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Increasing evidence links obstructive sleep apnea (OSA) to cognitive decline. Autonomic dysfunction assessed by heart rate variability is a promising early biomarker of cognitive impairment in populations without major neurocognitive disorder (MND). We aimed to determine whether nocturnal pulse rate variability (PRV) extracted from oximetry signal and OSA severity could predict MND onset among older OSA patients.This study relied on data collected within the multicenter longitudinal Pays de la Loire Sleep Cohort, linked to health administrative data to identify new-onset MND. We included patients ≥60 years with newly diagnosed OSA, and no history of MND or atrial fibrillation. Cox proportional-hazards models were used to evaluate the association of MND with indices of PRV and OSA severity generated from sleep recordings.After a median follow-up of 6.8 [4.7-9.4] years, 70 of 3283 patients (2.1%) had been diagnosed with MND. In multivariable Cox models, MND incidence was associated with age (p 0.0001), depression (p = 0.013), and PRV assessed by the root mean square of the successive normal-to-normal (NN) beat interval differences (RMSSD; p = 0.008) and standard deviation of NN beat intervals (SDNN; p = 0.02). Patients with the highest quartile of RMSSD had a 2.3-fold [95%CI 1.11-4.92] higher risk of being diagnosed with MND. Indices of OSA and nocturnal hypoxia severity were not associated with MND.Within a large clinic-based cohort of older patients with OSA, we found an association between oximetry-based indices of PRV and the onset of MND. Nocturnal oximetry-derived PRV indices could allow the early identification of OSA patients at higher risk of MND.

The objective of this study was to validate the use of spring water gargle (SWG) as an alternative to oral and nasopharyngeal swab (ONPS) for SARS‐CoV‐2 detection with a laboratory‐developed test. Healthcare workers and adults from the general population, presenting to one of two COVID‐19 screening clinics in Montréal and Québec City, were prospectively recruited to provide a gargle sample in addition to the standard ONPS. The paired specimens were analyzed using thermal lysis followed by a laboratory‐developed nucleic acid amplification test (LD‐NAAT) to detect SARS‐CoV‐2, and comparative performance analysis was performed. An individual was considered infected if a positive result was obtained on either sample. A total of 1297 adult participants were recruited. Invalid results (n = 18) were excluded from the analysis. SARS‐CoV‐2 was detected in 144/1279 (11.3%) participants: 126 from both samples, 15 only from ONPS, and 3 only from SWG. Overall, the sensitivity was 97.9% (95% CI: 93.7–99.3) for ONPS and 89.6% (95% CI: 83.4–93.6; p = 0.005) for SWG. The mean ONPS cycle threshold (Ct) value was significantly lower for the concordant paired samples as compared to discordant ones (22.9 vs. 32.1; p, Highlights Using a laboratory‐developed NAAT preceded by thermal lysis, the overall percent agreement between spring water gargle (SWG) and oral combined with nasopharyngeal swab (ONPS), sampled at the same time among 1297 participants, is excellent (98.6%).Although the SARS‐CoV‐2 NAAT from SWG is globally less sensitive than from ONPS (89.6% vs. 97.9%), the difference is markedly less in individuals symptomatic for

Introduction Quality training is a core component of successful home hemodialysis (HHD) and training duration varies significantly between dialysis centers as well as at the patient level. This study aimed to assess the adverse outcomes associated with HHD training duration. Methods All HHD patients successfully trained in a single dialysis center between January 2005 and July 2017 were included. A multivariable multiple-events (Andersen-Gill) survival model was built to evaluate the association between training time and main adverse events, including hospitalizations, technique failure, and death on HHD. Potential confounding factors were defined a priori (age, diabetes, coronary artery disease, and year of training start). Adjusted risk of vascular interventions (arteriovenous fistula angioplasties and central venous catheter replacements) was assessed as the secondary outcome in a negative binomial regression. Findings Forty-eight patients were included in the study. Median HHD training duration was 86 (67-108) days, using a thrice weekly training schedule. Over a follow-up median time of 2.0 (0.7-3.3) years, three patients died while on HHD, 10 had a definitive transfer to HD, and 18 experienced a least 1 hospitalization (38 hospitalizations in total). Training duration was associated with a higher risk of hospitalization, technique failure, and death in unadjusted (hazard ratio [HR] 1.16 per month, 95% confidence interval [CI] 1.08-1.24) and adjusted multiple events model (HR 1.21, 95% CI 1.04-1.43). Risk of vascular access intervention was also significantly higher with increased training time (adjusted incidence rate ratio 1.31, 95% CI 1.03-1.64, per training month). Discussion In this single-center observational study, HHD training duration was associated with a higher risk of adverse events including, death, technique failure, hospitalizations, and vascular access intervention. Enhanced clinical follow-up and home support should be offered to these more vulnerable patients to mitigate this heightened risk.

