Increased FH-Risk-Score and Diabetes Are Cardiovascular Risk Equivalents in Heterozygous Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic condition causing premature atherosclerotic cardiovascular disease (ASCVD). It is well established that patients with FH should be treated with statin therapy. However, there exists discordance concerning low-density lipoprotein cholesterol-lowering goals in the management of these patients between different guidelines worldwide. The objective was to compare the 10-year ASCVD risk of different subgroups of patients with and without FH including those with diabetes or a history of ASCVD and patients with FH within different FH-Risk-Score categories. METHODS: This multinational observational study used data from 3 different prospective cohorts. A total of 3383 FH and 6917 non-FH controls matched for age and sex were included (104 363 person-years of follow-up). The 10-year incident ASCVD risk was assessed using Kaplan-Meier estimates, whereas the relative risk was estimated using Cox proportional hazards regression models. RESULTS: FH patients with a high (score >20%) FH-Risk-Score (hazard ratio, 8.45 [95% CI, 6.69-10.67]; P<0.0001), FH patients with diabetes (hazard ratio, 7.67 [95% CI, 4.82-12.21]; P<0.0001), and non-FH patients with ASCVD (hazard ratio, 6.78 [95% CI, 5.45-8.42]; P<0.0001) had a significantly higher incident ASCVD risk over 10 years than the reference group (non-FH without ASCVD or diabetes). The observed 10-year risks in these groups were 32.1%, 30.8%, 30.0%, and 5.1%, respectively. The 10-year ASCVD risk associated with both FH and ASCVD was extremely high (observed risk of 50.7%; hazard ratio, 14.53 [95% CI, 12.14-17.38]; P<0.0001). CONCLUSIONS: This study strongly suggests that the observed risk of FH patients with diabetes, history of ASCVD, and FH-Risk-Score >20% is as high or higher than non-FH individuals with a history of ASCVD. More aggressive management should be recommended for these patients.

Ibrutinib improves survival compared with chemotherapy in mantle cell lymphoma with central nervous system relapse.

Central nervous system (CNS) relapse of mantle cell lymphoma (MCL) is a rare phenomenon with dismal prognosis, where no standard therapy exists. Since the covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in relapsed/refractory MCL and penetrates the blood-brain barrier (BBB), on behalf of Fondazione Italiana Linfomi and European Mantle Cell Lymphoma Network we performed a multicenter retrospective international study to investigate the outcomes of patients treated with ibrutinib or chemoimmunotherapy. In this observational study, we recruited patients with MCL with CNS involvement at relapse who received CNS-directed therapy between 2000 and 2019. The primary objective was to compare the overall survival (OS) of patients treated with ibrutinib or BBB crossing chemotherapy. A propensity score based on a multivariable binary regression model was applied to balance treatment cohorts. Eighty-eight patients were included. The median age at study entry was 65 years (range, 39-87), 76% were males, and the median time from lymphoma diagnosis to CNS relapse was 16 months (range, 1-122). Patients were treated with ibrutinib (n = 29, ibrutinib cohort), BBB crossing chemotherapy (ie, high-dose methotrexate ± cytarabine; n = 29, BBB cohort), or miscellaneous treatments (n = 30, other therapy cohort). Both median OS (16.8 vs 4.4 months; P = .007) and median progression-free survival (PFS) (13.1 vs 3.0 months; P = .009) were superior in the ibrutinib cohort compared with the BBB cohort. Multivariable Cox regression model revealed that ibrutinib therapeutic choice was the strongest independent favorable predictive factor for both OS (hazard ratio [HR], 6.8; 95% confidence interval [CI], 2.2-21.3; P < .001) and PFS (HR, 4.6; 95% CI, 1.7-12.5; P = .002), followed by CNS progression of disease (POD) >24 months from first MCL diagnosis (HR for death, 2.4; 95% CI, 1.1-5.3; P = .026; HR for death or progression, 2.3; 95% CI, 1.1-4.6; P = .023). The addition of intrathecal (IT) chemotherapy to systemic CNS-directed therapy was not associated with superior OS (P = .502) as the morphological variant (classical vs others, P = .118). Ibrutinib was associated with superior survival compared with BBB-penetrating chemotherapy in patients with CNS relapse of MCL and should be considered as a therapeutic option.

