Search

Background: Successful recanalization does not lead to complete tissue reperfusion in a considerable percentage of ischemic stroke patients. This study aimed to identify biomarkers associated with futile recanalization. Leukoaraiosis predicts poor outcomes of this phenomenon. Soluble tumour necrosis factor‐like weak inducer of apoptosis (sTWEAK), which is associated with leukoaraiosis degrees, could be a potential biomarker. Methods: This study includes two cohorts of ischemic stroke patients in a multicentre retrospective observational study. Effective reperfusion, defined as a reduction of ≥8 points in the National Institutes of Health Stroke Scale (NIHSS) within the first 24 h, was used as a clinical marker of effective reperfusion. Results: In the first cohort study, female sex, age, and high NIHSS at admission (44.7% vs. 81.1%, 71.3 ± 13.7 vs. 81.1 ± 6.7; 16 [13, 21] vs. 23 [17, 28] respectively; p <.0001) were confirmed as predictors of futile recanalization. ROC curve analysis showed that leukocyte levels (sensitivity of 99%, specificity of 55%) and sTWEAK level (sensitivity of 92%, specificity of 88%) can discriminate between poor and good outcomes. Both biomarkers simultaneously are higher associated with outcome after effective reperfusion (OR: 2.17; CI 95% 1.63–4.19; p <.0001) than individually (leukocytes OR: 1.38; CI 95% 1.00–1.64, p =.042; sTWEAK OR: 1.00; C I95% 1.00–1.01, p =.019). These results were validated using a second cohort, where leukocytes and sTWEAK showed a sensitivity of 100% and specificity of 66.7% and 75% respectively. Conclusions: Leukocyte and sTWEAK could be biomarkers of reperfusion failure and subsequent poor outcomes. Further studies will be necessary to explore its role in reperfusion processes. [ABSTRACT FROM AUTHOR]

Aim: To assess whether periodontitis is associated with cognitive decline and its progression as well as with certain blood‐based markers of Alzheimer's disease. Materials and Methods: Data from a 2‐year follow‐up prospective cohort study (n = 101) was analysed. Participants with a previous history of hypertension and aged ≥60 years were included in the analysis. All of them received a full‐mouth periodontal examination and cognitive function assessments (Addenbrooke's Cognitive Examination (ACE) and Mini‐Mental State Examination [MMSE]). Plasma levels of amyloid beta (Aβ)1‐40, Aβ1‐42, phosphorylated and total Tau (p‐Tau and t‐Tau) were determined at baseline, 12 and 24 months. Results: Periodontitis was associated with poor cognitive performance (MMSE: β = −1.5 [0.6]) and progression of cognitive impairment (hazard ratio [HR] = 1.8; 95% confidence interval: 1.0–3.1). Subjects with periodontitis showed greater baseline levels of p‐Tau (1.6 [0.7] vs. 1.2 [0.2] pg/mL, p <.001) and Aβ1‐40 (242.1 [77.3] vs. 208.2 [73.8] pg/mL, p =.036) compared with those without periodontitis. Concentrations of the latter protein also increased over time only in the periodontitis group (p =.005). Conclusions: Periodontitis is associated with cognitive decline and its progression in elderly patients with a previous history of hypertension. Overexpression of p‐Tau and Aβ1‐40 may play a role in this association. [ABSTRACT FROM AUTHOR]

Background: Right ventricular (RV) echocardiographic changes such as dilation or systolic dysfunction, and pulmonary arterial hypertension were observed in patients with COVID‐19. The aim of our study was to determine the frequency of RV echocardiographic changes in patients who have recovered from COVID‐19 and to verify the association between severe acute respiratory syndrome (SARS) and echocardiographic findings. Methods: Patients who had recovered from COVID‐19 undergoing outpatient follow‐up underwent transthoracic echocardiography, and based on the findings, were divided into two groups: normal and abnormal. It was then verified whether there is an association between SARS and RV echocardiographic abnormalities in recovered patients. Results: The study included 61 patients, with a mean age of 54.2 ± 12.0 years, 57.4% had presented with SARS. The mean period of time between COVID‐19 and the echocardiographic examination was 11.9 ± 7.0 months. Patients presented normal left ventricular systolic function. The frequency of RV echocardiographic changes in patients who had recovered from COVID‐19 was 44.3%. RV systolic dysfunction was identified in 31.1%, followed by ventricular dilation in 14.7% and pulmonary hypertension in 9.8%. An association was observed between SARS and RV echocardiographic changes in recovered patients during outpatient follow‐up (OR: 4.96; 95% CI: 1.37–17.9; p = 0.015). An association was also demonstrated between SARS and RV dilation (p = 0.007) and between SARS and systolic dysfunction (p = 0.028). Conclusion: SARS is a risk factor for abnormal RV echocardiographic findings in patients recovered from COVID‐19. [ABSTRACT FROM AUTHOR]

Objective: To analyze the impact of the foot health and health behavior and the characteristics of outdoor footwear among minority ethnic groups. Design and measures: A cross‐sectional study design using the Foot Health Status Questionnaire: foot pain, foot function, shoe, general foot health, general health, physical activity, social capacity, and vigor. Outcomes included the self‐reported type of outdoor footwear and clinical characteristics by sex were collected in 2019–2020. Sample: A total of 78 Roma participants self‐identified as members of this ethnic minority and 72 participants non‐Roma were assessed (n = 150). Results: The lower score values was recorded in the footwear and general foot health domains in Roma population. General population obtained higher scores in general health domains. The most common outdoor footwear types were running shoes and walking shoes in non‐Roma population, versus flip flops and slippers in Roma population. Clinical characteristics did not show any statistically significant differences (p <.05). Conclusion: Roma people wear flip flops and slippers and non‐Roma people running shoes and walking shoes. These findings reveal cultural differences that make it easier for the Roma population to experience a greater burden of foot health problems. General foot health and foot pain dimensions show statistically significant differences among ethnicity. [ABSTRACT FROM AUTHOR]

Objective: Leukoaraiosis (LA) refers to white matter lesions of undetermined etiology associated with the appearance and worsening of vascular pathologies. The aim is to confirm an increased frequency and intensity of LA in symptomatic patients with neurovascular pathology compared with asymptomatic subjects, and its association with circulating serum levels of soluble tumor necrosis factor‐like weak inducer of apoptosis (sTWEAK). Methods: An observational study was conducted in which two groups of patients were compared. Group I (N = 242) comprised of asymptomatic subjects with arterial hypertension and/or diabetes or with a history of transient ischemic attacks, and Group II (N = 382) comprised patients with lacunar stroke or deep hemispheric intracerebral hemorrhage (ICH) of hypertensive origin. Serum levels of sTWEAK were analyzed and correlated with prevalence and intensity of LA according to the Fazekas scale. Results: The prevalence of LA was higher in symptomatic (85.1%) versus asymptomatic patients (62.0%). Logistic regression model showed a significant relation of LA with neurovascular pathologies (OR: 2.69, IC 95%: 1.10–6.59, p = 0.003). When stratified according to the Fazekas scale, LA of grade II (OR: 3.53, IC 95%: 1.10–6.59, p = 0.003) and specially grade III (OR: 4.66, 95% CI: 1.09–19.84, p = 0.037) showed correlation with neurovascular pathologies. Increased sTWEAK levels were found in the symptomatic group in all LA grades (p < 0.0001), and associated with 5.06 times more risk of presenting clinical symptoms (OR: 5.06, 95% CI: 2.66–9.75, p < 0.0001). Interpretation: LA showed a higher prevalence in patients with symptomatic lacunar stroke or deep hemispheric ICH. There is an association between sTWEAK levels and LA degree. [ABSTRACT FROM AUTHOR]

