The expression of CD73 on pathological B-cells is associated with shorter overall survival of patients with CLL.

CD73 is a membrane-bound enzyme that catalyzes the extracellular conversion of adenosine monophosphate to adenosine. Adenosine is thought to play a role in promoting tumor growth and survival together with suppressing the host immune responses, which contribute to the multistep process of tumorigenesis. Here, we studied the expression of this antigen in chronic lymphocytic leukemia (CLL). The expression of CD73 was analyzed by multiparametric flow cytometry on normal and pathological B-cells from peripheral blood and bone marrow samples from 71 patients with CLL. Pathological B-cells expressed significantly lower levels of CD73 than normal B-cells (p<0.01). Patients with splenomegaly showed a higher expression of CD73 on pathological B-cells than patients without splenomegaly (p<0.05). The expression of CD73 also correlated with beta-2-microglobulin levels (p<0.05). Clinically, patients with higher levels of CD73 versus those with lower expression presented with shorter overall survival (median OS of 65 vs. 113 months, p<0.05). Our data indicate that CD73 may play a role in CLL pathophysiology, is correlated with poor clinical and biological prognostic factors and may be of potential value as a prognostic marker and therapeutic target.

Early Changes during Skin Repair Using Tissue-Engineered Dermal Template in a Full-Thickness Burn.

Rapid wound closure in extensively burned patients has remained one of the major unresolved issues of medicine. Integra® is the most widely established artificial skin, which is composed of a porous matrix of cross-linked bovine collagen and chondroitin 6-sulphate covered by a semi-permeable silicone layer. We present here a (immuno)histological study of a severely burned patient with a full-thickness burn treated with a tissue-engineered dermal template (Integra®) and split-thickness skin graft-based protocol. Immunohistochemical investigation of the artificial dermis revealed that immune cell infiltration reached its peak on day 10. Tissue immunophenotyping found an increase in CD3+ cells over the course of the study as well as CD4 and CD8 positivity on day 40, indicating remaining T-cell subpopulations. We observed weak/no infiltration of NK cells (CD56+). In conclusion, the use of bi-layer Integra® represents a feasible and safe procedure resulting in formation of non-irritating dermal substitutes.

Organic waste as a sustainable feedstock for platform chemicals.

Biorefineries have been established since the 1980s for biofuel production, and there has been a switch lately from first to second generation feedstocks in order to avoid the food versus fuel dilemma. To a lesser extent, many opportunities have been investigated for producing chemicals from biomass using by-products of the present biorefineries, simple waste streams. Current facilities apply intensive pre-treatments to deal with single substrate types such as carbohydrates. However, most organic streams such as municipal solid waste or algal blooms present a high complexity and variable mixture of molecules, which makes specific compound production and separation difficult. Here we focus on flexible anaerobic fermentation and hydrothermal processes that can treat complex biomass as a whole to obtain a range of products within an integrated biorefinery concept.

Study of association of CTLA4 gene variants to non-anterior uveitis.

This study was undertaken to investigate the possible genetic association of functional CTLA4 polymorphisms with susceptibility to non-anterior uveitis. Four hundred and seventeen patients with endogenous non-anterior uveitis and 1517 healthy controls of Spanish Caucasian origin were genotyped for the CTLA4 polymorphisms rs733618, rs5742909 and rs231775, using predesigned TaqMan(©) allele discrimination assays. PLINK software was used for the statistical analyses. No significant associations between the CTLA4 polymorphisms and susceptibility to global non-anterior uveitis were found. It was also the case when the potential association of these genetic variants with the anatomical localization of the disease, such as intermediate, posterior or panuveitis, was assessed. Our results do not support a relevant role of these CTLA4 polymorphisms in the non-anterior uveitis genetic predisposition.

Integrated side-stream reactor for biological nutrient removal and minimization of sludge production.

Integrated processes to reduce in situ the sludge production in wastewater treatment plants are gaining attention in order to facilitate excess sludge management. In contrast to post-treatments, such as anaerobic digestion which is placed between the activated sludge system and dewatering processes, integrated technologies are placed in the sludge return line. This study evaluates the application of an anoxic side-stream reactor (SSR) which creates a physiological shock and uncouples the biomass metabolism and diverts the activity from assimilation for biosynthesis to non-growth activities. The effect of this system in biological nutrient removal for both nitrogen and phosphorus was evaluated for the anaerobic, anoxic and aerobic reactors. The RedOx potential within the SSR was maintained at -150 mV while the sludge loading rate was modified by increasing the percentage of recycled activated sludge feed to the SSR (0 and 40% at laboratory scale and 0, 10, 50 and 100% at pilot scale). The use of the SSR presented a slight reduction of phosphorus removal but maintained the effluent quality to the required discharge values. Nitrogen removal efficiency increased from 75 to 86% while reducing the sludge production rate by 18.3%.