Health-related quality of life in patients with hematologic malignancies treated with chimeric antigen receptor T-cell therapy: review and current progress.

Chimeric antigen receptor (CAR) T-cell therapy has transformed the care of patients with relapsed/refractory B-cell derived hematologic malignancies. To date, six CAR T-cell therapies, targeting either CD19 or B-cell maturation antigen, have received regulatory approval. Along with the promising survival benefit, CAR T-cell therapy is associated with potentially lifethreatening adverse events (AE), including cytokine release syndrome and immune effector cellassociated neurotoxicity syndrome. While clinical trials evaluating CAR T-cell therapy consistently report the incidence of these AE, most trials do not collect health-related quality of life (HRQoL) data. As such, the impact of CAR T-cell therapy process and related AE on the physical and psychological well-being of patients remains uncertain. HRQoL and other patientreported outcome (PRO) assessments in patients with relapsed or refractory hematologic malignancies are of utmost importance, as individuals may have unmet needs and a high demand for tolerable therapy if a cure is not obtained. In addition, it is important to standardize methods of data collection to better assess the impact of CAR T-cell therapy on quality of life, optimize patient care and costs, and enable comparison between different studies. We conducted a literature search up to June 2023 to identify the HRQoL tools used in clinical trials and in realworld studies investigating CAR T-cell therapy in patients with lymphomas or leukemias. In the present comprehensive review, we summarize the most commonly used CAR T-cell specific and non-specific HRQoL tools and discuss how the use of HRQoL and other PRO tools may be optimized.

Diagnosis of remnant hyperlipidaemia.

PURPOSE OF REVIEW: In recent years, there has been interest for the development of simplified diagnosis algorithms of dysbetalipoproteinemia (DBL) in order to avoid the complex testing associated with the Fredrickson criteria (reference method). The purpose of this review is to present recent advances in the field of DBL with a focus on screening and diagnosis. RECENT FINDINGS: Recently, two different multi-step algorithms for the diagnosis of DBL have been published and their performance has been compared to the Fredrickson criteria. Furthermore, a recent large study demonstrated that only a minority (38%) of DBL patients are carriers of the E2/E2 genotype and that these individuals presented a more severe phenotype. SUMMARY: The current literature supports the fact that the DBL phenotype is more heterogeneous and complex than previously thought. Indeed, DBL patients can present with either mild or more severe phenotypes that can be distinguished as multifactorial remnant cholesterol disease and genetic apolipoprotein B deficiency. Measurement of apolipoprotein B as well as APOE gene testing are both essential elements in the diagnosis of DBL.

Hepatic steatosis is associated with anthropometry, cardio-metabolic disease risk, sex, age and urbanisation, but not with ethnicity in adult Kenyans.

OBJECTIVE: We aimed to determine the associations of non-alcoholic fatty liver disease (NAFLD) with cardio-metabolic risk factors for diabetes in adult Kenyans. METHODS: A cross-sectional study was undertaken among rural and urban Kenyans of different ethnic origin. Ultrasonography scanning (USS) methods were used for the assessment of hepatic fat accumulation for NAFLD assessment and abdominal fat distribution, and simple anthropometry measurements were performed. All participants underwent a 2-h oral glucose tolerance test, and biochemical, haemodynamic and lifestyle data were obtained. Multivariate logistic regression analyses were used to assess sex, age, residency and ethnic differences in the association between NAFLD and various metabolic parameters. RESULTS: In total, 743 individuals (59.1% women) with a mean age of 38.0 (range 18-68) years participated in the study. Overall, 118 individuals (15.9%) had NAFLD, of whom 94.1% had mild steatosis. Age >40 years was significantly associated with having NAFLD compared with <30 years of age with no difference found in NAFLD between ethnic groups (Luo, Kamba, Maasai). All body composition and clinical measurements were associated with NAFLD (p < 0.045 for OR). CONCLUSION: Finding lower odds for NAFLD in men was unexpected, as was the lack of differences in NAFLD among the ethnic groups, while higher odds for NAFLD with increasing age and in urban vs. rural populations was expected. Especially the sex-specific results warrant further studies in black African populations on biology of body composition for having NAFLD, and whether this translates into insulin resistance and higher risk of diabetes and consequently cardiovascular disease in black African women.