The fetal inflammatory response (FIR) increases the risk of perinatal brain injury, particularly in extremely low gestational age newborns (ELGANs, < 28 weeks of gestation). One of the mechanisms contributing to such a risk is a postnatal intermittent or sustained systemic inflammation (ISSI) following FIR. The link between prenatal and postnatal systemic inflammation is supported by the presence of well‐established inflammatory biomarkers in the umbilical cord and peripheral blood. However, the extent of molecular changes contributing to this association is unknown. Using RNA sequencing and mass spectrometry proteomics, we profiled the transcriptome and proteome of archived neonatal dried blood spot (DBS) specimens from 21 ELGANs. Comparing FIR‐affected and unaffected ELGANs, we identified 782 gene and 27 protein expression changes of 50% magnitude or more, and an experiment‐wide significance level below 5% false discovery rate. These expression changes confirm the robust postnatal activation of the innate immune system in FIR‐affected ELGANs and reveal for the first time an impairment of their adaptive immunity. In turn, the altered pathways provide clues about the molecular mechanisms triggering ISSI after FIR, and the onset of perinatal brain injury. Databases: EGAS00001003635 (EGA); PXD011626 (PRIDE). [ABSTRACT FROM AUTHOR]

In vivo corneal confocal microscopy (IVCM) is a non‐invasive ophthalmic imaging technique that provides images of the cornea at the cellular level. Despite the uses in ocular surface pathologies, in the last decades IVCM has been used to provide more knowledge in refractive surgery wound healing (LASIK and PRK), dry eye disease, and in some corneal infections (amoebas and filamentous fungi). The observation of the corneal cells, both normal and inflammatory, and the possibility of quantification of the corneal nerve density and quality with manual or automated tools, makes IVCM have a significant potential to improve the diagnosis and prognosis in several systemic and corneal conditions. Neuropathic pain has multiple aetiologies, but a major feature is small fibre dysfunction or damage. IVCM has been utilized to show small nerve fibre loss in patients with diabetic and other neuropathies. IVCM has comparable diagnostic utility to intraepidermal nerve fibre density for diabetic neuropathy, fibromyalgia and amyloid neuropathy and predicts the development of diabetic neuropathy. Moreover, in clinical intervention trials of patients with diabetic and sarcoid neuropathy, corneal nerve regeneration occurs early and precedes an improvement in symptoms and neurophysiology. Corneal nerve fibre loss also occurs and is associated with disease progression in multiple sclerosis, Parkinson's disease, and dementia. Patients with small fibre neuropathy have IVCM nerve changes. In conclusion, IVCM has good diagnostic and prognostic capability and fulfils the criteria as an end point for clinical trials in corneal, and peripheral and central neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether elevated serum levels of sTWEAK (soluble tumor necrosis factor‐like inducer of apoptosis) might be involved in a higher frequency of symptomatic hemorrhagic transformation (HT) through the presence of leukoaraiosis (LA) in patients with acute ischemic stroke (IS) undergoing reperfusion therapies. Methods: This is a retrospective observational study. The primary endpoint was to study the sTWEAK‐LA‐HT relationship by comparing results with biomarkers associated to HT and evaluating functional outcome at 3‐months. Clinical factors, neuroimaging variables and biomarkers associated to inflammation, endothelial/atrial dysfunction or blood‐brain barrier damage were also investigated. Results: We enrolled 875 patients (mean age 72.3 ± 12.2 years; 46.0% women); 710 individuals underwent intravenous thrombolysis, 87 endovascular therapy and 78 both. HT incidence was 32%; LA presence was 75.4%. Patients with poor functional outcome at 3‐months showed higher sTWEAK levels at admission (9844.2 [7460.4–12,542.0] vs. 2717.3 [1489.7–5852.3] pg/mL, P < 0.0001). By means of logistic regression models, PDGF‐CC and sTWEAK were associated with mechanisms linked simultaneously to HT and LA. Serum sTWEAK levels at admission ≥6700 pg/mL were associated with an odds ratio of 13 for poor outcome at 3‐months (OR: 13.6; CI 95%: 8.2–22.6, P < 0.0001). Conclusions: Higher sTWEAK levels are independently associated with HT and poor functional outcome in patients with IS undergoing reperfusion therapies through the presence of LA. sTWEAK could become a therapeutic target to reduce HT incidence in patients with IS. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether periodontitis is associated with amyloid beta (Aβ) peptides and whether systemic inflammation could act as a potential mediator of this link. Materials and Methods: A case–control study was designed including 75 patients with periodontitis (cases) and 75 age‐balanced and gender‐matched participants without periodontitis (controls). Full‐mouth periodontal evaluation was performed in all participants. Demographic, clinical and behaviour data were also recorded. Fasting blood samples were collected, and serum levels of interleukin 6 (IL‐6), high‐sensitivity C‐reactive protein (hs‐CRP), Aβ1‐40 and Aβ1‐42 were determined. Results: Cases showed higher levels of IL‐6 (8.7 ± 3.2 vs. 4.8 ± 0.5 pg/ml), hs‐CRP (3.3 ± 1.2 vs. 0.9 ± 0.7 mg/L), Aβ1‐40 (37.3 ± 6.0 vs. 30.3 ± 1.8 pg/ml) and Aβ1‐42 (54.5 ± 10.6 vs. 36.5 ± 10.0 pg/ml) when compared to controls (all p <.001). Diagnosis of periodontitis was statistically significantly associated with circulating Aβ1‐40 (βcoefficientadjusted = 6.9, 95% CI: 5.4–8.3; p <.001) and Aβ1‐42 (βcoefficientadjusted = 17.8, 95% CI: 14.4–21.3; p <.001). Mediation analysis confirmed hs‐CRP and IL‐6 as mediators of this association. Conclusions: Periodontitis is associated with increased peripheral levels of Aβ. This finding could be explained by enhanced systemic inflammation that can be seen in patients with periodontitis. [ABSTRACT FROM AUTHOR]

Importance Rare transforming growth factor beta‐induced (TGFBI) gene variants are involved in autosomal dominant corneal dystrophies (CDs) with heterogeneous clinical features. Background: The purpose of this study was to analyse TGFBI gene variants and genotype‐phenotype correlations in a cohort affected by atypical stromal CD. Design Retrospective cohort study (from May 2014 to September 2017). Participants: Thirty‐five individuals from 10 unrelated South European families presenting atypical lattice CD (LCD) were included. Methods: Corneal phenotypes were assessed by slit‐lamp examination and optical coherence tomography (OCT). Contrast sensitivity was measured under mesopic conditions. Genomic DNA was obtained from blood samples, and all 17 TGFBI exons were screened for variants by Sanger sequencing. Main Outcome Measures: p.(L558P) variant of TGFBI gene. Results: The p.(L558P) variant was identified in 22 members of the 10 families diagnosed with atypical LCD, characterized by late‐onset and absence of recurrent erosion syndrome. OCT revealed punctiform deposits in the deep‐mid stroma and normal anterior stroma. This variant was demonstrated to be transmitted with the disease according to autosomal dominant inheritance in most families. Conclusions and Relevance: To the best of our knowledge, we describe a detailed clinical characterization of the largest CD cohort carrying the TGFBI p.(L558P) variant. We propose that the atypical phenotype of this recently reported alteration can be classified as a form of LCD type IV. The results show that OCT and anterior‐posterior analysis of the stromal location of the opacities, along with a genetic analysis of TGFBI, are required to ensure accurate diagnosis and management of CDs. [ABSTRACT FROM AUTHOR]