Evaluation of non-exudative tomographic signs in cases of exudative age-related macular degeneration.

OBJECTIVE: To analyse the prevalence of non-exudative tomographic signs (onion sign, pseudoswelling, external retinal tubulation, pseudocysts, subretinal clefts and macular atrophy) in patients with neovascular age-related macular degeneration. MATERIAL AND METHODS: A total of 174 eyes of patients with neovascular age-related macular degeneration who had not received previous treatment were included in the study. Visual acuity, neovascularization activity, and the appearance or not of the different signs under study were assessed at times 0 (initial visit), 4 months, one year, year and a half, and at 2 and 3 years of follow-up. The following were also evaluated: age, sex, affected eye and type of neovascularization (1, 2, 3, polypoid or mixed). The analysis were performed using the statistical software R (version 3.3.2) and the glmmADMB package (version 0.8.3.3). RESULTS: The presence of pseudocysts and external retinal tubulation increases throughout the follow-up. The onion sign begins with an ascending frequency up to 12 months, then decreases at 18 months and increases again at 24 months. Regarding pseudowelling, it maintains an increase until 18 months to finally decrease. Subretinal clefts is the rarest sign, presenting in 1.1% on the first visit. Finally, macular atrophy, present in 12.6% of the eyes initially, is found in 25% after 2 years. CONCLUSION: Pseudocysts, external retinal tubulation and macular atrophy were the most prevalent signs, while subretinal clefts were the most infrequent.

Activation of glycogen synthase kinase-3 beta mediates ß-amyloid induced neuritic damage in Alzheimer's disease.

ß-Amyloid (Aß) plaques in Alzheimer (AD) brains are surrounded by severe dendritic and axonal changes, including local spine loss, axonal swellings and distorted neurite trajectories. Whether and how plaques induce these neuropil abnormalities remains unknown. We tested the hypothesis that oligomeric assemblies of Aß, seen in the periphery of plaques, mediate the neurodegenerative phenotype of AD by triggering activation of the enzyme GSK-3ß, which in turn appears to inhibit a transcriptional program mediated by CREB. We detect increased activity of GSK-3ß after exposure to oligomeric Aß in neurons in culture, in the brain of double transgenic APP/tau mice and in AD brains. Activation of GSK-3ß, even in the absence of Aß, is sufficient to produce a phenocopy of Aß-induced dendritic spine loss in neurons in culture, while pharmacological inhibition of GSK-3ß prevents spine loss and increases expression of CREB-target genes like BDNF. Of note, in transgenic mice GSK-3ß inhibition ameliorated plaque-related neuritic changes and increased CREB-mediated gene expression. Moreover, GSK-3ß inhibition robustly decreased the oligomeric Aß load in the mouse brain. All these findings support the idea that GSK3ß is aberrantly activated by the presence of Aß, and contributes, at least in part, to the neuronal anatomical derangement associated with Aß plaques in AD brains and to Aß pathology itself.

Ocular complications secondary to diode laser-assisted eyebrow epilation.

We describe two cases of ocular complications secondary to Diode laser assisted eyebrow epilation. Both included patients were women who underwent an eyebrow epilation procedure with Diode laser. A few hours after the procedure they started complaining with photophobia and blurred vision. They were diagnosed with anterior acute uveitis and treated with topical steroids and mydriatics. During the follow-up the presence of sequelae derived from the laser procedure (mydriasis and corectopia in both patients, cataract in the second one) was confirmed. Laser hair removal of the eyebrows can induce irreversible eye damage. Complete and reliable information regarding the potential side effects of this procedure and proper use of appropriate safety devices is mandatory. We point out the importance of the potential ocular side effects associated with these cosmetic devices.

Simultaneous domestic wastewater treatment and renewable energy production using microbial fuel cells (MFCs).

