Prognostic accuracy of qSOFA score, SIRS criteria, and EWSs for in-hospital mortality among adult patients presenting with suspected infection to the emergency department (PASSEM) Multicenter prospective external validation cohort study protocol.

BACKGROUND: Early identification of a patient with infection who may develop sepsis is of utmost importance. Unfortunately, this remains elusive because no single clinical measure or test can reflect complex pathophysiological changes in patients with sepsis. However, multiple clinical and laboratory parameters indicate impending sepsis and organ dysfunction. Screening tools using these parameters can help identify the condition, such as SIRS, quick SOFA (qSOFA), National Early Warning Score (NEWS), or Modified Early Warning Score (MEWS). We aim to externally validate qSOFA, SIRS, and NEWS/NEWS2/MEWS for in-hospital mortality among adult patients with suspected infection who presenting to the emergency department. METHODS AND ANALYSIS: PASSEM study is an international prospective external validation cohort study. For 9 months, each participating center will recruit consecutive adult patients who visited the emergency departments with suspected infection and are planned for hospitalization. We will collect patients' demographics, vital signs measured in the triage, initial white blood cell count, and variables required to calculate Charlson Comorbidities Index; and follow patients for 90 days since their inclusion in the study. The primary outcome will be 30-days in-hospital mortality. The secondary outcome will be intensive care unit (ICU) admission, prolonged stay in the ICU (i.e., ≥72 hours), and 30- as well as 90-days all-cause mortality. The study started in December 2021 and planned to enroll 2851 patients to reach 200 in-hospital death. The sample size is adaptive and will be adjusted based on prespecified consecutive interim analyses. DISCUSSION: PASSEM study will be the first international multicenter prospective cohort study that designated to externally validate qSOFA score, SIRS criteria, and EWSs for in-hospital mortality among adult patients with suspected infection presenting to the ED in the Middle East region. STUDY REGISTRATION: The study is registered at ClinicalTrials.gov (NCT05172479).

Bacteriological Profile and Antibiotic Susceptibility Patterns of Sepsis-Causing Bacteria at the Neonatal Intensive Care Unit of a Tertiary Health Care Facility in Ghana.

Background: Neonatal sepsis is a clinical emergency that requires sound evaluation supported by accurate laboratory analysis and timely clinical intervention for its management. This study, therefore, was conducted to identify bacteria causing neonatal sepsis and their susceptibility to the commonly prescribed antibiotic at the Neonatal Intensive Care Unit of a tertiary health care facility in the Northern Region of Ghana. Methods: Neonatal biodata were collected from patient folders, after which identification, isolation, and susceptibility of isolated bacteria to prescribed anti-bacterial (Kirby-Bauer disk diffusion method) were carried out on single venipuncture blood samples aseptically drawn from 275 neonates clinically diagnosed with sepsis. Results: 275 neonates took part in the study, of which 218 (79.3%) presented with early-onset sepsis (EOS) and 57 (20.7%) with late-onset sepsis (LOS). The laboratory results confirmed a septicemia prevalence of 70.3% among neonates clinically diagnosed with sepsis. Preterm delivery (P = .01), hypothermia (P = .001), and delivery at the tertiary healthcare facility were significantly associated with EOS (P < .000), while low birth weight (P = .012), duration of hospital stay (P = .001), and delivery at the tertiary healthcare facility (P < .000) were found to be significantly associated with LOS. Gram-positive cocci constituted 54.9% (107), with Gram-negative constituting 45.1% (88) of all the bacteria isolates. Coagulase-negative staphylococcus (CoNS) 70.1% (75) and Klebsiella species 39.8% (35) were the dominant Gram-positive and Gram-negative isolates, respectively. 57.8% and 55.8% of CoNS isolates were susceptible to ampicillin and amoxicillin/clavulanic acid, respectively. 93.5% of CoNS and all the isolated Staphylococcus aureus and Klebsiella species were susceptible to amikacin. Conclusions: Coagulase-negative staphylococcus (CoNS) and Klebsiella species were the predominant Gram-positive and negative sepsis-causing agents at the NICU, respectively. Amikacin exhibited the highest sensitivity to Gram-positive and negative causative agents, making it a strong candidate for consideration in the facility's empirical treatment of neonatal sepsis.

