Symptomatic and asymptomatic domoic acid exposure in zebrafish (Danio rerio) revealed distinct non-overlapping gene expression patterns in the brain.

Domoic acid (DA) is a naturally produced neurotoxin synthesized by marine diatoms in the genus Pseudo-nitzschia. DA accumulates in filter-feeders such as shellfish, and can cause severe neurotoxicity when contaminated seafood is ingested, resulting in Amnesic Shellfish Poisoning (ASP) in humans. Overt clinical signs of neurotoxicity include seizures and disorientation. ASP is a significant public health concern, and though seafood regulations have effectively minimized the human risk of severe acute DA poisoning, the effects of exposure at asymptomatic levels are poorly understood. The objective of this study was to determine the effects of exposure to symptomatic and asymptomatic doses of DA on gene expression patterns in the zebrafish brain. We exposed adult zebrafish to either a symptomatic (1.1 ± 0.2 µg DA/g fish) or an asymptomatic (0.31 ± 0.03 µg DA/g fish) dose of DA by intracelomic injection and sampled at 24, 48 and 168 h post-injection. Transcriptional profiling was done using Agilent and Affymetrix microarrays. Our analysis revealed distinct, non-overlapping changes in gene expression between the two doses. We found that the majority of transcriptional changes were observed at 24 h post-injection with both doses. Interestingly, asymptomatic exposure produced more persistent transcriptional effects - in response to symptomatic dose exposure, we observed only one differentially expressed gene one week after exposure, compared to 26 in the asymptomatic dose at the same time (FDR <0.05). GO term analysis revealed that symptomatic DA exposure affected genes associated with peptidyl proline modification and retinoic acid metabolism. Asymptomatic exposure caused differential expression of genes that were associated with GO terms including circadian rhythms and visual system, and also the neuroactive ligand-receptor signaling KEGG pathway. Overall, these results suggest that transcriptional responses are specific to the DA dose and that asymptomatic exposure can cause long-term changes. Further studies are needed to characterize the potential downstream neurobehavioral impacts of DA exposure.

Prevalence, Types, and Outcomes of Cerebral Palsy at a Tertiary Center in Jeddah, Saudi Arabia.

BACKGROUND: In developed countries, cerebral palsy (CP) is the most common neurological disorder in children. It is defined as a non-progressive disturbance to the developing brain leading to motor impairment that affects the child's activity. CP is classified into three main subtypes: ataxic, spastic, and mixed.  Objectives: This study aimed to estimate the prevalence of CP and its subtypes in a single tertiary center located in Jeddah, Saudi Arabia. METHOD: This retrospective record review study included 98 patients diagnosed with CP from 2004 to 2019. Data were extracted from the hospital medical record and assessed using various tools.  Result: The total number of patients was 98, with an estimated CP prevalence of 1.6 per 1000 lives. Most of the patients (74.8%) had spastic CP subtype, and 54.8% had quadriplegia. The mean age of the live children was 7.45 ± 3.76 years. Moreover, gastrostomy was the most favorable feeding method.  Conclusion: The prevalence of CP is almost equivalent to the national and worldwide figures. Spastic CP has the highest rates. Furthermore, the male gender has been identified as a significant risk factor for CP in the local community.

Recovery of cardiac function following COVID-19 - ECHOVID-19: a prospective longitudinal cohort study.

