Inhibition of the renal apical sodium dependent bile acid transporter prevents cholemic nephropathy in mice with obstructive cholestasis.

BACKGROUND & AIMS: Cholemic nephropathy (CN) is a severe complication of cholestatic liver diseases for which there is no specific treatment. We revisited its pathophysiology with the aim of identifying novel therapeutic strategies. METHODS: Cholestasis was induced by bile duct ligation (BDL) in mice. Bile flux in kidneys and livers was visualized by intravital imaging, supported by MALDI mass spectrometry imaging and liquid chromatography-tandem mass spectrometry. The effect of AS0369, a systemically bioavailable apical sodium-dependent bile acid transporter (ASBT) inhibitor, was evaluated by intravital imaging, RNA-sequencing, histological, blood, and urine analyses. Translational relevance was assessed in kidney biopsies from patients with CN, mice with a humanized bile acid (BA) spectrum, and via analysis of serum BAs and KIM-1 (kidney injury molecule 1) in patients with liver disease and hyperbilirubinemia. RESULTS: Proximal tubular epithelial cells (TECs) reabsorbed and enriched BAs, leading to oxidative stress and death of proximal TECs, casts in distal tubules and collecting ducts, peritubular capillary leakiness, and glomerular cysts. Renal ASBT inhibition by AS0369 blocked BA uptake into TECs and prevented kidney injury up to 6 weeks after BDL. Similar results were obtained in mice with humanized BA composition. In patients with advanced liver disease, serum BAs were the main determinant of KIM-1 levels. ASBT expression in TECs was preserved in biopsies from patients with CN, further highlighting the translational potential of targeting ASBT to treat CN. CONCLUSIONS: BA enrichment in proximal TECs followed by oxidative stress and cell death is a key early event in CN. Inhibiting renal ASBT and consequently BA enrichment in TECs prevents CN and systemically decreases BA concentrations. IMPACT AND IMPLICATIONS: Cholemic nephropathy (CN) is a severe complication of cholestasis and an unmet clinical need. We demonstrate that CN is triggered by the renal accumulation of bile acids (BAs) that are considerably increased in the systemic blood. Specifically, the proximal tubular epithelial cells of the kidney take up BAs via the apical sodium-dependent bile acid transporter (ASBT). We developed a therapeutic compound that blocks ASBT in the kidneys, prevents BA overload in tubular epithelial cells, and almost completely abolished all disease hallmarks in a CN mouse model. Renal ASBT inhibition represents a potential therapeutic strategy for patients with CN.

The TGF-ß1 target WISP1 is highly expressed in liver cirrhosis and cirrhotic HCC microenvironment and involved in pro- and anti-tumorigenic effects.

INTRODUCTION: WNT1-inducible signalling pathway protein 1 (WISP1) promotes progression of several tumor entities often correlating with worse prognosis. Here its expression regulation and role in the progression of chronic liver diseases (CLD) was investigated. METHODS: WISP1 expression was analyzed in human HCC datasets, in biopsies and serum samples and an HCC patient tissue microarray (TMA) including correlation to clinicopathological parameters. Spatial distribution of WISP1 expression was determined using RNAscope analysis. Regulation of WISP1 expression was investigated in cytokine-stimulated primary mouse hepatocytes (PMH) by array analysis and qRT-PCR. Outcome of WISP1 stimulation was analyzed by IncuCyte S3-live cell imaging, qRT-PCR, and immunoblotting in murine AML12 cells. RESULTS: In a TMA, high WISP1 expression was positively correlated with early HCC stages and male sex. Highest WISP1 expression levels were detected in patients with cirrhosis as compared to healthy individuals, patients with early fibrosis, and non-cirrhotic HCC in liver biopsies, expression datasets and serum samples. WISP1 transcripts were predominantly detected in hepatocytes of cirrhotic rather than tumorous liver tissue. High WISP1 expression was associated with better survival. In PMH, AML12 and HepaRG, WISP1 was identified as a specific TGF-ß1 target gene. Accordingly, expression levels of both cytokines positively correlated in human HCC patient samples. WISP1-stimulation induced the expression of Bcl-xL, PCNA and p21 in AML12 cells. CONCLUSIONS: WISP1 expression is induced by TGF-ß1 in hepatocytes and is associated with cirrhotic liver disease. We propose a crucial role of WISP1 in balancing pro- and anti-tumorigenic effects during premalignant stages of CLD.

