN AND METHODS: Between November 1989 and January 1997, 50 patients with AML in CR1 underwent ABSCT using two consecutive protocols. In the first one (Group A, 25 patients) peripheral blood stem cells (PBSC) were collected after induction and consolidation chemotherapy courses, and ABSCT was performed immediately thereafter. In the subsequent 25 patients (Group B), PBSC were collected after consolidation alone, and a further chemotherapy course with intermediate dose cytarabine (Ara-C 1 g/m2/12 h x3 days) and mitoxantrone (12 mg/m2/d x3 days) was administered as early intensification. The conditioning regimen consisted of busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg) in every case. RESULTS: Hematopoietic engraftment was slightly quicker in Group B, with median times to reach 0.5 x 10(9) neutrophils/L and 20 x 10(9) platelets/L being 13 and 12 days in Group A and 12 and 11 days in Group B, respectively. There were three graft failures (8%) (2 in Group A and 1 in Group B) and three transplant-related deaths (8%) (2 in Group A and 1 in Group B). No significant differences were observed between the groups in terms of relapse (64% at 4-years in Group A and 81% in Group B). Likewise, the actuarial 4-year disease-free survival (DFS) was not significantly different between the two groups (32% v 18%). INTERPRETATION AND CONCLUSIONS: Our study confirms that AML patients in CR1 receiving ABSCT have rapid engraftment with low mortality. However, autologous transplants with PBSC collected after consolidation chemotherapy were still associated with a high rate of relapse (RR). This RR was not apparently reduced by the administration of intermediate dose Ara-C before transplantation.     

Prothrombotic state and signs of endothelial lesion in plasma of patients with inflammatory bowel disease

Recent investigations suggest that microthrombi formation in bowel capillaries could be a determinant factor in inflammatory bowel disease (IBD) pathogenesis. To evaluate the implication of the hemostatic system during these thrombotic events, we analyzed plasmatic values of prothrombotic state markers, physiologic inhibitors of coagulation, and endothelial lesion markers in 112 IBD patients. We found an increase in thrombin-antithrombin complexes and a decrease in antithrombin III, probably due to consumption, demonstrating an increase in thrombin generation. High levels ofd-dimer reflect increased fibrin formation, but there is no correlation between thrombin generation markers andd-dimer, possibly suggesting the presence of inadequate fibrinolysis. Levels of tissue factor pathway inhibitor were higher in patients than in controls. Nine patients with Crohn's disease (35% of our sample) had levels of this marker under 70% (range 37–69%). Von Willebrand factor values were increased and those of thrombomodulin only in active patients. Most of the changes were detected in patients with inflammatory activity, and there were no differences between ulcerative colitis and Crohn's disease. In conclusion, these results support the hypothesis that there is an endothelial lesion with sustained coagulation activation in IBD patients.     

Cardiac autonomic blockade in sinus disease and indication for a pacemaker

Functional autonomic blockade (FAB) with metoprolol (0.2 mg/kg body weight) and atropine sulphate (0.04 mg/kg) was carried out in 23 patients, 20 to 81 years old (mean age 61 years) with symptomatic sick sinus syndrome with clinical indication for permanent pacing. Several measurements were determined before and after FAB, 7 had normal intrinsic heart rate (IHR) and 16 abnormal. With normal IHR, 3 had severe autonomic regulation disturbances and in only two patients the corrected sinus nodal recovery time (SNRTC) and the sinoatrial conduction time (SACT) were prolonged after FAB. On the 16 patients with abnormal IHR only 4 had severe extrinsic autonomic influence and 15 had SACT and SNRTC prolonged after FAB. All measurements were determined by standard electrocardiographic surface tracings. Indications for permanent pacing were reduced to intrinsic sick sinus syndrome and bradycardia with severe autonomic disturbances in symptomatic patients.     

The two-component PhoR-PhoP system controls both primary metabolism and secondary metabolite biosynthesis in Streptomyces lividans

The biosynthesis of most secondary metabolites in different bacteria is strongly depressed by inorganic phosphate. The two-component phoR-phoP system of Streptomyces lividans has been cloned and characterized. PhoR showed all of the characteristics of the membrane-bound sensor proteins, whereas PhoP is a member of the DNA-binding OmpR family. Deletion mutants lacking phoP or phoR-phoP, were unable to grow in minimal medium at low phosphate concentration (10 microM). Growth was fully restored by complementation with the phoR-phoP genes. Both S. lividans DeltaphoP and DeltaphoR-phoP deletion mutants were unable to synthesize extracellular alkaline phosphatase (AP) as shown by immunodetection with anti-AP antibodies and by enzymatic analysis, suggesting that the PhoR-PhoP system is required for expression of the AP gene (phoA). Synthesis of AP was restored by complementation of the deletion mutants with phoR-phoP. The biosynthesis of two secondary metabolites, actinorhodin and undecylprodigiosin, was significantly increased in both solid and liquid medium in the DeltaphoP or DeltaphoR-phoP deletion mutants. Negative phosphate control of both secondary metabolites was restored by complementation with the phoR-phoP cluster. These results prove that expression of both phoA and genes implicated in the biosynthesis of secondary metabolites in S. lividans is regulated by a mechanism involving the two-component PhoR-PhoP system.     

Seven-day proton pump inhibitor, amoxicillin and clarithromycin triple therapy. factors that influence Helicobacter pylori eradications success.

AIM: To evaluate which factors influence eradication success with standard triple therapy for Helicobacter pylori. PATIENTS AND METHODS: A prospective study was made of 891 patients infected by H. pylori and diagnosed with duodenal ulcer (n=422), gastric ulcer (n=221), or functional dyspepsia (n=248). Initially, an endoscopy with biopsies of antrum and body (haematoxylin-eosin stain), and a 13C-urea breath test were performed. All patients were treated for seven days with either omeprazole 20 mg twice daily in 442 patients (OCA) or pantoprazole 40 mg twice daily in 449 patients (PCA), associated to clarithromycin (500 mg twice a day) and amoxicillin (1 g twice a day). Two months after completing therapy urea breath test was repeated to confirm eradication. RESULTS: Mean age +/- SD was 51.6 +/- 15 years, 61% were male. Overall eradication rate was 73.7% (95% CI 69-77%) and 80.8% (77-84%) with OCA and PCA therapy, respectively, showing significant difference between treatment regimens (chi 2 =6.3; p= 0.01). As refers to underlying diseases, H. pylori eradication was achieved in 77.4% (74-80%) of peptic ulcers and 77% (71-82%) of functional dyspepsia (p=n.s.). With our two treatment regimens (OCA/PCA) eradication success was 74/81% in peptic ulcer (p=0.03), and 72/80% in functional dyspepsia (p=0.1). In the multivariate analysis, type of therapy was the only variable that correlated with eradication success (odds ratio 1.5; 95% CI: 1.1-2.1) (chi2 model: 6,4; p=0.01). CONCLUSIONS: Standard triple therapy containing a proton pump inhibitor, clarithromycin and amoxicillin for seven days achieves in our community a moderate eradication success; this result could improve by using pantoprazole instead of omeprazole. This therapy is equally effective in patients with peptic ulcer and functional dyspepsia.