Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group.

OBJECTIVE: The purpose of this study was to compare the short-term efficacy and safety of risperidone and clozapine in treatment-resistant chronic schizophrenic patients. METHOD: In a controlled double-blind, multicenter study, 86 inpatients with chronic schizophrenia (DSM-III-R), who were resistant to or intolerant of conventional neuroleptics, were randomly assigned to receive risperidone or clozapine for 8 weeks after a 7-day washout period. After a 1-week dose-titration phase, doses were fixed at 6 mg/day of risperidone and 300 mg/day of clozapine for 1 week and then adjusted according to each patient's response. The final mean doses were 6.4 mg/day of risperidone and 291.2 mg/day of clozapine. Treatment efficacy and safety were evaluated with several well-known rating scales. RESULTS: Both risperidone and clozapine significantly reduced the severity of psychotic symptoms (scores on the Positive and Negative Syndrome Scale and the Clinical Global Impression scale) from baseline, with no significant between-group differences. At endpoint, 67% of the risperidone group and 65% of the clozapine group were clinically improved (reduction of 20% or more in total Positive and Negative Syndrome Scale score). Risperidone appeared to have a faster onset of action. In both groups extrapyramidal symptoms and other adverse events were few, and their severity was generally mild. Neither group showed evidence of a relation between drug plasma concentrations and clinical effectiveness. CONCLUSIONS: Risperidone was well tolerated and as effective as medium doses of clozapine in patients with chronic schizophrenia who had been resistant to or intolerant of conventional neuroleptics.

The PPARgamma agonist pioglitazone modifies the vascular sodium-angiotensin II relationship in insulin-resistant rats.

Glitazones are efficient insulin sensitizers that blunt the effects of angiotensin II (ANG II) in the rat. Sodium chloride is another important modulator of the systemic and renal effects of ANG II. Whether glitazones interfere with the interaction between sodium and the response to ANG II is not known. Therefore, we investigated the effects of pioglitazone on the relationship between sodium and the systemic and renal effects of ANG II in rats. Pioglitazone, or vehicle, was administered for 4 wk to 8-wk-old obese Zucker rats. Animals were fed a normal-sodium (NS) or a high-sodium (HS) diet. Intravenous glucose tolerance tests, systemic and renal hemodynamic responses to ANG II, and the renal ANG II binding and expression of ANG II type 1 (AT(1)) receptors were measured. The results of our study were that food intake and body weight increased, whereas blood pressure, heart rate, filtration fraction, and insulin levels decreased significantly with pioglitazone in obese rats on both diets. Pioglitazone blunted the systemic response to ANG II and abolished the increased responsiveness to ANG II induced by a HS diet. Pioglitazone modified the renal hemodynamic response to changes in salt intake while maintaining a lower filtration fraction with ANG II perfusion. These effects were associated with a decrease in the number and expression of the AT(1) receptor in the kidney. In conclusion, these data demonstrate that the peroxisome proliferator-activated receptor-gamma agonist pioglitazone modifies the physiological relationship between sodium chloride and the response to ANG II in insulin-resistant rats.

Leishmania major induces distinct neutrophil phenotypes in mice that are resistant or susceptible to infection.

Polymorphonuclear neutrophils (PMN) are key components of the inflammatory response contributing to the development of pathogen-specific immune responses. Following infection with Leishmania major, neutrophils are recruited within hours to the site of parasite inoculation. C57BL/6 mice are resistant to infection, and BALB/c mice are susceptible to infection, developing unhealing, inflammatory lesions. In this report, we investigated the expression of cell surface integrins, TLRs, and the secretion of immunomodulatory cytokines by PMN of both strains of mice, in response to infection with L. major. The parasite was shown to induce CD49d expression in BALB/c-inflammatory PMN, and expression of CD49d remained at basal levels in C57BL/6 PMN. Equally high levels of CD11b were expressed on PMN from both strains. In response to L. major infection, the levels of TLR2, TLR7, and TLR9 mRNA were significantly higher in C57BL/6 than in BALB/c PMN. C57BL/6 PMN secreted biologically active IL-12p70 and IL-10. In contrast, L. major-infected BALB/c PMN transcribed and secreted high levels of IL-12p40 but did not secrete biologically active IL-12p70. Furthermore, IL-12p40 was shown not to associate with IL-23 p19 but formed IL-12p40 homodimers with inhibitory activity. No IL-10 was secreted by BALB/c PMN. Thus, following infection with L. major, in C57BL/6 mice, PMN could constitute one of the earliest sources of IL-12, and in BALB/c mice, secretion of IL-12p40 could contribute to impaired, early IL-12 signaling. These distinct PMN phenotypes may thus influence the development of L. major-specific immune response.

