Influenza A/H1N1 vaccination of patients with SLE: can antimalarial drugs restore diminished response under immunosuppressive therapy?

Objective. To assess the efficacy and safety of pandemic 2009 influenza A (H1N1) in SLE under different therapeutic regimens. Methods. A total of 555 SLE patients and 170 healthy controls were vaccinated with a single dose of a non-adjuvanted preparation. According to current therapy, patients were initially classified as SLE No Therapy (n = 75) and SLE with Therapy (n = 480). Subsequent evaluations included groups under monotherapy: chloroquine (CQ) (n = 105), prednisone (PRED) epsilon 20 mg (n = 76), immunosuppressor (IS) (n = 95) and those with a combination of these drugs. Anti-H1N1 titres and seroconversion (SC) rate were evaluated at entry and 21 days post-vaccination. Results. The SLE with Therapy group had lower SC compared with healthy controls (59.0 vs 80.0%; P < 0.0001), whereas the SLE No Therapy group had equivalent SC (72 vs 80.0%; P = 0.18) compared with healthy controls. Further comparison revealed that the SC of SLE No Therapy (72%) was similar to the CQ group (69.5%; P = 0.75), but it was significantly reduced in PRED epsilon 20 mg (53.9%; P = 0.028), IS (55.7%; P = 0.035) and PRED epsilon 20 mg + IS (45.4%; P = 0.038). The concomitant use of CQ in each of these later regimens was associated with SC responses comparable with SLE No Therapy group (72%): PRED epsilon 20 mg + CQ (71.4%; P = 1.00), IS + CQ (65.2%; P = 0.54) and PRED epsilon 20 mg + IS + CQ (57.4%; P = 0.09). Conclusion. Pandemic influenza A H1N1/2009 vaccine response is diminished in SLE under immunosuppressive therapy and antimalarials seems to restore this immunogenicity.

Inhibition of nuclear factor-kappa B by dehydroxymethylepoxyquinomicin induces schedule-dependent chemosensitivity to anticancer drugs and enhances chemoinduced apoptosis in osteosarcoma cells

Osteosarcoma (OS) is the most common primary malignant bone tumor, usually developing in children and adolescents, and is highly invasive and metastatic, potentially developing chemoresistance. Thus, novel effective treatment regimens are urgently needed. This study was the first to investigate the anticancer effects of dehydroxymethylepoxyquinomicin (DHMEQ), a highly specific nuclear factor-kappa B (NF-kappa B) inhibitor, on the OS cell lines HOS and MG-63. We demonstrate that NF-kappa B blockade by DHMEQ inhibits proliferation, decreases the mitotic index, and triggers apoptosis of OS cells. We examined the effects of combination treatment with DHMEQ and cisplatin, doxorubicin, or methotrexate, drugs commonly used in OS treatment. Using the median effect method of Chou and Talalay, we evaluated the combination indices for simultaneous and sequential treatment schedules. In all cases, combination with a chemotherapeutic drug produced a synergistic effect, even at low single-agent cytotoxic levels. When cells were treated with DHMEQ and cisplatin, a more synergistic effect was obtained using simultaneous treatment. For the doxorubicin and methotrexate combination, a more synergistic effect was achieved with sequential treatment using DHMEQ before chemotherapy. These synergistic effects were accompanied by enhancement of chemoinduced apoptosis. Interestingly, the highest apoptotic effect was reached with sequential exposure in both cell lines, independent of the chemotherapeutic agent used. Likewise, DHMEQ decreased cell invasion and migration, crucial steps for tumor progression. Our data suggest that combining DHMEQ with chemotherapeutic drugs might be useful for planning new therapeutic strategies for OS treatment, mainly in resistant and metastatic cases. Anti-Cancer Drugs 23:638-650 (C) 2012 Wolters Kluwer Health broken vertical bar Lippincott Williams & Wilkins.

