Impact of known risk factors on endometrial cancer burden in Chinese women.
This study aimed to provide data on the impact of known risk factors on endometrial cancer burden. Using data on 1199 endometrial cancer cases and 1212 frequency matched controls from a population-based case-control study carried out in urban Shanghai, China from 1997 to 2003, multivariable adjusted odds ratios were obtained from unconditional logistic regression analyses. Partial population-attributable risks were calculated and corresponding 95% confidence intervals were estimated using a bootstrap method. An estimated 16.94% of endometrial cancer cases were attributed to overweight or obesity; 8.39% to meat intake; 5.45% to nonregular tea drinking; 5.23% to physical inactivity; and 1.77% to family history of endometrial, breast, or colorectal cancers. Overall, these risk factors accounted for 36.01% (95% confidence interval: 28.55-43.11%) of total endometrial cancer cases. Similar results were observed when analysis was restricted to postmenopausal women. Among modifiable lifestyle factors, overweight and obesity accounted for the largest proportion of endometrial cancer in the study population. Lifestyle alterations, such as maintenance of healthy weight, regular exercise, consumption of less meat, and tea drinking, could potentially reduce endometrial cancer by more than one-third.


Mechanoreception at the cellular level: the detection, interpretation, and diversity of responses to mechanical signals.
Cells from diverse tissues detect mechanical load signals by similar mechanisms but respond differently. The diversity of responses reflects the genotype of the cell and the mechanical demands of the resident tissue. We hypothesize that cells maintain a basal equilibrium stress state that is a function of the number and quality of focal adhesions, the polymerization state of the cytoskeleton, and the amount of extrinsic, applied mechanical deformation. A load stimulus detected by a mechano-electrochemical sensory system, including mechanically sensitive ion channels, integrin-cytoskeleton machinery, and (or) a load-conformation sensitive receptor or nonreceptor tyrosine kinase, may activate G proteins, induce second messengers, and activate an RPTK or JAK/STAT kinase cascade to elicit a response. We propose the terms autobaric to describe a self-loading process, whereby a cell increases its stress state by contracting and applying a mechanical load to itself, and parabaric, whereby a cell applies a load to an adjacent cell by direct contact or through the matrix. We predict that the setpoint for maintaining this basal stress state is affected by continuity of incoming mechanical signals as deformations that activate signalling pathways. A displacement of the cytoskeletal machinery may result in a conformational change in a kinase that results in autophosphorylation and cascade initiation. pp60Src is such a kinase and is part of a mechanosensory protein complex linking integrins with the cytoskeleton. Cyclic mechanical load induces rapid Src phosphorylation. Regulation of the extent of kinase activation in the pathway(s) may be controlled by modulators such as G proteins, kinase phosphorylation and activation, and kinase inhibitors or phosphatases. Intervention at the point of ras-raf interaction may be particularly important as a restriction point.


Immunological features of primary anti-phospholipid syndrome in connection with endothelial dysfunction.
To describe how certain peripheral immune parameters reflect the inflammatory alterations in patients with primary APS. Twenty-eight patients with newly diagnosed primary APS were studied. The control group included 26 patients with stable coronary disease and 38 healthy individuals. Peripheral blood lymphocyte subgroups were quantified, intracellular cytokines were measured by flow cytometry, soluble cytokines and auto-antibodies were assessed using ELISA. Endothelial dysfunction was evaluated by measuring endothelium-dependent (flow-mediated; FMD) vasodilation. Carotid duplex ultrasound was performed to quantify the carotid artery intima-media thickness (IMT). Stiffness parameters, augmentation index (AIx) and pulse wave velocity (PWV) were assessed by TensioClinic technology. Serum IL-4 and IL-6 levels were significantly higher in APS. CD4+IL10+ and CD8+IL10+ cell percentages in APS were significantly increased compared with controls. Th 0 and T cytotoxic 0 cell percentages were significantly decreased in patients compared with controls. FMD in APS was significantly lower, while IMT was higher than that of controls. FMD showed strong association with stiffness parameters, AIx and PWV. A significant negative linear correlation was detected between PWV and CD8+IL10+ cell percentages and significant positive linear correlation was found between PWV and CD8+IL10- cell percentage. In APS, the orchestrated pro-inflammatory cascade can eventually result in endothelial dysfunction, leading to the characteristic vascular abnormalities of the disease.


Integration of visuospatial and effector information during symbolically cued limb movements in monkey lateral intraparietal area.
Natural behavior requires close but flexible coordination between attention, defined as selection for perception, and action. In recent years a distributed network including the lateral intraparietal area (LIP) has been implicated in visuospatial selection for attention and rapid eye movements (saccades), but the relation between the attentional and motor functions of this area remains unclear. Here we tested LIP neurons in a task that involved not an ocular but a manual operant response. Monkeys viewed a display containing one cue and several distractors and reported the orientation of the cue (right- or left-facing) by releasing one of two bars grasped, respectively, with the right or left hand. The movement in this task thus was associated with (cued by), but not directed toward, the visual stimulus. A large majority of neurons responded more when the cue rather than when a distractor was in their receptive field, suggesting that they contribute to the attentional selection of the cue. A fraction of these neurons also was modulated by limb release, thus simultaneously encoding cue location and the active limb. The results suggest that the LIP links behaviorally relevant visual information with motor variables relevant for solving a task in a wide range of circumstances involving goal-directed or symbolically cued movements and eye as well as limb movements. A central function of the LIP may be to coordinate visual and motor selection during a wide variety of behaviors.


Transcranial Electric Current Stimulation During Associative Memory Encoding: Comparing tACS and tDCS Effects in Healthy Aging.
Associative memory is one of the first cognitive functions negatively affected by healthy and pathological aging processes. Non-invasive brain stimulation (NIBS) techniques are easily administrable tools to support memory. However, the optimal stimulation parameters inducing a reliable positive effect on older adult's memory performance remain mostly unclear. In our randomized, double-blind, cross-over study, 28 healthy older adults (16 females; 71.18 + 6.42 years of age) received anodal transcranial direct (tDCS), alternating current in the theta range (tACS), and sham stimulation over the left ventrolateral prefrontal cortex (VLPFC) each once during encoding. We tested associative memory performance with cued recall and recognition tasks after a retention period and again on the following day. Overall, neither tDCS nor tACS showed effects on associative memory performance. Further analysis revealed a significant difference for performance on the cued recall task under tACS compared to sham when accounting for age. Our results suggest that tACS might be more effective to improve associative memory performance than tDCS in higher aged samples.


Mortality and knockdown effects of imidacloprid and methomyl in house fly (Musca domestica L., Diptera: Muscidae) populations.
In this study, the knockdown and mortality effects of imidacloprid and methomyl were investigated. The residual surface applications were carried out to determine the knockdown effects (KDt50 and KDt95) and mortality (LD50 and LD95) induced by each insecticide. For mortality comparisons, the susceptible house fly (Musca domestica L., Diptera: Muscidae) of a WHO population and three natural field-collected M. domestica populations from Turkey were used. In conclusion, it was found that the resistance to imidacloprid and methomyl was significantly higher in the field populations when compared to the susceptible population from WHO. The results showed that applicators and pest management decision-makers should control and conduct an integrated pest management strategy by including biological agents to prevent the development of high levels of resistance in the field populations.


