[Effectiveness and safety of robotic assisted-bronchoscopy system in locating and removing spring coils placed in the peripheral lung of beagle dogs: a pilot study].
Objective: To evaluate the effectiveness and safety of the robotic assisted bronchoscope system for localizing and removing the spring coils that placed in the peripheral lung of beagle dogs. Methods: The study was conducted from June 18th to June 20th, 2021. Metallic lung coils were placed as the simulated lesions to the periphery of the lungs of two adult male beagle dogs using a bronchoscope under general anesthesia. The navigation path was planned by the navigation function that built in the robotic bronchoscope system. After training, the doctors operated the robotic bronchoscope system to locate and remove the coils from the lung. The navigation success rate, sampling success rate, position of the coil, navigation time, sampling time, and operation time were evaluated. The damage to the airway mucosa during the operation and the vital signs of the beagles during and post-operation were accessed. Chest computerized tomography (CT) was performed post-operation to detect if there were complications such as pneumothorax and bleeding. Results: A total of 12 spring coils were successfully inserted into the two beagles. All the navigation paths of the simulated lesions were successfully planned. The navigation success rate was 12/12. The navigation time was (43.9±19.8) seconds. The distance between the tip of the flexible endoscope arm and the target point measured by the navigation system was (6.93±2.15) mm. The locations of the simulated lesions were distributed in the 6th-8th generation of bronchi. The sampling success rate was 12/12. The sampling time was (42.4±11.3) seconds. There was no pneumothorax or mediastinal emphysema after the placement of the coil. The vital signs of the beagle dogs were stable throughout the operation, and no operation-related or postoperative complications occurred. Conclusions: The robotic bronchoscope system can be used to locate and remove the spring coils from the peripheral lung of beagle dogs, and the procedure is simple and safe. It suggests that the robotic bronchoscopy system has great clinical significance in the sampling and diagnosis of peripheral lung lesions.


Photobiomodulation Therapy Improves Acute Inflammatory Response in Mice: the Role of Cannabinoid Receptors/ATP-Sensitive K+ Channel/p38-MAPK Signalling Pathway.
Although photobiomodulation therapy (PBM) has been applied clinically for the treatment of pain and inflammation, wound healing, sports and soft tissue injuries, as well as to repair injured spinal cords and peripheral nerves, it remains unclear which molecular substrates (receptor) are implicated in the cellular mechanisms of PBM. Here, we reported that PBM (660 nm, 30 mW, 0.06 cm2, 50 J/cm2, plantar irradiation) significantly inhibited carrageenan-induced paw oedema, but not noxious thermal response, through positive modulation to both CB1 and CB2 cannabinoid receptors. The use of CB1 antagonist AM281 or CB2 antagonist AM630 significantly reversed the anti-inflammatory effect of PBM. Analysis of signalling pathway downstream of cannabinoid receptors activation reveals that anti-inflammatory effects of PBM depend, in great extent, on its ability to activate ATP-dependent K+ channels and p38 mitogen-activated protein kinase. Moreover, PBM therapy significantly reduced the levels of pro-inflammatory cytokine IL-6 in both paw and spinal cord, and restored the reduction of the level of anti-inflammatory cytokine IL-10 in spinal cord after carrageenan injection. Unlike the potent cannabinoid receptor agonist (WIN 55212-2), PBM did not exert any CNS-mediated effects in the tetrad assay. Finally, PBM does not reduce inflammation and noxious thermal response induced by LPS and zymosan, a TLR4 and TLR2/dectin-1 ligand, respectively. Thus, cannabinoid receptors and, possibly, the endocannabinoid system, represent an important site of action of PBM that opens the possibility of complementary and nonpsychotropic therapeutic interventions in clinical practice. Graphical Abstract .


Chorea-acanthocytosis: clinical and genetic findings in three families from the Arabian peninsula.
Chorea-acanthocytosis is a rare autosomal recessive disorder. Its characteristics are orofacial dyskinesia, hyporeflexia, seizures, aberrant behavior, atrophy of the caudate and putamen, and acanthocytes in the blood with a normal level of lipoproteins. We describe three families with chorea-acanthocytosis. The inheritance pattern was recessive and the average age at onset was 27 years (range, 18-35 years). The presenting symptoms were seizures, aberrant behaviour, chorea, tics, and/or abnormal gait. Phase-contrast and electron microscopy examinations of blood showed 10 to 40% acanthocytes. The lipid profile was normal except that, in one family, no prebetalipoprotein bands corresponding to the fraction of very low-density lipoprotein were seen in high-resolution lipoprotein electrophoresis. Magnetic resonance imaging of the brain showed marked atrophy in the caudate and putamen; 18-fluorodeoxyglucose positron emission tomography scan showed hypometabolism in the striatum. In all three families, the disease was linked to a 6-cM region of chromosome 9q21 flanked by the recombinant markers GATA 89a11 and D9S1843. This finding strongly suggests the involvement of a single locus for this syndrome. Three different homozygous mutations of this gene have been identified. Although the clinical presentation was variable, the genetic studies on these three Saudi Arabian families with chorea-acanthocytosis provide strong evidence for a genetic locus for chorea-acanthocytosis at chromosome 9q21.


Evaluating physician impact analysis. Methods, results, and uses in Ontario Hospitals.
Physician impact analysis (PIA) is a planning tool intended to bring greater predictability to hospital medical staff resource planning by providing a means to predict the impact of a new or replacement physician's practice profile on a hospital's clinical program priorities, staffing resources, and costs. Two key methods advocated to undertake PIAs are the Department Survey Method and the Hospital Medical Records Institute Case-Mix Groups/Resource Intensity Weights Methods developed by the Hospital Medical Records Institute. This article discusses issues related to the methods, results, and uses of PIA information in Ontario hospitals. Further evaluation of the PIA process is recommended to increase our understanding of both the strengths and limitations of this planning tool.


Ratio of mitochondrial to nuclear DNA affects contamination estimates in ancient DNA analysis.
In the last decade, ancient DNA research has grown rapidly and started to overcome several of its earlier limitations through Next-Generation-Sequencing (NGS). Among other advances, NGS allows direct estimation of sample contamination from modern DNA sources. First NGS-based approaches of estimating contamination measured heterozygosity. These measurements, however, could only be performed on haploid genomic regions, i.e. the mitochondrial genome or male X chromosomes, but provided no measures of contamination in the nuclear genome of females with their two X chromosomes. Instead, female nuclear contamination is routinely extrapolated from mitochondrial contamination estimates, but it remains unclear if this extrapolation is reliable and to what degree variation in mitochondrial to nuclear DNA ratios affects this extrapolation. We therefore analyzed ancient DNA from 317 samples of different skeletal elements from multiple sites, spanning a temporal range from 7,000 BP to 386 AD. We found that the mitochondrial to nuclear DNA (mt/nc) ratio negatively correlates with an increase in endogenous DNA content and strongly influenced mitochondrial and nuclear contamination estimates in males. The ratio of mt to nc contamination estimates remained stable for overall mt/nc ratios below 200, as found particularly often in petrous bones but less in other skeletal elements and became more variable above that ratio.


Dietary conjugated linoleic acid changes belly and bacon quality from pigs fed varied lipid sources.
The objective of this experiment was to determine the effects of dietary lipid source with or without the addition of CLA on bacon composition and quality. Forty-eight barrows at a beginning BW of 55 kg +/- 2.2 were fed 1 of 6 diets for 56 d. These diets consisted of: 1) normal corn (NC), 2) NC + 1.25% CLA-60 oil (NC + CLA), 3) high-oil corn (HOC), 4) HOC + 1.25% CLA-60 oil (HOC-CLA), 5) NC + choice white grease (CWG; NC + CWG), and 6) NC + CWG + 1.25% CLA-60 oil (NC + CWG + CLA). The CLA-60 contains 60% CLA isomers in the oil, and therefore, 1.25% oil was needed to achieve 0.75% CLA in the diet. Soy oil replaced CLA in control diets. Choice white grease and high-oil corn were selected as fat sources for this study because of their utility in energy density for growing-finishing pigs, especially in hot weather. Pigs were slaughtered at an average BW of 113 kg +/- 4.1, and carcasses were fabricated at 24 h postmortem. Statistical analysis was performed using the mixed model procedure of SAS, and the main effects tested were dietary lipid source, CLA, and 2-way interaction. The addition of CLA to each basal diet improved (P < 0.05) belly firmness measured either lean side down or fat side down from the belly bar firmness test [4.39 cm vs. 7.01 cm (lean down) and 5.75 cm vs. 10.54 cm (fat down)] for 0 and 0.75% dietary CLA, respectively. The compression test used on bacon slabs showed that bacon from CLA-supplemented pigs was approximately 20% firmer than that from controls. Pigs fed the HOC diets had softer bellies compared (P < 0.05) with pigs fed the NC diet as measured by the belly bar test [6.94 cm vs. 9.26 cm (fat down)], respectively. Conjugated linoleic acid did not, however, improve bacon sliceability. No differences were observed for moisture, protein, or lipid percentages between any treatments. Overall, there was a CLA effect (P < 0.04) for lipid oxidation, in which the addition of CLA decreased bacon oxidation (0.1498 CLA vs. 0.1638 no CLA). Dietary CLA increased the percentage of SFA in tissues from pigs supplemented with CLA. Dietary inclusion of CLA increased the concentration of all measured isomers of CLA in bacon. Sensory scores of bacon showed no differences for any of the sensory attributes measured between any of the treatments. Our results indicate that inclusion of dietary CLA will improve belly firmness, extend the shelf life stability of bacon, and increase the degree of fat saturation.