Phosphorus utilization by corn as affected by green manure, nitrogen and phosphorus fertilizers

The objective of this work was to evaluate the utilization by corn plants of P from triple superphosphate fertilizer labeled with P-32 (P-32-TSP), and of P from soil as affected by N rates and by the green manures (GM) sunn hemp (Crotalaria juncea) and millet (Pennisetum glaucum). The experiment was carried out using pots filled with 5 kg Oxisol (Rhodic Hapludox). A completely randomized design was used, in a 4x4x2 factorial arrangement, with four replicates. The treatments were: four P rates as TSP (0, 0.175, 0.350, and 0.700 g P per pot); four N rates as urea (0, 0.75, 1.50, and 2.25 g N per pot); and sunn hemp or millet as green manure. The additions of N and P by the GM were taken into account. After grain physiologic maturation, corn dry matter, P contents, accumulated P, and P recovery in the different treatments were measured. P-32-TSP recovery by corn increased with N increasing rates, and decreased with increasing rates of P-32-TSP. The mineral fertilizer provides most of the accumulated P by corn plants. The recovery of P-32-TSP by corn was 13.12% in average. The green manure species influence the assimilation of P-32-TSP by the plants.

A NEO-KALECKIAN MODEL OF PROFIT SHARING, CAPACITY UTILIZATION AND ECONOMIC GROWTH

This paper sets forth a Neo-Kaleckian model of capacity utilization and growth with distribution featuring a profit-sharing arrangement. While a given proportion of firms compensate workers with only a base wage, the remaining proportion do so with a base wage and a share of profits. Consistent with the empirical evidence, workers hired by profit-sharing firms have a higher productivity than their counterparts in base-wage firms. While a higher profit-sharing coefficient raises capacity utilization and growth irrespective of the distribution of compensation strategies across firms, a higher frequency of profit-sharing firms does likewise only if the profit-sharing coefficient is sufficiently high.

Blood transfusion utilization and recipient survival at Hospital das Clinicas in Sao Paulo, Brazil

BACKGROUND: The characteristics of blood recipients including diagnoses associated with transfusion and posttransfusion survival are unreported in Brazil. The goals of this analysis were: 1) to describe blood utilization according to clinical diagnoses and patient characteristics and 2) to determine the factors associated with survival of blood recipients. STUDY DESIGN AND METHODS: A retrospective cross-sectional analysis was conducted on all inpatients in 2004. Data came from three sources: The first two files consist of data about patient characteristics, clinical diagnosis, and transfusion. Analyses comparing transfused and nontransfused patients were conducted. The third file was used to determine survival recipients up to 3 years after transfusion. Logistic regression was conducted among transfused patients to examine characteristics associated with survival. RESULTS: In 2004, a total of 30,779 patients were admitted, with 3835 (12.4%) transfused. These patients had 10,479 transfusions episodes, consisting of 39,561 transfused components: 16,748 (42%) red blood cells, 15,828 (40%) platelets (PLTs), and 6190 (16%) plasma. The median number of components transfused was three (range, 1-656) per patient admission. Mortality during hospitalization was different for patients whose admissions included transfusion or not (24% vs. 4%). After 1 year, 56% of transfusion recipients were alive. The multivariable model of factors associated with mortality after transfusion showed that the most significant factors in descending order were hospital ward, increasing age, increasing number of components transfused, and type of components received. CONCLUSION: Ward and transfusion are markers of underlying medical conditions and are associated with the probability of survival. PLT transfusions are common and likely reflect the types of patients treated. This comprehensive blood utilization study, the first of its kind in Brazil, can help in developing transfusion policy analyses in South America.