Cetuximab In Combination With Docetaxel In Patients (Pts) With Metastatic Castration Resistant (Mcrpc) And Docetaxel-Refractory Prostate Cancer: Final Analysis Of The Multicenter Phase Ii Trial Sakk 08/07

There is no registered treatment (ttr) for pts with mCRPC who have progressive disease during or shortly after docetaxel (doc). EGFR overexpression increases in prostate cancer during the course of the disease. We investigated efficacy and safety of the combination of the monoclonal EGFR antibody cetuximab (cet) and doc in pts with mCRPC who are doc-refractory. Methods: Pts with mCRPC progressing during or < 90 days after at least 12 weeks of doc were included. Ttr consisted of the same doc regimen as prior to progression (35mg/m2 d1,8,15 q4w or 75mg/m2 q3w) in combination with cet (400mg/m2 d1, then 250mg/m2 weekly). Primary endpoint was progression free survival (PFS) at 12 weeks defined as absence of PSA progression or progression of metastases (mets). Secondary endpoints included toxicity, PFS at 24 weeks, PSA response, response of measureable disease and overall survival. 35 pts were needed in a Simon's two stage optimal design with a power of 90% and a significance level of 5% in order to test PFS rate at 12 weeks of £10% vs ?30%. Results: 35 evaluable pts were enrolled at 15 Swiss centers between 7/08 and 9/09. Median follow up was 14.8 months. Confirmed PFS at 12 weeks was 34% (95%CI 19-52%), PFS at 24 weeks was 20% and overall survival was 12.0 months (95%CI 7.1 -15.6). 20% (7/35) had a confirmed decline in PSA ? 50% and 31% (11/35) had a confirmed PSA decline ? 30%. Of pts with measurable disease (n=24) PR, SD and PD at week 12 was 4%, 54% and 25%, respectively (17% not evaluable). 3/9 (33%) pts with PDduring last doc ttr before inclusion reached the primary endpoint compared to 7/18 (39%) with PR or SD to last doc. 54% of evaluable pts experienced grade 3 and 6% grade 4 toxicity. Discussion: The result of the primary endpoint was promising in this first trial to test cet in combination with doc in pts with docetaxel-refractory mCRPC. Because this goal was achieved in such a highly pretreated pts population it appears that inhibition of the EGFR pathway may play a more important and persistent role in the treatment of prostate cancer than perceived so far. Further research is therefore warranted. Disclosure: R. Cathomas: - Membership on advisory board for sanofi aventis (suisse) and Merck. S. Gillessen: - Membership in advisory board for Sanofi Aventis. All other authors have declared no conflicts of interest.

4550. The beautiful Church of S. Sebastian, built of steel, Manila / [photogr. Underwood & Underwood]

Donateur : Vassal, Gabrielle Maud (1880-1959)

HIV-1 superinfection with a triple-class drug-resistant strain in a patient successfully controlled with antiretroviral treatment.

We report a case of HIV-1 superinfection (HSI) with a clade B, triple-class resistant virus in a patient successfully controlling viremia with continuous combination antiretroviral therapy started 8 years earlier during primary HIV infection. The course of HIV infection prior to HSI was monitored in both the source partner and recipient (8 and 11 years, respectively) and 4 years following HSI. This case report demonstrates re-infection with HIV-1 despite effective combination antiretroviral therapy.

