Distribution Of Compartment Research Articles

Prediction quality of patients’ composited outcomes of interest and how much variations on the outcomes explained by the patients’ sodium levels

Background: Hypernatremia can be caused by medications, glucose/urea-related hyperosmolarity, overdiuresis, compartmental fluid distribution imbalances, iatrogenic hypertonic saline excess, renal concentrating performance defects, overdiuresis, and hypermetabolic states. Patients who are in critical condition, encompassing ailments of the heart, liver, lungs, brain, and kidneys, frequently manifest hyponatremia (sodium < 135 mEq/L). Similar to hypernatremia, hyponatremia signifies the severity of the illness and a bleak prognosis. Hyponatremia is less lethal than central pontine myelinolysis, which overcorrects sodium concentrations urgently. Aim: The objective of this research endeavour was to investigate the strength of correlations, the extent to which the independent variables account for the overall variability in the dependent variable, and the accuracy of the dependent variable's predictions. In addition, the purpose of this test was to extract the coefficients required to present the Binary Logistic Regression models that were investigated. Methods: Between May 2018 and May 2021, this study examined two Na-based prognosticators for overall mortality in critically ill patients admitted to the King Hussein Medical Centre. An investigation was conducted on 2155 cases utilising Receiver Operating Characteristic (ROC) and Sensitivity Indices Test analyses to ascertain the most effective cut-off points, specificities, sensitivity, predictive values, likelihood ratios, Youden and accuracy indices, and mortality rates. The research discovered that serial termination points with lower values suggested more robust evidence for a positive actual state, whereas higher values suggested less robust evidence for a negative actual state. A Binary Logistic Regression (BLgR) test was performed to examine correlations, the extent of total variations in the dependent variable, and the accuracy of the prediction for each Na-related mortality prognosticator in relation to overall mortality. The analysis was conducted utilising version 25 of SPSS for Windows. Results: The research revealed that the AUROC for cNa was considerably greater in magnitude compared to its prognosticator that is genealogically related to Na. 129.35 mEq/l and 131.05 mEq/l were the optimal cut-off points, TPRs, TNRs, PPVs, NLRs, YIs, and AIs for the two comparative Na investigated statutes. The BLgR models were developed in order to simulate the relationship between the corrected and measured Na levels of patients and their overall mortality rate. For critically ill patients, the probabilities of overall mortality at the optimal cutoff operating Na levels were 79.59 and 81.62 percent, respectively.

RAB3 phosphorylation by pathogenic LRRK2 impairs trafficking of synaptic vesicle precursors.

Gain-of-function mutations in the LRRK2 gene cause Parkinson's disease (PD), characterized by debilitating motor and non-motor symptoms. Increased phosphorylation of a subset of RAB GTPases by LRRK2 is implicated in PD pathogenesis. We find that increased phosphorylation of RAB3A, a cardinal synaptic vesicle precursor (SVP) protein, disrupts anterograde axonal transport of SVPs in iPSC-derived human neurons (iNeurons) expressing hyperactive LRRK2-p.R1441H. Knockout of the opposing protein phosphatase 1H (PPM1H) in iNeurons phenocopies this effect. In these models, the compartmental distribution of synaptic proteins is altered; synaptophysin and synaptobrevin-2 become sequestered in the neuronal soma with decreased delivery to presynaptic sites along the axon. We find that RAB3A phosphorylation disrupts binding to the motor adaptor MADD, potentially preventing the formation of the RAB3A-MADD-KIF1A/1Bβ complex driving anterograde SVP transport. RAB3A hyperphosphorylation also disrupts interactions with RAB3GAP and RAB-GDI1. Our results reveal a mechanism by which pathogenic hyperactive LRRK2 may contribute to the altered synaptic homeostasis associated with characteristic non-motor and cognitive manifestations of PD.

