ATPergic signaling disruption in human sepsis as a potential source of biomarkers for clinical use.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated inflammatory response to infection. To date, there is no specific treatment established for sepsis. In the extracellular compartment, purines such as adenosine triphosphate (ATP) and adenosine play essential roles in the immune/inflammatory responses during sepsis and septic shock. The balance of extracellular levels among ATP and adenosine is intimately involved in the signals related to immune stimulation/immunosuppression balance. Specialized enzymes, including CD39, CD73, and adenosine deaminase (ADA), are responsible to metabolize ATP to adenosine which will further sensitize the P2 and P1 purinoceptors, respectively. Disruption of the purinergic pathway had been described in the sepsis pathophysiology. Although purinergic signaling has been suggested as a potential target for sepsis treatment, the majority of data available were obtained using pre-clinical approaches. We hypothesized that, as a reflection of deregulation on purinergic signaling, septic patients exhibit differential measurements of serum, neutrophils and monocytes purinergic pathway markers when compared to two types of controls (healthy and ward). It was observed that ATP and ADP serum levels were increased in septic patients, as well as the A2a mRNA expression in neutrophils and monocytes. Both ATPase/ADPase activities were increased during sepsis. Serum ATP and ADP levels, and both ATPase and ADPase activities were associated with the diagnosis of sepsis, representing potential biomarkers candidates. In conclusion, our results advance the translation of purinergic signaling from pre-clinical models into the clinical setting opening opportunities for so much needed new strategies for sepsis and septic shock diagnostics and treatment.

Comparison of meniscal T1rho- and T2*-relaxation times in professional female volleyball players and healthy controls using 3T MRI: A pilot study.

PURPOSE: Comparison of meniscal T1rho- and T2*-relaxation times in professional female volleyball players and healthy controls to determine if relaxation times are prolonged in athletes due to compositional meniscal alterations based on extensive and repetitive joint loading. METHODS: The right knee of 20 asymptomatic professional female volleyball players and 20 female controls were examined at 3T MRI. T1rho- and T2*-measurements were performed in sagittal orientation. For quantitative measurements, two readers independently defined two consecutive central slices with the greatest area of the anterior and posterior horn of the lateral (AHLAT; PHLAT) and medial meniscus (AHMED; PHMED). Both readers repeated measurements after a six-week interval on the original MR images. Statistical analysis included intraclass correlation coefficient (ICC), Wilcoxon signed-rank-, Shapiro-Wilk- & Kolmogorov-Smirnov- and Mann-Whitney U-tests. RESULTS: Mean T1rho-relaxation times in the PHMED were significantly prolonged in professional female volleyball players when compared to controls (24.2 ± 4.0 vs 21.1 ± 2.6 ms; p < 0.005). There were no significant differences for the remaining three meniscal horns. T2*-relaxation times revealed no significant differences between athletes and controls. Prolonged T1rho-relaxation times in the PHMED of female volleyball players did not correlate with significant change in T2*-relaxation times within all meniscal subregions. Reproducibility levels were excellent in all segments (Interobserver-ICC: 0.93-0.97 and intraobserver-ICC: 0.97-0.99). CONCLUSION: T1rho-relaxation times were significantly increased in the PHMED of female volleyball players, potentially indicating a predilection to early degenerative meniscal changes. T1rho may serve as a sensitive biomarker at detecting early compositional meniscal alterations in athletes.

TLR4 expression and functionality are downregulated in glioblastoma cells and in tumor-associated macrophages: A new mechanism of immune evasion?

Glioblastoma (GB) is the most common and aggressive form of primary brain tumor, in which the presence of an inflammatory environment, composed mainly by tumor-associated macrophages (TAMs), is related to its progression and development of chemoresistance. Toll-Like Receptors (TLRs) are key components of the innate immune system and their expression in both tumor and immune-associated cells may impact the cell communication in the tumor microenvironment (TME), further modeling cancer growth and response to therapy. Here, we investigated the participation of TLR4-mediated signaling as a mechanism of induced-immune escape in GB. Initially, bioinformatics analysis of public datasets revealed that TLR4 expression is lower in GB tumors when compared to astrocytomas (AST), and in a subset of TAMs. Further, we confirmed that TLR4 expression is downregulated in chemoresistant GB, as well as in macrophages co-cultured with GB cells. Additionally, TLR4 function is impaired in those cells even following stimulation with LPS, an agonist of TLR4. Finally, experiments performed in a cohort of clinical primary and metastatic brain tumors indicated that the immunostaining of TLR4 and CD45 are inversely proportional, and confirmed the low TLR4 expression in GBs. Interestingly, the cytoplasmic/nuclear pattern of TLR4 staining in cancer tissues suggests additional roles of this receptor in carcinogenesis. Overall, our data suggest the downregulation of TLR4 expression and activity as a strategy for GB-associated immune escape. Additional studies are necessary to better understand TLR4 signaling in TME in order to improve the benefits of immunotherapy based on TLR signaling.