AIMS: The degree of cardiovascular sequelae following COVID-19 remains unknown. The aim of this study was to investigate whether cardiac function recovers following COVID-19. METHODS AND RESULTS: A consecutive sample of patients hospitalized with COVID-19 was prospectively included in this longitudinal study. All patients underwent an echocardiographic examination during hospitalization and 2 months later. All participants were successfully matched 1:1 with COVID-19-free controls by age and sex. A total of 91 patients were included (mean age 63 ± 12 years, 59% male). A median of 77 days (interquartile range: 72-92) passed between the two examinations. Right ventricular (RV) function improved following resolution of COVID-19: tricuspid annular plane systolic excursion (TAPSE) (2.28 ± 0.40 cm vs. 2.11 ± 0.38 cm, P < 0.001) and RV longitudinal strain (RVLS) (25.3 ± 5.5% vs. 19.9 ± 5.8%, P < 0.001). In contrast, left ventricular (LV) systolic function assessed by global longitudinal strain (GLS) did not significantly improve (17.4 ± 2.9% vs. 17.6 ± 3.3%, P = 0.6). N-terminal pro-B-type natriuretic peptide decreased between the two examinations [177.6 (80.3-408.0) ng/L vs. 11.7 (5.7-24.0) ng/L, P < 0.001]. None of the participants had elevated troponins at follow-up compared to 18 (27.7%) during hospitalization. Recovered COVID-19 patients had significantly lower GLS (17.4 ± 2.9% vs. 18.8 ± 2.9%, P < 0.001 and adjusted P = 0.004), TAPSE (2.28 ± 0.40 cm vs. 2.67 ± 0.44 cm, P < 0.001 and adjusted P < 0.001), and RVLS (25.3 ± 5.5% vs. 26.6 ± 5.8%, P = 0.50 and adjusted P < 0.001) compared to matched controls. CONCLUSION: Acute COVID-19 affected negatively RV function and cardiac biomarkers but recovered following resolution of COVID-19. In contrast, the observed reduced LV function during acute COVID-19 did not improve post-COVID-19. Compared to the matched controls, both LV and RV function remained impaired.

Using vibration controlled transient elastography and FIB-4 to assess liver cirrhosis in a hepatitis C virus infected population.

ABSTRACT: We assessed the performance characteristics of the Fibrosis-4 (FIB-4) score in a veteran population with chronic hepatitis C virus (HCV) infection and used vibration controlled transient elastography (VCTE) as the gold standard.All VCTE studies were performed by a single operator on United States veterans with HCV infection presenting for care at the Atlanta VA Medical Center (AVAMC) over a 2 year period. VCTE liver stiffness measurements (LSM) were categorized as cirrhotic if LSM was >12.5 kPa and non-cirrhotic if LSM was ≤12.5 kPa. FIB-4 scores ≤3.25 were considered non-cirrhotic and scores >3.25 were considered cirrhotic. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the FIB-4 score. A second analysis was done which identified and excluded indeterminate FIB-4 scores, defined as any value between 1.45 and 3.25.When FIB-4 was used to screen for liver cirrhosis using VCTE as the gold standard, sensitivity was 42%, specificity was 88%, PPV was 62%, and NPV was 76%. When indeterminate FIB-4 scores were excluded from the analysis, sensitivity was 95%, specificity was 61%, PPV was 62%, and NPV was 94.4%. In a veteran population with chronic HCV infection, we found the sensitivity of the FIB-4 score to be unacceptably low for ruling out liver cirrhosis when using a binary cutoff at 3.25. Using a second staging method like VCTE may be an effective way to screen for liver cirrhosis in persons with chronic HCV, especially when the FIB-4 score is in the indeterminate range.

Dunning-Kruger Effect: Intuitive Errors Predict Overconfidence on the Cognitive Reflection Test.

The Cognitive Reflection Test (CRT) is a measure of analytical reasoning that cues an intuitive but incorrect response that must be rejected for successful performance to be attained. The CRT yields two types of errors: Intuitive errors, which are attributed to Type 1 processes; and non-intuitive errors, which result from poor numeracy skills or deficient reasoning. Past research shows that participants who commit the highest numbers of errors on the CRT overestimate their performance the most, whereas those with the lowest error-rates tend to slightly underestimate. This is an example of the Dunning-Kruger Effect (DKE). The present study examined how intuitive vs. non-intuitive errors contribute to overestimation in the CRT at different levels of performance. Female undergraduate students completed a seven-item CRT test and subsequently estimated their raw score. They also filled out the Faith in Intuition (FI) questionnaire, which is a dispositional measure of intuitive thinking. Data was separated into quartiles based on level of performance on the CRT. The results demonstrated the DKE. Additionally, intuitive and non-intuitive errors predicted miscalibration among low, but not high performers. However, intuitive errors were a stronger predictor of miscalibration. Finally, FI was positively correlated with CRT self-estimates and miscalibration, indicating that participants who perceived themselves to be more intuitive were worse at estimating their score. These results taken together suggest that participants who perform poorly in the CRT and also those who score higher in intuitive thinking disposition are more susceptible to the influences of heuristic-based cues, such as answer fluency, when judging their performance.