International audience; Electrocaloric refrigeration is one of the most promising, environmentallyfriendly technology to replace current cooling platforms—if a notable electrocaloric effect (ECE) is realized around room temperature where the highest need is. Here, a straight-forward, one-pot chemical modification of P(VDF-ter-TrFE-ter-CTFE) is reported through the controlled introduction of small fractions of double bonds within the backbone that, very uniquely, decreases the lamellar crystalline thickness while, simultaneously, enlarging the crystalline coherence along the a-b plane. This increases the polarizability and polarization without affecting the degree of crystallinity or amending the crystal unit cell—undesirable effects observed with other approaches. Specifically, the permittivity increases by >35%, from 52 to 71 at 1 kHz, and ECE improves by >60% at moderate electric fields. At 40 °C, an adiabatic temperature change >2 K is realized at 60 MV m−1 (>5.5 K at 192 MV m−1), compared to ≈1.3 K for pristine P(VDF-ter-rFE-ter-CTFE), highlighting the promise of a simple, versatile approach that allows direct film deposition without requiring any post-treatment such as mechanical stretching or high-temperature annealing for achieving the desired performance.

This paper addresses the issue of how sustainable supply practices are actually used as a leverage for sustainable development (SD). In order to assess the level of sustainable supply management within an organization, the authors have reviewed the literature extensively and then developed a five‐step maturity model around five management dimensions. A qualitative exploratory approach based on two detailed case studies of organizations whose reputation for SD is recognized internationally has been used. This methodology allowed us to show (1) how sustainable supply practices could be used as a leverage for an organization's sustainable development approach and (2) that sustainable supply practices still have quite a distance to go with regards to the maturity model for sustainable supply, even in organizations that are often mentioned as leaders in the SD area. In these organizations, managers still emphasize environmental considerations, while neglecting practices that would make it possible to reach the three SD objectives simultaneously. Copyright © 2017 John Wiley & Sons, Ltd and ERP Environment

Purpose To investigate sunitinib in the real-life first-line treatment of metastatic renal cell carcinoma (mRCC). Methods SANTORIN is a French observational multicentre cohort. Patients initiating sunitinib in first-line mRCC therapy were included (January 2008 to April 2010) and followed for 24 months. Data were collected from medical files. The outcomes were 24-month overall survival (OS) and progression-free survival (PFS), response and safety. Results Three hundred two patients were included: median age, 64.8 years; male, 73.2%; clear cell mRCC, 83.1%; prior nephrectomy, 85.4%; >1 metastatic sites, 64.2%; brain metastases, 6.3%; ECOG-PS ≥ 2, 9.9%. Median duration of first-line therapy with sunitinib was 10.7 months. Initial sunitinib dose was 50 mg/day for 83.4% of patients; dose reduction occurred in 65.2%. Sunitinib was discontinued in 73.2% of the patients: for progression (61.1%), death (31.2%) or adverse events (6.8%). More than half (58.3%) had grade ≥3 adverse events, mainly hypertension (12.6%) and hand–foot syndrome (12.3%). The 24-month OS and PFS rates [95%CI] were 49.5% [43.7;55.0] and 16.4% [12.5;20.9], respectively. Median OS was 23.6 months [20.2;–] and median PFS 8.4 months [7.6;9.9]. Overall best response rate was 31.1%. Conclusions Results from this large observational study suggest that effectiveness of sunitinib in first-line mRCC as predicted by clinical trials is maintained in real-life clinical practice. The expected benefit in poor-prognosis patients that were not evaluated in the pivotal clinical trial remains; however, questionable and long-term safety monitoring is still warranted. Copyright © 2017 John Wiley & Sons, Ltd.

