Safety and on-treatment efficacy of telaprevir: the early access programme for patients with advanced hepatitis C.

BACKGROUND AND AIM: Severe adverse events (AEs) compromise the outcome of direct antiviral agent-based treatment in patients with advanced liver fibrosis due to HCV infection. HEP3002 is an ongoing multinational programme to evaluate safety and efficacy of telaprevir (TVR) plus pegylated-interferon-α (PEG-IFNα) and ribavirin (RBV) in patients with advanced liver fibrosis caused by HCV genotype 1 (HCV-1). METHODS: 1782 patients with HCV-1 and bridging fibrosis or compensated cirrhosis were prospectively recruited from 16 countries worldwide, and treated with 12 weeks of TVR plus PEG-IFN/RBV, followed by 12 or 36 weeks of PEG-IFN and RBV (PR) alone dependent on virological response to treatment and previous response type. RESULTS: 1587 patients completed 12 weeks of triple therapy and 4 weeks of PR tail (53% cirrhosis, 22% HCV-1a). By week 12, HCV RNA was undetectable in 85% of naives, 88% of relapsers, 80% of partial responders and 72% of null responders. Overall, 931 patients (59%) developed grade 1-4 anaemia (grade 3/4 in 31%), 630 (40%) dose reduced RBV, 332 (21%) received erythropoietin and 157 (10%) were transfused. Age and female gender were the strongest predictors of anaemia. 64 patients (4%) developed a grade 3/4 rash. Discontinuation of TVR due to AEs was necessary in 193 patients (12%). Seven patients died (0.4%, six had cirrhosis). CONCLUSIONS: In compensated patients with advanced fibrosis due to HCV-1, triple therapy with TVR led to satisfactory rates of safety, tolerability and on-treatment virological response with adequate managements of AEs.

[Differential perception of gender violence by Romanian immigrants resident in the metropolitan area of Madrid]. / Percepción diferencial de la violencia de género por las inmigrantes rumanas residentes en una zona de la corona metropolitana de Madrid.

INTRODUCTION: Battered women have poorer health. Immigrant women have a higher risk of suffering abuse by their partner, with the most frequent type being psychological abuse. A large percentage of the population living in the health district of Coslada are of Romanian origin, therefore we designed a study aimed at determining whether there are differences between Spanish and Romanian women regarding the perception of different types of violence, expecting to find significant differences. MATERIAL AND METHODS: A total of 93 people (61.26% Romanian) were included in the study, and who were given a questionnaire with sociodemographic variables, family APGAR, and a questionnaire on perceptions of behaviors related to gender violence. Descriptive statistics and a hierarchical multiple regression analysis was performed on the results. RESULTS AND CONCLUSIONS: Nearly 30% of women from Romania and 10% of Spanish respondents were considering or had considered being victims of abuse. According to the data, the Romanian-born women in the sample identified easier those behaviours involving physical or sexual violence easier; while, like Spanish women had more difficulty recognizing psychological violence.

Evaluation of ceftobiprole activity against a variety of gram-negative pathogens, including Escherichia coli, Haemophilus influenzae (ß-lactamase positive and ß-lactamase negative), and Klebsiella pneumoniae, in a rabbit meningitis model.

Ceftobiprole medocaril, a new cephalosporin, is highly active against a broad spectrum of Gram-positive and Gram-negative clinical pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant pneumococci. In this study, we tested ceftobiprole against various Gram-negative pathogens in a rabbit meningitis model and determined its penetration into the cerebrospinal fluid (CSF). In this animal model, ceftobiprole produced an antibacterial activity similar to that of cefepime against an Escherichia coli strain, a Klebsiella pneumoniae strain, and a ß-lactamase-negative Haemophilus influenzae strain. Against a ß-lactamase-positive H. influenzae strain, ceftobiprole was significantly superior. The penetration of ceftobiprole through inflamed meninges reached about 16% of serum levels compared to about 2% of serum levels through uninflamed meninges.

[Nutritional aspects of attention-deficit/hyperactive disorder]. / Aspectos nutricionales en el trastorno por déficit de atención/hiperactividad.