Use of a phage display technique to identify potential osteoblast binding sites within osteoclast lacunae.
There is a temporal coupling between the processes of bone resorption and bone formation in normal skeletal remodeling. That is, osteoblastic activity usually follows episodes of osteoclastic activity. However, what has not been universally appreciated is that there also is a spatial coupling between these processes. Bone formation only occurs in the immediate vicinity of the resorptive event. In this study, we describe a phage display technique that has been used to identify the mechanisms by which osteoblasts recognize components of the prior resorbed lacunar surface. Using a type V tartrate-resistant acid phosphatase (TRAP) as the bait and a random peptide M13 phage display library as the probe, we have identified specific sequences that show a very high affinity for TRAP. One of these peptides, designated clone 5, has a subnanomolar Kd for TRAP, interacts with TRAP in a Far-Western assay, binds exclusively to TRAP within osteoclast lacunae, is present in osteoblasts, and can effectively block osteoblast binding to resorption surfaces. The clone 5 peptide shows a high homology to glypican 4 (GPC4), a proteoglycan attachment receptor found in a number of cell types.


Estrogen treatment enhances hereditary renal tumor development in Eker rats.
Hormonal influences are known to affect the development of renal cell carcinoma in man and laboratory animal models. We tested the hypothesis that estrogen treatment or ovariectomy of rats modulates renal tumor development using tuberous sclerosis 2 (Tsc2) heterozygous mutant (Eker) rats in which a germline mutation predisposes the animals to renal cell tumor development. Two-month-old female wild-type and Eker rats were ovariectomized or sham-operated and treated with placebo or 5 mg 17beta-estradiol in s.c. pellets for 6 or 10 months. Rats were examined at 8 or 12 months of age, at which time the numbers of renal tumors and preneoplastic foci were quantitated and the severity of nephropathy was assessed. In contrast to what may have been expected, prolonged estrogen treatment enhanced the development of hereditary renal cell tumors, with a 2-fold greater number of preneoplastic and neoplastic renal lesions compared with untreated Eker rats. Ovariectomized Eker rats had 33% fewer renal lesions than the unmanipulated control group. No tumors or preneoplastic lesions were present in wild-type rats at either time point. Estrogen treatment increased the severity of nephropathy in both wild-type and Eker rats, whereas ovariectomy was protective against nephropathic changes. Although estrogen is not a rat renal carcinogen, it enhanced the development of hereditary renal cell tumors when administered to Eker rats. Eker rats heterozygous for a mutation in the Tsc2 locus provide a good model in which to study how genetic and hormonal factors contribute to the development of renal cell tumors and to understand the influence genetic susceptibility has on the development of renal cell carcinoma.


Dilation of the influenza hemagglutinin fusion pore revealed by the kinetics of individual cell-cell fusion events.
We have monitored kinetics of fusion between cell pairs consisting of a single influenza hemaglutinin (HA)-expressing cell and a single erythrocyte (RBC) that had been labeled with both a fluorescent lipid (Dil) in the membrane and a fluorescent solute (calcein) in the aqueous space. Initial fusion pore opening between the RBC and HA-expressing cell produced a change in RBC membrane potential (delta psi) that was monitored by a decrease in Dil fluorescence. This event was followed by two distinct stages of fusion pore dilation: the flux of fluorescent lipid (phi L) and the flux of a large aqueous fluorescent dye (phi s). We have analyzed the kinetics of events that occur as a result of transitions between a fusion pore (FP) and a solute permissive fusion pore (FPs). Our data are consistent with a fusion pore comprising six HA trimers.


GFAP-BDP as an acute diagnostic marker in traumatic brain injury: results from the prospective transforming research and clinical knowledge in traumatic brain injury study.
Reliable diagnosis of traumatic brain injury (TBI) is a major public health need. Glial fibrillary acidic protein (GFAP) is expressed in the central nervous system, and breakdown products (GFAP-BDP) are released following parenchymal brain injury. Here, we evaluate the diagnostic accuracy of elevated levels of plasma GFAP-BDP in TBI. Participants were identified as part of the prospective Transforming Research And Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study. Acute plasma samples (<24 h post-injury) were collected from patients presenting with brain injury who had CT imaging. The ability of GFAP-BDP level to discriminate patients with demonstrable traumatic lesions on CT, and with failure to return to pre-injury baseline at 6 months, was evaluated by the area under the receiver operating characteristic curve (AUC). Of the 215 patients included for analysis, 83% had mild, 4% had moderate, and 13% had severe TBI; 54% had acute traumatic lesions on CT. The ability of GFAP-BDP level to discriminate patients with traumatic lesions on CT as evaluated by AUC was 0.88 (95% confidence interval [CI], 0.84-0.93). The optimal cutoff of 0.68 ng/mL for plasma GFAP-BDP level was associated with a 21.61 odds ratio for traumatic findings on head CT. Discriminatory ability of unfavorable 6 month outcome was lower, AUC 0.65 (95% CI, 0.55-0.74), with a 2.07 odds ratio. GFAP-BDP levels reliably distinguish the presence and severity of CT scan findings in TBI patients. Although these findings confirm and extend prior studies, a larger prospective trial is still needed to validate the use of GFAP-BDP as a routine diagnostic biomarker for patient care and clinical research. The term "mild" continues to be a misnomer for this patient population, and underscores the need for evolving classification strategies for TBI targeted therapy. (ClinicalTrials.gov number NCT01565551; NIH Grant 1RC2 NS069409).


Lateralized response of skull bone marrow via osteopontin signaling in mice after ischemia reperfusion.
Skull bone marrow is thought to be an immune tissue closely associated with the central nervous system (CNS). Recent studies have focused on the role of skull bone marrow in central nervous system disorders. In this study, we performed single-cell RNA sequencing on ipsilateral and contralateral skull bone marrow cells after experimental stroke and then performed flow cytometry and analysis of cytokine expression. Skull marrow showed lateralization in response to stroke. Lateralization is demonstrated primarily by the proliferation and differentiation of myeloid and lymphoid lineage cells in the skull bone marrow adjacent to the ischemic region, with an increased proportion of neutrophils compared to monocytes. Analysis of chemokines in the skull revealed marked differences in chemotactic signals between the ipsilateral and contralateral skull, whereas sympathetic signals innervating the skull did not affect cranial bone marrow lateralization. Osteopontin (OPN) is involved in region-specific activation of the skull marrow that promotes inflammation in the meninges, and inhibition of OPN expression improves neurological function.


The transcription factor, Lmx1b, is necessary for the development of the principal trigeminal nucleus-based lemniscal pathway.
Little is known of transcriptional mechanisms underlying the development of the trigeminal (V) principal sensory nucleus (PrV), the brainstem nucleus responsible for the development of the whisker-to-barrel cortex pathway. Lmx1b, a LIM homeodomain transcription factor, is expressed in embryonic PrV. In Lmx1b knockout ((-)(/)(-)) mice, V primary afferent projections to PrV are normal, albeit reduced in number, whereas the PrV-thalamic lemniscal pathway is sparse and develops late. Excess cell death occurs in the embryonic Lmx1b(-)(/)(-) PrV, but not in Lmx1b/Bax double null mutants. Expression of Drg11, a downstream transcription factor essential for PrV development and pattern formation, is abolished in PrV, but not in the V ganglion. Consequently, whisker patterns fail to develop in PrV by birth. Rescued PrV cells in Lmx1b/Bax double (-)(/)(-)s failed to rescue whisker-related PrV pattern formation. Thus, Lmx1b and Drg11 may act in the same genetic signaling pathway that is essential for PrV pattern formation.