Predictors of the onset of neonatal sepsis at the Neonatal Intensive Care Unit of a tertiary hospital in Ghana: A cross-sectional study.

Background and Aim: Neonatal sepsis is a systemic inflammatory response to infection during the first 4 weeks of an infant's life. It is a significant cause of neonatal morbidity and mortality in low- and middle-income countries. This study aimed to determine the predictors of the onset of sepsis at the Neonatal Intensive Care Unit of the Tamale Teaching Hospital, Ghana. Methods: A cross-sectional study was conducted among 275 mothers and their singleton neonates diagnosed clinically with sepsis. A univariate and multivariate logistic regression analysis adjusted for maternal occupational status was performed to determine the maternal and neonatal predictors of early-onset (EOS) and late-onset sepsis (LOS), respectively. Results: Single motherhood (AOR = 1.882, 95% CI = 0.926-3.822, p = .08) and home delivery (AOR = 3.667, 95% CI = 0.584-23.026, p = .17) were predictors of EOS, with single motherhood being the predictor for LOS (AOR = 2.906, 95% CI = 0.715-11.805, p = .14) in a univariate analysis. When maternal occupation was adjusted for in a multivariate analysis, single mother (AOR = 2.167, 95% CI = 1.010-4.648, p = .04) was the main predictor of EOS, with low neonatal birth weight being the main predictor of LOS (AOR = 0.193, 95% CI = 0.038-0.971, p = .04). Conclusion: Maternal marital status is a significant predictor of both EOS and LOS, with predictors of EOS being lower gestational age and low birth weight, while for LOS, low birth weight is the main predictor. Findings from this study can serve as a commencement point for developing predictive models for the onset of sepsis in neonates in the study facility.

Drivers of household antibiotic use in urban informal settlements in Northern Ghana: Implications for antimicrobial resistance control.

Background: Urban informal settlements have been described as the epicenters of frequent antibiotic misuse, which has local and global consequences on the goals of antimicrobial stewardship. The aim of this study was to assess the relationship between knowledge, attitude, and practices of antibiotic use among households in urban informal settlements in the Tamale metropolis of Ghana. Method: This study was a prospective cross-sectional survey of the two major informal settlements in the Tamale metropolis, namely Dungu-Asawaba and Moshie Zongo. In all, 660 households were randomly selected for this study. Households with an adult and at least a child under 5 years old were randomly chosen. An adult with knowledge of household healthcare practices was selected  to respond to a structured questionnaire. Results: In all, 291 (44.1%) of the 660 households reported taking at least one type of antibiotic within the last month before the study and 30.9% (204/660) had used antibiotics without a prescription. Information on which antibiotics to use was obtained mostly from friends/family members 50 (24.5%) and were commonly purchased from a medical store or a pharmacy 84 (41.2%), saved up from a previously used antibiotic 46 (22.5%), a friend/family members 38 (18.6%), and drug hawkers 30 (14.7%). Amoxicillin 95 (26.0%) was the most frequently used antibiotic and the commonest indication for antibiotics use was diarrhea 136 (37.9%). Female respondents (odds ratio [OR] = 3.07; 95% confidence interval [CI] = 2.199-4.301; p < 0.0001), larger households (OR = 2.02; 95% CI = 1.337-3.117; p = 0.0011) and those with higher monthly household income (OR = 3.39; 95% CI = 1.945-5.816; p < 0.0001) were more likely to have good knowledge of appropriate antibiotic use and antibiotic resistance. Furthermore, bad attitudes influenced participants' use of antibiotics without prescription (OR = 2.41; 95% CI = 0.432-4.05; p = 0.0009). Conclusion: This study exposes the drivers of inappropriate use of antibiotics at the household level, particularly in urban informal settlements. Policy interventions aimed at controlling the indiscriminate use of antibiotics in such settlements could improve the responsible use of antibiotics. Keywords: antibiotic resistance, informal settlements, Tamale, Ghana.

