Health technology assessment in evolution - focal therapy in localised prostate cancer.

Focal therapy in prostate cancer aims to treat only the part of the gland harboring clinically significant disease while preserving the rest of the tissue. This approach may substantially reduce treatment-related toxicity without compromising disease control outcomes. Short- to medium-term functional and oncological results in prospective interventional studies are promising, but comparative effectiveness research against standard of care is required to incorporate focal therapy among standard options. In this review, we discuss the actual stage of assessment and results of sources of energy commonly used to deliver focal therapy. We also provide our viewpoint on how the field will evolve in the near future.

Activity of beta-glucosidase and levels of isoflavone glucosides in soybean cultivars affected by the environment

The enzyme beta-glucosidase hydrolyses the isoflavone glucosides developing aglycones, which are compounds with anticancer effects, that are also related with the astringency observed in soybean flavor. Due to the importance of this enzyme, a study was carried out to determine beta-glucosidase activity in soybean (Glycine max (L.) Merrill) cultivars with different contents of isoflavone glucosides (enzyme substrate). The enzyme activity was determined in 51 soybean cultivars sowed in Londrina (latitude 23ºS), in Paraná State, Brazil, and in the cultivar IAS 5 from soybean production regions of different Brazilian states. Among the cultivars, a range of variability of 176.1 to 96.3 units of enzyme activity (cultivars IAC-2 and Embrapa 2, respectively) was observed. A significant variability among cultivars could suggest genetic differences. In the states of Rio Grande do Sul, Paraná and Mato Grosso do Sul, the cultivar IAS 5 presented similar average of beta-glucosidase activity: 132.1, 131.9 and 132.5 units, respectively. Among locations in the states, the cultivar IAS 5 presented a variability for enzyme activity from 138.8 to 124.8 units, which were statistically different. In spite of statistics, the numerical values were not too different to assume that environmental conditions affected enzyme activity. A non-significative correlation for isoflavone glucoside concentrations and enzyme activity was observed among cultivars.

Neuroborréliose, méningo-encéphalite verno-estivale et neurosyphilis [Neuroborreliosis, tick-borne encephalitis and neurosyphilis].

Infections affecting frequently the nervous system include Lyme disease, tick-borne encephalitis and syphilis. These three most dreaded neuro-infectious diseases observed in Switzerland are discussed, based on diagnostic criteria, screening testing, and treatments modalities. Neuroborreliosis and neurosyphilis are bacterial infectious diseases treatable by antibiotics, whereas the treatment of tick-borne encephalitis, a viral disease, is only based on preventive vaccination.

Metabolic adaptation to cancer growth: from the cell to the organism.

Tumour cells proliferate much faster than normal cells; nearly all anticancer treatments are toxic to both cell types, limiting their efficacy. The altered metabolism resulting from cellular transformation and cancer progression supports cellular proliferation and survival, but leaves cancer cells dependent on a continuous supply of energy and nutrients. Hence, many metabolic enzymes have become targets for new cancer therapies. In addition to its well-described roles in cell-cycle progression and cancer, the cyclin/CDK-pRB-E2F1 pathway contributes to lipid synthesis, glucose production, insulin secretion, and glycolytic metabolism, with strong effects on overall metabolism. Notably, these cell-cycle regulators trigger the adaptive "metabolic switch" that underlies proliferation.

Toll-interacting protein modulates colitis susceptibility in mice.

BACKGROUND: The intestinal epithelium accommodates with a myriad of commensals to maintain immunological homeostasis, but the underlying mechanisms regulating epithelial responsiveness to flora-derived signals remain poorly understood. Herein, we sought to determine the role of the Toll/interleukin (IL)-1 receptor regulator Toll-interacting protein (Tollip) in intestinal homeostasis. METHODS: Colitis susceptibility was determined after oral dextran sulfate sodium (DSS) administration or by breeding Tollip on an IL-10 background. The intestinal flora was depleted with 4 antibiotics before DSS exposure to assess its contribution in colitis onset. Bone marrow chimeras were generated to identify the cellular compartment, whereby Tollip may negatively regulate intestinal inflammation in response to DSS. Tollip-dependent epithelial barrier functions were studied in vitro by using Tollip-knockdown in Caco-2 cells and in vivo by immunohistochemistry and fluorescein isothiocyanate-labeled dextran gavage. RESULTS: Genetic ablation of Tollip did not lead to spontaneous intestinal inflammatory disorders. However, Tollip deficiency aggravated spontaneous disease onset in IL-10 mice and increased susceptibility to DSS colitis. Increased colitis severity in Tollip-deficient mice was not improved by bacterial flora depletion using broad-spectrum antibiotics. In addition, DSS exposure of bone marrow chimeric mice revealed a protective role for Tollip in nonhematopoietic cells. Knockdown of Tollip in epithelial cells led to exaggerated NFκ-B activity and proinflammatory cytokine secretion. Finally, DSS-treated Tollip mice showed enhanced intestinal permeability and increased epithelial apoptosis when compared with wild-type controls, a finding that coincided with tight junction alterations on injury. CONCLUSION: Overall, our data show an essential role for Tollip on colitis susceptibility in mice.

