Traumatic epidural hematomas of the posterior cranial fossa.
Traumatic EDHs of the posterior cranial fossa are rare and have a higher mortality than supratentorial localizations. Early diagnosis of TEHPCF and prompt surgical evacuation provide excellent recovery. Active use of cranial CT scanning has taken a major role in the diagnosis, surgical indication, close observation, and strategy planning. As a result, better prognosis is achieved. In this study, we represent our results and experiences in the management of TEHPCF. Between 1993 and 2006, 65 patients with TEHPCF were treated in Istanbul University Faculty Of Medicine, Neurosurgery and Emergency Surgery Departments. The hospital records of these patients were analyzed retrospectively. Of 65 patients, whose diagnosis and management decisions were determined by cranial CT scans, 53 were treated through surgery and 12 by conservative methods. Of the 53 surgically treated patients, 2 (3%) patients died, and 2 (3%) other patients remained moderately disabled during their discharge. As a result, 61 (94%) of 65 patients had excellent recovery. When compared with the literature, our mortality rate was superior to other previously reported studies. In our opinion, this is a result of extensive use of the cranial CT scan together with aggressive surgery. Patients with occipital trauma should be evaluated using cranial CT scans, and those showing mass effect should be immediately treated surgically. The patients that have no mass effect on CT scans can be closely observed by planned serial control CT scans.


The significance of leptin, adiponectin, and resistin serum levels in non-small cell lung cancer (NSCLC).
Adipose tissue secretes adipokines with proinflammatory and anti-inflammatory properties. Our aim was to assess the role of adipose tissue in generalized inflammatory state of advanced NSCLC patients and the possible use of leptin, adiponectin and resistin as diagnostic and prognostic markers. Correlation of adipose tissue with weight loss in advanced NSCLC patients was also studied. Fasting serum levels of leptin, adiponectin and resistin were determined in 101 advanced NSCLC patients (76 without weight loss and 25 with weight loss) and 51 healthy volunteers using commercially available ELISA. Adipokine serum levels were determined at diagnosis, at the end of first-line chemotherapy and at the time of disease progression for those who responded to treatment. Epidemiological, anthropometrical and laboratory data were assessed. Serum leptin and adiponectin levels presented no differences. Serum resistin levels were significantly increased in NSCLC patients after adjustment for age, sex and BMI. Multivariate analysis showed that these adipokines at diagnosis could not be used as predictive factors for overall survival or time to progression. Only serum resistin levels were associated with weight loss. Despite no direct involvement of leptin and adiponectin, resistin as a proinflammatory cytokine may play a role in the pathogenesis of weight loss in NSCLC patients.


Glucocorticoids regulate the concentration of glial fibrillary acidic protein throughout the brain.
The role of glucocorticoids in the in vivo regulation of glial fibrillary acidic protein (GFAP) was examined. Corticosterone administration to adult rats resulted in decreased levels of GFAP throughout the brain whereas adrenalectomy caused levels of GFAP to increase. Corticosterone administration to adrenalectomized rats lowered GFAP levels to values below those of sham controls. Thus, the expression of GFAP throughout the brain appears to be physiologically regulated by adrenal glucocorticoids.


Combined Use of Chitosan-PGLA Nerve Grafts and Bone Marrow Mononuclear Cells to Repair a 50-mm-long Median Nerve Defect Combined with an 80-mm-long Ulnar Nerve Defect in the Human Upper Arm.
Severe peripheral nerve injury, especially the long-distance peripheral nerve defect, causes severe functional disability in patients. There is always a lack of effective repair methods for clinic, and those in practice are associated with side effects. A case study was performed to observe the regenerative outcomes of the surgical repair of long-distance peripheral nerve defects in the upper arm with chitosan-poly(glycolide-co-lactide) (PGLA) nerve grafts combined with bone marrow mononuclear cells (BMMCs). The right upper arm of a 29-year-old woman was injured, leaving a 50-mm-long median nerve defect, an 80-mm-long ulnar nerve defect, and muscle and blood vessel disruptions. The nerve defects were repaired by implanting BMMC-containing chitosan-PGLA nerve grafts on the 40th day after injury. A series of functional assessments were carried out from 2 weeks to 66 months after surgical repair. Sensory function was assessed by the pinprick test, two-point discrimination test and Semmes-Weinstein monofilament test. Motor function was evaluated by the range of motion of the wrist joint and muscle power. Autonomic function was monitored by laser-Doppler perfusion imaging (LDPI). Tissue morphology was observed through ultrasonic investigations. No adverse events, such as infection, allergy, or rejection, caused by the treatment were detected during the follow-up period. Sensory and pinprick nociception in the affected thumb, index, and middle fingers gradually restored at 6th month after surgery. The monofilament tactile sensation was 0.4 g in the terminal finger pulp of the thumb and index finger, 2.0 g in the middle finger, and greater than 300 g in the ring finger and little finger at the 66th month. Motor function recovery was detected at the 5th month after surgery, when the muscle strength of the affected forearm flexors began to recover. At the 66th month after surgery, the patient's forearm flexor strength was grade 4, with 80° of palmar flexion, 85° of dorsal extension, 8° of radial deviation, 40° of ulnar deviation, 40° of anterior rotation, and 85° of posterior rotation of the affected wrist. The patient could perform holding, picking up, and some other daily activities with the affected hand. The patient's sweating function of the affected hand was close to the level of the healthy hand. LDPI showed that the skin blood flow perfusion was significantly increased, with perfusion similar to on the normal side in some areas. Neuromusculoskeletal ultrasonography showed the presence of nerve structures. These results suggest that chitosan-PGLA nerve grafts combined with BMMCs could effectively repair long-distance nerve defects and achieve good clinical results.


Redistribution of lipofuscin in aged neurons induced by colchicine.
The effect of a single, 40 micrograms, intracerebroventricular injection of colchicine on the distribution of neuronal lysosomes and lipofuscin granules in aged mice was studied. At the light microscope level we observed that colchicine induced a redistribution of dipeptidyl aminopeptidase II (Dpp II), a lysosomal and lipofuscin granule marker enzyme, from the cell bodies of neurons to the dendrites; cell bodies became depleted of Dpp II while dendrites became enriched with this enzyme. Quantitation of this phenomenon at the electron microscope level demonstrated that colchicine induced a rapid and significant decrease in the density of lysosomes and lipofuscin granules from the somata of neurons whereas in dendrites we observed a significant increase in the density of these organelles.


Local effect of transdermal isosorbide dinitrate ointment on hand vein diameter.
To assess the effect of topically applied isosorbide dinitrate (ISDN) ointment on superficial hand veins preconstricted with phenylephrine. Using the hand vein compliance technique, venous diameter changes were measured in a double-blind, randomised, placebo-controlled cross-over trial in 12 healthy volunteers. During preconstriction with phenylephrine, placebo or ISDN ointment was administered to assess the dilator effect of transdermal ISDN. Finally a single i.v. dose of nitroglycerine was administered into the hand vein to assess the maximal venous response to organic nitrovasodilators. ISDN ointment (equivalent to 13.4 +/- 3.61 mg ISDN) caused a significant dilator effect of 39.1 +/- 21.7% (mean +/- SEM, P=0.02) which reached its maximum after 42.5 +/- 16.6 min. Maximum ISDN effects were inversely correlated with venous baseline diameter (r2=0.38, P=0.03) and independent of the amount of ointment applied or the extent of preconstriction (P > 0.3). Similar to nitroglycerine, topical ISDN may relax superficial hand veins within 60 min after application, suggesting that it might ease venepuncture particularly of small vessels. The large variability of the effect and the time to reach the effect, however, restrict its practical usefulness.


Aflatoxin B1 hepatotoxicity in rats pretreated with ethanol.
Ethanol pretreatment has the potentiation of the aflatoxin B1-induced hepatotoxicity was indicated by an increase in the activities of plasma GPT, plasma GOT and in the severity of liver necrosis. The effect of ethanol pretreatment on an increase in the accumulation of liver triglycerides is additive in nature.


Comparative study of Ki-67 immunostaining and nuclear DNA content in histiofibrous tumors.
A comparative assessment was made of dermatofibroma, dermatofibrosarcoma protuberans, and malignant fibrous histiocytoma. The study was comprised of an immunohistochemical investigation using the Ki-67 monoclonal antibody and a quantitative analysis of cell nuclear DNA using flow cytometry. It was found that the index of Ki-67 monoclonal antibody labeling, the histogram pattern, and DNA index correlated with clinical malignancy, suggesting the usefulness of these indices for differential diagnosis and evaluation of prognosis.


Prognostic importance of quantitative exercise Doppler echocardiography in asymptomatic valvular aortic stenosis.
In patients with asymptomatic valvular aortic stenosis, exercise testing may help to stratify the clinical risk. However, data are limited, and the role of quantitative exercise Doppler echocardiography has never been investigated. Sixty-nine consecutive patients with severe asymptomatic aortic stenosis (aortic valve area <1 cm2) who prospectively underwent quantitative Doppler echocardiographic measurements at rest and during semisupine exercise test were followed up for 15+/-7 months. Of these, 26 had an abnormal response to exercise [occurrence of > or =1 of the following findings: angina, dyspnea, > or =2 mm ST segment depression, or fall or small (<20 mm Hg) rise in systolic blood pressure during the test] and 18 presented cardiac events during follow-up (symptoms in 2 patients, acute pulmonary edema in 2, aortic valve replacement in 12, and cardiac death in 2). In univariate analysis, patients who had cardiac events exhibited a higher increase in both peak (29+/-16 versus 22+/-14 mm Hg; P=0.019) and mean (23+/-8 versus 12+/-7 mm Hg; P=0.000003) transvalvular pressure gradients, whereas the left ventricular ejection fraction reached at peak stress was lower. These patients experienced more frequently symptoms during exercise (14 of 18 versus 12 of 51; P=0.0008). By multivariate Cox regression analysis, independent predictors of cardiac events were as follows: an increase in mean transaortic pressure gradient by > or =18 mm Hg during exercise (P=0.0015), an abnormal exercise test (P=0.0026), and an aortic valve area <0.75 cm2 (P=0.0031). Exercise Doppler echocardiographic findings provided incremental prognostic value over resting echocardiographic and exercise electrocardiographic parameters. Quantitative Doppler exercise echocardiography could be useful to identify a high-risk subset of patients with asymptomatic valvular aortic stenosis and help for clinical decision making.


Galea and periosteum flap filled with bone fragments in rabbits.
To study the bone viability of a vascularized galea and periosteum flap filled with bone fragments, as a substitute of the bone graft in facial reconstructive surgery. Forty rabbits were studied, and divided in two groups. One had a simple galea and periosteum flap done and the other had the same flap done and filled with bone fragments of the calvaria. The bone formation was evaluated by radiographies, macroscopic and microscopic analysis. The bone neoformation in both groups with differences in bone morphology and structure especially at histological analysis. This study demonstrated osseous formation in both groups of galea and periosteum flaps, with and without bone fragments.