Assessment of proline function in higher plants under extreme temperatures.

Climate change and abiotic stress factors are key players in crop losses worldwide. Among which, extreme temperatures (heat and cold) disturb plant growth and development, reduce productivity and, in severe cases, lead to plant death. Plants have developed numerous strategies to mitigate the detrimental impact of temperature stress. Exposure to stress leads to the accumulation of various metabolites, e.g. sugars, sugar alcohols, organic acids and amino acids. Plants accumulate the amino acid 'proline' in response to several abiotic stresses, including temperature stress. Proline abundance may result from de novo synthesis, hydrolysis of proteins, reduced utilization or degradation. Proline also leads to stress tolerance by maintaining the osmotic balance (still controversial), cell turgidity and indirectly modulating metabolism of reactive oxygen species. Furthermore, the crosstalk of proline with other osmoprotectants and signalling molecules, e.g. glycine betaine, abscisic acid, nitric oxide, hydrogen sulfide, soluble sugars, helps to strengthen protective mechanisms in stressful environments. Development of less temperature-responsive cultivars can be achieved by manipulating the biosynthesis of proline through genetic engineering. This review presents an overview of plant responses to extreme temperatures and an outline of proline metabolism under such temperatures. The exogenous application of proline as a protective molecule under extreme temperatures is also presented. Proline crosstalk and interaction with other molecules is also discussed. Finally, the potential of genetic engineering of proline-related genes is explained to develop 'temperature-smart' plants. In short, exogenous application of proline and genetic engineering of proline genes promise ways forward for developing 'temperature-smart' future crop plants.

The Prevalence of Multidrug-Resistant Escherichia coli Producing ESBL among Male and Female Patients with Urinary Tract Infections in Riyadh Region, Saudi Arabia.

The Escherichia coli that produces extended-spectrum lactamases (ESBL-E. coli) can develop resistance to many antibiotics. The control of ESBL-E. coli disorders is challenging due to their restricted therapeutic approaches, so this study aims to determine the prevalence and pattern of the antibiotic resistance of ESBL-E. coli among male and female patients with urinary tract infections in Riyadh, Saudi Arabia. During the period of 2019 to 2020 at King Fahd Medical City, Riyadh, 2250 urine samples from patients with urinary tract infections (UTIs) were collected, and microbial species were cultured and identified using standard biochemical techniques. A double-disc synergy test was used to identify ESBL-producing strains of E. coli, and an in vitro method and the clinical laboratory standard institute (CLSI) criteria were employed to determine the resistance of these strains to antimicrobial drugs. ESBL-E. coli was detected in 510 (33.49%) of the 1523 E. coli isolates, 67.27% of which were recovered from women and 33.7% of which were recovered from men. A total of 284 (55.69%) ESBL-E. coli isolates were found in patients under 50 years of age, and 226 (44.31%) were found in patients over 50 years of age. Nearly all the isolates of ESBL-E. coli were resistant to cephalosporins (ceftriaxone, cefotaxime, cefepime, cefuroxime, and cephalothin) and penicillin (ampicillin), whereas the majority of the isolates were sensitive to several carbapenems (imipenem, meropenem, and ertapenem), aminoglycosides (amikacin), and nitrofurantoins. The development of antibiotic resistance by ESBL-E. coli, the most frequent pathogen linked to urinary tract infections, plays a crucial role in determining which antibiotic therapy is appropriate.

Nox (NADPH Oxidase) 1, Nox4, and Nox5 Promote Vascular Permeability and Neovascularization in Retinopathy.

