Therapeutic advances in non-small cell lung cancer.

Despite decades of research, therapeutic advances in non-small cell lung cancer (NSCLC) have progressed at a painstaking slow rate with few improvements in standard surgical resection for early stage disease and chemotherapy or radiotherapy for patients with advanced disease. In the past 18 months, however, we seemed to have reached an inflexion point: therapeutic advances that are centred on improvements in the understanding of patient selection, surgery that is undertaken through smaller incisions, identification of candidate mutations accompanied by the development of targeted anticancer treatments with a focus on personalised medicine, improvements to radiotherapy technology, emergence of radiofrequency ablation (RFA), and last but by no means least, the recognition of palliative care as a therapeutic modality in its own right. The contributors to this review are a distinguished international panel of experts who highlight recent advances in each of the major disciplines.

French summaries of product characteristics: content in relation to therapeutic monitoring of psychotropic drugs.

The prescription information (summary of product characteristics, SPC) is compiled by the pharmaceutical industry as required by the national regulatory authorities. They vary in their content about the properties of drugs and about the usefulness of therapeutic drug monitoring (TDM) in the blood of patients. Based on a previous study carried out in Germany, the degree of agreement of French SPC for 59 psychotropic drugs with the existing medico-scientific evidence in the area of TDM was examined using a recently developed instrument. A summary score of SPC content (SPCC) related to TDM (SPCC(TDM)) has been calculated and compared with the level of recommendation of TDM of the AGNP-TDM expert group consensus guidelines for TDM in psychiatry [AGNP: Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (Association for neuropsychopharmacology and pharmacopsychiatry)]. Among the antidepressants, antipsychotics, tranquillizers/hypnotic agents and mood stabilizers, the highest SPCC(TDM) scores in the French SPC were reached for imipramine (16), haloperidol (6), clonazepam (8) and lithium (23), respectively. Results were similar to those obtained from the analysis of German SPC, and considerable disagreement was found between the information on TDM in SPC and existing medico-scientific evidence, albeit less in the case of mood stabilizers. Taking into account the recommendations of the AGNP-TDM expert group guidelines, there is a deficit in the French SPC concerning TDM-relevant information. An amelioration of this situation could help to improve the clinical practice of TDM of psychotropic drugs, as the SPC is a widely used tool.

Role of glutathione deficit in the disconnectivity syndrome in schizophrenia: from pathogenetic mechanisms to therapeutic interventions

In the cerebrospinal fluid of 26 drug-naive schizophrenics (DSM-III- R), we observed that the level of glutathione ([GSH]) and of its metabolite γ-Glu-Gln was decreased by 27% and 16% respectively. Using a new in-vivo method based on magnetic resonance spec- troscopy, [GSH] was measured in the medial prefrontal cortex of 18 schizophrenics and found to be 52 % lower than in controls (n = 20). This is consistent with the recently observed decreased mRNA levels in fibroblasts of patients (n=32) of the two GSH synthesizing en- zymes (glutathione synthetase (GSS), and glutamate-cysteine ligase M (GCLM) the modulatory subunit of glutamate-cysteine ligase). Moreover, the level of GCLM expression in fibroblasts correlates neg- atively with the psychopathology (positive, general and some nega- tive symptoms). Thus, the observed difference in gene expression is not only the cause of low brain [GSH], but is also related to the sever- ity of symptoms, suggesting that fibroblasts are adequate surrogate for brain tissue. A hypothesis was proposed, based on a central role of GSH in the pathophysiology of schizophrenia. GSH is an important endogenous redox regulator and neuroactive substance. GSH is pro- tecting cells from damage by reactive oxygen species generated, among others, by the metabolism of dopamine. A GSH deficit-in- duced oxidative stress would lead to lipid peroxidation and micro-le- sions in the surrounding of catecholamine terminals, affecting the synaptic contacts on dendritic spines of cortical neurones, where ex- citatory glutamatergic terminals converge with dopaminergic ones. This would lead to spines degeneration and abnormal nervous con- nections or structural disconnectivity, possibly responsible for posi- tive, perceptive and cognitive symptoms of schizophrenia. In addi- tion, a GSH deficit could also lead to a functional disconnectivity by depressing NMDA neurotransmission, in analogy to phencyclidine effects. Present experimental biochemical, cell biological and behav- ioral data are consistent with the proposed mechanism: decreasing pharmacologically [GSH] in experimental models, with or without blocking DA uptake (GBR12909), induces morphological and behav- ioral changes similar to those observed in patients. Dendritic spines: (a) In neuronal cultures, low [GSH] and DA induce decreased density of neural processes; (b) In developing rats (p5-p16), [GSH] deficit and GBR induce a decrease in normal spines in prefrontal pyramids and in GABA-parvalbumine but not of -calretinine immunoreactivity in anterior cingulate. NMDA-dependant synaptic plasticity: GSH deple- I/13 tion in hippocampal slices impairs long-term potentiation. Develop- ing rats with low [GSH] and GBR have deficit in olfactory integration and in object recognition which appears earlier in males than fe- males, in analogy to the delay of the psychosis onset between man and woman. In summary, a deficit of GSH and/or GSH-related enzymes during early development could constitute a major vulnerability fac- tor in schizophrenia.

