Digital single-operator cholangioscopy in treating difficult biliary stones: results from a multicenter experience.

BACKGROUND: In clinical practice, standard endoscopic treatment of biliary stones fails in up to 10% of patients, and more invasive procedures such as percutaneous trans-hepatic interventions or surgery might become necessary. The aim of this multicenter retrospective study, based on prospectively-collected data, was to evaluate both the efficacy and the safety of digital-single operator cholangioscopy (D-SOC) to treat difficult biliary stones in cases with a previous failure of conventional endoscopic methods. METHODS: Only patients with a previous failure of endoscopic standard treatment and a D-SOC-based biliary stone treatment using electrohydraulic lithotripsy (EHL) or laser lithotripsy (LL) were included. The primary endpoint was to evaluate the stone clearance rate per procedure and per patient. RESULTS: Out of 1258 ERCP performed at our centers, 31 cholangioscopes in 21 patients were solely performed for the treatment of difficult biliary stones using EHL or LL. A complete biliary stone removal was achieved in 67.7% (21/31) of all procedures including initial and repeated examinations, while in 35.4% (11/31) of all procedures an incomplete removal was accomplished of which 36.3% had a partial stone removal. In 22 procedures EHL was adopted as techniques to fragment and remove biliary stones, while in 9 procedures LL was used. In both the techniques, the complete stone removal rate and the incomplete stone removal rate were similar (75% vs. 77.7%, P>0.05). Furthermore, the success rate of digital D-SOC to treat difficult biliary stones was assessed per patient: overall, 100% of patients with difficult biliary stones were successfully treated using D-SOC. Only one patient experienced mild cholangitis classified ad mild adverse event following ASGE (American Society of Gastrointestinal Endoscopy) lexicon. CONCLUSIONS: Our data indicate that digital D-SOC assisted biliary stone treatment is highly efficient for the treatment of difficult biliary stones even in such patients in whom previous conventional endoscopic methods to treat biliary stones have failed. Therefore, D-SOC might be considered the new standard of care for these patients, being both, effective and safe.

Use of catheter-based cholangioscopy in the diagnosis of indeterminate stenosis: a multi-centre experience.

BACKGROUND: Direct bile ducts visualization through cholangioscopy has gained popularity due to its better diagnostic accuracy than a standard ERCP in indeterminate biliary stricture. AIM: We aimed to review our catheter-based cholangioscopy interventions in patients with indeterminate biliary stenosis, using the SpyGlass Direct Visualization System (SDVS) and summarize our experience in terms of procedures and results. RESULTS: we collected 25 consecutive patients with indeterminate biliary stricture over 3 years. The overall procedural success in our cohort amounted to 96% (24/25). If we focus on the diagnostic procedures, the ability to merely visualize the region of interest/lesion and perform biopsy of the lesion was possible in 96 % (24/25) In our cohort localization in the common bile duct (P = 0.03; 95 % CI 0.27-0.96) was found as positive determining factor for diagnosis. Sensitivity, specificity and accuracy for visual diagnosis by SDVS in our cohort were 100, 83.3 and 96 %, respectively. The use of biopsy or obtaining a histological diagnosis to assist in identifying patients with malignant stenosis, to exclude malignancy and to correctly classify diagnosed patients resulted in a sensitivity of 100 %, a specificity of 73% % with an overall accuracy of 94.4 %. Only a mild adverse event (cholangitis, treated conservatively) occurred. CONCLUSIONS: Today, the SDVS should be considered essential in diagnosing indeterminate biliary strictures, since the procedure is associated with high procedural success in terms of diagnostic accuracy, alters clinical outcome in over 80 % of considered insolvable cases, with an acceptable safety profile.

Insulin-Requiring Versus Noninsulin-Requiring Diabetes and Thromboembolic Risk in Patients With Atrial Fibrillation: PREFER in AF.