Networks of people in specialty production: family firms in the iron and steel Wire industries in Spain (1870-2000)

Capital intensive industries in specialized niches of production have constituted solid ground for family firms in Spain , as evidenced by the experience of the iron and steel wire industries between 1870 and 2000. The embeddedness of these firms in their local and regional environments have allowed the creation of networks that, together with favourable institutional conditions, significantly explain the dominance of family entrepreneurship in iron and steel wire manufacturing in Spain, until the end of the 20 th century. Dominance of family firms at the regional level has not been not an obstacle for innovation in wire manufacturing in Spain, which has taken place even when institutional conditions blocked innovation and traditional networking. Therefore, economic theories about the difficulties dynastic family firms may have to perform appropriately in science-based industries must be questioned

In vivo survival of teicoplanin-resistant Staphylococcus aureus and fitness cost of teicoplanin resistance.

Glycopeptide resistance, in a set of in vitro step-selected teicoplanin-resistant mutants derived from susceptible Staphylococcus aureus SA113, was associated with slower growth, thickening of the bacterial cell wall, increased N-acetylglucosamine incorporation, and decreased hemolysis. Differential transcriptome analysis showed that as resistance increased, some virulence-associated genes became downregulated. In a mouse tissue cage infection model, an inoculum of 10(4) CFU of strain SA113 rapidly produced a high-bacterial-load infection, which triggered MIP-2 release, leukocyte infiltration, and reduced leukocyte viability. In contrast, with the same inoculum of the isogenic glycopeptide-resistant derivative NM67, CFU initially decreased, resulting in the elimination of the mutant in three out of seven cages. In the four cages in which NM67 survived, it partially regained wild-type characteristics, including thinning of the cell wall, reduced N-acetylglucosamine uptake, and increased hemolysis; however, the survivors also became teicoplanin hypersusceptible. The elimination of the teicoplanin-resistant mutants and selection of teicoplanin-hypersusceptible survivors in the tissue cages indicated that glycopeptide resistance imposes a fitness burden on S. aureus and is selected against in vivo, with restoration of fitness incurring the price of resistance loss.

Use of steel slag to neutralize acid mine drainage (AMD) in sulfidic material from a uranium mine

Acid Mine Drainage (AMD) is one of the main environmental impacts caused by mining. Thus, innovative mitigation strategies should be exploited, to neutralize acidity and prevent mobilization of trace elements in AMD. The use of industrial byproducts has been considered an economically and environmentally effective alternative to remediate acid mine drainage. Therefore, the objective of this study was to evaluate the use of steel slag to mitigate acid mine drainage in a sulfidic material from a uranium mine, as an alternative to the use of limestone. Thus, increasing doses of two neutralizing agents were applied to a sulfidic material from the uranium mine Osamu Utsumi in Caldas, Minas Gerais State. A steel slag from the company ArcelorMittal Tubarão and a commercial limestone were used as neutralizing agents. The experiment was conducted in leaching columns, arranged in a completely randomized, [(2 x 3) + 1] factorial design, consisting of two neutralizing agents, three doses and one control, in three replications, totaling 21 experimental units. Electrical conductivity (EC), pH and the concentrations of Al, As, Ca, Cd, Cu, Fe, Mn, Ni, S, Se, and Zn were evaluated in the leached solutions. The trace element concentration was evaluated by ICP-OES. Furthermore, the CO2 emission was measured at the top of the leaching columns by capturing in NaOH solution and titration with HCl, in the presence of BaCl2. An increase in the pH of the leachate was observed for both neutralizing agents, with slightly higher values for steel slag. The EC was lower at the higher lime dose at an early stage of the experiment, and CO2 emission was greater with the use of limestone compared to steel slag. A decrease in trace element mobilization in the presence of both neutralizing agents was also observed. Therefore, the results showed that the use of steel slag is a suitable alternative to mitigate AMD, with the advantage of reducing CO2 emissions to the atmosphere compared to limestone.

Molecular epidemiology of methicillin-resistant Staphylococcus aureus in Switzerland: sampling only invasive isolates does not allow a representative description of the local diversity of clones.

We conducted a molecular study of MRSA isolated in Swiss hospitals, including the first five consecutive isolates recovered from blood cultures and the first ten isolates recovered from other sites in newly identified carriers. Among 73 MRSA isolates, 44 different double locus sequence typing (DLST) types and 32 spa types were observed. Most isolates belonged to the NewYork/Japan, the UK-EMRSA-15, the South German and the Berlin clones. In a country with a low to moderate MRSA incidence, inclusion of non-invasive isolates allowed a more accurate description of the diversity.

