Robust In Vitro and In Vivo Immunosuppressive and Anti-inflammatory Properties of Inducible Caspase-9-mediated Apoptotic Mesenchymal Stromal/Stem Cell.

Mesenchymal stromal stem/cells (MSC) therapies are clinically used in a wide range of disorders based on their robust HLA-independent immunosuppressive and anti-inflammatory properties. However, the mechanisms underlying MSC therapeutic activity remain elusive as demonstrated by the unpredictable therapeutic efficacy of MSC infusions reported in multiple clinical trials. A seminal recent study showed that infused MSCs are actively induced to undergo apoptosis by recipient cytotoxic T cells, a mechanism that triggers in vivo recipient-induced immunomodulation by such apoptotic MSCs, and the need for such recipient cytotoxic cell activity could be replaced by the administration of ex vivo-generated apoptotic MSCs. Moreover, the use of MSC-derived extracellular vesicles (MSC-EVs) is being actively explored as a cell-free therapeutic alternative over the parental MSCs. We hypothesized that the introduction of a "suicide gene" switch into MSCs may offer on-demand in vivo apoptosis of transplanted MSCs. Here, we prompted to investigate the utility of the iCasp9/AP1903 suicide gene system in inducing apoptosis of MSCs. iCasp9/AP1903-induced apoptotic MSCs (MSCiCasp9+) were tested in vitro and in in vivo models of acute colitis. Our data show a very similar and robust immunosuppressive and anti-inflammatory properties of both "parental" alive MSCGFP+ cells and apoptotic MSCiCasp9+ cells in vitro and in vivo regardless of whether apoptosis was induced in vivo or in vitro before administering MSCiCasp9+ lysates. This development of an efficient iCasp9 switch may potentiate the safety of MSC-based therapies in the case of an adverse event and, will also circumvent current logistic technical limitations and biological uncertainties associated to MSC-EVs.

Association of Lipids, Lipoproteins, and Apolipoproteins with Stroke Subtypes in an International Case Control Study (INTERSTROKE) / 대한뇌졸중학회지

Background@#and Purpose The association of dyslipidemia with stroke has been inconsistent, which may be due to differing associations within etiological stroke subtypes. We sought to determine the association of lipoproteins and apolipoproteins within stroke subtypes. @*Methods@#Standardized incident case-control STROKE study in 32 countries. Cases were patients with acute hospitalized first stroke, and matched by age, sex and site to controls. Concentrations of total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (apoA1), and apoB were measured. Non-HDL-C was calculated. We estimated multivariable odds ratio (OR) and population attributable risk percentage (PAR%). Outcome measures were all stroke, ischemic stroke (and subtypes), and intracerebral hemorrhage (ICH). @*Results@#Our analysis included 11,898 matched case-control pairs; 77.3% with ischemic stroke and 22.7% with ICH. Increasing apoB (OR, 1.10; 95% confidence interval [CI], 1.06 to 1.14 per standard deviation [SD]) and LDL-C (OR, 1.06; 95% CI, 1.02 to 1.10 per SD) were associated with an increase in risk of ischemic stroke, but a reduced risk of ICH. Increased apoB was significantly associated with large vessel stroke (PAR 13.4%; 95% CI, 5.6 to 28.4) and stroke of undetermined cause. Higher HDL-C (OR, 0.75; 95% CI, 0.72 to 0.78 per SD) and apoA1 (OR, 0.63; 95% CI, 0.61 to 0.66 per SD) were associated with ischemic stroke (and subtypes). While increasing HDL-C was associated with an increased risk of ICH (OR, 1.20; 95% CI, 1.14 to 1.27 per SD), apoA1 was associated with a reduced risk (OR, 0.80; 95% CI, 0.75 to 0.85 per SD). ApoB/A1 (OR, 1.38; 95% CI, 1.32 to 1.44 per SD) had a stronger magnitude of association than the ratio of LDL-C/HDL-C (OR, 1.26; 95% CI, 1.21 to 1.31 per SD) with ischemic stroke (P<0.0001). @*Conclusions@#The pattern and magnitude of association of lipoproteins and apolipoproteins with stroke varies by etiological stroke subtype. While the directions of association for LDL, HDL, and apoB were opposing for ischemic stroke and ICH, apoA1 was associated with a reduction in both ischemic stroke and ICH. The ratio of apoB/A1 was the best lipid predictor of ischemic stroke risk.