BACKGROUND: Diabetes is a known risk predictor for thromboembolic events in patients with atrial fibrillation (AF), but no study has explored the prognostic weight of insulin in this setting. OBJECTIVES: This study evaluated the differential role of insulin versus no insulin therapy on thromboembolic risk in patients with diabetes and AF. METHODS: We accessed individual patient data from the prospective, real-world, multicenter, PREFER in AF (European Prevention of thromboembolic events-European Registry in Atrial Fibrillation). We compared the rates of stroke/systemic embolism at 1 year according to diabetes status (no diabetes, diabetes without insulin therapy, diabetes on insulin therapy). RESULTS: In an overall population of 5,717 patients, 1,288 had diabetes, 22.4% of whom were on insulin. For patients with diabetes who were on insulin, there was a significantly increased risk of stroke/systemic embolism at 1 year versus either no diabetes (5.2% vs. 1.9%; hazard ratio: 2.89; 95% confidence interval: 1.67 to 5.02; p = 0.0002) or diabetes without insulin treatment (5.2% vs. 1.8%; hazard ratio: 2.96; 95% confidence interval: 1.49 to 5.87; p = 0.0019). Notably, rates of stroke/embolism were similar in patients with diabetes not receiving insulin versus patients without diabetes (hazard ratio: 0.97; 95% confidence interval: 0.58 to 1.61; p = 0.90). The selective predictive role of insulin-requiring diabetes was independent of potential confounders, including diabetes duration, and was maintained in various subpopulations, including the subgroup receiving anticoagulant therapy. CONCLUSIONS: In this cohort of anticoagulated patients with AF, the sole presence of diabetes not requiring insulin did not imply an increased thromboembolic risk. Conversely, insulin-requiring diabetes contributed most, if not exclusively, to the overall increase of thromboembolic risk in AF.

The management of patients with venous thromboembolism in Italy: insights from the PREFER in VTE registry.

Venous thromboembolism (VTE) is the third most common cardiovascular disease. Real-life data on the clinical presentation, risk factors, diagnosis, and treatment of VTE in Italy and Europe are required to optimize the management of this disease. The PREFER in VTE registry, a prospective non-interventional real-life study, was designed to assess clinical characteristics and management of patients with VTE, use of health care resources, and on-treatment patient quality of life. Eligible consecutive patients with objectively diagnosed VTE were enrolled in the registry and followed up for 12 months. Between January and December 2013, 816 Italian and 1027 patients from 6 European countries other than Italy (European patients) were enrolled in the registry, and followed up until December 2014. Italian patients were the oldest (mean age 65.7 years) among the European patients. The Italian patients with a history of cancer were 24.6 % of whom 63.2 % had an active cancer (18.2 and 57.0 %, respectively, in Europe). Parenteral heparin was given, as initial treatment, in 73.8 % of Italian patients (66.4 % in Europe); VKA in combination with other treatments in 45.8 % (34.7 % in Europe); and VKA as the only anticoagulant treatment in 24.4 % (17.2 % in Europe). Of the Italian patients, 43.2 and 90.6 % of patients were hospitalized for deep vein thrombosis and pulmonary embolism, respectively; 65.4 % were admitted to the hospital through the emergency department. Following a real world approach, PREFER in VTE shows that the Italian patients, among and compared to the European patients, are the oldest, have a history of cancer more commonly, receive an initial treatment with heparin more commonly, and are more commonly hospitalized, particularly if affected by PE.

Microalbuminuria predicts the recurrence of cardiovascular events in patients with essential hypertension.

OBJECTIVES: Microalbuminuria (MAU) is associated with an enhanced risk of cardiovascular events. The prevalence of MAU and its prognostic impact has an important role in the stratification of cardiovascular risk in patients with essential hypertension. This is an observational, prospective study performed by 13 general practitioners aiming at assessing the prevalence and prognostic relevance of MAU in essential hypertension. METHODS: Patients with essential hypertension and with recent determination of MAU were enrolled into the study by general practitioners, and were followed up for 3 years. Primary end point was the occurrence of major cardiovascular events during the follow-up. RESULTS: Out of 1024 unselected patients, consecutively enrolled from January 2009 to March 2010, 804 completed the 3-year follow-up. Patients were categorized into two groups according to the absence (n = 523, 65%) or presence (n = 281, 35%) of MAU. During the follow-up, 41 cardiovascular events (1.69 events/100 patient-years) were reported. The presence of MAU was not associated with increased risk of cardiovascular events (adjusted hazard ratio = 1.32; 95% confidence interval 0.290-4.340, P = 0.097). When the analysis was restricted to the patients with previous cardiovascular event, MAU (adjusted hazard ratio = 2.18; 95% confidence interval 0.42-2.43, P = 0.031), together with age, metabolic syndrome, diabetes, and smoking, independently predicted the occurrence of cardiovascular events. CONCLUSION: Presence of MAU in patients with essential hypertension is not associated with increased risks of cardiovascular events. At the variance, in patients with previous cardiovascular events, MAU was found to predict recurrent events. Thus, the assessment of MAU could be considered a useful tool in secondary prevention.

