Maximising the duration of disease control in metastatic renal cell carcinoma with targeted agents: an expert agreement.

With six targeted agents approved (sorafenib, sunitinib, temsirolimus, bevacizumab [+interferon], everolimus and pazopanib), many patients with metastatic renal cell carcinoma (mRCC) will receive multiple therapies. However, the optimum sequencing approach has not been defined. A group of European experts reviewed available data and shared their clinical experience to compile an expert agreement on the sequential use of targeted agents in mRCC. To date, there are few prospective studies of sequential therapy. The mammalian target of rapamycin (mTOR) inhibitor everolimus was approved for use in patients who failed treatment with inhibitors of vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFR) based on the results from a Phase III placebo-controlled study; however, until then, the only licensed agents across the spectrum of mRCC were VEGF(R) inhibitors (sorafenib, sunitinib and bevacizumab + interferon), and as such, a large body of evidence has accumulated regarding their use in sequence. Data show that sequential use of VEGF(R) inhibitors may be an effective treatment strategy to achieve prolonged clinical benefit. The optimal place of each targeted agent in the treatment sequence is still unclear, and data from large prospective studies are needed. The Phase III AXIS study of second-line sorafenib vs. axitinib (including post-VEGF(R) inhibitors) has completed, but the data are not yet published; other ongoing studies include the Phase III SWITCH study of sorafenib-sunitinib vs. sunitinib-sorafenib (NCT00732914); the Phase III 404 study of temsirolimus vs. sorafenib post-sunitinib (NCT00474786) and the Phase II RECORD 3 study of sunitinib-everolimus vs. everolimus-sunitinib (NCT00903175). Until additional data are available, consideration of patient response and tolerability to treatment may facilitate current decision-making regarding when to switch and which treatment to switch to in real-life clinical practice.

Les réformes au prisme de l'autonomie et du contrôle des agents publics de base : le cas de la politique suisse du chômage

Cet article se propose de réfléchir aux réformes de l'administration en étudiant ce qu'elles deviennent au niveau des agents publics de base ou 'street-level bureaucrats'. Si la littérature qui leur est consacrée a jusqu'ici mis en avant à la fois l'autonomie décisionnelle de ces acteurs ainsi que les stratégies de contrôle de celle-ci, nous proposons ici de revisiter la problématique de l'autonomie et du contrôle à ce niveau en rendant compte de la manière dont elle est affectée par les réformes de « nouvelle gestion publique » d'une part, et les « nouvelles technologies de l'information et de la communication » d'autre part. Pour ce faire, la partie empirique présente les résultats préliminaires d'une recherche de l'auteur portant sur un type d'agent public aux premières lignes de la mise en oeuvre de la politique suisse du chômage, à savoir les taxateurs d'une caisse cantonale d'indemnisation, laquelle fonctionne selon une logique « néo-managériale ». Les données analysées montrent que si les éléments du dispositif NGP/TIC conduisent globalement à un renforcement considérable du contrôle hiérarchique et organisationnel d'une autonomie qui reste néanmoins importante, ceci s'accompagne également de modes d'appropriation spécifiques et intéressants dans ce qu'ils ont d'inattendu, de créatif voire de subversif au niveau des agents sur le terrain.

Fastidious intracellular bacteria as causal agents of community-acquired pneumonia.

Intracellular bacteria are common causes of community-acquired pneumonia that grow poorly or not at all on standard culture media and do not respond to beta-lactam antibiotic therapy. Apart from well-established agents of pneumonia such as Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia pneumoniae, Chlamydia psittaci and Coxiella burnetii, some new emerging pathogens have recently been recognized, mainly Parachlamydia acanthamoebae and Simkania negevensis, two Chlamydia-related bacteria. Most of them are causes of benign and self-limited infections. However, they may cause severe pneumonia in some cases (i.e., Legionnaires' disease) and they may cause outbreaks representing a public health problem deserving prompt recognition and appropriate therapy. Although extrapulmonary manifestations are often present, no clinical features allow them to be distinguished from classical bacterial agents of pneumonia such as Streptococcus pneumoniae. Thus, specific molecular diagnostic tools are very helpful for early recognition of the offending bacteria, whereas serology often only allows retrospective or late diagnosis. Macrolides remain the best empirical treatment of intracellular respiratory pathogens, although some observational studies suggest that quinolones may be superior for the treatment of legionellosis.

Effects of anti-resorptive agents on trabecular bone score (TBS) in older women.