Intestinal ultrasonography and fecal calprotectin for monitoring inflammation of ileal Crohn’s disease: two complementary tests

Background/Aims@#Tight control of inflammation and adjustment of treatment if activity persists is the current strategy for the management of Crohn’s disease (CD). The usefulness of fecal calprotectin (FC) in isolated involvement of the small intestine in CD is controversial. To assess the usefulness of FC to determine the inflammatory activity detected by intestinal ultrasonography (IUS) in ileal CD. @*Methods@#Patients with exclusively ileal involvement CD who underwent IUS and an FC were prospectively included. Simple ultrasound index was used to determine inflammatory activity. The usual statistical tests for comparison of diagnostic techniques were used. @*Results@#One hundred and five patients were included, IUS showed inflammatory activity in 59% of patients and complications in 18.1%. FC showed a significant correlation with IUS in the weak range (Spearman coefficient r=0.502; P<0.001); the area under the receiver operating characteristic curve was 0.79 (95% confidence interval, 0.70–0.88; P<0.001). The FC value that best reflected the activity in IUS was 100 μg/g with sensitivity, specificity, and positive and negative predictive values of 73.0%, 71.4%, 79.3% and 63.8%, respectively. There were no differences in FC concentration between patients with or without transmural complications. The addition of serum C-reactive protein to FC did not improve the ability to assess IUS activity. @*Conclusions@#FC has a significant correlation with IUS to monitor ileal CD activity. This correlation is weak and it does not allow assessing the presence of CD complications. Both tests should be used in conjunction for tight control of ileal CD. More studies on noninvasive tests in this location are needed.

Mortality of hemodialysis patients is associated with their clinical situation at the start of treatment.

INTRODUCTION: Previous reports have shown very high mortality among hemodialyisis patients. Our goal was to analyze the mortality of patients in the Renal Registry of Patients who remained exclusively on hemodialysis treatment. METHODS: The cohort of patients who started treatment in the community of Castilla-La Mancha between 2010 and 2012 and remained on hemodialysis treatment was analysed until the end of 2017. Age, sex, primary kidney disease, vascular access, hemoglobin, Charlson index and serum albumin were included. RESULTS: Mortality rate was 63,4% after 5 years and 76% at the end of the study, with no difference between males and females, and was linked to an older age, urgent onset or in those with acute deterioration of chronic kidney disease, the use of catheters or albumin less than 3.5 g/dl. CONCLUSIONS: Mortality in patients who remain on hemodialysis is very high and is associated with non-modifiable factors such as age but also others that we can prevent or treat such as type of vascular access or nutrition status at the beginning of treatment.

Mitigation of nivalenol using alcoholic fermentation and magnetic field application.

This study aimed at evaluating mitigation of nivalenol (NIV) in alcoholic fermentation with magnetic field application (MF). Mitigation was related to both the glutathione (GSH) redox molecule and the enzyme peroxidase (PO), which were synthesized by Saccharomyces cerevisiae US-05. Conditions under evaluation were NIV (0.2 µg mL-1), MF application (35 mT) and simultaneous use of mycotoxin and MF. The GSH content and the PO activity were increased when the culture contained NIV and the alcohol profile was altered after 48 h of fermentation. At the end of the alcoholic fermentation, NIV was mitigated by 56.5%. Therefore, this process is a promising method to reduce contamination by NIV, although the mycotoxin affects the chemical characteristics of the final product.

Laparoscopic Right Adrenalectomy in a Large Right Adrenal Oncocytic Carcinoma.