Evaluation of Knee Radiograph and its Interrelation between Body Mass Index and Range of Motion in Osteoarthritic Knee

Abstract Context: Assessing knee osteoarthritis (OA) radiologically is a well-recognised investigation technique. Range of motion (ROM) measurement gives an idea about the functional status of the joint. Body mass index (BMI) increment is one of the risk factors of worsening knee OA. Aim: The aim of this study was to evaluate OA radiologically and to search the status of BMI, ROM and Kellgren–Lawrence (KL) score of osteoarthritic knee patients and find their interrelations. Settings: This study was conducted at the department of physical medicine and rehabilitation in a tertiary hospital of Bangladesh. Designs: This was a cross-sectional study. Methodology: Purposive selection of 66 primary OA knees was done. Compartmental distribution of osteoarthritic knee was determined. Radiographics were determined by KL score system. BMI was calculated conventionally. Maximum flexion, extension and total excursion were measured by a universal goniometer. Results: Fifty per cent of participants had tricompartmental OA. Patients with maximum KL score 2 had significantly more total excursion (127.44 ± 2.89) compared to maximum KL score 3 (121.51 ± 3.14) and 4 (110.00 ± 3.58). Subjects with normal BMI had significantly more total excursion (125.00 ± 4.21) compared to overweight (121.03 ± 6.84) and obese patients (122.54 ± 4.31) (P = 0.044). 60.9% of subjects with normal BMI had significantly more maximum KL score 2 compared to overweight (33.3%) and obese patients (7.7%). A positive correlation was present between BMI and maximal KL score (r = 0.345, P = 0.005). A significant strong negative correlation was found between maximal KL score and total excursion (r = −0.825, P < 0.001). Conclusion: Different percentages of unicompartmental, bicompartmental and tricompartmental knee OA were found. Osteoarthritic patients with higher BMI had lower ROM and increased KL radiographic scores.

Role Of Computed Tomography in Evaluating Mediastinal Masses

Background: The diaphragm is located inferiorly, the thoracic inlet is located superiorly, and the pleural cavities are located laterally to define the mediastinum. According to various anatomists 4 it is further split into anterior, middle, and posterior compartments. Including thymoma, teratoma, thyroid illness, and lymphoma, anterior mediastinal tumours make up 50% of all mediastinal masses.5 While tumours that develop in the posterior mediastinum are frequently neurogenic tumours, middle mediastinum masses are typically congenital cysts. Objectives: 1. To study the computed tomographic characteristics of Mediastinal lesion/masses in Plain and Contrast enhanced scans. 2. To locate, differentiate and diagnose mediastinal masses. Material & Methods: A prospective hospital based observational study. Department of Radio diagnosis, Al Ameen Medical College & Hospital, Vijayapura, Karnataka. All cases referred to the department of Radio-Diagnosis for clinically suspected Mediastinal masses. study consisted of 40 subjects. Purposive sampling technique. All the cases were studied on a SIEMENS ACQUISITION computed tomography machine. Patients were kept nil orally 4 hrs prior to the CT scan to avoid complications while administrating contrast medium. Risks of contrast administration were explained to the patient and consent was obtained prior to the contrast study. Results: CT and Histopathology Diagnosis was Malignant in 90.0%, Benign in 100.0%. CT was Benign and Histopathology Diagnosis was Malignant in 10%. There was a significant difference in CT and HPE classification of mediastinal masses and comparison. Conclusion: we conclude that computed tomography definitely has a major role to play in the evaluation of a mediastinal mass regarding the compartmental distribution, mass effect upon adjacent structure and provisional diagnosis with Sensitivity of 90 % and Diagnostic Accuracy of 97.5%.

Dopamine Agonist Cotreatment Alters Neuroplasticity and Pharmacology of Levodopa-Induced Dyskinesia.