[Management of thromboembolic risk in patients with atrial fibrillation in Italy: baseline data from the PREFER in AF European Registry]. / La gestione del rischio tromboembolico nei pazienti con fibrillazione atriale in Italia: dati al basale del Registro Europeo PREFER in AF.

BACKGROUND: Atrial fibrillation (AF) is a common heart rhythm disorder associated with an increased risk of stroke, heart failure and death. Although available evidence supports the administration of oral anticoagulants with respect to other treatment options to prevent thromboembolism, the use of oral anticoagulation therapy remains suboptimal. The PREFER in AF registry was conducted to evaluate patterns of prescriptions and patient adherence to guidelines, clinical features, quality of life and treatment satisfaction. METHODS: The PREFER in AF registry enrolled consecutive patients with AF recruited in high-volume cardiology centers, with AF documented during the previous 12 months. Patients were assessed at baseline and at 1-year follow-up. The present report provides Italian baseline data compared with data from other European countries participating in the registry. RESULTS: The registry enrolled 1888 Italian patients (out of 7243 in Europe), with an average age of 70.9 years. Main comorbidities included hypertension (73.5%), dyslipidemia (38.7%) and obesity (21.9%). The risk of thromboembolism was assessed using the CHA2DS2-VASc score, according to which only 4.7% of Italian patients scored 0, whereas 11.3% scored 1 and 84% scored ≥2. Italy is the Western European country with the lowest use of vitamin K antagonists (71.6%; average rate in Europe: 78.3%) and the highest average INR measurements, whereas time in therapeutic range is 72.2%, lower than in any other Western European country with the exception of Spain. Most Italian patients are unsatisfied with treatment, and only 36% report no difficulties in taking anticoagulation therapy compared with 70.3% of patients in other Western European countries. CONCLUSIONS: Among Western European countries included in the registry, Italy has the lowest prescription rate of vitamin K antagonists and the highest rate of INR measurements. Italian patients also report lower levels of satisfaction with treatment and a higher subjective difficulty in managing anticoagulation therapy. The new oral anticoagulants may favor treatment management, thus having the potential of improving medication adherence and persistence as well as quality of life.

Accuracy of narrow-band imaging in predicting colonoscopy surveillance intervals and histology of distal diminutive polyps: results from a multicenter, prospective trial.

BACKGROUND: In vivo prediction of colorectal polyp histology by narrow-band imaging (NBI) could potentially avoid post-polypectomy histologic examination or resection of diminutive lesions, thereby reducing costs and risk. OBJECTIVE: To assess whether NBI is able to predict colonoscopy surveillance intervals and histology of distal diminutive polyps according to American Society for Gastrointestinal Endoscopy (ASGE) criteria. DESIGN: Prospective, multicenter study. SETTING: Five endoscopic centers. PATIENTS: Consecutive patients undergoing colonoscopy in 5 centers were included. INTERVENTION: Participating endoscopists were required to pass a before-study qualifying examination. Histology of polyps that were <10 mm was predicted at NBI and assigned a designation of high or low confidence. MAIN OUTCOME MEASUREMENTS: Accuracy of high-confidence NBI prediction for polyps ≤5 mm in predicting surveillance intervals and negative predictive value (NPV) for adenomatous histology in the rectosigmoid colon were compared with the ASGE thresholds (90% agreement, 90% NPV). RESULTS: A total of 278 patients (mean age, 63 years; 58% male) were enrolled. At colonoscopy, 574 (97.3%) polyps <10 mm (429 ≤5 mm, 60% adenomatous) were retrieved for histologic analysis. Sensitivity, specificity, positive and negative predictive values, and accuracy of high confidence-NBI predictions for adenomatous histology in lesions ≤5 mm were 90%, 88%, 89%, 89%, and 89%, respectively. High-confidence characterization of polyps ≤5 mm predicted the correct surveillance interval in 92% to 99% of cases, according to the American and European guidelines. NPV of high-confidence NBI for adenomatous histology for the rectosigmoid colon lesions ≤5 mm was 92%. LIMITATIONS: Only experienced endoscopists were included. CONCLUSION: High-confidence prediction of histology for polyps ≤5 mm appears to be sufficiently accurate to avoid post-polypectomy histologic examination of the resected lesions as well as to allow rectosigmoid hyperplastic polyps to be left in place without resection. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01675752.).