The significance of left ventricular ejection time in heart failure with reduced ejection fraction.

Left ventricular ejection time (LVET) is defined as the time interval from aortic valve opening to aortic valve closure, and is the phase of systole during which the left ventricle ejects blood into the aorta. LVET has been used for several decades to assess left ventricular function and contractility. However, there is a recent interest in LVET as a measure of therapeutic action for novel drugs in patients with heart failure with reduced ejection fraction (HFrEF), since LVET is shortened in these patients. This review provides an overview of the available information on LVET including methods of measuring LVET, mechanistic understanding of LVET, association of LVET with outcomes, mechanisms behind shortened LVET in HFrEF and the potential implications of drugs that affect and normalize LVET.

Glucose modulates copper induced changes in photosynthesis, ion uptake, antioxidants and proline in Cucumis sativus plants.

Glucose is recognized as signaling molecule that regulates growth and development of plants under various environmental cues, but their effect in regulation of copper induced toxicity in plants is not yet investigated. This study revealed the effect of exogenously sourced glucose on Cucumber plants exposed to increasing concentration of copper. Glucose mediated response on growth performance, photosynthetic efficiency, antioxidant enzymes, oxidative stress markers, ion uptake were analyzed in the presence and absence of copper. Glucose alone and in combination with lower concentration of copper improved the growth, photosynthetic performance, and antioxidant capacity of cucumber plants. However, higher concentrations of copper alone showed oxidative damage through increased electrolyte leakage, H2O2 accumulation, lipid peroxidation and reduced uptake of macronutrients. Application of glucose to copper-stressed plants enhanced activities of Rubisco, antioxidant enzymes, proline accumulation and maintained copper level in aerial parts of plants. These enhanced activities of antioxidant enzymes, proline accumulation, uptake of NPK and maintained equilibrium of copper in plants, leading to detoxification of copper stress in cucumber plants. This study provides an understanding that exogenous application of glucose can be employed as vital biochemical approach in alleviating copper-induced toxicity and could be utilized as phytoremediation technique for removal of excess transition metal from polluted soil.

Left ventricular systolic ejection time is an independent predictor of all-cause mortality in heart failure with reduced ejection fraction.

AIMS: Colour tissue Doppler imaging (TDI) M-mode through the mitral leaflet is an easy and precise method to obtain cardiac time intervals including isovolumic contraction time (IVCT), isovolumic relaxation time (IVRT) and systolic ejection time (SET). The myocardial performance index (MPI) is defined as [(IVCT + IVRT)/SET]. Whether cardiac time intervals obtained by the TDI M-mode method can be used to predict outcome in patients with heart failure with reduced ejection fraction (HFrEF) remains unknown. METHODS AND RESULTS: A total of 997 patients with HFrEF (mean age 67 ± 11 years, 74% male) underwent an echocardiographic examination including TDI. During a median follow-up of 3.4 years (interquartile range 1.9-4.8 years), 165 (17%) patients died. The risk of mortality increased by 9% per 10 ms decrease in SET [per 10 ms decrease: hazard ratio (HR) 1.09, 95% confidence interval (CI) 1.06-1.13; P < 0.001]. The association remained significant even after multivariable adjustment for clinical and echocardiographic parameters (per 10 ms decrease: HR 1.06, 95% CI 1.01-1.11; P = 0.030). The MPI was a significant predictor in an unadjusted model (per 0.1 increase: HR 3.06, 95% CI 1.16-8.06; P = 0.023). However, the association did not remain significant after multivariable adjustment. No significant associations between IVCT or IVRT and mortality were found in unadjusted nor adjusted models. Additionally, SET provided incremental prognostic information with regard to predicting mortality when added to established clinical predictors of mortality in patients with HFrEF. CONCLUSION: In patients with HFrEF, SET provides independent and incremental prognostic information regarding all-cause mortality.