Somatic multicomorbidity and disability in patients with psychiatric disorders in comparison to the general population: a quasi-epidemiological investigation in 54,826 subjects from 40 countries (COMET-G study).

BACKGROUND: The prevalence of medical illnesses is high among patients with psychiatric disorders. The current study aimed to investigate multi-comorbidity in patients with psychiatric disorders in comparison to the general population. Secondary aims were to investigate factors associated with metabolic syndrome and treatment appropriateness of mental disorders. METHODS: The sample included 54,826 subjects (64.73% females; 34.15% males; 1.11% nonbinary gender) from 40 countries (COMET-G study). The analysis was based on the registration of previous history that could serve as a fair approximation for the lifetime prevalence of various medical conditions. RESULTS: About 24.5% reported a history of somatic and 26.14% of mental disorders. Mental disorders were by far the most prevalent group of medical conditions. Comorbidity of any somatic with any mental disorder was reported by 8.21%. One-third to almost two-thirds of somatic patients were also suffering from a mental disorder depending on the severity and multicomorbidity. Bipolar and psychotic patients and to a lesser extent depressives, manifested an earlier (15-20 years) manifestation of somatic multicomorbidity, severe disability, and probably earlier death. The overwhelming majority of patients with mental disorders were not receiving treatment or were being treated in a way that was not recommended. Antipsychotics and antidepressants were not related to the development of metabolic syndrome. CONCLUSIONS: The finding that one-third to almost two-thirds of somatic patients also suffered from a mental disorder strongly suggests that psychiatry is the field with the most trans-specialty and interdisciplinary value and application points to the importance of teaching psychiatry and mental health in medical schools and also to the need for more technocratically oriented training of psychiatric residents.

Integrated data from intravital imaging and HPLC-MS/MS analysis reveal large interspecies differences in AFB1 metabolism in mice and rats.

Large interspecies differences between rats and mice concerning the hepatotoxicity and carcinogenicity of aflatoxin B1 (AFB1) are known, with mice being more resistant. However, a comprehensive interspecies comparison including subcellular liver tissue compartments has not yet been performed. In this study, we performed spatio-temporal intravital analysis of AFB1 kinetics in the livers of anesthetized mice and rats. This was supported by time-dependent analysis of the parent compound as well as metabolites and adducts in blood, urine, and bile of both species by HPLC-MS/MS. The integrated data from intravital imaging and HPLC-MS/MS analysis revealed major interspecies differences between rats and mice: (1) AFB1-associated fluorescence persisted much longer in the nuclei of rat than mouse hepatocytes; (2) in the sinusoidal blood, AFB1-associated fluorescence was rapidly cleared in mice, while a time-dependent increase was observed in rats in the first three hours after injection followed by a plateau that lasted until the end of the observation period of six hours; (3) this coincided with a far stronger increase of AFB1-lysine adducts in the blood of rats compared to mice; (4) the AFB1-guanine adduct was detected at much higher concentrations in bile and urine of rats than mice. In both species, the AFB1-glutathione conjugate was efficiently excreted via bile, where it reached concentrations at least three orders of magnitude higher compared to blood. In conclusion, major differences between mice and rats were observed, concerning the nuclear persistence, formation of AFB1-lysine adducts, and the AFB1-guanine adducts.

Acetaminophen overdose causes a breach of the blood-bile barrier in mice but not in rats.

