Intérêt des faibles doses de rt-PA dans les syndromes inflammatoires et hémorragiques du segment antérieur: étude clinique et revue de la littérature [Treatment of anterior segment fibrinous reactions and hemorrhage with intracameral low dose rt-PA: clinical study and review of the literature].

PURPOSE: to evaluate the efficacy and the safety of low dose intraocular tissue plasminogen activator (rt-PA) in the treatment of traumatic hyphema and postoperative fibrinous membrane. METHODS: Six microg to 10 microg of rt-PA was injected into the anterior chamber to treat severe fibrinous postoperative membranes and total traumatic hyphemae. RESULTS: Thirteen eyes of 13 patients were treated. Four cases of traumatic hyphema and 9 cases of fibrinous membranes were included. Complete fibrinolysis within 24 hours was observed in 4 cases (30.8%). A partial success was noted in 7 eyes (53.8%). No beneficial effect was observed in two cases of traumatic hyphema associated with intravitreal hemorrhage after penetrating trauma. No side effect attributable to rt-PA occurred. CONCLUSION: Low dose intraocular rt-PA appears to be safe and effective in the treatment of postoperative fibrinous membrane and endocular hemorrhage limited to the anterior chamber.

The high road and the low road: trafficking choices in plants.

Polar transport of the signaling molecule auxin is critical for plant development and depends on both the polar distribution of auxin efflux carriers, which pump auxin out of the cell and the alignment of these polarized cells. Two papers in this issue of Cell (Michniewicz et al., 2007; Jaillais et al., 2007) address how polar transport of these carriers occurs and describe the endosomal pathways involved.

Manufacturing and characterization of a recombinant adeno-associated virus type 8 reference standard material.

Gene therapy approaches using recombinant adeno-associated virus serotype 2 (rAAV2) and serotype 8 (rAAV8) have achieved significant clinical benefits. The generation of rAAV Reference Standard Materials (RSM) is key to providing points of reference for particle titer, vector genome titer, and infectious titer for gene transfer vectors. Following the example of the rAAV2RSM, here we have generated and characterized a novel RSM based on rAAV serotype 8. The rAAV8RSM was produced using transient transfection, and the purification was based on density gradient ultracentrifugation. The rAAV8RSM was distributed for characterization along with standard assay protocols to 16 laboratories worldwide. Mean titers and 95% confidence intervals were determined for capsid particles (mean, 5.50×10(11) pt/ml; CI, 4.26×10(11) to 6.75×10(11) pt/ml), vector genomes (mean, 5.75×10(11) vg/ml; CI, 3.05×10(11) to 1.09×10(12) vg/ml), and infectious units (mean, 1.26×10(9) IU/ml; CI, 6.46×10(8) to 2.51×10(9) IU/ml). Notably, there was a significant degree of variation between institutions for each assay despite the relatively tight correlation of assay results within an institution. This outcome emphasizes the need to use RSMs to calibrate the titers of rAAV vectors in preclinical and clinical studies at a time when the field is maturing rapidly. The rAAV8RSM has been deposited at the American Type Culture Collection (VR-1816) and is available to the scientific community.

Subclinical hypothyroidism and the risk of coronary heart disease and mortality.

CONTEXT: Data regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants' age, sex, thyroid-stimulating hormone (TSH) levels, or preexisting cardiovascular disease. OBJECTIVE: To assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism. DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (1950 to May 31, 2010) were searched without language restrictions for prospective cohort studies with baseline thyroid function and subsequent CHD events, CHD mortality, and total mortality. The reference lists of retrieved articles also were searched. DATA EXTRACTION: Individual data on 55,287 participants with 542,494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25,977 participants from 7 cohorts with available data. Euthyroidism was defined as a TSH level of 0.50 to 4.49 mIU/L. Subclinical hypothyroidism was defined as a TSH level of 4.5 to 19.9 mIU/L with normal thyroxine concentrations. RESULTS: Among 55,287 adults, 3450 had subclinical hypothyroidism (6.2%) and 51,837 had euthyroidism. During follow-up, 9664 participants died (2168 of CHD), and 4470 participants had CHD events (among 7 studies). The risk of CHD events and CHD mortality increased with higher TSH concentrations. In age- and sex-adjusted analyses, the hazard ratio (HR) for CHD events was 1.00 (95% confidence interval [CI], 0.86-1.18) for a TSH level of 4.5 to 6.9 mIU/L (20.3 vs 20.3/1000 person-years for participants with euthyroidism), 1.17 (95% CI, 0.96-1.43) for a TSH level of 7.0 to 9.9 mIU/L (23.8/1000 person-years), and 1.89 (95% CI, 1.28-2.80) for a TSH level of 10 to 19.9 mIU/L (n = 70 events/235; 38.4/1000 person-years; P <.001 for trend). The corresponding HRs for CHD mortality were 1.09 (95% CI, 0.91-1.30; 5.3 vs 4.9/1000 person-years for participants with euthyroidism), 1.42 (95% CI, 1.03-1.95; 6.9/1000 person-years), and 1.58 (95% CI, 1.10-2.27, n = 28 deaths/333; 7.7/1000 person-years; P = .005 for trend). Total mortality was not increased among participants with subclinical hypothyroidism. Results were similar after further adjustment for traditional cardiovascular risk factors. Risks did not significantly differ by age, sex, or preexisting cardiovascular disease. CONCLUSIONS: Subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater.