Profilaxis antibiótica en cirugía bucal

Los antibióticos pueden administrarse de forma terapéutica -en una infección ya establecida-o de forma profiláctica. La necesidad de profilaxis antibiótica en cirugía bucal es un tema controvertido, así como su correcta administración. Debe realizarse únicamente en aquellos procedimientos que supongan un elevado riesgo de infección (extracciones traumáticas del tercer molar o qúe haya sufrido repetidos procesos de pericoronaritis) y en determinados casos de pacientes médicamente comprometidos. El antibiótico de elección es la penicilina, aunque en determinados casos puede usarse algún medicamento alternativo como el metronidazol. En pacientes sanos debe administrarse una dosis preoperatoria doble a la terapéutica y una o dos dosis postoperatorias. En pacientes médicamente comprometidos con riesgo a sufrir una endocarditis bacteriana se seguirán las recomendaciones de la British Society for Antimicrobial Chemoterapy (BSAC) o de la American Heart Association (AHA).

The integrin antagonist cilengitide activates alphaVbeta3, disrupts VE-cadherin localization at cell junctions and enhances permeability in endothelial cells.

Cilengitide is a high-affinity cyclic pentapeptdic alphaV integrin antagonist previously reported to suppress angiogenesis by inducing anoikis of endothelial cells adhering through alphaVbeta3/alphaVbeta5 integrins. Angiogenic endothelial cells express multiple integrins, in particular those of the beta1 family, and little is known on the effect of cilengitide on endothelial cells expressing alphaVbeta3 but adhering through beta1 integrins. Through morphological, biochemical, pharmacological and functional approaches we investigated the effect of cilengitide on alphaVbeta3-expressing human umbilical vein endothelial cells (HUVEC) cultured on the beta1 ligands fibronectin and collagen I. We show that cilengitide activated cell surface alphaVbeta3, stimulated phosphorylation of FAK (Y(397) and Y(576/577)), Src (S(418)) and VE-cadherin (Y(658) and Y(731)), redistributed alphaVbeta3 at the cell periphery, caused disappearance of VE-cadherin from cellular junctions, increased the permeability of HUVEC monolayers and detached HUVEC adhering on low-density beta1 integrin ligands. Pharmacological inhibition of Src kinase activity fully prevented cilengitide-induced phosphorylation of Src, FAK and VE-cadherin, and redistribution of alphaVbeta3 and VE-cadherin and partially prevented increased permeability, but did not prevent HUVEC detachment from low-density matrices. Taken together, these observations reveal a previously unreported effect of cilengitide on endothelial cells namely its ability to elicit signaling events disrupting VE-cadherin localization at cellular contacts and to increase endothelial monolayer permeability. These effects are potentially relevant to the clinical use of cilengitide as anticancer agent.

Generation of biological association networks: A novel strategy to detect new targets in cancer therapy

The aim of this work was to design a novel strategy to detect new targets for anticancer treatments. The rationale was to build Biological Association Networks from differentially expressed genes in drug-resistant cells to identify important nodes within the Networks. These nodes may represent putative targets to attack in cancer therapy, as a way to destabilize the gene network developed by the resistant cells to escape from the drug pressure. As a model we used cells resistant to methotrexate (MTX), an inhibitor of DHFR. Selected node-genes were analyzed at the transcriptional level and from a genotypic point of view. In colon cancer cells, DHFR, the AKR1 family, PKC¿, S100A4, DKK1, and CAV1 were overexpressed while E-cadherin was lost. In breast cancer cells, the UGT1A family was overexpressed, whereas EEF1A1 was overexpressed in pancreatic cells. Interference RNAs directed against these targets sensitized cells towards MTX.