Electrocaloric device structures have been developed as multilayer ceramics (MLCs) based on fundamental research carried out on PMN-8PT bulk ceramics. Two different MLC structures were prepared with nine layers each and layer thicknesses of 86 μm and 39 μm. The influence of the device design on its properties has been characterized by microstructural, dielectric, ferroelectric, and direct electrocaloric measurement. For direct characterization two different methods, ie temperature reading (thermistor and thermocouple) and heat flow measurement (differential scanning calorimetry), were used. A comparison of results revealed a highly satisfactory agreement between the different methods. This study confirms that MLCs are promising candidates for implementation into energy-efficient electrocaloric cooling systems providing large refrigerant volume and high electrocaloric effect. Due to their micron-sized active layers, they allow for the application of high electric fields under low operation voltages. We measured a maximum electrocaloric temperature change of ΔT=2.67 K under application/withdrawal of an electric field of ΔE=16 kV mm−1, which corresponds to operation voltages below 1.5 kV.

Objective To describe a biopsy technique in standing horses with minimal morbidity that consistently provides a substantial bone biopsy with intact, undamaged architecture. Study Design Experimental, prospective study. Animals Ten Thoroughbred horses. Methods Biopsies were obtained from the tuber coxae of 10 sedated, standing horses using an oscillating saw. Bilateral biopsies, separated by 60 days, were evaluated with micro-computed tomography (microCT). The first biopsy was prepared for decalcified histology; the second for undecalcified histology. Both biopsies were evaluated qualitatively for histologic quality. Results The biopsy technique did not result in any significant complications, was well tolerated and all biopsies were of good histologic quality. Conclusion Cortical and trabecular bone biopsies can be successfully collected from the tuber coxa using a simple technique that creates minimal morbidity and allows sequential samples to be collected. The biopsies were larger than those described previously, provided adequate bone for multiple histologic sections, and had intact, undamaged architecture on examination with microCT and light microscopy.

Rationale Venous thromboembolic disease is a source of significant morbidity in hospitalized patients. The American College of Chest Physicians published the ninth edition of antithrombotic therapy and prevention guidelines (AT9) in 2012, addressing thromboprophylaxis in hospitalized patients. A notable difference from previous guidelines was utilization of risk assessment models for thrombosis and bleeding to classify patients into risk categories. Aim This study's objective was to evaluate thromboprophylaxis adherence to AT9 guidelines in a population of patients at the Centre integre universitaire de sante et de service sociaux de l'Estrie – Centre hospitalier universitaire de Sherbrooke. Method A cross-sectional study at the Centre integre universitaire de sante et de service sociaux de l'Estrie – Centre hospitalier universitaire de Sherbrooke was performed between June and December 2012. Patients' risk factors for thrombosis and bleeding, and thromboprophylaxis use were documented. The Padua and Caprini models were used to determine thrombotic risk, and the International Medical Prevention Registry on Venous Thromboembolism bleeding risk score was used for bleeding risk. Results A total of 290 patients were included for analysis. Overall, 200 patients (70%) received some form of thromboprophylaxis. However, according to AT9 guidelines, only 162 patients (55.9%) received recommended prophylaxis, 91 (31.4%) had overuse of prophylaxis and 37 (12.7%) had underuse of prophylaxis. Appropriate prophylaxis use was higher in surgical (61.8%) than in medical (46.7%) patients. Conclusions There was a high rate of inappropriate thromboembolic prophylaxis in our centre according to AT9 guidelines, mostly from overuse of prophylaxis. Utilization of risk assessment models in AT9 guidelines adds to the complexity of physician's decisions to prescribe thromboprophylaxis and needs further validation.