INTRODUCTION: Attention-deficit/hyperactive disorder (ADHD) has received in the past years a lot of attention from the paediatrician's specialties. Even though the studies of its etiopathology have advanced, mainly the ones related with genetics and neuroimaging, the final cause today is still unclear. DEVELOPMENT: It has been related to many factors such as diet, like some allergies to additives, toxicity to heavy metals and other toxic substances from the environment, due to low protein diets with a high carbohydrate content, unbalanced minerals, essential fatty acids and phospholipid deficit, amino acid deficits, thyroid disorders, and vitamin B complex disorders and phytochemicals. The way our lifestyle has changed in general and the diet in particular nowadays is being considered as a hypothesis for many disorders and health problems, but what about ADHD? One of the changes that we want to emphasize is related to vegetable fat and oils that dominate human consumption and the reduction income of fatty acids from the omega-3 family, including alpha-linolenic acid, eicosapentaenoic acid and docosapentaenoic acid. The fact is even worse when the amount of omega-6 increases and the ratio between both changes. CONCLUSIONS: It is a fact that these kinds of nutrients play an important role in the nervous system development. In this paper the essential fatty acids in neuropsychiatric disorders in general, ADHD in particular, is reviewed.

[Update on attention-deficit/hyperactive disorder treatment]. / Actualización en el tratamiento del trastorno por déficit de atención/hiperactividad.

INTRODUCTION: Attention-deficit/hyperactive disorder (ADHD) is one of the most common and investigated childhood neuropsychiatric disorder witch has an important repercussion in patient's every day life. AIM. To make an update on psychopharmacological and psychological treatment for ADHD and to asses his efficacy as a single drug treatment as well as a combined treatment. DEVELOPMENT: As a chronic disorder ADHD needs a carefully designed and complete treatment plan. That takes into account psychoeducation and the most recent medical evidences as well as preferences and worries of their families and patients. Psychostimulants are the most studied drugs and the gold-standard in the ADHD treatment with responses as high as 65 to 85%. Atomoxetine is another alternative for treating this patients with Food and Drug Administration and European Medicines Agency approval seal. CONCLUSIONS: The treatment plan for these patients must be chosen, not only by their treating doctor but should include patients and patient's family preferences and should be suited to each patient. Comorbidities are an important issue in the ADHD treatment planning, mainly in non responders' patients.

Long-term outcomes in patients with schizophrenia treated with risperidone long-acting injection or oral antipsychotics in Spain: results from the electronic Schizophrenia Treatment Adherence Registry (e-STAR).

BACKGROUND: The electronic Schizophrenia Treatment Adherence Registry (e-STAR) is a prospective, observational study of patients with schizophrenia designed to evaluate long-term treatment outcomes in routine clinical practice. METHODS: Parameters were assessed at baseline and at 3 month intervals for 2 years in patients initiated on risperidone long-acting injection (RLAI) (n=1345) or a new oral antipsychotic (AP) (n=277; 35.7% and 36.5% on risperidone and olanzapine, respectively) in Spain. Hospitalization prior to therapy was assessed by a retrospective chart review. RESULTS: At 24 months, treatment retention (81.8% for RLAI versus 63.4% for oral APs, p<0.0001) and reduction in Clinical Global Impression Severity scores (-1.14 for RLAI versus -0.94 for APs, p=0.0165) were significantly higher with RLAI. Compared to the pre-switch period, RLAI patients had greater reductions in the number (reduction of 0.37 stays per patient versus 0.2, p<0.05) and days (18.74 versus 13.02, p<0.01) of hospitalizations at 24 months than oral AP patients. CONCLUSIONS: This 2 year, prospective, observational study showed that, compared to oral antipsychotics, RLAI was associated with better treatment retention, greater improvement in clinical symptoms and functioning, and greater reduction in hospital stays and days in hospital in patients with schizophrenia. Improved treatment adherence, increased efficacy and reduced hospitalization with RLAI offer the opportunity of substantial therapeutic improvement in schizophrenia.

[Abuse, tolerance and dependence of zolpidem: three case reports]. / Abuso, tolerancia y dependencia de zolpidem: a propósito de tres casos.