Current models of levodopa (L-dopa)-induced dyskinesia (LID) are obtained by treating dopamine-depleted animals with L-dopa. However, patients with LID receive combination therapies that often include dopamine agonists. Using 6-hydroxydopamine-lesioned rats as a model, we aimed to establish whether an adjunct treatment with the D2/3 agonist ropinirole impacts on patterns of LID-related neuroplasticity and drug responses. Different regimens of L-dopa monotreatment and L-dopa-ropinirole cotreatment were compared using measures of hypokinesia and dyskinesia. Striatal expression of ∆FosB and angiogenesis markers were studied immunohistochemically. Antidyskinetic effects of different drug categories were investigated in parallel groups of rats receiving either L-dopa monotreatment or L-dopa combined with ropinirole. We defined chronic regimens of L-dopa monotreatment and L-dopa-ropinirole cotreatment inducing overall similar abnormal involuntary movement scores. Compared with the monotreatment group, animals receiving the L-dopa-ropinirole combination exhibited an overall lower striatal expression of ∆FosB with a distinctive compartmental distribution. The expression of angiogenesis markers and blood-brain barrier hyperpermeability was markedly reducedafter L-dopa-ropinirole cotreatment compared withL-dopa monotreatment. Moreover, significant group differences were detected upon examining the response to candidate antidyskinetic drugs. In particular, compounds modulating D1 receptor signaling had a stronger effect in the L-dopa-only group, whereas both amantadine and the selective NMDA antagonist MK801 produced a markedly larger antidyskinetic effect in L-dopa-ropinirole cotreated animals. Cotreatment with ropinirole altered LID-related neuroplasticity and pharmacological response profiles. The impact of adjuvant dopamine agonist treatment should be taken into consideration when investigating LID mechanisms and candidate interventionsin both clinical and experimental settings. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Real-time metabolic monitoring under exhaustive exercise and evaluation of ventilatory threshold by breathomics: Independent validation of evidence and advances.

Breath analysis was coupled with ergo-spirometry for non-invasive profiling of physio-metabolic status under exhaustive exercise. Real-time mass-spectrometry based continuous analysis of exhaled metabolites along with breath-resolved spirometry and heart rate monitoring were executed while 14 healthy adults performed ergometric ramp exercise protocol until exhaustion. Arterial blood lactate level was analyzed at defined time points. Respiratory-cardiac parameters and exhalation of several blood-borne volatiles changed continuously with the course of exercise and increasing workloads. Exhaled volatiles mirrored ventilatory and/or hemodynamic effects and depended on the origin and/or physicochemical properties of the substances. At the maximum workload, endogenous isoprene, methanethiol, dimethylsulfide, acetaldehyde, butanal, butyric acid and acetone concentrations decreased significantly by 74, 25, 35, 46, 21, 2 and 2%, respectively. Observed trends in exogenous cyclohexadiene and acetonitrile mimicked isoprene profile due to their similar solubility and volatility. Assignment of anaerobic threshold was possible via breath acetone. Breathomics enabled instant profiling of physio-metabolic effects and anaerobic thresholds during exercise. Profiles of exhaled volatiles indicated effects from muscular vasoconstriction, compartmental distribution of perfusion, extra-alveolar gas-exchange and energy homeostasis. Sulfur containing compounds and butyric acid turned out to be interesting for investigations of combined diet and exercise programs. Reproducible metabolic breath patterns have enhanced scopes of breathomics in sports science/medicine.

Heterogeneous Immunolocalisation of Zinc Transporters ZIP6, ZIP10 and ZIP14 in Human Normo- and Asthenozoospermic Spermatozoa.

Zinc (in the form of Zn2+) is necessary for male fertility. Both Zn2+ quantity and its localisation have been detected in seminal plasma and ejaculated spermatozoa, suggesting its active uptake via zinc import transporters (ZIPs). Immunofluorescence was used to characterise the expression and localisation of three distinct types of ZIP transporters in ejaculated spermatozoa of normo- and asthenozoospermic sperm samples. ZIP6, ZIP10 and ZIP14 showed heterogeneous sperm cell expression and different compartmental distribution. In both types of sperm samples, ZIP6 and ZIP14 were predominantly localised in the sperm head, while ZIP10 was found along the sperm tail. Compartmental localisation of ZIPs in asthenozoospermia was not changed. However, regarding sub-compartmental localisation in sperm head regions, for ZIP6 asthenozoospermia only decreased its acorn/crescent-like pattern. In contrast, ZIP14 immunostaining was altered in favour of crescent-like, as opposed to acorn-like and acorn/crescent-like patterns. The specific ZIPs localisation may reflect their different roles in sperm cell integrity and motility and may change over time. This is the first report of their specific compartmental and sub-compartmental localisation in ejaculated human sperm cells. Further research will lead to a greater understanding of the roles of ZIPs in sperm cell biology, which could positively influence procedures for human infertility therapy.

New Pharmacokinetic Parameters of Imaging Substrates Quantified from Rat Liver Compartments.