Familial Hypercholesterolemia-Risk-Score: A New Score Predicting Cardiovascular Events and Cardiovascular Mortality in Familial Hypercholesterolemia.

Objective: Familial hypercholesterolemia (FH) is associated with a high risk of premature atherosclerotic cardiovascular disease (ASCVD). However, this risk is highly heterogeneous and current risk prediction algorithms for FH suffer from limitations. The primary objective of this study was to develop a score predicting incident ASCVD events over 10 years in a large multinational FH cohort. The secondary objective was to investigate the prediction of major adverse cardiovascular events and cardiovascular mortality using this score. Approach and Results: We prospectively followed 3881 patients with adult heterozygous FH with no prior history of ASCVD (32 361 person-years of follow-up) from 5 registries in Europe and North America. The FH-Risk-Score incorporates 7 clinical variables: sex, age, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, hypertension, smoking, and lipoprotein (a) (Lp(a)) with a Harrell C-index for 10-year ASCVD event of 0.75, which was superior to the SAFEHEART-RE (Spanish Familial Hypercholesterolemia Cohort; 0.69). Subjects with an elevated FH-Risk-Score had decreases in 10-year ASCVD-free survival, 10-year major adverse cardiovascular event-free survival, and 30-year survival for CV mortality compared with the low-risk group, with hazard ratios of 5.52 (3.94-7.73), 4.64 (2.66-8.11), and 10.73 (2.51-45.79), respectively. The FH-Risk-Score showed a similar performance in subjects with and without an FH-causing mutation. Conclusions: The FH-Risk-Score is a stronger predictor of future ASCVD than the SAFEHEART-RE and was developed in FH subjects with no prior cardiovascular event. Furthermore, the FH-Risk-Score is the first score to predict CV death and could offer personalized cardiovascular risk assessment and treatment for patients with FH. Future studies are required to validate the FH-Risk-Score in different ethnic groups.

Audiovestibular Consequences of Congenital Cytomegalovirus Infection: Greater Vulnerability of the Vestibular Part of the Inner Ear.

OBJECTIVES: To investigate the impact of congenital cytomegalovirus infection on cochlear and vestibular function. DESIGN: This retrospective study conducted between March 2014 and March 2020 included children with confirmed congenital cytomegalovirus infection who underwent a complete audio-vestibular evaluation. It included a bithermal caloric test, a video head impulse test and a cervical vestibular evoked myogenic potential associated with a complete hearing assessment. RESULTS: The cohort of 130 children included in the study had a median age of 21 months (interquartile range: 12 to 37 months). Eighty-three children (64%) showed an inner ear impairment (both cochlear and vestibular). The vestibular part of the inner ear was significantly more frequently impaired than the cochlear part (ρ = 0.003). Sixty-two children (48%) showed confirmed hearing impairment. The severity of hearing loss was variable, with a high proportion of profound hearing loss (30/62, 48%), which was often bilateral (47/62, 76%). The vestibular assessment showed a canal function disorder in 67 children (88%) and an otolith function disorder in 63 children (83%; ρ = 0.36). The video head impulse test was significantly less altered (64%) compared with the bithermal caloric test (80%; ρ = 0.02) and the cervical vestibular evoked myogenic potential (83%; ρ = 0.009). Only seven out of 83 children (8%) showed hearing loss without vestibular dysfunction, of which only one had a normal hearing screening test at birth. For the children who passed the hearing screening test at birth and presented an inner ear impairment [n = 36, median age: 16 (11 to 34) months], vestibular disorders were later found in 35 children (97%) and 17 of them (47%) developed hearing loss secondarily. This underlines the importance of assessing both vestibular and auditory parts of the inner ear. When comparing the agreement of cochlear and vestibular impairment, the severity and the laterality of the impairment were low [Cohen's kappa 0.31 (0.22 to 0.40) and 0.43 (0.32 to 0.55), respectively]. CONCLUSION: In our study, we demonstrated that although both cochlear and vestibular parts of the inner ear can be impaired by congenital cytomegalovirus infection, the vestibular part seems more often impaired compared with the cochlear part. This underlines the importance of vestibular evaluation in the follow-up of cytomegalovirus-infected children associated with hearing assessment.

