Beneficial effect of insulin-like growth factor-1 on hypoxemic renal dysfunction in the newborn rabbit.

Acute normocapnic hypoxemia can cause functional renal insufficiency by increasing renal vascular resistance (RVR), leading to renal hypoperfusion and decreased glomerular filtration rate (GFR). Insulin-like growth factor 1 (IGF-1) activity is low in fetuses and newborns and further decreases during hypoxia. IGF-1 administration to humans and adult animals induces pre- and postglomerular vasodilation, thereby increasing GFR and renal blood flow (RBF). A potential protective effect of IGF-1 on renal function was evaluated in newborn rabbits with hypoxemia-induced renal insufficiency. Renal function and hemodynamic parameters were assessed in 17 anesthetized and mechanically ventilated newborn rabbits. After hypoxemia stabilization, saline solution (time control) or IGF-1 (1 mg/kg) was given as an intravenous (i.v.) bolus, and renal function was determined for six 30-min periods. Normocapnic hypoxemia significantly increased RVR (+16%), leading to decreased GFR (-14%), RBF (-19%) and diuresis (-12%), with an increased filtration fraction (FF). Saline solution resulted in a worsening of parameters affected by hypoxemia. Contrarily, although mean blood pressure decreased slightly but significantly, IGF-1 prevented a further increase in RVR, with subsequent improvement of GFR, RBF and diuresis. FF indicated relative postglomerular vasodilation. Although hypoxemia-induced acute renal failure was not completely prevented, IGF-1 elicited efferent vasodilation, thereby precluding a further decline in renal function.

Treatment of velopharyngeal insufficiency by autologous fat injection.

Velopharyngeal insufficiency (VPI) is a structural or functional trouble, which causes hypernasal speech. Velopharyngeal flaps, speech therapy and augmentation pharyngoplasty, using different implants, have all been used to address this trouble. We hereby present our results following rhinopharyngeal autologous fat injection in 18 patients with mild velopharyngeal insufficiency (12 soft palate clefts, 4 functional VPI, 2 myopathy). 28 injections were carried out between 2004 and 2007. The degree of hypernasal speech was evaluated pre- and postoperatively by a speech therapist and an ENT specialist and quantified by an acoustic nasometry (Kay Elemetrics). All patients were exhaustively treated with preoperative speech therapy (average, 8 years). The mean value of the nasalance score was 37% preoperatively and 23% postoperatively (p = 0.015). The hypernasality was reduced postoperatively in all patients (1-3 degrees of the Borel-Maisonny score). There were no major complications, two minor complications (one hematoma, one cervical pain). The autologous fat injection is a simple, safe, minimally invasive procedure. It proves to be efficient in cases of mild velopharyngeal insufficiency or after a suboptimal velopharyngoplasty.

Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors.

The role of the gluco-incretin hormones GIP and GLP-1 in the control of beta cell function was studied by analyzing mice with inactivation of each of these hormone receptor genes, or both. Our results demonstrate that glucose intolerance was additively increased during oral glucose absorption when both receptors were inactivated. After intraperitoneal injections, glucose intolerance was more severe in double- as compared to single-receptor KO mice, and euglycemic clamps revealed normal insulin sensitivity, suggesting a defect in insulin secretion. When assessed in vivo or in perfused pancreas, insulin secretion showed a lack of first phase in Glp-1R(-/-) but not in Gipr(-/-) mice. In perifusion experiments, however, first-phase insulin secretion was present in both types of islets. In double-KO islets, kinetics of insulin secretion was normal, but its amplitude was reduced by about 50% because of a defect distal to plasma membrane depolarization. Thus, gluco-incretin hormones control insulin secretion (a) by an acute insulinotropic effect on beta cells after oral glucose absorption (b) through the regulation, by GLP-1, of in vivo first-phase insulin secretion, probably by an action on extra-islet glucose sensors, and (c) by preserving the function of the secretory pathway, as evidenced by a beta cell autonomous secretion defect when both receptors are inactivated.

Intravitreal ranibizumab in the treatment of choroidal neovascularization associated with idiopathic central serous chorioretinopathy.

