Reconnaissance of tumor immune microenvironment spatial heterogeneity in metastatic renal cell carcinoma and correlation with immunotherapy response.

A clearer understanding of the tumor immune microenvironment (TIME) in metastatic clear cell renal cell carcinoma (ccRCC) may help to inform precision treatment strategies. We sought to identify clinically meaningful TIME signatures in ccRCC. We studied tumors from 39 patients with metastatic ccRCC using quantitative multiplexed immunofluorescence and relevant immune marker panels. Cell densities were analyzed in three regions of interest (ROIs): tumor core, tumor-stroma interface and stroma. Patients were stratified into low- and high-marker density groups using median values as thresholds. Log-rank and Cox regression analyses while controlling for clinical variables were used to compare survival outcomes to patterns of immune cell distributions. There were significant associations with increased macrophage (CD68+ CD163+ CD206+ ) density and poor outcomes across multiple ROIs in primary and metastatic tumors. In primary tumors, T-bet+ T helper type 1 (Th1) cell density was highest at the tumor-stromal interface (P = 0·0021), and increased co-expression of CD3 and T-bet was associated with improved overall survival (P = 0·015) and survival after immunotherapy (P = 0·014). In metastatic tumor samples, decreased forkhead box protein 3 (FoxP3)+ T regulatory cell density correlated with improved survival after immunotherapy (P = 0·016). Increased macrophage markers and decreased Th1 T cell markers within the TIME correlated with poor overall survival and treatment outcomes. Immune markers such as FoxP3 showed consistent levels across the TIME, whereas others, such as T-bet, demonstrated significant variance across the distinct ROIs. These findings suggest that TIME profiling outside the tumor core may identify clinically relevant associations for patients with metastatic ccRCC.

An original fibular shortening osteotomy technique in tibiotalar arthrodesis.

Tibiotalar arthrodesis (TTA) is the gold-standard treatment for advanced ankle osteoarthritis. We describe an original fibular shortening osteotomy (FSO) performed during TTA, to allow complete talar ascension and reduce the nonunion rate. Forty-two FSOs were associated to TTA (19 fixed by cross-screwing and 23 by anatomic plates) and assessed clinically and radiographically. At 24.7 months' follow-up, fusion rates were 97.6% for TTA and 100% for FSO, with mean fusion time of 5.2 months. One infection and 1 nonunion (4.7%) required further surgery, with complete resolution. Radiological and clinical outcome in TTA, lack of specific complications of FSO and ease of implementation encourage us to publish the technique.

General and specific combining abilities in a maize (Zea mays L.) test-cross hybrid panel: relative importance of population structure and genetic divergence between parents.

KEY MESSAGE: General and specific combining abilities of maize hybrids between 288 inbred lines and three tester lines were highly related to population structure and genetic distance inferred from SNP data. Many studies have attempted to provide reliable and quick methods to identify promising parental lines and combinations in hybrid breeding programs. Since the 1950s, maize germplasm has been organized into heterotic groups to facilitate the exploitation of heterosis. Molecular markers have proven efficient tools to address the organization of genetic diversity and the relationship between lines or populations. The aim of the present work was to investigate to what extent marker-based evaluations of population structure and genetic distance may account for general (GCA) and specific (SCA) combining ability components in a population composed of 800 inter and intra-heterotic group hybrids obtained by crossing 288 inbred lines and three testers. Our results illustrate a strong effect of groups identified by population structure analysis on both GCA and SCA components. Including genetic distance between parental lines of hybrids in the model leads to a significant decrease of SCA variance component and an increase in GCA variance component for all the traits. The latter suggests that this approach can be efficient to better estimate the potential combining ability of inbred lines when crossed with unrelated lines, and limits the consequences of tester choice. Significant residual GCA and SCA variance components of models taking into account structure and/or genetic distance highlight the variation available for breeding programs within structure groups.

Association mapping for phenology and plant architecture in maize shows higher power for developmental traits compared with growth influenced traits.

Plant architecture, phenology and yield components of cultivated plants have repeatedly been shaped by selection to meet human needs and adaptation to different environments. Here we assessed the genetic architecture of 24 correlated maize traits that interact during plant cycle. Overall, 336 lines were phenotyped in a network of 9 trials and genotyped with 50K single-nucleotide polymorphisms. Phenology was the main factor of differentiation between genetic groups. Then yield components distinguished dents from lower yielding genetic groups. However, most of trait variation occurred within group and we observed similar overall and within group correlations, suggesting a major effect of pleiotropy and/or linkage. We found 34 quantitative trait loci (QTLs) for individual traits and six for trait combinations corresponding to PCA coordinates. Among them, only five were pleiotropic. We found a cluster of QTLs in a 5 Mb region around Tb1 associated with tiller number, ear row number and the first PCA axis, the latter being positively correlated to flowering time and negatively correlated to yield. Kn1 and ZmNIP1 were candidate genes for tillering, ZCN8 for leaf number and Rubisco Activase 1 for kernel weight. Experimental repeatabilities, numbers of QTLs and proportion of explained variation were higher for traits related to plant development such as tillering, leaf number and flowering time, than for traits affected by growth such as yield components. This suggests a simpler genetic determinism with larger individual QTL effects for the first category.