Acetaminophen (APAP) is known to cause a breach of the blood-bile barrier in mice that, via a mechanism called futile bile acid (BA) cycling, increases BA concentrations in hepatocytes above cytotoxic thresholds. Here, we compared this mechanism in mice and rats, because both species differ massively in their susceptibility to APAP and compared the results to available human data. Dose and time-dependent APAP experiments were performed in male C57BL6/N mice and Wistar rats. The time course of BA concentrations in liver tissue and in blood was analyzed by MALDI-MSI and LC-MS/MS. APAP and its derivatives were measured in the blood by LC-MS. APAP-induced liver damage was analyzed by histopathology, immunohistochemistry, and by clinical chemistry. In mice, a transient increase of BA in blood and in peri-central hepatocytes preceded hepatocyte death. The BA increase coincided with oxidative stress in liver tissue and a compromised morphology of bile canaliculi and immunohistochemically visualized tight junction proteins. Rats showed a reduced metabolic activation of APAP compared to mice. However, even at very high doses that caused cell death of hepatocytes, no increase of BA concentrations was observed neither in liver tissue nor in the blood. Correspondingly, no oxidative stress was detectable, and the morphology of bile canaliculi and tight junction proteins remained unaltered. In conclusion, different mechanisms cause cell death in rats and mice, whereby oxidative stress and a breach of the blood-bile barrier are seen only in mice. Since transient cholestasis also occurs in human patients with APAP overdose, mice are a clinically relevant species to study APAP hepatotoxicity but not rats.

Optimization of Phenolic Compounds Extraction from Aerial Parts of Fabiana punensis S. C. Arroyo by Ultrasound- and Microwave-Assisted Extraction.

Fabiana punensis S. C. Arroyo is a subshrub or shrub that is indigenous to the arid and semiarid region of northern Argentina and is known to possess several medicinal properties. The objective of this study was to optimize the extraction conditions so as to maximize the yield of bioactive total phenolic compound (TPC) and flavonoids (F) of F. punensis' aerial parts by using non-conventional extraction methods, namely ultrasound-assisted extraction, UAE, and microwave-assisted extraction, MAE, and to compare the biological activities and toxicity of optimized extracts vs. conventional extracts, i.e., those gained by maceration. Response Surface Methodology (RSM) was used to apply factorial designs to optimize the parameters of extraction: solid-to-liquid ratio, extraction time, ultrasound amplitude, and microwave power. The experimental values for TPC and F and antioxidant activity under the optimal extraction conditions were not significantly different from the predicted values, demonstrating the accuracy of the mathematical models. Similar HPLC-DAD patterns were found between conventional and UAE- and MAE-optimized extracts. The main constituents of the extracts correspond to phenolic compounds (flavonoids and phenolic acids) and apigenin was identified. All extracts showed high scavenger capacity on ABTS•+, O2•- and H2O2, enabling the inhibition of the pro-inflammatory enzymes xanthine oxidase (XO) and lipoxygenase (LOX). They also showed an antimutagenic effect in Salmonella Typhimurium assay and cytotoxic/anti-proliferative activity on human melanoma cells (SKMEL-28). Toxicological evaluation indicates its safety. The results of this work are important in the development of efficient and sustainable methods for obtaining bioactive compounds from F. punensis for the prevention of chronic degenerative diseases associated with oxidative stress, inflammation, and DNA damage.

SAR study of niclosamide derivatives for neuroprotective function in SH-SY5Y neuroblastoma.

Neurodegenerative disease is a debilitating and incurable condition that affects millions of people around the world. The loss of functions or malfunctions of neural cells are the causes of mortality. A proteosome inhibitor, MG132, is well known to cause neurodegeneration in vitro when model neuronal-derived cell lines are exposed to it. Niclosamide, an anthelmintic drug, which has been used to treat tapeworm infections for more than 50 years, has recently attracted renewed attention in drug repurposing because it has been found to be a good candidate in many drug development screenings. We recently found that all markers of MG132-induced neuronal cell toxicity, including the accumulation of ubiquitinated proteins, were prevented by the presence of niclosamide. In addition, niclosamide was shown to enhance autophagy induced by MG132. There results suggested that niclosamide could act as a neuroprotective agent. In the present study, niclosamide derivatives were synthesized, and the structure-activity relationship (SAR) were determined with respect to protein ubiquitination induced by MG132 and effect on cell survival signaling pathways for neuroprotective function. Our results indicate that phenol OH plays a significant role in neuroprotective activity while the niclosamide derivatives without Cl (5- or 2'-Cl) showed almost the same neuroprotective effect. 4'-NO2 can be replaced by N3 or CF3 whereas NH2 significantly decreased activity. These findings provide guidance for the development of new niclosamide analogues against neurodegenerative diseases including Parkinson's disease.