Lower PDL1, PDL2, and AXL Expression on Lung Myeloid Cells Suggests Inflammatory Bias in Smoking and Chronic Obstructive Pulmonary Disease.
Lung myeloid cells are important in pulmonary immune homeostasis and in the pathogenesis of chronic obstructive pulmonary disease (COPD). Multiparameter immunophenotypic characterization of these cells is challenging because of their autofluorescence and diversity. We evaluated the immunophenotypic landscape of airway myeloid cells in COPD using time of flight mass cytometry. Cells from BAL, which were obtained from never-smokers (n = 8) and smokers with (n = 20) and without (n = 4) spirometric COPD, were examined using a 44-parameter time of flight mass cytometry panel. Unsupervised cluster analysis was used to identify cellular subtypes that were confirmed by manual gating. We identified major populations of CD68+ and CD68- cells with 22 distinct phenotypic clusters, of which 18 were myeloid cells. We found a higher abundance of putative recruited myeloid cells (CD68+ classical monocytes) in BAL from patients with COPD. CD68+ classical monocyte population had distinct responses to smoking and COPD that were potentially related to their recruitment from the interstitium and vasculature. We demonstrate that BAL cells from smokers and subjects with COPD have lower AXL expression. Also, among subjects with COPD, we report significant differences in the abundance of PDL1high and PDL2high clusters and in the expression of PDL1 and PDL2 across several macrophage subtypes suggesting modulation of inflammatory responses. In addition, several phenotypic differences in BAL cells from subjects with history of COPD exacerbation were identified that could inform potential disease mechanisms. Overall, we report several changes to the immunophenotypic landscape that occur with smoking, COPD, and past exacerbations that are consistent with decreased regulation and increased activation of inflammatory pathways.


Relationships between exploratory behaviour and genic heterozygosity in the oldfield mouse.
Exploratory behaviour by adult male oldfield mice (Peromyscus polionotus) from mainland and beach localities in the southeastern United States was examined in relation to mean genic heterozygosity. Heterozygosity was estimated from allelic variation in 31 proteins detectable by starch-gel electrophoresis. Mean latency to enter the open field decreased and mean ambulatory behaviour gel mainland samples of mice increased with increasing mean genic heterozygosity. Ambulatory behaviour was realted to the number of heterozygous loci per mouse in mainland mice as a group. The exploratory behaviour of beach mice diverged from relationships between behavioural performance and heterozygosity observed for mainland mice.


MicroRNA in lung cancer.
MicroRNAs (miRNAs) are small non-protein-coding RNAs that function as endogenous negative gene regulators. Dysfunctions of miRNAs are frequently found in malignancies, including lung cancer. In this review, we summarise the current understanding of miRNAs in lung cancer tumourigenesis, and highlight their potential in overcoming drug resistance, abetting histological sub-classification techniques, and serving as biomarkers for lung cancer risk stratification and outcome prediction.


Effects of amino-acids on pancreatic hormones and gut glucagon-like immunoreactivity in the goose.
In the goose, alanine and arginine, intravenously or orally administered, act in the same way on pancreatic hormones; they both stimulate insulin and glucagon secretions. Conversely, whereas alanine treatment has no effect on plasma gut GLI, oral arginine stimulates gut GLI secretion. Since stimulation of gut GLI secretion does not occur with i.v. arginine, it may be assumed that this secretion depends on the intestinal transit of arginine and, as already described (Sitbon and Mialhe 1979), of glucose. The results, compared with studies on a similar species (duck) and on mammals, point out that i.v. infusion of alanine stimulates IRI and GLI secretions in the goose and not in the duck. In the same way, arginine i.v. infusion, contrarily to the observation made in the duck, is without effect on gut GLI secretion in the goose. Furthermore, insulin seems to be able to inhibit the alpha cell response to arginine infusion, as in mammals, whereas this is not the case in ducks.


Iodoacetic acid inhibits follicle growth and alters expression of genes that regulate apoptosis, the cell cycle, estrogen receptors, and ovarian steroidogenesis in mouse ovarian follicles.
The reaction between disinfectants and organic matter or inorganic matter in source water generates disinfection by-products (DBPs) such as iodoacetic acid (IAA). DBPs are associated with health effects such as bladder cancer and adverse reproductive outcomes, but the effects of IAA on the ovary are not well known. This study determined whether IAA exposure affects ovarian follicle growth, steroidogenesis, and expression of apoptotic factors, cell cycle regulators, estrogen receptors, and steroidogenic factors in vitro. IAA exposure significantly decreased follicle growth, expression of cell cycle stimulators, and the proliferation marker Ki67. In contrast, IAA increased expression of the cell cycle inhibitor Cdkn1a. Moreover, IAA exposure increased expression of pro-apoptotic factors, whereas it decreased expression of anti-apoptotic factors. IAA exposure also altered expression of steroidogenic factors and estrogen receptors, disrupting steroidogenesis. These data demonstrate that IAA exposure inhibits follicle growth, decreases cell proliferation, and alters steroidogenesis in mouse ovarian follicles in vitro.


The role of social structural factors in treatment of mental health disorder.
Mental disorder implies a biopsychosocial condition, so adequate mental health treatment involves not just medical and pharmacological care but also psychotherapy or counseling. The present study determined how social structural factors might explain accessing of primary care providers and specialty care providers in response to mental disorder, hypothesizing that the two broad types of care differ as to the likelihood of offering minimally adequate treatment. We analyzed data from the cross-sectional study called "2000-2001 Healthcare for Communities", employing five imputed data sets to handle missing data and defining minimally adequate treatment of mental disorder as "at least four counseling sessions at any provider and prescribed medication". Results While mental disorder can be treated in primary care or specialty facilities, our results show that minimally adequate treatment (as defined) is most likely to be obtained via specialty care. For individuals with mental disorder, accessing only primary care creates social inequity, because care from specialty facilities is comparatively more adequate.


A novel mesoporous silica nanosphere matrix for the immobilization of proteins and their applications as electrochemical biosensor.
A mesoporous silica nanoshpere (MSN) was proposed to modify glassy carbon electrode (GCE) for the immobilization of protein. Using glucose oxidase (GOD) as a model, direct electrochemistry of protein and biosensing at the MSN modified GCE was studied for the first time. The MNS had large surface area and offered a favorable microenvironment for facilitating the direct electron transfer between enzyme and electrode surface. Scanning electron microscopy, transmission electron microscopy, UV-vis spectroscopy and cyclic voltammetry were used to examine the interaction between GOD and the MSN matrix. The results demonstrated that the immobilized enzyme on the MSN retained its native structure and bioactivity. In addition, the electrochemical reaction showed a surface controlled, reversible two-proton and two-electron transfer process with the apparent electron transfer rate constant of 3.96 s(-1). The MNS-based glucose biosensor exhibited the two linear ranges of 0.04-2.0 mM and 2.0-4.8 mM, a high sensitivity of 14.5 mA M(-1) cm(-2) and a low detection limit of 0.02 mM at signal-to-noise of 3. The proposed biosensor showed excellent selectivity, good reproducibility, acceptable stability and could be successfully applied in the reagentless detection of glucose in real samples at -0.45 V. The work displayed that mesoporous silica nanosphere provided a promising approach for immobilizing proteins and fabrication of excellent biosensors.


Analyzing user-generated content using natural language processing: a case study of public satisfaction with healthcare systems.
While user-generated online content (UGC) is increasingly available, public opinion studies are yet to fully exploit the abundance and richness of online data. This study contributes to the practical knowledge of user-generated online content and machine learning techniques that can be used for the analysis of UGC. For this purpose, we explore the potential of user-generated content and present an application of natural language pre-processing, text mining and sentiment analysis to the question of public satisfaction with healthcare systems. Concretely, we analyze 634 online comments reflecting attitudes towards healthcare services in different countries. Our analysis identifies the frequency of topics related to healthcare services in textual content of the comments and attempts to classify and rank national healthcare systems based on the respondents' sentiment scores. In this paper, we describe our approach, summarize our main findings, and compare them with the results from cross-national surveys. Finally, we outline the typical limitations inherent in the analysis of user-generated online content and suggest avenues for future research.


Different modes of grip force control: voluntary and externally guided arm movements with a hand-held load.
When we move hand-held objects that exhibit stable physical properties grip force is regulated in anticipation of movement-induced inertial loads. In contrast, when the object's behaviour is unpredictable, grip force is adjusted in response to sensory feedback with the consequence that grip tends to lag behind load. Previous studies analysed reactive and predictive grip force behaviour by systematically varying the predictability of the physical object properties. This study examines if anticipatory force control also depends on the predictability of the limb dynamics interfering with external objects. The coupling between grip and load force profiles was comparatively analysed during voluntary and externally guided vertical arm movements with an instrumented hand-held object. Voluntary and externally guided movements were performed with and without visual feedback. During voluntary arm movements grip force was precisely regulated in anticipation of movement-induced inertial load fluctuations with grip force increasing in parallel with load force without an obvious time delay. In contrast, during externally guided movements grip force was regulated in reaction to the imposed load fluctuations. However, the reflex-mediated grip force responses were still flexible to account for the differential loading requirements of movement direction. There was no difference of grip force performance between movements performed with and without visual feedback. The results suggest that predictability of both the external object and the dynamics of the own body is essential to establish an anticipatory mode of grip force regulation. Unpredictability of the own limb dynamics results in a reactive mode of grip force control. Reactive grip force control appears to be both highly automatised and flexible reflecting differential loading requirements of movement direction.


Interposition of the hernia sac as a protective layer in repair of giant incisional hernia with polypropylene mesh.
Repair of giant incisional hernia is still associated with high postoperative morbidity and recurrence rates. We evaluated the effectiveness of placing the hernia sac between the viscera and the polypropylene mesh in the repair. The subjects of this study were patients with an incisional hernia at least 15 cm in diameter, diagnosed between June 2004 and October 2010 and treated with on-lay polypropylene mesh at least 25 cm in length. We operated using a simplified method of placing the hernia sac between the viscera and the mesh, and fixing the mesh with interrupted trans-fascial U sutures. We evaluated the patient demographics and postoperative complications retrospectively. A total of 25 patients (mean age 57.1 ± 10 years) were included. The mean length of hospital stay was 1.8 ± 1.2 days. Seroma developed in four patients (16 %), but only two with cystic seroma required excision of the cyst wall with preservation of the mesh. Twenty-two patients (88 %) were followed up for a mean period of 42.6 ± 23 months. There was no incidence of chronic pain, hospitalization for intestinal obstruction, or enterocutaneous fistulization. There was only one recurrence (4.55 %). The hernia sac can be interposed in all patients undergoing giant incisional hernia repair if direct contact between the polypropylene mesh and intestine is unavoidable.