Microbial fuel cells (MFCS) can be used in wastewater treatment and to simultaneously produce electricity (renewable energy). MFC technology has already been applied successfully in lab-scale studies to treat domestic wastewater, focussing on organic matter removal and energy production. However, domestic wastewater also contains nitrogen that needs to be treated before being discharged. The goal of this paper is to assess simultaneous domestic wastewater treatment and energy production using an air-cathode MFC, paying special attention to nitrogen compound transformations. An air-cathode MFC was designed and run treating 1.39 L d(-1) of wastewater with an organic load rate of 7.2 kg COD m(-3) d(-1) (80% removal efficiency) and producing 1.42 W m(-3). In terms of nitrogen transformations, the study demonstrates that two different processes took place in the MFC: physical-chemical and biological. Nitrogen loss was observed increasing in line with the power produced. A low level of oxygen was present in the anodic compartment, and ammonium was oxidised to nitrite and nitrate.

Genistein does not inhibit TGF-beta1-induced conversion of human dermal fibroblasts to myofibroblasts.

Transforming growth factor beta 1 (TGF-beta1) is a pro-fibrotic cytokine with a key role in wound repair and regeneration, including induction of fibroblast-to-myofibroblast transition. Genistein is a naturally occurring selective estrogen receptor modulator with promising anti-fibrotic properties. In the present study we aimed to investigate whether genistein modulates TGF-beta1 (canonical and non-canonical) signaling in normal dermal fibroblasts at the protein level (Western blot and immunofluorescence). We demonstrated that TGF-beta1 induces the myofibroblast-like phenotype in the studied fibroblast signaling via canonical (SMAD) and non-canonical (AKT, ERK1/2, ROCK) pathways. Genistein induced only ERK1/2 expression, whereas the combination of TGF-beta1 and genistein attenuated the ERK1/2 and ROCK signaling. Of note, the other studied pathways remained almost unaffected. From this point of view, genistein does not impair conversion of normal fibroblasts to myofibroblast-like cells.

Triflusal reduces dense-core plaque load, associated axonal alterations and inflammatory changes, and rescues cognition in a transgenic mouse model of Alzheimer's disease.

Inflammation has been associated with the two classic lesions in the Alzheimer's (AD) brain, amyloid deposits and neurofibrillary tangles. Recent data suggest that Triflusal, a compound with potent anti-inflammatory effects in the central nervous system in vivo, might delay the conversion from amnestic mild cognitive impairment to a fully established clinical picture of dementia. In the present study, we investigated the effect of Triflusal on brain Abeta accumulation, neuroinflammation, axonal curvature and cognition in an AD transgenic mouse model (Tg2576). Triflusal treatment did not alter the total brain Abeta accumulation but significantly reduced dense-cored plaque load and associated glial cell proliferation, proinflammatory cytokine levels and abnormal axonal curvature, and rescued cognitive deficits in Tg2576 mice. Behavioral benefit was found to involve increased expression of c-fos and BDNF, two of the genes regulated by CREB, as part of the signal transduction cascade underlying the molecular basis of long-term potentiation. These results add preclinical evidence of a potentially beneficial effect of Triflusal in AD.

Effect of cycle changes on simultaneous biological nutrient removal in a sequencing batch reactor (SBR).

The destabilization of a microbial population is sometimes hard to solve when different biological reactions are coupled in the same reactor as in sequencing batch reactors (SBRs). This paper will try to guide through practical experiences the recovery of simultaneous nitrogen and phosphorus removal in an SBR after increasing the demand of wastewater treatment by taking advantage of its flexibility. The results demonstrate that the length of phases and the optimization of influent distribution are key factors in stabilizing the system for long-term periods with high nutrient removal (88%, 93% and 99% of carbon, nitrogen and phosphorus, respectively). In order to recover a biological nutrient removal (BNR) system, different interactions such as simultaneous nitrification and denitrification and also phosphorus removal must be taken into account. As a general conclusion, it can be stated there is no such thing as a perfect SBR operation, and that much will depend on the state of the BNR system. Hence, the SBR operating strategy must be based on a dynamic cycle definition in line with process efficiency.

Role of health-related quality of life measurements in the design of drug clinical trials.

OBJECTIVE: Health-related quality of life (HRQL) measurements enable us to take patient perception into account when evaluating treatment outcomes from clinical trials (CTs). The purpose of this study was to evaluate the use of HRQL questionnaires as a measurement of efficacy in CT design. METHODS: A duplicate systematic review of the CTs examined by a Clinical Research Ethics Committee between 1995 and 2006 was performed to check for use of HRQL. We gathered data concerning general aspects including medical specialty, drugs evaluated, methodological quality and inclusion of economic variables. For CTs including HRQL measurements, we analysed the type of questionnaire in use. Where there were no HRQL measurements, we analysed the methodological possibilities for including them, and the relevance of their absence. RESULTS: A total of 242 CTs were analysed; 69 (28.5%) included HRQL measurements, and 10 CTs (4.1%) used them as a primary endpoint. Only 22 CTs used more than one questionnaire. Data analysis by therapeutic area showed that HRQL was most commonly studied in the fields of rheumatology, urology, psychiatry and oncology. Only 33 CTs included economic variables. CONCLUSIONS: Measurements based on clinical parameters are the most commonly used means of measuring efficacy. Only a small percentage of CTs take the patient's perception of his/her health into account, despite the increasing importance given to this parameter. Including HRQL questionnaires in CTs design is still far from common.