Predictors of cochleovestibular dysfunction in children with congenital cytomegalovirus infection.

The purpose of this study is to assess the predictive factors of both hearing and vestibular impairment in congenitally cytomegalovirus-infected children (cCMV) through a multivariate analysis of clinical and imaging characteristics collected during pregnancy and at birth. This retrospective study was conducted between March 2014 and March 2020, including confirmed congenitally CMV-infected children with a complete vestibular and hearing assessment. Data concerning pregnancy, date of infection, clinical characteristics, and symptomatology at birth were collected. In total, 130 children were included, with a median age of 21 months. Eighty-three children (64%) presented with an inner ear impairment (both cochlear and vestibular impairment). Sex, modality of maternal infection (seroconversion or reactivation), pregnancy term, weight and head circumference at birth, neonatal clinical signs of infection, and treatment were not significantly correlated with inner ear impairment. However, multivariate analysis confirmed that there are two independent predictive factors of inner ear impairment: antenatal imaging lesions (ORa = 8.02 [1.74; 60.27], p-value = 0.01) and infection during the first trimester (ORa = 4.47 [1.21; 19.22], p-value = 0.03). Conversely, infections occurring during the second trimester were rarely associated with inner ear impairment: 4/13 (31%) in our series, with vestibular impairment alone (4/4) and no hearing loss. None of the children infected during the third trimester developed inner ear dysfunction. CONCLUSION: Besides the symptomatic status of the CMV infection at birth, we found that antenatal imaging brain damage and early infection (mainly during the first trimester) constitute the two best independent predictive factors of inner ear involvement in congenitally CMV-infected children. WHAT IS KNOWN: • Congenital cytomegalovirus infection is the leading infectious cause of neurological disabilities and sensorineural hearing loss in children and responsible of vestibular disorders, which are probably underestimated. • No articles have yet defined the predictive factors of the entire inner ear impairment (vestibule and cochlea). WHAT IS NEW: • The timing of the infection during pregnancy (first and second trimester, ORa=4.47) and antenatal imaging lesions (ORa=8.02) are independently predictive (in a multivariate analysis) of inner ear involvement. • The symptomatic status at birth is a poor predictor of inner ear impairment.

Effect of a Bacillus subtilis strain on flax protection against Fusarium oxysporum and its impact on the root and stem cell walls.

In Normandy, flax is a plant of important economic interest because of its fibres. Fusarium oxysporum, a telluric fungus, is responsible for the major losses in crop yield and fibre quality. Several methods are currently used to limit the use of phytochemicals on crops. One of them is the use of plant growth promoting rhizobacteria (PGPR) occurring naturally in the rhizosphere. PGPR are known to act as local antagonists to soil-borne pathogens and to enhance plant resistance by eliciting the induced systemic resistance (ISR). In this study, we first investigated the cell wall modifications occurring in roots and stems after inoculation with the fungus in two flax varieties. First, we showed that both varieties displayed different cell wall organization and that rapid modifications occurred in roots and stems after inoculation. Then, we demonstrated the efficiency of a Bacillus subtilis strain to limit Fusarium wilt on both varieties with a better efficiency for one of them. Finally, thermo-gravimetry was used to highlight that B. subtilis induced modifications of the stem properties, supporting a reinforcement of the cell walls. Our findings suggest that the efficiency and the mode of action of the PGPR B. subtilis is likely to be flax variety dependent.

Effect of caloric restriction with or without physical activity on body composition and epicardial fat in type 2 diabetic patients: A pilot randomized controlled trial.