Terpenoids from the Roots of Stellera chamaejasme (L.) and Their Bioactivities.
An undescribed diterpene, stellerterpenoid A (1), and two undescribed sesquiterpenoids, stellerterpenoids B and C (2-3), together with six known compounds, prostratin (4) stelleraguaianone B (5), chamaejasnoid A (6), auranticanol L (7), wikstronone C (8), and oleodaphnone (9), were isolated from the roots of Stellera chamaejasme L. Their structures were elucidated by extensive spectroscopic data (1D, 2D NMR, IR, UV, and HR-ESI-MS). The absolute configuration of 1-3 was elucidated based on ECD calculation. Among them, stellerterpenoid A was a rare 13, 14-seco nortigliane diterpenoid and stellerterpenoid B was a guaiacane-type sesquiterpenoid with an unusual 1, 2-diketone moiety. The known stelleraguaianone B (5) exhibited moderate activity for suppressing NO production in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages cells with an IC50 value of 24.76 ± 0.4 μM. None of the compounds showed anti-influenza virus or anti-tumor activity in vitro.


Histamine and gastric acid secretion. A review.
Histamine was found to be a potent stimulus for acid secretion in 1920. It was then for about 20 years considered to be identical to the antral factor gastrin. It stimulates the parietal cells--the site of acid production--via an H2-receptor in a dynamic manner--that is, there is a continuous turnover of histamine at the receptor site. Cyclic AMP is formed by the receptor stimulation, but how this is coupled to the proton transport is unknown. It could even be possible that the main function of the histamine action is to initiate the drastic morphologic transformation of the parietal cells which occurs in connection with acid secretion. Possible sites for some acid inhibitors are elucidated.


Hepatitis C Virus-Induced FUT8 Causes 5-FU Drug Resistance in Human Hepatoma Huh7.5.1 Cells.
Hepatitis C virus (HCV) is a major cause of human chronic liver disease and hepatocellular carcinoma. Our recent studies showed that α1,6-fucosyltransferase (FUT8), a key glycosyltransferase, was the most up-regulated glycosyltransferase after the HCV infection of human hepatocellular carcinoma Huh7.5.1 cells. Here, we further studied the effects and possible mechanism of FUT8 on the proliferation of HCV and chemotherapy-resistance of HCV-infected Huh7.5.1 cells. The effects of FUT8 on the proliferation and drug resistance of HCV-infected Huh7.5.1 cells were analyzed by flow cytometry analysis (FCM), quantitative real-time polymerase chain reaction (qRT-PCR), Western blot analysis and lactate dehydrogenase (LDH) release assay. Results: We found that FUT8 not only promoted Huh7.5.1 proliferation by activating PI3K-AKT-NF-κB signaling, but also stimulated the expression of the drug-resistant proteins P-glycoprotein (P-gp) and multidrug resistance related protein 1 (MRP1) and enhanced the 5-fluorouracil (5-FU) chemo-resistance of Huh7.5.1 cells. Silencing of FUT8 reduced the cell proliferation and increased the 5-FU sensitivity of HCV-infected Huh7.5.1 cells. Inhibition of P-gp and MRP1 increased the 5-FU drug sensitivity in HCV infected Huh7.5.1 cells. HCV-induced FUT8 promotes proliferation and 5-FU resistance of Huh7.5.1 cells. FUT8 may serve as a therapeutic target to reverse chemotherapy resistance in HCV-infected Huh7.5.1 cells.


Form-birefringent space-variant inhomogeneous medium element for shaping point-spread functions.
We experimentally characterize the properties of an element that generates a doughnutlike point-spread function by converting the linearly polarized incident field to radially or azimuthally polarized light utilizing space-variant inhomogeneous medium (SVIM) form-birefringent subwavelength structures. To fabricate the high-aspect-ratio SVIM structures, we developed a chemically assisted ion-beam-etching process that permits control of the fabricated form-birefringent structure profile to optimize the effect of birefringence and the impedance mismatch on the substrate-air interface. Fabricated elements perform efficient polarization conversion for incident angles as large as 30 degrees, where the extinction ratio is found to be better than 4.5. The intensity distribution in the far field shows that our SVIM device generates a doughnut point-spread function that may prove useful for various applications.


Mammary analog secretory carcinoma of thyroid: A case report.
Mammary analog secretory carcinoma (MASC) is a recently described rare neoplasm that was first reported in the salivary gland with an associated ETV6-NTRK3 fusion. We present a case of MASC involving and presumably arising in the thyroid, which was originally diagnosed as papillary thyroid carcinoma on fine needle aspiration and surgical resection. The later correct diagnosis of MASC was confirmed by immunohistochemistry and molecular studies. The cytopathological features of MASC in the salivary gland are previously described; however, we present the first cytopathological description of MASC arising in the thyroid with the unique feature of prominent nuclear grooves. Differentiating MASC from overlapping features of cytopathologic mimics such as papillary thyroid carcinoma may carry crucial therapeutic implications. Diagn. Cytopathol. 2017;45:45-50. © 2016 Wiley Periodicals, Inc.


Deep brain stimulation between 1947 and 1987: the untold story.
Deep brain stimulation (DBS) is the most rapidly expanding field in neurosurgery. Movement disorders are well-established indications for DBS, and a number of other neurological and psychiatric indications are currently being investigated. Numerous contemporary opinions, reviews, and viewpoints on DBS fail to provide a comprehensive account of how this method came into being. Misconceptions in the narrative history of DBS conveyed by the wealth of literature published over the last 2 decades can be summarized as follows: Deep brain stimulation was invented in 1987. The utility of high-frequency stimulation was also discovered in 1987. Lesional surgery preceded DBS. Deep brain stimulation was first used in the treatment of movement disorders and was subsequently used in the treatment of psychiatric and behavioral disorders. Reports of nonmotor effects of subthalamic nucleus DBS prompted its use in psychiatric illness. Early surgical interventions for psychiatric illness failed to adopt a multidisciplinary approach; neurosurgeons often worked "in isolation" from other medical specialists. The involvement of neuro-ethicists and multidisciplinary teams are novel standards introduced in the modern practice of DBS for mental illness that are essential in avoiding the unethical behavior of bygone eras. In this paper, the authors examined each of these messages in the light of literature published since 1947 and formed the following conclusions. Chronic stimulation of subcortical structures was first used in the early 1950s, very soon after the introduction of human stereotaxy. Studies and debate on the stimulation frequency most likely to achieve desirable results and avoid side effects date back to the early days of DBS; several authors advocated the use of "high" frequency, although the exact frequency was not always specified. Ablative surgery and electrical stimulation developed in parallel, practically since the introduction of human stereotactic surgery. The first applications of both ablative surgery and chronic subcortical stimulation were in psychiatry, not in movement disorders. The renaissance of DBS in surgical treatment of psychiatric illness in 1999 had little to do with nonmotor effects of subthalamic nucleus DBS but involved high-frequency stimulation of the very same brain targets previously used in ablative surgery. Pioneers in functional neurosurgery mostly worked in multidisciplinary groups, including when treating psychiatric illness; those "acting in isolation" were not neurosurgeons. Ethical concerns have indeed been addressed in the past, by neurosurgeons and others. Some of the questionable behavior in surgery for psychiatric illness, including the bygone era of DBS, was at the hands of nonneurosurgeons. These practices have been deemed as "dubious and precarious by yesterday's standards."