We evaluated the longitudinal effects of anti-resorptive agents (534 treated women vs. 1,150 untreated) on lumbar spine bone mineral density (BMD) and trabecular bone score (TBS). TBS was responsive to treatment in women over age 50. The treatment-related increase in TBS was less than the increase in BMD, which is consistent with bone texture preservation. INTRODUCTION: In addition to inducing an increase in BMD, anti-resorptive agents also help to preserve bone architecture. TBS, a new gray-level texture measurement, correlates with 3D parameters of bone micro-architecture independent of BMD. Our objective was to evaluate the longitudinal effects of anti-resorptive agents on lumbar spine BMD and TBS. METHODS: Women (≥50 years), from the BMD program database for the province of Manitoba, Canada, who had not received any anti-resorptive drug prior to their initial dual X-ray absorptiometry (DXA) exam were divided into two groups: untreated, those without any anti-resorptive drug over the course of follow-up, and treated, those with a non-estrogen anti-resorptive drug (86 % bisphosphonates, 10 % raloxifene, and 4 % calcitonin). Lumbar spine TBS was calculated for each lumbar spine DXA examination. Changes in TBS and BMD between baseline and follow-up (mean follow-up 3.7 years), expressed in percentage per year, were compared between the two groups. RESULTS: A total of 1,150 untreated women and 534 treated women met the inclusion criteria. Only a weak correlation was seen between BMD and TBS in either group. Significant intergroup differences in BMD change and TBS change were observed over the course of follow-up (p < 0.001). Similar mean decreases in BMD and TBS (-0.36 %/year and -0.31 %/year, respectively) were seen for untreated subjects (both p < 0.001). Conversely, treated subjects exhibited a significant mean increase in BMD (+1.86 %/year, p < 0.002) and TBS (+0.20 %/year, p < 0.001). CONCLUSION: TBS is responsive to treatment with non-estrogen anti-resorptive drug therapy in women over age 50. The treatment-related increase in TBS is less than the increase in BMD, which is consistent with bone texture preservation.

Le nébivolol: un bêta-bloquant pourvu de propriétés vasodilatatrices [Nebivolol: a beta blocker with vasodilator properties]

Nebivolol is a new cardioselective beta-blocking agent possessing vasodilatory properties involving the endothelium. This compound is a dl-racemic mixture. The d-enantiomer is responsible for the beta-blocking properties whereas the l-enantiomer induces a vasodilation via a nitric oxide (NO) mechanism. Nebivolol is an unique agent that appears promising for the management of patients with hypertension, coronary heart disease or congestive heart failure.

Psychopharmacology in supportive care of cancer: a review for the clinician. IV. Other psychotropic agents

Besides benzodiazepine, antidepressant and neuroleptic agents, all of which have established roles in supportive care, other psychotropic drugs deserve consideration in selected conditions affecting patients with advanced cancer. This article briefly reviews relevant aspects of miscellaneous psychotropics available for secondline treatment, including nonbenzodiazepine sedative, hypnotic and anxiolytic drugs, anaesthetic agents, stimulants, and analgesic adjuvants acting on the central nervous system. The proper use of such subsidiary psychotropic agents requires that both their specificities and the particular characteristics of palliative care patients are taken into account.

Exploring the space of histidine containing dipeptides in search of novel efficient RCS sequestering agents.

The study reports a set of forty proteinogenic histidine-containing dipeptides as potential carbonyl quenchers. The peptides were chosen to cover as exhaustively as possible the accessible chemical space, and their quenching activities toward 4-hydroxy-2-nonenal (HNE) and pyridoxal were evaluated by HPLC analyses. The peptides were capped at the C-terminus as methyl esters or amides to favor their resistance to proteolysis and diastereoisomeric pairs were considered to reveal the influence of configuration on quenching. On average, the examined dipeptides are less active than the parent compound carnosine (βAla + His) thus emphasizing the unfavorable effect of the shortening of the βAla residue as confirmed by the control dipeptide Gly-His. Nevertheless, some peptides show promising activities toward HNE combined with a remarkable selectivity. The results emphasize the beneficial role of aromatic and positively charged residues, while negatively charged and H-bonding side chains show a detrimental effect on quenching. As a trend, ester derivatives are slightly more active than amides while heterochiral peptides are more active than their homochiral diastereoisomer. Overall, the results reveal that quenching activity strongly depends on conformational effects and vicinal residues (as evidenced by the reported QSAR analysis), offering insightful clues for the design of improved carbonyl quenchers and to rationalize the specific reactivity of histidine residues within proteins.

Ultra high performance supercritical fluid chromatography coupled with tandem mass spectrometry for screening of doping agents. I: Investigation of mobile phase and MS conditions.