Gastroprotective and cicatrizing activity of the Ziziphus joazeiro Mart. leaf hydroalcoholic extract.

Ziziphus joazeiro Mart., popularly known as 'juazeiro', is a species used in popular medicine for the treatment of bronchitis, gastric ulcers, skin wounds, and in the manufacture of cosmetic and food products. The objective of this study is to evaluate the gastroprotective and cicatrizing activity of the Z. joazeiro Mart. leaf hydroalcoholic extract (EHFZJ). The acute pre-clinical toxicity was determined by the single administration of the EHFZJ (2000 mg/kg/p.o.) and by assessing clinical signs of toxicity, according to established criteria by Malone, or mortality. Gastroprotective activity was identified through classical models of acute gastric lesions induced by indomethacin, absolute and acidified ethanol (100, 200 and 400 mg/kg/per os) and the physical barrier mechanism (400 mg/kg/per os or intraperitoneally). The cicatrizing activity of the EHFZJ was investigated by measuring the speed of wound closure and the percentage of contraction. The acute pre-clinical toxicity of EHFZJ showed no signs of toxicity and mortality. The EHFZJ demonstrated a gastroprotective effect at the 400 mg/kg dose in the classical models of acute gastric injury induced by indomethacin, absolute and acidified ethanol. The EHFZJ administration (orally) demonstrated significant inhibition, suggesting a possible physical barrier mechanism exists. The EHFZJ showed no significant differences in terms of percentage of contraction or the speed of wound closure during the observation times (0, 3, 7, 11 and 14 days). The results obtained in this study provide evidence of a potential gastroprotective activity for the Ziziphus joazeiro Mart. Leaf hydroalcoholic extract.

Brain MR Imaging of Patients with Perinatal Chikungunya Virus Infection.

Since 2005, it has been known that mother-to-child transmission of the chikungunya virus is possible. Transmission generally occurs in the perinatal period. In the present study, we describe the brain lesions seen on MR imaging of 6 cases of perinatal chikungunya infection. Patients who underwent brain MR imaging in the acute phase presented with areas of restricted diffusion in the white matter, suggesting a perivascular distribution, whereas those in the subacute/late phase showed cystic lesions, also with a perivascular distribution, with or without brain atrophy. One patient also presented with scattered hemorrhages in the frontal and parietal lobes. Important differential diagnoses include rotavirus, Parechovirus, herpes simplex infection, and hypoxic-ischemic encephalopathy, depending on the disease phase.

Association Between Neonatal Neuroimaging and Clinical Outcomes in Zika-Exposed Infants From Rio de Janeiro, Brazil.

Importance: Congenital Zika virus (ZIKV) infection may present with a spectrum of clinical and neuroradiographic findings. Objective: To determine whether neuroimaging findings for infants with a history of ZIKV exposure are associated with infant clinical outcomes and gestational age at antenatal ZIKV infection. Design, Setting, and Participants: This cohort study retrospectively reviewed neuroimaging results (computed tomography and/or magnetic resonance imaging scans) of 110 ZIKV-exposed infants from a maternity and children's hospital in Rio de Janeiro, Brazil, following the 2015 to 2016 ZIKV epidemic. Neuroimaging from March 1, 2016, to June 30, 2017, was evaluated to determine whether findings were associated with clinical outcomes and the timing of maternal ZIKV infection. Data were analyzed from July 1, 2017, to August 30, 2018. Exposures: Neuroimaging (computed tomography and/or magnetic resonance imaging) was performed on ZIKV-exposed infants after birth. Blood and/or urine specimens from mothers and infants were tested for ZIKV by polymerase chain reaction assay. Main Outcomes and Measures: Neuroimaging studies were evaluated for structural abnormalities and other forms of brain injury. Results: A total of 110 infants with a mean (SD) gestational age of 38.4 (2.1) weeks had neuroimaging and clinical outcome data reviewed. Of these, 71 (65%) had abnormal neuroimaging findings, with the majority (96%) classified as having severe ZIKV infection at birth. The most common neuroimaging abnormalities were structural abnormalities including brain calcifications, especially at the cortico-subcortical white matter junction, cortex malformations, ventriculomegaly, and reduced brain volumes, followed by brainstem hypoplasia, cerebellar hypoplasia, and corpus callosum abnormalities. Frequency of abnormal imaging was higher in infants with specific clinical findings as opposed to those without them; these findings included fetal brain disruption sequence (100% vs 35%), microcephaly (100% vs 30%), congenital contractures (100% vs 58%), ophthalmologic abnormalities (95% vs 44%), hearing abnormalities (100% vs 58%), and neurologic symptoms (94% vs 10%). Four of 39 infants (10%) without initial evidence of severe ZIKV infection and normal findings on neurologic evaluation at birth had abnormal neuroimaging findings. Neuroimaging abnormalities differed by trimester of maternal ZIKV infection, with 63% of infants born to mothers infected in the first trimester, 13% of infants born to mothers infected in the second trimester, and 1% of infants born to mothers infected in the third trimester exhibiting neuroimaging abnormalities. The odds of abnormal neuroimaging were 7.9 times greater for infants with first trimester ZIKV exposure compared with other trimesters combined (odds ratio, 7.9; 95% CI, 3.0-20.4; P < .001). Conclusions and Relevance: Neuroimaging abnormalities of computed tomography and/or magnetic resonance imaging scans were common in ZIKV-exposed infants. While neuroimaging abnormalities were seen in 10% of infants without clinically severe ZIKV, most occurred almost exclusively among those with clinically severe ZIKV, especially among those with a history of ZIKV exposure in the first trimester.