Comparison of polyethylene wear in anatomical and reversed shoulder prostheses.

Wear of polyethylene is associated with aseptic loosening of orthopaedic implants and has been observed in hip and knee prostheses and anatomical implants for the shoulder. The reversed shoulder prostheses have not been assessed as yet. We investigated the volumetric polyethylene wear of the reversed and anatomical Aequalis shoulder prostheses using a mathematical musculoskeletal model. Movement and joint stability were achieved by EMG-controlled activation of the muscles. A non-constant wear factor was considered. Simulated activities of daily living were estimated from in vivo recorded data. After one year of use, the volumetric wear was 8.4 mm(3) for the anatomical prosthesis, but 44.6 mm(3) for the reversed version. For the anatomical prosthesis the predictions for contact pressure and wear were consistent with biomechanical and clinical data. The abrasive wear of the polyethylene in reversed prostheses should not be underestimated, and further analysis, both experimental and clinical, is required.

Garnet-chloritoid-kyanite metapelites from the Raspas Complex (SW Ecuador): a key eclogite-facies assemblage

The Raspas Complex (Ecuador) contains one of the few eclogitic bodies in the northern Andes. It consists of metaperidotites, eclogites, and metapelites. The latter display three assemblages: (i) garnet + chloritoid + kyanite, (ii) garnet + chloritoid and (iii) garnet + chlorite, in all cases with quartz and muscovite in addition. The growth of these assemblages was coeval with the main ductile deformation, and was followed by minor reequilibration (chlorite growth in garnet + chloritoid samples and chloritoid + quartz aggregates replacing garnet and kyanite in garnet + chloritoid + kyanite samples). Detailed microprobe analyses show increasing magnesian compositions for garnet (from core to rim) and chloritoid (inclusions within garnet compared to matrix grains) in kyanite-bearing samples. The above data are interpreted in the framework of the KFMASH system. Reaction progress along the divariant reaction Cld = Grt + Ky explains the change in chemistry of coexisting phases. The divariant Grt-Cld-Ky assemblage has a narrow stability field, and the P-T conditions are estimated at about 20 kbar, 550-600degreesC. Decompression, recorded by chloritoid-quartz pseudomorphs of garnet, probably occurred as temperature decreased.

GENCODE: the reference human genome annotation for The ENCODE Project.

The GENCODE Consortium aims to identify all gene features in the human genome using a combination of computational analysis, manual annotation, and experimental validation. Since the first public release of this annotation data set, few new protein-coding loci have been added, yet the number of alternative splicing transcripts annotated has steadily increased. The GENCODE 7 release contains 20,687 protein-coding and 9640 long noncoding RNA loci and has 33,977 coding transcripts not represented in UCSC genes and RefSeq. It also has the most comprehensive annotation of long noncoding RNA (lncRNA) loci publicly available with the predominant transcript form consisting of two exons. We have examined the completeness of the transcript annotation and found that 35% of transcriptional start sites are supported by CAGE clusters and 62% of protein-coding genes have annotated polyA sites. Over one-third of GENCODE protein-coding genes are supported by peptide hits derived from mass spectrometry spectra submitted to Peptide Atlas. New models derived from the Illumina Body Map 2.0 RNA-seq data identify 3689 new loci not currently in GENCODE, of which 3127 consist of two exon models indicating that they are possibly unannotated long noncoding loci. GENCODE 7 is publicly available from gencodegenes.org and via the Ensembl and UCSC Genome Browsers.