BACKGROUND AND AIMS: There is debate over the independent and combined effects of caloric restriction (CR) and physical activity (PA) on reduction in fat mass and in epicardial fat thickness. We compared the impact of a similar energy deficit prescription by CR or by CR combined with PA on total fat mass, epicardial fat thickness, and cardiometabolic profile in individuals with type 2 diabetes. METHODS AND RESULTS: In this 16-week randomized controlled study, 73 individuals were randomly enrolled to receive: 1) a monthly motivational phone call (Control), 2) a caloric deficit of -700 kilocalories/day (CR), or 3) a caloric deficit of -500 kilocalories/day combined with a PA program of -200 kilocalories/day (CR&PA). Total fat mass, epicardial fat, and cardiometabolic profile were measured at baseline and after 16 weeks. While comparable weight loss occurred in both intervention groups (-3.9 ± 3.5 kg [CR], -5.1 ± 4.7 kg [CR&PA], -0.2 ± 2.9 kg [Control]), changes in total fat mass were significantly different between all groups (-2.4 ± 2.9 kg [CR], -4.5 ± 3.4 kg [CR&PA], +0.1 ± 2.1 kg [Control]; p < 0.05) as well as epicardial fat thickness (-0.4 ± 1.6 mm [CR], -1.4 ± 1.4 mm [CR&PA], +1.1 ± 1.3 mm [Control]; p < 0.05). There were no significant differences in trends for cardiometabolic parameters improvement between groups. CONCLUSIONS: For a similar energy deficit prescription and comparable weight loss, the combination of CR&PA provides a greater reduction in fat mass and epicardial fat thickness than CR alone in individuals with comparable weight loss and with a similar energy deficit prescription. These results, however, do not translate into significant improvements in cardiometabolic profiles. CLINICALTRIALS. GOV IDENTIFIER: NCT01186952.

Improved time to treatment failure and survival in ibrutinib-treated malignancies with a pharmaceutical care program: an observational cohort study.

Ibrutinib treatment has been shown to increase survival in patients with B cell malignancies. Real-life data suggest a large part of discontinuations are due to toxicities, impairing ibrutinib efficacy. We aimed to assess the impact of a pharmaceutical care program on the efficacy and safety of ibrutinib. This single-center, cohort, observational study enrolled patients with B cell malignancies. Patients were either assigned to the program or to receive usual care, based on physician decision. The program was conducted by clinical pharmacists specializing in oncology and included patient education for management of toxicities, adherence monitoring, interventions to reduce drug-drug interactions, and follow-up of transition from hospital to community. Between February 2014 and May 2017, we enrolled 155 patients, including 42 (27%) who were allocated to the program group and 113 (73%) to the usual care group. The effect of the program was beneficial in terms of time to treatment failure (p = 0.0005). The 30-month progression-free and overall survivals were significantly superior in the program group (respectively p = 0.002 and p = 0.004). Grade 3 or higher adverse events occurred more frequently for patients in the usual care group (15%) than program group (8%). A pharmaceutical care program provides a personalized environment for outpatient monitoring and control of the key risks associated with oral anticancer agents. This study shows evidence that management of ibrutinib treatment by clinical pharmacists results in significant improvement in survival and better tolerance than usual care.