Low dietary magnesium intake alters vitamin D-parathyroid hormone relationship in adults who are overweight or obese.
Vitamin D metabolism is dependent on magnesium (Mg) as a cofactor; therefore, poor Mg status may alter the relationship between vitamin D metabolite serum 25-hydroxyvitamin D (s25OHD) and serum parathyroid hormone (sPTH). We hypothesized that low dietary Mg intake may alter sPTH response to s25OHD in a population with excess body weight, thereby leading to a worsening of cardiometabolic health. To explore this hypothesis, we conducted a cross-sectional study on adults who were either overweight or obese (owt/ob). Dietary Mg intake was measured using a Mg food frequency questionnaire (MgFFQ). Body composition information was measured using Dual Energy X-ray Absorptiometry (DXA). Blood samples were obtained for all biochemical analyses. A total of 57 participants, 22 to 65 years of age, with a body mass index between 25 to 45 kg/m2 were divided into 3 groups, according to dietary Mg intake percentiles (Low Mg Group = <33 percentile, Medium Mg Group = 33 to 66 percentile, High Mg Group = >66 percentile). Higher s25OHD was negatively associated with lower sPTH in the High Mg Intake group (r = -0.472, P = .041), but not in other groups. A positive relationship between s25OHD and serum high-molecular weight adiponectin concentrations was observed in the High Mg Group (r = 0.532, r = 0.022), but not in other groups. Serum Interleukin-6 concentrations were negatively associated with s25OHD (r = -0.316, P = .017) for the entire study group. Based on these results, our study demonstrated that a low dietary Mg intake may alter PTH response to 25OHD.


Use of Potyvirus Vectors to Produce Carotenoids in Plants.
Potyviruses are plus-strand RNA viruses that can be easily transformed into expression vectors to quickly express one carotenogenic enzyme or transcription factor, or more, in plant tissues. Unlike the technically challenging and time-consuming process of plant transformation, manipulation of a roughly 10,000 nt-long viral genome is rather straightforward via common molecular biology techniques. Here I describe how to insert the cDNAs of the proteins of interest into two particular positions of the cDNA of a Tobacco etch virus (TEV) mutant that lacks the viral NIb cistron and only infects the plants in which this protein is expressed. This deletion increases the space to harbor foreign sequences. The selection of the expression site must be made according to subcellular localization requirements. The recombinant virus is then inoculated into Nicotiana benthamiana plants by means of Agrobacterium tumefaciens. The expression of the viral genome entails the production of carotenogenic proteins in the plant tissues with a consequent effect on the plant carotenoid pathway.


In vitro preconditioning of insulin-producing cells with growth factors improves their survival and ability to release insulin.
Glucose-induced oxidative stress in the diabetic pancreas directly affects viability and the consequent therapeutic outcome of transplanted stem cells. Pretreatment of stem cells with growth factors induces tolerance in them against various stresses (hypoxia, thermal or hyperglycaemic). This study investigated the effect of pretreatment on insulin-producing cells (IPCs) differentiated from adipose-derived mesenchymal stem cells (ADMSCs), with a combination of stromal cell-derived factor 1 alpha (SDF1 α) and basic fibroblast growth factor (bFGF) against hyperglycaemic stress (17 or 33 mM glucose). The results showed that IPCs pretreated with a combination of SDF1α and bFGF exhibited maximally alleviated apoptosis, senescence and cell damage with a concomitantly increased release of insulin, enhanced cell proliferation and greater upregulation of Insulin 1, Insulin 2, Ngn3, Pdx1 and Nkx6.2 when stressed with 33 mM glucose. These findings may offer an improved therapeutic outcome for the treatment of diabetes.


[Serotonin metabolism in the duodenal tissue of intact rabbits].
Serotonin, 5-oxyindolacetic acid content, and monoaminooxidase activity proved to exceed such in the kidney of rabbit. This pointed to the high capacity of the intestine in respect to the accumulation of serotonin and the processes of its catabolism. The reverse regularity was noted for 5-oxytryptophanedecarboxylase, the activity of which was about 12 times greater in the kidney than in the intestine, this apparently characterizing a low capacity of this tissue in the course of decarboxylation of 5-oxytryptophane.


Granular cell tumor of the trachea mimicking an infiltrating thyroid cancer. A case report.
Granular cell tumor (GCT) is a rare neurogenic neoplasm originating from Schwann cells that predominantly affects women and can involve skin and mucousae. In the respiratory system it most frequently involves bronchi and larynx, while it is rare in the trachea. A 26-year old female smoker was hospitalized for a suspected hypoechoic nodule in the right thyroid lobe closely adherent to the trachea. At preoperative computed tomography tracheal lumen was totally clear. The patient underwent a total thyroidectomy with lymph node dissection and tracheal shaving. The postoperative course was complicated by an extensive subcutaneous bilatreral emphysema associated with respiratory distress appeared on the fifth day. Bronchoscopy revealed a right anterolateral subcentimeter lesion near the second tracheal ring. Histologically, the diagnosis was consistent with a tracheal GCT developing into the thyroid parenchyma. The patient was discharged on the twentieth postoperative day. At the follow-up bronchoscopy the lesion was completely healed and at the last 12 month follow-up the patient is doing well. Tracheal tumors are uncommon neoplasms accounting for about 2% of the total respiratory tree tumors. In literature we found <50 papers concerning tracheal GCT and in almost all of the cases patients complained about respiratory symptoms. We report here a rare case of benign GCT of the trachea with extraluminal development, in a young patient who did not complain about preoperative respiratory symptoms, presented on ultrasound as a thyroid nodule with suspected cytology.


The Contribution of BaTiO3 to the Stability Improvement of Ethylene-Propylene-Diene Rubber: Part II-Doped Filler.
The thermal and radiation stabilities of the formulations based on ethylene-propylene-diene rubber (EPDM), which contain barium titanate (BaTiO3) doped with lanthanum and cerium oxides, were investigated by chemiluminescence and mechanical testing. The contributions of these doped fillers are related to the surface interaction between the structural defects (doping atoms, i.e., lanthanum and cerium) implanted in the filler lattice and the molecular fragments formed during the progress of degradation. These composite materials present extended durabilities with respect to the references; the oxidation periods are a minimum of three times longer than the corresponding times for pristine polymers. This behavior is associated with the scavenging activity of dopants. Mechanical testing has demonstrated the contributions of doped filler to the improvement of tensile strength and elongation at break by the restructuration of the polymer phase. Scanning electron microscopy images revealed the densification of materials in the presence of doped barium titanates. All the investigations constitute valid proof for the qualification of BaTiO3 doped with Ce as the more efficient stabilizer compared to the same inorganic filler doped with La.


Disruption of insulin-like growth factor-II imprinting during embryonic development rescues the dwarf phenotype of mice null for pregnancy-associated plasma protein-A.
Pregnancy-associated plasma protein-A (PAPP-A), an insulin-like growth factor-binding protein (IGFBP) protease, increases insulin-like growth factor (IGF) activity through cleavage of inhibitory IGFBP-4 and the consequent release of IGF peptide for receptor activation. Mice homozygous for targeted disruption of the PAPP-A gene are born as proportional dwarfs and exhibit retarded bone ossification during fetal development. Phenotype and in vitro data support a model in which decreased IGF-II bioavailability during embryogenesis results in growth retardation and reduction in overall body size. To test the hypothesis that an increase in IGF-II during embryogenesis would overcome the growth deficiencies, PAPP-A-null mice were crossed with DeltaH19 mutant mice, which have increased IGF-II expression and fetal overgrowth due to disruption of IgfII imprinting. DeltaH19 mutant mice were 126% and PAPP-A-null mice were 74% the size of controls at birth. These size differences were evident at embryonic day 16.5. Importantly, double mutants were indistinguishable from controls both in terms of size and skeletal development. Body size programmed during embryo development persisted post-natally. Thus, disruption of IgfII imprinting and consequent elevation in IGF-II during fetal development was associated with rescue of the dwarf phenotype and ossification defects of PAPP-A-null mice. These data provide strong genetic evidence that PAPP-A plays an essential role in determining IGF-II bioavailability for optimal fetal growth and development.


Lower Baseline Variability Gives Rise to Lower Detection Thresholds in Midbrain than Hindbrain Electrosensory Neurons.
Understanding how the brain decodes sensory information to give rise to behaviour remains an important problem in systems neuroscience. Across various sensory modalities (e.g. auditory, visual), the time-varying contrast of natural stimuli has been shown to carry behaviourally relevant information. However, it is unclear how such information is actually decoded by the brain to evoke perception and behaviour. Here we investigated how midbrain electrosensory neurons respond to weak contrasts in the electrosensory system of the weakly electric fish Apteronotus leptorhynchus. We found that these neurons displayed lower detection thresholds than their afferent hindbrain electrosensory neurons. Further analysis revealed that the lower detection thresholds of midbrain neurons were not due to increased sensitivity to the stimulus. Rather, these were due to the fact that midbrain neurons displayed lower variability in their firing activities in the absence of stimulation, which is due to lower firing rates. Our results suggest that midbrain neurons play an active role towards enabling the detection of weak stimulus contrasts, which in turn leads to perception and behavioral responses.


Artificial intelligence in early diagnosis and prevention of oral cancer.
The global occurrence of oral cancer (OC) has increased in recent years. OC that is diagnosed in its advanced stages results in morbidity and mortality. The use of technology may be beneficial for early detection and diagnosis and thus help the clinician with better patient management. The advent of artificial intelligence (AI) has the potential to improve OC screening. AI can precisely analyze an enormous dataset from various imaging modalities and provide assistance in the field of oncology. This review focused on the applications of AI in the early diagnosis and prevention of OC. A literature search was conducted in the PubMed and Scopus databases using the search terminology "oral cancer" and "artificial intelligence." Further information regarding the topic was collected by scrutinizing the reference lists of selected articles. Based on the information obtained, this article reviews and discusses the applications and advantages of AI in OC screening, early diagnosis, disease prediction, treatment planning, and prognosis. Limitations and the future scope of AI in OC research are also highlighted.