Preliminary Results of Primary Gastrocnemius-Soleus Recession for Midfoot Charcot Arthropathy.

UNLABELLED: Background Treatment of Charcot arthopathy of the foot can be challenging. The goal of this investigation was to determine whether primary gastrocnemius-soleus recession could decrease rate of new ulcers, progression of deformity, and amputation in patients with Charcot arthropathy of the midfoot.Methods A retrospective chart review revealed 28 feet in 24 diabetic patients with radiographic evidence of Charcot arthropathy of the midfoot. They were treated with primary gastrocnemius-soleus recession. Eleven feet in 11 patients had concurrent plantar midfoot ulcers. Three feet in 3 patients were lost to follow-up. Twenty-five feet in 21 patients were followed for an average of 37 months postoperatively (range = 18-79).Results A favorable outcome was defined as healing of existing ulcers, no new ulcers, no obvious progression of deformity, and no amputation. Favorable outcomes were obtained in 22 of 25 feet (18 of 21 patients). Only one patient had a persistent ulcer after gastrocnemius-soleus recession. The other 10 patients with preexisting ulcers healed. Deformity of midfoot progressed in one patient, leading ultimately to transtibial amputation. Another patient developed a knee joint infection and had a transfemoral amputation at another institution.Discussion These preliminary data suggest that primary gastrocnemius-soleus recession is followed by a much lower rate of persistent, recurrent, and new ulceration than previously reported studies. Gastrocnemius-soleus recession seems to aid in the treatment of Charcot arthropathy of the midfoot. LEVELS OF EVIDENCE: Level IV.

Dent and Flint maize diversity panels reveal important genetic potential for increasing biomass production.

KEY MESSAGE: Genetic and phenotypic analysis of two complementary maize panels revealed an important variation for biomass yield. Flowering and biomass QTL were discovered by association mapping in both panels. The high whole plant biomass productivity of maize makes it a potential source of energy in animal feeding and biofuel production. The variability and the genetic determinism of traits related to biomass are poorly known. We analyzed two highly diverse panels of Dent and Flint lines representing complementary heterotic groups for Northern Europe. They were genotyped with the 50 k SNP-array and phenotyped as hybrids (crossed to a tester of the complementary pool) in a western European field trial network for traits related to flowering time, plant height, and biomass. The molecular information revealed to be a powerful tool for discovering different levels of structure and relatedness in both panels. This study revealed important variation and potential genetic progress for biomass production, even at constant precocity. Association mapping was run by combining genotypes and phenotypes in a mixed model with a random polygenic effect. This permitted the detection of significant associations, confirming height and flowering time quantitative trait loci (QTL) found in literature. Biomass yield QTL were detected in both panels but were unstable across the environments. Alternative kinship estimator only based on markers unlinked to the tested SNP increased the number of significant associations by around 40% with a satisfying control of the false positive rate. This study gave insights into the variability and the genetic architectures of biomass-related traits in Flint and Dent lines and suggests important potential of these two pools for breeding high biomass yielding hybrid varieties.

[Minimally invasive dynamic hip screw technique: Shorter surgical time with similar post-surgical results compared to conventional DHS technique. A retrospective cohort study]. / Técnica DHS mínimamente invasiva: menor tiempo quirúrgico con similares resultados en el postoperatorio inmediato respecto al DHS convencional. Estudio retrospectivo de cohortes.

AIM: The treatment of intertrochanteric fractures using a minimally invasive dynamic hip screw (MIDHS) technique has been reported to provide better results than the conventional technique (CDHS). The present study aims to determine whether there are any differences in terms of transfusion needs, morbidity, length of hospital stay, and economical costs, based on a study of two retrospective cohorts. MATERIAL AND METHOD: Cohorts study of 80 patients with intertrochanteric femoral fractures (31-A1 and 31-A2.1) who underwent DHS procedure from July 2005 to September 2007; 40 of them were treated using the traditional technique (CDHS), and the other 40 using the minimally invasive technique (MIDHS). RESULTS: No differences were found in terms of blood loss, transfusion requirements or morbidity. Mean hospital stay for MIDHS group was 1.3 days lower, reducing the costs regarding the CDHS group by €306.3, but this difference was not statistically significant (P=.3). The time required to perform the surgery was shorter for the MIDHS group: 49.3 versus 78.8minutes (p=0.0001). DISCUSSION: Contrary to previous studies published, the present study did not show any advantage for the MIDHS technique, except for a shorter surgical time to perform the procedure. We consider that the MIDHS could help in improving operating room productivity and efficiency.