Therapeutic targeting of tumor growth and angiogenesis with a novel anti-S100A4 monoclonal antibody

S100A4, a member of the S100 calcium-binding protein family secreted by tumor and stromal cells, supports tumorigenesis by stimulating angiogenesis. We demonstrated that S100A4 synergizes with vascular endothelial growth factor (VEGF), via the RAGE receptor, in promoting endothelial cell migration by increasing KDR expression and MMP-9 activity. In vivo overexpression of S100A4 led to a significant increase in tumor growth and vascularization in a human melanoma xenograft M21 model. Conversely, when silencing S100A4 by shRNA technology, a dramatic decrease in tumor development of the pancreatic MiaPACA-2 cell line was observed. Based on these results we developed 5C3, a neutralizing monoclonal antibody against S100A4. This antibody abolished endothelial cell migration, tumor growth and angiogenesis in immunodeficient mouse xenograft models of MiaPACA-2 and M21-S100A4 cells. It is concluded that extracellular S100A4 inhibition is an attractive approach for the treatment of human cancer.

Quorum-sensing systems in staphylococci as therapeutic targets.

The staphylococci are an ever-present threat in our world, capable of causing a wide range of infections, and are a persistent presence in the clinical environment. As the number of antimicrobial compounds effective against staphylococci decreases, because of the acquisition and spread of antibiotic resistance, there is a growing need for novel therapeutic molecules. Intra and inter-species communication (quorum sensing) is a biologically significant phenomenon that has been associated with virulence, intracellular survival, and biofilm formation. Quorum sensing molecules of staphylococci and other species (e.g. Pseudomonas aeruginosa) can inhibit virulence factor production and/or growth of staphylococci, leading to the possibility that interference with staphylococcal quorum-sensing systems could be a way of controlling the diverse infections caused by the staphylococci. In this article, we discuss the potential of quorum-sensing systems of staphylococci as therapeutic targets.

Identification of Practices, Design, Construction, and Repair Using Trenchless Technology, TR-570, 2010

Trenchless technologies are methods used for the construction and rehabilitation of underground utility pipes. These methods are growing increasingly popular due to their versatility and their potential to lower project costs. However, the use of trenchless technologies in Iowa and their effects on surrounding soil and nearby structures has not been adequately documented. Surveys of and interviews with professionals working in trenchless-related industries in Iowa were conducted, and the results were analyzed and compared to survey results from the United States as a whole. The surveys focused on method familiarity, pavement distress observed, reliability of trenchless methods, and future improvements. Results indicate that the frequency of pavement distress or other trenchless-related issues are an ongoing problem in the industry. Inadequate soil information and quality control/quality assurance (QC/QA) are partially to blame. Fieldwork involving the observation of trenchless construction projects was undertaken with the purpose of documenting current practices and applications of trenchless technology in the United States and Iowa. Field tests were performed in which push-in pressure cells were used to measure the soil stresses induced by trenchless construction methods. A program of laboratory soil testing was carried out in conjunction with the field testing. Soil testing showed that the installations were made in sandy clay or well-graded sand with silt and gravel. Pipes were installed primarily using horizontal directional drilling with pipe diameters from 3 to 12 inches. Pressure cell monitoring was conducted during the following construction phases: pilot bore, pre-reaming, and combined pipe pulling and reaming. The greatest increase in lateral earth pressure was 5.6 psi and was detected 2.1 feet from the centerline of the bore during a pilot hole operation in sandy lean clay. Measurements from 1.0 to 2.5 psi were common. Comparisons were made between field measurements and analytical and finite element calculation methods.

Repensar el asesoramiento en educación. ¿Qué prácticas para los nuevos retos? = Rethink the advice in education. What practices for the new challenges?