Abdominal infections in the intensive care unit: characteristics, treatment and determinants of outcome.

BACKGROUND: Abdominal infections are frequent causes of sepsis and septic shock in the intensive care unit (ICU) and are associated with adverse outcomes. We analyzed the characteristics, treatments and outcome of ICU patients with abdominal infections using data extracted from a one-day point prevalence study, the Extended Prevalence of Infection in the ICU (EPIC) II. METHODS: EPIC II included 13,796 adult patients from 1,265 ICUs in 75 countries. Infection was defined using the International Sepsis Forum criteria. Microbiological analyses were performed locally. Participating ICUs provided patient follow-up until hospital discharge or for 60 days. RESULTS: Of the 7,087 infected patients, 1,392 (19.6%) had an abdominal infection on the study day (60% male, mean age 62 ± 16 years, SAPS II score 39 ± 16, SOFA score 7.6 ± 4.6). Microbiological cultures were positive in 931 (67%) patients, most commonly Gram-negative bacteria (48.0%). Antibiotics were administered to 1366 (98.1%) patients. Patients who had been in the ICU for ≤ 2 days prior to the study day had more Escherichia coli, methicillin-sensitive Staphylococcus aureus and anaerobic isolates, and fewer enterococci than patients who had been in the ICU longer. ICU and hospital mortality rates were 29.4% and 36.3%, respectively. ICU mortality was higher in patients with abdominal infections than in those with other infections (29.4% vs. 24.4%, p < 0.001). In multivariable analysis, hematological malignancy, mechanical ventilation, cirrhosis, need for renal replacement therapy and SAPS II score were independently associated with increased mortality. CONCLUSIONS: The characteristics, microbiology and antibiotic treatment of abdominal infections in critically ill patients are diverse. Mortality in patients with isolated abdominal infections was higher than in those who had other infections.

Residual effects of successive exposure of soybean Bradyrhizobium strains to aluminium on solid defined medium

The aim of these studies was to investigate whether residual toxic effects of exposing soybean root nodule bacteria to Al in a solid defined media (SDM) alter tolerance to Al, survival, sensitivity to antibiotics, N2 fixation effectiveness and genetic diversity of Bradyrhizobium strains. After being exposed four times to Al, strains showed variation in Al tolerance but there was no evidence of change in their original Al tolerance, sensitivity to the antibiotics or genetic diversity. Exposure of Bradyrhizobium strains to SDM plus Al did not alter biological N2 fixation effectiveness of five strains. Strain SEMIA 587 showed a reduction in its N2 fixation effectiveness but it seems that it was just a superficial toxic effect because one single passage through the plant eliminated this effect. Residual Al did not cause increases in Al tolerance and reductions in the survival and N2 fixation effectiveness of Bradyrhizobium strains USDA 143, SEMIA 586, SEMIA 5019, SEMIA 5039 and SEMIA 5073. It also did not alter the resistance to antibiotics of strains USDA 143, SEMIA 5039 and SEMIA 5073, and the genetic diversity of the strains SEMIA 587 and SEMIA 5019.

Targeting endoplasmic reticulum signaling pathways in cancer.

The endoplasmic reticulum (ER) orchestrates the production of membrane-bound and secreted proteins. However, its capacity to process the synthesis and folding of protein is limited. Protein overload and the accumulation of misfolded proteins in the ER trigger an adaptive response known as the ER-stress response that is mediated by specific ER-anchored signaling pathways. This response regulates cell functions aimed at restoring cellular homeostasis or at promoting apoptosis of irreparably damaged cells. Activation or deregulation of ER-signaling pathways has been associated with various diseases including cancer. Here we discuss how tumors engage ER-signaling pathways to promote tumorigenesis and how manipulation of this process by anticancer drugs may contribute to cancer treatment.

Report of the Iowa Antibiotic Resistance Task Force, January 24, 2012

On January 29, 1998, a task force was convened by the Iowa Department of Public Health (IDPH) to address the development of bacterial resistance to antibiotics in Iowa. The purpose of this task force was to evaluate and monitor the prevalence of resistance in Iowa, to monitor the status of the problem, and to develop strategies to diminish the risk to the population of Iowa. The goals of the Iowa Antibiotic Resistance Task Force (IARTF) are to facilitate appropriate use of antibiotics, discourage prescribing practices that promote the development of antibiotic resistance, and decrease the spread of antibiotic-resistant organisms with appropriate prevention and control measures. This group has been meeting since 1998 to accomplish these goals.