Preclinical therapy of breast cancer with a radioiodinated humanized anti-EGP-1 monoclonal antibody: advantage of a residualizing iodine radiolabel.
A humanized monoclonal antibody (MAb), hRS7, labeled with 131I-IMP-R4, was evaluated for the preclinical radioimmunotherapy (RAIT) of breast cancer. 131I-IMP-R4 is an improved residualizing form of 131I that overcomes the short tumor residence time associated with conventionally radioiodinated MAbs. RS7, an internalizing MAb, recognizes epithelial glycoprotein-1, which is highly expressed in the carcinomas of breast, lung, ovary, and prostate. A humanized version of RS7 was generated by CDR-grafting and transfection. In vivo experiments were carried out in nude mice bearing subcutaneous MDA-MB-468 human breast cancer xenografts. Therapy experiments were performed using established tumors with mean tumor volume (MTV) of 0.3 cm3, and single administrations, at approximately 70% of the estimated maximum tolerated doses (MTD), of the residualizing 131I-IMP-R4-hRS7 and 131I-hRS7 prepared by the conventional chloramine-T method [131I-hRS7 (CT)]. Therapeutic specificity was determined by comparison with untreated and non-specific MAb controls. hRS7 was functionally very similar to murine and chimeric RS7. A biodistribution study using 125I-IMP-R4-hRS7 and 131I-hRS7 (CT) indicated a dosimetric advantage for the former. The MTVs 8 weeks post-treatment were 20, 163, and 280% of the starting MTVs of 131I-IMP-R4-hRS7-treated, 131I-hRS7 (CT)-treated, and untreated groups, respectively. Complete remissions were seen in 5 of 11 [and 6 of 8] mice treated with 131I-IMP-R4-hRS7, and in 1 of 11 mice treated with 131I-hRS7(CT). 131I-IMP-R4-hRS7 was significantly more efficacious than 131I-hRS7 (CT) [ P = 0.01 for AUC] and the control 131I-IMP-R4-MAb. 131I-IMP-R4-hRS7 is a promising new agent for RAIT, providing significant therapeutic advantage in comparison to the conventionally 131I-labeled antibody.


Maternal medication and herbal use and risk for hypospadias: data from the National Birth Defects Prevention Study, 1997-2007.
To investigate associations between maternal use of common medications and herbals during early pregnancy and risk for hypospadias in male infants. We used data from the National Birth Defects Prevention Study, a multi-site, population-based, case-control study. We analyzed data from 1537 infants with second-degree or third-degree isolated hypospadias and 4314 live-born male control infants without major birth defects, with estimated dates of delivery from 1997 to 2007. Exposure was reported use of prescription or over-the-counter medications or herbal products, from 1 month before to 4 months after conception. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, adjusting for maternal age, race/ethnicity, education, pre-pregnancy body mass index, previous live births, maternal subfertility, study site, and year. We assessed 64 medication and 24 herbal components. Maternal uses of most components were not associated with an increased risk of hypospadias. A new associations was observed for venlafaxine (aOR 2.4; 95%CI 1.0, 6.0) [Correction made here after initial online publication.]. The previously reported association for clomiphene citrate was confirmed (aOR 1.9; 95%CI 1.2, 3.0). Numbers were relatively small for exposure to other specific patterns of fertility agents, but elevated aORs were observed for the most common of them. Overall, findings were reassuring that hypospadias is not associated with most medication components examined in this analysis. New associations will need to be confirmed in other studies. Increased risks for hypospadias associated with various fertility agents raise the possibility of confounding by underlying subfertility.


Incidence, risk factors, and outcome of blood stream infections during the first 100 days post-pediatric allogeneic and autologous hematopoietic stem cell transplantations.
Bloodstream infections (BSI) are a frequently observed complication after hematopoietic stem cell transplant (HSCT). Retrospective analysis of clinical and microbiological data during the first 100 days from 302 consecutive pediatric patients who underwent HSCT for a malignant disease at our institute between January 2013 and June 2017. A total of 164 patients underwent autologous and 138 allogeneic HSCT. The overall incidence of BSI was 37% with 92% of infectious episodes occurring during the pre-engraftment phase. Gram-positive bacteria (GPB) accounted for 54.6% of the isolated pathogens, gram-negative bacteria (GNB) for 43.9%, and fungi for 1.4%. Coagulase-negative staphylococci and Escherichia coli were the most commonly isolated GPB and GNB, respectively. Forty-five percent of GNB were extended-spectrum beta-lactamase producers and 21% were multidrug-resistant organisms. Fluoroquinolone resistance was 92% and 68%, among GPB and GNB, respectively. Risk factors for BSI in univariate analysis were allogeneic HSCT, delayed time to engraftment more than 12 days, previous BSI before HSCT, and alternative donor. In multivariate analysis, only HSCT type (allogeneic vs autologous P = .03) and previous BSI within 6 months before HSCT (P = .016) were significant. Overall survival at day 100 was 98% and did not differ significantly between patients with and without BSI (P = .76). BSI is common in children undergoing HSCT for malignant diseases. Allogeneic HSCT recipients and previous BSI within 6 months before HSCT are associated with increased risk of post-transplant BSI. With current supportive measures, BSI does not seem to confer an increased risk for 100-day mortality.


Motion-robust MR imaging of the shoulder using compressed SENSE MultiVane.
Motion artifacts caused by breathing or involuntary motion of patients, which may lead to reduced image quality and a loss of diagnostic information, are a major problem in shoulder magnetic resonance imaging (MRI). The MultiVane (MV) technique decreases motion artifacts; however, it tends to prolong the acquisition time. As a parallel imaging technique, SENSitivity Encoding (SENSE) can be combined with the compressed sensing method to produce compressed SENSE (C-SENSE), resulting in a markedly reduced acquisition time. This study aimed to evaluate the use of C-SENSE MV for MRI of the shoulder joint. Thirty-one patients who were scheduled to undergo MRI of the shoulder were included. This prospective study was approved by our institution's medical ethics committee, and written informed consent was obtained from all 31 patients. Two sets of oblique coronal images derived from the standard protocol were acquired without (standard) or with C-SENSE MV: proton-density weighted imaging (PDWI), PDWI with C-SENSE MV, T2-weighted imaging (T2WI) with fat suppression (fs), and T2WI fs with C-SENSE MV. Two radiologists graded motion artifacts and the detectability of anatomical shoulder structures on a 4-point scale (3, no artifacts/excellent delineation; 0, severe artifacts/difficulty with delineation). The Wilcoxon signed-rank test was used to compare the data for the standard and C-SENSE MV images. Motion artifacts were significantly reduced on the C-SENSE MV images (p < 0.001). Regarding the detectability of anatomical structures, the ratings for the C-SENSE MV sequences were significantly better (p < 0.001).In conclusion, in shoulder MRI the newly developed C-SENSE MV technique reduces motion artifacts and increases the detectability of anatomical structures compared with standard sequences.


Differential expression carcinoembryonic antigen and secretory component during colonic epithelial cell differentiation and in colonic carcinomas.
The cellular and ultrastructural distribution of carcinoembryonic antigen and secretory component during differentiation of normal colonic epithelium and in colonic carcinomas was evaluated by peroxidase-labeled antibody immunocytochemistry. Carcinoembryonic antigen and secretory component were found to be markers of distinctly different stages of normal colonocyte differentiation. Whereas secretory component was expressed principally by proliferating absorptive cells in the midcrypt, carcinoembryonic antigen expression was diminished in this crypt zone and was associated principally with mature columnar cells at the luminal surface and with undifferentiated cells at the crypt base. Carcinoembryonic antigen was preferentially expressed on the microvillar plasma membrane and secretory component on the basolateral plasma membrane in the normal colon. In 13 colon cancers studied, carcinoembryonic antigen was expressed on the entire surface of all the colon cancers except one anaplastic tumor, whereas secretory component was only expressed on five well or moderately differentiated cancers. These observations suggest that differentiation of colon cancers as assessed by morphology and phenotypic markers is not totally analogous to that found in the normal colon.


A catalytic mechanism that explains a low catalytic activity of serine dehydratase like-1 from human cancer cells: crystal structure and site-directed mutagenesis studies.
SDH (l-serine dehydratase, EC 126.96.36.199) is a pyridoxal-5'-phosphate (PLP)-dependent enzyme that catalyzes dehydration of l-Ser/Thr to yield pyruvate/ketobutyrate and ammonia. A SDH isoform (cSDH) found in human cancer cell lines has relatively low catalytic activity in comparison with the liver enzyme (hSDH). The crystal structure of cSDH has been determined at 2.8 angstroms resolution. A PLP is covalently attached to K48 by Schiff-base linkage in the active site. The ring nitrogen of PLP is involved in a H-bonding with C309, but is apparently not protonated. Twenty-three amino residues that compose the active site surfaces were identified. The human and rat liver enzymes (hSDH and rSDH) have the same residues, while residues G72, A172, and S228 in cSDH are replaced with A66, S166, and A222, respectively, in hSDH. These residues in hSDH and cSDH were mutated to make complementary pairs of mutated enzymes, and their kinetic parameters were determined. C303 of hSDH and C309 of cSDH which are H-bonding partner of the ring nitrogen of PLP were mutated to alanine and their kinetic parameters were also determined. The crystal structures and the mutation data suggest that having a glycine at residue 72 of cSDH is the major reason for the reduction of catalytic activity of cSDH. Changing alanine to glycine at residue 72 increases the flexibility of the substrate binding-loop (71S(G/A)GN74), so that the bound substrate and PLP are not pushed deep into the active cleft. Consequently, the proton transfer rate from S(G) of C309 to N1 of the bound PLP is decreased, which determines the rate of catalytic reaction.


Progressive multifocal leucoencephalopathy with magnetic resonance imaging verification and therapeutic trials with interferon.
Progressive multifocal leucoencephalopathy was diagnosed by magnetic resonance imaging (MRI) and brain biopsy in a 44-year-old woman, for whom therapeutic trials with various antiviral agents were made. Despite early diagnosis and treatment, her neurological deterioration and extension of MRI-detectable lesions were not halted for a period of about 8 months. After the introduction of intrathecal beta-interferon therapy, her neurological status and MRI findings became stable and showed minimal improvement. Early diagnosis of this fatal disorder is important and intrathecal interferon therapy should be considered.


Secretory activity of equine polymorphonuclear leukocytes: stimulus specificity and priming effects of bacterial lipopolysaccharide.
Neutrophil (PMN) contributions to the acute inflammatory process and host defense include generation of bioreactive oxygen metabolites and secretion of granule enzymes. We assessed equine PMN secretion using several PMN stimuli, singly and in combination with bacterial lipopolysaccharide (LPS). LPS avidly associated with equine PMN, as shown by strong PMN labeling with FITC-conjugated LPS. LPS alone (1 or 10 micrograms ml-1) was a weak stimulus for PMN superoxide anion (O2-) generation, but preincubation with LPS followed by phorbol ester (PMA, 10 ng ml-1) significantly augmented (P less than 0.01) secretion of O2- (19.38 nmol O2- per 2 x 10(6) PMN per 5 min) over the amount generated by PMA stimulation alone (13.75 nmol O2-). A qualitatively similar, but smaller O2(-)-generation response occurred when either opsonized zymosan or recombinant human C5a was used as the PMN stimulus. Arachidonic acid (ArA; 50-200 microM) was a potent stimulus, with secreted O2- levels similar to those from PMA-stimulated PMN. Preincubation of PMN with either the formyl peptide, fMLP, or platelet-activating factor before stimulation with ArA did not significantly increase O2- generation over levels obtained using ArA alone. Release of PMN granule enzymes was also quantitated. A small amount of lysozyme secretion resulted when PMN were exposed to LPS alone (8.20% of total cell content), and PMA stimulation caused marked release of PMN lysozyme (44.45%). Non-specific proteolytic activity in PMN supernatants, assessed by cleavage of a collagen-rich substrate, was minimal with LPS as a sole stimulus (5.08%). There was significant proteolytic activity (P less than 0.01) in supernatants from PMA-stimulated PMN (27.21%), and preincubation with LPS followed by PMA stimulation slightly enhanced (P less than 0.05) the release of PMN proteases (34.62%). The activities of beta-glucuronidase, acid phosphatase, and alkaline phosphatase were minimal in PMN supernatants when using LPS and PMA as stimuli. The activity of PMN granule enzymes was found to be sensitive to the presence of normal equine serum, and proteolytic activity was markedly reduced (80.13% reduction) in the presence of 10% pooled serum.