A Study to Evaluate the Efficacy of an 810-nm Diode Laser in the Maintenance of Dental Implants: A Peri-Implant Sulcular Fluid Analysis.

Biological implant failures are primarily related to biofilm, which can lead to peri-mucositis and, further on, peri-implantitis. The 810-nm diode laser has an affinity for pigmented chromophores, so its use in the peri-implant sulcus has a significant bactericidal effect on the black-pigmented anaerobes such as Porphyromonas gingivalis. Therefore, it can be used to eliminate or reduce the bacterial count in the peri-implant sulcular fluid (PISF), thus increasing the life of the implants and reducing the chances of failure. The purpose of this study was to evaluate the efficacy of the 810-nm diode laser for the maintenance of dental implants and its use as a regular in-office tool for limiting the microbiological count in the PISF. Twenty patients undergoing implant treatment at the Department of Periodontology and Oral Implantology were randomly selected for the study. PISF samples were collected before and after the sulcus was lased with an 810-nm diode laser and sent for quantitative microbiological analysis using universal bacterial count, and the quantity of P gingivalis was evaluated using real-time polymerase chain reaction (PCR). The analysis revealed that after diode application, the median percentage drop in the microbial count was 76.67% and the median percentage drop in P gingivalis count was 99.28%. The use of an 810-nm diode laser resulted in the following outcomes: (1) drastic reduction in the total bacterial count around the implant and (2) significant reduction in the P gingivalis count, as evaluated by real-time PCR.

Epidural analgesia for percutaneous kyphoplasty in a patient with multiple medical comorbidities.

Kyphoplasty is a minimally invasive procedure intended to stabilize the fractured bone and restore bone height. It involves percutaneous introduction of an inflatable bone tamp into a fractured vertebral body, followed by injection of bone cement into the ballooned pocket. Anesthetic options typically considered for this procedure include intravenous sedation or general anesthesia. These patients are often elderly, frail, in significant pain, and may poorly tolerate sedation or general anesthesia in the prone position. Spinal anesthesia has been suggested as an alternative method. However, it has major limitations. We would like to report a case of a 79-year-old patient with multiple comorbidities, who presented for kyphoplasty, where epidural anesthesia was conducted and successfully provided adequate analgesia as well as optimal surgical conditions.

Vitamin D levels do not predict the stage of hepatic fibrosis in patients with non-alcoholic fatty liver disease: A PRISMA compliant systematic review and meta-analysis of pooled data.

AIM: To investigate the relationship between 25-hydroxyvitamin D [25(OH)D] levels and fibrosis stage in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: Two individual reviewers identified relevant studies using the PubMed, EMBASE, Cochrane, and Scopus databases. Inclusion criteria were as follows: (1) Studies that evaluated adults with NAFLD and serum or plasma 25(OH)D levels; and (2) assessed fibrosis stage using liver biopsy. A rigorous analysis yielded six articles as having sufficient data to employ in evaluating the association of serum vitamin D levels in patients with NAFLD based on their liver fibrosis stage by histopathological analysis. The lead investigators of each of the six studies were contacted and the data were collected. To meta-analyze vitamin D levels in F0-F2 vs F3-F4 fibrosis, a random-effects meta-analysis fit using restricted maximum likelihood was applied. To examine trends across each stage of fibrosis with respect to vitamin D levels, a meta-regression was performed. P < 0.05 was considered statistically significant. RESULTS: A total of 937 subjects from six studies were included in the final analysis to evaluate the association of serum vitamin D levels in patients with NAFLD based on their liver fibrosis stage by histopathological analysis. The lead investigators of each of the six studies were contacted and the data were collected. First, the investigators performed a meta-analysis to compare serum vitamin D levels in patients with NAFLD with stage F0-F2 compared to F3-F4, which did not show significance [meta-estimate of the pooled mean difference = -0.86, P = 0.08 (-4.17, 2.46)]. A meta-regression evaluation of serum vitamin 25 (OH)D levels across the individual stages (F0-F4) of fibrosis did not show an association for the six included studies. CONCLUSION: Low vitamin D status is not associated with higher stages of liver fibrosis in patients with NAFLD.