PURPOSE: We evaluate the functional and anatomic outcome after intravitreal ranibizumab treatment in patients with choroidal neovascularization (CNV) related to chronic central serous chorioretinopathy (CSC). METHODS: This is a small case series of 5 eyes with CNV associated with chronic CSC treated with intravitreal injection of 0.5 mg ranibizumab in the Jules Gonin University Eye Hospital from July 2007 to July 2009. Baseline and monthly follow-up visits included best-corrected visual acuity (BCVA), fundus examination, and optical coherence tomography (OCT). Fluorescein and indocyanine green angiography (ICG) were performed at baseline and repeated at least every 6 months. RESULTS: We studied 5 eyes of 4 patients with a mean age of 66 years. Mean follow-up was 21 months (SD 1.9). The mean number of intravitreal injections administered for each patient was 10 (SD 4.6). The mean initial BCVA was 0.23 (decimal equivalent) (logMAR 0.64, SD 0.13). At the last follow-up, mean BCVA was 0.44 decimal equivalent (logMAR 0.36, SD 0.31). Mean central macular thickness (CMT) measured with OCT was 330 microm (SD 43) at baseline and decreased at the final follow-up to 243 microm (SD 44 ). Persistent intraretinal or subretinal fluid on OCT and/or multifocal areas of increased choroidal permeability on ICG angiographies were present in all patients at the last follow-up visit. CONCLUSIONS: Intravitreal ranibizumab appeared to be an effective treatment of CNV related to chronic CSC. However, residual intraretinal or subretinal fluid and increased choroidal permeability persisted. Prospective controlled studies are warranted to evaluate the long-term safety and efficacy of intravitreal ranibizumab.

Néoplasie épithéliale de l'appendice: quoi de neuf [Epithelial neoplasia of the appendix: what has recently changed?].

Appendicular tumors are mostly found incidentally in up to 1.5% of all appendectomies. Neuroendocrine tumors are the commonest malignancies, and are associated with an excellent long-term prognosis. While small lesions located at the appendicular tip can be treated with simple appendectomy, advanced tumors require right hemicolectomy. Goblet cell carcinoids are rare tumors showing a mixed phenotype. Long-term outcome is impaired, and for most cases a right hemicolectomy is mandatory. Colonic-type adenocarcinomas have a similar behavior like conventional colonic cancer and should be treated similarly. Mucinous neoplasias possess the characteristic of extensive mucin production with intraperitoneal spread. Treatment options are ranging from right hemicolectomy to multivisceral resection with intraperitoneal chemotherapy.

Randomised trial of oral versus sequential intravenous/oral cephalosporins in children with pyelonephritis.

The hypothesis was tested that oral antibiotic treatment in children with acute pyelonephritis and scintigraphy-documented lesions is equally as efficacious as sequential intravenous/oral therapy with respect to the incidence of renal scarring. A randomised multi-centre trial was conducted in 365 children aged 6 months to 16 years with bacterial growth in cultures from urine collected by catheter. The children were assigned to receive either oral ceftibuten (9 mg/kg once daily) for 14 days or intravenous ceftriaxone (50 mg/kg once daily) for 3 days followed by oral ceftibuten for 11 days. Only patients with lesions detected on acute-phase dimercaptosuccinic acid (DMSA) scintigraphy underwent follow-up scintigraphy. Efficacy was evaluated by the rate of renal scarring after 6 months on follow-up scintigraphy. Of 219 children with lesions on acute-phase scintigraphy, 152 completed the study; 80 (72 females, median age 2.2 years) were given ceftibuten and 72 (62 females, median age 1.6 years) were given ceftriaxone/ceftibuten. Patients in the intravenous/oral group had significantly higher C-reactive protein (CRP) concentrations at baseline and larger lesion(s) on acute-phase scintigraphy. Follow-up scintigraphy showed renal scarring in 21/80 children treated with ceftibuten and 33/72 with ceftriaxone/ceftibuten (p = 0.01). However, after adjustment for the confounding variables (CRP and size of acute-phase lesion), no significant difference was observed for renal scarring between the two groups (p = 0.2). Renal scarring correlated with the extent of the acute-phase lesion (r = 0.60, p < 0.0001) and the grade of vesico-ureteric reflux (r = 0.31, p = 0.03), and was more frequent in refluxing renal units (p = 0.04). The majority of patients, i.e. 44 in the oral group and 47 in the intravenous/oral group, were managed as out-patients. Side effects were not observed. From this study, we can conclude that once-daily oral ceftibuten for 14 days yielded comparable results to sequential ceftriaxone/ceftibuten treatment in children aged 6 months to 16 years with DMSA-documented acute pyelonephritis and it allowed out-patient management in the majority of these children.

Mynodbcsv: Lightweight Zero-Config Database Solution for Handling Very Large CSV Files.