Thermoelectric (TE) effects result from the interference of electrical current and heat flow in various materials. This chapter presents a retrospective view on some of the milestones in the development of thermoelectricity. It reviews the thermodynamic theory of galvano- and thermomagnetic effects. As for TE materials, the galvano- and thermomagnetic effects can be found to be more pronounced in semiconductor materials. The chapter considers a basic thermodynamic system and thermodynamics of the ideal Fermi gas. Classical thermodynamics, which is useful for describing equilibrium states, provides very incomplete information on the actual physical phenomena, which are characterized by irreversibility and nonequilibrium states. Since the TE process implies the coupling of the heat flux and electric current, these two fluxes should be driven optimally. They derived two key parameters of the compatibility approach, the relative current and the TE potential.

A 27-year-old woman underwent a first vaginal delivery at our institution. She returned four days after delivery, presenting with abdominal pain and an unexplained drop in her hemoglobin value, without external bleeding. The initial computed tomography abdominal scan revealed an isolated diffuse hemoperitoneum. A laparoscopy did not find the cause of bleeding. A second computed tomography scan, performed 15 days later, revealed hemoperitoneum associated with a false aneurysm of the right uterine artery. Treatment consisted of embolization of the uterine arteries, with clinical success. False aneurysms are a rare cause of intra-abdominal non-exteriorized bleeding in late post-partum hemorrhage.

Data regarding the efficacy of Rapid HIV tests (RHTs) in detecting non-B subtype HIV-1 are limited. We evaluated the sensitivity of the INSTI® test for the detection of HIV-1 antibodies for the diagnosis of HIV-1 non-B subtypes and recombinant variants. We identified adults with HIV-1 infection due to non-B subtypes and recombinant variants. The participants were re-tested with INSTI® test. We included 258 patients. Overall, the INSTI® test sensitivity was 98.4% (95%CI: 96.9–99.9%). For the major CRF_02AG subtype, the sensitivity was 99.0% (95%CI: 97.1–100%). The HIV INSTI® test is reliable for the detection of various non-B HIV-1 antibodies. J. Med. Virol. 88:180–183, 2016. © 2015 Wiley Periodicals, Inc.

Estrogens are implicated in male gonad function, although their physiological roles remain uncertain. In the present study, we take advantage of the original model of spatio-temporal organization of trout spermatogenesis to revisit the synthesis and action sites of estrogens in fish testis. Within this system, somatic cell and germ cell development are synchronized due to a strict seasonal spermatogenetic cycle and the cystic organization of gonads. We evaluated the expression patterns and regulation of three aromatase isoforms (cyp19a, cyp19b-I, and cyp19b-II) and four estrogen receptors (esr1a, esr1b, esr2a, and esr2b) by quantitative reverse-transcriptase PCR during testicular maturation and in isolated germ cell populations. Our data demonstrated a reciprocal relationship between cyp19a and cyp19b (I and II) expression during testicular development (cyp19a decreased while cyp19b increased with maturation). Furthermore, cyp19b is significantly expressed in late germ cells. At the protein level, aromatase was immunohistochemically identified in interstitial tissue and in germ cells. Remarkable elevation of esr1a and esr2a was observed during the final stage of spermiation, while esr1b was expressed in an early stage of spermatogenetic development. Estrogen implants reduced testicular cyp19a transcript abundance while up-regulating cyp19b levels, whereas androgens up-regulated testicular esr1a, esr2a, and esr2b. Together, the distinct spatio-temporal expression profiles and regulation of aromatases and estrogen receptors suggest that estrogens have discrete physiological functions during an early step of spermatogenesis and in the final stages of germ cell maturation and/or excretion.