Capitalism, socialism, and the physical quality of life.
This study compared capitalist and socialist countries in measures of the physical quality of life (PQL), taking into account the level of economic development. The World Bank was the principal source of statistical data, which pertained to 123 countries and approximately 97 percent of the world's population. PQL variables included indicators of health, health services, demographic conditions, and nutrition (infant mortality rate, child death rate, life expectancy, crude death rate, crude birth rate, population per physician, population per nursing person, and daily per capita calorie supply); measures of education (adult literacy rate, enrollment in secondary education, and enrollment in higher education); and a composite PQL index. All PQL measures improved as economic development increased. In 30 of 36 comparisons between countries at similar levels of economic development, socialist countries showed more favorable PQL outcomes (p less than .05 by two-tailed t-test). This work with the World Bank's raw data included cross-tabulations, analysis of variance, and regression techniques, which all confirmed the same conclusions. The data indicated that the socialist countries generally have achieved better PQL outcomes than the capitalist countries at equivalent levels of economic development.


Late Onset of Estrogen Therapy Impairs Carotid Function of Senescent Females in Association with Altered Prostanoid Balance and Upregulation of the Variant ERα36.
Recent analysis of clinical trials on estrogen therapy proposes the existence of a therapeutic window of opportunity for the cardiovascular benefits of estrogens, which depend on women's age and the onset of therapy initiation. In this study, we aimed to determine how vascular senescence and the onset of estrogen treatment influence the common carotid artery (CCA) function in senescent and non-senescent females. Ovariectomized female senescence-accelerated (SAMP8) or non-senescent (SAMR1) mice were treated with vehicle (OVX) or 17β-estradiol starting at the day of ovariectomy (early-onset, E2E) or 45 days after surgery (late-onset, E2L). In SAMR1, both treatments, E2E and E2L, reduced constriction to phenylephrine (Phe) in CCA [(AUC) OVX: 193.8 ± 15.5; E2E: 128.1 ± 11.6; E2L: 130.2 ± 15.8, p = 0.004] in association with positive regulation of NO/O2- ratio and increased prostacyclin production. In contrast, E2E treatment did not modify vasoconstrictor responses to Phe in OVX-SAMP8 and, yet, E2L increased Phe vasoconstriction [(AUC) OVX: 165.3 ± 10; E2E: 183.3 ± 11.1; E2L: 256.3 ± 30.4, p = 0.005]. Increased vasoconstriction in E2L-SAMP8 was associated with augmented thromboxane A2 and reduced NO production. Analysis of wild-type receptor alpha (ERα66) expression and its variants revealed an increased expression of ERα36 in E2L-SAMP8 in correlation with unfavorable effects of estrogen in those animals. In conclusion, estrogen exerts beneficial effects in non-senescent CCA, regardless of the initiation of the therapy. In senescent CCA, however, estrogen loses its beneficial action even when administered shortly after ovariectomy and may become detrimental when given late after ovariectomy. Aging and onset of estrogen treatment are two critical factors in the mechanism of action of this hormone in CCA.


Progressive decline of decision-making performances during multiple sclerosis.
The purpose of this study was to evaluate longitudinally, using the Iowa Gambling Task (IGT), the dynamics of decision-making capacity at a two-year interval (median: 2.1 years) in a group of patients with multiple sclerosis (MS) (n = 70) and minor neurological disability [Expanded Disability Status Scale (EDSS) < or = 2.5 at baseline]. Cognition (memory, executive functions, attention), behavior, handicap, and perceived health status were also investigated. Standardized change scores [(score at retest-score at baseline)/standard deviation of baseline score] were computed. Results showed that IGT performances decreased from baseline to retest (from 0.3, SD = 0.4 to 0.1, SD = 0.3, p = .005). MS patients who worsened in the IGT were more likely to show a decreased perceived health status and emotional well-being (SEP-59; p = .05 for both). Relapsing rate, disability progression, cognitive, and behavioral changes were not associated with decreased IGT performances. In conclusion, decline in decision making can appear as an isolated deficit in MS.


Spatial screening solitons as particles
Photorefractive spatial screening solitons are treated as rays using geometrical optics. The ray picture is transformed into a classical mechanics picture, in which solitons move self-consistently as particles in a potential created by the induced change in the refractive index. The Hamiltonian equations of motion are integrated to yield trajectories that agree with the optical center-of-mass trajectories. The motion in the transverse plane is found to be not central and the orbits are not closed, preventing the spiraling of solitons.


[Structuro-functional organization of the vegetative (autonomic) nervous system].
On the basis of a number of structural and functional indices, application of pharmacological analysis as well as recording of neuronal activity, the autonomic nervous system is subdivided into the sympathetic, parasympathetic and metasympathetic parts. The metasympathetic system includes the complex of microganglia situated in the walls of vosceral organs and having marked motility activity (the heart, ureters, intestine, stomach). According to the localization, separate areas of this system can be defined by its site (for example, the cardiometasympathetic area in the heart). The metasympathetic system attains the features of true autonomy. Its cells have no direct connection with the high centers: this connection is established through mono- and polysynaptic sensory and afferent units of sympathetic and parasympathetic nature. The system has a definite set of functional elements including sensory ones (mechano-, chemo- and thermosensitive those), oscillators, interneurons, tonic neurons. Neurons of the metasympathetic system are incorporated through interganglionic connections into the common functional network of the organ. A typical excitatory pattern suggests the presence of a temorary connection in the work of at least two neurons according to the "driver--follower" type. In addition to excitatory patterns there are also patterns showing inhibitory interactions. Besides well known systems of mediation including cholinergic and adrenergic ones, the metasympathetic system has its peculiar purinergic transmission.


Procalcitonin and MR-Proadrenomedullin Combination with SOFA and qSOFA Scores for Sepsis Diagnosis and Prognosis: A Diagnostic Algorithm.
The third Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as an organ dysfunction consequent to infection. A Sequential Organ Failure Assessment (SOFA) score at least 2 identifies sepsis. In this study, procalcitonin (PCT) and midregional pro-adrenomedullin (MR-proADM) were evaluated along with SOFA and quick SOFA (qSOFA) scores in patients with sepsis or septic shock. A total of 109 septic patients and 50 patients with noninfectious disease admitted at the Department of Internal Medicine and General Surgery of the University Hospital Campus Bio-Medico of Rome were enrolled. PCT and MR-proADM were measured with immunoluminometric assays (Brahms, Hennigsdorf, Germany). Data were analyzed with receiver-operating characteristic (ROC) curve analysis, likelihood ratios, and Mann-Whitney U test using MedCalc 126.96.36.199 package. At ROC curve analysis, PCT showed the highest area under the curve and positive likelihood ratio values of 27.42 in sepsis and 43.62 in septic shock. MR-proADM and SOFA score showed a comparable performance. In septic shock, lactate showed the most accurate diagnostic ability. In sepsis, the best combination was PCT with MR-proADM with a posttest probability of 0.988. Based upon these results, an algorithm for sepsis and septic shock diagnosis has been developed. MR-proADM, SOFA, and qSOFA scores significantly discriminated survivors from nonsurvivors. PCT and MR-proADM test combination represent a good tool in sepsis diagnosis and prognosis suggesting their inclusion in the diagnostic algorithm besides SOFA and qSOFA scores. Furthermore, MR-proADM as marker of organ dysfunction, with a turn around time of about 30 min, has the advantage to be more objective and rapid than SOFA score.