Hepatobiliary imaging is increasingly used by pharmacologists to quantify liver concentrations of transporter-dependent drugs. However, liver imaging does not quantify concentrations in extracellular space, hepatocytes, and bile canaliculi. Our study compared the compartmental distribution of two hepatobiliary substrates gadobenate dimeglumine [BOPTA; 0.08 liver extraction ratio (ER)] and mebrofenin (MEB; 0.93 ER) in a model of perfused rat liver. A gamma counter placed over livers measured liver concentrations. Livers were preperfused with gadopentetate dimeglumine to measure extracellular concentrations. Concentrations coming from bile canaliculi and hepatocytes were calculated. Transporter activities were assessed by concentration ratios between compartments and pharmacokinetic parameters that describe the accumulation and decay profiles of hepatocyte concentrations. The high liver concentrations of MEB relied mainly on hepatocyte and bile canaliculi concentrations. In contrast, the three compartments contributed to the low liver concentrations obtained during BOPTA perfusion. Nonlinear regression analysis of substrate accumulation in hepatocytes revealed that cellular efflux is measurable ∼4 minutes after the start of perfusion. The hepatocyte-to-extracellular concentration ratio measured at this time point was much higher during MEB perfusion. BOPTA transport by multidrug resistance associated protein 2 induced an aquaporin-mediated water transport, whereas MEB transport did not. BOPTA clearance from hepatocytes to bile canaliculi was higher than MEB clearance. MEB did not efflux back to sinusoids, whereas BOPTA basolateral efflux contributed to the decrease in hepatocyte concentrations. In conclusion, our ex vivo model quantifies substrate compartmental distribution and transport across hepatocyte membranes and provides an additional understanding of substrate distribution in the liver. SIGNIFICANCE STATEMENT: When transporter-dependent drugs target hepatocytes, cellular concentrations are important to investigate. Low concentrations on cellular targets impair drug therapeutic effects, whereas excessive hepatocyte concentrations may induce cellular toxicity. With a gamma counter placed over rat perfused livers, we measured substrate concentrations in the extracellular space, hepatocytes, and bile canaliculi. Transport across hepatocyte membranes was calculated. The study provides an additional understanding of substrate distribution in the liver.

Concentrations and pharmacokinetic parameters of MRI and SPECT hepatobiliary agents in rat liver compartments

BackgroundIn hepatobiliary imaging, systems detect the total amount of agents originating from extracellular space, bile canaliculi, and hepatocytes. They add in situ concentration of each compartment corrected by its respective volume ratio to provide liver concentrations. In vivo contribution of each compartment to liver concentration is inaccessible. Our aim was to quantify the compartmental distribution of two hepatobiliary agents in an ex vivo model and determine how their liver extraction ratios and cholestasis (livers lacking canalicular transporters) might modify it.MethodsWe perfused labelled gadobenate dimeglumine (Bopta, 200 μM, 7% liver extraction ratio) and mebrofenin (Meb, 64 μM, 94% liver extraction ratio) in normal (n = 18) and cholestatic (n = 6) rat livers. We quantified liver concentrations with a gamma counter placed over livers. Concentrations in hepatocytes and bile canaliculi were calculated. Mann-Whitney and Kruskal-Wallis tests were used.ResultsHepatocyte concentrations were 2,043 ± 333 μM (Meb) versus 360 ± 69 μM (Bopta, p < 0.001). Meb extracellular concentrations did not contribute to liver concentrations (1.3 ± 0.3%). The contribution of Bopta extracellular concentration was 12.4 ± 1.9% (p < 0.001 versus Meb). Contribution of canaliculi was similar for both agents (16%). Cholestatic livers had no Bopta in canaliculi but their hepatocyte concentrations increased in comparison to normal livers.ConclusionHepatocyte concentrations are correlated to liver extraction ratios of hepatobiliary agents. When Bopta is not present in canaliculi of cholestatic livers, hepatocyte concentrations increase in comparison to normal livers. This new understanding extends the interpretation of clinical liver images.