Treatment-resistant depression increases health costs and resource utilization

Objective: Major Depressive Disorder (MDD) is a debilitating condition with a marked social impact. The impact of MDD and Treatment-Resistant Depression (TRD+) within the Brazilian health system is largely unknown. The goal of this study was to compare resource utilization and costs of care for treatment-resistant MDD relative to non-treatment-resistant depression (TRD-). Methods: We retrospectively analyzed the records of 212 patients who had been diagnosed with MDD according to the ICD-10 criteria. Specific criteria were used to identify patients with TRD+. Resource utilization was estimated, and the consumption of medication was annualized. We obtained information on medical visits, procedures, hospitalizations, emergency department visits and medication use related or not to MDD. Results: The sample consisted of 90 TRD+ and 122 TRD-patients. TRD+ patients used significantly more resources from the psychiatric service, but not from non-psychiatric clinics, compared to TRD-patients. Furthermore, TRD+ patients were significantly more likely to require hospitalizations. Overall, TRD+ patients imposed significantly higher (81.5%) annual costs compared to TRD-patients (R$ 5,520.85; US$ 3,075.34 vs. R$ 3,042.14; US$ 1,694.60). These findings demonstrate the burden of MDD, and especially of TRD+ patients, to the tertiary public health system. Our study should raise awareness of the impact of TRD+ and should be considered by policy makers when implementing public mental health initiatives.

On the search for potential anti-Trypanosoma cruzi drugs: Synthesis and biological evaluation of 2-hydroxy-3-methylamino and 1,2,3-triazolic naphthoquinoidal compounds obtained by click chemistry reactions

Five 2-hydroxy-3-substituted-aminomethyl naphthoquinones, nine 1,2,3-triazolic para-naphthoquinones, five nor-beta-lapachone-based 1,2,3-triazoles, and several other naphthoquinonoid compounds were synthesized and evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease, continuing our screening program for new trypanocidal compounds. Among all the substances, 16-18, 23, 25-29 and 30-33 were herein described for the first time and fifteen substances were identified as more potent than the standard drug benznidazole, with IC50/24 h values in the range of 10.9-101.5 mu M. Compounds 14 and 19 with Selectivity Index of 18.9 and 6.1 are important structures for further studies. (C) 2012 Elsevier Masson SAS. All rights reserved.

Using Fluid Bed Granulation to Improve the Dissolution of Poorly Water-Soluble Drugs

In this study, fluid bed granulation was applied to improve the dissolution of nimodipine and spironolactone, two very poorly water-soluble drugs. Granules were obtained with different amounts of sodium dodecyl sulfate and croscarmellose sodium and then compressed into tablets. The dissolution behavior of the tablets was studied by comparing their dissolution profiles and dissolution efficiency with those obtained from physical mixtures of the drug and excipients subjected to similar conditions. Statistical analysis of the results demonstrated that the fluid bed granulation process improves the dissolution efficiency of both nimodipine and spironolactone tablets. The addition of either the surfactant or the disintegrant employed in the study proved to have a lower impact on this improvement in dissolution than the fluid bed granulation process.

In vitro action of antiparasitic drugs, especially artesunate, against Toxoplasma gondii

Introduction: Toxoplasmosis is usually a benign infection, except in the event of ocular, central nervous system (CNS), or congenital disease and particularly when the patient is immunocompromised. Treatment consists of drugs that frequently cause adverse effects; thus, newer, more effective drugs are needed. In this study, the possible activity of artesunate, a drug successfully being used for the treatment of malaria, on Toxoplasma gondii growth in cell culture is evaluated and compared with the action of drugs that are already being used against this parasite. Methods: LLC-MK2 cells were cultivated in RPMI medium, kept in disposable plastic bottles, and incubated at 36 degrees C with 5% CO2. Tachyzoites of the RH strain were used. The following drugs were tested: artesunate, cotrimoxazole, pentamidine, pyrimethamine, quinine, and trimethoprim. The effects of these drugs on tachyzoites and LLC-MK2 cells were analyzed using nonlinear regression analysis with Prism 3.0 software. Results: Artesunate showed a mean tachyzoite inhibitory concentration (IC50) of 0.075 mu M and an LLC MK2 toxicity of 2.003 mu M. Pyrimethamine was effective at an IC50 of 0.482 mu M and a toxicity of 11.178 mu M. Trimethoprim alone was effective against the in vitro parasite. Cotrimoxazole also was effective against the parasite but at higher concentrations than those observed for artesunate and pyrimethamine. Pentamidine and quinine had no inhibitory effect over tachyzoites. Conclusions: Artesunate is proven in vitro to be a useful alternative for the treatment of toxoplasmosis, implying a subsequent in vivo effect and suggesting the mechanism of this drug against the parasite.