BACKGROUND: Adrenocortical carcinomas are rare and aggressive tumors. The recently described oncocytic subtype has been reported approximately 40 times in the literature.1 In this video, we describe an unusual case of a large adrenal oncocytic carcinoma, its minimally invasive approach, and its anatomopathological features. CASE DESCRIPTION: A 43-year-old male presented to the emergency room with acute abdominal pain and fever. Blood tests showed 20,000 white blood cells and a reactive C-protein of 25. Tomography showed a large right adrenal tumor with necrosis. Antibiotics were started at the intensive care unit. A complete study showed normal tests, including hormones, cortisol, and metanephrines. At the multidisciplinary team meeting it was decided to perform a right transabdominal laparoscopic adrenalectomy. The tumor was approached from the medial side to the lateral side, always controlling the inferior vena cava. Indocyanine green was used to identify vascular structures. Anatomical pathology revealed a 15 cm lesion corresponding to a malignant adrenal oncocytic carcinoma according to the modified Lin-Weis-Bisceglia criteria.2 The patient was discharged without complications on the fifth day. He is receiving mitotane and is disease-free 5 months after surgery. CONCLUSIONS: Oncocytic subtype is a rare entity described only a few times in the literature. Surgical treatment is of choice due to its curative potential, and the open versus laparoscopic approach will be chosen depending on the size of the tumor and the surgeon's experience. It is believed that this subtype may have a less aggressive behavior than the typical adrenal carcinoma,1 therefore its better understanding may help to define therapeutic decisions and prognosis in the future.

Bone Marrow Clonogenic Myeloid Progenitors from NPM1-Mutated AML Patients Do Not Harbor the NPM1 Mutation: Implication for the Cell-Of-Origin of NPM1+ AML.

The cell-of-origin of NPM1- and FLT3-mutated acute myeloid leukemia (AML) is still a matter of debate. Here, we combined in vitro clonogenic assays with targeted sequencing to gain further insights into the cell-of-origin of NPM1 and FLT3-ITD-mutated AML in diagnostic bone marrow (BM) from nine NPM1+/FLT3-ITD (+/-) AMLs. We reasoned that individually plucked colony forming units (CFUs) are clonal and reflect the progeny of a single stem/progenitor cell. NPM1 and FLT3-ITD mutations seen in the diagnostic blasts were found in only 2/95 and 1/57 individually plucked CFUs, suggesting that BM clonogenic myeloid progenitors in NPM1-mutated and NPM1/FLT3-ITD-mutated AML patients do not harbor such molecular lesions. This supports previous studies on NPM1 mutations as secondary mutations in AML, likely acquired in an expanded pool of committed myeloid progenitors, perhaps CD34-, in line with the CD34-/low phenotype of NPM1-mutated AMLs. This study has important implications on the cell-of-origin of NPM1+ AML, and reinforces that therapeutic targeting of either NPM1 or FLT3-ITD mutations might only have a transient clinical benefit in debulking the leukemia, but is unlikely to be curative since will not target the AML-initiating/preleukemic cells. The absence of NPM1 and FLT3-ITD mutations in normal clonogenic myeloid progenitors is in line with their absence in clonal hematopoiesis of indeterminate potential.

Nonconvex image reconstruction via expectation propagation.

The problem of efficiently reconstructing tomographic images can be mapped into a Bayesian inference problem over the space of pixels densities. Solutions to this problem are given by pixels assignments that are compatible with tomographic measurements and maximize a posterior probability density. This maximization can be performed with standard local optimization tools when the log-posterior is a convex function, but it is generally intractable when introducing realistic nonconcave priors that reflect typical images features such as smoothness or sharpness. We introduce a new method to reconstruct images obtained from Radon projections by using expectation propagation, which allows us to approximate the intractable posterior. We show, by means of extensive simulations, that, compared to state-of-the-art algorithms for this task, expectation propagation paired with very simple but non-log-concave priors is often able to reconstruct images up to a smaller error while using a lower amount of information per pixel. We provide estimates for the critical rate of information per pixel above which recovery is error-free by means of simulations on ensembles of phantom and real images.

Incidence of Hypersensitivity Reactions During Hemodialysis.