Hypertension is a risk factor for the vascular permeability and neovascularization that threatens vision in diabetic retinopathy. Excess reactive oxygen species derived from the Nox (NADPH oxidase) isoforms, Nox1 and Nox4, contributes to vasculopathy in diabetic retinopathy; however, if Nox1/4 inhibition is beneficial in hypertensive diabetic retinopathy is unknown. Here, we determined that diabetic spontaneously hypertensive rats had exacerbated retinal vascular permeability and expression of angiogenic and inflammatory factors, compared with normotensive diabetic Wistar Kyoto rats. GKT136901, a specific dual inhibitor of Nox1 and Nox4, prevented these events in diabetic Wistar Kyoto rats and spontaneously hypertensive rats. Retinal neovascularization does not develop in diabetic rodents, and therefore, the oxygen-induced retinopathy model is used to evaluate this pathology. We previously demonstrated that Nox1/4 inhibition reduced retinal neovascularization in oxygen-induced retinopathy. However, although Nox5 is expressed in human retina, its contribution to retinopathy has not been studied in vivo, largely due to its absence from the rodent genome. We generated transgenic mice with inducible human Nox5 expressed in endothelial cells (vascular endothelial-cadherin+Nox5+ mice). In vascular endothelial-cadherin+Nox5+ mice with oxygen-induced retinopathy, retinal vascular permeability and neovascularization, as well as the expression of angiogenic and inflammatory factors, were increased compared with wild-type littermates. In bovine retinal endothelial cells, which express Nox1, Nox4, and Nox5, Nox1/4 inhibition, as well as Nox5 silencing RNA, reduced the high glucose-induced upregulation of oxidative stress, angiogenic, and inflammatory factors. Collectively, these data indicate the potential of Nox1, Nox4, and Nox5 inhibition to reduce vision-threatening damage to the retinal vasculature.

Correction to: Cross-cultural adaptation, reliability, and validity of the Vertigo symptom scale-short form in the central Kurdish dialect.

The original article [1] contained a minor typo in Fig. 1 affecting the motif 'VSS-SF-CK'; this has since been corrected.

Cross-cultural adaptation, reliability, and validity of the Vertigo symptom scale-short form in the central Kurdish dialect.

BACKGROUND: Core vestibular symptoms are vague, hard for patients to describe, and difficult for examiners to quantify. Reliable and validated patient-reported outcome measures (PROMs) have obtained acceptance and popularity in the specialty of vestibular disorders. In Kurdish, there is a critical shortage of such measures. The aim of this survey was to assess the psychometric properties of a central Kurdish version (VSS - SF - CK) of the Vertigo Symptom Scale-Short Form (VSS - SF). METHODS: The study utilized a regulated process of cross-cultural adaptation to produce the VSS - SF - CK. We examined its psychometric properties by using a cross-sectional survey. Owing to a non-normal distribution, both principal axis factoring and polychoric correlation were used to examine the structure. The internal consistency of the scales was evaluated using Cronbach's alpha coefficient (α) and composite reliability. The discriminant validity was evaluated using the heterotrait-monotrait ratio of correlations (HTMT.85) and the Fornell-Larcker criterion. To assess convergent validity, the instrument was correlated with two comparators. RESULTS: The participants (n = 195) were composed of 165 patients with vestibular symptoms (mean - age 45 ± 15.8, range 61 years; 56.4% women) and 30 healthy participants (mean - age 35 ± 18.6; range 52 years; 60% women). Based on the scree plot, along with other criteria such as Horn's parallel analysis and minimum average partial, two factors were extracted: vestibular (VSS - V) and autonomic-anxiety (VSS - AA). Both constructs showed a robust structure in terms of adequate loadings and weak cross-loadings. The scales' αs were 0.81, 0.81, and 0.87 for VSS-V, VSS-AA, and the total scale (VSS - T), respectively. Discriminant validity was established with a value of 0.71 for HTMT (< 0.85). Spearman's correlation supported the study's hypotheses and confirmed the convergent validity. Intraclass correlation coefficients revealed high external reliability: test-retest results were 0.93, 0.94, and 0.97 for VSS-V, VSS - AA, and VSS - T, respectively. CONCLUSION: Given a critical shortage in PROMs for the vestibular field, the psychometric properties of VSS - SF - CK were evaluated. The results were promising, as they revealed external consistency and construct validity. The goodness of fit indices showed that the VSS - SF - CK is a reliable and validated PROM that can be used by clinicians and researchers in the Kurdish-speaking population.