Aim: To analyse the incidence, risk factors and clinical outcomes of late graft failure after heart transplantation.Methods and Results: We conducted an observational, single-centre study based on 547 patients who underwent cardiac transplantation from 1991 to 2014 and who survived the in-hospital postoperative period. Late graft failure was defined as the first hospitalization due to this condition after discharge. Over a mean follow-up of 8.4 ± 6 years, 178 (32.5%) patients were hospitalized due to late graft failure [incidence rate: 3.6 cases per 100 patient-years, 95% confidence interval (CI) 3.1-4.2]. Pre-transplant diabetes, higher pre-transplant transpulmonary pressure gradient and lower donor-recipient weight ratio were independently associated with higher risk of graft failure. Cardiac allograft vasculopathy, cellular rejection grade ≥1R, and antibody-mediated rejection grade ≥1 were detected in 50.6%, 44.9% and 19.2% patients, respectively, admitted due to graft failure. Left ventricular ejection fraction was ≥50% in 60.1% of these patients. Re-transplant free survival 1, 5, 10 and 15 years after the diagnosis of late graft failure was 72.2%, 38.4%, 18.4%, and 7.5%, respectively; the incidence rate of re-hospitalization due to decompensated heart failure was 40.9 episodes per 100 patient-years (95% CI 36.6-46.1). The need for inotropes, the presence of cardiac allograft vasculopathy, higher creatinine serum levels, lower ejection fraction and lower sodium serum levels were independent predictors of worse outcomes.Conclusions: Late graft failure is frequent after heart transplantation, as it is associated with poor outcomes. Rejection and cardiac allograft vasculopathy are the most frequent underlying causes. [ABSTRACT FROM AUTHOR]

Summary: Accurate estimation of the absolute number of a particular cell‐type in whole organs is increasingly important in studies on organogenesis, and the remodelling and repair of diseased tissues. The unbiased estimation of the absolute number of cells in an organ is complicated, and design‐based stereology remains the method of choice. This has led investigators to explore alternative approaches – such as flow cytometry – as a faster and less labour‐intensive replacement for stereology. To address whether flow cytometry might substitute stereology, design‐based stereology was compared with microfluorosphere‐controlled flow cytometry, for estimation of the absolute number of alveolar epithelial type 2 cells (AEC2) in the lungs of two mouse strains: wild‐type C57BL/6J mice and Sftpc‐YFP mice. Using design‐based stereology, ≈10.7 million and ≈9.0 million AEC2 were estimated in the lungs of wild‐type C57BL/6J mice and Sftpc‐YFP mice, respectively. Substantially fewer AEC2 were estimated using flow cytometry. In wild‐type C57/BL6J mouse lungs, 59% of the AEC2 estimated by design‐based stereology were estimated by flow cytometry (≈6.3 million), using intracellular staining for pro‐surfactant protein C. Similarly, in Sftpc‐YFP mouse lungs, 23% of the AEC2 estimated by design‐based stereology were estimated by flow cytometry (≈2.1 million), using yellow fluorescent protein fluorescence. Our data suggest that flow cytometry underestimates AEC2 number, possibly due to impaired recoverability of AEC2 from dissociated lung tissue. These data suggest design‐based stereology as the method of choice for the unbiased estimation of the absolute number of cells in an organ. Lay Description: There is much interest in studies on the pathological changes that accompany disease, to be able to count or estimate the number of a particular cell‐type in solid tissue, such as an organ. The easiest way to do this is to make liquid suspensions of single cells from solid tissue, and then to count the number of cells of interest, using either a microscope, or automated cell counting (for example, a flow cytometer). Alternatively, solid tissue may be examined microscopically, where the cell‐type of interest might also be counted 'by eye' or in an automated manner using software (called planimetry). All of these approaches to counting cells in solid organs come with serious drawbacks, and estimation of the cell number may thus be inaccurate. To overcome this, we have employed a combination of mathematical tools and statistical principles together with microscopy (called 'design‐based stereology') that permits the unbiased counting of cells in microscopic fields, which can then be extrapolated to the entire solid tissue volume, to accurately estimate the number of a cell‐type of interest in the solid tissue. We have compared this method with the estimation of cell number using a flow cytometer. Our data reveal that flow cytometry appreciably underestimates the total number of cells in solid tissue, where we used the lung as an example of solid tissue, and estimated the number of a unique cell‐type in the lung: the alveolar epithelial type 2 cell, to compare stereology with flow cytometry. We believe that flow cytometry underestimates the cell number due to the difficulty of breaking up solid tissue into single cells, and being able to recover all of those single cells for analysis. Our data supports the recommendation to use stereology, not flow cytometry, to accurately estimate the number of a particular cell‐type in solid tissue. Accurate estimation of the absolute number of a particular cell‐type in whole organs is increasingly important in studies on organogenesis, and the remodelling and repair of diseased tissues. Although estimation of the relative number of cells might be straightforward, unbiased estimation of the absolute number of cells in an organ is complicated, and design‐based stereology remains the method of choice. This has led investigators to explore alternative approaches – such as flow cytometry – as a faster and less labour‐intensive replacement for stereology. To address whether flow cytometry might substitute stereology, design‐based stereology was compared with microfluorosphere‐controlled flow cytometry, for estimation of the absolute number of alveolar epithelial type 2 cells (AEC2) in the lungs of two mouse strains: wild‐type C57BL/6J mice and Sftpc‐YFP mice. Using design‐based stereology, ≈10.7 million and ≈9.0 million AEC2 were estimated in the lungs of wild‐type C57BL/6J mice and Sftpc‐YFP mice, respectively. Substantially fewer AEC2 were estimated using flow cytometry. In wild‐type C57/BL6J mouse lungs, 59% of the AEC2 estimated by design‐based stereology were estimated by flow cytometry (≈6.3 million), using intracellular staining for pro‐surfactant protein C. Similarly, in Sftpc‐YFP mouse lungs, 23% of the AEC2 estimated by design‐based stereology were estimated by flow cytometry (≈2.1 million), using yellow fluorescent protein fluorescence. Our data suggest that flow cytometry underestimates AEC2 number, possibly due to impaired recoverability of AEC2 from dissociated lung tissue. These data suggest design‐based stereology as the method of choice for the unbiased estimation of the absolute number of cells in an organ. [ABSTRACT FROM AUTHOR]