Flow-controlled expiration (FLEX) homogenizes pressure distribution in a four compartment physical model of the respiratory system with chest wall compliance

Objective. Flow-controlled expiration (FLEX) has been shown to attenuate ventilator-induced lung injury in animal models. It has also shown to homogenize compartmental pressure distribution in a physical model of the inhomogeneous respiratory system having independent compartments. We hypothesized that the homogenizing effects of FLEX are also effective in this regard when the independence of compartments is suspended by simulated chest wall compliance. Approach. A four compartment physical model of the respiratory system having chest wall compliance (137 ml/cmH2O) was developed. Two of the four compartments had high compliance (18 ml/cmH2O) and two had low compliance (10 ml/cmH2O). These compartments were each combined with either high (6.8 cmH2O·s/l) or low resistance (3.5 cmH2O·s/l). The model was ventilated in the volume-controlled ventilation mode with either passive expiration or with FLEX. The maximal pressure differences (ΔP max) and the maximal differences of mean pressure (ΔP mean) between the compartments during expiration were determined. Main results. With passive expiration ΔP max reached up to 3.4 ± 0.03 cmH2O but only 0.9 ± 0.01 cmH2O with FLEX (p < 0.001). Maximal differences of ΔP mean were significantly lower with FLEX as compared to passive expiration (extending up to 0.4 ± 0.04 cmH2O versus 2.0 ± 0.15 cmH2O, p < 0.001). Significance. The homogenizing effects of FLEX on compartmental pressure distribution could be reproduced in a more complex physical model of the inhomogeneous respiratory system having chest wall compliance and might be a mechanism underlying the lung protective effects of ventilation with FLEX.

Magic DIAMOND: Multi-fascicle diffusion compartment imaging with tensor distribution modeling and tensor-valued diffusion encoding.

Diffusion tensor imaging provides increased sensitivity to microstructural tissue changes compared to conventional anatomical imaging but also presents limited specificity. To tackle this problem, the DIAMOND model subdivides the voxel content into diffusion compartments and draws from diffusion-weighted data to estimate compartmental non-central matrix-variate Gamma distributions of diffusion tensors. It models each sub-voxel fascicle separately, resolving crossing white-matter pathways and allowing for a fascicle-element (fixel) based analysis of microstructural features. Alternatively, specific features of the intra-voxel diffusion tensor distribution can be selectively measured using tensor-valued diffusion-weighted acquisition schemes. However, the impact of such schemes on estimating brain microstructural features has only been studied in a handful of parametric single-fascicle models. In this work, we derive a general Laplace transform for the non-central matrix-variate Gamma distribution, which enables the extension of DIAMOND to tensor-valued encoded data. We then evaluate this "Magic DIAMOND" model in silico and in vivo on various combinations of tensor-valued encoded data. Assessing uncertainty on parameter estimation via stratified bootstrap, we investigate both voxel-based and fixel-based metrics by carrying out multi-peak tractography. We demonstrate using in silico evaluations that tensor-valued diffusion encoding significantly improves Magic DIAMOND's accuracy. Most importantly, we show in vivo that our estimated metrics can be robustly mapped along tracks across regions of fiber crossing, which opens new perspectives for tractometry and microstructure mapping along specific white-matter tracts.

The Central Role and Possible Mechanisms of Bacterial DNAs in Sepsis Development.

The pathological roles of bacterial DNA have been documented many decades ago. Bacterial DNAs are different from mammalian DNAs; the latter are heavily methylated. Mammalian cells have sensors such as TLR-9 to sense the DNAs with nonmethylated CpGs and distinguish them from host DNAs with methylated CpGs. Further investigation has identified many other types of DNA sensors distributed in a variety of cellular compartments. These sensors not only sense foreign DNAs, including bacterial and viral DNAs, but also sense damaged DNAs from the host cells. The major downstream signalling pathways includeTLR-9-MyD88-IKKa-IRF-7/NF-κB pathways to increase IFN/proinflammatory cytokine production, STING-TBK1-IRF3 pathway to increase IFN-beta, and AIM2-ASC-caspas-1 pathway to release IL-1beta. The major outcome is to activate host immune response by inducing cytokine production. In this review, we focus on the roles and potential mechanisms of DNA sensors and downstream pathways in sepsis. Although bacterial DNAs play important roles in sepsis development, bacterial DNAs alone are unable to cause severe disease nor lead to death. Priming animals with bacterial DNAs facilitate other pathological factors, such as LPS and other virulent factors, to induce severe disease and lethality. We also discuss compartmental distribution of DNA sensors and pathological significance as well as the transport of extracellular DNAs into cells. Understanding the roles of DNA sensors and signal pathways will pave the way for novel therapeutic strategies in many diseases, particularly in sepsis.