Maximizing the reliability of genomic selection by optimizing the calibration set of reference individuals: comparison of methods in two diverse groups of maize inbreds (Zea mays L.).

Genomic selection refers to the use of genotypic information for predicting breeding values of selection candidates. A prediction formula is calibrated with the genotypes and phenotypes of reference individuals constituting the calibration set. The size and the composition of this set are essential parameters affecting the prediction reliabilities. The objective of this study was to maximize reliabilities by optimizing the calibration set. Different criteria based on the diversity or on the prediction error variance (PEV) derived from the realized additive relationship matrix-best linear unbiased predictions model (RA-BLUP) were used to select the reference individuals. For the latter, we considered the mean of the PEV of the contrasts between each selection candidate and the mean of the population (PEVmean) and the mean of the expected reliabilities of the same contrasts (CDmean). These criteria were tested with phenotypic data collected on two diversity panels of maize (Zea mays L.) genotyped with a 50k SNPs array. In the two panels, samples chosen based on CDmean gave higher reliabilities than random samples for various calibration set sizes. CDmean also appeared superior to PEVmean, which can be explained by the fact that it takes into account the reduction of variance due to the relatedness between individuals. Selected samples were close to optimality for a wide range of trait heritabilities, which suggests that the strategy presented here can efficiently sample subsets in panels of inbred lines. A script to optimize reference samples based on CDmean is available on request.

Permanent pacemaker insertion after CoreValve transcatheter aortic valve implantation: incidence and contributing factors (the UK CoreValve Collaborative).

BACKGROUND: Permanent pacemaker (PPM) requirement is a recognized complication of transcatheter aortic valve implantation. We assessed the UK incidence of permanent pacing within 30 days of CoreValve implantation and formulated an anatomic and electrophysiological model. METHODS AND RESULTS: Data from 270 patients at 10 centers in the United Kingdom were examined. Twenty-five patients (8%) had preexisting PPMs; 2 patients had incomplete data. The remaining 243 were 81.3±6.7 years of age; 50.6% were male. QRS duration increased from 105±23 to 135±29 milliseconds (P<0.01). Left bundle-branch block incidence was 13% at baseline and 61% after the procedure (P<0.001). Eighty-one patients (33.3%) required a PPM within 30 days. Rates of pacing according to preexisting ECG abnormalities were as follows: right bundle-branch block, 65.2%; left bundle-branch block, 43.75%; normal QRS, 27.6%. Among patients who required PPM implantation, the median time to insertion was 4.0 days (interquartile range, 2.0 to 7.75 days). Multivariable analysis revealed that periprocedural atrioventricular block (odds ratio, 6.29; 95% confidence interval, 3.55 to 11.15), balloon predilatation (odds ratio, 2.68; 95% confidence interval, 2.00 to 3.47), use of the larger (29 mm) CoreValve prosthesis (odds ratio, 2.50; 95% confidence interval, 1.22 to 5.11), interventricular septum diameter (odds ratio, 1.18; 95% confidence interval, 1.10 to 3.06), and prolonged QRS duration (odds ratio, 3.45; 95% confidence interval, 1.61 to 7.40) were independently associated with the need for PPM. CONCLUSION: One third of patients undergoing a CoreValve transcatheter aortic valve implantation procedure require a PPM within 30 days. Periprocedural atrioventricular block, balloon predilatation, use of the larger CoreValve prosthesis, increased interventricular septum diameter and prolonged QRS duration were associated with the need for PPM.

Prevalence of antibodies against Kilham virus in experimental rat colonies of Argentina.

The Kilham rat virus (KRV) is a parvovirus originally isolated from a rat sarcoma in the late 1950s. The clinical signs associated with a natural KRV infection include foetal resorption in dams, runting, ataxia, cerebellar hypoplasia and jaundice in suckling rats, and sudden death, scrotal cyanosis, abdominal swelling and dehydration in juvenile rats. The ability of this virus to produce persistent infections has resulted in a high frequency of contamination of cell cultures and transplantable-tumor system. In addition, the virus may interfere with research in other ways. The remarkable resistance to environmental conditions determines the importance of the detection and control of this agent, especially in the laboratory animal production. This study determines the seroprevalence of Kilham antibodies from sera of adult rats from conventional facilities, using the haemagglutination inhibition test. The seroprevalence varied between 27.8% and 75%. This result confirms that the virus is circulating in Argentinean conventional facilities and might be interfering with research. The recognized Kilham virus may be prevented from supply sources by implementing a health monitoring schedule including a regular serological surveillance, and by keeping the animals under barrier systems.

