Adoptive transfer of dendritic cells from allergic mice induces specific immunoglobulin E antibody in naïve recipients in absence of antigen challenge without altering the T helper 1/T helper 2 balance

Dendritic cells (DCs) are important in the regulation of immune responses and it has been proposed that these cells play an important role in asthma; however, their role in food allergy is still largely unknown. Our aim was to study specific immunoglobulin E (IgE) and immunoglobulin G (IgG) responses in naïve recipients following adoptive transfer of myeloid DCs from allergic and control mice. The phenotypic features and lymphokine production of DCs were also investigated. CD11c ^{+ /hi} B220^? DCs isolated from spleen and Peyer's patches (PP) of cow's milk (CM) allergic and control mice were transferred intravenously (i.v.) into naïve syngeneic recipients, and IgE‐ and IgG‐specific responses were evaluated. Experiments were also carried out to determine the levels of interferon‐γ (IFN‐γ) and interleukin (IL)‐4 produced by splenocytes from naïve recipients following the adoptive transfer, and CD40 ligand (CD40L)‐mediated IL‐10 production by DCs from allergic and control mice. DCs isolated from spleen and PP of allergic mice, but not control groups, induced CM‐specific IgG and IgE antibody production in naïve recipients in the absence of previous immunization, but did not modify the T helper 1 (Th1) and T helper 2 (Th2) balance. Furthermore, although no difference was observed in the expression of canonical DC surface markers, PP DCs from allergic mice produced less IL‐10 than DCs from controls. We interpret these data as showing that DCs play a pivotal role in allergen‐specific IgE responses and that a Th2‐skewed response may not be involved in the early phase of allergic responses. The identification of the mechanisms underlying these events may help to design novel strategies of therapeutic intervention in food allergy.     

ASY1 mediates AtDMC1-dependent interhomolog recombination during meiosis in Arabidopsis

ASY1 is an Arabidopsis protein required for synapsis and crossover formation during meiosis. The chronology of meiotic recombination has been investigated in wild type and an asy1 mutant. We observe a delay between the appearance of chromatin-associated AtSPO11-1 foci and DNA double-strand break (DSB) formation, which occurs contemporaneously with chromosome axis formation and transition of ASY1 from chromatin-associated foci to a linear axis-associated signal. DSBs are formed independently of ASY1 in an AtSPO11-1-dependent manner. They are partially restored in Atspo11-1-3 using cisplatin, but their control appears abnormal. Axis morphogenesis is independent of ASY1, but axis structure may be compromised in asy1. Localization of the strand exchange proteins AtRAD51 and AtDMC1 to the chromatin occurs asynchronously shortly after DSB formation, with AtDMC1 localizing in advance of AtRAD51. In wild-type nuclei, both recombinases form numerous foci that persist for approximately 12 h before gradually decreasing in number. In asy1, initial localization of AtDMC1 is normal, but declines abruptly such that interhomolog recombination is severely compromised. Limited ASY1-independent, DMC1-dependent interhomolog recombination remains, but appears restricted to subtelomeric sequences where the homologs are fortuitously in proximity. Thus, ASY1 plays a key role in coordinating the activity of the RecA homologs to create a bias in favor of interhomolog recombination.     

Combination of biomarkers to predict mortality in elderly patients with myocardial infarction

OBJECTIVE: The elderly subjects affected by Acute Myocardial Infarction (AMI) have the highest risk of mortality. Our study was designed to improve the capability of mortality risk stratification in elderly AMI patients through the concurrent evaluations of different biomarkers, including genetic markers. METHODS AND RESULTS: One-year follow-up study was performed in 250 elderly AMI patients. The combination of high total Homocysteine (tHcy), low folate and vitamin B12 plasma levels (18.0+/-9.0 micromol/l; 4.4+/-1.2 ng/ml; 404.2+/-287.5 pg/ml, respectively) and elevated CRP plasma levels (> or =6 mg/dl) identify the highest-risk pathway of heart mortality (RR=4.20, IC 95% 1.62-10.89, P<0.002) with respect to the combination of low total tHcy, high folate and vitamin B12 plasma levels (12.4+/-5.2 micromol/l; 8.9+/-2.5 ng/ml; 546.9+/-379.8 pg/ml, respectively) and low CRP plasma levels (<6 mg/dl). CONCLUSION: In elderly AMI patients the concomitant elevation of CRP and tHcy, associated with folate and vitamin B12 low levels, could be considered a significant predictive heart mortality risk factor.     

Recessive mutations in MSTO1 cause mitochondrial dynamics impairment,leading to myopathy and ataxia

We report here the first families carrying recessive variants in the MSTO1 gene: compound heterozygous mutations were identified in two sisters and in an unrelated singleton case, who presented a multisystem complex phenotype mainly characterized by myopathy and cerebellar ataxia. Human MSTO1 is a poorly studied protein, suggested to have mitochondrial localization and to regulate morphology and distribution of mitochondria. As for other mutations affecting genes involved in mitochondrial dynamics, no biochemical defects typical of mitochondrial disorders were reported. Studies in patients’ fibroblasts revealed that MSTO1 protein levels were strongly reduced, the mitochondrial network was fragmented, and the fusion events among mitochondria were decreased, confirming the deleterious effect of the identified variants and the role of MSTO1 in modulating mitochondrial dynamics. We also found that MSTO1 is mainly a cytosolic protein. These findings indicate recessive mutations in MSTO1 as a new cause for inherited neuromuscular disorders with multisystem features.     