BACKGROUND/AIMS: A recent alert from Spanish health authorities warned of a higher incidence of reported hypersensitivity reactions to hemodialysis membranes with polysulfone, in the 2017 review of acute reactions to dialyzers found only published reports in the 21st century on polysulfone and its derivatives. The aim is to assess/evaluate the current incidence and characteristics of hypersensitivity reactions in hemodialysis patients. METHODS: A retrospective multicentre study in 9 Spanish hospitals evaluated patients in whom a hypersensitivity reaction required a change in dialyzer membrane. RESULTS: A total of 37 patients out of 1561 (2.37%) had hypersensitivity reactions and clinical, epidemiological and analytical data were available for 33 patients (2.11%). The membranes involved were polysulfone (n=23), polynephron (n=8), polyethersulfone (n=1) and polyacrylonitrile (n=1). This distribution reflected the frequency of use of membranes in the participating dialysis units. The reactions were described as type A in 18 cases and type B in 15 cases. There were no significant differences between the two types in clinical symptoms, the composition of the membrane involved, the method of sterilization, the season, or the time during the session in which they occurred. The most frequent symptom was dyspnea/breathlessness (64% of reactions). Eosinophilia was common (74%). 54% of the reactions occurred within the first 30 minutes of hemodialysis, 64% occurred during the first year of dialysis, and 54% required discontinuation of dialysis session. Cellulose triacetate was used as an alternative dialyzer in 78% of the cases. CONCLUSION: The incidence of hypersensitivity reactions was in the range found in reports from 20 years ago and is observed associated with synthetic membranes, not just polysulfones. Cellulose triacetate appears to be a good alternative for these patients.

Universal behavior of the full particle statistics of one-dimensional Coulomb gases with an arbitrary external potential.

We present a complete theory for the full particle statistics of the positions of bulk and extremal particles in a one-dimensional Coulomb gas (CG) with an arbitrary potential, in the typical and large deviations regimes. Typical fluctuations are described by a universal function which depends solely on the general properties of the external potential. The rate function controlling large deviations is, rather unexpectedly, not strictly convex and has a discontinuous third derivative around its minimum for both extremal and bulk particles. This implies, in turn, that the rate function cannot predict the anomalous scaling of the typical fluctuations with the system size for bulk particles, and it may indicate the existence of an intermediate phase in this case. Moreover, its asymptotic behavior for extremal particles differs from the predictions of the Tracy-Widom distribution. Thus many of the paradigmatic properties of the full particle statistics of Dyson log gases do not carry over into their one-dimensional counterparts, hence proving that one-dimensional CG belongs to a different universality class. Our analytical expressions are thoroughly compared with Monte Carlo simulations, showing excellent agreement.

Different cell disruption methods for obtaining carotenoids by Sporodiobolus pararoseus and Rhodothorula mucilaginosa.

Since carotenoids are synthesized inside the cell, it is desirable to find an efficient method to extract carotegenic pigments. This study aimed at comparing the effectiveness of different chemical and mechanical techniques to disrupt the cell wall of Sporidiobolus pararoseus and Rhodotorula mucilaginosa yeasts isolated from environmental samples. Among the techniques under study, the ultrasonic bath and the abrasion with glass beads yielded the most promising results for S. pararoseus (84.8 ± 2.3 and 76.9 ± 2.1 µg/g, respectively). The ultrasonic bath yielded the highest specific concentration of carotenoids for R. mucilaginosa (193.5 ± 25.8 µg/g), while the biomass freezing process improved neither the extractability nor the specific concentration of carotenoids. Lyophilization increased the specific concentrations of carotenoids from S. pararoseus and R. mucilaginosa by 20 and 13.7%, respectively, while the freezing process did not significantly affect (p > 0.05) the recovery of carotenoids from both yeasts; thus, it may be eliminated from the process.

Therapeutic effect of the immunomodulatory drug lenalidomide, but not pomalidomide, in experimental models of rheumatoid arthritis and inflammatory bowel disease

Thalidomide is an immunomodulatory drug (IMiD) with proven therapeutic action in several autoimmune/inflammatory diseases; however, its inherent high toxicity has led to the development of more powerful and safer thalidomide analogs, including lenalidomide and pomalidomide. These are new generation IMiDs that exhibit direct antitumor activity as well as anti-inflammatory/immunomodulatory properties, and are FDA-approved for the treatment of several hematological malignances. Here we investigated the potential therapeutic effects of lenalidomide and pomalidomide in several experimental murine models of autoimmune/inflammatory diseases: 2,4,6-trinitrobenzene sulfonic acid- and dextran sulfate sodium-induced inflammatory bowel disease and type II collagen-induced arthritis. Lenalidomide displayed a strong therapeutic effect in all these models of autoimmune/inflammatory diseases, while the effect of pomalidomide was less pronounced. In vitro experiments confirmed the immunosuppressive effect of both IMiDs on the proliferative response of stimulated human lymphocytes and on the balance of secreted cytokines toward an anti-inflammatory profile. We conclude that lenalidomide may offer a therapeutic opportunity against autoimmune/inflammatory diseases.

