Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen

Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7-1 (CD80) and only a subset express B7-2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7-1 and B7-2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.     

Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1)

Unconjugated bilirubin (UCB) causes encephalopathy in severely jaundiced neonates by damaging astrocytes and neurons. Astrocytes, which help defend the brain against cytotoxic insults, express the ATP-dependent transporter, multidrug resistance-associated protein 1 (Mrp1), which mediates export of organic anions, probably including UCB. We therefore studied whether exposure to UCB affects the expression and intracellular localization of Mrp1 in cultured mouse astroglial cells (>95% astrocytes). Mrp1 was localized and quantitated by confocal laser scanning microscopy and double immunofluorescence labeling by using specific antibodies against Mrp1 and the astrocyte marker glial fibrillary acidic protein, plus the Golgi marker wheat germ agglutinin (WGA). In unexposed astrocytes, Mrp1 colocalized with WGA in the Golgi apparatus. Exposure to UCB at a low unbound concentration (Bf) of 40 nM caused rapid redistribution of Mrp1 from the Golgi throughout the cytoplasm to the plasma membrane, with a peak 5-fold increase in Mrp1 immunofluorescence intensity from 30 to 120 min. Bf above aqueous saturation produced a similar but aborted response. Exposure to this higher Bf for 16 h markedly decreased Trypan blue exclusion and methylthiazoletetrazoilum activity and increased apoptosis 5-fold by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay. These toxic effects were modestly increased by inhibition of Mrp1 activity with 3-([3-(2-[7-chloro-2-quinolinyl]ethenyl)phenyl-(3-dimethylamino-3-oxopropyl)-thio-methyl]thio)propanoic acid (MK571). By contrast, Bf=40 nM caused injury only if Mrp1 activity was inhibited by MK571, which also blocked translocation of Mrp1. Our conclusion is that in astrocytes, UCB up-regulates expression of Mrp1 and promotes its trafficking from the Golgi to the plasma membrane, thus moderating cytotoxicity from UCB, presumably by limiting its intracellular accumulation.     

Increase in Hepatitis A Cases Linked to Imported Strains to Rio de Janeiro,Brazil: A Cross-Sectional Study

This study aims to evaluate the epidemiological and molecular features associated with HAV transmission in adults in Rio de Janeiro during a period of increased registered cases of HAV (2017–2018). Socio-epidemiological data and serum samples from anti-HAV IgM+ individuals were obtained. HAV RNA was RT-PCR amplified and sequenced for further phylogenetic and phylogeographic analyses. From fifty-two HAV IgM+ individuals, most were men (78.85%; p = 0.024), aged 20–30 years old (84.61%; p < 0.001), resided in the Rio de Janeiro north zone (31/52; 59.62%; p = 0.001), and are men who have sex with men (MSM) (57.69%; p = 0.002). Sexual practices were more frequent (96%) than others risk factors (food-borne (44%), water-borne (42.31%), and parenteral (34.62%)). Individuals who traveled to endemic regions had a 7.19-fold (1.93–36.04; p < 0.01) increased risk of HAV. Phylogenetic analysis revealed four distinct clades of subgenotype IA, three of them comprised sequences from European/Asian MSM outbreaks and one from Brazilian endemic strains. Bayesian Inference showed that the imported strains were introduced to Brazil during large mass sportive events. Sexual orientation and sexual practices may play a role in acquiring HAV infection. Public policies targeting key populations must be implemented to prevent further dissemination of HAV and other STIs.     

Anxiety,depression,and quality of life in Parkinson's disease:the implications of multidisciplinary treatment

Anxiety and depression in Parkinson's disease(PD) reduce well-being of the patients.Emotional alterations influence motor skills and cognitive performance;moreover,they contribute significantly and independently to worsen rehabilitative treatment response.We investigated anxiety,depression,and quality of life in PD patients subjected to multidisciplinary rehabilitative training.The self-controlled study included 100 PD patients(49 males and 51 females with the mean age of 64.66 years) admitted to 60 days hospitalization rehabilitative program,between January 2017 and December 2018.Motor,cognitive,linguistic abilities,and functional independence were evaluated at admission(T0 baseline visit) and 60 days after(T1) the multidisciplinary rehabilitation including motor exercises,speech therapies,and cognitive intervention.The multidisciplinary rehabilitation improved functional status in PD patients and exerted its positive effects on mood,motor abilities,autonomy in the activities of daily life,perception of quality of life,cognitive performance and speech skills.Non-motor symptoms may worsen severe disability and reduce quality of life.They are often poorly recognized and inadequately treated.Nonetheless,multidisciplinary rehabilitative training represents an optimal strategy to improve disease management.The study was approved by Istituito di Ricovero e Cura a Carattere Scientifico(IRCCS) Centro Neurolesi "Bonino-Pulejo" Ethical Committee(approval No.6/2016) in June 2016.     