Sorafenib fourth-line treatment in imatinib-, sunitinib-, and nilotinib-resistant metastatic GIST : a retrospective analysis : 10564

Background: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors usually caused by mutations in the KIT or PDGFRA gene. Advanced disease generally cannot be cured by surgery nor by tyrosine kinase inhibitors (TKI), but TKIs have considerably improved outcome for patients (pts) with advanced GIST. Patients failing TKI treatment with imatinib (IM), sunitinib (SU) or nilotinib (NI) have a poor prognosis. Sorafenib is a multi kinase inhibitor that blocks not only receptor tyrosine kinases such as KIT, VEGFR and PDGFR but also serine/threonine kinases along the RAS/RAF/MEK/ERK pathway. Recently, clinical activity of sorafenib in third-line treatment in patients with GIST after IM and SU failure has been shown (Wiebe et al. ASCO 2008, #10502). Methods: We report herein preliminary data of 32 pts treated with sorafenib in nine European centers. Centers were selected based on their previous and known experience in GIST and reported all pts treated. Pts received sorafenib after failure of IM, SU and NI in fourth-line treatment. Baseline characteristics and treatment details have been retrieved via questionary. Results: Median age at sorafenib treatment start was 62 years (range 33-81 y), and the majority of pts were male (63 %). Primary tumor site was gastric or small intestine in 25% and 41% of pts, respectively. All pts had failed IM, SU, NI. 19 % of pts achieved partial remission and 44% disease stabilization. Approximately half of the pts had an improvement of symptoms and/or performance. Half of the pts were on treatment longer than 4 months (actuarial data) and 41% of pts continue to receive sorafenib. Median progression-free survival is 20 weeks and median overall survival 42 weeks (Kaplan-Meier), at a median follow-up of 22 weeks (range 3-54). Conclusions: This is the largest series assessing efficacy of sorafenib fourth-line treatment for IM, SU and NI refractory GIST reported yet. Sorafenib displays significant clinical activity in this heavily pretreated group of patients.

Céphalées pharmacorésistantes: nouvelles approches du casse-tête [Drug-resistant headache: is it the end?].

Chronic primary headache often cause significant interference with function and quality of life despite acute and preventive medicines. New treatments are emerging for pharmacologically intractable cluster headache and migraine. Occipital nerve stimulation in chronic cluster headache and botulinum toxin in chronic migraine represent the most promising therapies.

Verteilung des roten Zahnschmelzes im Gebiss der Soricidae (Mammalia, Insectivora)

The distribution of red, iron-containing enamel in the teeth of shrews (Soricidae) was investigated by optical and scanning electron microscopy in order to determine its function. Transverse and longitudinal sections of crania with mandibles in occlusion demonstrate that the red enamel in molars is restricted to corresponding wear facets (lingual side of upper molars, buccal side of lower molars). The projecting, scissor-like cutting edges produced by wear are composed of iron-containing enamel which wears away more slowly than adjacent white enamel. Therefore, this red enamel must be more resistant to abrasion and serves to prolong the usefullness of cutting edges. Finally, two alternative hypotheses are proposed to explain the secondary loss of the red, iron-bearing enamel in members of the Soricidae which lack this material.

Novel Macrocyclic Amidinoureas: Potent Non-Azole Antifungals Active against Wild-Type and Resistant Candida Species.

Novel macrocyclic amidinourea derivatives 11, 18, and 25 were synthesized and evaluated as antifungal agents against wild-type and fluconazole resistant Candida species. Macrocyclic compounds 11 and 18 were synthesized through a convergent approach using as a key step a ring-closing metathesis macrocyclization reaction, whereas compounds 25 were obtained by our previously reported synthetic pathway. All the macrocyclic amidinoureas showed antifungal activity toward different Candida species higher or comparable to fluconazole and resulted highly active against fluconazole resistant Candida strains showing in many cases minimum inhibitory concentration values lower than voriconazole.