BACKGROUND Ethyl levulinate (EL) is an important chemical that can be used as a bio‐based replacement of fuel additives such as methyl tert‐butyl ether (MTBE) and tert‐amyl methyl ether (TAME). EL production from lactic acid and ethanol is a viable option, as both precursors can be obtained from biomass. However, the problem of EL production by esterification is that this reaction is hindered by the chemical equilibrium limitations and the boiling points ranking, which is not the most favorable. RESULTS: This study provides novel optimally designed reactive distillation (RD) processes for the production of EL, taking into account costs, environmental impact and safety. The thermally coupled RD process is the most appealing, with the lowest energy use (1.667 MJ kg−1 EL), minimal investment cost, major energy savings (up to 54.3% lower than other RD processes), reduced environmental impact (up to 51% lower ECO99 index value) and similar safety as other RD processes considered (less than 2% differences in the individual risk (IR) indicator). CONCLUSION: The multi‐objective optimization approach used here showed its robustness, practicality and flexibility to provide multiple optimal designs of intensified processes that are economically attractive, environmentally friendly and inherently safe. © 2019 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Background: Periodontitis has been associated with lacunar infarct (LI), a type of cerebral small vessel disease. The objective of this study was to ascertain whether periodontitis is associated with increased circulating levels of systemic inflammation and endothelial dysfunction biomarkers in patients with LI.Methods: One hundred twenty patients with LI and 120 healthy controls underwent a full-mouth periodontal examination. The periodontal inflamed surface area (PISA) was calculated for each participant. Demographic, medical, and neurological information were recorded from all of them. In addition, blood samples were collected in order to investigate differences in terms of interleukin (IL)-6, IL-10, pentraxin (PTX) 3, soluble fragment of tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and amyloid-beta (Aβ) peptides (i.e., Aβ1-40 , and Aβ1-42 ) measured in serum.Results: Periodontitis was independently associated with increased levels of IL-6 (R2  = 0.656, P < 0.001), PTX3 (R2  = 0.115, P < 0.001), sTWEAK (R2  = 0.527, P < 0.001), and Aβ1-40 (R2  = 0.467, P < 0.001) in patients with LI. Within patients with poor outcome, PISA positively correlated with IL-6 (r = 0.738, P < 0.001), PTX3 (r = 0.468, P = 0.008), sTWEAK (r = 0.771, P < 0.001), and Aβ1-40 (r = 0.745, P < 0.001).Conclusions: Our data suggest a link between periodontitis, systemic inflammatory response, and disruption of the vascular endothelial function in patients with LI. Experimental studies are needed to elucidate possible pathways through which periodontitis could lead to this systemic inflammatory state with impairment of the endothelial function in LI. Further longitudinal studies with large samples are warranted to confirm our findings. [ABSTRACT FROM AUTHOR]

Summary: Many species in the order Bacillales form a specialized cell type called a spore that is resistant to a range of environmental stresses. Transmission electron microscopy (TEM) reveals that the spore is comprised of a series of concentric shells, surrounding an interior compartment harbouring the spore DNA. The outermost of these shells varies considerably in morphology among species, likely reflecting adaptations to the highly diverse niches in which spores are found. To better characterize the variation in spore ultrastructure among diverse species, we used TEM to analyse spores from a collection of 23 aerobic spore‐forming bacteria from the Solo do Distrito Federal (SDF strains), spanning the genera Bacillus, Lysinibacillus, Paenibacillus and Brevibacillus, isolated from soil from central Brazil. We found that the structures of these spores varied widely, as expected. Interestingly, even though these isolates are novel strains of each species, they were structurally very similar to the known examples of each species in the literature. Because in most cases, the species we analysed are poorly characterized, our data provide important evidence regarding which structural features are likely to be constant within a taxon and which are likely to vary. [ABSTRACT FROM AUTHOR]

Corneal nerves are key components of the physiological system that controls ocular surface homeostasis. The cornea is primarily innervated by the ophthalmic branch of the trigeminal nerves (cranial nerve V), which distend bilaterally from the pons. The nasociliary branch (afferent) of the ophthalmic nerve is sensory for cornea, eyelid and conjunctiva. These nerve fibres play a role in sensing temperature, chemical and mechanical stimuli, and pain, whereas, branches of the facial nerve (cranial nerve VII) contain motor nerves that control blinking and autonomic (sympathetic and a paucity of parasympathetic) fibres that stimulate tear production and secretion via feedback loops between the ocular surface, lacrimal glands and brain. Disruption of these nerves with interruption of neural feedback loops between the ocular surface and lacrimal glands can lead to corneal diseases such as dry eye disease (DED) and neurotrophic keratopathy (NK). Inversely, hypersensitivity of the nerve fibres and/or dysregulation of pain‐controlling nervous centres may lead to neuropathic pain. Recently, medications that specifically target regeneration of corneal nerves have started to become available – and considering the high prevalence of diseases associated with corneal nerve dysfunction, these agents promise to fulfil a hitherto important unmet need. In this review, we explore the physiology of corneal nerves, the pathology of corneal nerve diseases and how these relate to neuropathic pain, NK and DED. We also discuss what novel treatments may be useful against diseases involving corneal nerves. [ABSTRACT FROM AUTHOR]

Aim: To investigate the association between periodontitis (PD) and lacunar infarct (LI) as well as to analyse whether PD could be a predictor of poor functional prognosis in patients with LI. Material and Methods: Full‐mouth periodontal examination was done in 120 cases (patients with LI) and 157 healthy controls. Demographic, clinical, medical and neurological information were collected from all of them. In addition, a measure of periodontal inflammation and disease activity, namely the periodontal inflamed surface area (PISA), was also calculated for each patient. Poor functional outcome was considered as a modified Rankin Scale >2 at 3 months. Results: PD was independently associated with the presence of LI (OR = 3.3, p < 0.001). Poor outcome was observed in 31 patients with LI (25.8%), of which 90.3% had PD. A PISA value ≥727 mm2 was an independent predictor of poor prognosis, after adjusting for clinical confounders (OR = 6.5, p = 0.001). Conclusions: PD and LI were associated. Active moderate to severe PD predicted poor prognosis in patients with LI. Further evidence is warranted to confirm our results and investigate potential mechanisms behind this association. [ABSTRACT FROM AUTHOR]

Objective: Blood/brain-glutamate grabbing is an emerging concept in the treatment of acute ischemic stroke, where essentially the deleterious effects of glutamate after ischemia are ameliorated by coaxing glutamate to enter the bloodstream and thus reducing its concentration in the brain. Aiming to demonstrate the clinical efficacy of blood glutamate grabbers in patients with stroke, in this study, we resorted to a drug-repositioning strategy for the discovery of new glutamate-grabbing drugs.Methods: The glutamate-grabbing ability of 1,120 compounds (90% of which were drugs approved by the US Food and Drug Administration) was evaluated during an in vitro high-throughput screening campaign. Subsequently, the protective efficacy of the selected drugs was probed in an ischemic animal model and finally tested in stroke patients.Results: Riboflavin (vitamin B2 ) was identified as the main hit compound. In ischemic animal models treated with riboflavin (1mg/kg), it was confirmed that blood glutamate reduction was associated with a significant reduction of infarct size. These results led to a randomized, double-blind, phase IIb clinical trial with patients with stroke. Fifty patients were randomized to 1 of the 2 study arms: the control group (placebo) and the experimental group (20mg of riboflavin [vitamin B2 Streuli@ ). Decrease in glutamate concentration was significantly greater (p < 0.029) in the treated group. Comparative analysis of the percentage improvement on the National Institutes of Health Stroke Scale score at discharge was slightly higher in the riboflavin-treated group than in the placebo group (33.7 ± 43.7 vs 48.9 ± 42.4%, p = 0.050).Interpretation: This translational study represents the first human demonstration of the efficacy of blood glutamate grabbers in the treatment of patients with stroke, paving the way for the development of a promising novel protective therapy. Ann Neurol 2018;84:260-273. [ABSTRACT FROM AUTHOR]