Burkholderia caballeronis sp. nov., a nitrogen fixing species isolated from tomato (Lycopersicon esculentum) with the ability to effectively nodulate Phaseolus vulgaris.

During a survey of Burkholderia species with potential use in agrobiotechnology, a group of 12 strains was isolated from the rhizosphere and rhizoplane of tomato plants growing in Mexico (Nepantla, Mexico State). A phylogenetic analysis of 16S rRNA gene sequences showed that the strains are related to Burkholderia kururiensis and Burkholderia mimosarum (97.4 and 97.1 %, respectively). However, they induced effective nitrogen-fixing nodules on roots of Phaseolus vulgaris. Based on polyphasic taxonomy, the group of strains represents a novel species for which the name Burkholderia caballeronis sp. nov. is proposed. The type species is TNe-841(T) (= LMG 26416(T) = CIP 110324(T)).

Integration of global spectral karyotyping, CGH arrays, and expression arrays reveals important genes in the pathogenesis of glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary tumor of the central nervous system in adults. Patients with GBM have few treatment options, and their disease is invariably fatal. Molecularly targeted agents offer the potential to improve patient treatment; however, the use of these will require a fuller understanding of the genetic changes in this complex tumor. METHODS: We analyzed a series of 32 patients with GBM with array comparative genomic hybridization in combination with gene expression analysis. We focused on the recurrent breakpoints found by spectral karyotyping (SKY). RESULTS: By SKY we identified 23 recurrent breakpoints of the 202 translocations found in GBM cases. Gains and losses were identified in chromosomal regions close to the breakpoints by array comparative genomic hybridization. We evaluated the genes located in the regions involved in the breakpoints in depth. A list of 406 genes that showed a level of expression significantly different between patients and control subjects was selected to determine their effect on survival. Genes CACNA2D3, PPP2R2B, SIK, MAST3, PROM1, and PPP6C were significantly associated with shorter survival (median 200 days vs. 450 days, P≤0.03). CONCLUSIONS: We present a list of genes located in regions of breakpoints that could be grounds for future studies to determine whether they are crucial in the pathogenesis of this type of tumor, and we provide a list of six genes associated with the clinical outcome of patients with GBM.

[Hormonal treatment in biochemical recurrence after radical prostatectomy]. / Tratamiento hormonal en la recidiva bioquímica tras prostatectomía radical.

To date, the role of hormonal therapy (HT) after biochemical failure, when to initiate it, the therapeutic scheme and duration remains controversial due to the absence of well designed randomized trials analyzing the overall survival of patients. In clinical practice, the most widely spread treatment in this scenario is hormonal therapy with LH-RH analogues. However, the scientific support for this issue is very weak. We are extrapolating the benefits proven for early vs delayed HT in advanced prostate cancer, to asymptomatic patients presenting just an increase in PSA. These patients usually have a long time disease-history until development of metastasis. It should also be noticed the harmful secondary effects acquired with the time of employment of hormotherapy. Probably patients suffering a Gleason score >8 and PSA doubling time <12 months could obtain a benefit from an early castration treatment, even more if they are young (grade 2c). Except in selected cases of local treatment as radiotherapy, the decision for early or delayed hormonal therapy should be taken carefully with patient consensus. The alternatives for hormonal treatment to preserve sexual function, as intermittent treatment, antiandrogen monotherapy, or antiandrogen plus 5 alpha reductase inhibitors, are very attractive in this scenario. However due to the short time experience with these modalities of treatment should be evaluated with caution.

Infectious complications after transrectal ultrasound-guided prostatic biopsy. Analysis of our experience.