Maize non-photosynthetic ferredoxin precursor is mis-sorted to the intermembrane space of chloroplasts in the presence of light.
Preprotein translocation across the outer and inner envelope membranes of chloroplasts is an energy-dependent process requiring ATP hydrolysis. Several precursor proteins analyzed so far have been found to be imported into isolated chloroplasts equally well in the dark in the presence of ATP as in the light where ATP is supplied by photophosphorylation in the chloroplasts themselves. We demonstrate here that precursors of two maize (Zea mays L. cv Golden Cross Bantam) ferredoxin isoproteins, pFdI and pFdIII, show distinct characteristics of import into maize chloroplasts. pFdI, a photosynthetic ferredoxin precursor, was efficiently imported into the stroma of isolated maize chloroplasts both in the light and in the dark. In contrast pFdIII, a non-photosynthetic ferredoxin precursor, was mostly mis-sorted to the intermembrane space of chloroplastic envelopes as an unprocessed precursor form in the light but was efficiently imported into the stroma and processed to its mature form in the dark. The mis-sorted pFdIII, which accumulated in the intermembrane space in the light, could not undergo subsequent import into the stroma in the dark, even in the presence of ATP. However, when the mis-sorted pFdIII was recovered and used for a separate import reaction, pFdIII was capable of import into the chloroplasts in the dark. pFNRII, a ferredoxin-NADP+ reductase isoprotein precursor, showed import characteristics similar to those of pFdIII. Moreover, pFdIII exhibited similar import characteristics with chloroplasts isolated from wheat (Pennisetum americanum) and pea (Pisum sativum cv Alaska). These findings suggest that the translocation of precursor proteins across the envelope membranes of chloroplasts may involve substrate-dependent light-regulated mechanisms.


Screening studies and markers.
Primary hepatocellular carcinoma (HCC) is an important cause of death in patients with chronic liver disease and in carriers of hepatitis B virus. Because of its relative frequency in certain geographic areas, such as Asia and sub-Saharan Africa, mass screening programs have been instituted to implement secondary prevention. It is believed that early diagnosis provides the best chance of successful surgical resection and hopefully prolonged survival. Although a number of serological and imaging tests are available, the most cost-effective modality is serum alphafetoprotein (AFP) and real-time ultrasound (USS) used together. The current recommendation is recognition of high-risk groups (cirrhosis, chronic active hepatitis, and chronic hepatitis B carriers) and provision of AFP and USS testing at 3 to 6 months intervals, with recourse to fine-needle aspiration biopsy and celiac angiography for individuals who test positive with either test.


Volatiles produced by the mycophagous soil bacterium Collimonas.
It is increasingly recognized that volatile organic compounds play an import role during interactions between soil microorganisms. Here, we examined the possible involvement of volatiles in the interaction of Collimonas bacteria with soil fungi. The genus Collimonas is known for its ability to grow at the expense of living fungi (mycophagy), and antifungal volatiles may contribute to the attack of fungi by these bacteria. We analyzed the composition of volatiles produced by Collimonas on agar under different nutrient conditions and studied the effect on fungal growth. The volatiles had a negative effect on the growth of a broad spectrum of fungal species. Collimonas bacteria did also produce volatiles in sand microcosms supplied with artificial root exudates. The production of volatiles in sand microcosms was enhanced by the presence of fungi. The overall picture that we get from our study is that antifungal volatiles produced by Collimonas could play an important role in realizing its mycophagous lifestyle. The current work is also interesting for understanding the ecological relevance of volatile production by soil bacteria in general as we found strong influences of root exudates composition and incubation conditions on the spectrum of volatiles produced.


Comparative lymphocyte stimulation studies on whole blood from vaccinated and nonvaccinated cattle with paratuberculosis.
The lymphocyte stimulation test was evaluated in the diagnosis of bovine paratuberculosis, using whole blood samples from cattle. These samples were incubated with a purified protein derivative of Mycobacterium paratuberculosis. Samples from vaccinated and nonvaccinated cattle from paratuberculosis-free herds and from paratuberculous herds were used. Vaccinated and nonvaccinated groups from the paratuberculous herds each included fecal culture-positive cattle, fecal culture-negative cattle, and calves. All groups included some cattle with a stimulation index (SI) greater than or equal to 2, and all groups except 2 of the 4 vaccinated groups had some cattle with a SI less than or equal to 2. In paratuberculosis-free herds, 16% of the nonvaccinated cattle had a SI greater than or equal to 2, and 0.7% had a SI greater than or equal to 4. In paratuberculous herds, 42% of the nonvaccinated cattle that were negative on fecal culture had a SI greater than or equal to 2 and 24% had a SI greater than or equal to 4. Vaccinated cattle greater than 1 year old could not be distinguished from infected cattle by means of the lymphocyte stimulation test. If a SI of 2 or 4 had been used as a basis to cull individual animals, some paratuberculous cattle would have been identified incorrectly as noninfected, and some paratuberculosis-free cattle would have been identified incorrectly as infected.


Measurement of Body and Liver Fat in Small Animals Using Peripheral Quantitative Computed Tomography.
Peripheral quantitative computed tomography (pQCT) was used to determine percent body fat in mice, and relative liver fat in lemmings fasted for 0, 6, 12 or 18 hours to induce a wide range of liver fat content. Accuracy of the pQCT was determined by comparing pQCT-derived fat to that from chemical extraction using 30 male mice (whole body) and 26 female lemmings (liver only). To determine whether pQCT could measure changes in liver fat (%) in live animals, two groups of lemmings were scanned on 4 consecutive days under anesthesia. Controls (n = 3) had ad libitum access to food, whereas the fasted group (n = 5) was deprived of food for 18 hr before being measured on day 2 and then refed. The coefficient of variation (CV) for determining percent body fat in mice using the pQCT was 3.9% (±1.8 SD). Percent body fat determined by pQCT significantly overestimated percent fat as measured by chemical extraction (14.5 ± 3.2 vs 12.3 ± 2.9% respectively, P < 0.01, mean ± SD). However, percent body fat by pQCT was highly related to chemical extraction percent fat (r = 0.95, P < 0.001). The liver attenuation values from pQCT were highly related to percent liver fat (r=0.98, P<0.001) in lemmings. The technique showed excellent precision with a CV of 0.3 ± 0.1%. The two groups (control vs fasted) did not differ in their percent liver fat on day 1 (5.4% vs 5.8%). On day 2 the fasted group had a significantly higher percent liver fat than controls (5.9% vs 17.3%; p<0.05). Following refeeding, there were no significant group differences in percent liver fat on days 3 and 4. Our data indicate that pQCT has good accuracy and precision for determining percent body fat, and liver fat in small animals and can be used to track changes in liver fat over time.


Variable protein expression in marine-derived filamentous fungus Penicillium chrysogenum in response to varying copper concentrations and salinity.
Copper is one of the essential trace dietary minerals for all living organisms, but is potentially toxic at higher concentrations, mainly due to the redox reactions in its transition state. Tolerance of microbes towards copper is primarily attributed to chelation and biosorption. In this study, marine-derived filamentous fungi were evaluated for their ability to remove Cu(ii) from a culture medium. Further, the cellular response of a select isolate to salinity stress (0, 35 and 100 PSU) and Cu(ii) stress (0, 100, and 500 ppm) was studied using the peptide mass fingerprinting technique, which revealed expression of 919 proteins, of which 55 proteins were commonly expressed across all conditions. Housekeeping proteins such as citrate synthase, pyruvate carboxylase, ribosomal proteins, ATP synthases, and more were expressed across all conditions. Reactive oxygen species scavenging proteins such as glutaredoxin, mitochondrial peroxiredoxins and thioredoxins were expressed under Cu(ii) and salinity stresses individually as well as in combination. Up-regulation of glutaredoxin under Cu(ii) stress with fold change values of 18.3 and 13.9 under 100 ppm and 500 ppm of Cu(ii) indicated active scavenging of free radicals to combat oxidative damage. The common mechanisms reported were enzymatic scavenging of free radicals, activation of DNA damage and repair proteins and probable intracellular metal chelation. This indicated multiple stress mechanisms employed by the isolate to combat the singular and synergistic effects of Cu(ii) and salinity stress.