Structural and electronic properties of the liver fluke hemoglobin heme cavity by nuclear magnetic resonance: hemin isotope labeling.
Reconstitution of liver fluke (Dicrocoelium dendriticum) apo-hemoglobin with hemins selectively deuterated at specific positions has permitted the assignment of several heme resonances in the proton nuclear magnetic resonance spectrum of the Met-aquo and Met-cyano forms of the holoprotein. It was established that in the Met-aquo form the meso protons resonate at positions characteristic of a six-co-ordinated in-plane iron. From this, we deduced that the Met-aquo species retains a bound water molecule at pH values as low as 4.5. The orientation of the proximal histidine imidazole ring with respect to the heme group in the cavity was determined through the identification of the heme methyl signals and the analysis of the hyperfine shift pattern in the Met-cyano hemoglobin proton nuclear magnetic resonance spectrum. Compared to sperm whale myoglobin, the heme appears to be rotated by 180 degrees about the alpha, gamma meso-axis. Protein isomers with the heme group in a reversed orientation were not detected, even shortly after reconstitution. In the Met-cyano form, the resonances most affected by the Bohr transition were shown to arise from the heme propionates.


Non-pegylated liposomal doxorubicin combined with gemcitabine as first-line treatment for metastatic or locally advanced breast cancer. Final results of a phase I/II trial.
Doxorubicin and gemcitabine are active as single agents in breast cancer, have different mechanisms of action, and mainly have non-overlapping side effects. Dose-dependent doxorubicin-related cardiac toxicity is the principal limitation in the metastatic setting. This open, multicenter, single-arm phase I/II study assessed the safety and activity of gemcitabine in combination with non-pegylated liposomal doxorubicin (Myocet), a more cardiac-friendly anthracycline, in the first-line treatment of patients with advanced breast cancer. We aimed to determine the optimal recommended dose (RD) of gemcitabine combined with Myocet in a population, with performance status >or=2 and LVEF >or=50%. A formal phase II study was performed afterwards. A total of 53 patients were recruited. Gemcitabine 900 mg/m(2) intravenously day 1 and 8 combined with Myocet 55 mg/m(2) intravenously day 1, every 21 days, was the final RD. The principal toxicity observed was hematological, and 48% of patients developed grade 3-4 neutropenia. Other toxicities were mild and infrequent, including nausea and vomiting. There were no symptomatic cardiac events despite the fact that 36% of the patients had received prior treatment with adjuvant anthracyclines. Objective responses were observed in 51.1% of 47 evaluable patients (95% CI: 36-66%), including two complete response. In addition, 14 patients (29.8%) demonstrated stable disease. The combination of Myocet and gemcitabine at the RD is safe and has encouraging clinical activity in patients with advanced breast cancer, without apparent cardiac toxicity in anthracycline-pretreated patients. These data support further development of this combination.


Human parvovirus infection: rheumatic manifestations, angioedema, C1 esterase inhibitor deficiency, ANA positivity, and possible onset of systemic lupus erythematosus.
To investigate the clinical and serological characteristics of parvovirus infection. during 1993-4, 9 adult patients presented with polyarthralgias/polyarthritis. Clinical evaluation and serological studies of antinuclear antibodies, rheumatoid factor (RF), IgM and IgG antibodies to human parvovirus were done in all patients. Other serologies including anti-DNA, serum complement, and C1 esterase inhibitor levels were obtained in some patients. All 9 patients had polyarthralgias/polyarthritis, serological evidence of parvovirus B19 IgM and IgG antibodies, and normal sedimentation rate. All patients were seronegative for RF. Four women had positive ANA titers. In 2 of them the ANA positivity was transient. One developed systemic lupus erythematosus (SLE). Three women had angioedema of the face and tongue; one had transient C1 esterase inhibitor deficiency and another a transient decrease in C4 levels. Parvovirus may be implicated in the development of SLE as well as other chronic arthropathies. This is the first reported case of angioedema and decreased C1 esterase inhibitor levels associated with parvovirus infection.


Tumor-specific cholinergic CD4+ T lymphocytes guide immunosurveillance of hepatocellular carcinoma.
Cholinergic nerves are involved in tumor progression and dissemination. In contrast to other visceral tissues, cholinergic innervation in the hepatic parenchyma is poorly detected. It remains unclear whether there is any form of cholinergic regulation of liver cancer. Here, we show that cholinergic T cells curtail the development of liver cancer by supporting antitumor immune responses. In a mouse multihit model of hepatocellular carcinoma (HCC), we observed activation of the adaptive immune response and induction of two populations of CD4+ T cells expressing choline acetyltransferase (ChAT), including regulatory T cells and dysfunctional PD-1+ T cells. Tumor antigens drove the clonal expansion of these cholinergic T cells in HCC. Genetic ablation of Chat in T cells led to an increased prevalence of preneoplastic cells and exacerbated liver cancer due to compromised antitumor immunity. Mechanistically, the cholinergic activity intrinsic in T cells constrained Ca2+-NFAT signaling induced by T cell antigen receptor engagement. Without this cholinergic modulation, hyperactivated CD25+ T regulatory cells and dysregulated PD-1+ T cells impaired HCC immunosurveillance. Our results unveil a previously unappreciated role for cholinergic T cells in liver cancer immunobiology.


Immune response induced by candidate Sarcoptes scabiei var. cuniculi DNA vaccine encoding paramyosin in mice.
Sarcoptes scabiei is the causal agent of the highly contagious disease sarcoptic mange (scabies) that affects animals and humans worldwide. An increasing number of cases of treatment failure is being reported because of drug resistance. The development of a specific vaccine would be a sustainable option for control of this disease. In this study, we cloned and expressed a S. scabiei gene encoding paramyosin (PAR) and investigated the immune response elicited by DNA encoding PAR in mice. The ability of the DNA vaccine to express antigen in COS-7 cells was confirmed by RT-PCR and IFA. The immune response induced by DNA vaccine was investigated by ELISA, splenocyte proliferation assay, and cytokine production assay. Compared to the pVAX1 control group, the PAR DNA vaccination group showed the higher levels of IgG, IgG1, IgG2a, IgE, IgM, stronger lymphocyte proliferation in mouse spleen, and larger production of IL-2, IL-4, IL-5, and IFN-γ in the supernatant of cultures from splenocytes. These results indicated that the PAR DNA vaccine induced a mixed Th1/Th2 response in mice. In conclusion, our results revealed that the S. scabiei PAR DNA vaccine induced both a humoral and cellular immune response, which would provide basic data for the further study to develop an effective vaccine against sarcoptic mange.


Graft rejection in the xenogeneic transplantation of mice: diagnosis with in vivo MR imaging using the homing trait of macrophages.
To evaluate the feasibility of magnetic resonance (MR) imaging to depict the in vivo recruitment of superparamagnetic iron oxide (SPIO)-labeled macrophages and to diagnose graft rejection in xenogeneic transplantation. We transplanted the trachea of SD rat (xenogeneic) or C3H/HeN mouse (syngeneic) into the left thighs of six male C3H/HeN mice. The SPIO-labeled macrophage was administered through the tail vein 2 days (acute) or 14 days (chronic) after transplantation in each group. The left thighs of the mice were imaged on a 4.7-T MR scanner 24 h after macrophage administration. We evaluated the extent and pattern of the susceptibility effect (macrophage distribution) and compared them in the two groups. The MR findings were then correlated with the histopathologic results. We also measured in both groups the monocyte chemoattractant protein (MCP)-1 level before and 2 days, 2 weeks, and 4 weeks after transplantation. The band-shaped lower signal intensity (SI) zone was noted around the graft in the acute and chronic phases of xenogeneic group and in the acute phase of syngeneic group, but it was not noted in the chronic phase of syngeneic transplantation. The lower SI zone corresponded to the distribution of SPIO-labeled macrophages on histopathological analyses. On histologic examination, the severe inflammation developed around the xenogeneic graft, but only slightly around the syngeneic graft. MCP-1 was elevated 2 days after transplantation in both groups, but then gradually decreased in the syngeneic group; in xenogenic group, the MCP-1 value decreased by week 2 but then increased by week 4. This study demonstrates that the homing of intravenously administered SPIO-labeled macrophages can be monitored on MR imaging and is correlated with the MCP-1 level and the histopathologic findings of the xenograft rejection.


Exercise Improves Recognition Memory and Acetylcholinesterase Activity in the Beta Amyloid-Induced Rat Model of Alzheimer's Disease.
A correlation between physical exercise and cognitive improvement has been found in Alzheimer's disease (AD). This study aimed to investigate the effects of aerobic and resistance exercise on the recognition memory and acetylcholinesterase (AChE) activity in beta amyloid (Aβ) model of AD in rat. Fifty male 8-week-old Wistar rats (250-280 g) were divided into 5 groups (n = 10 each) of control, sham surgery, Aβ-received sedentary, Aβ-received with aerobic exercise and Aβ-received with resistance exercise. AD was induced by intracerebroventricular injection of Aβ25-35 peptide. The sham surgery group received normal saline using the same route and condition. Two groups of Aβ-received animals were trained by treadmill for aerobic exercise and by ladder for strength exercise for 8 weeks (4 days/week). Novel object recognition (NOR) task was used to assess recognitional memory in groups. AChE activity in the brain tissue was assessed using the Spectrophotometry method. There was no significant difference in memory index and AChE activity between the sham surgery and control groups (p > 0.05). Also, impairment of NOR indices was seen in the Aβ-injected sedentary rats (p < 0.05). However, both aerobic and strength training improved the exploration index in this test (p < 0.05). Further, AChE activity increased in the Aβ-injected sedentary group but declined in the aerobic and resistance exercise groups (p < 0.01). Aerobic and resistance exercise could improve recognition memory and decrease AChE activity in Aβ-induced AD in rats. The decrease in AChE activity may be one of the mechanisms by which exercise improves cognition and memory in AD.