A linearized expiration flow homogenizes the compartmental pressure distribution in a physical model of the inhomogeneous respiratory system

Objective: Flow-controlled expiration (FLEX) and flow-controlled ventilation (FCV) imply a linearized expiration, and were suggested as new approaches for lung-protective ventilation, especially in the case of an inhomogeneous lung. We hypothesized that a linearized expiration homogenizes the pressure distribution between compartments during expiration, compared to volume-controlled (VCV) and pressure-controlled (PCV) ventilation. Approach: We investigated the expiratory pressure decays in a physical model of an inhomogeneous respiratory system. The model contained four compartments of which two had a high (25 ml cmH2O-1) and two a low compliance (10 ml cmH2O−1). These were combined with either a high (6.5 cmH2O s l−1) or low resistance (2.8 cmH2O s l−1), respectively. The model was ventilated in all modes at various tidal volumes and peak pressures, and we determined in each compartment the expiratory time at which the pressure declined to 50% (t50) of the end-inspiratory pressure, and the maximal differences of t50 (Δt50) and pressure (Δpmax) between all compartments. Main results: During FLEX and FCV, t50 was 6- to 7-fold higher compared to VCV and PCV (all P < 0.001). During VCV and PCV, Δt50 was higher (128 ± 18 ms) compared to FLEX and FCV (49 ± 19 ms; all P < 0.001). Δpmax reached up to 3.8 ± 0.2 cmH2O during VCV and PCV, but only 0.6 ± 0.1 cmH2O during FLEX and FCV (P < 0.001). Significance: FLEX and FCV provide a more homogeneous expiratory pressure distribution between compartments with different mechanical properties compared with VCV and PCV. This may reduce shear stress within inhomogeneous lung tissue.

Compartmental fat distribution in the abdomen of dogs relative to overall body fat composition

BackgroundAdipose tissue may have different metabolic and endocrine functions depending on the region of the body in which it is located. While visceral or intra-abdominal fat has been found to contribute to leptin concentrations, insulin resistance and obesity-related diseases, there are only a few imaging studies documenting the preferential distribution of body fat to either the intra-abdominal or subcutaneous compartments in dogs. This study aimed to determine if CT-measured abdominal fat distributed preferentially to the visceral space (V) relative to the subcutaneous space (SQ), with increasing DXA-determined total body fat percentage; and if ultrasound measurements of the ventral midline subcutaneous (SAT) and visceral adipose thickness (VAT) can be used to estimate the distribution of fat to the subcutaneous and visceral abdominal spaces, in a sample of 22 dogs with variable body condition.ResultsMultivariate analysis showed no statistically significant correlation between visceral to subcutaneous fat ratio (V/SQ) and increasing total body fat percentage (β = − 0.07, p = 0.733), but strong correlation with age (β = 0.71 p = 0.002). A substantial amount of variation for the ultrasound visceral adipose thickness to subcutaneous fat thickness (VAT/SAT) could be explained by both CT V/SQ and sex (R2Adjusted = 0.477, p = 0.001), with female dogs having significant lower VAT/SAT ratios compared to the male dogs (p = 0.047). The ultrasound fat measurements appeared moderately reliable, but a larger sample number is required to confirm this.ConclusionsThe findings suggest that dogs with a relatively healthy to slightly overweight body condition score, distribute fat relatively similarly between their peritoneal (visceral) and subcutaneous abdominal compartments with increasing total body fat percentage. However, there was increased fat distribution to the peritoneal space relative to the subcutaneous space with increasing age. Further, abdominal ultrasound may be useful in estimating the ratio of fat distribution to both the abdominal visceral and subcutaneous spaces.

The Safety and Exploration of the Pharmacokinetics of Intrapleural Liposomal Curcumin.