Effect of inulin on the human gut microbiota: stimulation of Bifidobacterium adolescentis and Faecalibacterium prausnitzii.
Prebiotics are food ingredients that improve health by modulating the colonic microbiota. The bifidogenic effect of the prebiotic inulin is well established; however, it remains unclear which species of Bifidobacterium are stimulated in vivo and whether bacterial groups other than lactic acid bacteria are affected by inulin consumption. Changes in the faecal microbiota composition were examined by real-time PCR in twelve human volunteers after ingestion of inulin (10 g/d) for a 16-d period in comparison with a control period without any supplement intake. The prevalence of most bacterial groups examined did not change after inulin intake, although the low G+C % Gram-positive species Faecalibacterium prausnitzii exhibited a significant increase (10.3% for control period v. 14.5% during inulin intake, P=0.019). The composition of the genus Bifidobacterium was studied in four of the volunteers by clone library analysis. Between three and five Bifidobacterium spp. were found in each volunteer. Bifidobacterium adolescentis and Bifidobacterium longum were present in all volunteers, and Bifidobacterium pseudocatenulatum, Bifidobacterium animalis, Bifidobacterium bifidum and Bifidobacterium dentium were also detected. Real-time PCR was employed to quantify the four most prevalent Bifidobacterium spp., B. adolescentis, B. longum, B. pseudocatenulatum and B. bifidum, in ten volunteers carrying detectable levels of bifidobacteria. B. adolescentis showed the strongest response to inulin consumption, increasing from 0.89 to 3.9% of the total microbiota (P=0.001). B. bifidum was increased from 0.22 to 0.63% (P<0.001) for the five volunteers for whom this species was present.


A Real-Time Automated Machine Learning Algorithm for Predicting Mortality in Trauma Patients: Survey Says it's Ready for Prime-Time.
Though artificial intelligence ("AI") has been increasingly applied to patient care, many of these predictive models are retrospective and not readily available for real-time decision-making. This survey-based study aims to evaluate implementation of a new, validated mortality risk calculator (Parkland Trauma Index of Mortality, "PTIM") embedded in our electronic healthrecord ("EHR") that calculates hourly predictions of mortality with high sensitivity and specificity. This is a prospective, survey-based study performed at a level 1 trauma center. An anonymous survey was sent to surgical providers and regarding PTIM implementation. The PTIM score evaluates 23 variables including Glasgow Coma Score (GCS), vital signs, and laboratory data. Of the 40 completed surveys, 35 reported using PTIM in decision-making. Prior to reviewing PTIM, providers identified perceived top 3 predictors of mortality, including GCS (22/38, 58%), age (18/35, 47%), and maximum heart rate (17/35, 45%). Most providers reported the PTIM assisted their treatment decisions (27/35, 77%) and timing of operative intervention (23/35, 66%). Many providers agreed that PTIM integrated into rounds and patient assessment (22/36, 61%) and that it improved efficiency in assessing patients' potential mortality (21/36, 58%). Artificial intelligence algorithms are mostly retrospective and lag in real-time prediction of mortality. To our knowledge, this is the first real-time, automated algorithm predicting mortality in trauma patients. In this small survey-based study, we found PTIM assists in decision-making, timing of intervention, and improves accuracy in assessing mortality. Next steps include evaluating the short- and long-term impact on patient outcomes.


Infection of bovine fetuses at 120 days' gestation with virulent and avirulent strains of bluetongue virus serotype 11.
Bluetongue virus infection in sheep and cattle during fetal development causes neuropathology. Two strains of bluetongue virus serotype 11 designated as UC-2 and UC-8 have different virulence patterns in newborn mice. These viruses have distinctly different electropherotype patterns on polyacrylamide gel electrophoresis indicating a genetic difference in these two viruses of the same serotype. Four bovine fetuses each were inoculated intramuscularly with either UC-2 or UC-8, and one fetus was inoculated with placebo. The inoculation was made intramuscularly through the uterine wall at 120 days' gestation, and the bovine fetuses were recovered by cesarean section 12 or 20 days after inoculation. Fetal blood was collected for virus isolation and serology. Virus was reisolated from brain, blood, lung and liver. Both strains, UC-2 and UC-8, cause severe lesions in the 120 day fetuses. The encephalomalacic lesions occurred earlier and were more severe in fetuses inoculated with UC-8 as compared to those inoculated with UC-2. The subtle differences observed in the fetuses inoculated with the two different strains suggest that there is a difference in pathogenic potential of the two viruses. These differences do not appear to be completely dependent upon the host species.


Controlled proteolysis of flavocytochrome b2. Characterization of a 15000-dalton heme-binding core and comparison with detergent solubilized cytochrome b5.
It is known that each subunit of the tetrameric flavocytochrome b2 can be cleaved by yeast proteases to fragments of molecular weight 33-36000 and 21 000, with some modification of catalytic properties, but without destruction of the oligomeric state of the protein. We report here experimental conditions which enabled us to simulate this specific cleavage in a controlled fashion with chymotrypsin and subtilisin. With trypsin and papain, on the other hand, it was not found possible to stop the digestion in such a way as to obtain a homogeneous still active product. A characterization of the enzymatic forms obtained by digestion with chymotrypsin and subtilisin at 0 degrees C shows that modification of enzymatic and solubility properties occurs in a stepwise fashion. It is also ccluded that cleavage by yeast proteases is accompanied by loss of 10 to 25 residues. At 37 degrees C, chymotrypsin digestion yields a heme-binding core of molecular weight 15 000, larger than the already characterized tryptic heme-binding core by about 40 residues. Although the latter is known to be very similar to trypsin-solubilized cytochrome b5, the lack of aggregation of the former in aqueous solution, its amino acid composition and circular dichroism spectra do not point to a similarity of its additional peptide segment with the hydrophobic tail of detergent-solubilized cytochrome b5.


Impact of Full Vaccination with mRNA BNT162b2 on SARS-CoV-2 Infection: Genomic and Subgenomic Viral RNAs Detection in Nasopharyngeal Swab and Saliva of Health Care Workers.
SARS-CoV-2 infection was monitored in 1898 health care workers (HCWs) after receiving full vaccination with BNT162b2. Untill 30 June 2021, 10 HCWs tested positive for SARS-CoV-2 using real time RT-PCR, resulting in a 4-month cumulative incidence of 0.005%. The infection was mildly symptomatic in six (60%) and asymptomatic in four (40%) individuals. Among the infected HCWs, eight consenting individuals provided paired NPS and saliva during the course of infection, for the purpose of the analysis performed in the present study. Genomic and subgenomic viral RNAs were investigated using real-time RT-PCR in both biological specimens. The temporal profile of viral load was measured using ddPCR. Viral mutations were also analysed. Subgenomic viral RNA was detected in 8/8 (100%) NPS and in 6/8 (75%) saliva specimens at the baseline. The expression of subgenomic RNA was observed for up to 7 days in 3/8 (38%) symptomatic cases. Moreover, concordance was observed between NPS and saliva in the detection of viral mutations, and both N501Y and 69/70del (associated with the B.1.1.7 variant) were detected in the majority 6/8 (75%) of subjects, while the K417T mutation (associated with the P.1-type variants) was detected in 2/8 (25%) individuals. Overall, our findings report a low frequency of infected HCWs after full vaccination. It is, therefore, important to monitor the vaccinees in order to identify asymptomatic infected individuals. Saliva can be a surrogate for SARS-CoV-2 surveillance, particularly in social settings such as hospitals.