Effect of the Processing Parameters on the Porosity and Mechanical Behavior of Titanium Samples with Bimodal Microstructure Produced via Hot Pressing

Commercially pure (c.p.) titanium grade IV with a bimodal microstructure is a promising material for biomedical implants. The influence of the processing parameters on the physical, microstructural, and mechanical properties was investigated. The bimodal microstructure was achieved from the blends of powder particles with different sizes, while the porous structure was obtained using the space-holder technique (50 vol.% of ammonium bicarbonate). Mechanically milled powders (10 and 20 h) were mixed in 50 wt.% or 75 wt.% with c.p. titanium. Four different mixtures of powders were precompacted via uniaxial cold pressing at 400 MPa. Then, the specimens were sintered at 750 °C via hot pressing in an argon gas atmosphere. The presence of a bimodal microstructure, comprised of small-grain regions separated by coarse-grain ones, was confirmed by optical and scanning electron microscopies. The samples with a bimodal microstructure exhibited an increase in the porosity compared with the commercially available pure Ti. In addition, the hardness was increased while the Young’s modulus was decreased in the specimens with 75 wt.% of the milled powders (20 h).     

It's time for Mohs: Micrographic surgery for the treatment of high‐risk basal cell carcinomas of the head and neck regions

Basal cell carcinoma (BCC) is the most common variety of non‐melanoma skin cancer and its incidence is increasing worldwide. The centrofacial sites (area H) are considered a high‐risk factor for BCC local recurrence. Mohs micrographic surgery (MMS) is a technique that allows intraoperative microscopic control of the surgical margins and is a good treatment option when tissue conservation is required for esthetic or functional reasons or for high‐risk lesions. The present study aimed to evaluate the recurrence rate of head and neck high‐risk BCCs comparing MMS vs conventional surgical excision. Clinical data of patients diagnosed from September 2014 to March 2017, referring to the Dermatology Unit of the Policlinico Sant'Orsola‐Malpighi, University of Bologna, were retrospectively evaluated (285 treated with MMS and 378 treated with traditional surgery). Of the 285 patients treated with MMS, 9 experienced a recurrence (3.1%). Of the 378 patients treated with traditional surgery, 53 relapsed (14%), 13 of whom presented residual tumor on the deep or lateral margins of the main surgical specimen. Our study confirms the trend reported in the literature that MMS represents the best treatment option for high‐risk BCCs arising in the head and neck region or presenting as a recurrence (P < .00001). Many more MMS centers and more trained dermatologists are needed worldwide in order to deal with the increasing number of BCC diagnosed every year.     

New Echocardiographic Techniques in the Evaluation of Left Ventricular Mechanics in Subclinical Thyroid Dysfunction

The new echocardiographic techniques for the study of physiopathological intramyocardial phenomena include video densitometry (VD), integrated backscatter (IBS), and color Doppler myocardial imaging (CDMI). Being more independent from cardiac load and from rotational and translational heart motion, these new sensible, noninvasive techniques such as CDMI and IBS show a real incremental value in comparison with conventional echocardiography and allow to detect subtle functional and textural abnormalities of intramural myocardium, partially undetectable by conventional two-dimensional Doppler echocardiography. Subclinical thyroid dysfunction (STD), both in its hypo- and hyperthyroidism form, has a relatively high prevalence in general population (9–15% with a lower percentage of adult males), hence it could be very useful to study more deeply heart involvement in these physiopathological conditions and understand the complex relationship between thyroid and heart. The use of these new ultrasonic techniques in subclinical hypothyroidism helps to detect the early simultaneous involvement of both cardiac cycle phases, which causes a decrease of intramyocardial contractility and an impairment of both active and passive phases of diastole. In subclinical hyperthyroidism, these new ultrasonic techniques permitted to discover more complex and different early cardiac abnormalities of both systolic and diastolic phases.