High efficacy of endoscopic submucosal dissection for rectal laterally spreading tumors larger than 3 cm.

BACKGROUND: Endoscopic submucosal dissection (ESD) was recently developed to allow en bloc resection of early neoplasia of the GI tract, including colorectal neoplasia. The endoscopic technique is technically demanding and not yet standardized, and new devices are needed. OBJECTIVE: This study aimed to evaluate the efficacy and safety of a new device that combines the functions of injection and cutting. DESIGN: Prospective, pilot, single-arm study. METHODS: Consecutive patients with rectal laterally spreading tumors (LSTs) 3 cm or larger unsuitable for en bloc resection were enrolled. ESD was performed with a new device that allows cutting and coagulation as well as a needleless, tissue-selective mucosal and submucosal elevation through an axial water-jet channel. MAIN OUTCOME MEASUREMENT: The primary endpoint of the study was the en bloc resection rate achieved with ESD in a Western hospital setting. RESULTS: Overall, ESD was attempted in 40 consecutive patients (27 male, mean age 65.3 years) with rectal LSTs larger than 3 cm (72.5% LSTs, nongranular type, 5% depressed type, 22.5% protruding type). The mean lesion size was 46.8 ± 10.9 mm (range 33-80 mm). The mean procedure time was 86.1 ± 35.5 minutes (range 40-190 minutes). The en bloc resection rate was 90% (36/40). In the remaining patients, resection was completed with a piecemeal approach. The rate of curative resection (R0) was 32 of 40 LSTs (80%). Two patients with submucosal invasion were referred for surgery. Perforation occurred in 1 patient (2.5%), which was managed conservatively. Postoperative bleeding occurred in 2 patients (5%) and was treated by endoscopic hemostasis. LIMITATIONS: Single-center study with a relatively small number of patients. CONCLUSIONS: ESD is a safe and effective method to provide en bloc and curative resection of large rectal LSTs. The operating time and adverse event rate were comparable to those of previously published data from Japanese experts.

Balanced propofol sedation administered by nonanesthesiologists: The first Italian experience.

AIM: To assess the efficacy and safety of a balanced approach using midazolam in combination with propofol, administered by non-anesthesiologists, in a large series of diagnostic colonoscopies. METHODS: Consecutive patients undergoing diagnostic colonoscopy were sedated with a single dose of midazolam (0.05 mg/kg) and low-dose propofol (starter bolus of 0.5 mg/kg and repeated boluses of 10 to 20 mg). Induction time and deepest level of sedation, adverse and serious adverse events, as well as recovery times, were prospectively assessed. Cecal intubation and adenoma detection rates were also collected. RESULTS: Overall, 1593 eligible patients were included. The median dose of propofol administered was 70 mg (range: 40-120 mg), and the median dose of midazolam was 2.3 mg (range: 2-4 mg). Median induction time of sedation was 3 min (range: 1-4 min), and median recovery time was 23 min (range: 10-40 min). A moderate level of sedation was achieved in 1561 (98%) patients, whilst a deep sedation occurred in 32 (2%) cases. Transient oxygen desaturation requiring further oxygen supplementation occurred in 8 (0.46%; 95% CI: 0.2%-0.8%) patients. No serious adverse event was observed. Cecal intubation and adenoma detection rates were 93.5% and 23.4% (27.8% for male and 18.5% for female, subjects), respectively. CONCLUSION: A balanced sedation protocol provided a minimalization of the dose of propofol needed to target a moderate sedation for colonoscopy, resulting in a high safety profile for non-anesthesiologist propofol sedation.

Low to negligible photoactivity of lake-water matter in the size range from 0.1 to 5 µm.

We found that the photochemical generation of reactive transients such as singlet oxygen and triplet states upon irradiation of different lake water samples is mostly accounted for by components smaller than 0.10 µm. Larger components often showed a much lower absorption and/or scattering of radiation compared with the smaller ones, with one exception where the minor to negligible photochemical activity of larger species was associated with significant radiation absorption/scattering. It is also shown that filtration of the lake water samples at 0.10 µm was able to effectively remove the suspended particles, differently from the usually suggested filtration at 0.45 µm.

The impact of a psychoeducational intervention on family members' views about schizophrenia: results from the OASIS Italian multi-centre study.