Abstract: Trophic functions for macrophages are emerging as key mediators of developmental processes, including bone, vessel, and mammary gland development. Yolk sac‐derived macrophages mature in the distal lung shortly after birth. Myeloid‐lineage macrophages are recruited to the lung and are activated under pathological conditions. These pathological conditions include bronchopulmonary dysplasia (BPD), a common complication of preterm birth characterized by stunted lung development, where the formation of alveoli is blocked. No study has addressed causal roles for immune cells in lung alveolarization. We employed antibody‐based and transgenic death receptor‐based depletion approaches to deplete or prevent lung recruitment of immune cell populations in a hyperoxia‐based mouse model of BPD. Neither neutrophils nor exudate macrophages (which might include lung interstitial macrophages) contributed to structural perturbations to the lung that were provoked by hyperoxia; however, cells of the Csf1r‐expressing monocyte/macrophage lineage were implicated as causal mediators of stunted lung development. We propose that resident alveolar macrophages differentiate into a population of CD45+ CD11c+ SiglecF+ CD11b+ CD68+ MHCII+ cells, which are activated by hyperoxia, and contribute to disturbances to the structural development of the immature lung. This is the first report that causally implicates immune cells in pathological disturbances to postnatal lung organogenesis. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Dry eye disease (DED) is a common, multifactorial ocular condition with major impact on vision and quality of life. It is now well recognized that the pathophysiology of chronic DED can include a cycle of inflammation involving both innate and adaptive immune responses. Recently, in vitro/in vivo models have been used to obtain a better understanding of DED‐related inflammatory processes at molecular/cellular levels although they do not truly reproduce the complex and chronic hallmarks of human DED. In clinical DED research, advanced techniques such as impression cytology, conjunctival biopsy, in vivo confocal microscopy and multiplex tear analyses have allowed an improved assessment of inflammation in DED patients. This was supported by the identification of reliable inflammatory markers including matrix metalloproteinase‐9, human leucocyte antigen‐DR or intercellular adhesion molecule‐1 in tears and impression cytology samples. One of the current therapeutic strategies focuses on breaking the inflammatory cycle perpetuating the ocular surface disease, and preclinical/clinical research has led to the development of promising anti‐inflammatory compounds. For instance, cyclosporine, already approved in the United States, has recently been authorized in Europe to treat DED associated with severe keratitis. In addition, other agents such as corticosteroids, doxycycline and essential fatty acids, through their anti‐inflammatory properties, show encouraging results. We now have a clearer understanding of the inflammatory processes involved in DED, and there is hope that the still emerging preclinical/clinical findings will be translated into new and highly effective therapies for patients in the near future. [ABSTRACT FROM AUTHOR]

Abstract: The quantitative assessment of the lung architecture forms the foundation of many studies on lung development and lung diseases, where parameters such as alveoli number, alveolar size, and septal thickness are quantitatively influenced by developmental or pathological processes. Given the pressing need for robust data that describe the lung structure, there is currently much enthusiasm for the development and refinement of methodological approaches for the unbiased assessment of lung structure with improved precision. The advent of stereological methods highlights one such approach. However, design‐based stereology is both expensive and time‐demanding. The objective of this study was to examine whether ‘limited’ stereological analysis, such as the stereological analysis of a single mouse lung lobe, may serve as a surrogate for studies on whole, intact mouse lungs; both in healthy lungs and in diseased lungs, using an experimental animal model of bronchopulmonary dysplasia (BPD). This served the dual‐function of exploring BPD pathobiology, asking whether there are regional (lobar) differences in the responses of developing mouse lungs to oxygen injury, by examining each mouse lung lobe separately in the BPD model. Hyperoxia exposure resulted in decreased alveolar density, alveoli number, and gas‐exchange surface area in all five mouse lung lobes, and increased the arithmetic mean septal thickness in all mouse lung lobes except the lobus cardialis. The data presented here suggest that – in healthy developing mice – a single mouse lung lobe might serve as a surrogate for studies on whole, intact mouse lungs. This is not the case for oxygen‐injured developing mouse lungs, where a single lobe would not be suitable as a surrogate for the whole, intact lung. Furthermore, as the total number of alveoli can only be determined by an analysis of the entire lung, and given regional differences in lung structure, particularly under pathological conditions, the stereological assessment of the whole, intact lung remains desirable. [ABSTRACT FROM AUTHOR]

Objective The aim of this study is to find a relation between several biomarkers in peripheral blood and outcome after treatment with onabotulinumtoxin A (OnabotA). Background OnabotA is an effective treatment in chronic migraine (CM). Different studies have tried to find predictors of response to treatment, either with clinical characteristics, neuroimaging features, or molecular biomarkers; however, it is still not possible to predict the individual outcome. Methods We measured serum levels of biomarkers of inflammation (IL-6, IL-10, TNF-α, and hs-CRP), endothelial dysfunction (PTX3 and sTWEAK), blood-brain barrier disruption (cFN), brain damage (S100b, NSE), and trigemino-vascular activation (CGRP) by ELISA in a group of CM patients treated with OnabotA and healthy controls. After 24 weeks, patients were classified in two groups according to their outcome considering variations in headache frequency: nonresponders (nonimprovement or improvement <50%) and responders (improvement >50%). We compared baseline levels of biomarkers between these groups. Results Sixty-two patients diagnosed with CM (IHS 2013 criteria) who fulfilled criteria for treatment with OnabotA and 24 healthy controls were included. Fifteen patients did not respond to treatment (24.2%) and 47 were responders (75.8%). Pentraxin 3 (PTX3) serum levels (1455.4 ± 487.5 pg/mL versus 720.3 ± 334.1 pg/mL, P < .0001) and calcitonin gene-related peptide (CGRP) serum levels (133.1 ± 86.6 ng/mL versus 58.2 ± 91.7 ng/mL, P = .004) were significantly higher in responders than nonresponders. Serum basal levels of PTX3 >1000 pg/mL (AUC 0.908; 95% CI: 0.827-0.990) and CGRP >50 ng/mL (AUC 0.800; 95% CI: 0.652-0.947) were associated with good response to OnabotA treatment. Conclusions These results show that molecular markers of trigeminovascular activation (CGRP) and endothelial dysfunction (PTX3) are associated with response to OnabotA and may act as new biomarkers for the selection of treatment in chronic migraineurs. [ABSTRACT FROM AUTHOR]