OBJECTIVES: To establish the rate of infectious complications derived from the use of transrectal ultrasound-guided prostate biopsy (TRUS), identify its microbiological profile and related risk factors. METHODS: We designed a prospective non-randomized study in which we enrolled 220 patients undergoing TRUS biopsy at our centre between April and September 2008. The inclusion criteria were: suspicious digital rectal examination, PSA >10 ng/ml, and free/total ratio of PSA is assessed in patients with PSA 4-10 ng/ml. The exclusion criteria were: having an indwelling urinary catheter, the administration of antibiotic treatment in the week before the needle biopsy, manipulation of the urinary tract in the month prior to the needle biopsy, allergy to quinolones and risk of endocarditis, failure to comply with the antibiotic prophylaxis regimen and loss to follow-up. We analyzed the relationship between diabetes, immunodepression, previous UTI or prostatitis and positive prebiopsy urine culture with the appearance of fever, dysuria or bacteriuria following needle biopsy. RESULTS: Mean age was 69.5 years (+/-7.9), mean total PSA 12.7 ng/ml (+/-28.7), mean prostate volume 50.6 cc (+/-29.6) and mean number of cores obtained by needle biopsy 13.5 (+/-1.7). 25% of the patients had dysuria following needle biopsy, 3.2% fever and 4.5% bacteriuria. E.coli was the pathogen most frequently found in pre- and post-biopsy urine cultures. No statistically significant relationship was found between the appearance of dysuria and fever and being diabetic, having immunosuppression, previous UTI or prostatitis, prostate volume and number of cores obtained in the biopsy. Only the existence of a positive pre-biopsy urine culture and biopsy with more than 14 cores proved to have a statistically significant association with the existence of bacteriuria following biopsy, p=0.007 and p= 0.018, respectively. CONCLUSIONS: Our rate of infectious complications was similar to that described in other series. The existence of a positive prebiopsy urine culture and obtaining more than 14 cores per biopsy was related, with statistical significance, to the existence of bacteriuria following the biopsy. E.coli was the most frequently isolated pathogen.

Saturation biopsies for prostate cancer detection: effectiveness, safety and predictive factors.

OBJECTIVES: To determine the effectiveness and safety of saturation biopsies for prostate cancer detection of and to identify predictive variables for cancer. METHODS: We conducted a retrospective transversal study in which we analyzed 144 saturation biopsies (January '06 - July '09). INCLUSION CRITERIA: at least two sets of biopsies without evidence of malignancy and Prostate Specific Antigen (PSA)levels >10 ng/ml or PSA kinetics suggestive of malignancy (rate >0.75 ng/ml/year)and patients with atypia in a previous biopsy.The variables analyzed were: age, abnormal digital rectal examination (DRE), total PSA, free/total PSA ratio, prostate volume, PSA density, previous histopathology, number of cylinders obtained and complications. Statistical analysis was performed using the Chi-square test, Student's t-test and logistic regression. RESULTS: Mean age was 66 years (SD ± 6.4), mean total PSA 14.4 ng/ml (SD ± 12.6), mean free/total PSA ratio 0.09 (SD ± 0.09), mean prostate volume 61.6 cc (SD ± 27.4), mean PSA density 0.27 (SD ± 0.26) and mean number of cylinders obtained 30.45 (SD ± 3.8). We diagnosed 32% of the patients with prostatic adenocarcinoma. We observed PSA density was higher in the prostate cancer group, 0.39 (SD ± 0.36), compared to 0.21 (SD ± 0.18) in patients without cancer (p=0.003). Adenocarcinoma was found in 58% of the biopsies in patients with suspicious DRE, compared to 28% with normal DRE (p=0.009). Mean prostate volume in the prostate cancer group was 52.5 (SD ± 24.7)compared to 66.0 (SD ± 27.7)in the group without cancer (p=0.006). In the multivariate analysis, the PSA density (p=0.02; 95% CI 1.36 - 37.36) was the only variable that independently predicted the presence of adenocarcinoma. No statistically significant differences were found in either univariate or multivariate analysis for the remaining variables analyzed. The incidence of complications was similar to that described in the literature for other series. CONCLUSIONS: Saturation biopsy is safe and effective for detection of prostate cancer. PSA density was the only factor that was shown to be independent predictive variable for tumor diagnosis.