Neuroimaging Findings of Zika Virus-Associated Neurologic Complications in Adults.

When the first suspected cases of neurologic disorders associated with the Zika virus were noticed in Brazil in late 2015, several studies had been conducted to understand the pathophysiology of the disease and its associated complications. In addition to its well-established association with microcephaly in neonates, the Zika virus infection has also been suggested to trigger other severe neurologic complications in adults, such as Guillain-Barré syndrome, radiculomyelitis, and meningoencephalitis. Hence, the Zika virus should be deemed a global threat that can cause devastating neurologic complications among individuals in all age ranges. The aim of this review was to further describe neuroimaging findings of Zika virus infection and associated neurologic complications found in adults.

Central Nervous System Effects of Intrauterine Zika Virus Infection: A Pictorial Review.

Relatively few agents have been associated with congenital infections involving the brain. One such agent is the Zika virus, which has caused several outbreaks worldwide and has spread in the Americas since 2015. The Zika virus is an arbovirus transmitted by infected female mosquito vectors, such as the Aedes aegypti mosquito. This virus has been commonly associated with congenital infections of the central nervous system and has greatly increased the rates of microcephaly. Ultrasonography (US) remains the method of choice for fetal evaluation of congenital Zika virus infection. For improved assessment of the extent of the lesions, US should be complemented by magnetic resonance (MR) imaging. Postnatal computed tomography and MR imaging can also unveil additional findings of central nervous system involvement, such as microcephaly with malformation of cortical development, ventriculomegaly, and multifocal calcifications in the cortical-subcortical junction, along with associated cortical atrophy. The calcifications may be punctate, dystrophic, linear, or coarse and may follow a predominantly bandlike distribution. A small anterior fontanelle with prematurely closed sutures is also observed with Zika virus infection. In this review, the prenatal and postnatal neurologic imaging findings of congenital Zika virus infection are covered. Radiologists must be aware of this challenging entity and have knowledge of the various patterns that may be depicted with each imaging modality and the main differential diagnosis of the disease. As in other neurologic infections, serial imaging is able to help demonstrate the progression of the findings. ©RSNA, 2017.

Black patients sustain vision loss while White and South Asian patients gain vision following delamination or segmentation surgery for tractional complications associated with proliferative diabetic retinopathy.

PurposeThis retrospective comparative case series aims to determine whether patient ethnicity (White versus South Asian versus Black) is related to the outcome of surgical treatment for traction complications of severe proliferative diabetic retinopathy (PDR).SettingMoorfields Eye Hospital London, UK.MethodsAll patients who underwent vitrectomy with, delamination and/or segmentation for PDR over a 5-year period (2009-2014) were reviewed retrospectively. Patients were divided into White, South Asian or Black groups, and their age, gender, HbA1C and type of diabetes were recorded. A total of 484 patients (253 White, 117 South Asian, 114 Black) were included. Twenty-one patients were excluded due to inadequate documentation.OutcomesLogMAR Visual acuity (converted from Snellen) (VA), was recorded pre-operatively and ~6 months post surgery (range 5-8 months). Surgical outcome was classified according to the type and duration of tamponade required post-operatively.ResultsPre-operative VA and HbA1C values were similar across all three ethnic groups (P=0.64 and 0.569, respectively). Change in VA (mean±SD) was 0.41±0.78, 0.14±0.76 and -0.26±0.57 in White, South Asian and Black patient groups respectively (P<0.001). Multiple regression analysis showed that post-op VA was significantly related to race and pre-op VA only (both P<0.001). The Black patient group were more likely to require silicone oil tamponade (P<0.001) and long-term retention of silicone oil (P<0.001) than the White and South Asian patient groups.ConclusionsThis study demonstrates that Black patients on average lose vision following delamination surgery for traction complications of PDR while White and South Asian patients gain vision. The same group is also at higher risk of retaining silicone more than 6 months after surgery. This difference remains even when corrected for glycaemic control. The higher risk of visual loss and long-term retention of silicone oil in black patients requires further investigation. If these results are confirmed, surgeons should consider their patients' ethnicity before proceeding with surgical treatment of diabetic tractional detachment.