Interaction between the lipoamide-containing H-protein and the lipoamide dehydrogenase (L-protein) of the glycine decarboxylase multienzyme system. 1. Biochemical studies.
Lipoamide dehydrogenase or dihydrolipoamide dehydrogenase (EC 1.8.1. 4) is the E3-protein component of the mitochondrial 2-oxoacid dehydrogenase multienzyme complexes. It is also the L-protein component of the glycine decarboxylase system. Although the enzymology of this enzyme has been studied exhaustively using free lipoamide as substrate, no data are available concerning the kinetic parameters of this enzyme with its physiological substrates, the dihydrolipoyl domain of the E2 component (dihydrolipoyl acyltransferase) of the 2-oxoacid dehydrogenase multienzyme complexes or the dihydrolipoyl H-protein of the mitochondrial glycine decarboxylase. In this paper, we demonstrate that Tris(2-carboxyethyl)phosphine, a specific disulfide reducing agent, allows a continuous reduction of the lipoyl group associated with the H-protein during the course of the reaction catalysed by the L-protein. This provided a valuable new tool with which to study the catalytic properties of the lipoamide dehydrogenase. The L-protein displayed a much higher affinity for the dihydrolipoyl H-protein than for free dihydrolipoamide. The oxidation of the dihydrolipoyl H-protein was not affected by the presence of structurally related analogues (apoH-protein or octanoylated H-protein). In marked contrast, these analogues strongly and competitively inhibited the decarboxylation of the glycine molecule catalysed by the P-protein component of the glycine decarboxylase system. Small unfolded proteolytic fragments of the H-protein, containing the lipoamide moiety, displayed Km values for the L-protein close to that found for the H-protein. On the other hand, these fragments were not able to promote the decarboxylation of the glycine in the presence of the P-protein. New highly hydrophilic lipoate analogues were synthesized. All of them showed Km and kcat/Km values very close to that found for the H-protein. From our results we concluded that no structural interaction is required for the L-protein to catalyse the oxidation of the dihydrolipoyl H-protein. We discuss the possibility that one function of the H-protein is to maintain a high concentration of the hydrophobic lipoate molecules in a nonmicellar state which would be accessible to the catalytic site of the lipoamide dehydrogenase.


Predictive factors of adrenal insufficiency in patients admitted to acute medical wards: a case control study.
Adrenal insufficiency is a rare and potentially lethal disease if untreated. Several clinical signs and biological markers are associated with glucocorticoid failure but the importance of these factors for diagnosing adrenal insufficiency is not known. In this study, we aimed to assess the prevalence of and the factors associated with adrenal insufficiency among patients admitted to an acute internal medicine ward. Retrospective, case-control study including all patients with high-dose (250 μg) ACTH-stimulation tests for suspected adrenal insufficiency performed between 2008 and 2010 in an acute internal medicine ward (n = 281). Cortisol values <550 nmol/l upon ACTH-stimulation test were considered diagnostic for adrenal insufficiency. Area under the ROC curve (AROC), sensitivity, specificity, negative and positive predictive values for adrenal insufficiency were assessed for thirteen symptoms, signs and biological variables. 32 patients (11.4%) presented adrenal insufficiency; the others served as controls. Among all clinical and biological parameters studied, history of glucocorticoid withdrawal was the only independent factor significantly associated with patients with adrenal insufficiency (Odds Ratio: 6.71, 95% CI: 3.08 -14.62). Using a logistic regression, a model with four significant and independent variable was obtained, regrouping history of glucocorticoid withdrawal (OR 7.38, 95% CI [3.18 ; 17.11], p-value <0.001), nausea (OR 3.37, 95% CI [1.03 ; 11.00], p-value 0.044), eosinophilia (OR 17.6, 95% CI [1.02; 302.3], p-value 0.048) and hyperkalemia (OR 2.41, 95% CI [0.87; 6.69], p-value 0.092). The AROC (95% CI) was 0.75 (0.70; 0.80) for this model, with 6.3 (0.8 - 20.8) for sensitivity and 99.2 (97.1 - 99.9) for specificity. 11.4% of patients with suspected adrenal insufficient admitted to acute medical ward actually do present with adrenal insufficiency, defined by an abnormal response to high-dose (250 μg) ACTH-stimulation test. A history of glucocorticoid withdrawal was the strongest factor predicting the potential adrenal failure. The combination of a history of glucocorticoid withdrawal, nausea, eosinophilia and hyperkaliemia might be of interest to suspect adrenal insufficiency.


Cottus schitsuumsh, a new species of sculpin (Scorpaeniformes: Cottidae) in the Columbia River basin, Idaho-Montana, USA.
Fishes of the genus Cottus have long been taxonomically challenging because of morphological similarities among species and their tendency to hybridize, and a number of undescribed species may remain in this genus. We used a combination of genetic and morphological methods to delineate and describe Cottus schitsuumsh, Cedar Sculpin, a new species, from the upper Columbia River basin, Idaho-Montana, USA. Although historically confused with the Shorthead Sculpin (C. confusus), the genetic distance between C. schitsuumsh and C. confusus (4.84-6.29%) suggests these species are distant relatives. Moreover, the two species can be differentiated on the basis of lateral-line pores on the caudal peduncle, head width, and interpelvic width. Cottus schitsuumsh is also distinct from all other Cottus in this region in having a single small, skin-covered, preopercular spine. Haplotypes of mtDNA cytochrome oxidase c subunit 1 of C. schitsuumsh differed from all other members of the genus at three positions, had interspecific genetic distances typical for congeneric fishes (1.61-2.74% to nearest neighbors), and were monophyletic in maximum-likelihood trees. Microsatellite analyses confirmed these taxonomic groupings for species potentially sympatric with C. schitsuumsh and that fish used in morphological comparisons were unlikely to be introgressed. Its irregular distribution, in the Spokane River basin in Idaho and portions of the Clark Fork River basin in Montana, may have resulted from human-assisted translocation.


Neuropathology as a consequence of neonatal ventilation in premature growth-restricted lambs.
Fetal growth restriction (FGR) and prematurity are associated with high risk of brain injury and long-term neurological deficits. FGR infants born preterm are commonly exposed to mechanical ventilation, but it is not known whether ventilation differentially induces brain pathology in FGR infants compared with appropriate for gestational age (AGA) infants. We investigated markers of neuropathology in moderate- to late-preterm FGR lambs, compared with AGA lambs, delivered by caesarean birth and ventilated under standard neonatal conditions for 24 h. FGR was induced by single umbilical artery ligation in fetal sheep at 88-day gestation (term, 150 days). At 125-day gestation, FGR and AGA lambs were delivered, dried, intubated, and commenced on noninjurious ventilation, with surfactant administration at 10 min. A group of unventilated FGR and AGA lambs at the same gestation was also examined. Over 24 h, circulating pH, Po2, and lactate levels were similar between groups. Ventilated FGR lambs had lower cerebral blood flow compared with AGA lambs ( P = 0.01). The brain of ventilated FGR lambs showed neuropathology compared with unventilated FGR, and unventilated and ventilated AGA lambs, with increased apoptosis (caspase-3), blood-brain barrier dysfunction (albumin extravasation), activated microglia (Iba-1), and increased expression of cellular oxidative stress (4-hydroxynonenal). The neuropathologies seen in the ventilated FGR brain were most pronounced in the periventricular and subcortical white matter but also evident in the subventricular zone, cortical gray matter, and hippocampus. Ventilation of preterm FGR lambs increased brain injury compared with AGA preterm lambs and unventilated FGR lambs, mediated via increased vascular permeability, neuroinflammation and oxidative stress.


Key Performance Indicators for program scale-up and divergent practice styles: a study from NSW, Australia.
Implementing programs at scale has become a vital part of the government response to the continuing childhood obesity epidemic. We are studying the largest ever scale-up of school and child care obesity prevention programs in Australia. Health promotion teams support primary schools and early childhood services in their area to achieve a number of specified, evidence-based practices aimed at organizational changes to improve healthy eating and physical activity. Key performance indicators (KPIs) were devised to track program uptake across different areas-measuring both the proportion of schools and early childhood services reached and the proportion of practices achieved in each setting (i.e. the proportion of sites implementing programs as planned). Using a 'tight-loose-tight' model, all local health districts receive funding and are held accountable to reaching KPI implementation targets. However, local teams have independent discretion over how to best use funds to reach targets. Based on 12 months of ethnographic fieldwork and interviews across all districts, this study examines variations in the decision making and strategizing processes of the health promotion teams. We identified three distinct styles of practice: KPI-driven practice (strategic, focussed on targets); relationship-driven practice (focussed on long-term goals); and equity-driven practice (directing resources to sites most in need). In adapting to KPIs, teams make trade-offs and choices. Some teams struggled to balance a moral imperative to attend to equity issues, with a practical need to meet implementation targets. We discuss how models of program scale-up and tracking could possibly evolve to recognize this complexity.


Muscle Belly Gearing Positively Affects the Force-Velocity and Power-Velocity Relationships During Explosive Dynamic Contractions.
Changes in muscle shape could play an important role during contraction allowing to circumvent some limits imposed by the fascicle force-velocity (F-V) and power-velocity (P-V) relationships. Indeed, during low-force high-velocity contractions, muscle belly shortening velocity could exceed muscle fascicles shortening velocity, allowing the muscles to operate at higher F-V and P-V potentials (i.e., at a higher fraction of maximal force/power in accordance to the F-V and P-V relationships). By using an ultrafast ultrasound, we investigated the role of muscle shape changes (vastus lateralis) in determining belly gearing (muscle belly velocity/fascicle velocity) and the explosive torque during explosive dynamic contractions (EDC) at angular accelerations ranging from 1000 to 4000°.s-2. By means of ultrasound and dynamometric data, the F-V and P-V relationships both for fascicles and for the muscle belly were assessed. During EDC, fascicle velocity, belly velocity, belly gearing, and knee extensors torque data were analysed from 0 to 150 ms after torque onset; the fascicles and belly F-V and P-V potentials were thus calculated for each EDC. Absolute torque decreased as a function of angular acceleration (from 80 to 71 Nm, for EDC at 1000 and 4000°.s-1, respectively), whereas fascicle velocity and belly velocity increased with angular acceleration (P < 0.001). Belly gearing increased from 1.11 to 1.23 (or EDC at 1000 and 4000°.s-1, respectively) and was positively corelated with the changes in muscle thickness and pennation angle (the changes in latter two equally contributing to belly gearing changes). For the same amount of muscle's mechanical output (force or power), the fascicles operated at higher F-V and P-V potential than the muscle belly (e.g., P-V potential from 0.70 to 0.56 for fascicles and from 0.65 to 0.41 for the muscle belly, respectively). The present results experimentally demonstrate that belly gearing could play an important role during explosive contractions, accommodating the largest part of changes in contraction velocity and allowing the fascicle to operate at higher F-V and P-V potentials.