Impact of the halitosis on QoL in overweight and obese patients: Based on six years of experience in two centers in sulaimani governorate, Kurdistan Region/Iraq, and case series study.

BACKGROUND/OBJECTIVES: The patients who are overweight and obese, are under stress of excess body weight, embarrassed, one may imagine the impact of halitosis on this group of patients, this is an attempt to evaluate this extra impact, and which aspect of quality of life will be affect in the overweight and obese. SUBJECTS/METHODS: A prospective case series study including 885 overweight or obese patients, they were consulting for advice, diet and or drugs and various bariatric operations. A group of normal weight patients with halitosis, matched in age group and gender were enrolled as a control group for comparison. Patients who have either oral causes of the condition or pseudo halitosis or halite-phobia or were using drugs like phenytoin, cyclosporine or calcium channel blockers, isosorbide di-nitrate, Chloral hydrate, Nitrites and Nitrates, Dimethyl sulphoxide, Disulphiram, cytotoxic agents, Phenothiazine were excluded. INTERVENTIONS/METHODS: The work conducted over a period of 6 years from February 1st, 2012 to March 1st, 2018. Prospective evaluation of the type and etiology of halitosis was done by using organoleptic measurement, which is not a slandered but evaluated by a group of academic colleagues. The patients were advised to avoid eating odiferous foods for 48 hours before the assessment and both the patient and the examiner should refrain from drinking coffee, tea or juice, smoking and using scented cosmetics before the assessment. RESULTS: Halitosis in the overweight and obese patients magnifies the negative aspects of quality of life: avoidance, narrow social circle (P Value = 0.3415, 95% confidence interval = 11.43924-29.67085), avoidance of sex by partner (P Value = 0.0143, 95% confidence interval = 04.11537-17.08480), low self-esteem (P Value = 0.0100, 95% confidence interval = 10.66794-28.44776), teasing by others and negative thoughts (P Value = 0.4013, 95% confidence interval = 11.43924-29.67085). While obesity was not a cause of avoidance of to be kissed by partner in obese patients, but was a direct cause for this avoidance in obese patients with halitosis (P Value = 0.0143, 95% confidence interval = 04.11537-17.08480). Halitosis in normal weight patients affects the quality of life remarkably but not to the extent of halitosis in overweight and obese patients, especially social life and self-esteem which will suffer most. CONCLUSIONS: The quality of life of overweight and obese, especially emotional and social aspects was significantly disturbed by halitosis more than normal weight subjects with halitosis.

Reliability and validity of a Central Kurdish version of the Dizziness Handicap Inventory.

We cross-culturally adapted the Dizziness Handicap Inventory (DHI) into Central Kurdish dialect (DHI-CK) and verified its reliability and validity. A cross-sectional study was utilised to measure the impacts of vestibular disorders. Along with the DHI-CK, two comparators were introduced: the Visual Analogue Scale and the Clinical Test of Sensory Interaction and Balance. External and internal reliability were tested with intraclass correlation coefficient (ICC) and Cronbach's alpha/composite reliability, respectively. Patients (n = 301; mean age = 44.5 ± 15.2 years; 59.8% women) presenting with vestibular symptoms for at least 30 days who were diagnosed with a vestibular disorder and healthy participants (n = 43; mean age = 42 ± 17.9 years; 62.8% women) (N = 344). The DHI-CK and its three sub-scales-Physical, Emotional, Functional-exhibited good to excellent external reliability: ICCs in the test-retest were 0.93, 0.88, 0.91, and 0.92, respectively. Cronbach's alphas were 0.87, 0.71, 0.75, and 0.73, respectively. Convergent validity was supported by Spearman's correlations between the DHI-CK and the comparators. The receiver operating characteristic curve analysis confirmed discriminating validity. The DHI-CK was cross-culturally validated. It is a reliable and valid tool that can be used by clinicians and researchers to quantify vestibular disorder outcomes in Kurdish-speaking populations.