Antiresorptive drugs (bisphosphonates), atypical fractures and rebound effect: new evidence of similitude

Background: Homeopathy is based on treatment by similitude ('like cures like') administering to sick individuals substances that cause similar symptoms in healthy individuals, employing the secondary and paradoxical action of the organism as therapeutic response. This vital or homeostatic reaction of the organism can be scientifically explained by the rebound effect of drugs, resulting in worsening of symptoms after suspension of treatment. Bisphosphonates (BPs) reduce 'typical' fractures in patients with osteoporosis, but recent studies report 'atypical' fractures of the femur after stopping the BPs, a rebound effect may be the causal mechanism. Method: Review of the literature concerning the relationship between atypical femoral fractures and antiresorptive drugs (bisphosphonates), identifying the pathogenesis of this adverse event. Results: Several studies have described multiple cases of 'atypical' low-impact subtrochanteric stress fractures or complete fractures of the femur. These fractures are often bilateral, preceded by pain in the affected thigh, may have a typical X-ray appearance, and may delayed healing. Rebound of osteoclastic activity after suspension of antiresorptive drugs is a plausible mechanism to explain this phenomenon. Conclusion: As for other classes of drugs, the rebound effect of antiresorptive drugs supports Hahnemann's similitude principle (primary action of the drugs followed by secondary and opposite action of the organism), and clarifies this 'unresolved' issue. Unfortunately, the rebound effect is little discussed among health professionals, depriving them of important knowledge ensure safe management of drugs. Homeopathy (2012) 101, 231-242.

A broad study of two new promising antimycobacterial drugs: Ag(I) and Au(I) complexes with 2-(2-thienyl)benzothiazole

Synthesis, characterization, DFT simulation and biological assays of two new metal complexes of 2-(2-thienyl)benzothiazole - BTT are reported. The complexes [Ag(BTT)(2)NO3] - AgBTT2 and [Au(BTT)Cl]center dot 1/2H(2)O - AuBTT were obtained by mixing the ligand with silver (I) nitrate or gold(I) chloride in methanolic solution. Characterization of the complexes were based on elemental (C, H, N and S), thermal (TG-DTA) analysis, C-13 and H-1 NMR, FT-IR and UV-Vis spectroscopic measurements, as well as the X-ray structure determination for AgBTT2. Spectroscopic data predicted by DFT calculations were in agreement with the experimental data for both complexes. The ligand BTT was synthesized by the condensation of 2-thiophenecarboxaldehyde and 2-aminothiophenol in a microwave furnace. AgBTT2 has a monomeric structure. Both complexes show a good activity against Mycobacterium tuberculosis. Free BIT shows low antitubercular activity. (C) 2012 Elsevier Ltd. All rights reserved.

Genotoxic and mutagenic effects of erythrosine B, a xanthene food dye, on HepG2 cells

Erythrosine (ErB) is a xanthene and an US Food and Drug Administration approved dye used in foods, drugs and cosmetics. Although its utilization is permitted, ErB is described as inhibitor of enzymes and protein-protein interactions and is toxic to pituitary and spermatogenesis processes. However, the genotoxicity and mutagenicity of ErB is inconclusive in the literature. This study aimed to analyze the genotoxicity of this dye using the alkaline comet assay and is the first investigation to evaluate ErB mutagenicity using the cytokinesis block micronucleus cytome (CBMN-Cyt) assay in HepG2 cells. These cells were chosen because they produce phase I and phase II enzymes that can mimic in vivo metabolism. The cells were treated with seven concentrations (0.1-70.0 mu g mL(-1)) of ErB, and the results showed genotoxicity at the two highest concentrations and mutagenicity at six concentrations. Furthermore, as micronuclei result from clastogenic and aneugenic processes, while comet assay is often considered more sensitive and detects DNA single strain breaks, we suggest that an aneugenic is responsible for the observed damage. Although ErB is approved for use in the food, cosmetic and pharmaceutical industries, it must be used carefully because it damages the DNA structure. (C) 2012 Elsevier Ltd. All rights reserved.