Volumes of data used in science and industry are growing rapidly. When researchers face the challenge of analyzing them, their format is often the first obstacle. Lack of standardized ways of exploring different data layouts requires an effort each time to solve the problem from scratch. Possibility to access data in a rich, uniform manner, e.g. using Structured Query Language (SQL) would offer expressiveness and user-friendliness. Comma-separated values (CSV) are one of the most common data storage formats. Despite its simplicity, with growing file size handling it becomes non-trivial. Importing CSVs into existing databases is time-consuming and troublesome, or even impossible if its horizontal dimension reaches thousands of columns. Most databases are optimized for handling large number of rows rather than columns, therefore, performance for datasets with non-typical layouts is often unacceptable. Other challenges include schema creation, updates and repeated data imports. To address the above-mentioned problems, I present a system for accessing very large CSV-based datasets by means of SQL. It's characterized by: "no copy" approach - data stay mostly in the CSV files; "zero configuration" - no need to specify database schema; written in C++, with boost [1], SQLite [2] and Qt [3], doesn't require installation and has very small size; query rewriting, dynamic creation of indices for appropriate columns and static data retrieval directly from CSV files ensure efficient plan execution; effortless support for millions of columns; due to per-value typing, using mixed text/numbers data is easy; very simple network protocol provides efficient interface for MATLAB and reduces implementation time for other languages. The software is available as freeware along with educational videos on its website [4]. It doesn't need any prerequisites to run, as all of the libraries are included in the distribution package. I test it against existing database solutions using a battery of benchmarks and discuss the results.

Manifestations neurologiques des troubles musculosquelettiques [Neurological manifestations in musculoskeletal disorders].

Musculoskeletal disorders are a crossroad among diverse specialties: neurology, rehabilitation, orthopedics, occupational medicine and psycho-traumatology. They are integrated into occupational medicine and encompass overuse syndromes, repeated micro-trauma and focal compressive neuropathies linked with professional or sports' activity. Neurological manifestations are omnipresent. Yet, their importance is not always recognized despite frequent resort to neurologists specialized in peripheral nervous system disorders and neurophysiology, as well as, to behavioral cognition specialists. Therapeutic approaches require preventive and work organization measures, neurophysiologic investigations and imaging in expert hands, and conservative treatment with physiotherapy, with or without paraneural and intra-articular injections.

Supervised injection services : what has been demonstrated? A systematic literature review

BACKGROUND: Supervised injection services (SISs) have been developed to promote safer drug injection practices, enhance health-related behaviors among people who inject drugs (PWID), and connect PWID with external health and social services. Nevertheless, SISs have also been accused of fostering drug use and drug trafficking. AIMS: To systematically collect and synthesize the currently available evidence regarding SIS-induced benefits and harm. METHODS: A systematic review was performed via the PubMed, Web of Science, and ScienceDirect databases using the keyword algorithm [("supervised" or "safer") and ("injection" or "injecting" or "shooting" or "consumption") and ("facility" or "facilities" or "room" or "gallery" or "centre" or "site")]. RESULTS: Seventy-five relevant articles were found. All studies converged to find that SISs were efficacious in attracting the most marginalized PWID, promoting safer injection conditions, enhancing access to primary health care, and reducing the overdose frequency. SISs were not found to increase drug injecting, drug trafficking or crime in the surrounding environments. SISs were found to be associated with reduced levels of public drug injections and dropped syringes. Of the articles, 85% originated from Vancouver or Sydney. CONCLUSION: SISs have largely fulfilled their initial objectives without enhancing drug use or drug trafficking. Almost all of the studies found in this review were performed in Canada or Australia, whereas the majority of SISs are located in Europe. The implementation of new SISs in places with high rates of injection drug use and associated harms appears to be supported by evidence.

CT-guided cervical foraminal injection: Is a direct foraminal approach still necessary?

Purpose: Cervical foraminal injection performed with a direct foraminal approach may induce serious neurologic complications. We describe a technique of CT-guided cervical facet joint (CFJ) injection as an indirect foraminal injection, including feasibility and diffusion pathways of the contrast agent. Methods and materials: Retrospective study included 84 punctures in 65 consecutive patients presenting neck pain and/or radiculopathy related to osteoarthritis or soft disc herniation. CT images were obtained from C2 to T1 in supine position, with a metallic landmark on the skin. CFJ punctures were performed by MSK senior radiologists with a lateral approach. CT control of the CFJ opacification was performed after injections of contrast agent (1 ml), followed by slow-acting corticosteroid (25 mg). CFJ opacification was considered as successful when joint space and/or capsular recess opacification occurred. The diffusion of contrast agent in foraminal and epidural spaces was recorded. We assessed the epidural diffusion both on axial and sagittal images, with a classification in two groups (small diffusion or large diffusion). Results: CFJ opacification was successful in 82% (69/84). An epidural and/or foraminal opacification was obtained in 74% (51/69). A foraminal opacification occurred in 92% (47/51) and an epidural opacification in 63% (32/51), with small diffusion in 47% (15/32) and large diffusion in 53% (17/32). No complication occurred. Conclusion: CT- guided CFJ injection is easy to perform and safe. It is most often successful, with a frequent epidural and/or foraminal diffusion of the contrast agent. This technique could be an interesting and safe alternative to foraminal cervical injection.