The conditions for the analysis of selected doping substances by UHPSFC-MS/MS were optimized to ensure suitable peak shapes and maximized MS responses. A representative mixture of 31 acidic and basic doping agents was analyzed, in both ESI+ and ESI- modes. The best compromise for all compounds in terms of MS sensitivity and chromatographic performance was obtained when adding 2% water and 10mM ammonium formate in the CO2/MeOH mobile phase. Beside mobile phase, the nature of the make-up solvent added for interfacing UHPSFC with MS was also evaluated. Ethanol was found to be the best candidate as it was able to compensate for the negative effect of 2% water addition in ESI- mode and provided a suitable MS response for all doping agents. Sensitivity of the optimized UHPSFC-MS/MS method was finally assessed and compared to the results obtained in conventional UHPLC-MS/MS. Sensitivity was improved by 5-100-fold in UHPSFC-MS/MS vs. UHPLC-MS/MS for 56% of compounds, while only one compound (bumetanide) offered a significantly higher MS response (4-fold) under UHPLC-MS/MS conditions. In the second paper of this series, the optimal conditions for UHPSFC-MS/MS analysis will be employed to screen >100 doping agents in urine matrix and results will be compared to those obtained by conventional UHPLC-MS/MS.

Alteration of neuromuscular function in squash

The alteration in neuromuscular function of knee extensor muscles was characterised after a squash match in 10 trained players. Maximal voluntary contraction (MVC) and surface EMG activity of vastus lateralis (VL) and vastus medialis (VM) muscles were measured before and immediately after a 1-h squash match. M-wave and twitch contractile properties were analysed following single stimuli. MVC declined (280.5+/-46.8 vs. 233.6+/-35.4 Nm, -16%; P<0.001) after the exercise and this was accompanied by an impairment of central activation, as attested by decline in voluntary activation (76.7+/-10.4 vs. 71.3+/-9.6%, -7%; P<0.05) and raw EMG activity of the two vastii (-17%; P<0.05), whereas RMS/M decrease was lesser (VL: -5%; NS and VM: -12%; P=0.10). In the fatigued state, no significant changes in M-wave amplitude (VL: -9%; VM: -5%) or duration were observed. Following exercise, the single twitch was characterised by lower peak torque (-20%; P<0.001) as well as shorter half-relaxation time (-13%; P<0.001) and reduced maximal rate of twitch tension development (-23%; P<0.001) and relaxation (-17%; P<0.05). A 1-h squash match play caused peripheral fatigue by impairing excitation-contraction coupling, whereas sarcolemmal excitability seems well preserved. Our results also emphasise the role of central activation failure as a possible mechanism contributing to the torque loss observed in knee extensors. Physical conditioners should consider these effects when defining their training programs for squash players.

A peptide inhibitor of c-Jun N-terminal kinase protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss.

Hearing loss can be caused by a variety of insults, including acoustic trauma and exposure to ototoxins, that principally effect the viability of sensory hair cells via the MAP kinase (MAPK) cell death signaling pathway that incorporates c-Jun N-terminal kinase (JNK). We evaluated the otoprotective efficacy of D-JNKI-1, a cell permeable peptide that blocks the MAPK-JNK signal pathway. The experimental studies included organ cultures of neonatal mouse cochlea exposed to an ototoxic drug and cochleae of adult guinea pigs that were exposed to either an ototoxic drug or acoustic trauma. Results obtained from the organ of Corti explants demonstrated that the MAPK-JNK signal pathway is associated with injury and that blocking of this signal pathway prevented apoptosis in areas of aminoglycoside damage. Treatment of the neomycin-exposed organ of Corti explants with D-JNKI-1 completely prevented hair cell death initiated by this ototoxin. Results from in vivo studies showed that direct application of D-JNKI-1 into the scala tympani of the guinea pig cochlea prevented nearly all hair cell death and permanent hearing loss induced by neomycin ototoxicity. Local delivery of D-JNKI-1 also prevented acoustic trauma-induced permanent hearing loss in a dose-dependent manner. These results indicate that the MAPK-JNK signal pathway is involved in both ototoxicity and acoustic trauma-induced hair cell loss and permanent hearing loss. Blocking this signal pathway with D-JNKI-1 is of potential therapeutic value for long-term protection of both the morphological integrity and physiological function of the organ of Corti during times of oxidative stress.

Averting inflammation by targeting the cytokine environment.

Cytokines are key instigators and regulators of immune responses and therefore hold great potential as targets for new therapeutic strategies. However, the selection of which cytokines to target, and in particular the identification of which cytokines regulate the rate-limiting steps of disease pathways, is crucial to the success of such strategies. Moreover, balancing the need for ablating pathological inflammatory responses and simultaneously maintaining the ability to control infectious agents is a key consideration. Recent advances in our understanding of cytokine networks, as well as technical progress in blocking cytokines in vivo, are likely to be a source for new drugs that can control chronic inflammatory diseases.