Results of the COVID-19 mental health international for the health professionals (COMET-HP) study: depression, suicidal tendencies and conspiracism.

INTRODUCTION: The current study aimed to investigate the rates of anxiety, clinical depression, and suicidality and their changes in health professionals during the COVID-19 outbreak. MATERIALS AND METHODS: The data came from the larger COMET-G study. The study sample includes 12,792 health professionals from 40 countries (62.40% women aged 39.76 ± 11.70; 36.81% men aged 35.91 ± 11.00 and 0.78% non-binary gender aged 35.15 ± 13.03). Distress and clinical depression were identified with the use of a previously developed cut-off and algorithm, respectively. STATISTICAL ANALYSIS: Descriptive statistics were calculated. Chi-square tests, multiple forward stepwise linear regression analyses, and Factorial Analysis of Variance (ANOVA) tested relations among variables. RESULTS: Clinical depression was detected in 13.16% with male doctors and 'non-binary genders' having the lowest rates (7.89 and 5.88% respectively) and 'non-binary gender' nurses and administrative staff had the highest (37.50%); distress was present in 15.19%. A significant percentage reported a deterioration in mental state, family dynamics, and everyday lifestyle. Persons with a history of mental disorders had higher rates of current depression (24.64% vs. 9.62%; p < 0.0001). Suicidal tendencies were at least doubled in terms of RASS scores. Approximately one-third of participants were accepting (at least to a moderate degree) a non-bizarre conspiracy. The highest Relative Risk (RR) to develop clinical depression was associated with a history of Bipolar disorder (RR = 4.23). CONCLUSIONS: The current study reported findings in health care professionals similar in magnitude and quality to those reported earlier in the general population although rates of clinical depression, suicidal tendencies, and adherence to conspiracy theories were much lower. However, the general model of factors interplay seems to be the same and this could be of practical utility since many of these factors are modifiable.

A Potential Role for Neuroinflammation in ADHD.

Attention deficit hyperactivity disorder (ADHD) is a neurobehavioural disorder in children and adolescents. Although increases in oxidative stress and disturbances of neurotransmitter system such as the dopaminergic and abnormalities in several brain regions have been demonstrated, the pathophysiology of ADHD is not fully understood. Nevertheless, ADHD involves several factors that have been associated with an increase in neuroinflammation. This chapter presents an overview of factors that may increase neuroinflammation and play a potential role in the development and pathophysiology of ADHD. The altered immune response, polymorphisms in inflammatory-related genes, ADHD comorbidity with autoimmune and inflammatory disorders and prenatal exposure to inflammation are associated with alterations in offspring brain development and are a risk factor; genetic and environmental risk factors that may increase the risk for ADHD and medications can increase neuroinflammation. Evidence of an association between these factors has been an invaluable tool for research on inflammation in ADHD. Therefore, evidence studies have made it possible to generate alternative therapeutic interventions using natural products as anti-inflammatories that could have great potential against neuroinflammation in ADHD.

Exploring the clinical value of tumor microenvironment in platinum-resistant ovarian cancer.

Platinum resistance in epithelial ovarian cancer (OvCa) is rising at an alarming rate, with recurrence of chemo-resistant high grade serous OvCa (HGSC) in roughly 75 % of all patients. Additionally, HGSC has an abysmal five-year survival rate, standing at 39 % and 17 % for FIGO stages III and IV, respectively. Herein we review the crucial cellular interactions between HGSC cells and the cellular and non-cellular components of the unique peritoneal tumor microenvironment (TME). We highlight the role of the extracellular matrix (ECM), ascitic fluid as well as the mesothelial cells, tumor associated macrophages, neutrophils, adipocytes and fibroblasts in platinum-resistance. Moreover, we underscore the importance of other immune-cell players in conferring resistance, including natural killer cells, myeloid-derived suppressive cells (MDSCs) and T-regulatory cells. We show the clinical relevance of the key platinum-resistant markers and their correlation with the major pathways perturbed in OvCa. In parallel, we discuss the effect of immunotherapies in re-sensitizing platinum-resistant patients to platinum-based drugs. Through detailed analysis of platinum-resistance in HGSC, we hope to advance the development of more effective therapy options for this aggressive disease.