Role of hypochlorous acid and chloramines in the extracellular cytolysis by neutrophil polymorphonuclear leukocytes.
The lysis of human red blood cells (HRBC) by neutrophil polymorphonuclear leukocytes (PMN), triggered with opsonized zymosan (OPZ) particles, was inhibited by azide, catalase, Cl- -free medium and amino acids indicating the involvement of myeloperoxidase (MPO), hydrogen peroxide (H2O2), Cl- ions and hypochlorous acid (HOCl) respectively. Thus, the cytolytic process depends on the following reaction: (Formula: see text). Because the oxidizing agent HOCl is also the precursor of the chloramines, a group of oxidants formed by the reaction between HOCl and PMN-derived ammonia (NH4+) or amines (R-NH2), the observed HRBC lysis can be theoretically due to HOCl and/or chloramines. Nevertheless, we found that PMN-mediated cytotoxicity occurs as an unidirectional process, being HRBC targets lysed and PMN unaffected. This finding indicates that the cytotoxin must be relatively more efficient against HRBC as compared with PMN. In fact, reagent HOCl (used at concentrations comparable to those generated by PMN) but not chloramines displayed such a type of property. Taken together, the data suggest that HRBC are killed by PMN-derived HOCl without the requirement for chloramines: this implies that NH4+ and R-NH2, released by PMN, act as down-modulators of the cytotoxic process, serving as HOCl trapping agents.


Primary hyperparathyroidism presenting as cervical myelopathy.
Quadriplegia as a presenting syndrome in a case of primary hyperparathyroidism is reported. The clinical picture was misdiagnosed as a space-occupying lesion in the cervical spinal canal, for which an unnecessary laminectomy was performed. The neurologic deficits disappeared following the removal of a parathyroid adenoma. The neurologic presentations of hyperparathyroidism are reviewed and discussed.


Peer Victimization in Extremely Low Birth Weight Survivors.
Extremely low birth weight (ELBW; <1000 g) children may be at risk for experiencing peer victimization. We examined retrospectively reported peer victimization in ELBW and control children in the oldest known, prospectively followed, population-based birth cohort of ELBW survivors. We compared levels of verbal and physical peer victimization in ELBW and control children. We also predicted peer victimization in the ELBW sample from child characteristics. ELBW children, especially girls, were at an increased risk for verbal, but not physical victimization. In addition, ELBW children with a higher IQ reported higher levels of verbal victimization, although ELBW females who had a lower body mass index in childhood reported higher levels of physical victimization. Findings highlight the need for parents and clinicians to be aware that ELBW girls, especially those with a lower body mass index in childhood, may be at increased risk of peer victimization, as are ELBW children with a higher IQ.


Serum angiotensin-converting-enzyme in Crohn's disease.
The serum angiotensin-converting-enzyme levels in patients with Crohn's disease have been determined. There is no significant difference in the serum levels of angiotensin-converting-enzyme in patients with active Crohn's disease, inactive Crohn's disease or Crohn's disease with demonstrated granuloma and normal controls. Patients with active Crohn's disease who are no steroid treatment do have significantly lower levels.


Involvement of proapoptotic molecules Bax and Bak in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced mitochondrial disruption and apoptosis: differential regulation of cytochrome c and Smac/DIABLO release.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L induces apoptosis in a wide variety of cancer and transformed cells. Activation of BID, a "BH3-domain-only" Bcl-2 family member, triggers the oligomerization of proapoptotic family members Bak or Bax, resulting in the release of mitochondrial proteins to cytosol. In this study, we have shown the importance of Bax and Bak in TRAIL-induced apoptosis by studying in murine embryonic fibroblasts (MEFs) from Bax(-/-) and Bak(-/-) animals. TRAIL induced cytochrome c release and apoptosis in wild-type, Bid(-/-), Bax(-/-), or Bak(-/-) MEFs, but not in Bax(-/-) Bak(-/-) double knockout (DKO) MEFs. Bid, which functions upstream of cytochrome c release, was cleaved in all of the knockout cells except in Bid(-/-) MEFs. The release of cytochrome c was correlated with caspase-9 activity. TRAIL increased caspase-3 activity in all of the cells except in DKO cells. TRAIL-induced drop in mitochondrial membrane potential was not observed in DKO MEFs. Unlike cytochrome c release, TRAIL-induced Smac/DIABLO release was blocked in Bid(-/-), Bax(-/-), Bak(-/-), or DKO MEFs, suggesting the differential regulation of these mitochondrial proteins during apoptosis. The apoptotic events downstream of mitochondria were intact in DKO MEFs, because microinjection of cytochrome c, or ectopic expression of mature Smac/DIABLO or pretreatment of Smac N7 peptide completely restored TRAIL sensitivity. In conclusion, the data suggest that Bax and Bak differentially regulate the release of cytochrome c and Smac/DIABLO from mitochondria, and Smac/DIABLO can be used to sensitize cells that are deficient in Bax and Bak genes, or resistant to TRAIL.


Scaling-up HCV prevention and treatment interventions in rural United States-model projections for tackling an increasing epidemic.
Effective strategies are needed to address dramatic increases in hepatitis C virus (HCV) infection among people who inject drugs (PWID) in rural settings of the United States. We determined the required scale-up of HCV treatment with or without scale-up of HCV prevention interventions to achieve a 90% reduction in HCV chronic prevalence or incidence by 2025 and 2030 in a rural US setting. An ordinary differential equation model of HCV transmission calibrated to HCV epidemiological data obtained primarily from an HIV outbreak investigation in Indiana. Scott County, Indiana (population 24 181), USA, a rural setting with negligible baseline interventions, increasing HCV epidemic since 2010, and 55.3% chronic HCV prevalence among PWID in 2015. PWID. Required annual HCV treatments per 1000 PWID (and initial annual percentage of infections treated) to achieve a 90% reduction in HCV chronic prevalence or incidence by 2025/30, either with or without scaling-up syringe service programmes (SSPs) and medication-assisted treatment (MAT) to 50% coverage. Sensitivity analyses considered whether this impact could be achieved without re-treatment of re-infections, and whether greater intervention scale-up was required due to the increasing epidemic in this setting. To achieve a 90% reduction in incidence and prevalence by 2030, without MAT and SSP scale-up, 159 per 1000 PWID (initially 24.9% of infected PWID) need to be HCV-treated annually. However, with MAT and SSP scaled-up, treatment rates are halved (89 per 1000 annually or 14.5%). To reach the same target by 2025 with MAT and SSP scaled-up, 121 per 1000 PWID (19.9%) need treatment annually. These treatment requirements are threefold higher than if the epidemic was stable, and the impact targets are unattainable without retreatment. Combined scale-up of hepatitis C virus treatment and prevention interventions is needed to decrease the increasing burden of hepatitis C virus incidence and prevalence in rural Indiana, USA, by 90% by 2025/30.


The UAF1-USP1 Deubiquitinase Complex Stabilizes cGAS and Facilitates Antiviral Responses.
Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects cytoplasmic microbial DNA and self-DNA from genomic instability, initiates innate immunity, and plays fundamental roles in defense against viruses and the development of various diseases. The cellular cGAS level determines the magnitude of the response to DNA. However, the underlying mechanisms of the control of cGAS stability, especially its feedback regulation during viral infection, remain largely unknown. In this study, we show that viral infection induces the expression of the UAF1-USP1 deubiquitinase complex in primary peritoneal macrophages (PMs) of C57BL/6J mice. UAF1-USP interacts with cGAS, selectively cleaves its K48-linked polyubiquitination, and thus stabilizes its protein expression in PMs and HEK293T cells. Concordantly, the UAF1-USP1 deubiquitinase complex enhances cGAS-dependent type I IFN responses in PMs. Uaf1 deficiency and ML323 (a specific inhibitor of UAF1-USP1 deubiquitinase complex) attenuates cGAS-triggered antiviral responses and facilitates viral replication both in vitro and in vivo. Thus, our study uncovers a positive feedback mechanism of cGAS-dependent antiviral responses and suggests the UAF1-USP1 complex as a potential target for the treatment of diseases caused by aberrant cGAS activation.


Live-cell imaging Unveils stimulus-specific dynamics of Nrf2 activation in UV-exposed melanoma cells: Implications for antioxidant compound screening.
The transcription factor Nuclear factor e2-related factor 2 (Nrf2) is pivotal in orchestrating cellular antioxidant defense mechanisms, particularly in skin cells exposed to ultraviolet (UV) radiation and electrophilic phytochemicals. To comprehensively investigate Nrf2's role in maintaining cellular redox equilibrium following UV-induced stress, we engineered a novel Nrf2 fusion-based reporter system for real-time, live-cell quantification of Nrf2 activity in human melanoma cells. Utilizing live quantitative imaging, we dissected the kinetic profiles of Nrf2 activation in response to an array of stimuli, including UVA and UVB radiation, as well as a broad spectrum of phytochemicals including ferulic acid, gallic acid, hispidulin, p-coumaric acid, quercetin, resveratrol, tannic acid, and vanillic acid as well as well-known Nrf2 inducers, tert-butylhydroquinone (tBHQ) and sulforaphane (SFN). Intriguingly, we observed distinct dynamical patterns of Nrf2 activity contingent on the specific stimuli applied. Sustained activation of Nrf2 was empirically correlated with the increased antioxidant response element (ARE) activity. Our findings demonstrate the nuanced impact of different phenolic compounds on Nrf2 activity and the utility of our Nrf2-CTΔ16-YFP reporter in characterizing the dynamics of Nrf2 translocation in response to diverse stimuli. In summary, our innovative reporter system not only revealed compounds capable of modulating UVA-induced Nrf2 activity but also showcased its utility as a robust tool for future antioxidant compound screening efforts.


Characterizing Firearm Assault Injury Among Young Black Men Using Arkansas Hospital Discharge Data.
Using statewide hospital discharge data from 2005 to 2014, this study aimed to describe and identify predictors of firearm assault among young Black men ages 18 to 44 in Arkansas. Descriptive analyses of data were performed for patient demographics (age, marital status, residential location, etc.), injury, and health care information (hospital charges, length of stay, mortality, time, day and season of injury, etc.). Logistic regression analysis was performed to identify significant predicting factors for firearm assault among this population. Most of the sample survived firearm assault injury, were ages 18-35, were not married, resided in Central Arkansas, and were admitted to a Central Arkansas hospital during night hours on weekends. The majority had a short hospital stay, and total charges exceeded $34 million during the study observation years. Most patients had no diagnosis of a mental disorder, and a little less than half had drug use disorders. Being ages 18-25, living in the Central region of Arkansas, and being married were all significant predictors of firearm assault for this population. Death was also significantly associated with firearm assault. Our findings lay the groundwork for understanding firearm assault injury among young Black men in Arkansas. Research should be expanded to examine other important data sources for firearm assault and to further explore the context of predicting factors, in order to provide a more comprehensive understanding of firearm assault and to better inform future prevention efforts.