The burden of familial chylomicronemia syndrome in Canadian patients.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by persistent extreme hypertriglyceridemia as a result of lipoprotein lipase deficiency. Canada is an important region for FCS research due to the high prevalence rates. The burden of illness and quality of life of Canadian patients, however, have been inadequately addressed in the literature. OBJECTIVE: To understand the burden of illness of FCS on Canadian patients' lives. METHODS: IN-FOCUS is a global web-based survey open to patients with FCS, including patients in Canada. This survey captured information on diagnostic experience, symptoms, comorbidities, disease management, and impact on multiple life dimensions. RESULTS: A total of 37 Canadian patients completed the IN-FOCUS survey. Patients saw a mean of 4 physicians before their FCS diagnosis despite 89% reporting an FCS family history. Patients experience multiple physical, emotional, and cognitive symptoms in addition to FCS-related comorbidities. Notably, 35% of those who answered the survey have experienced acute pancreatitis, averaging 14 lifetime episodes per patient. In the preceding 12 months, 46% of patients had an FCS-related hospitalization, averaging 3 nights' stay. All respondents restricted fat intake, with 27% following an extremely low-fat diet. Despite this, 100% of patients reported fasting TG levels above the normal range. FCS impacted career choice in nearly all patients (97%) and employment status in all patients who were employed part time, disabled, or homemakers, causing many (> 75%) to choose careers below their level of abilities. Furthermore, 2/3 of patients reported FCS had a significant impact on their decision regarding whether to have children. Most report significant interference with their emotional/mental well-being, social relationships, and the majority were concerned about the long-term impact of FCS on their health (89%). CONCLUSIONS: This study provides the first and largest study to investigate the multi-faceted psychosocial and cognitive impacts of FCS on patients. Canadian patients with FCS experience significant multi-faceted burdens that diminish their quality of life, employment opportunities, social relationships, and mental/emotional well-being. These results highlight the need for greater disease awareness, improved clinical diagnosis, broader clinical management for heterogenous symptoms, and more effective treatment options for FCS.

In vitro characterization of root extracellular trap and exudates of three Sahelian woody plant species.

MAIN CONCLUSION: Arabinogalactan protein content in both root extracellular trap and root exudates varies in three Sahelian woody plant species that are differentially tolerant to drought. At the root tip, mature root cap cells, mainly border cells (BCs)/border-like cells (BLCs) and their associated mucilage, form a web-like structure known as the "Root Extracellular Trap" (RET). Although the RET along with the entire suite of root exudates are known to influence rhizosphere function, their features in woody species is poorly documented. Here, RET and root exudates were analyzed from three Sahelian woody species with contrasted sensitivity to drought stress (Balanites aegyptiaca, Acacia raddiana and Tamarindus indica) and that have been selected for reforestation along the African Great Green Wall in northern Senegal. Optical and transmission electron microscopy show that Balanites aegyptiaca, the most drought-tolerant species, produces only BC, whereas Acacia raddiana and Tamarindus indica release both BCs and BLCs. Biochemical analyses reveal that RET and root exudates of Balanites aegyptiaca and Acacia raddiana contain significantly more abundant arabinogalactan proteins (AGPs) compared to Tamarindus indica, the most drought-sensitive species. Root exudates of the three woody species also differentially impact the plant soil beneficial bacteria Azospirillum brasilense growth. These results highlight the importance of root secretions for woody species survival under dry conditions.

Adverse events associated with currently used medical treatments for cystinuria and treatment goals: results from a series of 442 patients in France.

OBJECTIVE: To evaluate medical treatments, in terms of adverse events (AEs) and therapeutic goals, in a large series of patients with cystinuria. PATIENTS AND METHODS: Data from 442 patients with cystinuria were recorded retrospectively. Crystalluria was studied in 89 patients. A mixed-effects logistic regression model was used to estimate how urine pH, specific gravity and cysteine-binding thiols (CBT) correlate with risk of cystine crystalluria. RESULTS: Alkalizing agents and CBT agents were given to 88.8% (n = 381) and 55.3% (n = 238) of patients, respectively. Gastrointestinal AEs were reported in 12.3%, 10.4% and 2.6% of patients treated with potassium bicarbonate, potassium citrate and sodium bicarbonate, respectively (P = 0.008). The percentages of patients who experienced at least one AE with tiopronin (24.6%) and with D-penicillamine (29.5%) were similar (P = 0.45). Increasing urine pH and decreasing urine specific gravity significantly reduced the risk of cystine crystalluria, whereas D-penicillamine and tiopronin treatments did not reduce this risk (odds ratio [OR] 1 for pH ≤6.5; OR 0.52 [95% confidence interval {95% CI} 0.28-0.95] for 7.0 8.0, P <0.001). CONCLUSION: Adverse events were frequent with D-penicillamine and tiopronin. Alkaline hyperdiuresis was well tolerated and reduced cystine crystalluria. Urine specific gravity ≤1.005 and urine pH >7.5, while warning about calcium-phosphate crystallization, should be the goals of medical therapy.