Interruption of bile acid uptake by hepatocytes after acetaminophen overdose ameliorates hepatotoxicity.

BACKGROUND & AIMS: Acetaminophen (APAP) overdose remains a frequent cause of acute liver failure, which is generally accompanied by increased levels of serum bile acids (BAs). However, the pathophysiological role of BAs remains elusive. Herein, we investigated the role of BAs in APAP-induced hepatotoxicity. METHODS: We performed intravital imaging to investigate BA transport in mice, quantified endogenous BA concentrations in the serum of mice and patients with APAP overdose, analyzed liver tissue and bile by mass spectrometry and MALDI-mass spectrometry imaging, assessed the integrity of the blood-bile barrier and the role of oxidative stress by immunostaining of tight junction proteins and intravital imaging of fluorescent markers, identified the intracellular cytotoxic concentrations of BAs, and performed interventions to block BA uptake from blood into hepatocytes. RESULTS: Prior to the onset of cell death, APAP overdose causes massive oxidative stress in the pericentral lobular zone, which coincided with a breach of the blood-bile barrier. Consequently, BAs leak from the bile canaliculi into the sinusoidal blood, which is then followed by their uptake into hepatocytes via the basolateral membrane, their secretion into canaliculi and repeated cycling. This, what we termed 'futile cycling' of BAs, led to increased intracellular BA concentrations that were high enough to cause hepatocyte death. Importantly, however, the interruption of BA re-uptake by pharmacological NTCP blockage using Myrcludex B and Oatp knockout strongly reduced APAP-induced hepatotoxicity. CONCLUSIONS: APAP overdose induces a breach of the blood-bile barrier which leads to futile BA cycling that causes hepatocyte death. Prevention of BA cycling may represent a therapeutic option after APAP intoxication. LAY SUMMARY: Only one drug, N-acetylcysteine, is approved for the treatment of acetaminophen overdose and it is only effective when given within ∼8 hours after ingestion. We identified a mechanism by which acetaminophen overdose causes an increase in bile acid concentrations (to above toxic thresholds) in hepatocytes. Blocking this mechanism prevented acetaminophen-induced hepatotoxicity in mice and evidence from patients suggests that this therapy may be effective for longer periods after ingestion compared to N-acetylcysteine.

Access and Attitudes Toward Palliative Care Among Movement Disorders Clinicians.

BACKGROUND: Neuropalliative care is an emerging field for those with neurodegenerative illnesses, but access to neuropalliative care remains limited. OBJECTIVE: We sought to determine Movement Disorder Society (MDS) members' attitudes and access to palliative care. METHODS: A quantitative and qualitative survey instrument was developed by the MDS Palliative Care Task Force and e-mailed to all members for completion. Descriptive statistics and qualitative analysis were triangulated. RESULTS: Of 6442 members contacted, 652 completed the survey. Completed surveys indicating country of the respondent overwhelmingly represented middle- and high-income countries. Government-funded homecare was available to 54% of respondents based on patient need, 25% limited access, and 21% during hospitalization or an acute defined event. Eighty-nine percent worked in multidisciplinary teams. The majority endorsed trigger-based referrals to palliative care (75.5%), while 24.5% indicated any time after diagnosis was appropriate. Although 66% referred patients to palliative care, 34% did not refer patients. Barriers were identified by 68% of respondents, the most significant being available workforce, financial support for palliative care, and perceived knowledge of palliative care physicians specific to movement disorders. Of 499 respondents indicating their training in palliative care or desire to learn these skills, 55% indicated a desire to gain more skills. CONCLUSIONS: The majority of MDS member respondents endorsed a role for palliative care in movement disorders. Many members have palliative training or collaborate with palliative care physicians. Although significant barriers exist to access palliative care, the desire to gain more skills and education on palliative care is an opportunity for professional development within the MDS. © 2021 International Parkinson and Movement Disorder Society.