BACKGROUND: The opinions of relatives of patients with schizophrenia about this disorder can influence its course and outcome. AIMS: In 2003, the Italian Psychiatric Association promoted a study on family psychoeducational intervention to explore its effectiveness in improving relatives' opinions and beliefs about schizophrenia. METHODS: In each of the 10 Italian mental health centres, 30 patients with schizophrenia and 30 key relatives were randomly recruited to receive the experimental intervention or the standard care. The experimental intervention consisted of 12 manual-based informative sessions on schizophrenia. Each relative filled in the self-reported questionnaire on family opinions about schizophrenia. RESULTS: The treated sample included 107 patients and 112 relatives; the control group consisted of 105 patients and 118 relatives. In both groups, stress, traumas, heredity and family difficulties were most frequently mentioned as causing the disorder. Relatives' opinions about patients' civil rights and social competence, in particular the right to get married, to have children and to vote, improved and the belief that patients with schizophrenia are unpredictable decreased at the end of the intervention. CONCLUSIONS: These results confirm that relatives of patients with schizophrenia should receive psychoeducational interventions, particularly in Italy where family involvement in schizophrenia care is particularly frequent.

Efficacy and safety of biodegradable stents for refractory benign esophageal strictures: the BEST (Biodegradable Esophageal Stent) study.

BACKGROUND: Benign esophageal strictures refractory to standard dilation therapy present a challenging problem. Temporary plastic and metal stents have been proposed with inconclusive results. OBJECTIVE: To evaluate the efficacy and safety of a new biodegradable stent for the treatment of refractory benign esophageal strictures (RBESs). DESIGN AND SETTING: Prospective study from 2 European endoscopy centers. PATIENTS AND INTERVENTION: Twenty-one patients (11 men/10 women, mean age 60.2 ± 17.6 years) with RBESs defined according to the Kochman criteria treated by placement of a biodegradable stent (Ella stent). MAIN OUTCOME MEASUREMENTS: Clinical and endoscopic follow-up was scheduled at 1, 2, 3, and 6 months and later only in case of dysphagia recurrence. Pre- and poststenting dysphagia status was graded according to a 5-point scale. Minor and major complication rates were prospectively assessed. RESULTS: Stent insertion was technically successful in all of the patients. At 4 and 7 weeks, stent migration occurred in 2 patients (9.5%). At 3-month endoscopy, the stent appeared to be almost completely fragmented in all remaining patients. The median pre- and poststenting dysphagia scores were 3 (range 3-4) and 1 (range 0-2), respectively (P < .01), with a median follow-up of 53 weeks (range 25-88 weeks). In detail, 9 of 20 patients (45%) were dysphagia free at the end of the follow-up. No major complications occurred. Severe poststenting pain requiring analgesics developed in 3 patients, and minor bleeding was observed in 1 patient. LIMITATIONS: Limited follow-up; nonrandomized study. CONCLUSIONS: In this preliminary study, the biodegradable stent showed a favorable risk/benefit ratio, achieving complete relief of dysphagia in nearly 50% of RBES patients without the occurrence of major complications. The use of this stent may be a valuable alternative to repeat endoscopic dilation. Larger studies with longer follow-up are needed.

Endoscopic submucosal dissection in patients with early esophageal squamous cell carcinoma: results from a prospective Western series.

BACKGROUND: Although endoscopic submucosal dissection (ESD) is becoming accepted as an established treatment for superficial esophageal squamous cell neoplasia, the majority of data on this endoscopic modality has been provided by Japanese series. OBJECTIVE: To assess the efficacy and safety of ESD for esophageal squamous cell neoplasia in a consecutive series of patients treated in a Western setting. DESIGN AND SETTING: Single-center, prospective observational study. PATIENTS AND INTERVENTION: From January 2005 to July 2008, 20 patients with superficial esophageal squamous cell neoplasia were treated by ESD. MAIN OUTCOME MEASUREMENTS: Rates of en bloc resection, complete resection, and complications were evaluated as short-term outcomes. Overall survival, local or distant recurrence, and postoperative stricture rates were evaluated as long-term outcomes. RESULTS: ESD was performed in 20 patients (mean age 64 years, range 46-81 years; 16 men). The mean size of the lesion was 32 mm (range 15-60 mm); it was 30 mm or larger in 14 patients (70%). The mean time of ESD was 89 minutes (range 58-180 minutes). En bloc resection with resection-free margins was achieved in 18 patients (90%), whereas 2 patients presented with incomplete or indeterminate resection. Two cases (10%) of mediastinal emphysema without overt perforation and 1 case (5%) of post-ESD symptomatic stricture were reported. No local or distant post-ESD recurrence occurred in those with resection-free margins at a median follow-up of 18 months. LIMITATIONS: Small number of patients and limited follow-up. CONCLUSION: This Western series study confirms that ESD is a potentially curative treatment for superficial esophageal squamous cell neoplasia. Early and late complication rates were comparable to those of Japanese series. ESD should be probably considered as the treatment of choice in all large lesions amenable to endoscopic treatment.

Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study.

This 18-week, randomized, flexible-dose, double-blind, double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients. Patients had a DSM-IV diagnosis of schizophrenia, a history of resistance and/or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses, PANSS score >or= 80, and CGI-S score >or= 4. Patients were randomized to ziprasidone (80-160 mg/day, n = 73) or clozapine (250-600 mg/day, n = 74). On the primary ITT-LOCF analysis, baseline-to-endpoint decreases in PANSS total scores were similar in the ziprasidone (- 25.0 +/- 22.0, 95% CI - 30.2 to - 19.8) and clozapine (- 24.5 +/- 22.5, 95% CI - 29.7 to - 19.2) groups. A progressive and significant reduction from baseline in PANSS total score was observed from day 11 in both study arms. There were also significant improvements on PANSS subscales, CGI-S, CG-I, CDSS, and GAF, without between-drug differences. The two treatment groups had similar rates of early discontinuations due to AEs. AEs were mostly of similar mild-moderate severity in the two groups. There were also no detrimental effects on prolactin, renal and liver function, hematology, and cardiovascular parameters. However, ziprasidone but not clozapine showed a significant reduction of SAS and AIMS scores. Moreover, when compared with clozapine, ziprasidone also had a more favorable metabolic profile, with significant endpoint differences in weight, fasting glucose, total cholesterol, LDL cholesterol, and triglycerides. In conclusion, this trial indicates that both ziprasidone and clozapine, having comparable efficacy coupled with satisfactory general safety and tolerability, may be regarded as valuable options for the short-term treatment of difficult-to-treat schizophrenia patients with a history of multiple resistance and/or intolerance to antipsychotics. The more favorable metabolic profile of ziprasidone may represent an added value that could guide clinicians, at least in the presence of patients at high risk for metabolic disorders.

Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study.

This 18-week, randomized, flexible-dose, double-blind, double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients. Patients had a DSM-IV diagnosis of schizophrenia, a history of resistance and/or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses, PANSS score >or=80, and CGI-S score >or=4. Patients were randomized to ziprasidone (80-160 mg/day, n=73) or clozapine (250-600 mg/day, n=74). On the primary ITT-LOCF analysis, baseline-to-endpoint decreases in PANSS total scores were similar in the ziprasidone (-25.0+/-22.0, 95% CI -30.2 to -19.8) and clozapine (-24.5+/-22.5, 95% CI -29.7 to -19.2) groups. A progressive and significant reduction from baseline in PANSS total score was observed from day 11 in both study arms. There were also significant improvements on PANSS subscales, CGI-S, CG-I, CDSS, and GAF, without between-drug differences. The two treatment groups had similar rates of early discontinuations due to AEs. AEs were mostly of similar mild-moderate severity in the two groups. There were also no detrimental effects on prolactin, renal and liver function, hematology, and cardiovascular parameters. However, ziprasidone but not clozapine showed a significant reduction of SAS and AIMS scores. Moreover, when compared with clozapine, ziprasidone also had a more favorable metabolic profile, with significant endpoint differences in weight, fasting glucose, total cholesterol, LDL cholesterol, and triglycerides. In conclusion, this trial indicates that both ziprasidone and clozapine, having comparable efficacy coupled with satisfactory general safety and tolerability, may be regarded as valuable options for the short-term treatment of difficult-to-treat schizophrenia patients with a history of multiple resistance and/or intolerance to antipsychotics. The more favorable metabolic profile of ziprasidone may represent an added value that could guide clinicians, at least in the presence of patients at high risk for metabolic disorders.

The role of MAPK in governing lymphocyte adhesion to and migration across the microvasculature in inflammatory bowel disease.