Integrated hybrid polystyrene-polydimethylsiloxane device for monitoring cellular release with microchip electrophoresis and electrochemical detection.
In this work, a polystyrene (PS)-polydimethylsiloxane (PDMS) hybrid device was developed to enable the integration of cell culture with analysis by microchip electrophoresis and electrochemical detection. It is shown that this approach combines the fundamental advantages of PDMS devices (the ability to integrate pumps and valves) and PS devices (the ability to permanently embed fluidic tubing and electrodes). The embedded fused-silica capillary enables high temporal resolution measurements from off-chip cell culture dishes and the embedded electrodes provide close to real-time analysis of small molecule neurotransmitters. A novel surface treatment for improved (reversible) adhesion between PS and PDMS is described using a chlorotrimethylsilane stamping method. It is demonstrated that a Pd decoupler is efficient at handling the high current (and cathodic hydrogen production) resulting from use of high ionic strength buffers needed for cellular analysis; thus allowing an electrophoretic separation and in-channel detection. The separation of norepinephrine (NE) and dopamine (DA) in highly conductive biological buffers was optimized using a mixed surfactant system. This PS-PDMS hybrid device integrates multiple processes including continuous sampling from a cell culture dish, on-chip pump and valving technologies, microchip electrophoresis, and electrochemical detection to monitor neurotransmitter release from PC 12 cells.


Serratiopeptidase loaded chitosan nanoparticles by polyelectrolyte complexation: in vitro and in vivo evaluation.
The aim of the present study was to formulate serratiopeptidase (SER)-loaded chitosan (CS) nanoparticles for oral delivery. SER is a proteolytic enzyme which is very sensitive to change in temperature and pH. SER-loaded CS nanoparticles were fabricated by ionic gelation method using tripolyphosphate (TPP). Nanoparticles were characterized for its particle size, morphology, entrapment efficiency, loading efficiency, percent recovery, and in vitro dissolution study. SER-CS nanoparticles had a particle size in the range of 400-600 nm with polydispersity index below 0.5. SER association was up to 80 ± 4.2%. SER loading and CS/TPP mass ratio were the primary parameters having direct influence on SER-CS nanoparticles. SER-CS nanoparticles were freeze dried using trehalose (20%) as a cryoprotectant. In vitro dissolution showed initial burst followed by sustained release up to 24 h. In vivo anti-inflammatory activity was carried out in rat paw edema model. In vivo anti-inflammatory activity in rat paw edema showed prolonged anti-inflammatory effect up to 32 h relative to plain SER.


Influence of marker models on ankle kinematics in persons with partial foot amputation: an investigation using a mechanical model.
Previous studies have found that ankle dorsiflexion increases in persons with partial foot amputation walking shod or in "below-ankle" devices compared with walking barefoot. However, a logical biomechanical explanation for these findings has not been offered. The purpose of this project was to determine whether marker location might explain the exaggerated dorsiflexion reported in the literature and, if so, whether more accurate data could be obtained with a different marker set. An articulated mechanical model of the shank and partial foot residuum was constructed with a potentiometer located within the mechanical ankle joint. Ankle angles measured with the calibrated potentiometer were compared with those obtained with both the Helen Hayes marker set and an alternative "residual end" marker set. Results indicated that both marker sets provided accurate and comparable measures at the metatarsophalangeal and transmetatarsal levels. At the Lisfranc level, the Helen Hayes marker set overestimated the ankle angles, primarily because of deformation of the prosthetic forefoot. These results confirm that the choice of kinematic model does influence measurements of ankle motion in persons with partial foot amputation and that the residual end marker set more accurately measures ankle motion at the Lisfranc level.


A Phase 2 Randomized, Sham-Controlled Trial of Internal Carotid Artery Infusion of Autologous Bone Marrow-Derived ALD-401 Cells in Patients With Recent Stable Ischemic Stroke (RECOVER-Stroke).
Ischemic stroke has no approved treatments to enhance recovery. ALD-401 is an enriched population of aldehyde dehydrogenase-bright stem cells, capable of reducing neurological deficits in animal models. The primary objective of this trial was to determine the safety of internal carotid artery, intra-arterially delivered autologous bone marrow-derived ALD-401 in patients with disabling middle cerebral artery stroke in comparison with sham harvest with sham infusion. Secondary objectives were to determine feasibility and efficacy. This was a prospective phase 2, industry-funded, randomized, sham-controlled, parallel-group, multicenter study with blinded assessments. One hundred subjects were planned, aged 30 to 83 years, with confirmed first-time middle cerebral artery ischemic stroke with modified Rankin scale ≥3. Study patients were randomly assigned 3:2 to bone marrow harvest at 11 to 17 days after stroke followed 2 days later by intracarotid infusion of ALD-401 versus sham harvest and then sham infusion in the same timeframe. The primary study outcome was safety based on the incidence of a 4-point National Institutes of Health Stroke Scale worsening and the proportion of serious adverse events. Efficacy was based on modified Rankin scale change at 90 days. Other secondary outcomes were the proportions of patients experiencing adverse events, disability by Barthel Index, quality of life using EQ-5D, rehabilitation utilization, disability at 1 year, and MRI evidence of complications. There were no infusional or allergic reactions and no difference in treatment emergent adverse events. Four patients had small areas of asymptomatic restricted diffusion on MRI in the treatment group. There was no significant difference between the ALD-401 and placebo groups on the modified Rankin scale for the intent-to-treat population at day 90 (mean difference, 0.3; 95% CI, -0.3 to 0.8; P=0.330). There were no significant differences between the groups on any of the secondary efficacy measures. Intracarotid infusion of ALD-401 does not lead to clinical adverse events in patients with subacute ischemic stroke, although there was a higher incidence of small lesions on MRI in the treatment group. There was no difference in the primary efficacy end point between the groups. The study provides a framework for the design and conduct of future intra-arterial cell therapy trials in stroke. URL: https://www.clinicaltrials.gov . Unique identifier: NCT01273337.


Rapid diagnosis of typhoid fever by detection of Barber protein and Vi antigen of Salmonella serotype typhi.
Co-agglutination (coagg) and latex agglutination (LA) tests were used for the detection of Salmonella serotype Typhi Vi and Barber protein (BP) antigens in sera from five groups of individuals (A-E). Group A consisted of 30 blood culture-positive cases of typhoid fever and group B consisted of 30 suspected cases of typhoid fever who had sterile blood cultures but positive Widal tests. Thirty cases of pyrexia of unknown origin (PUO) were placed in group C, while group D consisted of 15 cases of septicaemia caused by organisms other than Salmonella serotype Typhi. Group E comprised 50 normal healthy individuals with no history of typhoid fever or TAB vaccination in the previous 5 years. The Vi-LA test performed best with 96.7% of group A sera and 90% of group B sera giving positive results. No false positive results and only 2.58% false negative results were obtained with this test. Considering patients with positive blood culture results or positive Widal tests as true positives, the sensitivities of the Vi-LA, BP-LA, Vi-coagg and BP-coagg tests were 93.3, 91.7, 83.3 and 86.7%, respectively. The specificities of these tests were 100, 98.5, 98.5 and 98.5%, respectively. It is suggested that the Vi-LA test can be used for the rapid and early diagnosis of typhoid fever.


[Invasive disease caused by Streptococcus pneumoniae: serotypes and antimicrobial susceptibility in a Health Care Area in Galicia].
In the Health Care Area of Santiago de Compostela, during three years (2004-2006), we studied 218 Streptococcus pneumoniae isolates from invasive disease (10 CSF, 133 blood culture, 7 pleural fluid, 9 corneal ulcer and 59 lower respiratory tract), to determine the predominant serotypes and antimicrobial susceptibility. 77.1% of the isolates were from adults and 22.9% from pediatric patients. There were 33 different serotypes, six of them occurring in more than 5% of cases, in decreasing order: 19 (16.97%), 3 (11.46%), 1 (10.55%), 14 (10.55%), 23 (6.88%) and 6 (6.88%). The predominant serogroup in CSF was 19 and in blood culture predominant serogroups were 19, 1, 14 and 3. 63.76% of the isolates were susceptible to all antibiotics tested. The most frequent resistance phenotypes were to erythromycin (24.31%), followed by penicillin (18.34%). Both phenotypes were associated with serotypes 19, 14 and 6. The resistance to levofloxacin was 0.9% and 0.5% to cefotaxime. We did not find any vancomycin resistance.


Ultrahigh Numerical Aperture Metalens at Visible Wavelengths.
Subwavelength imaging requires the use of high numerical aperture (NA) lenses together with immersion liquids in order to achieve the highest possible resolution. Following exciting recent developments in metasurfaces that have achieved efficient focusing and novel beam-shaping, the race is on to demonstrate ultrahigh-NA metalenses. The highest NA that has been demonstrated so far is NA = 1.1, achieved with a TiO2 metalens and back-immersion. Here, we introduce and demonstrate a metalens with a high NA and high transmission in the visible range, based on crystalline silicon (c-Si). The higher refractive index of silicon compared to TiO2 allows us to push the NA further. The design uses the geometric phase approach also known as the Pancharatnam-Berry (P-B) phase, and we determine the arrangement of nanobricks using a hybrid optimization algorithm (HOA). We demonstrate a metalens with NA = 0.98 in air, a bandwidth (full width at half-maximum, fwhm) of 274 nm, and a focusing efficiency of 67% at 532 nm wavelength, which is close to the transmission performance of a TiO2 metalens. Moreover, and uniquely so, our metalens can be front-immersed into immersion oil and achieve an ultrahigh NA of 1.48 experimentally and 1.73 theoretically, thereby demonstrating the highest NA of any metalens in the visible regime reported to the best of our knowledge. The fabricating process is fully compatible with microelectronic technology and therefore scalable. We envision the front-immersion design to be beneficial for achieving ultrahigh-NA metalenses as well as immersion metalens doublets, thereby pushing metasurfaces into practical applications such as high resolution, low-cost confocal microscopy and achromatic lenses.