Zolpidem is an imidazopyridine, which acts at the benzodiacepine omega1 receptor subtype. Zolpidem was marketed as a short-acting hypnotic and it was assumed that had a lower potential for abuse than benzodiacepines. Since 1993, several cases of zolpidem dependence have been reported. We have observed three patients with abuse, dependence and withdrawal syndrome to zolpidem. Two of them had history of drugs abuse and all of them developed withdrawal symptoms when discontinuing it. In Spain, zolpidem may be sold without medical prescription like other non benzodiacepines hypnotics and it may be playing an important role in the increase of abuse cases. We think zolpidem should be considered as a benzodiacepine with the same control and regulation.

PACAP mediates the neural proliferative pathway of Mastomys enterochromaffin-like cell transformation.

BACKGROUND AND AIM: Pituitary adenylate-cyclase activating peptide (PACAP) is a more potent proliferative agent than gastrin for rat enterochromaffin-like (ECL) cell proliferation in vitro. The role of this neurotransmitter during gastrin-mediated ECL cell tumor formation and gastrin-autonomous ECL cell neoplasia is unknown. METHODS AND RESULTS: ECL cell transformation was induced in the Mastomys using 16 wk H2 receptor blockade of acid inhibition. Examination of the epithelial fundic mucosa demonstrated that PACAP-immunoreactivity significantly increased in the tumor mucosa compared to the naïve stomach, and was associated with ECL cells. Naïve and tumor ECL cells were then purified (approximately 95%) from Mastomys and the presence of all three PACAP/VPAC receptor subtypes was demonstrated by polymerase chain-reaction amplification. Thereafter, cells were maintained in short-term (48 h) primary cultures. PACAP significantly (p<0.05) increased 24 h bromo-deoxyuridine uptake (approximately 4-fold) in both cell types with estimated EC(50) values of approximately 4x10(-16) M and approximately 2x10(-16) M, respectively. Specific receptor antagonists (PAC1/VPAC1) of PACAP competitively inhibited these proliferative effects in naïve cells. Oligonucleotide antisense directed against PAC1 significantly inhibited PACAP-stimulated DNA synthesis by approximately 85% (p<0.05) in tumor cells. CONCLUSION: PACAP is a potent and effective modulator of ECL cell proliferation. The expression of this neuropeptide and its receptors, particularly PAC1, suggest the existence of a neural regulatory pathway of ECL cell proliferation and transformation.

Functional donor-site morbidity during level and uphill gait after a gastrocnemius or soleus muscle-flap procedure.

BACKGROUND: There is only limited objective information about functional donor-site morbidity after harvest of one head of the triceps surae muscles to cover a severe soft-tissue defect of the leg. The purpose of the present study was to investigate whether a functional deficit is present during level and uphill walking after such a procedure. METHODS: Five subjects who had completely recovered from the initial injury were studied with use of comprehensive gait analysis during free level, fast level, and uphill walking on a ramp at a 10 degrees inclination. RESULTS: Gait analysis revealed no relevant donor-site morbidity affecting level gait at a free walking speed (mean, 1.27 m/sec; range, 1.18 to 1.40 m/sec). When the subjects walked at a higher velocity (mean, 1.89 m/sec; range, 1.58 to 2.43 m/sec), an asymmetry of the ground-reaction forces was seen. The second vertical peak force during push-off was reduced by a mean of 7.3% (range, 0.94% to 12.24%), and the impulse in the direction of progression was reduced by a mean of 8.7% (range, 0.13% to 17.87%) on the affected side (p = 0.04). During uphill walking, a compensatory strategy to reduce the demand on the posterior calf muscles was seen in all subjects-that is, they shortened the length of the step on the contralateral side by a mean of 3.9 cm (range, 2.2 to 6.2 cm), which corresponded to a mean side-to-side difference of 5.6% (range, 2.18% to 6.18%) (p = 0.04). A calcaneal motion pattern, denoted as increased ankle dorsiflexion, was seen in three of the five subjects during uphill walking as a sign of decreased function of the posterior calf muscles. Two of them (both with a soleus flap) also had a calcaneal pattern during fast gait. CONCLUSIONS: We concluded from this study that the functional donor-site morbidity after harvest of one head of the triceps surae muscles is mild in subjects who have had a complete recovery from their initial injury. Normal level gait is possible. However, deficits are seen in more demanding tasks such as fast walking or uphill walking.