BackgroundMalignant pleural effusion (MPE) is the accumulation of fluid in the pleural cavity as a result of malignancies affecting the lung, pleura and mediastinal lymph nodes. Curcumin, a compound found in turmeric, has anti-cancer properties that could not only treat MPE accumulation but also reduce cancer burden. To our knowledge, direct administration of curcumin into the pleural cavity has never been reported, neither in animals nor in humans.PurposeTo explore the compartmental distribution, targeted pharmacokinetics and the safety profile of liposomal curcumin following intrapleural and intravenous administration.MethodsLiposomal curcumin (16 mg/kg) was administered into Fischer 344 rats by either intrapleural injection or intravenous infusion. The concentration of curcumin in plasma and tissues (lung, liver and diaphragm) were measured using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Blood and tissues were examined for pathological changes.ResultsNo pleural or lung pathologies were observed following intrapleural liposomal curcumin administration. Total curcumin concentration peaked 1.5 hrs after the administration of intrapleural liposomal curcumin and red blood cell morphology appeared normal. A red blood cells abnormality (echinocytosis) was observed immediately and at 1.5 hrs after intravenous infusion of liposomal curcumin.ConclusionThese results indicate that liposomal curcumin is safe when administered directly into the pleural cavity and may represent a viable alternative to intravenous infusion in patients with pleural-based tumors.

Correlation between amyloid deposits affecting renal compartments and glomerular filtration rate during renal biopsy in a renal amyloidosis case series.

Amyloidosis comprises a group of disorders that accumulate modified autologous proteins in organs, mainly the kidneys. Few studies have addressed the amyloid compartmental distribution and associated clinical outcomes. The aim of this study was to present a case series of renal amyloidosis correlating histopathological data with glomerular filtration rate (GFR) during kidney biopsy. We studied 53 cases reviewed by nephropathologists from 2000 to 2018 in a single kidney biopsy center in Brazil. GFR was estimated using the CKD-EPI formula. Cases were divided into Group A ≥60 and Group B <60 mL·min−1·(1.73 m2)−1 using the estimated GFR during kidney biopsy. Semiquantitative histopathological study was performed, including extension and distribution of amyloid deposits by compartments (glomeruli, tubulointerstitial tissue, and vessels). Statistical analyses were made to understand associations with lower GFR. No difference was seen for age, gender, proteinuria, hematuria, subtype of amyloid protein, arteriosclerosis, interstitial fibrosis/infiltrate, or glomerular and interstitial amyloid deposits. After a previous P value <0.1 in the descriptive analysis, the following variables were selected: globally sclerotic glomeruli, high blood pressure, and the extension of vascular amyloid deposition. A binary logistic regression model with GFR as the dependent variable showed history of hypertension and vascular amyloid to be robust and independent predictors of Group B <60 mL·min−1·(1.73 m2)−1. Beyond the histopathologic diagnosis of amyloidosis, a semiquantitative approach on renal biopsy could provide new insights. Vascular amyloid is an independent predictor of renal dysfunction in cases of renal amyloidosis.

Evaluation of mediastinal masses using computed tomography

The Objective of this study is to determine the accuracy of the diagnosis of mediastinal masses by Computed Tomography and to correlate its findings with histopathology. This study reviews the variety of the disease processes involving the mediastinum. Emphasis is based on illustrating the specific diagnostic CT features and its correlation with histopathology findings that allow one to distinguish between the different types of mediastinal masses. Total Number of 30 cases referred to the department of Radio-Diagnosis for clinically suspected Mediastinal masses at Teaching and General Hospital over a period of one year were included in the study. In our study, anterior mediastinum was the most commonly involved compartment, followed by superior mediastinum, posterior mediastinum and middle mediastinum. Lymphoma is most common lesion in anterior mediastinum and superior mediastinum, Teratoma in middle mediastinum and Schwannoma in posterior mediastinum. We conclude that computed tomography definitely has a major role to play in the evaluation of a mediastinal mass regarding the compartmental distribution, mass effect upon adjacent structure and provisional diagnosis.

Pharmacokinetic parameters and mechanism of action of an efficient anti-Aβ single chain antibody fragment.