Esta publicación aborda, de manera monográfica, el tema del asesoramiento en educación. Han transcurrido prácticamente treinta años desde que a finales de los 70 y principios de los 80 surgieran en nuestro país los Servicios de Orientación Educativa y Vocacional (SOEV), que junto a los Institutos de Orientación Educativa y Profesional (IOEP) y los Equipos Multiprofesionales (EM) dan origen –en los 90– a los actuales Equipos de Orientación Educativa y Psicopedagógica (EOEP). Han pasado veinticinco años desde el nacimiento en España –a mediados de los 80– de los Centros de Profesores (CEP). Inspirados en los ‘Teachers Centers’ británicos, los CEP vienen a cubrir las necesidades de formación permanente del profesorado como respuesta a la inoperancia de los Institutos de Ciencias de la Educación (ICE) del momento. Han sido, pues, treinta años de lo que ha venido a llamarse asesoramiento institucional, esto es, asesoramiento organizado y estructurado, ofertado desde sistemas de apoyo a la escuela, dando cabida en u actuación a multitud de iniciativas y prácticas de apoyo entre las que se encuentran las de asesoramiento, entremezclándose y confundiéndose a veces como prácticas de orientación, a veces como formación, o simplemente como actividades de asistencia y colaboración entre profesionales para la resolución de necesidades y problemas en el seno de nuestras escuelas. Y tal ha sido su diversidad y tipología, su riqueza y amplitud, que se han invertido no pocos esfuerzos, debates y ríos de tinta para comprender y definir, clasificar y etiquetar un ingente y variopinto conjunto de prácticas que convenimos en llamar, de asesoramiento

Therapeutic applications of viscous and injectable poly(ortho esters).

Poly(ortho esters) (POE) are hydrophobic and bioerodible polymers that have been investigated for pharmaceutical use since the early 1970s. Among the four described generations of POE, the third (POE III) and fourth (POE IV) are promising viscous and injectable materials which have been investigated in numerous biomedical applications. POE III has been extensively studied for ophthalmic drug delivery, it presents an excellent biocompatibility and is currently being investigated as a vehicle for sustained drug delivery to treat diseases of the posterior segment of the eye. POE IV is distinguishable by a highly reproducible and controlled synthesis, a higher hydrophobicity, and an excellent biocompatibility. It is currently under development for a variety of applications, such as ocular delivery, periodontal disease treatment and applications in veterinary medicine. This review will also focus on new perspectives for this promising family of polymers, such as guided tissue regeneration, treatment of osteoarthritis, as well as peptide and protein delivery.

The Effectiveness of Domestic Abuse Protective Orders and Court Practices in Sentencing Violators, July 2011

Deterring abuse is important to ensuring safety among domestic violence and assault victims. Protective orders are tools aimed at restricting contact between the victim and the abuser to prevent subsequent violence. While empirical research has indicated that protective orders are effective, the extent of the effectiveness is uncertain because violation rates have varied widely from study to study. In addition, little research exists to explain how violations of protective orders are handled, which factors are considered when giving penalties, and whether certain situations lead to a given type of penalty.

AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint eff ort.

Vascular Integrins: Therapeutic and Imaging Targets of Tumor Angiogenesis

Cells, including endothelial cells, continuously sense their surrounding environment and rapidly adapt to changes in order to assure tissues and organs homeostasis. The extracellular matrix (ECM) provides a physical scaffold for cell positioning and represents an instructive interface allowing cells to communicate over short distances. Cell surface receptors of the integrin family emerged through evolution as essential mediators and integrators of ECM-dependent communication. In preclinical studies, pharmacological inhibition of vascular integrins suppressed angiogenesis and inhibited tumor progression. alpha(V)beta(3) and alpha(V)beta(5) were the first integrins targeted to suppress tumor angiogenesis. Subsequently, additional integrins, in particular alpha(1)beta(1), alpha(2)beta(1), alpha(5)beta(1), and alpha(6)beta(4), emerged as potential therapeutic targets. Integrin inhibitors are currently tested in clinical trials for their safety and antiangiogenic/antitumor activity. In this chapter, we review the role of integrins in angiogenesis and present recent advances in the use of integrin antagonists as potential therapeutics in cancer and discuss future perspectives.

HIV Testing Practices by Clinical Service before and after Revised Testing Guidelines in a Swiss University Hospital.

OBJECTIVES: To determine 1) HIV testing practices in a 1400-bed university hospital where local HIV prevalence is 0.4% and 2) the effect on testing practices of national HIV testing guidelines, revised in March 2010, recommending Physician-Initiated Counselling and Testing (PICT). METHODS: Using 2 hospital databases, we determined the number of HIV tests performed by selected clinical services, and the number of patients tested as a percentage of the number seen per service ('testing rate'). To explore the effect of the revised national guidelines, we examined testing rates for two years pre- and two years post-PICT guideline publication. RESULTS: Combining the clinical services, 253,178 patients were seen and 9,183 tests were performed (of which 80 tested positive, 0.9%) in the four-year study period. The emergency department (ED) performed the second highest number of tests, but had the lowest testing rates (0.9-1.1%). Of inpatient services, neurology and psychiatry had higher testing rates than internal medicine (19.7% and 9.6% versus 8%, respectively). There was no significant increase in testing rates, either globally or in the majority of the clinical services examined, and no increase in new HIV diagnoses post-PICT recommendations. CONCLUSIONS: Using a simple two-database tool, we observe no global improvement in HIV testing rates in our hospital following new national guidelines but do identify services where testing practices merit improvement. This study may show the limit of PICT strategies based on physician risk assessment, compared to the opt-out approach.