Objective By-the-book implementation of non-invasive prenatal test and clinical validation for trisomy 21. Study Design Publicly funded prospective study of 225 cases. Women at risk for trisomy 21 > 1/250 based on combined ultrasound and serum markers during first or second trimester were eligible following an informed consent. The technique was established from the available literature and performed on 10 mL of venous blood collected prior to chorionic villus sampling or amniocentesis. Investigators were blinded to the fetal karyotype. Results were expressed in Z-scores of the percentage of each chromosome. Results Among 976 eligible cases, 225 were processed: 8 were used for pretesting phase and 23 to build a reference set. One hundred thirty six euploid cases and 47 with trisomy 21 were then run randomly. Eleven cases yielded no result (4.8%). Z-scores were above 3 (7.58+/−2.41) for chromosome 21 in all 47 trisomies and in none of the euploid cases (0.11+/−1.0). Z-scores were within normal range for the other chromosomes in both groups. Using a cut-off of 3, sensitivity and specificity were of 100% 95% CI [94.1, 100] and 100% 95% CI [98, 100], respectively. Conclusion Non-invasive prenatal test for trisomy 21 is a robust strategy that can be translated from seminal publications. Publicly funded studies should refine its indications and cost-effectiveness in prenatal screening and diagnosis. © 2015 John Wiley & Sons, Ltd.

Demonstration of unilateral aldosterone production by adrenal venous sampling (AVS) is required to select appropriate candidates for adrenalectomy in patients with primary aldosteronism (PA). During AVS, aldosterone and cortisol levels are measured to assess successful cannulation and lateralization. In patients with aldosterone-producing adenoma (APA), concurrent autonomous cortisol secretion might confound AVS results.We retrospectively examined results in eight patients with cortisol-producing adenoma (CPA), but without PA, who underwent AVS.In all eight, cortisol was higher on the CPA side than contralateral (CL) (median 6·7-fold [range 2·4-27·2]; P = 0·012]). By cortisol criteria, CL catheter placement would have been labelled inadequate in six despite adrenal venous aldosterone levels markedly higher than peripheral (41·6-fold [7·2-510·5]; P 0·001), suggesting successful cannulation. In all eight, adrenal venous aldosterone/cortisol (A/C) ratios on the CL side were indicative of increased aldosterone production (≥2 times peripheral), but in only three patients on the CPA side (difference CL side 44·5-fold [6·0-109·0] vs CPA side 1·65-fold [1·0-23·0]; P = 0·017). A/C ratios were higher on the CL vs the CPA side in seven (20·0-fold [4·7-76·0]).These results in patients with CPA suggest that in patients with APA, concurrent autonomous unilateral cortisol hypersecretion could confound AVS accuracy by increasing cortisol levels (reducing A/C ratio) on the CPA side, while reducing levels (increasing A/C ratio and suggesting failed cannulation) on the CL side. Misclassification of PA subtype or repeat AVS could result, underscoring the importance of adequately assessing cortisol production prior to AVS and the need to consider alternatives.