In BALB/c mice, IL-4 production during the initial phase of infection with Leishmania major is necessary and sufficient to instruct Th2 cell development resulting in progressive disease.

In contrast to intact BALB/c mice, BALB/c mice rendered deficient in Vbeta4+ CD4+ T cells develop a Th1 response to infection with Leishmania major and are resistant. Vbeta4-deficient BALB/c mice are unable to generate the early IL-4 transcription occurring in Vbeta4 Valpha8 CD4+ T cells of BALB/c mice within 1 day of infection. Here we demonstrate that treatment of Vbeta4-deficient BALB/c mice with IL-4 during the first 64 h after infection instructs Th2 cell development and susceptibility to infection. The demonstrated inability of IL-4 to reverse the resistant phenotype of BALB/c mice treated with anti-CD4 mAb the day before infection suggest that these effects of IL-4 require its interaction with CD4+ T cells. In contrast to draining lymph node cells from BALB/c mice, cells from Vbeta4-deficient BALB/c mice remain responsive to IL-12 following infection. Strikingly, administration of IL-4 to Vbeta4-deficient BALB/c mice renders their lymph node cells unresponsive to IL-12 by down-regulating IL-12R beta2-chain expression. This study directly demonstrates that in BALB/c mice IL-4 is necessary and sufficient to initiate the molecular events steering Th2 cell maturation and susceptibility to L. major.

A next step in adeno-associated virus-mediated gene therapy for neurological diseases: regulation and targeting.

Recombinant adeno-associated virus (rAAV) vectors mediating long term transgene expression are excellent gene therapy tools for chronic neurological diseases. While rAAV2 was the first serotype tested in the clinics, more efficient vectors derived from the rh10 serotype are currently being evaluated and other serotypes are likely to be tested in the near future. In addition, aside from the currently used stereotaxy-guided intraparenchymal delivery, new techniques for global brain transduction (by intravenous or intra-cerebrospinal injections) are very promising. Various strategies for therapeutic gene delivery to the central nervous system have been explored in human clinical trials in the past decade. Canavan disease, a genetic disease caused by an enzymatic deficiency, was the first to be approved. Three gene transfer paradigms for Parkinson's disease have been explored: converting L-dopa into dopamine through AADC gene delivery in the putamen; synthesizing GABA through GAD gene delivery in the overactive subthalamic nucleus and providing neurotrophic support through neurturin gene delivery in the nigro-striatal pathway. These pioneer clinical trials demonstrated the safety and tolerability of rAAV delivery in the human brain at moderate doses. Therapeutic effects however, were modest, emphasizing the need for higher doses of the therapeutic transgene product which could be achieved using more efficient vectors or expression cassettes. This will require re-addressing pharmacological aspects, with attention to which cases require either localized and cell-type specific expression or efficient brain-wide transgene expression, and when it is necessary to modulate or terminate the administration of transgene product. The ongoing development of targeted and regulated rAAV vectors is described.

Plasmid electrotransfer of eye ciliary muscle: principles and therapeutic efficacy using hTNF-alpha soluble receptor in uveitis.

Due to its small size and particular isolating barriers, the eye is an ideal target for local therapy. Recombinant protein ocular delivery requires invasive and painful repeated injections. Alternatively, a transfected tissue might be used as a local producer of transgene-encoded therapeutic protein. We have developed a nondamaging electrically mediated plasmid delivery technique (electrotransfer) targeted to the ciliary muscle, which is used as a reservoir tissue for the long-lasting expression and secretion of therapeutic proteins. High and long-lasting reporter gene expression was observed, which was restricted to the ciliary muscle. Chimeric TNF-alpha soluble receptor (hTNFR-Is) electrotransfer led to elevated protein secretion in aqueous humor and to drastic inhibition of clinical and histological inflammation scores in rats with endotoxin-induced uveitis. No hTNFR-Is was detected in the serum, demonstrating the local delivery of proteins using this method. Plasmid electrotransfer to the ciliary muscle, as performed in this study, did not induce any ocular pathology or structural damage. Local and sustained therapeutic protein production through ciliary muscle electrotransfer is a promising alternative to repeated intraocular protein administration for a large number of inflammatory, degenerative, or angiogenic diseases.