Correlation of antimicrobial prescription rate and county income in medicare part D.
The objective of this study was to examine whether patient income has an impact on likelihood of being prescribed an antimicrobial agent at the county level. A better understanding of factors that influence antimicrobial prescription is needed to efficiently mitigate rates of antimicrobial agents prescribed.This cross-sectional study used data from two publicly available datasets. The 2015 Medicare Part D PUF data quantifies the antimicrobial prescription rate at the county level and data from US Census Bureau provides information on socioeconomic status at the county level.At the county level, we explained 48% of the variation in antimicrobial prescriptions by socioeconomic status, age, gender, and race. More specifically, socioeconomic status accounted for 26% of the variation in antimicrobial rate and as income increased, correlation with antimicrobial prescription rate trended down.We determined patient income and other sociodemographics to influence the prescription of antimicrobial agents. Interventions should consider these factors to effectively evaluate antimicrobial prescription methods. Findings from this study can help guide intervention efforts which aim to minimize the number of inappropriate antimicrobials prescribed, such as antimicrobial stewardship programs. Effective interventions have the capability of decreasing levels of inappropriate antimicrobials prescribed and prevent future cases of resistance.


Plasma leptin concentrations and esophageal hypomotility in obese patients.
Although esophageal hypomotility is prevalent in obese patients, its cause remains unknown. Leptin, a hormone derived from adipose tissue, may be involved in this phenomenon because it has been shown to decrease gastric and intestinal motility in animals. It has been hypothesized that elevated plasma leptin concentration is a risk factor for esophageal dysmotility in obese patients. To determine whether plasma leptin concentrations are higher in obese patients with esophageal hypomotility than in obese patients with a normal motility profile. Fasting plasma leptin concentration (assessed by radioimmuoassay) was measured in all patients who were included in a study protocol investigating esophageal manometry before bariatric surgery. The patients completed standardized surveys regarding epidemiological data, upper gastrointestinal symptoms, medical history and medication(s). Basal levels of leptin, as well as corrected leptin scores adjusted for sex and body mass index, were compared in patients with and without esophageal dysmotility. Nine patients without dysmotility and eight with dysmotility were included. Both groups were comparable with regard to age (42±9 versus 38±9 years), sex (78% versus 75% women) and body mass index (49±10 kg⁄m2 versus 42±7 kg⁄m2). There were no significant differences regarding medication(s) and comorbidities between the two groups. When compared with normal predicted values, the corrected leptin scores were 30% higher in patients with dysmotility than in the control group with normal motility (P≤0.05). Obese patients with esophageal dysmotility exhibited elevated plasma leptin concentrations, suggesting a role for leptin in promoting esophageal hypomotility.


Influence of the dopamine antagonist domperidone on the vernal transition in seasonally anoestrous mares.
The aim of the present study was to determine the effect of prolonged administration of the dopamine antagonist domperidone on follicular development, ovulation and endocrine profiles in anoestrous mares. Anoestrous mares (n=16) were maintained under natural photoperiod and ambient temperature. Eight of the mares were treated with domperidone each day from 15 January until the first ovulation of the year. The mean number and size of follicles > or =20 mm in diameter were significantly greater in domperidone-treated mares than in control mares by day 14 of treatment. The day of first ovulation was significantly earlier in domperidone-treated mares than in control mares (mean +/- SEM: 51 +/- 8.2 and 129 +/- 13.6 days, respectively; P < 0.01). The eight domperidone-treated mares all ovulated during treatment and the mean interval from the start of treatment to the day of first ovulation was 27 days (range 15-55 days). Six of the eight domperidone-treated mares underwent normal cycles after the first ovulation, whereas there was a prolonged interval (mean = 67 days) before the second ovulation in the other two mares. Domperidone administration resulted in significantly higher plasma prolactin concentrations measured at 0, 4, 8, 12 and 24 h on day 7 of treatment compared with untreated controls (25.5 +/- 15.8 versus 2.5 +/- 3.0 ng ml(-1)). The concentrations of LH and oestrogen conjugates were significantly higher in domperidone-treated mares compared with control mares by day 28 of treatment. There were no differences in FSH concentrations in domperidone-treated and control mares. The significant increases in follicular development and concentrations of oestrogen conjugates that were observed to occur without concurrent increases in FSH concentration indicate that either domperidone or prolactin may have a direct effect on the ovary.


Correction to Nguyen et al. (2020).
Reports an error in "When poor communication does and does not matter: The moderating role of stress" by Teresa P. Nguyen, Benjamin R. Karney and Thomas N. Bradbury (Journal of Family Psychology, Advanced Online Publication, Feb 20, 2020, np). There are two errors in the last sentence of the fifth paragraph (Model 4: Fluctuations in Cumulative Stress X Fluctuations in Behavior) of the Results section whereby the text "less cumulative stress" and "less stress" should have read "more cumulative stress" and "more stress," respectively. Thus, the correct sentence is as follows: "Specifically, relative increases in observed dyadic negativity were associated with decreases in husbands' relationship satisfaction when husbands also experienced more cumulative stress, whereas decreases in observed negativity in the presence of more stress were associated with increases in husbands' satisfaction (t = -2.00, p = .045, see Figure 1 and Table 2, Model 4)." Note that the findings are correctly stated elsewhere in the article. (The following abstract of the original article appeared in record 2020-11898-001.) Although a number of theoretical perspectives in relationship science argue that variability in couples' relationship satisfaction over time is driven by changes in their communication, tests of this hypothesis have been limited to single assessments of behavior. To address this gap, we examine within-couple, across-time changes in communication, and we argue further that couples' external circumstances might combine with these behavioral changes to generate changes in relationship satisfaction. Using self-reports of satisfaction and in-home observational data collected 4 times at 9-month intervals from 414 newlywed couples, we show that fluctuations in dyadic behavior and spousal stress covary with fluctuations in spousal satisfaction. Tests of the interaction between fluctuations in stress and behavior reveal that husbands who experience upward fluctuations in negativity also experience decreases in relationship satisfaction at the same wave but only if they are concurrently experiencing greater stress than usual. Downward fluctuations in problem-solving effectiveness are associated with lower relationship satisfaction but only among spouses who had chronically high levels of cumulative stress; when chronic stress is low, reduced problem-solving effectiveness is unrelated to satisfaction. Exclusive focus on between-couple variability in couple communication, without regard for the stressors that couples face, will likely restrict the understanding and prevention of relationship distress. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Simulating sulfadimidine transport in surface runoff and soil at the microplot and field scale.
To prevent residues of veterinary medicinal products (VMPs) from contaminating surface waters and ground water, an environmental impact assessment is required before a new product is allowed on the market. Physically based simulation models are advocated for the calculation of predicted environmental concentrations at higher tiers of the assessment process. However, the validation status of potentially useful models is poor for VMP transport. The objective of this study was to evaluate the dual-permeability model MACRO for simulation of transport of sulfonamide antibiotics in surface runoff and soil. Special focus was on effects of solute application in liquid manure, which may alter the hydraulic properties at the soil surface. To this end we used data from a microplot runoff experiment and a field experiment, both conducted on the same clay loam soil prone to preferential flow. Results showed that the model could accurately simulate concentrations of sulfadimidine and the nonreactive tracer bromide in runoff and in soil from the microplot experiments. The use of posterior parameter distributions from calibrations using the microplot data resulted in poor simulations for the field data of total sulfadimidine losses. The poor results may be due to surface runoff being instantly transferred off the field in the model, whereas in reality re-infiltration may occur. The effects of the manure application were reflected in smaller total and micropore hydraulic conductivities compared with the application in aqueous solution. These effects could easily be accounted for in regulatory modeling.


Biodegradable Eri silk nanoparticles as a delivery vehicle for bovine lactoferrin against MDA-MB-231 and MCF-7 breast cancer cells.
This study used the Eri silk nanoparticles (NPs) for delivering apo-bovine lactoferrin (Apo-bLf) (~2% iron saturated) and Fe-bLf (100% iron saturated) in MDA-MB-231 and MCF-7 breast cancer cell lines. Apo-bLf and Fe-bLf-loaded Eri silk NPs with sizes between 200 and 300 nm (±10 nm) showed a significant internalization within 4 hours in MDA-MB-231 cells when compared to MCF-7 cells. The ex vivo loop assay with chitosan-coated Fe-bLf-loaded silk NPs was able to substantiate its future use in oral administration and showed the maximum absorption within 24 hours by ileum. Both Apo-bLf and Fe-bLf induced increase in expression of low-density lipoprotein receptor-related protein 1 and lactoferrin receptor in epidermal growth factor (EGFR)-positive MDA-MB-231 cells, while transferrin receptor (TfR) and TfR2 in MCF-7 cells facilitated the receptor-mediated endocytosis of NPs. Controlled and sustained release of both bLf from silk NPs was shown to induce more cancer-specific cytotoxicity in MDA-MB-231 and MCF-7 cells compared to normal MCF-10A cells. Due to higher degree of internalization, the extent of cytotoxicity and apoptosis was significantly higher in MDA-MB-231 (EGFR+) cells when compared to MCF-7 (EGFR-) cells. The expression of a prominent anticancer target, survivin, was found to be downregulated at both gene and protein levels. Taken together, all the observations suggest the potential use of Eri silk NPs as a delivery vehicle for an anti-cancer milk protein, and indicate bLf for the treatment of breast cancer.


Long-term conservative treatment outcomes for midshaft clavicle fractures: a 10-to-30-year follow-up.
Few reports exist on the long-term outcomes of midshaft clavicle fracture conservative treatments. Therefore, this study investigated the long-term outcome of this treatment in patients with midshaft clavicle fractures. Patients were treated conservatively for midshaft clavicle fractures with a figure-of-eight bandage between 10 and 30 years ago. Subsequently, a telephone survey was used to follow-up these patients, and 38 were successfully evaluated. The mean term after trauma was 17.0 years. Afterward, the American Shoulder and Elbow Surgeons Shoulder (ASES) score and Shoulder pain and disability index (SPADI) on the affected and unaffected sides were calculated based on the filled questionnaires. We defined patients whose ASES and SPADI on the affected side were worse than the unaffected side as the symptomatic group. Furthermore, plain radiographs measured proportional changes in clavicular length and displacement. The ASES scores of the affected side were significantly lower than those of the unaffected side, and the SPADI of the affected side was significantly higher than that of the unaffected side. Furthermore, the symptomatic group's proportional changes in clavicular length and displacement were significantly larger than the asymptomatic group. The affected shoulder side was more symptomatic than the unaffected side 10 to 30 years after the trauma when midshaft clavicle fractures were treated conservatively. Moreover, several patients became symptomatic for fractures with a larger proportional change in clavicular length or displacement.