Intravitreal administration of endothelin type A receptor or endothelin type B receptor antagonists attenuates hypertensive and diabetic retinopathy in rats.

Hypertension is an independent risk factor for diabetic retinopathy, yet anti-hypertensive medications such as blockade of angiotensin II do not completely protect against vision-threatening vascular disease. We hypothesized that the potent vasoactive factor, endothelin (ET), is up-regulated in diabetic retinopathy and antagonism of the ET type A receptor (ETRA) or ET type B receptor (ETRB) ameliorates retinal vascular leakage independently of any blood pressure lowering effects. Spontaneously hypertensive rats (SHR) and their normotensive and genetic controls, Wistar Kyoto rats, were randomized to become diabetic or non-diabetic and studied for 8 weeks. Rats were further randomized to receive by intravitreal injection the ETRA antagonist, BQ123, the ETRB antagonist, BQ788, or vehicle, 5 days after the induction of streptozotocin diabetes and 4 weeks later. The treatments had no effect on systolic blood pressure which remained elevated in SHR. ET-1, ET-2, ETRA and ETRB were expressed in retina and retinal pigment epithelium (RPE)/choroid and increased by hypertension or diabetes. BQ123 reduced ET-1 and ET-2 expression in retina and RPE/choroid, while BQ788 had a similar effect but did not influence the mRNA levels of ET-1 in retina. Retinal vascular leakage and Müller cell stress as well as vascular endothelial growth factor (VEGF) expression in retina and RPE/choroid, were increased by hypertension or diabetes and there was an additive effect of these conditions. Treatment with BQ123 or BQ788 effectively reduced these events as well as the elevated levels of inflammatory factors in the retina. Our findings indicate that local ET systems exist in the retina and RPE/choroid that are up-regulated by hypertension and diabetes. The ability of locally delivered ET receptor antagonists to supress these overactive ET systems and reduce retinal vascular leakage and VEGF in the presence of hypertension indicate the potential of these approaches for the treatment of diabetic retinopathy.

Nrf2 Activation Is a Potential Therapeutic Approach to Attenuate Diabetic Retinopathy.

Purpose: Oxidative stress is a causal factor in the development of diabetic retinopathy; however, clinically relevant strategies to treat the disease by augmenting antioxidant defense mechanisms have not been fully explored. We hypothesized that boosting nuclear factor erythroid-2-related factor 2 (Nrf2) antioxidant capacity with the novel Nrf2 activator dh404, would protect the retina in diabetes including vision-threatening breakdown of the blood-retinal barrier (BRB) and associated damage to macroglial Müller cells. Methods: Sprague-Dawley rats were randomized to become diabetic or nondiabetic and administered dh404 by gavage for 10 weeks. Complementary in vitro studies were performed in cultured Müller cells exposed to hyperglycemia. Results: In diabetes, dh404 prevented vascular leakage into the retina and vitreous cavity as well as upregulation of the vascular permeability and angiogenic factors, VEGF, and angiopoietin-2, and inflammatory mediators, including TNF-α and IL-6. Müller cells, which maintain BRB integrity and become gliotic in diabetes with increased immunolabeling for glial fibrillary acidic protein, were protected by dh404. In diabetes, dh404 bolstered the antioxidant capacity of the retina with an increase in hemeoxygenase-1, nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) quinine oxidoreductase-1, and Nrf2. Further, dh404 attenuated the diabetes-induced increase in oxidative stress as measured by dihydroethidium and 8-oxo-2'-deoxyguanosine (8-OHdG) immunolabeling as well as NADPH oxidase isoform expression. Studies in Müller cells supported these findings with dh404 attenuating the hyperglycemia-induced increase in vascular permeability, angiogenic and inflammatory mediators, and oxidative stress. Conclusions: Our data demonstrate the ability of dh404 to protect the retina against diabetes-induced damage and potentially prevent vision loss.