Meibomian gland dysfunction (MGD) is the most frequent cause of evaporative dry eye disease (DED). Until now, the only available treatments were as follows: warm compresses, massage, omega 3, and antibiotics. As a result, multiple devices have appeared in the marketplace designed to use heat and pressure to alleviate MG blockages, as well as to remove residue along the lid margins. The mechanism of action of Lipiflow®, Miboflo®, iLux® and Jett Plasma Lift® is thermal expression. The Lipiflow® consists of a console and a single‐use sterile device that uses sensor‐regulated heat and peristaltic motion to evacuate obstructed meibum. One section of the device goes behind the eyelids, providing the warmth; an outer section gently massages the lids against the inner section. Its effects last usually 12 months. Jett Plasma Lift also remove keratinized material from de lid margin. ILux® system is not available in Europe. ​Intense pulsed light (IPL) was originally developed for use in dermatology. Brief, powerful bursts of light at specific wavelengths (in this case, between 500 and 800 nm) cause changes in blood vessels near the surface of the skin, raise skin temperature and eliminate problematic flora on the skin and eyes, all of which may have a beneficial effect on meibomian gland dysfunction. Closing the abnormal vessels decrease inflammation and oxygen supply to meibocytes (they work in anaerobic conditions). Usually four sessions are needed. Expression with forceps and the treatment directly of the lids improve results. There are multiple platforms and not all are the same. BlephEx® produces microblepharoexfoliation. It's typically repeated at four to six‐month intervals. It is useful for anterior blepharitis. Rexon‐Eye® is an electro‐medical device for the treatment of DED. The applied electrical stimulation is based on the principle of quantum molecular resonance. Transferring energy to biological tissues in the form of high frequency oscillating electrical fields biostimulate the lachrymal and the MG. Thus, it is helpful for evaporative and aqueous‐deficient DED. ​The use of these devices reset the MG. They should be used on the glands before they atrophy. A combination of these treatments will probably work best for difficult patients. Independent clinical trials and studies comparing these devices and the new coming instruments are needed. [ABSTRACT FROM AUTHOR]

Purpose: Liposomes composed of soy phosphatidylcholine (PC) have been widely used in artificial tears for the treatment of dry eye disease (DED) due to their ability to supplement the lipid layer of the ocular surface. The disadvantage of PC extracted from natural sources is the difficulty of standardizing its fatty acid composition. Therefore, the use of synthetic phospholipids such as 1,2‐dioleoyl‐sn‐glycero‐3‐phosphocholine (DOPC) and Dimyristoylphosphatidylcholine (DMPC) allows better characterization and standardization than those from natural sources, being of interest in the preparation of ophthalmic liposomal formulations for DED. Methods: Liposomal formulations comprised of DOPC (F1) and DOPC combined with DMPC (F2) were prepared according to the Bangham technique and dispersed in a borate‐trehalose buffer. Formulations were characterized in terms of pH, size, osmolarity and surface tension. In vitro tolerance was performed in human corneal epithelial cells and compared with soy PC liposomal formulation. Results: Both F1 and F2 synthetic liposomal formulations showed suitable properties for topical ophthalmic administration for DED such as hypotonicity (F1: 244.8 ± 0.74; F2: 252.5 ± 0.08 mOsm/L), neutral pH (F1: 7.52 ± 0.01; F2: 7.54 ± 0.02), low surface tension (F1: 24.53 ± 0.70; F2: 26.93 ± 0.49 mN/m) and a vesicle size of 150.8 ± 59.60 and 181.00 ± 49.83 nm for F1 and F2 respectively. Synthetic phospholipids outperformed soy PC liposomes regarding in vitro tolerance in a very sensitive corneal line, exhibiting cell viability values after 1 hour exposure of 88.71 ± 7.32% and 82.36 ± 8.84% for F1 and F2 respectively compared to soy PC liposomes (73.08 ± 8.74%). After simulated chronic exposure (4 h), cell viability of F1 (78.26 ± 1.65%) and F2 (79.08 ± 1.75%) were higher than the one obtained for PC liposomal formulation (64.53 ± 6.73%). Conclusions: Liposomes composed of synthetic phospholipids are potential candidates for the development of artificial tears for DED treatment. [ABSTRACT FROM AUTHOR]

Aim: Fetal blood contains higher concentrations of glutamate-oxaloacetate transaminase (GOT; a blood enzyme able to metabolize glutamate) than maternal blood. The aim of this study was to determine the relationship between GOT and glutamate levels in arterial blood samples from umbilical cord in control newborn infants and newborn infants with hypoxic-ischaemic insult and/or symptoms of hypoxia-ischemia after delivery.Method: A total of 46 newborn infants (28 females, 18 males) were prospectively included in the study. Twenty-three infants (18 females, five males) were included as control participants and 23 (10 females, 13 males) were included as newborn infants at risk of adverse neurological outcome (defined as umbilical blood with pH <7.1).Results: Analysis of glutamate concentration and GOT activity in umbilical blood samples showed that newborn infants with pH <7.1 had higher levels of glutamate (142.4 μmol/L [SD 61.4] vs 62.8 μmol/L [SD 25.5]; p<0.001) and GOT (83.1 U/L [SD 60.9] vs 34.9 U/L [SD 18.2]; p<0.001) compared to newborn infants without fetal distress. Analysis of Apgar scores and blood pH values (markers of perinatal distress) showed that conditions of severe distress were associated with higher glutamate and GOT levels.Interpretation: During fetal development, the ability of GOT to metabolize glutamate suggests that this enzyme can act as an endogenous protective mechanism in the control of glutamate homeostasis. [ABSTRACT FROM AUTHOR]

Rationale, aims and objectives Transcatheter aortic valve implantation constitutes an example of a technology introduced into the Galician Health Care System basket and subjected to a post-introduction observational study after coverage. This paper aims to describe the process and results of this experience, illustrating the main challenges and opportunities in using these studies for supporting decision making. Methods The study protocol was developed by a multidisciplinary team consisting of experts from the Galician HTA Agency (avalia-t), interventional cardiologists and cardiac surgeons. Together they agreed on the information that was relevant and feasible for collection, and planned the study design, data collection and analysis of results. Results During the 1-year recruitment period, 94 patients underwent percutaneous aortic valve replacement in the three authorized centres. Implantation rate and prosthesis models differed substantially across the centres. Overall, procedural success rate was 96.8% and hospital mortality was 7.4%. Complications during post-surgical admission were recorded in 40.4% of patients. Moderate residual aortic regurgitation was observed in 10% of patients, and the procedure was associated with a stroke rate of 3.3% at 30 days and 5.3% at 1 year. Conclusions Post-introduction observation has made it feasible to determine the use of this procedure within the SERGAS context and has enabled the assessment of performance in real-life conditions. The proposed strategic actions and interventions have been drawn up based upon the collective judgement of a group of experienced professionals, and have served to establish recommendations on further research that would be required to optimize health benefits. [ABSTRACT FROM AUTHOR]

Brain ischaemia (stroke) triggers an intense inflammatory response predominately mediated by the accumulation of inflammatory cells and mediators in the ischaemic brain. In this context, regulatory T (Treg) cells, a subpopulation of CD4+ T cells with immunosuppressive and anti-inflammatory properties, are activated in the late stages of the disease. To date, the potential therapeutic usefulness of Treg cells has not been tested. In this study, we aimed to investigate whether Treg cells exert protection/repair following stroke. Both the adoptive transfer of Treg cells into ischaemic rats and the stimulation of endogenous T-cell proliferation using a CD28 superagonist reduced the infarct size at 3-28 days following the ischaemic insult. Moreover, T cell-treated animals had higher levels of FoxP3 and lower levels of IL-1β, CD11b+ and CD68+ cells in the infarcted hemisphere when compared with control animals. However, T-cell treatment did not alter the rate of proliferation of NeuN-, NCAM- or CD31-positive cells, thereby ruling out neurogenesis and angiogenesis in protection. These results suggest that adoptive transfer of T cells is a promising therapeutic strategy against the neurological consequences of stroke. [ABSTRACT FROM AUTHOR]