Prognostic value of pretreatment diffusion-weighted magnetic resonance imaging for outcome prediction of colorectal cancer liver metastases undergoing 90Y-microsphere radioembolization.
To investigate the clinical potential of pretreatment apparent diffusion coefficient (ADC) on diffusion-weighted magnetic resonance imaging (DWI) for therapy response and outcome prediction in patients with liver-predominant metastatic colorectal cancer (CRC) undergoing radioembolization with 90Yttrium-microspheres (90Y-RE). Forty-six consecutive patients with unresectable CRC liver metastases underwent standardized clinical DWI on a 1.5 T MR scanner prior to and 4-6 weeks after 90Y-RE. Pretreatment clinical parameters, ADC values derived from region-of-interest analysis, and the corresponding tumor sizes of three treated liver metastases per subject were recorded. Long-term tumor response to radioembolization was categorized into response (partial remission) and nonresponse (stable disease, progressive disease) according to Response Evaluation Criteria in Solid Tumors v1.1 (RECIST) 3 months after treatment. Associations between long-term tumor response and the clinical and imaging parameters were evaluated. The impact of pretreatment clinical and imaging parameters on progression-free survival (PFS) and overall survival (OS) was further assessed by Kaplan-Meier and multivariate Cox-regression analyses. Nonresponders had higher hepatic tumor burden (p = 0.021) and lower ADC values than patients responding to 90Y-RE, both pretreatment (986 ± 215 vs. 1162 ± 178; p = 0.036) and posttreatment (1180 ± 350 vs. 1598 ± 225; p = 0.002). ADC values higher than 935 × 10-6 mm2 (5 vs. 3 months; p = 0.022) and hepatic tumor burden ≤25% (6 vs. 3 months; p = 0.014) were associated with longer median PFS, whereas ADC >935 × 10-6 mm2 (14 vs. 6 months; p = 0.02), hepatic tumor burden ≤25% (14 vs. 6 months; p = 0.048), size of the largest metastasis <4.7 cm (18 vs. 7 months; p = 0.024), and Eastern Cooperative Oncology Group (ECOG) score <1 (8 vs. 5 months; p = 0.045) were associated with longer median OS. On multivariate analysis, ADC >935 × 10-6 mm2 and hepatic tumor burden ≤25% remained prognostic factors for PFS, and ADC >935 × 10-6 mm2 and size of the largest metastasis <4.7 cm were independent predictors of OS. Pretreatment ADC on DWI represents a valuable prognostic biomarker for predicting both the therapeutic efficacy and survival prognosis in CRC liver metastases treated by 90Y-RE, allowing risk stratification and potentially optimizing further treatment strategies.


Cost analysis of coronavirus disease 2019 test strategies using pooled reverse transcriptase-polymerase chain reaction technique.
This study aimed to compare the testing strategies for COVID-19 (i.e., individual, simple pooling, and matrix pooling) in terms of cost. We simulated the total expenditures of each testing strategy for running 10,000 tests. Three parameters were used: positive rate (PR), pool size, and test cost. We compared the total testing costs under two hypothetical scenarios in South Korea. We also simulated country-specific circumstances in India, South Africa, South Korea, the UK, and the USA. At extreme PRs of 0.01% and 10%, simple pooling was the most economic option and resulted in cost reductions of 98.0% (pool size ≥80) and 36.7% (pool size = 3), respectively. At moderate PRs of 0.1%, 1%, 2%, and 5%, the matrix pooling strategy was the most economic option and resulted in cost reductions of 97.0% (pool size ≥88), 86.1% (pool size = 22), 77.9% (pool size = 14), and 59.2% (pool size = 7), respectively. In both hypothetical scenarios of South Korea, simple pooling costs less than matrix pooling. However, the preferable options for achieving cost savings differed depending on each country's cost per test and PRs. Both pooling strategies resulted in notable cost reductions compared with individual testing in most scenarios pertinent to real-life situations. The appropriate type of testing strategy should be chosen by considering the PR of COVID-19 in the community and the test cost while using an appropriate pooling size such as five specimens.


William Allen Miller (1817-70): a distinguished scientist re-discovered.
Dr William Allen Miller developed an early interest in science and astronomy at secondary school. Although qualifying in medicine, he pursued a career in Chemistry at King's College, London. A particular interest in spectrum analysis led to a collaboration with Dr Huggins in examining the spectra of stars. For this work they each received the Gold Medal of the Royal Astronomical Society. His subsequent work at King's College, the Royal Society, the Courts of Law and for various Government enterprises earned him an outstanding scientific and advisory reputation.


The management of melanoma.
Total surgical excision of melanoma is necessary to prevent potentially fatal distant metastases in vital organs. Systemic management includes the use of hormones, chemotherapy, and immunotherapy.


Radioligand-labeled binding assay and immunochemical assay for estrogen receptor in 115 human breast cancers.
The aim of this study was to evaluate the results obtained from a new enzyme immunoassay (Abbott-ER-EIA) for the determination of estrogen receptor levels in tumor cytosols in comparison with the currently used DCC method. One hundred and fifteen consecutive primary breast cancer specimens were examined; 66 of the women were postmenopausal and 49 were premenopausal. A good correlation (r = 0.88, p less than 0.001 and a slope of 1.3) was found between ER-EIA and the steroid binding assay (DCC). When these data were analyzed according to menopausal status, no differences were observed for the slopes and correlation coefficients in pre' and postmenopausal groups. The ER-EIA appears to produce results comparable to those obtained with the conventional DCC method for the determination of ER in breast tumor cytosols.


Development of Laboratory Parameters-Based Formulas in Predicting Short Outcomes for Adult Hemophagocytic Lymphohistiocytosis Patients with Different Underlying Diseases.
Hemophagocytic lymphohistiocytosis (HLH) is a severe disease with high mortality. The purpose of this investigation was to build models to predict 30-day death in total and subgroup HLH patients based on available and cheap laboratory parameters. The research contained 431 adults HLH patients from January 2015 to September 2021 in the hospital. Logistic regression and receiver operating characteristic (ROC) were utilized to build models. Results suggested that age, ferritin, lymphocyte (LY), international normalized ratio (INR), thrombin time (TT), globulin, uric acid (UA), chloride, activated partial thromboplastin time (APTT), aspartate aminotransferase (AST), triglycerides (TG), total bilirubin (TB), and indirect bilirubin (IB) were independent factors in HLH and subgroups. Then, models adapted to patients with different underlying diseases were established based on these factors. Area under curve (AUC) of these models was excellent: HLH patients: 0.838 (p < 0.001); infection-associated HLH (I-HLH) patients: 0.913 (p < 0.001); malignancy-associated HLH (M-HLH): 0.921 (p < 0.001) and 0.809 (p < 0.001) for two or more different etiologies-associated HLH (Mix-HLH patients). In addition, UA, TT, and chloride were firstly confirmed as independent factors in adult HLH. Four models depending on biomarkers that available and affordable in clinical practice were built. With these models, high-risk patients with different underlying diseases could be easily identified.


A further study of the cytotoxic constituents of a milnamide-producing sponge.
A reinvestigation of Auletta sp. yielded the novel compound milnamide C (3) plus the known compounds milnamide A (1), milnamide B (hemiasterlin) (2), jasplakinolide (5), and geodiamolides A (6), D (7), E (8), and G (9). The isolation work was guided by cytoskeletal bioactivity data. Compounds 2 and 3 were shown to cause microtubule depolymerization, and 6-9 were shown to cause microfilament disruption. This biological activity and the structural elucidation of 3, including X-ray analysis, are reported here. [structure: see text]


How to perform breast augmentation safely for a pectus excavatum patient.
Pectus excavatum is the most common chest wall deformity. Women with pectus excavatum may have associated hypoplastic breasts and often desire breast augmentation. This report describes how to perform breast augmentation safely for a pectus excavatum patient. In the past 5 years, the authors have treated 11 women with hypoplastic breasts and pectus excavatum. Their ages have varied from 21 to 39 years. The women generally were healthy without cardiovascular function impairment. Four of the women had breast asymmetry, with a smaller right breast. It was decided to use wide silicone implants to augment the breast and to camouflage the chest wall deformity. The implants were placed under the pectoralis major muscle in all cases. The follow-up period varied from 10 months to 4.5 years. No acute or late complications related to the breast augmentation were encountered. All the patients were satisfied with the result, and none desired further surgical treatment for pectus excavatum. For two patients, a small depression in the upper part of the breast was persistent after surgery due to insufficient implant coverage. Most women with pectus excavatum desire to have the deformity corrected with minimal or no scarring. The chest is known to be an area prone to hypertrophic or keloid scars. The reported approach is simple and safe, easily camouflaging the deformity. It is a short procedure that results in high satisfaction.


Left ventricular approach to multiple ventricular septal defects.
Multiple muscular ventricular septal defects were closed through an apical left ventriculotomy in 11 patients. The patients were divided into two groups: Group 1, 8 patients who had transposition of the great arteries, and group 2, 3 patients without transposition. There were 4 deaths in Group 1 and non in Group 2. Two of the deaths were caused by a hypoplastic right ventricle, 1 by airway obstruction, and 1 by heart failure and pulmonary edema in a patient who had additional unrecognized muscular defects. An apical left ventriculotomy provides excellent exposure of the septum. The field is not obscured by trabecular bands or papillary muscles. Although 1 patient died because of residual VSDs, this approach, compared with previously described methods, minimizes the risk of unrecognized defects.


C-reactive protein--an indicator of generalized bacterial infection in children with nephrotic syndrome.
The usefulness of C-reactive protein for detecting bacterial infections in children with nephrotic syndrome was studied in 12 children who had a total of 29 episodes of infection. Four episodes were septic, with CRP values of 127-270 mg/l and 25 superficial or focal with all CRP values below 47 mg/l; 13 were below 10 mg/l. CRP thus discriminated the invasive bacterial diseases from other infections. It was not affected by the nephrotic syndrome activity.


A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer. GOIM (Gruppo Oncologico Italia Meridionale) 9902 study.
The Gruppo Oncologico Italia Meridionale 9902 trial compared four cycles of high-dose epirubicin plus cyclophosphamide (EC) with four cycles of docetaxel (Taxotere, D) followed by four cycles of EC as adjuvant treatment of node-positive breast cancer. Patients were randomly assigned to EC (E 120 mg/m(2), C 600 mg/m(2), arm A) for four cycles or four cycles of D (100 mg/m(2)) followed by four cycles of EC (arm B), both regimens every 21 days. Hormone receptor-positive patients were given hormonal therapy for 5 years. Primary end point was 5-year disease-free survival (DFS). Secondary objectives were overall survival (OS) and safety. There were 750 patients enrolled. With a median follow-up of 64 months, 5-year DFS was 73.4% in both arms, and 5-year OS was 89.5% versus 90.7% in arm A and B [hazard ratio was 0.99 (95% confidence interval for DFS 0.75-1.31; P = 0.95)], respectively. Grade 3-4 toxicity was more common in arm B. This study did not show advantages from the addition of docetaxel to high-dose EC as adjuvant chemotherapy in node-positive breast cancer. The small sample size and low number of DFS events may have limited the ability to observe statistically significant difference between the two arms.