Ocular complications secondary to diode laser-assisted eyebrow epilation. / Complicaciones oculares secundarias a depilación de las cejas con láser diodo.

We describe two cases of ocular complications secondary to Diode laser assisted eyebrow epilation. Both included patients were women who underwent an eyebrow epilation procedure with Diode laser. A few hours after the procedure they started complaining with photophobia and blurred vision. They were diagnosed with anterior acute uveitis and treated with topical steroids and mydriatics. During the follow-up the presence of sequelae derived from the laser procedure (mydriasis and corectopia in both patients, cataract in the second one) was confirmed. Laser hair removal of the eyebrows can induce irreversible eye damage. Complete and reliable information regarding the potential side effects of this procedure and proper use of appropriate safety devices is mandatory. We point out the importance of the potential ocular side effects associated with these cosmetic devices.

Recommendations for eye care during the alarm state by the coronavirus disease pandemic COVID-19. / Recomendaciones para la atención oftalmológica durante el estado de alarma por la pandemia de enfermedad por coronavirus COVID-19.

OBJECTIVE: Minimize exposure to the SARS-CoV-2, reduce the chances of cross-transmission between patients and healthcare personnel, and prevent the development of postoperative complications from the management of patients with eye diseases during the 2019 coronavirus disease pandemic (COVID-19). METHODS: COVID-19 literature review and consensus establishment between different Spanish ophthalmology societies in order to provide guidelines and recommendations of maximum resources primarily conditioned by the state of alert, confinement and social distancing that occurs in Spain since March 16, 2020. RESULTS: The recommendations will promote the adoption of action and protection measures for eye care in outpatient clinics, surgical areas and hospitalization, for unconfirmed (asymptomatic and symptomatic) and confirmed COVID-19 patients. Measures must be adapted to the circumstances and availability of personal protective equipment in each of the centers and Autonomous Communities, which will be updated according to the pandemic phases and the measures adopted by the Spanish Government. CONCLUSIONS: During the COVID-19 pandemic, attention to the potential health risks to the population caused by coronavirus should prevail over the possible progression of the common eye diseases. Ophthalmologists and other eye care professionals must assume a possible progression of these diseases due to the impossibility of adequate patient follow-up.

A novel GSK-3beta inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo.

Amyloid deposits, neurofibrillary tangles, and neuronal cell death in selectively vulnerable brain regions are the chief hallmarks in Alzheimer's (AD) brains. Glycogen synthase kinase-3 (GSK-3) is one of the key kinases required for AD-type abnormal hyperphosphorylation of tau, which is believed to be a critical event in neurofibrillary tangle formation. GSK-3 has also been recently implicated in amyloid precursor protein (APP) processing/Abeta production, apoptotic cell death, and learning and memory. Thus, GSK-3 inhibition represents a very attractive drug target in AD and other neurodegenerative disorders. To investigate whether GSK-3 inhibition can reduce amyloid and tau pathologies, neuronal cell death and memory deficits in vivo, double transgenic mice coexpressing human mutant APP and tau were treated with a novel non-ATP competitive GSK-3beta inhibitor, NP12. Treatment with this thiadiazolidinone compound resulted in lower levels of tau phosphorylation, decreased amyloid deposition and plaque-associated astrocytic proliferation, protection of neurons in the entorhinal cortex and CA1 hippocampal subfield against cell death, and prevention of memory deficits in this transgenic mouse model. These results show that this novel GSK-3 inhibitor has a dual impact on amyloid and tau alterations and, perhaps even more important, on neuronal survival in vivo further suggesting that GSK-3 is a relevant therapeutic target in AD.

Leber's idiopathic stellate neuroretinitis: diagnostic and therapeutic conflicts. / Neurorretinitis estrellada idiopática de Leber: conflictos diagnósticos y terapéuticos.