Rationale, aims and objectives Transcatheter aortic valve implantation constitutes an example of a technology introduced into the Galician Health Care System basket and subjected to a post-introduction observational study after coverage. This paper aims to describe the process and results of this experience, illustrating the main challenges and opportunities in using these studies for supporting decision making. Methods The study protocol was developed by a multidisciplinary team consisting of experts from the Galician HTAAgency (avalia-t), interventional cardiologists and cardiac surgeons. Together they agreed on the information that was relevant and feasible for collection, and planned the study design, data collection and analysis of results. Results During the 1-year recruitment period, 94 patients underwent percutaneous aortic valve replacement in the three authorized centres. Implantation rate and prosthesis models differed substantially across the centres. Overall, procedural success rate was 96.8% and hospital mortalitywas 7.4%. Complications during post-surgical admission were recorded in 40.4% of patients. Moderate residual aortic regurgitation was observed in 10% of patients, and the procedure was associated with a stroke rate of 3.3% at 30 days and 5.3% at 1 year. Conclusions Post-introduction observation has made it feasible to determine the use of this procedure within the SERGAS context and has enabled the assessment of performance in real-life conditions. The proposed strategic actions and interventions have been drawn up based upon the collective judgement of a group of experienced professionals, and have served to establish recommendations on further research that would be required to optimize health benefits. [ABSTRACT FROM AUTHOR]

Key points Plasma membrane ClC-2 chloride channels are widely distributed in our body and are important for vision and fertility., ClC-2 channels are gated by changes in transmembrane voltage despite of lacking a voltage sensor device. It has been hypothesized that the interaction of an external proton with the gating machinery is responsible for voltage-dependent gating., Here we used electrophysiological recordings and quantitative analysis under different external proton and internal chloride concentrations and found that the voltage dependence of gating is due to interaction between the passing chloride ion and the permeation pathway, with the external proton stabilizing the open state of the channel., Abstract The interaction of either H+ or Cl− ions with the fast gate is the major source of voltage ( Vm) dependence in ClC Cl− channels. However, the mechanism by which these ions confer Vm dependence to the ClC-2 Cl− channel remains unclear. By determining the Vm dependence of normalized conductance ( Gnorm( Vm)), an index of open probability, ClC-2 gating was studied at different [H+]i, [H+]o and [Cl−]i. Changing [H+]i by five orders of magnitude whilst [Cl−]i/[Cl−]o= 140/140 or 10/140 m m slightly shifted Gnorm( Vm) to negative Vm without altering the onset kinetics; however, channel closing was slower at acidic pHi. A similar change in [H+]o with [Cl−]i/[Cl−]o= 140/140 m m enhanced Gnorm in a bell-shaped manner and shifted Gnorm( Vm) curves to positive Vm. Importantly, Gnorm was >0 with [H+]o= 10−10 m but channel closing was slower when [H+]o or [Cl−]i increased implying that ClC-2 was opened without protonation and that external H+ and/or internal Cl− ions stabilized the open conformation. The analysis of kinetics and steady-state properties at different [H+]o and [Cl−]i was carried out using a gating Scheme coupled to Cl− permeation. Unlike previous results showing Vm-dependent protonation, our analysis revealed that fast gate protonation was Vm and Cl− independent and the equilibrium constant for closed-open transition of unprotonated channels was facilitated by elevated [Cl−]i in a Vm-dependent manner. Hence a Vm dependence of pore occupancy by Cl− induces a conformational change in unprotonated closed channels, before the pore opens, and the open conformation is stabilized by Cl− occupancy and Vm-independent protonation. [ABSTRACT FROM AUTHOR]

It has been shown that the voltage ( Vm) dependence of ClC Cl− channels is conferred by interaction of the protopore gate with H+ ions. However, in this paper we present evidence which indicates that permeant Cl− ions contribute to Vm-dependent gating of the broadly distributed ClC-2 Cl− channel. The apparent open probability ( PA) of ClC-2 was enhanced either by changing the [Cl−]i from 10 to 200 mm or by keeping the [Cl−]i low (10 mm) and then raising [Cl−]o from 10 to 140 mm. Additionally, these changes in [Cl−] slowed down channel closing at positive Vm suggesting that high [Cl−] increased pore occupancy thus hindering closing of the protopore gate. The identity of the permeant anion was also important since the PA( Vm) curves were nearly identical with Cl− or Br− but shifted to negative voltages in the presence of SCN− ions. In addition, gating, closing rate and reversal potential displayed anomalous mole fraction behaviour in a SCN−/Cl− mixture in agreement with the idea that pore occupancy by different permeant anions modifies the Vm dependence ClC-2 gating. Based on the ec1-ClC anion pathway, we hypothesized that opening of the protopore gate is facilitated when Cl− ions dwell in the central binding site. In contrast, when Cl− ions dwell in the external binding site they prevent the gate from closing. Finally, this Cl−-dependent gating in ClC-2 channels is of physiological relevance since an increase in [Cl−]o enhances channel opening when the [Cl−]i is in the physiological range. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate contrast sensitivity and disability glare in patients with dry eye using the Contrast Glaretester 1000. Methods: Contrast sensitivity and disability glare were determined in 33 eyes of 33 patients with dry eye and 30 eyes of 30 healthy control subjects for six target sizes with a visual angle of 6.3–0.7 degrees using the Contrast Glaretester 1000, whose working mechanism is similar to that of the conventional perimetry instrument. Results: Contrast sensitivity was significantly worse in dry eye group when viewing all target sizes (reduction of 0.10–0.25 log contrast units, p < 0.01) except at 6.3 degrees. In the presence of glare, differences in log contrast sensitivity between the groups (0.10–0.25 units) were significant (p < 0.01) for all target sizes, with the dry eye group showing worse results. The reduction in contrast sensitivity induced by glare (disability glare) was significantly worse in the dry eye group versus the control group but only for the 2.5-degree size target, where 0.14 log contrast units were lost. Conclusions: Contrast sensitivity with and without glare was significantly reduced in patients with dry eye compared with control subjects, but the number of log contrast units lost with glare (disability glare) was similar in the two groups, except for the 2.5-degree size target. [ABSTRACT FROM AUTHOR]