Helicobacter pylori lipopolysaccharide alters ECL cell DNA synthesis via a CD14 receptor and polyamine pathway in mastomys.

Chronic Helicobacter pylori infection is associated with alterations in gastric mucosal cell proliferation. Despite the recognition that bacterial lipopolysaccharide (LPS) is present in biologically active quantities in the gastric mucosa, the mechanisms by which it stimulates cells are largely unknown. We have previously established a gastric enterochromaffin-like (ECL) cell neoplasia model in the African rodent species Mastomys and identified that tumor ECL cell proliferation is associated with polyamine biosynthesis and ornithine decarboxylase (ODC) activity. In addition, we have shown that H. pylori LPS exhibits a specific mitogenic effect on naive ECL cells in vitro. The aim of this study was to evaluate whether H. pylori has a direct effect on tumor ECL cell proliferation in vitro and further to evaluate the possible molecular mechanisms for this effect. ECL cell neoplasia was generated in Mastomys by endogenous hypergastrinemia induced by H(2) blockade (loxtidine 1 g/kg/day) and tumor ECL cells prepared. The DNA synthesis in 24-hour cultured tumor cells was measured by bromodeoxyuridine uptake and ODC activity by (14)CO(2) formation from (14)C-ornithine. The putative LPS receptor, CD14, was evaluated by reverse-transcription polymerase chain reaction. Our results demonstrated: (1) H. pylori LPS (10(-12) to 10(-7) M) stimulated basal DNA synthesis (2.2-fold) with an estimated EC(50) of 10(-10) M; (2) this proliferative response correlated with an increase in ODC activity (1.4-fold, EC(50) approximately 10(-10) M) which could be inhibited by a specific ODC inhibitor, difluoromethyl ornithine, at 10(-9) M; (3) the CD14 receptor was identified in both naive and transformed ECL cells by reverse-transcription polymerase chain reaction, and (4) the effects of LPS were inhibited by blocking the CD14 receptor with its specific monoclonal antibody (1:100). Thus, H. pylori LPS appears to influence tumor ECL cell proliferation by activation of the intracellular polyamine pathway and ODC activity via a CD14 receptor on the ECL cell.

Intrapancreatic accessory spleen. A rare cause of a pancreatic mass.

CONCLUSION: The clinical significance of intrapancreatic accessory spleens resides in the mimicry of pancreatic cancer. Radionuclide tests (Octreotide scan and Tc99m sulfur colloid scan) should be undertaken to distinguish these lesions from neuroendocrine tumors, hypervascular metastases and pancreatic carcinoma. If the tests are equivocal, diagnostic laparotomy or laparoscopy is recommended. BACKGROUND: Despite its relatively common occurrence, intrapancreatic ectopic splenic tissue is rarely detected owing to its asymptomatic nature. METHODS: We report a case of a clinically asymptomatic patient in which abdominal computed tomography (CT) scans revealed a mass of 1.5 cm in diameter in the distal pancreas. The tumor markers CA 19-9 and carcinoembryonic antigen (CEA) were slightly elevated, and pancreatic neoplasm was suspected. RESULTS: Left pancreatic resection and splenectomy were performed. The removed specimen disclosed the presence of an accessory spleen within the pancreatic tail.

Review article: current status of gastrointestinal carcinoids.

Carcinoid tumours are enigmatic, slow growing malignancies which occur most frequently (74%) in the gastrointestinal tract. In recent years, it has become apparent that the term 'carcinoid' represents a wide spectrum of different neoplasms originating from a variety of different neuroendocrine cell types. Carcinoid lesions are usually identified histologically by their affinity for silver salts, by general neuroendocrine markers, or more specifically by immunocytochemistry using antibodies against their specific cellular products. Within the gut, the most frequent sites are the small bowel (29%), the appendix (19%) and rectum (13%). Clinical manifestations are often vague or absent. Nevertheless, in approximately 10% of patients the tumours secrete bioactive mediators which may engender various elements of characteristic carcinoid syndrome. In many instances the neoplasms are detected incidentally at the time of surgery for other gastrointestinal disorders. The tendency for metastatic spread correlates with tumour size, and is substantially higher in lesions larger than 2.0 cm. An association with noncarcinoid neoplasms is ascribed in 8-17% of lesions. Treatment consists of radical surgical excision of the tumour, although gastric (type I and II) and rectal carcinoids may be managed with local excision. Overall 5-year survival is excellent for carcinoids of the appendix (86%) and rectum (72%), whereas small intestinal (55%), gastric (49%) and colonic carcinoids (42%) exhibit a far worse prognosis.