Photoelectron spectroscopic and computational study of hydrated pyrimidine anions.
The stabilization of the pyrimidine anion by the addition of water molecules is studied experimentally using photoelectron spectroscopy of mass-selected hydrated pyrimidine clusters and computationally using quantum-mechanical electronic structure theory. Although the pyrimidine molecular anion is not observed experimentally, the addition of a single water molecule is sufficient to impart a positive electron affinity. The sequential hydration data have been used to extrapolate to -0.22 eV for the electron affinity of neutral pyrimidine, which agrees very well with previous observations. These results for pyrimidine are consistent with previous studies of the hydrated cluster anions of uridine, cytidine, thymine, adenine, uracil, and naphthalene. This commonality suggests a universal effect of sequential hydration on the electron affinity of similar molecules.


Congenital muscle dystrophy and diet consistency affect mouse skull shape differently.
The bones of the mammalian skull respond plastically to changes in masticatory function. However, the extent to which muscle function affects the growth and development of the skull, whose regions have different maturity patterns, remains unclear. Using muscle dissection and 3D landmark-based geometric morphometrics we investigated the effect of changes in muscle function established either before or after weaning, on skull shape and muscle mass in adult mice. We compared temporalis and masseter mass and skull shape in mice with a congenital muscle dystrophy (mdx) and wild type (wt) mice fed on either a hard or a soft diet. We found that dystrophy and diet have distinct effects on the morphology of the skull and the masticatory muscles. Mdx mice show a flattened neurocranium with a more dorsally displaced foramen magnum and an anteriorly placed mandibular condyle compared with wt mice. Compared with hard diet mice, soft diet mice had lower masseter mass and a face with more gracile features as well as labially inclined incisors, suggesting reduced bite strength. Thus, while the early-maturing neurocranium and the posterior portion of the mandible are affected by the congenital dystrophy, the late-maturing face including the anterior part of the mandible responds to dietary differences irrespective of the mdx mutation. Our study confirms a hierarchical, tripartite organisation of the skull (comprising neurocranium, face and mandible) with a modular division based on development and function. Moreover, we provide further experimental evidence that masticatory loading is one of the main environmental stimuli that generate craniofacial variation.


Seasonal strategies differ between tropical and extratropical herbivores.
Seasonal diet shifts and migration are key components of large herbivore population dynamics, but we lack a systematic understanding of how these behaviours are distributed on a macroecological scale. The prevalence of seasonal strategies is likely related to herbivore body size and feeding guild, and may also be influenced by properties of the environment, such as soil nutrient availability and climate seasonality. We evaluated the distribution of seasonal dietary shifts and migration across large-bodied mammalian herbivores and determined how these behaviours related to diet, body size and environment. We found that herbivore strategies were consistently correlated with their traits: seasonal diet shifts were most prevalent among mixed feeding herbivores and migration among grazers and larger herbivores. Seasonality also played a role, particularly for migration, which was more common at higher latitudes. Both dietary shifts and migration were more widespread among extratropical herbivores, which also exhibited more intermediate diets and body sizes. Our findings suggest that strong seasonality in extratropical systems imposes pressure on herbivores, necessitating widespread behavioural responses to navigate seasonal resource bottlenecks. It follows that tropical and extratropical herbivores may have divergent responses to global change, with intensifying herbivore pressure in extratropical systems contrasting with diminishing herbivore pressure in tropical systems.


An Electromagnetic Vibration Energy Harvester with a Tunable Mass Moment of Inertia.
This paper presents a vibration-based electromagnetic energy harvester whose resonance frequency can be adjusted to match that of the excitation. Frequency adjustment is attained by controlling a rotatable arm, with tuning masses, at the tip of a cantilever-type energy harvester, thereby changing the effective mass moment of inertia of the system. The rotatable arm is mounted on a servomotor that is autonomously controlled through a microcontroller and a photo sensor to keep the device at resonance for maximum power generation. A mathematical model is developed to predict the system response for different design parameters and to estimate the generated power. The system is investigated analytically by a distributed-parameter model to study the natural frequency variation and dynamic response. The analytical model is verified experimentally where the frequency is tuned from 8 to 10.25 Hz. A parametric study is performed to study the effect of each parameter on the system behavior.


Human monocytopoiesis in acute and chronic inflammation.
Monocytopoiesis was analyzed in patients with severe, acute inflammations induced by surgical interventions as well as in others with mild, chronic inflammations in connection with gastric or duodenal ulcers. The state of acute inflammation was assumed to be associated with a high and steeply rising monocyte demand as opposed to the constant and relatively small monocyte recruitment in chronic inflammation. In chronic mild inflammatory reactions DNA synthesis activity of promonocytes was increased by a factor of about two; the promonocyte pool was normal. In patients who underwent surgical operations changes in the following parameters were observed during the first 15 h after start of surgery: (1) average increase in 3H-TDR labelling index by 38%; (2) average enlargement of promonocyte pool by 34%, (3) and relase of immature cells from the bone marrow into the blood. Increase in DNA synthesis activity as well as expansion of the promonocyte pool causes an enhanced monocyte production rate. The 'shift to the left' in monocyte egress is equivalent to a reduced stem-cell-to-blood transit time. These variations permit short-term adaptation of monocytopoiesis to varying demands.


[Assessing quality in the conducting of seminars for the advanced training of dentists].
Regular analysis of questionnaires distributed among students of self-supporting workshops carried out at the Training Center is aimed at elucidating the students' opinions about organization of workshops in order to optimize it and at collection of marketing information on the training and medical activities of the firm. The majority (90%) of respondents gave a positive answer to the question: "Will you advise your colleagues to go to workshops at the Training Center?" Exhibitions of materials offered by the firm and training of students to use these materials demonstrate the advantages thereof. Analysis of questionnaires showed that just a little part of dentists know the true price of their work and that the major part of the market of dental service is oriented, judging by the proposed costs, mainly at the solvent population.


A T-cell epitope encoded by a subset of HLA-DPB1 alleles determines nonpermissive mismatches for hematologic stem cell transplantation.
The importance of HLA-DPB1 matching for the outcome of allogeneic hematologic stem cell (HSC) transplantation is controversial. We have previously identified HLA-DPB1*0901 as a target of cytotoxic T cells mediating in vivo rejection of an HSC allograft. Here we show that HLA-DPB1*0901 encodes a T-cell epitope shared by a subset of DPB1 alleles that determines nonpermissive mismatches for HSC transplantation. Several T-cell clones obtained from the patient at the time of rejection showed HLA-DP restricted recognition of allogeneic targets expressing HLA-DPB1*0901, *1001, *1701, *0301, *1401, and *4501, but not other alleles. Based on these findings, we developed an algorithm for prediction of nonpermissive HLA-DPB1 mismatches. Retrospective evaluation of 118 transplantations showed that the presence of nonpermissive HLA-DPB1 mismatches was correlated with significantly increased hazards of acute grade II to IV graft-versus-host disease (HR = 1.87, P =.046) and transplantation-related mortality (HR = 2.69, P =.027) but not relapse (HR = 0.98, P =.939), as compared with the permissive group. There was also a marked but statistically not significant increase in the hazards of overall mortality (HR = 1.64, P =.1). These data suggest that biologic characterization of in vivo alloreactivity can be a tool for definition of clinically relevant nonpermissive HLA mismatches for unrelated HSC transplantation.