Neuroinflammation and galectins: a key relationship in neurodegenerative diseases.

Neurodegeneration is a pathological condition that is associated with the loss of neuronal function and structure. In neurodegenerative diseases, mounting evidence indicates that neuroinflammation is a common factor that contributes to neuronal damage and neurodegeneration. Neuroinflammation is characterized by the activation of microglia, the neuroimmune cells of the central nervous system (CNS), which have been implicated as active contributors to neuronal damage. Glycan structure modification is defining the outcome of neuroinflammation and neuronal regeneration; moreover, the expression of galectins, a group of lectins that specifically recognize ß-galactosides, has been proposed as a key factor in neuronal regeneration and modulation of the inflammatory response. Of the different galectins identified, galectin-1 stimulates the secretion of neurotrophic factors in astrocytes and promotes neuronal regeneration, whereas galectin-3 induces the proliferation of microglial cells and modulates cell apoptosis. Galectin-8 emerged as a neuroprotective factor, which, in addition to its immunosuppressive function, could generate a neuroprotective environment in the brain. This review describes the role of galectins in the activation and modulation of astrocytes and microglia and their anti- and proinflammatory functions within the context of neuroinflammation. Furthermore, it discusses the potential use of galectins as a therapeutic target for the inflammatory response and remodeling in damaged tissues in the central nervous system.

Inhibition of cytochrome P450 enhances the nephro- and hepatotoxicity of ochratoxin A.

The mycotoxin ochratoxin A (OTA) is a contaminant in food that causes nephrotoxicity and to a minor degree hepatotoxicity. Recently, we observed that OTA induces liver damage preferentially to the cytochrome P450 (CYP)-expressing pericentral lobular zone, similar to hepatotoxic substances known to be metabolically toxified by CYP, such as acetaminophen or carbon tetrachloride. To investigate whether CYP influences OTA toxicity, we used a single dose of OTA (7.5 mg/kg; intravenous) with and without pre-treatment with the pan CYP-inhibitor 1-aminobenzotriazole (ABT) 2 h before OTA administration. Blood, urine, as well as liver and kidney tissue samples were collected 24 h after OTA administration for biochemical and histopathological analyses. Inhibition of CYPs by ABT strongly increased the nephro- and hepatotoxicity of OTA. The urinary kidney damage biomarkers kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were increased > 126-fold and > 20-fold, respectively, in mice treated with ABT and OTA compared to those receiving OTA alone. The blood biomarkers of liver damage, alanine transaminase (ALT) and aspartate transaminase (AST) both increased > 21- and 30-fold, respectively, when OTA was administered to ABT pre-treated mice compared to the effect of OTA alone. Histological analysis of the liver revealed a pericentral lobular damage induced by OTA despite CYP-inhibition by ABT. Administration of ABT alone caused no hepato- or nephrotoxicity. Overall, the results presented are compatible with a scenario where CYPs mediate the detoxification of OTA, yet the mechanisms responsible for the pericental liver damage pattern still remain to be elucidated.

Colchicine overdose impairs the capacity of Kupffer cells to clear foreign particles and endotoxins.

Colchicine is an anti-inflammatory drug with a narrow therapeutic index. Its binding to tubulin prevents microtubule polymerization; however, little is known about how depolymerization of microtubules interferes with the phagocytosis function of Kupffer cells (KC). Here, we applied functional intravital imaging techniques to investigate the influence of microtubule disruption by colchicine on KC morphology, as well as its capacity to clear foreign particles and bacterial lipopolysaccharide (LPS) in anesthetized mice. Intravital imaging of KC in healthy mice showed the typical elongated morphology, localization at the luminal side of the sinusoidal endothelial cells, and moving cell protrusions. In contrast, at colchicine doses of 1 mg/kg and higher (intraperitoneal), KC appeared roundish with strongly reduced protrusions and motility. To study the functional consequences of these alterations, we analyzed the capacity of KC to phagocytose fluorescent nanospheres (100 nm-size) and LPS. After tail vein injection, the nanospheres formed aggregates of up to ~ 5 µm moving along the sinusoidal bloodstream. In controls, the nanosphere aggregates were rapidly captured by the Kupffer cell protrusions, followed by an internalization process that lasted up to 10 min. Similar capture events and internalization processes were observed after the administration of fluorescently labeled LPS. In contrast, capture and internalization of both nanospheres and LPS by KC were strongly reduced in colchicine-treated mice. Reduced phagocytosis of LPS was accompanied by aggravated production of inflammatory cytokines. Since 0.4 mg/kg colchicine in mice has been reported to be bio-equivalent to human therapeutic doses, the here-observed adverse effects on KC occurred at doses only slightly above those used clinically, and may be critical for patients with endotoxemia due to a leaky gut-blood barrier.