Pituitary adenylate cyclase-activating polypeptide modulates gastric enterochromaffin-like cell proliferation in rats.

BACKGROUND & AIMS: Gastric carcinoids (types I and II) involve the transformation of naive enterochromaffin-like (ECL) cells to the neoplastic state and are associated primarily with hypergastrinemia. In this study, we evaluated the effects of two related neuropeptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP), on ECL cell proliferation and characterized the receptor subtype(s) and signal transduction pathways that mediate this effect. METHODS: Purified rat ECL cells were analyzed in culture for DNA synthesis as measured by 24-hour 5-bromo-2-deoxyuridine (BrdU) uptake. Reverse-transcription polymerase chain reaction (RT-PCR) with gene-specific oligonucleotide primers was performed to characterize the PACAP/VIP receptor subtype(s). RESULTS: PACAP/VIP neuropeptide-stimulated BrdU uptake was significantly greater (3.4-3.8-fold greater than control) than that at the maximal dose of gastrin (2.2-fold greater than control). PACAP-stimulated ECL cell proliferation (EC50, approximately 3 x 10(-)14 mol/L) was approximately 100-fold more potent than VIP (EC50, approximately 3x 10(-)12 mol/L). The stimulated BrdU uptake by both PACAP and VIP was competitively inhibited by PACAP-receptor antagonist (IC50, 10(-)9 mol/L, 3 x 10(-)9 mol/L, respectively) and VIP-receptor antagonist (IC50, 3 x 10(-)7 mol/L, 5 x 10(-)7 mol/L, respectively). RT-PCR identified the presence of the PACAP-specific but not PACAP/VIP receptor subtypes. The PACAP-stimulated BrdU uptake was inhibited (70%-80%) by inhibitors of adenosine 3',5'-cyclic monophosphate, phosphatidylinositol 3 kinase, and protein tyrosine kinase as well as mitogen-activated protein kinase. CONCLUSIONS: PACAP/VIP-related peptides are more potent modulators of ECL cell proliferation than gastrin, and their effect is mediated by a PACAP-specific receptor whose activation is transduced by multiple intracellular messenger systems.

Multidisciplinary approach to palliation of obstructive jaundice caused by a central hepatocellular carcinoma.

BACKGROUND/AIMS: Obstructive jaundice due to intraductal tumour growth is a rare symptom in association with hepatocellular carcinoma (HCC). METHODS: We report a 65-year-old white male who was admitted to our department with a 2-week history of progressive jaundice. At laparotomy, the liver showed advanced cirrhosis due to long-standing biliary obstruction. Cholangiography confirmed total obstruction of the main bifurcation of the hepatic duct by intraductal tumour growth. Combination treatment with surgical segment III drainage, transcatheter arterial embolization and radioembolization with yttrium-90 resin particles and endoscopic stenting was performed. This form of treatment has never been reported before. RESULTS: With these combined procedures, relief of jaundice and a survival time of 32 months could be achieved. CONCLUSION: The combination of palliative methods may relieve jaundice, ensure a good quality of life and possibly prolong survival in patients with mechanical tumour obstruction of the biliary tree by HCC.

Celiac axis infusion chemotherapy in advanced nonresectable pancreatic cancer.