Alpha-lipoic acid: An inimitable feed supplement for poultry nutrition.

Alpha-lipoic acid (ALA) is a multifunction antioxidant that is produced in small amount by cells as well as its dietary provision facilitates fatty acid mobilization, energy expenditure as well as can scavenge free radicals in poultry birds. It exists in oxidized as well as reduced form, characterized by growth promoting, anti-inflammatory, antioxidative, immunostimulatory, and hypocholesterolemic properties when fed as dietary supplement to farm animals particularly chicken birds. Recently, several studies reported that dietary supplementation of ALA can influence growth performance indicators, immunological, biochemical characteristics, lipid metabolism, and oxidative stress as well as increase antioxidant potential and storability of poultry meat and meat products. Accordingly, this paper adds the reviews and discusses the outcomes of studies documenting the effect of lipoic acid dietary fortification on growth performance, biochemical, and immunological characteristics as well as the effects on lipid peroxidation of fresh meat and meat-based products. Furthermore, this paper also describes the possibilities of utilization of ALA as a feed additive in poultry nutrition to improve the growth performance of poultry as well as meat quality of resultant chicken birds.

Endothelin-2 Injures the Blood-Retinal Barrier and Macroglial Müller Cells: Interactions with Angiotensin II, Aldosterone, and NADPH Oxidase.

Although increasing evidence indicates that endothelin-2 (Edn2) has distinct roles in tissue pathology, including inflammation, glial cell dysfunction, and angiogenesis, its role in the retina and the factors that regulate its actions are not fully understood. We hypothesized that Edn2 damages the blood-retinal barrier (BRB) and that this is mediated by interactions with the renin-angiotensin-aldosterone system and reactive oxygen species derived from NADPH oxidase (Nox). C57BL/6J mice received an intravitreal injection of Edn2 or control vehicle to examine the blood pressure-independent effects of Edn2. Mice administered Edn2 were randomized to receive by intraperitoneal injection treatments that inhibited the Edn type a receptor, Edn type b receptor, angiotensin type 1 receptor, mineralocorticoid receptor, or Nox isoforms 1 to 4. One month later, mice administered Edn2 exhibited breakdown of the BRB with increased vascular leakage, vascular endothelial growth factor expression, and infiltrating macrophages (Ly6C+CD45highCD11b+). Further, macroglial Müller cells, which influence the integrity of the BRB and prevent retinal edema, became gliotic and expressed increased levels of water (aquaporin-4) and ion (Kir4.1) channels. This Edn2-mediated retinopathy was reduced by all treatments. Complementary in vitro studies in cultured Müller cells supported these findings and demonstrated the importance of reactive oxygen species in mediating these events. In conclusion, Edn2 has detrimental effects on the BRB and Müller cells that involve interactions with the renin-angiotensin aldosterone system and Nox1/4.

Pre-operative neutrophil count and neutrophil-lymphocyte count ratio (NLCR) in predicting the histological grade of paediatric brain tumours: a preliminary study.