Routine multi detector computed tomography evaluation of tracheal impairment compared to laryngo-tracheal endoscopy in children with vascular ring.

PURPOSE: The aim of this study is to compare free-breathing routine multi detector computed tomography (MDCT) and laryngo-tracheal (LT) flexible endoscopy in the evaluation of tracheal impairment in children with vascular ring (VR). MATERIALS AND METHODS: We performed a retrospective and monocentric study of all patients with VR from 1997 to 2014. Clinical data included: initial symptoms, type of surgery and clinical outcome. MDCT were blindly reviewed by two radiologists in consensus, independently of LT endoscopy results. Radiologic and endoscopic results were reviewed according to four criteria: percentage of tracheal narrowing, distance of the compression from carina, presence of bronchial compression and signs of tracheomalacia (TM). Concordance was evaluated for each criterion with a Spearman coefficient. RESULTS: From 1997 to 2016, 21 patients with a vascular ring were operated on, among which 57% by thoracoscopy: double aortic arch (n = 14), Neuhauser anomaly (n = 4) and Right aorta + aberrant right subclavian artery (n = 3). 90% of them presented with respiratory symptoms among which 43% of stridor. Chest X-ray was suggestive of VR in 87% of the cases. MDCT images and LT endoscopy results were available and analyzed for nine patients. Concordance (Spearman correlation coefficient) was excellent for percentage and level of tracheal narrowing (1) and good for TM (0.79). CONCLUSION: Free breathing routine MDCT is a reliable exam compared to LT endoscopy in the evaluation of tracheal impairment in children with VR. In case of respiratory symptoms (except stridor) and suggestive chest X-ray of VR, endoscopy could be avoided and routine MDCT alone performed.

Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse.

The risk of central nervous system (CNS) dissemination in mantle cell lymphoma (MCL) is low and occurs late in the course of the disease. However, prognosis in such cases remains extremely poor despite high-dose antimetabolite chemotherapy. Among novel drugs used to treat relapsing MCL patients, ibrutinib, an oral inhibitor of Bruton tyrosine kinase, shows great promise. Here we report the clinical observation of 3 MCL patients with symptomatic CNS relapse treated with single-agent ibrutinib. All 3 patients had dramatic and rapid responses with almost immediate recovery from symptoms. We also confirmed that ibrutinib crosses the blood-brain barrier with parallel pharmacokinetic analyses in plasma and cerebrospinal fluid using a validated LC-MS/MS method. All responses were ongoing after 2 months to 1 year of follow-up.

Ultrastructural Immunolocalization of Arabinogalactan Protein, Pectin and Hemicellulose Epitopes Through Anther Development in Brassica napus.

In this work, we performed an extensive and detailed analysis of the changes in cell wall composition during Brassica napus anther development. We used immunogold labeling to study the spatial and temporal patterns of the composition and distribution of different arabinogalactan protein (AGP), pectin, xyloglucan and xylan epitopes in high-pressure-frozen/freeze-substituted anthers, quantifying and comparing their relative levels in the different anther tissues and developmental stages. We used the following monoclonal antibodies: JIM13, JIM8, JIM14 and JIM16 for AGPs, LM5, LM6, JIM7, JIM5 and LM7 for pectins, CCRC-M1, CCRC-M89 and LM15 for xyloglucan, and LM11 for xylan. Each cell wall epitope showed a characteristic temporal and spatial labeling pattern. Microspore, pollen and tapetal cells showed similar patterns for each epitope, whereas the outermost anther layers (epidermis, endothecium and middle layers) presented remarkably different patterns. Our results suggested that AGPs, pectins, xyloglucan and xylan have specific roles during anther development. The AGP epitopes studied appeared to belong to AGPs specifically involved in microspore differentiation, and contributed first by the tapetum and then, upon tapetal dismantling, by the endothecium and middle layers. In contrast, the changes in pectin and hemicellulose epitopes suggested a specific role in anther dehiscence, facilitating anther wall weakening and rupture. The distribution of the different cell wall constituents is regulated in a tissue- and stage-specific manner, which seems directly related to the role of each tissue at each stage.