[Cardiorespiratory synchronism: revealing in human, dependence on properties of nervous system and functional states of an organism].
Cardiorespiratory synchronism (CRS) shows that at the breathing frequency, which as usual exceeds the baseline heart rhythm, the heart makes one contraction per each breathing. It is shown that CRS arises as a result of reproduction by the heart the rhythm of signals, coming to the heart via vagus nerves. CRS characterized by the synchronization range, duration of its development after the beginning of the rapid respiration, difference between the baseline heartbeat frequency and lower limit of synchronization range. The CRS parameters were determined in humans at the age of 5-65. The CRS parameters depends on nervous system type, vegetative tonus of the nervous system and functional states of an organism.


[Bypass surgery or angioplasty: which treatment for which patient?].
In patients with symptoms of ischaemic heart disease, despite optimal medical therapy, a PCI or CABG may be indicated if the coronary arteries are narrowed. Decisions regarding PCI or CABG need to be taken by the local heart team, consisting of a cardiothoracic surgeon and an interventional cardiologist. After a complete diagnostic work-up, the referring cardiologist presents the patient with accompanying written information supporting revascularisation. The decision of the heart team takes the characteristics of each individual patient into account and, most importantly, the coronary angiogram. Despite improvements in medical and interventional treatments, mortality and morbidity remain high among patients with NSTEMI. Early risk stratification is essential to determine those patients who can be treated safely with medical therapy and those who require interventional treatment. Ad hoc PCI is indicated in patients with STEMI or haemodynamic instability.


Pharmacogenetic variation in Neanderthals and Denisovans and implications for human health and response to medications.
Modern humans carry both Neanderthal and Denisovan (archaic) genome elements that are part of the human gene pool and affect the life and health of living individuals. The impact of archaic DNA may be particularly evident in pharmacogenes - genes responsible for the processing of exogenous substances such as food, pollutants, and medications - as these can relate to changing environmental effects, and beneficial variants may have been retained as modern humans encountered new environments. However, the health implications and contribution of archaic ancestry in pharmacogenes of modern humans remain understudied. Here, we explore eleven key cytochrome P450 genes (CYP450) involved in 75% of all drug metabolizing reactions in three Neanderthal and one Denisovan individuals and examine archaic introgression in modern human populations. We infer the metabolizing efficiency of these eleven CYP450 genes in archaic individuals and find important predicted phenotypic differences relative to modern human variants. We identify several single nucleotide variants shared between archaic and modern humans in each gene, including some potentially function-altering mutations in archaic CYP450 genes, which may result in altered metabolism in living people carrying these variants. We also identified several variants in the archaic CYP450 genes that are novel and unique to archaic humans as well as one gene, CYP2B6, that shows evidence for a gene duplication found only in Neanderthals and modern Africans. Finally, we highlight CYP2A6, CYP2C9, and CYP2J2, genes which show evidence for archaic introgression into modern humans and posit evolutionary hypotheses that explain their allele frequencies in modern populations.


Symptomatic hemangiomas and venous malformations in infants, children, and young adults: treatment with percutaneous injection of sodium tetradecyl sulfate.
The purpose of this study was to evaluate the efficacy and safety of percutaneous sclerosis therapy using sodium tetradecyl sulfate for treatment of symptomatic hemangiomas and venous malformations in infants, children, and young adults. Fifty-two sclerosis procedures were performed in 21 patients who were 13 months to 24 years old. Six of these patients had hemangiomas, and the remaining 15 patients had venous malformations. Sodium tetradecyl sulfate was injected solely percutaneously in 49 procedures, by both percutaneous and arterial routes in two procedures, and intraarterially only in one procedure. Thirteen patients had sclerosis therapy alone, and eight patients had sclerosis therapy followed by surgery within 48 hr. Sclerosis therapy alone or sclerosis therapy followed by surgery was judged beneficial in 18 (86%) of 21 patients, including five of the six patients who had hemangiomas and 13 of the 15 patients who had venous malformations. Two patients had an equivocal response to the therapy, and one patient had no apparent benefit. Three of the 21 patients had minor complications (skin ulcers) but no long-term sequelae. Percutaneous injection of sodium tetradecyl sulfate, either alone or before surgery, is a safe and effective method of managing symptomatic hemangiomas and venous malformations.


Predictable alteration of sequence recognition by RNA editing factors from Arabidopsis.
RNA editing factors of the pentatricopeptide repeat (PPR) family show a very high degree of sequence specificity in the recognition of their target sites. A molecular basis for target recognition by editing factors has been proposed based on statistical correlations but has not been tested experimentally. To achieve this, we systematically mutated the pentatricopeptide motifs in the Arabidopsis thaliana RNA editing factor CLB19 to investigate their individual contribution to RNA recognition. We find that the motifs contributing significantly to the specificity of binding follow the previously proposed recognition rules, distinguishing primarily between purines and pyrimidines. Our results are consistent with proposals that each motif recognizes one nucleotide in the RNA target with the protein aligned parallel to the RNA and contiguous motifs aligned with contiguous nucleotides such that the final PPR motif aligns four nucleotides upstream of the edited cytidine. By altering S motifs in CLB19 and another editing factor, OTP82, and using the modified proteins to attempt to complement the respective mutants, we demonstrate that we can predictably alter the specificity of these factors in vivo.


Combinatorial regulation of lipoprotein lipase by microRNAs during mouse adipogenesis.
MicroRNAs (miRNAs) regulate gene expression directly through base pairing to their targets or indirectly through participating in multi-scale regulatory networks. Often miRNAs take part in feed-forward motifs where a miRNA and a transcription factor act on shared targets to achieve accurate regulation of processes such as cell differentiation. Here we show that the expression levels of miR-27a and miR-29a inversely correlate with the mRNA levels of lipoprotein lipase (Lpl), their predicted combinatorial target, and its key transcriptional regulator peroxisome proliferator-activated receptor gamma (Pparg) during 3T3-L1 adipocyte differentiation. More importantly, we show that Lpl, a key lipogenic enzyme, can be negatively regulated by the two miRNA families in a combinatorial fashion on the mRNA and functional level in maturing adipocytes. This regulation is mediated through the Lpl 3'UTR as confirmed by reporter gene assays. In addition, a small mathematical model captures the dynamics of this feed-forward motif and predicts the changes in Lpl mRNA levels upon network perturbations. The obtained results might offer an explanation to the dysregulation of LPL in diabetic conditions and could be extended to quantitative modeling of regulation of other metabolic genes under similar regulatory network motifs.


Induction of apoptosis in human keratinocytes containing mutated p53 alleles and its inhibition by both the E6 and E7 oncoproteins.
Induction of apoptosis is a function of external stimuli and cellular gene expression. Many cells respond to DNA damage by the induction of apoptosis, which depends on a functional p53 protein and is signaled by elevation of p53 levels. We have investigated the response of immortalized human keratinocytes (HaCaT) bearing mutated alleles of p53 to genotoxic stress and the effect of human papillomavirus (HPV) 16 E6 and E7 on this response. UVC irradiation triggered HaCaT's cell death with several characteristics of apoptosis, including DNA laddering, chromatin condensation and fragmentation, and the appearance of cells with a low content of DNA (categorized as sub-G1 by cell sorter analysis). This response was accompanied by accumulation of cells in S phase of the cell cycle. HaCaT cells infected with retroviruses carrying HPV16 E6 or E7 showed a significant reduction in their apoptotic response, which was not observed in cells infected with the LXSN vector DNA-carrying virus. Reduced apoptosis in HaCaT cells expressing E6 or E7 also was observed after treatment with the alkylating agent mitomycin C. Western blot analysis of p53 and p21/WAF-1/CIP-1, a downstream effector of p53, did not reveal any changes in the levels of these proteins after UVC irradiation in either HaCaT cells or HaCaT cells expressing HPV16 E6 or E7.


Pheochromocytoma, "the Great Masquerader," Presenting as Severe Acute Decompensated Heart Failure in a Young Patient.
A 22-year-old man presented to the hospital with progressive shortness of breath, chest discomfort, sinus tachycardia, and emesis. The echocardiogram demonstrated global hypokinesis with a left ventricle ejection fraction of 15-20%. The patient was treated for acute systolic heart failure decompensation with diuresis and afterload reduction. Unexpectedly, an abdominal computed tomography showed a left adrenal mass and subsequent serum/urine metanephrine tests suggested pheochromocytoma. Once the patient had stabilized, he underwent an uneventful adrenalectomy with histology results confirming the diagnosis of pheochromocytoma. After six months follow-up, he is currently doing well with close outpatient follow-up by cardiology.


[Renovascular hypertension. Radionuclide renography for detection and prediction of clinical response to revascularization].
The most frequently used non invasive tests in the diagnosis of renovascular hypertension are the measurement of peripheral blood renin before and after captopril administration, intravenous pyelogram, renal Doppler examination and radionuclide renography without and with angiotensin converting enzyme inhibitor administration. Measurement of renal vein renin levels and renal angiography are invasive tests commonly used. The latter allows an anatomical diagnosis of renal vein stenosis but does not give information about the functional consequences of such lesion and thus, does not predict the response of blood pressure to revascularization. Radionuclide renography has become the most useful non invasive diagnostic test, with a sensitivity and specificity of 83-94 and 85-97% respectively. It also predicts clinical response to revascularization and is useful for follow up after surgery or angioplasty. It also has good results in patients with renal failure, bilateral stenosis or stenosis in a solitary kidney and in transplanted patients.


Predicting impact of Deep Brain Stimulation on Non-motor symptoms of Parkinson's disease.
This is the largest study on Radiomics analysis looking into the impact of Deep Brain Stimulation on Non-Motor Symptoms (NMS) of Parkinson's disease. Preoperative brain white matter radiomics of 120 patients integrated with clinical variables were used to predict the DBS effect on NMS after 1 year from the surgery. Patients were classified "suboptimal" vs "good" based on a 10% or more improvement in NMS score. The combined Radiomics-Clinical Random Forrest (RF) model achieved an AUC of 0.96, Accuracy of 0.91, Sensitivity of 0.94 and Specificity of 0.88. The Youden's index showed optimal threshold for the RF of 0.535. The confusion matrix of the RF classifier gave a TPR of 0.92 and a FPR of 0.03. This corresponds to a PPV of 0.93 and a NPV of 0.93. The predictive models can be easily interpreted and after careful large-scale validation be integrated in assisting clinicians and patients to make informed decisions.Clinical Relevance- This paper shows the lesser studied positive impact of Deep Brain Stimulation on Non motor symptoms of Parkinson's disease while allows clinicians to predict non responders to the therapy.