Deciphering the assembly history of the Milky Way is a formidable task, which becomes possible only if one can produce high-resolution chrono-chemo-kinematical maps of the Galaxy. Data from large-scale astrometric and spectroscopic surveys will soon provide us with a well-defined view of the current chemo-kinematical structure of the Milky Way, but it will only enable a blurred view on the temporal sequence that led to the present-day Galaxy. As demonstrated by the (ongoing) exploitation of data from the pioneering photometric missions CoRoT, Kepler, and K2, asteroseismology provides the way forward: solar-like oscillating giants are excellent evolutionary clocks thanks to the availability of seismic constraints on their mass and to the tight age–initial mass relation they adhere to. In this paper we identify five key outstanding questions relating to the formation and evolution of the Milky Way that will need precise and accurate ages for large samples of stars to be addressed, and we identify the requirements in terms of number of targets and the precision on the stellar properties that are needed to tackle such questions. By quantifying the asteroseismic yields expected from PLATO for red giant stars, we demonstrate that these requirements are within the capabilities of the current instrument design, provided that observations are sufficiently long to identify the evolutionary state and allow robust and precise determination of acoustic-mode frequencies. This will allow us to harvest data of sufficient quality to reach a 10% precision in age. This is a fundamental prerequisite to then reach the more ambitious goal of a similar level of accuracy, which will be possible only if we have at hand a careful appraisal of systematic uncertainties on age deriving from our limited understanding of stellar physics, a goal that conveniently falls within the main aims of PLATO's core science. We therefore strongly endorse PLATO's current design and proposed observational strategy, and conclude that PLATO, as it is, will be a legacy mission for Galactic archaeology., International Space Science Institute (ISSI), European Commission's Seventh Framework Programme, DFG, CH1188/2-1. COST (European Cooperation in Science and Technology), ChETEC COST Action, CA16117. The Danish National Research Foundation, DNRF106. UK Science and Technology Facilities Council (STFC), PRIN INAF 2014 – CRA 1.05.01.94.05, European Union FP7 program, ERC, 320360. Australian Research Council, DP150100250; FT160100402. NASA, NNX16AI09G. FCT; UID/FIS/04434/2013; FEDER (COMPETE); IF/00894/2012/; POPH/FSE (EC), CNES, DLR; NYUAD Institute, G1502. “Programme National de Physique Stellaire” (PNPS), “Programme National Cosmologie et Galaxies” (CNRS/INSU, France), CNES Fellowship, Swedish National Space Board (SNSB/Rymdstyrelsen), NASA, NNX16AJ17G. ERC Consolidator (STARKEY), 615604). Belspo (PRODEX PLATO), Australian Research Council Future Fellowship, FT1400147. ESP2015-66134-R (MINECO), VILLUM FONDEN, 10118.

Objective To review long-term oncological and functional outcomes of testicular-sparing surgery (TSS) in men presenting with bilateral or monorchide testicular tumours at one of five reference centres for testicular neoplasm and infertility. Patients and Methods We review 25 cases of bilateral synchrone and metachrone testicular tumours treated in five academic centres between 1984 and 2013. Clinical, biological, ultrasonography and pathological tumour findings, overall survival (OS) times, local or metastatic recurrence, pre- and postoperative hormonal profile, paternity and the need for androgen substitution were assessed. Results Eleven patients with a bilateral synchrone tumour and 14 patients with a testicular tumour on a solitary testicle underwent a tumorectomy. The mean (sem) patient age was 31.9 (1.04) years, total testosterone level was 4.5 (0.57) ng.mL and tumour size was 11.66 (1.49) mm. Tumour types were as follows: 11 seminoma, nine non-seminomatous or mixed germ cell tumours, four Leydig tumours, and one hamartoma. Frozen-section examination was performed in 14 patients, and matched the final pathological analysis in 11 patients. There was an OS rate of 100% and three patients (12%) presented with a local recurrence after a mean follow-up of 42.7 months. Radical orchiectomy was performed for six patients. No patient with a preserved testicle required androgen therapy; the mean postoperative total testosterone level was 4.0 ng/mL. No patient remained fertile after radiation therapy. Conclusions TSS for bilateral testicular tumour is safe and effective in selected patients, and should be considered to avoid definitive androgen therapy. Adjuvant radiotherapy remains poorly described in the literature, leading to adjuvant treatment heterogeneity for testicular tumours.

We report the synthesis of {100}c facets exposed single-crystalline BiFeO3 (BFO) nanoplates, with thickness ranging from 20 to 160 nm and lateral size of submicrometers, via a simple and very rapid (1–2 min) microwave-assisted hydrothermal approach. We show that the microwave treatment gives comparable improvement in crystallinity of BFO nanocrystals with respect to traditional hydrothermal processes while requiring significantly less time and energy. In addition, we show that microwave radiation power, reaction time, and alkali concentration play important roles in the crystallinity and morphology of the products. We discuss a possible formation mechanism of the nanoplates based on our experimental results. Additionally, the BFO nanoplates exhibit weak ferromagnetic properties at room temperature, which we attribute to the size-confinement effect on magnetic ordering. The present microwave hydrothermal method has great potential in large-scale fabrication of BFO nanomaterials as well as other composite functional materials due to significantly reduced time and energy.