Ranibizumab pretreatment in diabetic vitrectomy: a pilot randomised controlled trial (the RaDiVit study).

PurposeOur aim was to evaluate the impact of intravitreal ranibizumab pretreatment on the outcome of vitrectomy surgery for advanced proliferative diabetic retinopathy. The objective was to determine the feasibility of a subsequent definitive trial and estimate the effect size and variability of the outcome measure.Patients and methodsWe performed a pilot randomised double-masked single-centre clinical trial in 30 participants with tractional retinal detachment associated with proliferative diabetic retinopathy. Seven days prior to vitrectomy surgery, participants were randomly allocated to receive either intravitreal ranibizumab (Lucentis, Novartis Pharmaceuticals UK Ltd, Frimley, UK) or subconjunctival saline (control). The primary outcome was best-corrected visual acuity 12 weeks following surgery.ResultsAt 12 weeks, the mean (SD) visual acuity was 46.7 (25) ETDRS letters in the control group and 52.6 (21) letters in the ranibizumab group. Mean visual acuity improved by 14 (31) letters in the control group and by 24 (27) letters in the ranibizumab group. We found no difference in the progression of tractional retinal detachment prior to surgery, the duration of surgery, or its technical difficulty. Vitreous cavity haemorrhage persisted at 12 weeks in two of the control group but none of the ranibizumab group.ConclusionRanibizumab pretreatment may improve the outcome of vitrectomy surgery for advanced proliferative diabetic retinopathy by reducing the extent of post-operative vitreous cavity haemorrhage. However, the effect size appears to be modest; we calculate that a definitive study to establish a minimally important difference of 5.9 letters at a significance level of P<0.05 would require 348 subjects in each arm.

Micronucleus as biomarkers of cancer risk in anabolic androgenic steroids users.

The use of anabolic androgenic steroids (AAS) has grown among practitioners of recreational bodybuilding, with significant contributions of designer steroids, aiming muscle hypertrophy in healthy subjects. The abusive use of AAS in general is associated with adverse effects; one of the most worrisome is cancer development. The aim of this study was to evaluate the effectiveness of the cytokinesis block micronucleus (CBMN) test in human lymphocytes in identifying risk groups for cancer development in users of AAS. Blood was collected from 15 AAS users bodybuilders (G1), 20 non-users bodybuilders (G2) and 20 non-users sedentary (G3). MN analysis was performed on a minimum of 1000 binucleated lymphocytes. The occurrence of MN was significantly higher ( p < 0.05) in individuals of G1 compared to G2 and G3. The results indicate the sensitivity of CBMN in human lymphocytes in the identification of chromosomal damage in consequence of AAS.

Multiparametric MR Imaging in the Assessment of Brain Tumors.

Functional MR imaging methods make possible the quantification of dynamic physiologic processes that occur in the brain. Moreover, the use of these advanced imaging techniques in the setting of oncologic treatment of the brain is widely accepted and has found worldwide routine clinical use.

Neuroimaging and genetic influence in treating brain neoplasms.

The current treatment of glioblastoma patients based on surgery, radiation, and chemotherapy has achieved modest improvement in progression-free survival. In this direction, personalized treatment is the next achievement for better patient management and increased overall survival. Genetic characterization of high-grade gliomas by MR imaging is the goal in neuroimaging. The main genetic alterations described in these neoplasms, implications in patient treatment, and prognosis are reviewed. MR imaging features and novel techniques are correlated with the main genetic aspects of such tumors. Posttreatment phenomena, such as pseudoprogression and pseudoresponse, are analyzed in association with the genetic expression of these tumors.

A review and update on the current status of stem cell therapy and the retina.

INTRODUCTION OR BACKGROUND: Many diseases of the retina result in irreversible visual loss. Stem cell (SC) therapy is a rapidly developing field and represents a novel approach to replace non-functioning neuro-retinal cells. SOURCES OF DATA: A systematic computerized literature search was conducted on PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). AREAS OF AGREEMENT: The use of stem cells (SCs) in animal models of retinal diseases has resulted in improvement in visual function and performance. SC therapy represents an exciting prospect in restoring vision. Areas of controversy The use of human embryonic SCs raises ethical concerns. GROWING POINTS: Human trials using SCs in retinal diseases have recently been approved. AREAS TIMELY FOR DEVELOPING RESEARCH: The success of SCs in retinal therapy depends not only on implanted cell survival, but also on how well SCs migrate, integrate and form synapses. Further research will be needed to overcome these hurdles.