Fibromyalgia syndrome and depressive symptoms: Comorbidity and clinical correlates

ObjectiveFibromyalgia is characterized by chronic widespread musculoskeletal pain and higher pain perception in specific anatomic sites called tender points. Fibromyalgia is frequently associated with psychiatric symptoms, like depression and anxiety; indeed some authors have argued about the possibility to classify this syndrome into affective spectrum disorder. Few studies have analyzed the impact of depressive symptoms on pain threshold. This research is aimed at evaluating the prevalence and the clinical correlates of depressive symptoms in fibromyalgic patients, and investigating their impact on pain perception and quality of life.MethodsOutpatients between 18 and 75 years with diagnosis of fibromyalgia according to the criteria of the American College of Rheumatology have been included. All subjects have been evaluated with the following rating scales: HAM-D; VAS (to quantify pain); a visual analogical scale to evaluate quality of life; and Paykel's List of Recent Life Events.ResultsThirty subjects have been recruited. Most patients (83.3%) had clinically significant depressive symptoms as indicated by a HAM-D score > 7. Depressive symptoms are associated with higher pain perception, worse quality of life and more severe life events.ConclusionThe presence of depressive symptoms is associated with a great impairment in patients with fibromyalgia syndrome: indeed the psychiatric comorbidity lowers pain threshold and worsens the quality of life of our patients. Future studies should be conducted in order to identify the individual factors, e.g. stress or inflammatory processes, which drive the association between depression and higher severity of fibromyalgia syndrome.     

Regulation of biliary proliferation by neuroendocrine factors: implications for the pathogenesis of cholestatic liver diseases

The proliferation of cholangiocytes occurs during the progression of cholestatic liver diseases and is critical for the maintenance and/or restoration of biliary mass during bile duct damage. The ability of cholangiocytes to proliferate is important in many different human pathologic conditions. Recent studies have brought to light the concept that proliferating cholangiocytes serve as a unique neuroendocrine compartment in the liver. During extrahepatic cholestasis and other pathologic conditions that trigger ductular reaction, proliferating cholangiocytes acquire a neuroendocrine phenotype. Cholangiocytes have the capacity to secrete and respond to a variety of hormones, neuropeptides, and neurotransmitters, regulating their surrounding cell functions and proliferative activity. In this review, we discuss the regulation of cholangiocyte growth by neuroendocrine factors in animal models of cholestasis and liver injury, which includes a discussion of the acquisition of neuroendocrine phenotypes by proliferating cholangiocytes and how this relates to cholangiopathies. We also review what is currently known about the neuroendocrine phenotypes of cholangiocytes in human cholestatic liver diseases (ie, cholangiopathies) that are characterized by ductular reaction.     

Quantitative evaluation of upper-limb motor control in robot-aided rehabilitation

This paper is focused on the multimodal analysis of patient performance, carried out by means of robotic technology and wearable sensors, and aims at providing quantitative measure of biomechanical and motion planning features of arm motor control following rehabilitation. Upper-limb robotic therapy was administered to 24 community-dwelling persons with chronic stroke. Performance indices on patient motor performance were computed from data recorded with the InMotion2 robotic machine and a magneto-inertial sensor. Motor planning issues were investigated by means of techniques of motion decomposition into submovements. A linear regression analysis was carried out to study correlation with clinical scales. Robotic outcome measures showed a significant improvement of kinematic motor performance; improvement of dynamic components was more significant in resistive motion and highly correlated with MP. The analysis of motion decomposition into submovements showed an important change with recovery of submovement number, amplitude and order, tending to patterns measured in healthy subjects. Preliminary results showed that arm biomechanical functions can be objectively measured by means of the proposed set of performance indices. Correlation with MP is high, while correlation with FM is moderate. Features related to motion planning strategies can be extracted from submovement analysis.     

PML-RAR induces promyelocytic leukemias with high efficiency following retroviral gene transfer into purified murine hematopoietic progenitors

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations resulting in fusion proteins of the retinoic acid receptor (RAR). Here, we report a novel murine model system for APL, based on the transduction of purified murine hematopoietic progenitors (lin(-)) using high-titer retroviral vectors encoding promyelocytic leukemia-RAR (PML-RAR), and the green fluorescent protein (GFP) as a marker. PML-RAR-expressing lin(-) cells were impaired in their ability to undergo terminal myeloid differentiation and showed increased proliferative potential in vitro. Inoculation of transduced lin(-) cells into syngeneic, irradiated mice resulted in the development of retinoic acid-sensitive promyelocytic leukemias at high frequency (> 80%) and short latency (approximately 4 months). Morphologic and immunophenotypic analysis revealed no gross abnormalities of the preleukemic bone marrows. However, hematopoietic progenitors from PML-RAR preleukemic mice showed a severe impairment in their ability to undergo myeloid differentiation in vitro. This result, together with the monoclonality or oligoclonality of the leukemic blasts, supports a "multiple-hit" model, where the fusion protein causes a "preleukemic" phase, and leukemia occurs after additional genetic lesions. This model system faithfully reproduces the main characteristics of human APL and represents a versatile tool for the in vitro and in vivo study of mechanisms of leukemogenesis and the design of protocols for differentiation treatment.