Three cases of patients with decreased visual acuity and papillitis at onset with subsequent macular star development after a few weeks are presented. Complementary tests were unremarkable in all included patients. Based on this clinical context, they were diagnosed with Leber's idiopathic stellate neuroretinitis, were treated with corticosteroids, as well as with antibiotics in 2cases. All patients showed favourable outcomes, although signs of papillary atrophy were observed in the affected eyes. Leber's idiopathic stellate neuroretinitis diagnosis can be challenging due to the wide spectrum of conditions that have to be ruled out. In addition, macular star may appear later on, which should not exclude its diagnosis. Use of antibiotics and/or corticosteroids is controversial considering its benign nature, but should be considered in selected severe cases. Moreover, the routine use of complementary tests should be carefully evaluated, mainly those that can be aggressive and/or expensive, which should be rationally used.

Selection between alcohols and volatile fatty acids as external carbon sources for EBPR.

The purpose of this paper is to provide a basis for selecting alcohols (i.e. ethanol and methanol) or short-chain volatile fatty acids (VFAs) (i.e. acetate and propionate) as the external carbon sources for enhanced biological phosphorus removal (EBPR) from wastewaters in adapted or unadapted activated sludge. When ethanol is used in an unacclimated process, a period of adaptation is required by polyphosphate-accumulating organisms (PAOs). From 0 to 140 days of ethanol acclimatizing, the P release and uptake rates increased to 6.2 and 7.0 mgP-PO(3)4(-)g(-1)VSSh(-1), respectively. PAOs in ethanol-enriched sludge produced poly-beta-hydroxyvalerate (PHV) (81.9%) as the main polyhydroxyalkanoate (PHA) and reached an effluent phosphate concentration close to zero (0.10 mgP-PO(3)4(-)L(-1)). On the other hand, methanol was not used by PAOs in 30-day ethanol-acclimated sludge in short-term tests. If EBPR needs to be incidentally supported by substrate addition, VFAs are preferred; for long-term addition also ethanol can be considered.

The physiology and pathophysiology of nitric oxide in the brain.

Nitric oxide (NO) is a molecule with pleiotropic effects in different tissues. NO is synthesized by NO synthases (NOS), a family with four major types: endothelial, neuronal, inducible and mitochondrial. They can be found in almost all the tissues and they can even co-exist in the same tissue. NO is a well-known vasorelaxant agent, but it works as a neurotransmitter when produced by neurons and is also involved in defense functions when it is produced by immune and glial cells. NO is thermodynamically unstable and tends to react with other molecules, resulting in the oxidation, nitrosylation or nitration of proteins, with the concomitant effects on many cellular mechanisms. NO intracellular signaling involves the activation of guanylate cyclase but it also interacts with MAPKs, apoptosis-related proteins, and mitochondrial respiratory chain or anti-proliferative molecules. It also plays a role in post-translational modification of proteins and protein degradation by the proteasome. However, under pathophysiological conditions NO has damaging effects. In disorders involving oxidative stress, such as Alzheimer's disease, stroke and Parkinson's disease, NO increases cell damage through the formation of highly reactive peroxynitrite. The paradox of beneficial and damaging effects of NO will be discussed in this review.

Lack of oestrogen protection in amyloid-mediated endothelial damage due to protein nitrotyrosination.

Amyloid beta-peptide (Abeta) cytotoxicity, the hallmark of Alzheimer's disease, implicates oxidative stress in both neurons and vascular cells, particularly endothelial cells. Consequently, antioxidants have shown neuroprotective activities against Abeta-induced cytotoxicity. Among the different antioxidants used in both in vitro and in vivo studies, 17beta-oestradiol (E2) has garnered the most attention. Oestrogen attenuated Abeta(E22Q)-induced toxicity in neurons but failed to protect endothelial cells. Here we show that E2-mediated activation of endothelial nitric oxide synthase (eNOS) increases the production of nitric oxide (NO), which, under Abeta(E22Q)-induced oxidative damage, results in the formation of peroxynitrite and increased nitration of tyrosine residues. Inhibition of eNOS prevents nitrotyrosination and permits E2-mediated protection against Abeta(E22Q) on endothelial cells. The main nitrotyrosinated proteins in the presence of E2 and Abeta(E22Q) were identified by MALDI-TOF mass spectrometry. These proteins are key players in the regulation of energy production, cytoskeletal integrity, protein metabolism and protection against oxidative stress. Our data highlight the potential damaging consequences of E2 in vascular disorders dealing with oxidative stress conditions, such as cerebral amyloid angiopathy, stroke and ischaemia-reperfusion conditions.