Long noncoding RNA-mediated epigenetic regulation of auxin-related genes controls shade avoidance syndrome in Arabidopsis.
The long noncoding RNA (lncRNA) AUXIN-REGULATED PROMOTER LOOP (APOLO) recognizes a subset of target loci across the Arabidopsis thaliana genome by forming RNA-DNA hybrids (R-loops) and modulating local three-dimensional chromatin conformation. Here, we show that APOLO regulates shade avoidance syndrome by dynamically modulating expression of key factors. In response to far-red (FR) light, expression of APOLO anti-correlates with that of its target BRANCHED1 (BRC1), a master regulator of shoot branching in Arabidopsis thaliana. APOLO deregulation results in BRC1 transcriptional repression and an increase in the number of branches. Accumulation of APOLO transcription fine-tunes the formation of a repressive chromatin loop encompassing the BRC1 promoter, which normally occurs only in leaves and in a late response to far-red light treatment in axillary buds. In addition, our data reveal that APOLO participates in leaf hyponasty, in agreement with its previously reported role in the control of auxin homeostasis through direct modulation of auxin synthesis gene YUCCA2, and auxin efflux genes PID and WAG2. We show that direct application of APOLO RNA to leaves results in a rapid increase in auxin signaling that is associated with changes in the plant response to far-red light. Collectively, our data support the view that lncRNAs coordinate shade avoidance syndrome in A. thaliana, and reveal their potential as exogenous bioactive molecules. Deploying exogenous RNAs that modulate plant-environment interactions may therefore become a new tool for sustainable agriculture.


[Vacuum-therapy in treatment of festering wounds].
Treatment experience in 112 patients with festering wounds confirms, that vacuum-therapy has marked clinical efficacy at medical process organization on account of trophic ulcers and protractedly nonhealing soft tissue defects. In view of festing wound pathogenesis, vacuum therapy allows to change the course of traumatic process in biologically favorable direction. Influence of low-dosed negative pressure on wound surface allows to clear the wound rapidly and to prepare it for autotransplantation. After skin transplantation use of another type of vacuum-therapy (vacuum bandage) is appropriate. It helps to hold the skin graft safely in recipient until "natural" fixation process occurs, to change blood microcirculation in wound tissues and possess detoxication effect. Thus vacuum therapy allows to get clinically notable effect in the form of complete wound repair in 85.4% of patients with festering wounds.


Non-fatal healed transmural myocardial infarction and fatal non-cardiac disease. Qualification and quantification of coronary arterial narrowing and of left ventricular scarring in 18 necropsy patients.
A qualitative and quantitative analysis of the amount of myocardial scarring and the degree and extent of coronary arterial narrowing by atherosclerotic plaque in the entire lengths of each of the four major epicardial coronary arteries is described in 18 necropsy patients with healed transmural myocardial infarcts and death from a non-cardiac condition. An average of 30 per cent of the basal half and 38 per cent of the apical half of the left ventricular wall was scarred. The nine patients with clinical evidence of previous acute myocardial infarction tended to have larger left ventricular scars than the nine patients without such evidence but the difference was not significant. An average of 26 cm (51 5 mm segments) of coronary artery were examined from each patient ad 25 cm (49 5 mm segments) from each of 19 control subjects. Of 924 segments examined in the 18 patients, 292 (32%) were 76 to 100 per cent narrowed in cross-sectional area (controls = 5); 321 (35%) were 51 to 75 per cent narrowed (controls = 34%); 210 (23%) were 26 to 50 per cent narrowed (controls = 44%), and 101 (11%) were 0 to 25 per cent narrowed (controls = 17%). The extent of severe narrowing of 75 per cent or more was similar (25%) in the left anterior descending and left circumflex coronary arteries; the right was the most severely narrowed artery and the left main was not severely narrowed in any patient. Excluding, then, the left main artery, the amount of severe narrowing in the proximal and distal halves of the other three vessels was similar. The amount of severe narrowing was not related to the age at death or to heart weight, but was greater in patients with hypertension or with a history of acute myocardial infarction.


Patient characteristics of the Accident and Emergency Department of Kenyatta National Hospital, Nairobi, Kenya: a cross-sectional, prospective analysis.
Resource-limited settings are increasingly experiencing a 'triple burden' of disease, composed of trauma, non-communicable diseases (NCDs) and known communicable disease patterns. However, the epidemiology of acute and emergency care is not well characterised and this limits efforts to further develop emergency care capacity. To define the burden of disease by describing the patient population presenting to the Accident and Emergency Department (A&E) at Kenyatta National Hospital (KNH) in Kenya. We completed a prospective descriptive assessment of patients in KNH's A&E obtained via systematic sampling over 3 months. Research assistants collected data directly from patients and their charts. Chief complaint and diagnosis codes were grouped for analysis. Patient demographic characteristics were described using the mean and SD for age and n and percentages for categorical variables. International Classification of Disease 10 codes were categorised by 2013 Global Burden of Disease Study methods. Data were collected prospectively on 402 patients with an average age of 36 years (SD 19), and of whom, 50% were female. Patients were most likely to arrive by taxi or bus (39%), walking (28%) or ambulance (17%). Thirty-five per cent of patients were diagnosed with NCDs, 24% with injuries and 16% with communicable diseases, maternal and neonatal conditions. Overall, head injury was the single most common final diagnosis and occurred in 32 (8%) patients. The most common patient-reported mechanism for head injury was road traffic accident (39%). This study estimates the characteristics of the A&E population at a tertiary centre in Kenya and highlights the triple burden of disease. Our findings emphasise the need for further development of emergency care resources and training to better address patient needs in resource-limited settings, such as KNH.


The expression of LMO2 protein in acute B-cell and myeloid leukemia.
LIM domain only-2 (LMO2) is an important regulator of hematopoietic stem cell development. LMO2 is also expressed in blast cells of different types of acute leukemia. Here, we analyzed the LMO2 protein expression in acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL) and examined whether the LMO2 protein expression can predict outcomes of patients with acute leukemia. Patients with acute B-ALL (22 cases) and AML (57 cases) were examined using immunohistochemistry for LMO2 on paraffin-embedded bone marrow biopsies. We report that LMO2 protein is expressed in a significant proportion of B-ALL and AML and the staining of LMO2 protein does not predict survival in acute leukemia.


Testing the independence of self-reported interoceptive accuracy and attention.
It has recently been proposed that measures of the perception of the state of one's own body ("interoception") can be categorised as one of several types depending on both how an assessment is obtained (objective measurement vs. self-report) and what is assessed (degree of interoceptive attention vs. accuracy of interoceptive perception). Under this model, a distinction is made between beliefs regarding the degree to which interoceptive signals are the object of attention and beliefs regarding one's ability to perceive accurately interoceptive signals. This distinction is difficult to test, however, because of the paucity of measures designed to assess self-reported perception of one's own interoceptive accuracy. This article therefore reports on the development of such a measure, the Interoceptive Accuracy Scale (IAS). Use of this measure enables assessment of the proposed distinction between beliefs regarding attention to, and accuracy in perceiving, interoceptive signals. Across six studies, we report on the development of the IAS and, importantly, its relationship with measures of trait self-reported interoceptive attention, objective interoceptive accuracy, confidence in the accuracy of specific interoceptive percepts, and metacognition with respect to interoceptive accuracy. Results support the distinction between individual differences in perceived attention towards interoceptive information and the accuracy of interoceptive perception.


Low-renin hypertension. Occurrence in vascular complications.
Two hundred one patients with essential hypertension, who had studies of their renin-aldosterone system performed between April 1967 and December 1972, were surveyed for myocardial infraction or cerebrovascular accident. Of the patients, 42% had low plasma renin activity. Myocardial infractions or cerebrovascular accidents were documented in 15% of those with low plasms renin activity and in 5% of those with normal plasma renin activity. When adjustments were made for differences in afe and blood pressure , a protective effect in low-renin hypertension was evident. When black patients were considered separately,there was no difference in diastolic blood pressure; however, vascular complications were not less frequent in low-renin hypertensives. The results suggest that low plasma renin activity does not protect against the development of vascular complications in essential hypertension.


A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment.
The locus coeruleus is the initial site of Alzheimer's disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. Locus coeruleus dysfunction contributes to Alzheimer's pathobiology in experimental models, which can be rescued by increasing norepinephrine transmission. To test norepinephrine augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved norepinephrine transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer's disease. The design was a single-centre, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment and biomarker evidence of Alzheimer's disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of norepinephrine and metabolites. Prespecified primary outcomes were CSF levels of IL1α and TECK. Secondary/exploratory outcomes included clinical measures, CSF analyses of amyloid-β42, Tau, and pTau181, mass spectrometry proteomics and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and fluorodeoxyglucose-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF norepinephrine levels. IL-1α and TECK were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in amyloid-β42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK and osteoprotegerin proteins. Treatment was also associated with significantly increased brain-derived neurotrophic factor and reduced triglycerides in plasma. Resting state functional MRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. Fluorodeoxyglucose-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus and fusiform gyrus, with carry-over effects 6 months after treatment. In summary, atomoxetine treatment was safe, well tolerated and achieved target engagement in prodromal Alzheimer's disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer's disease progression.


The protective effect of boric acid on cholestatic rat liver ischemia reperfusion injury.
To evaluate the potential protective effects of boric acid (BA) in experimental cholestatic liver ischemia reperfusion (IR) injury model. The study included 24 female rats which were divided into 3 groups each containing 8 rats. The control group (Group 1) only received laparotomy. In the IR group (Group 2) biliary tract ligation was applied and 1 week later 45 min ischemia and 1 h reperfusion with relaparotomy without any treatment was implemented. In the treatment BA+IR group (Group 3). 1 week after the biliary ligation intraperitoneal administration of 200 mg/kg BA was given 10 min before the ischemia for 45 min and reperfusion for 1 h with relaparotomy. Liver tissue and blood samples were taken for histopathological and biochemical examination. Ischemia modified albumin (IMA), SCUBE1, total antioxidant status (TAS), and total oxidant status (TOS) levels were also examined. Compared to control, groups IR and BA+IR had higher serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total, and direct bilirubin levels. Albumin value was high in the control group and low in the other groups. In terms of IMA levels there was no significant difference between groups (p > 0.05). When SCUBE-1 levels were examined groups IR and BA+IR were significantly higher than the group 1. TAS was highest in the group BA+IR whereas TOS was highest in the group IR and lower in the group BA+IR. In histopathological analysis, loss of intercellular border loss in hepatocytes, diffuse nuclear pycnosis and mild to moderate neutrophilic cell infiltration were observed in the IR group. Statistically significant dissociation, hemorrhage and severe neutrophilic cell infiltration were seen in hepatocytes of rats with IR (p < 0.05). BA has promising results in the treatment of experimental IR injury of the cholestatic liver because of its antioxidant effects. It may be used in clinical practice after more extensive studies about the effects of BA on IR injury of the cholestatic liver.