Influence of vitamin D on liver fibrosis in chronic hepatitis C: A systematic review and meta-analysis of the pooled clinical trials data.

AIM: To investigate the relationship between vitamin D and liver fibrosis in hepatitis C-monoinfected or hepatitis C virus (HCV)-human immunodeficiency virus (HIV) co-infected patients. METHODS: Pertinent studies were located by a library literature search in PubMed/Embase/Cochrane/Scopus/LILACS by two individual reviewers. Inclusion criteria: (1) studies with patients with HCV or co-infected HCV/HIV; (2) studies with patients ≥ 18 years old; (3) studies that evaluated liver fibrosis stage, only based on liver biopsy; and (4) studies that reported serum or plasma 25(OH)D levels. Studies that included pediatric patients, other etiologies of liver disease, or did not use liver biopsy for fibrosis evaluation, or studies with inadequate data were excluded. Estimated measures of association reported in the literature, as well as corresponding measures of uncertainty, were recorded and corresponding odds ratios with 95%CI were included in a meta-analysis. RESULTS: The pooled data of this systematic review showed that 9 of the 12 studies correlated advanced liver disease defined as a Metavir value of F3/4 with 25(OH) D level insufficiency. The meta-analysis indicated a significant association across studies. CONCLUSION: Low vitamin D status is common in chronic Hepatitis C patients and is associated with advanced liver fibrosis.

Current Management of Alcoholic Hepatitis and Future Therapies.

Alcohol is one of the most common etiologies of liver disease, and alcoholic liver disease overall is the second most common indication for liver transplantation in the United States. It encompasses a spectrum of disease, including fatty liver disease, alcoholic hepatitis (AH), and alcoholic cirrhosis. AH can range from mild to severe disease, with severe disease being defined as: Discriminant Function (DF) ≥ 32, or Model for End-stage Liver Disease (MELD) ≥ 21, or presence of hepatic encephalopathy. Management of the mild disease consists mainly of abstinence and supportive care. Severe AH is associated with significant mortality. Currently, there is no ideal medical treatment for this condition. Besides alcohol cessation, corticosteroids have been used with conflicting results and are associated with an inherent risk of infection. Overall steroids have shown short term benefit when compared to placebo, but they have no obvious long term benefits. Pentoxifylline does not improve survival in patients with severe AH and is no longer recommended based on the results of the STOPAH (Steroid Or Pentoxifylline for Alcoholic Hepatitis) trial. Anti-tumor necrosis factor (TNF) agents are associated with increased risk of life threatening infections and death. Currently, early stage trials are underway, mainly targeting novel pathways based on disease pathogenesis, including modulation of innate immune system, inhibition of gut-liver axis and cell death pathways, and activation of transcription factor farnesyl X receptor (FXR). Future treatment may lie in human induced pluripotent stem cell (iPSC) technology, which is currently under investigation for the study of pathogenesis, drug discovery, and stem cell transplantation. Liver transplantation has been reported with good results in highly selected patients but is controversial due to limited organ supply.

In vitro effects of platinum compounds on renal cellular respiration in mice.