Background and Purpose.—The mechanisms responsible for headache in patients with intracerebral hemorrhage (ICH) are not completely understood. The present study was undertaken to analyze the headache-associated factors, the possible related biochemical mechanisms, and the headache potential predictors of outcome in spontaneous ICH. Methods.—We prospectively studied 189 patients from a large cohort of 266 consecutive patients with supratentorial ICH admitted within the first 12 hours of symptoms onset. The presence of headache at stroke onset was evaluated in these patients. The volumes of the initial ICH, peripheral edema at 48 hours, and the residual cavity at 3 months were measured on CT scan. Glutamate, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α levels were measured in blood samples obtained on admission. The Canadian Stroke Scale (CSS) and the modified Rankin Scale were used to evaluate stroke severity and neurological outcome, respectively. Results.—Headache at onset of stroke was observed in 65 patients (34.4%). Patients who experienced headache had a significantly higher frequency of history of infection ( P= .009) or inflammation ( P= .045), as well as higher body temperature ( P= .021), leukocyte count ( P= .038), ESR ( P= .011), and mass effect ( P= .017) on admission. Plasma concentrations of IL-6 and TNF-α were significantly higher in patients with headache than in those without. Headache was an independent predictor of the residual cavity volume in patients with spontaneous ICH (odds ratio 6.49; 95% CI 2.51 to 16.78; P= .0001). Conclusions.—Headache at ICH onset is associated with clinical and biochemical markers of inflammation and is an independent predictor of higher residual cavity volume after spontaneous ICH. [ABSTRACT FROM AUTHOR]

Microcin E492 is a low-molecular-weight, channel- forming bacteriocin produced and excreted by Kiebsiella pneumoniae RYC492. A 13 kb chromosomal DNA fragment from K. pneumoniae RYC492 was sequenced, and it was demonstrated by random Tn5 mutagenesis that most of this segment, which has at least 10 cistrons, is needed for the production of active microcin and its immunity protein. Genes mceG and mceH correspond to an ABC exporter and its accessory protein, respectively, and they are closely related to the colicin V ABC export systems The microcin E492 system also requires the product of gene moeF as an additional factor for export. Despite the fact that this bacteriocin lacks post-translational modifications, genes mceC, mcel and mceJ are needed for the production of active microcin. Genes mceC and mcel are homologous to a glycosyl transferase and acyltransferase, respectively, whereas mceJ has no known homologue. Mutants in these three genes secrete an inactive form of microcin, able to form ion channels in a phospholipidic bilayer, indicating that the mutation of these microcin genes does not alter the process of membrane insertion. On the other hand, microcin isolated from mutants in genes mceC and mceJ has a lethal effect when incubated with spheroplasts of sensitive cells, indicating that the microcin defects in these mutants are likely to alter receptor recognition at the outer membrane. A model for synthesis and export is proposed as well as a novel maturation pathway that would involve conformational changes to explain the production of active microcin E492. [ABSTRACT FROM AUTHOR]

When variational grid generation techniques are used to produce grids suitable for solving numerical partial differential equations in irregular geometrics, a reference grid can be used to determine the properties of the desired grid. Grid folding is a major problem in all methods of numerical grid generation; this paper studies the use of a reference grid, in variational smoothing methods, to prevent such foldings. The effects of various types of reference grid are compared and natural reference grids are shown to prevent foldings in the examples studied. The analysis is performed for a model problem with only one free point, and is then applied for finer grids. In addition, a short description of a discrete variational method is given. The reference grid concept applies to this discrete formulation. [ABSTRACT FROM AUTHOR]

Purpose: Anecdotal evidence suggests that eyelid disorders are common, although estimates of its prevalence vary. A cross‐sectional epidemiological survey was conducted among patients attending routine ophthalmological consultations to determine the prevalence of eyelid disorders, Meibomian Gland Dysfunction (MGD) and related pathologies (in particular ocular surface disease). Method: During the consultation a quality of life questionnaire and a clinical examination were completed by the ophthalmologist. In eleven countries, 349 investigator ophthalmologists were recruited who provided data from 6525 patients. Results: Patients were predominantly female (61.6%), mean age 57.0 ± 17.6 y. Eyelid disorders were diagnosed in 78.3% of patients and were statistically associated with atopic dermatitis, seborrheic dermatitis, dry eye, age‐related macular degeneration, diabetes, cataract, allergy and MGD. Eyelid abnormalities were identified in 38.5% of patients; abnormalities of the eyelid margin in 59.8%, and abnormal meibomian gland secretion in 34.5%. Conjunctival or corneal abnormalities were observed in 64.9% and 27.9% of patients respectively. MGD was diagnosed in 54.0% of patients and was statistically significantly associated with the presence of eyelid disorders and eyelid margin abnormality. Dry eye was diagnosed in 61.2% of patients and was concomitant with MGD in most cases. Most patients reported some degree of impairment of vision and daily/work activities. These effects on daily life were associated with the presence of MGD. Impact on contact lens usage and on emotions and quality of sleep were also reported. Conclusion: In conclusion, eyelid disorders were highly prevalent in this clinic population. Routine ophthalmological consultations may provide a useful opportunity to improve patients' quality of life and to modify topical therapy where this is an aetiological factor in eyelid disorders. [ABSTRACT FROM AUTHOR]

The article presents a study that analyzes the levels of glutamate pyruvate transaminase (GPT) and gamma glutamyl transferase (GGT) as the most specific markers of hepatic damage during fetal asphyxia. It outlines the method of the study which determines the level of GOT as the serum marker of liver injury among newborn infants. It mentions the result of the research which indicates that significant role of GOT as protective mechanism against neurotoxicity mediated by glutamate.

Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth characterized by arrested lung alveolarization, which generates lungs that are incompetent for effective gas exchange. We report here deregulated expression of miR‐34a in a hyperoxia‐based mouse model of BPD, where miR‐34a expression was markedly increased in platelet‐derived growth factor receptor (PDGFR)α‐expressing myofibroblasts, a cell type critical for proper lung alveolarization. Global deletion of miR‐34a; and inducible, conditional deletion of miR‐34a in PDGFRα+ cells afforded partial protection to the developing lung against hyperoxia‐induced perturbations to lung architecture. Pdgfra mRNA was identified as the relevant miR‐34a target, and using a target site blocker in vivo, the miR‐34a/Pdgfra interaction was validated as a causal actor in arrested lung development. An antimiR directed against miR‐34a partially restored PDGFRα+ myofibroblast abundance and improved lung alveolarization in newborn mice in an experimental BPD model. We present here the first identification of a pathology‐relevant microRNA/mRNA target interaction in aberrant lung alveolarization and highlight the translational potential of targeting the miR‐34a/Pdgfra interaction to manage arrested lung development associated with preterm birth. Synopsis: The pathogenic mechanisms underlying stunted lung development associated with bronchopulmonary dysplasia (BPD) are unknown. In this study, the interaction between miR 34a and the Pdgfra 3′‐UTR was validated as both a causal factor and a potentially "druggable" target in BPD driven by oxygen toxicity. miR‐34a expression was increased by elevated oxygen levels in PDGFRα+ cells.PDGFRα expression was negatively regulated by miR‐34a in vitro and in vivo.Lung development was protected by genetic ablation of miR‐34a expression in PDGFRα+ cells in vivo.PDGFRα+ cell abundance was partially restored by neutralization of miR‐34a using LNA antimiRs in developing lungs.Disrupting the miR‐34a/Pdgfra mRNA interaction revealed a new pathogenic pathway that could be pharmacologically manipulated. The pathogenic mechanisms underlying stunted lung development associated with bronchopulmonary dysplasia (BPD) are unknown. In this study, the interaction between miR 34a and the Pdgfra 3′‐UTR was validated as both a causal factor and a potentially "druggable" target in BPD driven by oxygen toxicity. [ABSTRACT FROM AUTHOR]