Inhibitors of BCR signalling interrupt the survival signal mediated by the micro-environment in mantle cell lymphoma.

Several studies provide evidences for mantle cell lymphoma (MCL) cell survival relying on B-cell receptor (BCR)-mediated signalling pathways, whereas the nature of this activation is unknown. Significant progress in MCL treatment is achieved through therapies targeting BCR-associated kinases, i.e., Ibrutinib and Fostamatinib, inhibitors of BTK and SYK, respectively. Our study addresses survival signals emanating from the BCR or the tumour environment and how inhibiting BCR signalling effectors might impact these survival signals. We found that BTK was constitutively activated and that SYK phosphorylation was highly increased and sustained upon BCR activation of primary MCL cells. Moreover, MCL cells from leukaemic patients secreted high amount of IL-1ß, IL-6, IL-8 and CCL5. Activation of the BCR induced (i) cell survival, (ii) STAT3 activation and (iii) increased autocrine secretion of IL-1ß, IL-6, IL-8, CCL5, IL-10, TNFα and VEGF. Specific inhibition of BTK by Ibrutinib or SYK by Fostamatinib (R406) reversed these protective effects and decreased both basal and BCR-induced autocrine cytokine secretions associated with STAT3 phosphorylation. Interestingly, targeting BTK and SYK prevented and inhibited BCR-induced MCL cell adhesion to human bone marrow stromal cells (HMSCs) in short- and long-term co-culture. We demonstrated that BCR-induced survival relies on autocrine secretion of IL-1ß, TNFα and CCL5 that might facilitate adhesion of MCL cells to HMSC. Treatment with Ibrutinib or Fostamatinib blocked the chemotactic signal thus increasing apoptosis.

Methyl jasmonate affects morphology, number and activity of endoplasmic reticulum bodies in Raphanus sativus root cells.

The endoplasmic reticulum (ER) bodies are ER-derived structures that are found in Brassicaceae species and thought to play a role in defense. Here, we have investigated the occurrence, distribution and function of ER bodies in root cells of Raphanus sativus using a combination of microscopic and biochemical methods. We have also assessed the response of ER bodies to methyl jasmonate (MeJA), a phytohormone that mediates plant defense against wounding and pathogens. Our results show that (i) ER bodies do occur in different root cell types from the root cap region to the differentiation zone; (ii) they do accumulate a PYK10-like protein similar to the major marker protein of ER bodies that is involved in defense in Arabidopsis thaliana; and (iii) treatment of root cells with MeJA causes a significant increase in the number of ER bodies and the activity of ß-glucosidases. More importantly, MeJA was found to induce the formation of very long ER bodies that results from the fusion of small ones, a phenomenon that has not been reported in any other study so far. These findings demonstrate that MeJA impacts the number and morphology of functional ER bodies and stimulates ER body enzyme activities, probably to participate in defense responses of radish root. They also suggest that these structures may provide a defensive system specific to root cells.

Congenital middle ear anomalies: anatomical and functional results of surgery.

The aim of this study was to describe the audiometric results following surgery in a consecutive series of pediatric patients with a congenital middle ear disorder. Retrospective chart review was performed for 29 consecutive children who underwent 33 middle ear surgeries for congenital ossicular chain anomaly between 1990 and 2012. Anomalies were classified into four groups according to the Teunissen and Cremers classification. Audiological parameters using four frequency averages (0.5, 1, 2 and 4 kHz) were assessed pre- and postoperatively. Clinical and audiometric follow-up times were, respectively, 49 ± 8 and 35 ± 5 months (mean ± SEM). Fifty-eight percent of all patients achieved an air-bone gap (ABG) ≤20 dB, 62.5% in class I, 50% in class II and 57.9% in class III. The improvement of the mean ABG was 13.6 dB, 19.2 dB for class I, 0.2 dB in class II and 15.4 dB in class III. Overall mean pure-tone averages improved 14.8 dB with 13.9 dB for class I; there was no improvement for class II and 20.2 dB for class III. The sensorineural hearing loss rate was 9%. This pediatric series showed that hearing results depend on type of anomaly. Class I and class III showed better hearing improvement than class II.