Lymphocyte recruitment is a key pathogenic event in inflammatory bowel disease (IBD). Adhesion of T cells to human intestinal microvascular endothelial cells (HIMEC) is mediated by ICAM-1, VCAM-1 and fractalkine (FKN), but the signaling molecules that orchestrate this process have yet to be identified. Because MAPK play an important role in the response of many cell types to pro-inflammatory stimuli, we assessed the functional role of p38 MAPK, p42/44 MAPK and JNK in the regulation of lymphocyte adhesion to and chemotaxis across the microvasculature in IBD. We found that the MAPK were phosphorylated in the bowel microvasculature and human intestinal fibroblasts of patients with IBD but not of healthy individuals. Stimulation of HIMEC with TNF-alpha triggered phosphorylation of the MAPK, and up-regulation of VCAM-1, FKN and ICAM-1. Blockade of p38 decreased the expression of all MAPK by 50% (p<0.01), whereas inhibition of p42/44 decreased the expression of ICAM-1 and FKN by 50% (p<0.01). Treatment of human intestinal fibroblasts with TNF-alpha elicited production of IL-8 and MCP-1, which was reduced (p<0.05) by blockade of p38 and p42/44. Finally, blockade of p38 and p42/44 reduced lymphocyte adhesion to (p<0.05) and transmigration across (p<0.05) HIMEC monolayers. These findings suggest a critical role for MAPK in governing lymphocyte influx into the gut in IBD patients, and their blockade may offer a molecular target for blockade of leukocyte recruitment to the intestine.

Assessment of clinical and metabolic status, and subjective well-being, in schizophrenic patients switched from typical and atypical antipsychotics to ziprasidone.

The objective of this paper was to assess the effects of switching from typical and/or atypical antipsychotics to ziprasidone, owing to inadequate response or intolerance, in chronic schizophrenic patients. A total of 312 patients were switched to an 8-week, open-label, flexible dose (40-160 mg/day) of ziprasidone. Psychiatric status was evaluated by Positive and Negative Syndrome Scale and Clinical Global Impression Severity scale. Other measures included functioning, subjective response and attitude toward therapy, and cognition. Laboratory tests and electrocardiography with QTc interval were carried out. Extrapyramidal symptoms and sexual dysfunction symptoms were also assessed. Of the 312 enrolled patients, 73.1% completed the study. Olanzapine, risperidone, and haloperidol were the most common psychotropic drugs taken before entry. Poor efficacy was the main reason for change in therapy. Significant improvements from baseline to endpoint were reported for mean Positive and Negative Syndrome Scale scores (P<0.0001), Clinical Global Impression Severity (P<0.0001), Global Assessment of Functioning (P<0.0001), Subjective Well-being scores (P<0.0001), and Trail Making Test (P<0.05). Significant improvements were also found for mean Simpson-Angus scale score (P<0.0001), sexual dysfunction, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. In addition, mean body weight significantly decreased from baseline (P<0.0001). A favorable profile for ziprasidone was found with regard to improved subjective tolerability, quality of life, and medication adherence behavior.

A randomized double-blind comparison of ziprasidone vs. clozapine for cognition in patients with schizophrenia selected for resistance or intolerance to previous treatment.

BACKGROUND: Recent data have suggested few differences in the cognitive effects of antipsychotic medications. However, assessment of such effects can be complex, due to a number of factors. Clozapine has previously shown greater clinical and lesser cognitive benefits than other atypicals. This study compared the cognitive benefits of clozapine and ziprasidone in schizophrenia patients (n=130) with a history of either failure to respond to or intolerance of previous adequate antipsychotic treatments. METHODS: Patients were randomized (double-blind) to either clozapine or ziprasidone in a single country (Italy), multi-site trial. The cognitive assessments examined episodic memory (RAVLT), executive functioning (Stroop test), and processing speed (Trail-making test (TMT) Parts A and B). RESULTS: Analyses found statistically significant within-group improvements for ziprasidone in learning and delayed recall on the RAVLT and on TMT Parts A and B. Clozapine-treated patients improved on the RAVLT, but not on the TMT. A composite cognitive score improved from baseline in both groups, but the improvements were significantly larger in the ziprasidone group (p=.029). IMPLICATIONS: These results indicated that cognitive functioning improved following treatment with ziprasidone in patients with a history of either treatment resistance or intolerance, and that the effects are comparable or greater than those observed with clozapine. One interpretation of these findings is that clozapine treatment interferes with the performance benefits associated with practice.