Pharmaceutical analysis by a novel spinel ferrite nanocomposite derived from a biomaterial-based activated carbon.
Microwave-assisted activated carbon was fabricated from lentil waste (LW) by K2CO3 chemical activation at optimum production conditions and the synthesized optimal activated carbon (LWAC) with a high surface area (1875 m2/g) was used as a matrix for spinel ferrite composite production. CuFe2O4 nanoparticles were embedded to LWAC and a novel magnetic composite material (M-LWAC) was synthesized. A detailed structural and textural analysis of M-LWAC was made by using various characterization techniques. M-LWAC was also used as an effectual remover for tetracycline (TC) bearing wastewater with 384.62 mg/g of adsorption capacity. Kinetic, isotherm and thermodynamic analyses indicated the fast, effective and spontaneous adsorption of TC by M-LWAC.


Response to standard of care antiviral treatment in patients with HCV liver cirrhosis - a systematic review.
Patients with HCV liver cirrhosis are a category difficult to treat. The aim of this study was to establish the sustained virological response (SVR) rates in HCV patients with liver cirrhosis treated with standard of care therapy (Pegylated Interferon and Ribavirin for 48 weeks in genotypes 1 and 4 and 24 weeks in genotypes 2 and 3). Searching the PubMed, Medline, Lilacs, Scopus, Ovid and Medscape databases we identified all the articles published until February 2011 that included only HCV cirrhotic patients. These studies evaluated the SVR after standard of care treatment: Pegylated Interferon alpha 2a (doses ranging between 135-180 µg/week) or Pegylated Interferon alpha 2b (1 or 1.5 µg/kg/week) and Ribavirin (doses ranging between 800-1200 mg/day). We used the following key words: HCV, liver cirrhosis, sustained virological response (SVR). The overall SVR rate was 33.3% (95%CI-confidence interval=30.6-36.2%). SVR was significantly higher in patients with genotypes 2 and 3 (422 patients) as compared to those with genotypes 1 and 4 (692 patients): 55.4% (95%CI=50.7-60.1) versus 21.7% (95%CI=18.7-25), p < 0.0001. The overall SVR rate in cirrhotic patients treated with standard of care therapy is 33.3%, but lower in cases affected by genotypes 1 and 4 (21.6%) which makes them a priority regarding the development of more potent drugs for effective treatment.


Metabolic changes during gonadotropin-releasing hormone agonist therapy for prostate cancer: differences from the classic metabolic syndrome.
In men with prostate cancer, gonadotropin-releasing hormone (GnRH) agonists increase fat mass, decrease insulin sensitivity, and increase triglycerides, features that are shared with metabolic syndrome. To the authors' knowledge, however, less is known regarding the effects of GnRH agonists on other attributes of the metabolic syndrome. In an open-label prospective study, 26 men with recurrent or locally advanced prostate cancer were treated with leuprolide for 12 months. Outcomes included changes in blood pressure, body composition, lipids, adipocytokines, and C-reactive protein. The mean weight, body mass index, and waist circumference increased significantly from baseline to Month 12 (P < .001 for each comparison). Fat mass increased by 11.2% +/- 1.5% (P < .001) and the percentage lean body mass decreased by 3.6% +/- 0.5% (P < .001). The total abdominal fat area increased by 16.5% +/- 2.6% (P < .001), with the accumulation of subcutaneous fat accounting for 94% of the observed increase. The waist-to-hip ratio and blood pressure did not change significantly. Serum high-density lipoprotein (HDL) cholesterol concentrations increased significantly (P = .002). Serum adiponectin levels increased by 36.4 +/- 5.9% from baseline to Month 3 and remained significantly elevated through Month 12 (P < .001). Resistin and C-reactive protein levels did not change significantly. The term metabolic syndrome does not appear to adequately describe the effects of GnRH agonists in men with prostate cancer. In contrast to the metabolic syndrome, GnRH agonists increase subcutaneous fat mass, HDL cholesterol, and adiponectin, and do not alter the waist-to-hip ratio, blood pressure, or C-reactive protein level.


Metagenomic Next-Generation Sequencing for Pathogens in Bronchoalveolar Lavage Fluid Improves the Survival of Patients with Pulmonary Complications After Allogeneic Hematopoietic Stem Cell Transplantation.
Unbiased metagenomic next-generation sequencing (mNGS) has been used for infection diagnosis. In this study, we explored the clinical diagnosis value of mNGS for pulmonary complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). From August 2019 to June 2021, a prospective study was performed to comparatively analyze the pathogenic results of mNGS and conventional tests for bronchoalveolar lavage fluid (BALF) from 134 cases involving 101 patients with pulmonary complications after allo-HSCT. More pathogens were identified by mNGS than with conventional tests (226 vs 120). For bacteria, the diagnostic sensitivity (P = 0.144) and specificity (P = 0.687) were similar between the two methods. For fungus except Pneumocystis jirovecii (PJ), conventional tests had a significantly higher sensitivity (P = 0.013) with a similarly high specificity (P = 0.109). The sensitivities for bacteria and fungi could be increased with the combination of the two methods. As for PJ, both the sensitivity (100%) and specificity (99.12%) of mNGS were very high. For viruses, the sensitivity of mNGS was significantly higher (P = 0.021) and the negative predictive value (NPV) was 95.74% (84.27-99.26%). Pulmonary infection complications accounted for 90.30% and bacterium was the most common pathogen whether in single infection (63.43%) or mixed infection (81.08%). The 6-month overall survival (OS) of 88.89% in the early group (mNGS ≤ 7 days) was significantly higher than that of 65.52% (HR 0.287, 95% CI 0.101-0.819, P = 0.006) in the late group (mNGS > 7 days). mNGS for BALF could facilitate accurate and fast diagnosis for pulmonary complications. Early mNGS could improve the prognosis of patients with pulmonary complications after allo-HSCT. ClinicalTrials.gov identifier, NCT04051372.


A flexible optoacoustic blood 'stethoscope' for noninvasive multiparametric cardiovascular monitoring.
Quantitative and multiparametric blood analysis is of great clinical importance in cardiovascular disease diagnosis. Although there are various methods to extract blood information, they often require invasive procedures, lack continuity, involve bulky instruments, or have complicated testing procedures. Flexible sensors can realize on-skin assessment of several vital signals, but generally exhibit limited function to monitor blood characteristics. Here, we report a flexible optoacoustic blood 'stethoscope' for noninvasive, multiparametric, and continuous cardiovascular monitoring, without requiring complicated procedures. The optoacoustic blood 'stethoscope' features the light delivery elements to illuminate blood and the piezoelectric acoustic elements to capture light-induced acoustic waves. We show that the optoacoustic blood 'stethoscope' can adhere to the skin for continuous and non-invasive in-situ monitoring of multiple cardiovascular biomarkers, including hypoxia, intravascular exogenous agent concentration decay, and hemodynamics, which can be further visualized with a tailored 3D algorithm. Demonstrations on both in-vivo animal trials and human subjects highlight the optoacoustic blood 'stethoscope''s potential for cardiovascular disease diagnosis and prediction.


Chicken collagen hydrolysate cryoprotection of natural actomyosin: Mechanism studies during freeze-thaw cycles and simulated digestion.
The cryoprotective effect of chicken collagen hydrolysate (CCH) obtained from chicken skin was investigated at 0%, 4%, 8% and 12% (w/w) on natural actomyosin (NAM) model system to elucidate the possible mechanism. Ice dimensions in the NAM dispersions were measured after 7 thermal cycles (stabilized at -20°C and cycled between -16°C to -12°C) using a polarized microscope, demonstrating a significant reduction of ice crystal size induced by CCH. To determine the ice-controlling effect of CCH on protein freeze-denaturation, NAM samples were subjected to 7 freeze-thaw cycles between -20°C and 4°C. The results suggest that the presence of CCH can inhibit the ice crystals growth in NAM to reduce protein freeze-denaturation and oxidation similarly to the commercial cryoprotectants, resulting in higher protein solubility and a better gel structure with higher digestibility after freeze-thaw cycles.


The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes.
Podocytes are specialized epithelial cells that maintain the glomerular filtration barrier. These cells are susceptible to lipotoxicity in the obese state and irreversibly lost during kidney disease leading to proteinuria and renal injury. PPARγ is a nuclear receptor whose activation can be renoprotective. This study examined the role of PPARγ in the lipotoxic podocyte using a PPARγ knockout (PPARγKO) cell line and since the activation of PPARγ by Thiazolidinediones (TZD) is limited by their side effects, it explored other alternative therapies to prevent podocyte lipotoxic damage. Wild-type and PPARγKO podocytes were exposed to the fatty acid palmitic acid (PA) and treated with the TZD (Pioglitazone) and/or the Retinoid X receptor (RXR) agonist Bexarotene (BX). It revealed that podocyte PPARγ is essential for podocyte function. PPARγ deletion reduced key podocyte proteins including podocin and nephrin while increasing basal levels of oxidative and ER stress causing apoptosis and cell death. A combination therapy of low-dose TZD and BX activated both the PPARγ and RXR receptors reducing PA-induced podocyte damage. This study confirms the crucial role of PPARγ in podocyte biology and that their activation in combination therapy of TZD and BX may be beneficial in the treatment of obesity-related kidney disease.


Synchronous bilateral breast carcinoma and axillary non-hodgkin lymphoma: a case report and review of the literature.
The use of staging imaging modalities with increased sensitivity has led to an increase in the incidence of detection of simultaneous malignancies. These cases require careful evaluation and discussion in a multidisciplinary setting to establish a treatment plan that optimizes the outcome with respect to each malignancy, particularly when treatment modalities overlap. We report a case of a patient diagnosed with axillary nodal diffuse large B-cell lymphoma (DLBCL) in a community hospital where staging workup also revealed synchronous bilateral breast carcinomas. To our knowledge, this is only the second case report of a patient with three synchronous primary malignancies: bilateral breast carcinomas and axillary DLBCL. The only other similar case report had no role for radiation or chemotherapy in the management of the indolent follicular lymphoma.