Frequency and Type of Side Effects of Immunomodulating Medication in the Swiss Inflammatory Bowel Disease Cohort

Background: Medical treatment of inflammatory bowel disease (IBD) is becoming more and more complex, as several classes of immuno-modulating drugs (IMD) are often used simultaneously. Thus, the probability of adverse effects is greatly increased. Most studies reporting on adverse effects focus on single therapy, and studies providing a global survey of side effects for multiple treatments are lacking. Aim: To assess the type and frequency of adverse events in IBD patients treated with single and multiple IMD therapy. Methods: Analysis of data from the Swiss IBD Cohort Study (SIBDCS) that collects data on a large sample of IBD patients from hospitals and private practices across Switzerland. The following IMD categories were analyzed: 5-ASA, azathioprine (Aza), 6-mercaptopurine (6-MP), methotrexate (MTX), anti-TNF (infliximab, adalimumab, certolizumab-pegol), cyclosporine, tacrolimus, and steroids. The following side effects were assessed: hepatitis, pancreatitis, leucopenia, thrombopenia, nephritis, allergic reaction, pneumonitis, infections (including tuberculosis), osteoporosis, abdominal pain/diarrhea (unrelated to IBD activity), cataract, diabetes, exanthema, hirsutism, lupus-like syndrome, myalgias, depression/psychosis, tumor development. Results: A total of 1,961 patients were analyzed (977 [50%] female, mean age 42.1 ± 14.4 years): 1,119 with Crohn's disease (CD), 800 with ulcerative colitis (UC), and 42 with indeterminate colitis (IC). Three-hundred eighteen (16.2%) patients were not treated with any of the above-mentioned medications, while 650 (33.2%), 569 (29%) and 424 (21.6%) patients had one-, two-, and three- or more- IMD therapy, respectively. Of the 1,643 patients treated with IMD, 535 (32.6%) patients reported at least one side effect. We found a significant correlation between the number of drugs used by a patient and the frequency of side effects (17.4% side effects for one drug, 29% for 2 drugs, and 60.6% for three or more drugs, p < 0.001). The frequency of side effects for the different IMD classes were as follows: 5-ASA (n = 980 treated patients) 10.8%, Aza/6-MP (n = 636) 51.9% (pancreatitis in 57 = 9%, hepatitis in 17 = 2.7% of treated patients), MTX (n = 146) 42.5% (hepatitis in 4 = 2.7% of treated patients), anti-TNF (n = 255) 23.1%, cyclosporine (n = 49) 10.2%, tacrolimus (n = 5) 20%, steroids (systemic or topical, n = 1,150) 9.6%. Conclusion: IBD treatment is associated with a significant number of side effects. A direct correlation between the number of IMD used simultaneously and the frequency of side effects was observed. The results of this study indicate that treating physicians should be vigilant for the occurrence of side effects in IBD patients under single and/or multiple drug therapy.

Isolation and characterization of 21 microsatellite markers in the barn owl (Tyto alba).

We report 21 new polymorphic microsatellite markers in the European barn owl (Tyto alba). The polymorphism of the reported markers was evaluated in a population situated in western Switzerland and in another from Tenerife, Canary Islands. The number of alleles per locus varies between two and 31, and expected heterozygosity per population ranges from 0.16 to 0.95. All loci are in Hardy-Weinberg equilibrium and no linkage disequilibrium was detected. Two loci exhibit a null allele in the Tenerife population.

Amyloïdose cardiaque: une urgence diagnostique [Echocardiographic analysis in cardiac amyloidosis]

Systemic amyloidosis with cardiac involvement may clinically be suspected in the presence of heart failure or arrhythmia of unknown origin. Herein two cases of cardiac amyloidosis are described with a clinical presentation of heart failure refractory to usual treatment. The key role of echocardiography in the diagnosis and prognosis evaluation of cardiac amyloidosis is discussed. A treatment targeted against the generation of amyloid fibril should ideally be initiated before apparition of heart failure.