CONCLUSION: Based on these data we suggest that regional intra-arterial chemotherapy for advanced pancreatic cancer seems not to be superior to common treatment modalities, such as combined radiochemotherapy. BACKGROUND: The prognosis for advanced pancreatic cancer is very poor. No standard treatment is available. Recently, better survival and quality of life was reported from regional cancer treatment via celiac axis infusion. In an attempt to confirm these results we conducted a phase II study of intra-arterial chemotherapy for nonresectable pancreatic cancer. METHODS: From May 1994 to February 1995, 12 consecutive patients with biopsy-proven advanced ductal carcinoma of the exocrine pancreas were given intra-arterial infusions consisting of Mitoxantrone, 5-FU + folinic acid, and Cisplatin via a transfemorally placed catheter in the celiac axis. Six patients were classified as UICC stage III and six as stage IV with the liver as the sole site of distant metastasis. Nine patients had primary and three had recurrent pancreatic carcinoma after a Whipple procedure. Nonresectability of primary tumors was assessed in all patients by laparotomy or laparoscopy. RESULTS: A total of 31 cycles of chemotherapy (mean 2.6 cycles/patient) was administered. Catheter placement was technically feasible in all cycles. A groin hematoma was the only catheter complication. The follow-up by CT scans at 2-mo intervals revealed partial remission in 1 patient (8%), temporary stable disease in 4 patients (33%), and disease progression in 7 patients (58%). The same response was obtained after analyzing the CA 19-9 course. Median survival in stage III patients was 8.5 mo (3-12 mo) and in stage IV patients 5 mo (2-11 mo). Toxicity according to WHO criteria consisted of grade III (4 events), grade II (10 events), and grade I (17 events), mainly resulting from leucopenia and diarrhea/vomiting. Nine of 11 patients experienced temporary relief of pain immediately after regional treatment.

Biliary cystadenocarcinoma of the liver: the need for complete resection.

We report on a patient with biliary cystadenocarcinoma and review 112 previously published cases of this rare cystic hepatic neoplasm. This tumour mainly occurs in women at a ratio of 62% (female) to 38% (male), and at an average age of 56.2 years (range 18-88 years). The origin of these neoplasms is intrahepatic in 97% of cases and extrahepatic in the remaining 3%. The clinical symptoms are nonspecific and are not distinctive from benign cystic liver lesions unless invasive growth of the tumour occurs or distant metastases are present. Sonography and computed tomography (CT), as well as magnetic resonance imaging (MRI) demonstrate the multilocular nature of the tumour with septal or mural nodules. Discrete soft tissue masses, thick and coarse calcifications and varying density on CT or intensity on MRI within the loculi are additional non-specific imaging findings. The best therapeutic result with a 5-year survival rate of 100% and a recurrence rate of only 13% was achieved by complete excision (n = 16). Surgical removal of the tumour by complete excision is, therefore, the treatment of choice for biliary cystadenocarcinomas.

Choledocholithiasis at the hepatic confluence mimicking a hilar cholangiocarcinoma.

Adenocarcinomas of the bifurcation of the hepatic ducts (Klatskin tumors) are a relatively rare cause of obstructive jaundice. Differential diagnosis includes other neoplastic lesions, sclerosing cholangitis, Mirizzi's syndrome and benign strictures. We present a 46 year-old white female with a 2 month history of epigastric pain and progressive jaundice. Endoscopic retrograde cholangiopancreaticography (ERCP) revealed a filiform stenosis of the right hepatic duct and an obstructed left hepatic duct, an image strongly suggestive of a Klatskin tumor. The correct diagnosis was achieved, however, by percutaneous transhepatic cholangiography (PTC), which disclosed a gallstone at the common hepatic duct bifurcation and multiple small concrements in the left hepatic duct. After endoscopic removal of the gallstones in the biliary tree and laparoscopic cholecystectomy, the patient was discharged on the third post-operative day. Protuberant tumors and round biliary stones may be confused at ERCP.

Clinical manifestations of lost gallstones after laparoscopic cholecystectomy: a case report with review of the literature.

Laparoscopic cholecystectomy has become the preferred treatment for patients with symptomatic gallstones. During this procedure, perforation of the gallbladder with spillage of stones into the peritoneal cavity is not uncommon. Finding and removing all of the spilled gallstones can be laborious and is often avoided. Left in the peritoneal cavity, however, the stones may lead to intraperitoneal abscess formation, which may require a second procedure. We report here on a patient with an intraperitoneal abscess located between the right liver lobe and the anterior abdominal wall, which contained a large gallstone (4 cm3), found 3 months after an undetected stone spillage during laparoscopic cholecystectomy. Healing was achieved after conventional laparotomy, removal of the gallstone, and surgical drainage of the abscess cavity. The review of the literature emphasizes the clinical manifestations of this rare laparoscopic complication.