The success of the targeting of amyloid-β (Aβ) oligomers through immunotherapy in Alzheimer’s disease (AD) mouse models has not been translated into the clinics. The use of single-chain variable fragments (scFvs) has been proposed to prevent the potential severe effects of full-length mAbs by precluding crystallizable fraction-mediated microglia activation. The efficacy of scFv-h3D6, a bapineuzumab-derived anti-Aβ scFv, has been extensively proven. In this work, we compared scFv-h3D6-EL, an elongated variant of the scFv-h3D6, with its original version to assess whether its characteristic higher thermodynamic stability improved its pharmacokinetic parameters. Although scFv-h3D6-EL had a longer half-life than its original version, its absorption from the peritoneal cavity into the systemic compartment was lower than that of the original version. Moreover, we attempted to determine the mechanism underlying the protective effect of scFv-h3D6. We found that scFv-h3D6 showed compartmental distribution and more interestingly crossed the blood–brain barrier. In the brain, scFv-h3D6 was engulfed by glial cells or internalized by Aβ peptide-containing neurons in the early phase post-injection, and was colocalized with the Aβ peptide almost exclusively in glial cells in the late phase post-injection. Aβ peptide levels in the brain decreased simultaneously with an increase in scFv-h3D6 levels. This observation in addition to the increased tumor necrosis factor-α levels in the late phase post-injection suggested that the engulfment of Aβ peptide/scFv-h3D6 complex extruded from large neurons by phagocytic cells was the mechanism underlying Aβ peptide withdrawal. The mechanism of action of scFv-h3D6 demonstrates the effectivity of Aβ-immunotherapy and lays the background for other studies focused on the finding of a treatment for AD.

Protein and surface expression of HCN2 and HCN4 subunits in mesocorticolimbic areas after cocaine sensitization

The Ih is a mixed depolarizing current present in neurons which, upon activation by hyperpolarization, modulates neuronal excitability in the mesocorticolimbic (MCL) system, an area which regulates emotions such as pleasure, reward, and motivation. Its biophysical properties are determined by HCN protein expression profiles, specifically HCN subunits 1–4. Previously, we reported that cocaine-induced behavioral sensitization increases HCN2 protein expression in all MCL areas with the Ventral Tegmental Area (VTA) showing the most significant increase. Recent evidence suggests that HCN4 also has an important expression in the MCL system. Although there is a significant expression of HCN channels in the MCL system their role in addictive processes is largely unknown. Thus, in this study we aim to compare HCN2 and HCN4 expression profiles and their cellular compartmental distribution in the MCL system, before and after cocaine sensitization. Surface/intracellular (S/I) ratio analysis indicates that VTA HCN2 subunits are mostly expressed in the cell surface in contrast to other areas tested. Our findings demonstrate that after cocaine sensitization, the HCN2 S/I ratio in the VTA was decreased whereas in the Prefrontal Cortex it was increased. In addition, HCN4 total expression in the VTA was decreased after cocaine sensitization, although the S/I ratio was not altered. Together, these results demonstrate differential cocaine effects on HCN2 and HCN4 protein expression profiles and therefore suggest a diverse Ih modulation of cellular activity during cocaine addictive processes.

Global environmental fate of short-chain chlorinated paraffins: Modeling with a single vs. multiple sets of physicochemical properties

While short-chain chlorinated paraffins (SCCPs) comprise a myriad of components whose physicochemical properties are extremely diverse, many previous studies characterized the SCCP mixtures collectively using a single set of physicochemical properties when modeling the global environmental fate and risk. In this work, we explore whether a discrepancy exists between simulations based on a single set of physicochemical properties and multiple component-specific ones in global fate and risk modeling, and the environmental condition (e.g., proximity to emission source vs. temperature) in which such a discrepancy is most notable. We simulated the environmental concentrations and compartmental distribution of SCCPs, using a mechanistic fugacity-based multimedia BETR-Global model. We observed a discrepancy between modeled concentrations based on a single and multiple sets of properties, which is more notable in regions with a low temperature and negligible emissions, e.g., the remote and cold background Arctic region. The modeled compartmental distribution differs slightly between simulations based on different sets of physicochemical properties. While using a single set of properties minimizes input data required for model-based evaluation of the risk of SCCPs, it tends to underestimate the environmental occurrence and risk in remote and cold regions, which are vulnerable and hence deserve a more conservative evaluation conclusion, and prevents us from drawing conclusions on which SCCP component is of greatest concern. The current work can be a relevant step towards improving the methodology for global environmental modeling and risk assessment of SCCPs and other complex halogenated chemical mixtures.