Cultured epithelial autografts in the management of burn injuries: a review of the literature

Introduction. The management of large burn victims has significantly improved in the last decades. Specifically autologous cultured keratinocytes (CEA) overcame the problem of limited donor sites in severely burned patients. Several studies testing CEA's in their burn centers give mixed results on the general outcomes of burn patients. Methods. A review of publications with a minimum of 15 patients per study using CEA for the management of severe burn injury from 1989 until 2011 were recruited by using an online database including Medline, Pub Med and the archives of the medical library of the CHUV in Lausanne. Results. 18 studies with a total of 977 patients were included into this review. Most of the studies did not specify if CEA's were grafted alone or in combination with split thickness skin grafts (STSG) although most of the patients seemed to have received both methodologies in reviewed studies. The mean TBSA per study ranged from 33% to 78% in patients that were grafted with CEA's. Here no common minimum TBSA making a patient eligible for CEA grafting could be found. The definition of the "take rate" is not standardized and varied largely from 26% to 73%. Mortality and hospitalization time could not be shown to correlate with CEA use in all of the studies. As late complications, some authors described the fragility of the CEA regenerated skin. Conclusion. Since the healing of large burn victims demands for a variety of different surgical and non-surgical treatment strategies and the final outcome mainly depends on the burned surface as well as the general health condition of the patient, no definitive conclusion could be drawn from the use of CEA's of reviewed studies. From our own experience, we know that selected patients significantly profit from CEA grafts although cost efficiency or the reduction of mortality cannot be demonstrated on this particular cases.

Immunotherapeutic strategies for bladder cancer.

Bladder cancer is a common urologic malignancy with rising incidence in the elderly population. In most cases, bladder cancer is non-muscle-invasive at diagnosis and shows dramatically high recurrence rates, although current treatments often reduce the risk of disease progression. Immunotherapy using intravesical instillation of Bacillus Calmette-Guérin (BCG) remains the most effective therapy for patients with high risk tumors. However, BCG-therapy has important limitations including substantial adverse events and frequent treatment failure. Thus, it appears crucial to either improve or replace current therapy using new immunotherapeutic strategies. Here, we discuss the clinical trials that assessed therapeutic vaccination of bladder cancer patients using tumor associated antigens and we also argue for novel approaches arising from murine models. Vaccination routes to induce appropriate T-cell homing in the tumor site as well as the use of local immunostimulation to enhance recruitment of vaccine-induced T cells are discussed to highlight what we believe is a promising therapeutic vaccination strategy for patients with non-muscle-invasive bladder cancer.

Regional and cellular gene expression changes in human Huntington's disease brain.

Huntington's disease (HD) pathology is well understood at a histological level but a comprehensive molecular analysis of the effect of the disease in the human brain has not previously been available. To elucidate the molecular phenotype of HD on a genome-wide scale, we compared mRNA profiles from 44 human HD brains with those from 36 unaffected controls using microarray analysis. Four brain regions were analyzed: caudate nucleus, cerebellum, prefrontal association cortex [Brodmann's area 9 (BA9)] and motor cortex [Brodmann's area 4 (BA4)]. The greatest number and magnitude of differentially expressed mRNAs were detected in the caudate nucleus, followed by motor cortex, then cerebellum. Thus, the molecular phenotype of HD generally parallels established neuropathology. Surprisingly, no mRNA changes were detected in prefrontal association cortex, thereby revealing subtleties of pathology not previously disclosed by histological methods. To establish that the observed changes were not simply the result of cell loss, we examined mRNA levels in laser-capture microdissected neurons from Grade 1 HD caudate compared to control. These analyses confirmed changes in expression seen in tissue homogenates; we thus conclude that mRNA changes are not attributable to cell loss alone. These data from bona fide HD brains comprise an important reference for hypotheses related to HD and other neurodegenerative diseases.

Serrated polyps of the colon: how reproducible is their classification?

For several years, the lack of consensus on definition, nomenclature, natural history, and biology of serrated polyps (SPs) of the colon has created considerable confusion among pathologists. According to the latest WHO classification, the family of SPs comprises hyperplastic polyps (HPs), sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs). The term SSA/P with dysplasia has replaced the category of mixed hyperplastic/adenomatous polyps (MPs). The present study aimed to evaluate the reproducibility of the diagnosis of SPs based on currently available diagnostic criteria and interactive consensus development. In an initial round, H&E slides of 70 cases of SPs were circulated among participating pathologists across Europe. This round was followed by a consensus discussion on diagnostic criteria. A second round was performed on the same 70 cases using the revised criteria and definitions according to the recent WHO classification. Data were evaluated for inter-observer agreement using Kappa statistics. In the initial round, for the total of 70 cases, a fair overall kappa value of 0.318 was reached, while in the second round overall kappa value improved to moderate (kappa = 0.557; p < 0.001). Overall kappa values for each diagnostic category also significantly improved in the final round, reaching 0.977 for HP, 0.912 for SSA/P, and 0.845 for TSA (p < 0.001). The diagnostic reproducibility of SPs improves when strictly defined, standardized diagnostic criteria adopted by consensus are applied.

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.