Hypoalbuminemia affects the spatio-temporal tissue distribution of ochratoxin A in liver and kidneys: consequences for organ toxicity.

Hypoalbuminemia (HA) is frequently observed in systemic inflammatory diseases and in liver disease. However, the influence of HA on the pharmacokinetics and toxicity of compounds with high plasma albumin binding remained insufficiently studied. The 'lack-of-delivery-concept' postulates that HA leads to less carrier mediated uptake of albumin bound substances into hepatocytes and to less glomerular filtration; in contrast, the 'concept-of-higher-free-fraction' argues that increased concentrations of non-albumin bound compounds facilitate hepatocellular uptake and enhance glomerular filtration. To address this question, we performed intravital imaging on livers and kidneys of anesthetized mice to quantify the spatio-temporal tissue distribution of the mycotoxin ochratoxin A (OTA) based on its auto-fluorescence in albumin knockout and wild-type mice. HA strongly enhanced the uptake of OTA from the sinusoidal blood into hepatocytes, followed by faster secretion into bile canaliculi. These toxicokinetic changes were associated with increased hepatotoxicity in heterozygous albumin knockout mice for which serum albumin was reduced to a similar extent as in patients with severe hypoalbuminemia. HA also led to a shorter half-life of OTA in renal capillaries, increased glomerular filtration, and to enhanced uptake of OTA into tubular epithelial cells. In conclusion, the results favor the 'concept-of-higher-free-fraction' in HA; accordingly, HA causes an increased tissue uptake of compounds with high albumin binding and increased organ toxicity. It should be studied if this concept can be generalized to all compounds with high plasma albumin binding that are substrates of hepatocyte and renal tubular epithelial cell carriers.

Association of photobiomodulation therapy and therapeutic exercises in relation to pain intensity and neck disability in individuals with chronic neck pain: a systematic review of randomized trials.

Exercise is often pointed out as an effective form of treatment in the clinical management of chronic neck pain (CNP). However, due to its complex range of causal factors and great diversity of signs and symptoms, other resources such as photobiomodulation therapy (PBMT) have been routinely used for the treatment of CNP. The aim of this study was to systematically review the literature on the use of the association of PBMT and therapeutic exercises in relation to pain intensity and neck disability in individuals with CNP. PubMed, Medline (via Ovid), Embase (via Ovid), Cinahl (via Ebsco), and Central (via Cochrane library) databases were searched using the following terms: "laser," "low-level laser," "photobiomodulation," "light emitting diodes," "phototherapy," "exercise," "chronic neck pain." After verification and implementation of eligibility criteria, seven manuscripts were considered eligible for data analysis. These manuscripts had methodological quality between 5 and 8 points on the PEDro scale. Most studies used low infrared laser therapy to perform PBMT, with a wide range of parameters and energy density between 2 and 7 J/cm2 and a total treatment time between 2 and 6 weeks. Four studies showed significant benefits in terms of pain intensity at short-term follow-up and one at intermediate-term follow-up. However, only one showed a minimal clinically important change. No studies have shown significant improvement in disability. This review demonstrates that the association of PBMT with therapeutic exercises in general promotes significant benefits only for the intensity of pain. However, it does not seem to promote a minimally effective clinical difference in individuals with CNP.