The compatibility approach enables the description of thermoelectric (TE) effects in terms of intensive state variables. Based on the new concept of a “Thomson cooler” (using the particular case of a u = s cooler as a demonstration) the authors present practically relevant results about fully self-compatible cooler elements where the compatibility factor s is adjusted locally at any position along the element. By means of a comparison u = s cooler vs. conventional Peltier cooler with (Bi_(0.5)Sb_(0.5))_2Te_3 material it is shown that there is a similar self-compatibility effect for different ΔT. Therewith, the paper completes results published in Phys. Rev. B 86, 045202 (2012).

Walking and paddling motions were studied in a semiaquatic bird, the ringed teal (Callonetta leucophrys), to investigate the motions associated with movements in two environments with radically divergent physical properties. A three-dimensional (3D) kinematic reconstruction based on nonsynchronous biplanar cineradiographic data was used to quantify the 3D trajectories of the body and hind limb segments. Our study revealed that two subsystems interact to provide propulsion in water and on land. During paddling, the trunk, the femur, and the tibiotarsus are in a stable position and play the role of the hull. The femur and tibiotarsus are positioned laterally and parasagittaly and the intertarsal joint is fixed and positioned caudally allowing large amplitude movements of the "paddle" (tarsometatarsus and palmate foot). During walking, the center of mass is held above the medially oriented foot, providing stability during the single support phase. During stance, the foot is medially oriented because of the lateral and parasagittal positions of the tibiotarsus and tarsometatarsus during both walking and paddling. This position of the foot during walking imposes trunk translation and results in the typical waddling motion of Anatidae. This study provides new insights into how waddling motion relates to semiaquatic birds' ability to move in both terrestrial and aquatic environments.

An increase in protein tyrosine phosphorylation occurs during sperm capacitation in numerous species. The involvement of Src-related tyrosine kinases in this phenomenon has been demonstrated using different inhibitors specifically targeting this family of enzymes. In mammals, this group of nonreceptor tyrosine kinases is made up of 8 members with similar SRC homology domain 3 (SH3) and SH2 domains. Although some members of this group of enzymes can compensate for one another, showing some redundancy, each is unique and may perform specific functions during male germ cell development. To further characterize the importance of Src-related tyrosine kinases in the events leading to proper sperm formation, and because no inhibitor affecting a single gene product exists, expression of Src, Yes1, Fyn, Lyn, Lck, Hck, Blk, and Fgr was assessed by real-time polymerase chain reaction in developing mouse testes and in enriched populations of mouse spermatogenic cells, revealing distinct expression profiles for each kinase during testis development and in isolated male germ cells. Immunolocalization of SRC, LYN, and HCK in adult mouse testes as well as in mature spermatozoa further confirmed differential localization of these kinases during spermatogenesis. Although mRNA levels of these latter kinases were higher in spermatogonia and spermatocytes than in spermatids, protein levels were highest in spermatids, suggesting delayed transcript translation. Taken together, these results clearly show an uneven expression of each kinase in different spermatogenic cells, indicating that each member may play a different role during spermatogenesis, in addition to highlighting the complexity of Src-related kinase expression regulation in male germ cells. Furthermore, differential localization of these tyrosine kinases in mature spermatozoa also suggests a specific role for each member in sperm function and integrity.

Because of the recent approval of several drugs for the treatment of renal cell carcinoma (including sorafenib, sunitinib, temsirolimus, and, in Europe, bevacizumab plus interferon), the use of sequential therapy has become routine practice. There is now evidence that administering these targeted agents sequentially provides clinical benefit by inducing tumor shrinkage and prolonged progression-free survival (PFS) in a large number of patients. However, data regarding overall survival (OS) are still pending. By adding these drugs in an adequate order, one can expect an increase in overall PFS of up to 27 months and a subsequent improvement in the OS of patients with renal cell carcinoma. It has been recently reported that the OS of patients treated with sunitinib in the first-line setting was 26 months. Expecting a survival of 40 months does appear possible based on currently available data, although this assumption will have to be proven in the future.