Evaluation of HIV-1 resistance to antiretroviral drugs among 150 patients after six months of therapeutic interruption

Most of the antiretroviral (ARV) studies in Brazil have been reported in treatment-experienced and naive patients rather than in the setting of treatment interruption (TI). In this study, we analysed reasons given for TI and resistance mutations occurring in 150 HIV-1-infected patients who underwent TI. Of the patients analysed, 110 (73.3%) experienced TI following medical advice, while the remaining patients stopped antiretroviral therapy (ART) of their own accord. The main justifications for TI were: ARV-related toxicities (38.7%), good laboratory parameters (30%) and poor adherence (20%). DNA sequencing of the partial pol gene was successful in 137 (91.3%) patients, of whom 38 (27.7%) presented mutations conferring ARV resistance. A higher viral load prior to TI correlated with drug resistance (P < 0.05). Our results demonstrate that there are diverse rationales for TI and that detection of resistant strains during TI most likely indicates a fitter virus than the wild type. High viral loads coupled with unprotected sex in this group could increase the likelihood of transmission of drug-resistant virus. Thus, treating physicians should be alerted to this problem when the use of ARVs is interrupted.

Neuronal NOS Inhibitor and Conventional Antidepressant Drugs Attenuate Stress-induced Fos Expression in Overlapping Brain Regions

Recent evidence indicates that the administration of inhibitors of neuronal nitric oxide synthase (nNOS) induces antidepressant-like effects in animal models such as the forced swimming test (FST). However, the neural circuits involved in these effects are not yet known. Therefore, this study investigated the expression of Fos protein, a marker of neuronal activity, in the brain of rats submitted to FST and treated with the preferential nNOS inhibitor, 7-nitroindazole (7-NI), or with classical antidepressant drugs (Venlafaxine and Fluoxetine). Male Wistar rats were submitted to a forced swimming pretest (PT) and, immediately after, started receiving a sequence of three ip injections (0, 5, and 23 h after PT) of Fluoxetine (10 mg/kg), Venlafaxine (10 mg/kg), 7-NI (30 mg/kg) or respective vehicles. One hour after the last drug injection the animals were submitted to the test session, when immobility time was recorded. After the FST they were sacrificed and had their brains removed and processed for Fos immunohistochemistry. Independent group of non-stressed animals received the same drug treatments, or no treatment (naive). 7-NI, Venlafaxine or Fluoxetine reduced immobility time in the FST, an antidepressant-like effect. None of the treatments induce significant changes in Fos expression per se. However, swimming stress induced significant increases in Fos expression in the following brain regions: medial prefrontal cortex, nucleus accumbens, locus coeruleus, raphe nuclei, striatum, hypothalamic nucleus, periaqueductal grey, amygdala, habenula, paraventricular nucleus of hypothalamus, and bed nucleus of stria terminalis. This effect was attenuated by 7-NI, Venlafaxine or Fluoxetine. These results show that 7-NI produces similar behavioral and neuronal activation effects to those of typical antidepressants, suggesting that these drugs share common neurobiological substrates.

Biotechnological Utilization of Biodiesel-Derived Glycerol for the Production of Ribonucleotides and Microbial Biomass

Ten yeast strains were evaluated concerning their capabilities to assimilate biodiesel-derived glycerol in batch cultivation. The influence of glycerol concentration, temperature, pH and yeast extract concentration on biomass production was studied for the yeast selected. Further, the effect of agitation on glycerol utilization by the yeast Hansenula anomala was also studied. The yeast H. anomala CCT 2648 showed the highest biomass yield (0.30 g g(-1)) and productivity (0.19 g L-1 h(-1)). Citric acid, succinic acid, acetic acid and ethanol were found as the main metabolites produced. The increase of yeast extract concentration from 1 to 3 g L-1 resulted in high biomass production. The highest biomass concentration (21 g L-1), yield (0.45 g g(-1)) and productivity (0.31 g L-1 h(-1)), as well as ribonucleotide production (13.13 mg g(-1)), were observed at 700 rpm and 0.5 vvm. These results demonstrated that glycerol from biodiesel production process showed to be a feasible substrate for producing biomass and ribonucleotides by yeast species.