Correlation Among Pain Intensity, Catastrophizing, and Falls in Older Individuals With Unilateral Knee Osteoarthritis: A Cross-Sectional Study.

OBJECTIVE: The purpose of this study was to investigate whether pain intensity and catastrophizing are associated with fear of falls and the number of falls in older persons with knee osteoarthritis (OA). METHODS: A cross-sectional study was conducted involving 100 volunteers (male and female participants), 60 to 80 years old, with a diagnosis of knee OA. Patients were recruited from a physical therapy clinic in the city of São Paulo, Brazil, from March 2019 to November 2019. The following measures were used for the evaluations: Numerical Rating Pain Scale (NRPS), Pain-Related Self-Statement Scale (PRSS), and Falls Efficacy Scale. In statistical analysis, histograms were created to determine the distribution of data. Spearman's correlation coefficients (rs) were then calculated to determine the strength of the associations among the variables. The receiver operating characteristic curve was used to identify the accuracy of PRSS and NRPS in differentiating participants with a history of falls from those without. RESULTS: No significant correlation was found among the pain intensity, pain catastrophizing, fear of falling, and number of falls (rs value ranging from -0.033 to -0.167; P value ranging from .096-.743). The accuracy of PRSS and NRPS in differentiating participants with falls from those without was insufficient, with area under the curve values of 0.46 and 0.42, respectively. CONCLUSION: Pain catastrophizing and intensity were not significantly associated with fear of falling and numbers of falls in older individuals with unilateral knee OA.

Photobiomodulation on trigeminal neuralgia: systematic review.

Trigeminal neuralgia is a recurrent episode of facial pain, that may be associated with other conditions such as multiple sclerosis, neoplasms, and nerve compromises or may occur due to an unknown cause. The available treatments are pharmacotherapy or surgery; however, both are susceptible to develop side effects. Photobiomodulation could be a promising alternative therapy for trigeminal neuralgia. A systematic review of literature was carried out using the PRISMA protocol, in the PubMed/MEDLINE, Embase, and Web of Science databases. Risk of bias by ROB 2.0 protocol was performed in included studies. Initially, 20 identified articles were collected varying between the years of 1983-2018, from which 6 were included. A total of 193 patients were evaluated; photobiomodulation was compared to conventional therapies, TENS, and therapy combinations with pharmacotherapy. The overall risk of bias was low, with some concerns in the randomization and double-blinding process; moreover, there are few reports in the literature. Photobiomodulation appears to be as effective as conventional therapies, being a coadjutant therapeutic opportunity for the treatment of trigeminal neuralgia.

Association between convergence insufficiency and temporomandibular disorder cross-sectional study.

OBJECTIVES: Evaluate whether there is an association between convergence insufficiency and temporomandibular disorder (TMD) and whether there is an association between pain and range of motion in different degrees of TMD. METHODS: We evaluated 138 individuals with TMD and 46 without TMD using the Research Diagnostic Criteria for temporomandibular disorders, the Fonseca Anamnestic Index (FAI), Numeric Pain Rating Scale, and the measurement of mandibular range of motion (ROM). Convergence insufficiency was diagnosed using the convergence test and Convergence Insufficiency Symptom Survey. Analysis of variance was used to compare age and mandibular ROM. The Kruskal-Wallis was used to compare mandibular ROM and pain between groups. The chi-square test was used to evaluate associations between TMD subgroups and the FAI, sex, and ocular convergence. RESULTS: The majority of individuals without TMD did not exhibit convergence insufficiency. The frequency convergence insufficiency was significantly higher among individuals with severe TMD (p < 0.003). Mean pain severity differed between individuals with and without TMD. Mandibular ROM diminished with the increase in TMD severity. CONCLUSIONS: Convergence insufficiency, age, the increase in pain, and the reduction in mandibular range of motion were associated with the degrees of TMD severity. Despite the significant associations between convergence insufficiency and both pain and TMD severity, these variables cannot be indicated as predictive factors due to the low variability in the linear regression analysis. CLINICAL RELEVANCE: The present findings can assist in decision making regarding the treatment of severe TMD and the evaluation of ocular convergence.