BACKGROUND: Cisplatin, carboplatin and oxaliplatin are structurally-related compounds, which are commonly used in cancer therapy. Cisplatin (Platinol(®)) has Boxed Warning stating: "Cumulative renal toxicity associated with PLATINOL is severe", while carboplatin and oxaliplatin are less nephrotoxic. These drugs form platinum adducts with cellular DNA. Their bindings to cellular thiols (e.g., glutathione and metallothionein) are known to contribute to drug resistance while thiol depletion augments platinum toxicity. METHODS: Using phosphorescence oxygen analyzer, this study investigated the effects of platinum drugs on renal cellular respiration (mitochondrial O2 consumption) in the presence and absence of the thiol blocking agent N-ethylmaleimide (used here as a model for thiol depletion). Renal cellular ATP was also determined. Kidney fragments from C57BL/6 mice were incubated at 37 °C in Krebs-Henseleit buffer (gassed with 95% O2:5% CO2) with and without 100 µM platinum drug in the presence and absence of 100 µM N-ethylmaleimide for ≤ 6 h. RESULTS: Platinum drugs alone had no effects on cellular respiration (P ≥ 0.143) or ATP (P ≥ 0.161). N-ethylmaleimide lowered cellular respiration (P ≤ 0.114) and ATP (P = 0.008). The combination of platinum drug and N-ethylmaleimide significantly lowered both cellular respiration (P ≤ 0.006) and ATP (P ≤ 0.003). Incubations with N-ethylmaleimide alone were associated with moderate-to-severe tubular necrosis. Incubations with cisplatin+N-ethylmaleimide vs. cisplatin alone produced similar severities of tubular necrosis. Tubular derangements were more prominent in carboplatin+N-ethylmaleimide vs. carboplatin alone and in oxaliplatin+N-ethylmaleimide vs. oxaliplatin alone. CONCLUSIONS: These results demonstrate the adverse events of thiol depletion on platinum-induced nephrotoxicities. The results suggest cellular bioenergetics is a useful surrogate biomarker for assessing drug-induced nephrotoxicities.

Acyl-lipid thioesterase1-4 from Arabidopsis thaliana form a novel family of fatty acyl-acyl carrier protein thioesterases with divergent expression patterns and substrate specificities.

Hydrolysis of fatty acyl thioester bonds by thioesterases to produce free fatty acids is important for dictating the diversity of lipid metabolites produced in plants. We have characterized a four-member family of fatty acyl thioesterases from Arabidopsis thaliana, which we have called acyl-lipid thioesterase1 (ALT1), ALT2, ALT3, and ALT4. The ALTs belong to the Hotdog fold superfamily of thioesterases. ALT-like genes are present in diverse plant taxa, including dicots, monocots, lycophytes, and microalgae. The four Arabidopsis ALT genes were found to have distinct gene expression profiles with respect to each other. ALT1 was expressed specifically in stem epidermal cells and flower petals. ALT2 was expressed specifically in root endodermal and peridermal cells as well as in stem lateral organ boundary cells. ALT3 was ubiquitously expressed in aerial and root tissues and at much higher levels than the other ALTs. ALT4 expression was restricted to anthers. All four proteins were localized in plastids via an N-terminal targeting sequence of about 48 amino acids. When expressed in Escherichia coli, the ALT proteins used endogenous fatty acyl-acyl carrier protein substrates to generate fatty acids that varied in chain length (C6-C18), degree of saturation (saturated and monounsaturated), and oxidation state (fully reduced and ß-ketofatty acids). Despite their high amino acid sequence identities, each enzyme produced a different profile of lipids in E. coli. The biological roles of these proteins are unknown, but they potentially generate volatile lipid metabolites that have previously not been reported in Arabidopsis.

Heterogeneity in skeletal load adaptation points to a role for modeling in the pathogenesis of osteoporotic fracture.

Genetic, environmental, or hormonal factors may cause heterogeneity in skeletal load response. Individuals with reduced sensitivity to load should require higher strains to generate an adaptive response, consequently have weaker bones and fracture more frequently. The purpose of our study was to determine if stresses (proportional to strains) at the femoral neck under equivalent loads were higher in women with a history of fractures compared with women without fractures. We studied postmenopausal women participating in the Canadian Multicentre Osteoporosis Study who had available hip structure analysis data from dual-energy X-ray absorptiometry scans (n = 2168). Women were categorized into 2 groups based on their number of self-reported fractures. We computed stress (megapascals) at the inferomedial margin of the femoral neck in a one-legged stance mode using a 2-dimensional engineering beam analysis. We used linear regression (SAS 9.3) to determine associations between stress, geometry parameters, and number of fractures. Postmenopausal women with 1 or more fractures had higher stress (2.6%), lower narrow neck bone mineral density (4.2%), cross-sectional area (3.9%), and section modulus (9.6%) than postmenopausal women without fractures (all p < 0.05). These findings provide evidence of heterogeneity in load response and suggest an important role for modeling in the pathogenesis of osteoporotic fracture.