INTRODUCTION: The neutrophil-lymphocyte count ratio (NLCR) is an established prognostic marker for renal, lung and colorectal carcinomas and has been suggested to be predictive of histological grade and outcome in adult intracranial tumours. The purpose of this study was to determine whether a correlation of the pre-operative neutrophil count (NC) and NLCR with the final histological grade exists in paediatric intracranial tumours. METHODS: A retrospective analysis was undertaken at a single centre. Patients less than 18 years old at the time of surgery who underwent tumour-related procedures from 2006 to 2015 were included. Patients with recurrent tumours, previous bone marrow transplant and metastases were excluded. Pre-operative full blood counts (FBC), collected before the diagnosis of intracranial pathology and before administration of steroids, were matched with histological diagnosis for each patient. Post-operative FBC was also recorded, together with survival data where applicable. RESULTS: A total of 116 patients (74 male, 42 female; mean age, 8 ± 0.9 years) with a diagnosis of primary intracranial tumours had pre-operative FBC that could be matched to final histological grade. Pre-operative NC and NLCR were higher with increasing grade of tumour: grade 1 (NC 4.29 109/l, NLCR 2.26), grade 2 (NC 4.59 109/l, NLCR 2.38), grade 3 (NC 5.67 109/l, NLCR 2.72) and grade 4 (NC 6.59 109/l, NLCR 3.31). Patients with WHO grade 1 and 2 tumours pooled together had a lower NC (4.37 95% CI ± 0.67 109/l) compared to WHO grade 3 and 4 patients (6.41 95% CI ± 0.99 109/l, p = 0.0013). The NLCR was lower in grade 1 and 2 tumours (2.29 ± 0.59) (compared to grade 3 and 4 tumours; 3.20 ± 0.76) but this did not reach significance (p = 0.069). The subgroup of patients with pilocytic astrocytoma had a significantly lower NC when compared to patients with high-grade tumours (p = 0.005). Medulloblastoma and supratentorial PNET subgroups had significantly higher NC compared to the low-grade group (p = 0.033, p = 0.002). Post-operative NC was significantly higher in the high-grade tumours (p = 0.034), but no difference was observed for NLCR (p = 0.28). CONCLUSIONS: No evidence exists to support the correlation of pre-operative NC or NLCR to histological diagnosis in paediatric intracranial tumours. Our results indicate that a higher pre-operative NC/NLCR correlates with a higher histological grade of tumour. This suggests that immunological mechanisms may be involved in the pathogenesis of paediatric brain tumours, and a further prospective study is required to substantiate and expand these findings.

Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory.

Non-fibrillar soluble oligomeric forms of amyloid-ß peptide (oAß) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAß initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aß, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAß levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAß to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aß on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aß and tau pathology.

Visual and anatomical outcomes after silicone oil removal in patients with complex retinal detachment.

To evaluate outcomes of temporary silicone oil (SO) tamponade in patients with complex retinal detachment. A retrospective study of 184 eyes of 177 consecutive patients who underwent SO removal (SOR) by one surgeon between 2000 and 2010. Indications for the use of SO were proliferative vitreoretinopathy (56 eyes), difficult rhegmatogenous retinal detachment (RRD) (58 eyes), diabetic traction retinal detachment (DTRD) (29 eyes), RRD due to macular hole in highly myopic eyes (16 eyes), giant retinal tears (13 eyes), and RRD after penetrating trauma (12 eyes). All eyes underwent prophylactic 360° laser retinopexy and encircling buckle at the time of primary surgery. The mean duration of SO tamponade was 47 weeks, with a mean follow-up of 66.9 weeks after SOR. Anatomical success after SOR was achieved in 96.73 %. Final visual outcome of ≥20/200 was significantly higher in eyes with RRD compared to eyes with DTRD. Young age (≤16 years), performance of pars plana lensectomy at primary procedure and presence of pseudophakia at last follow-up were factors associated with good visual outcome in eyes with RRD. Factors predicting attached retina at last follow-up were older age (>16 years), normal intraocular pressure (IOP) at initial presentation and no relaxing retinotomy performed during the primary procedure in eyes with RRD. Complications were cataract (100 %) in phakic eyes, increased IOP (15.7 %), keratopathy (3.8 %), and hypotony (2.1 %). The low redetachment rate after SOR in the present study might be due to prophylactic 360° retinopexy and use of encircling buckles at time of primary retinal reattachment.