Tumor necrosis factor-alpha and interleukin-18 modulate neuronal cell fate in embryonic neural progenitor culture.
Neural progenitor cells (NPCs) in developing and adult CNS are capable of giving rise to various neuronal and glial cell populations. Neurogenesis in the adult hippocampus has been found to be inhibited by a proinflammatory cytokine, interleukin-6 (IL-6), suggesting that activated microglia in the inflamed brain may control neurogenesis. Yet, little is known about the effect of microglia-derived factors on the cell fate of embryonic NPCs. In this study, we show that neurons with betaIII-tubulin immunoreactivity in the NPC culture were reduced by the condition media collected from microglia treated with endotoxin lipopolysaccharide (LPS/M-CM). Treatment with pentoxifylline (PTX), an inhibitor for tumor necrosis factor-alpha (TNF-alpha) secretion from LPS-activated microglia, blocked the reduction of betaIII-tubulin+ cells in NPC culture. Furthermore, treatment of NPCs with interleukin-18 (IL-18), a recently discovered proinflammatory cytokine, also decreased the number of betaIII-tubulin+ cells in a dose- and time-dependent manner. Surprisingly, we also observed that the remaining betaIII-tubulin+ cells in the LPS/M-CM-treated culture exhibited more branching neurites. Thus, the activated microglia-derived cytokines, TNF-alpha and IL-18, may either inhibit the neuronal differentiation or induce neuronal cell death in the NPC culture, whereas these cells may also produce factors to improve the neurite branching in the NPC culture.


Hypodiploidy has unfavorable impact on survival in pediatric acute myeloid leukemia: an I-BFM Study Group collaboration.
Hypodiploidy, defined as modal numbers (MNs) 45 or lower, has not been independently investigated in pediatric acute myeloid leukemia (AML) but is a well-described high-risk factor in pediatric acute lymphoblastic leukemia. We aimed to characterize and study the prognostic impact of hypodiploidy in pediatric AML. In this retrospective cohort study, we included children below 18 years of age with de novo AML and a hypodiploid karyotype diagnosed from 2000 to 2015 in 14 childhood AML groups from the International Berlin-Frankfurt-Münster (I-BFM) framework. Exclusion criteria comprised constitutional hypodiploidy, monosomy 7, composite karyotype, and t(8;21) with concurring sex chromosome loss. Hypodiploidy occurred in 81 patients (1.3%) with MNs, 45 (n = 66); 44 (n = 10) and 43 (n = 5). The most frequently lost chromosomes were chromosome 9 and sex chromosomes. Five-year event-free survival (EFS) and overall survival (OS) were 34% and 52%, respectively, for the hypodiploid cohort. Children with MN≤44 (n = 15) had inferior EFS (21%) and OS (33%) compared with children with MN = 45 (n = 66; EFS, 37%; OS, 56%). Adjusted hazard ratios (HRs) were 4.9 (P = .001) and 6.1 (P = .003). Monosomal karyotype or monosomy 9 had particular poor OS (43% and 15%, respectively). Allogeneic stem cell transplantation (SCT) in first complete remission (CR1) (n = 18) did not mitigate the unfavorable outcome of hypodiploidy (adjusted HR for OS was 1.5; P = .42). We identified pediatric hypodiploid AML as a rare subgroup with an inferior prognosis even in the patients treated with SCT in CR1.


Altered fecal microbiome and metabolome in adult patients with non-cystic fibrosis bronchiectasis.
Emerging experimental and epidemiological evidence highlights a crucial cross-talk between the intestinal flora and the lungs, termed the "gut-lung axis". However, the function of the gut microbiota in bronchiectasis remains undefined. In this study, we aimed to perform a multi-omics-based approach to identify the gut microbiome and metabolic profiles in patients with bronchiectasis. Fecal samples collected from non-CF bronchiectasis patients (BE group, n = 61) and healthy volunteers (HC group, n = 37) were analyzed by 16 S ribosomal RNA (rRNA) sequencing. The BE group was divided into two groups based on their clinical status: acute exacerbation (AE group, n = 31) and stable phase (SP group, n = 30). Further, metabolome (lipid chromatography-mass spectrometry, LC-MS) analyses were conducted in randomly selected patients (n = 29) and healthy volunteers (n = 31). Decreased fecal microbial diversity and differential microbial and metabolic compositions were observed in bronchiectasis patients. Correlation analyses indicated associations between the differential genera and clinical parameters such as bronchiectasis severity index (BSI). Disease-associated gut microbiota was screened out, with eight genera exhibited high accuracy in distinguishing SP patients from HCs in the discovery cohort and validation cohort using a random forest model. Further correlation networks were applied to illustrate the relations connecting disease-associated genera and metabolites. The study uncovered the relationships among the decreased fecal microbial diversity, differential microbial and metabolic compositions in bronchiectasis patients by performing a multi-omics-based approach. It is the first study to characterize the gut microbiome and metabolome in bronchiectasis, and to uncover the gut microbiota's potentiality as biomarkers for bronchiectasis. This study is registered with ClinicalTrials.gov, number NCT04490447.


Ca2+ entry pathways activated by the tumor promoter thapsigargin in human platelets.
Thapsigargin-activated Ca2+ entry into platelets was examined in the presence of S-145, a thromboxane A2 receptor antagonist, to inhibit indirect effects by endogenously formed prostaglandin H2/thromboxane A2. With external Ca2+ present, 0.2 microM thapsigargin caused a prompt increase in intracellular Ca2+ concentration ([Ca2+]i) followed by a gradual increase. Pretreatment with 6 microM wortmannin, a specific inhibitor of myosin light chain kinase, partly inhibited the increase in [Ca2+]i. In Ca(2+)-free EGTA buffer, thapsigargin induced a smaller increase in [Ca2+]i, and subsequent addition of Ca2+ to the buffer caused a further prompt increase in [Ca2+]i, demonstrating external Ca2+ entry. Wortmannin only partly inhibited this entry of external Ca2+. The wortmannin-insensitive Ca2+ entry pathway remained open for more than 6 min in Ca(2+)-free buffer. On the other hand, when receptor agonists such as thrombin and U46619 were substituted for thapsigargin, activation of the wortmannin-insensitive Ca2+ entry was transient (Hashimoto et al., J. Biol. Chem (1992) 267, 17078-17081). In the presence of S-145 and wortmannin, thapsigargin stimulated phosphorylation of neither the 20-kDa myosin light chain nor the 47-kDa protein, a substrate of protein kinase C. These results suggest that thapsigargin induces external Ca2+ entry by two mechanisms: (1) a mechanism involving myosin light chain kinase; (2) a mechanism, not activated by receptor agonists, that is independent of the major protein kinases of platelets.


Serial bideposition of anisotropic thin films with enhanced linear birefringence.
We describe a serial bideposition technique in which a tilted substrate is rotated stepwise by half a turn about a normal axis during the evaporation of a metal oxide from a single electron-beam source. Coatings formed by the new method develop a columnar nanostructure that is perpendicular to the substrate and has greatest width or bunching perpendicular to the common deposition plane. With appropriate choice of deposition parameters, the method produces biaxial films with large birefringence, principal axes aligned parallel and perpendicular to the substrate, and improved uniformity. Measured phase retardances for light incident normally on the films are double the corresponding values for tilted-columnar films.


Mutants of Escherichia coli K12 unable to grow on non-fermentable carbon substrates.
Among a number of mutants unable to utilize non-fermentable carbon substrates, scoring for membrane ATPase and for ATP-driven transhydrogenase activity permitted to distinguish two phenotypes: (A) mutants lacking ATPase and ATP-driven transhydrogenase; (B) one mutant with an ATPase which behaved according to several criteria as released into solution instead of being membrane bound, a.o it exhibited no ATP-driven transhydrogenase activity. All A and B mutants exhibited a common nutritional pattern. The ATPase-deficient group, when scored for ATPase-binding sites on its membrane particles revealed three different subgroups: (1) mutants having free ATPase-binding sites, (2) mutants with ATPase-binding sites made available by the procedure which releases ATPase from wild-type membrane, and (3) mutants with no detectable ATPase-binding sites. Membranes of the mutant B with unbound ATPase also exhibited a deficiency in ATPase-binding sites, but its soluble ATPase was also found unable to bind to ATPase-binding sites of wild type membranes. The double alteration, namely abnormal or inactive ATPase and absence of ATPase-binding sites on the membrane is compatible with a single mutational defect.


Customized guide for transmucosal pterygomaxillary disjunction: Proof of concept.
Potential complications related to pterygomaxillary disjunction have been widely described in the literature, most of them being due to the inaccurate and blind approach involved. The present study used preoperative virtual planning to establish a surgical cutting guide for pterygomaxillary osteotomy. It was placed in the maxillary tuberosity supported by molars, and a flapless vertical osteotomy was performed with a piezoelectric saw. Then, maxillary down-fracture was performed with slight pressure through an anterior approach. The use of the surgical guide added accuracy and predictability to the procedure, with no prolongation of the surgery time. There were no undesired fractures or bleeding. Regarding manipulation of the surgical guide in the posterior area, it was found to be easily manageable and very stable over the posterior teeth, due to its small size and precision, respectively. In conclusion, this technique seems to improve the accuracy of pterygomaxillary disjunction without prolonging the surgery time. Furthermore, it reduces potential complications related to the conventional procedure. Nevertheless, a larger body of patient data is needed to confirm the benefits of the technique.


Divergence, recombination and retention of functionality during protein evolution.
We have only a vague idea of precisely how protein sequences evolve in the context of protein structure and function. This is primarily because structural and functional contexts are not easily predictable from the primary sequence, and evaluating patterns of evolution at individual residue positions is also difficult. As a result of increasing biodiversity in genomics studies, progress is being made in detecting context-dependent variation in substitution processes, but it remains unclear exactly what context-dependent patterns we should be looking for. To address this, we have been simulating protein evolution in the context of structure and function using lattice models of proteins and ligands (or substrates). These simulations include thermodynamic features of protein stability and population dynamics. We refer to this approach as 'ab initio evolution' to emphasise the fact that the equilibrium details of fitness distributions arise from the physical principles of the system and not from any preconceived notions or arbitrary mathematical distributions. Here, we present results on the retention of functionality in homologous recombinants following population divergence. A central result is that protein structure characteristics can strongly influence recombinant functionality. Exceptional structures with many sequence options evolve quickly and tend to retain functionality--even in highly diverged recombinants. By contrast, the more common structures with fewer sequence options evolve more slowly, but the fitness of recombinants drops off rapidly as homologous proteins diverge. These results have implications for understanding viral evolution, speciation and directed evolutionary experiments. Our analysis of the divergence process can also guide improved methods for accurately approximating folding probabilities in more complex but realistic systems.


Cooperative effect of carborane and pyridine in the reaction of carboranyl alcohols with thionyl chloride: halogenation versus oxidation.
Thionyl chloride (SOCl2) acts as halogenation reagent in its reaction with 1-[phenyl(hydroxy)methyl]-2-R-1,2-dicarba-closo-dodecaborane 1a, b but unexpectedly behaves as an oxidant for 1-[2'-pyridyl(hydroxy)methyl]-2-R-1,2-dicarba-closo-dodecaboranes 2a, b. The synthesis and characterization of all new compounds, including structure determinations of 1a, 2a, 1-[phenyl(chloro)methyl]-2-methyl-1,2-dicarba-closo-dodecaborane 3a, and 1-[2'-pyridyl(oxo)methyl]-2-methyl-1,2-dicarba-closo-dodecaboranes 4a are reported and the possible pathways are discussed.