Targeting PI3KC2β Impairs Proliferation and Survival in Acute Leukemia, Brain Tumours and Neuroendocrine Tumours.

BACKGROUND: Eight human catalytic phosphoinositide 3-kinase (PI3K) isoforms exist which are subdivided into three classes. While class I isoforms have been well-studied in cancer, little is known about the functions of class II PI3Ks. MATERIALS AND METHODS: The expression pattern and functions of the class II PI3KC2β isoform were investigated in a panel of tumour samples and cell lines. RESULTS: Overexpression of PI3KC2β was found in subsets of tumours and cell lines from acute myeloid leukemia (AML), glioblastoma multiforme (GBM), medulloblastoma (MB), neuroblastoma (NB), and small cell lung cancer (SCLC). Specific pharmacological inhibitors of PI3KC2β or RNA interference impaired proliferation of a panel of human cancer cell lines and primary cultures. Inhibition of PI3KC2β also induced apoptosis and sensitised the cancer cells to chemotherapeutic agents. CONCLUSION: Together, these data show that PI3KC2β contributes to proliferation and survival in AML, brain tumours and neuroendocrine tumours, and may represent a novel target in these malignancies.

Apport des modèles expérimentaux: associations Synercid et beta-lactamines

SYNERCID ALONE IN A RAT MODEL OF EXPERIMENTAL ENDOCARDITIS: Trials conducted using 2 injections daily showed that animals infected with meti-R resistant Staphylococcus aureus strains sensitive to erythromycin were cured in 3 days. The same is not true for infections caused by C-MLSB-R staphylococci. The daily dose cannot be increased due to the venous toxicity of Synercid, leading to the idea of testing Synercid in combination with other antibiotics. IN VITRO STUDIES: Several antibiotics have been tested in combination with Synercid. Several beta-lactams have been shown to exhibit an additive or synergetic effect on a collection of meti-R and meti-S S. aureus strains. IN VIVO STUDIES: In animals infected with C-MLSB-R meti-R S. aureus, the combination Synercid + cefepime increases the activity of cefipime and prevents selection of beta-lactam highly resistant strains. The results obtained with the Synercid + cefpirome combination are even more eloquent. Finally, Synercid, alone or in combination with these 2 cephalosporins, does not select resistant strains.

Vancomycin exposure from active calcium sulfate bone filler

Objective: Bone cements and substitutes are commonly used in surgery to deliver antibiotics locally. The objective of this study was to assess the systemic absorption and disposition of vancomycin in patients treated with active calcium sulfate bone filler and to predict systemic concentrations under various conditions. Method: 277 blood samples were taken from 42 patients receiving vancomycin in bone cement during surgery. Blood samples were collected from 3h to 10 days after implantation. Vancomycin was measured by immunoenzymatic assay. Population pharmacokinetic (PK) analysis was performed using NONMEM to assess average estimates and variability of PK parameters. Based on the final model, simulations with various doses and renal function levels were performed. Results: The patients were 64 ± 20 years old, their body weight was 81 ± 22 kg and Cockcroft-Gault creatinine clearance (CLcr) 98 ± 55 mL/min. Vancomycin doses ranged from 200 mg to 6000 mg and implantation sites were hip (n=16), tibia (10) or others (16). Concentration profiles remained low and consistent with absorption rate-limited first-order release, while showing prominent variability. Mean clearance (CL) was 3.87 L/h (CV 35%), absorption rate constant (ka) 0.004 h-1 (66%) and volume of distribution (V) 9.5 L. Simulations with up to 8000 mg vancomycin implant showed systemic concentrations exceeding 20 mg/L for 3.5 days in 43% of the patients with CLcr 15 mL/min, whereas 7% of the patients with normal renal function had a concentration above 20 mg/L for 1.1 days. Subtherapeutic concentrations (0.4-4 mg/L) were predicted during a median of 22 days in patients with normal renal function and 4000 mg vancomycin implant, with limited influence of dose or renal function. Conclusion: Vancomycin-laden calcium sulfate implant does not raise toxicity concern. Selection of resistant bacteria, such as Enterococcus and Staphylococcus species, might however be a concern, as simulations show persistent subtherapeutic systemic concentrations during 3 to 4 weeks in these patients.