[Drepanocytosis with alpha and beta(o) thalassemia: a case report]. / Drépanocytose beta(o) thalassémique associée à une alpha thalassémie: à propos d'un cas.

We describe the case of a Sickle Cell Trait associated with alpha and beta(o) thalassemia at an young man without clinical abnormality. Capillary electrophoresis showed S haemoglobin at 67%, F haemoglobin at 29%, A2 haemoglobin at 4% and an absence of A haemoglobin. Accurate diagnosis was found by techniques of molecular biology.

Neuropathic toe ulcers treated with toe flexor tenotomies.

BACKGROUND: Foot ulcers are common causes of hospital admissions for infection and amputation in patients with neuropathy. This retrospective study evaluates the results of treating plantar neuropathic toe ulcers with percutaneous flexor tenotomy. METHODS: From 1996 to 2003, 28 toe ulcers in 18 patients were treated with tenotomy of the toe flexors. RESULTS: Fourteen of 18 patients had diabetic neuropathy. No patients were lost to followup. Average followup for the 28 ulcers was 36 (range 20 to 65) months. All ulcers healed. None of the 11 lesser toe ulcers recurred. Three of 17 first toe ulcers recurred but two that had repeat tenotomy healed and did not recur. There were no toe amputations, infections, or other complications of tenotomy. One patient had unrelated transtibial amputation. CONCLUSIONS: No long-term results of treating toe ulcers with toe flexor tenotomy by other authors have been found. Toe flexor tenotomies appear to be effective and safe treatment for neuropathic toe ulcers.

[Results of the French register of renal stenting: the Esternal study]. / Résultats du registre français du stenting rénal: étude Esternal.

Renal artery angioplasty using the same techniques employed for coronary arteries has developed considerably. A register was set up in France to evaluate the efficacy of this treatment for improving renal function and lowering blood pressure in cardiac patients. Between 2001 and 2005, 205 patients (234 lesions) were treated in 14 centres (mean age: 69.2 +/- 10.4 years, 59% male). All of the patients had hypertension and the majority of them (171) had renal failure (creatinine clearance<90 ml/min). Direct implantation of a stent was performed in 75.2% of the cases, successfully in 196 patients (96%) with 220 lesions (95.2%). The complications encountered were segmental renal infarction in two patients (0.9%), and four cases of minor vascular complications at the puncture site (2%). The mean value for pre-implantation creatinine clearance was 54.6 +/- 32.8 ml/min and 58.1 +/- 36.0 post- implantations. The duration of follow up was 5.9 +/- 2.7 months. Mortality was 3.5% (seven patients, of whom two died from renal causes). The mean systolic and diastolic blood pressure was 142.2 +/- 16.2 and 78.9 +/- 9.5 respectively versus 164.9 +/- 25.2 and 89.1 +/- 14.8 before treatment (p<0.0001). A non-significant improvement in creatinine clearance at six months was also observed in patients with renal failure prior to treatment: 48.7 +/- 17.1 ml/min vs. 69.2 +/- 160.3. Renal artery stenting in cardiac patients with renal artery stenosis is associated with a very high success rate, with few complications and an improvement in hypertension and renal function.

[Analytical interference in determination of procalcitonin by PCT-Q (Brahms)]. / Interférence analytique dans le dosage semi-quantitatif de la procalcitonine (PCT-Q Brahms).

Procalcitonin (PCT) is a biological marker of infection. We present the cas of a patient who has presented a high concentration of PCT with PCT-Q test (Brahms). At the same time, the concentration of CRP is remained low, which is no physiological. Then, PCT concentration has been determinated with an automatic system (Kryptor-Brahms) and finded at low than 0.5 microg/l. Brahms company has searched an analytical interference: human anti-mouse antibodies (HAMA) were positive. If PCT concentration stay a marker of infection for the most part, this case show that biologists have to keep in mind that immunological assays remain submitted to interferences.

Percutaneous implantation of an aortic valve prosthesis.

Recently, percutaneous aortic valve implantation has become an alternative technique to surgical valve replacement in patient at high risk for surgery. Our animal experimentation evaluated the technical feasibility of aortic valve replacement using a bovine pericardium valve sutured on a self-expandable stent in a sheep model. Precise implantation with satisfactory attachment on the adjacent tissues and absence of migration was obtain in 8 out of 14 animals. This study confirmed the feasibility of the endovascular implantation of a pericardium valve sutured on a self-expandable stent in a sheep model.