Large subcutaneous liposarcoma arising from the chest wall.
Liposarcoma usually occurs in the deep soft tissue of the extremities and the retroperitoneum. It rarely occurs in the cutaneous or subcutaneous tissues. We describe the case of a subcutaneous liposarcoma in a 63-year-old man, which arose from the chest wall. Magnetic resonance imaging showed a large subcutaneous tumor. Incisional biopsy revealed mature adipose cells with a slight variation in size and shape; no lipoblasts were observed. Therefore, at this stage we made the diagnosis of lipoma. However, the histological study of the tumor specimen subsequently obtained by surgery, showed mature adipose cells, atypical cells with bizarre nuclei, and lipoblasts with scalloped-shaped nuclei. We eventually diagnosed the tumor as a well-differentiated liposarcoma, adipocytic type (lipoma-like type). Patients with cutaneous and subcutaneous liposarcoma have a good prognosis, but there are reports of local recurrence after a long period, as well as high-grade change and dedifferentiation. Careful follow-up is required.


Survivin inhibition via EZN-3042 in canine lymphoma and osteosarcoma.
Canine lymphoma (LSA) and osteosarcoma (OS) have high mortality rates and remain in need of more effective therapeutic approaches. Survivin, an inhibitor of apoptosis (IAP) family member protein that inhibits apoptosis and drives cell proliferation, is commonly elevated in human and canine cancer. Survivin expression is a negative prognostic factor in dogs with LSA and OS, and canine LSA and OS cell lines express high levels of survivin. In this study, we demonstrate that survivin downregulation in canine LSA and OS cells using a clinically applicable locked nucleic acid antisense oligonucleotide (EZN-3042, Enzon Pharmaceuticals, Piscataway Township, NJ, USA) inhibits growth, induces apoptosis and enhances chemosensitivity in vitro, and inhibits survivin transcription and protein production in orthotopic canine OS xenografts. Our findings strongly suggest that survivin-directed therapies might be effective in treatment of canine LSA and OS and support evaluation of EZN-3042 in dogs with cancer.


Reduction-sensitive amphiphilic triblock copolymers self-assemble into stimuli-responsive micelles for drug delivery.
Polymeric nanostructures obtained through self-assembly of reduction-sensitive amphiphilic triblock copolymers were investigated as potential drug delivery systems. The characteristic feature of these polymers is their cleavable disulfide bond in the center of the hydrophobic block. Therefore, the triblock copolymers can be cleaved into amphiphilic diblock copolymers. A poly(2-hydroxyethyl methacrylate)-b-poly(butyl methacrylate)-S-S-poly(butyl methacrylate)-b-poly(2-hydroxyethyl methacrylate) (PHEMA-b-(PBMA-S-S-PBMA)-b-PHEMA) triblock copolymer was synthesized. It self-assembled into micelles which were used to encapsulate hydrophobic dye molecules (Nile Red, BodiPy 630/650) as model payloads. The self-assembled nanostructures disintegrated upon reduction of the disulfide bond, releasing their cargo and yielding larger particles that formed aggregates in solution after 24 h. A burst release of payload was shown within the first 15 min, followed by a constant release over several hours. As concentration gradients of reducing agents are commonly found in biological systems, the micelles could be used as redox-sensitive nanocarriers for the intracellular delivery of drugs.


A Narrative Review on Strategies for the Reversion of Prediabetes to Normoglycemia: Food Pyramid, Physical Activity, and Self-Monitoring Innovative Glucose Devices.
In 2019, "Nutrition Therapy for Adults with Diabetes or Prediabetes: A Consensus Report" was published. This consensus report, however, did not provide an easy way to illustrate to subjects with prediabetes (SwPs) how to follow a correct dietary approach. The purpose of this review is to evaluate current evidence on optimum dietary treatment of SwPs and to provide a food pyramid for this population. The pyramid built shows that everyday consumption should consist of: whole-grain bread or potatoes eaten with their skins (for fiber and magnesium) and low glycemic index carbohydrates (GI < 55%) (three portions); fruit and vegetables (5 portions), in particular, green leafy vegetables (for fiber, magnesium, and polyphenols); EVO oil (almost 8 g); nuts (30 g, in particular, pistachios and almonds); three portions of dairy products (milk/yogurt: 300-400 g/day); mineral water (almost 1, 5 L/day for calcium intake); one glass of wine (125 mL); and three cups of coffee. Weekly portions should include fish (four portions), white meat (two portions), protein plant-based food (four portions), eggs (egg portions), and red/processed meats (once/week). At the top of the pyramid, there are two pennants: a green one means that SwPs need some personalized supplementation (if daily requirements cannot be satisfied through diet, vitamin D, omega-3, and vitamin B supplements), and a red one means there are some foods and factors that are banned (simple sugar, refined carbohydrates, and a sedentary lifestyle). Three to four times a week of aerobic and resistance exercises must be performed for 30-40 min. Finally, self-monitoring innovative salivary glucose devices could contribute to the reversion of prediabetes to normoglycemia.


Haussknechtia elymatica: a plant with immunomodulatory effects.
Plant extracts have been widely investigated for possible immunomodulatory properties. To study the immunomodulatory functions of the methanol extract of Haussknechtia elymatica (Apioideae), an herb native to south-western Iran. Delayed type hypersensitivity (DTH) skin test and measurement of antibody titer after immunization with Sheep-RBC was performed. [3H]-thymidine incorporation assay on the human lymphocytes stimulated with PHA and determination of IL-2 production using ELISA method was carried out. Treatment of mice with increasing concentrations of the extract decreased the footpad thickness indicating a dose-related inhibitory effect of H. elymatica on delayed hypersensitivity. The mean antibody titers for all concentrations of the extract at primary and secondary responses were significantly less than the control. Addition of the extract to the culture of human peripheral blood lymphocytes in the presence of mitogen decreased cell proliferation dose-dependently. A dose related decrease in production of IL-2 in extract-treated cells was also observed. The decline of antibody titer and DTH response indicates that H. elymatica, by acting on the lymphocyte proliferation and IL-2 secretion, inhibits both humoral and cell-mediated immune responses.


Chromoendoscopy versus narrow band imaging for colonic surveillance in inflammatory bowel disease.
Mucosal dye spraying (chromoendoscopy [CE]) has been shown in controlled studies to enhance lesion detection in colitis surveillance. Narrow band imaging (NBI) potentially offers a more convenient mode of highlighting mucosal lesions. The primary objectives of this study were to compare CE and NBI in colitis surveillance with respect to lesion detection. A secondary objective was to assess the accuracy of the mucosal pit pattern (Kudo classification) with NBI in predicting mucosal histology. Patients with colitis of 8 years or greater disease duration underwent screening colonoscopy with NBI, followed immediately by CE by 2 endoscopists blinded to each other's results. All lesions were biopsied to confirm histology. Diagnostic yield of each modality for dysplastic lesions. Accuracy of Kudo classification by NBI for neoplasia. Forty-four participants were enrolled. One hundred forty-four colonic lesions were identified in total. Overall, CE identified more lesions than NBI (131 versus 102, P < 0.001); however, most were nondysplastic. CE detected 23 neoplastic (dysplastic or indefinite for dysplasia) lesions in 11 patients and NBI 20 lesions in 10 patients, P = 0.180. Kudo assessment by NBI had low sensitivity for dysplasia (42%) and modest accuracy (74%) for dysplasia. NBI detected fewer lesions than CE in chronic colitis; however, most were not dysplastic. There was a nonsignificant trend in favor of CE for detection of dysplasia. At present, NBI cannot be recommended as an alternative to CE for dysplasia surveillance in colitis.


Empirical determinants of measles metapopulation dynamics in England and Wales.
A key issue in metapopulation dynamics is the relative impact of internal patch dynamics and coupling between patches. This problem can be addressed by analysing large spatiotemporal data sets, recording the local and global dynamics of metapopulations. In this paper, we analyse the dynamics of measles meta-populations in a large spatiotemporal case notification data set, collected during the pre-vaccination era in England and Wales. Specifically, we use generalized linear statistical models to quantify the relative importance of local influences (birth rate and population size) and regional coupling on local epidemic dynamics. Apart from the proportional effect of local population size on case totals, the models indicate patterns of local and regional dynamic influences which depend on the current state of epidemics. Birth rate and geographic coupling are not associated with the size of major epidemics. By contrast, minor epidemics--and especially the incidence of local extinction of infection--are influenced both by birth rate and geographical coupling. Birth rate at a lag of four years provides the best fit, reflecting the delayed recruitment of susceptibles to school cohorts. A hierarchical index of spatial coupling to large centres provides the best spatial model. The model also indicates that minor epidemics and extinction patterns are more strongly influenced by this regional effect than the local impact of birth rate.


[Use of the antiandrogen niftolide for studying reserves of the hypothalamo-hypophyseal system in patients with male hypogonadism].
A study was made of a possibility to use a test with the administration of the nonsteroid antiandrogen flutamide to male patients with testicular hypogonadism to evaluate the gonadotropic reserves in this pathology and differential diagnosis of the pathogenetically different forms of this diseases in male patients aged 12 to 33. Flutamide was prescribed for internal use, 10 mg/kg a day for 5 days. Functional reserves of the hypothalamo-hypophyseal-gonadal system were estimated by the change of LH secretion with morning and daily urine after 3 and 5 days as well as by the LH, FSH and T content in the blood plasma. A significant rise of LH excretion with morning and daily urine was noted in patients with primary hypogonadism receiving flutamide. On the contrary, no significant changes in LH secretion under the influence of flutamide were detected in secondary hypogonadism. It is suggestive of the preservation of the gonadotropic reserves in primary hypogonadism and their absence in secondary hypogonadism. The test is proposed for differential diagnosis in diagnostic difficulties. The most accurate results are obtained by using LH in the urine collected for 3 days of flutamide intake.