Effects of tuning the applied voltage pulse periods on the electroluminescence spectra of host-guest white light-emitting electrochemical cells.
Solid-state white light-emitting electrochemical cells (LECs) are potential candidates in solid-state lighting due to their promising advantages of simple device structure, low-voltage operation and compatibility with inert cathode metals. Adjusting the correlated color temperature (CCT) of background illumination is highly desired for modern smart lighting systems. In this work, a novel technique to tune the CCT of electroluminescence (EL) from white LECs is proposed. Color tuning is based on adjusting the applied voltage pulse period on the host-guest white LECs and the working mechanism is illustrated. A shorter voltage pulse period is insufficient to completely charge the capacitive LEC device and thus the effective voltage applied on the device is lower. Since the host-guest energy level offsets favor carrier trapping, a lower effective applied voltage results in a more pronounced guest emission, rendering redder white EL with a lower CCT. On the other hand, a longer voltage pulse period facilitates more complete charging and the effective voltage applied on the white LEC is higher. A higher bias facilitates direct exciton formation on the host molecule and subsequent partial host-guest energy transfer generates bluer white EL with a higher CCT. By tuning the voltage pulse period from 0.2 to 20 ms, the CCT of EL resulting from white LECs ranges from 2482 to 5723 K. The CCT tuning range is sufficient for general lighting applications. In contrast to color tuning of white LECs under constant-voltage driving, in which >10× brightness enhancement is accompanied by higher-CCT white EL, the discharging half-period in pulse-voltage driving provides relaxation time to turn off the device and reduces the average brightness of the white LECs driven under a longer voltage pulse period. Therefore, similar brightness can be achieved for white EL with different CCTs. No additional optical filtering device is needed for this novel color tuning technique and it has potential for use in solid-state lighting.


Access to radiotherapy among circumpolar Inuit populations.
Cancer is a substantial health burden for Inuit populations, an Indigenous peoples who primarily inhabit the circumpolar regions of Alaska, Canada, Greenland, and Russia. Access to radiotherapy is lacking or absent in many of these regions, despite it being an essential component of cancer treatment. This Review presents an overview of factors influencing radiotherapy delivery in each of the four circumpolar Inuit regions, which include population and geography, health-systems infrastructure, and cancer epidemiology. This Review also provides insight into the complex patient pathways needed to access radiotherapy, and on radiotherapy use. The unique challenges in delivering radiotherapy to circumpolar Inuit populations are discussed, which, notably, include geographical and cultural barriers. Recommendations include models of care that have successfully addressed these barriers, and highlight the need for increased collaboration between circumpolar referral centres in Alaska, Canada, Greenland, and Russia to ultimately allow for better delivery of cancer treatment.


Efficiency of Portable X-ray Fluorescence for Distinguishing Lead Slag.
In the Minier Valley (France, Aveyron), an archaeological site excavation has led to the discovery of 25 kg of lead (Pb) slag, found in a secondary position. On a macroscopic level, these slags can be classified into two distinct categories, vitreous black and porous gray. This clear visual differentiation has been previously documented at other Pb-silver (Ag) metallurgy sites dating from the 12th century to the 14th century in Europe, and more particularly in the workshops of Mont Lozère, located approximately 80 km away from Le Minier. However, to date, scant evidence exists regarding the specific metallurgical process that produced this slag. This study presents the results of the analysis of 218 Pb slags (Supplemental Material) using portable X-ray fluorescence (pXRF). This method does not appear to be ideally suited for investigating this type of artifact, as it does not provide quantification of oxygen content. Nevertheless, it can be used to quickly identify trends and determine whether the two identified facies exhibit dissimilar chemical compositions. The results indicate that, based on the elemental compositions of the slags, no discernible distinction can be made to categorize them into two separate groups, both in bivariate and multivariate analyses. Consequently, it can be inferred that the gray and black slags originate from a single process executed within the same type of furnace. Scanning electron microscopy energy dispersive spectrometry analyses on selected samples demonstrate that variations in metal content are considerably exaggerated by pXRF, but that the trends observed are confirmed. The use of pXRF is therefore a relevant tool for determining whether or not Pb-Ag slag is the result of the same process. However, this initial approach needs to be refined by other analyses to confirm whether the smelted ores are of local origin and to be able to better define the details of the metallurgical process used.


Hydrogel Nanofilaments via Core-Shell Electrospinning.
Recent biomedical hydrogels applications require the development of nanostructures with controlled diameter and adjustable mechanical properties. Here we present a technique for the production of flexible nanofilaments to be used as drug carriers or in microfluidics, with deformability and elasticity resembling those of long DNA chains. The fabrication method is based on the core-shell electrospinning technique with core solution polymerisation post electrospinning. Produced from the nanofibers highly deformable hydrogel nanofilaments are characterised by their Brownian motion and bending dynamics. The evaluated mechanical properties are compared with AFM nanoindentation tests.


Commentary: Is the glass half empty? Code blue training in the modern era.
Skilled management of cardiopulmonary resuscitation, or responding to a "code blue," is widely considered an important training objective during internal medicine residency. Gaining proficiency in managing a code blue typically depends on event-based experiential learning. In this issue of Academic Medicine, Mickelsen and colleagues report their use of schedule-based stochastic simulation estimates matched with observed code blue data to model the number of annual opportunities a first-year resident has to participate in code blue events. Their data offer compelling evidence that trainees in 2008 had much less opportunity (83% less) to participate in code blue events than did their predecessors in 2002. Mickelsen and coinvestigators speculate that this reduction could be attributable to quality improvement initiatives that may have reduced the total number of code blue situations, as well as to duty hours restrictions that reduced the residents' overall availability to participate. The authors of this commentary discuss the general influence of secular trends on educational needs, and they describe possible strategies to compensate for less "in-the-field" exposure by maximizing the "learning yield per event" and using simulation training methods. Finally, the authors consider the question of whether code blue training remains an appropriate goal for general medicine trainees in the face of evolving trends in health care systems.


Improving continence services for older people from the service-providers' perspective: a qualitative interview study.
To examine in depth the views and experiences of continence service leads in England on key service and continence management characteristics in order to identify and to improve our understanding of barriers to a good-quality service and potential facilitators to develop and to improve services for older people with urinary incontinence (UI). Qualitative semistructured interviews using a purposive sample recruited across 16 continence services. 3 acute and 13 primary care National Health Service Trusts in England. 16 continence service leads in England actively treating and managing older people with UI. In terms of barriers to a good-quality service, participants highlighted a failure on the part of commissioners, managers and other health professionals in recognising the problem of UI and in acknowledging the importance of continence for older people and prevalent negative attitudes towards continence and older people. Patient assessment and continence promotion regardless of age, rather than pad provision, were identified as important steps for a good-quality service for older people with UI. More rapid and appropriate patient referral pathways, investment in service capacity, for example, more trained staff and strengthened interservice collaborations and a higher profile within medical and nurse training were specified as being important facilitators for delivering an equitable and high-quality continence service. There is a need, however, to consider the accounts given by our participants as perhaps serving the interests of their professional group within the context of interprofessional work. Our data point to important barriers and facilitators of a good-quality service for older people with UI, from the perspective of continence service leads. Further research should address the views of other stakeholders, and explore options for the empirical evaluation of the effectiveness of identified service facilitators.


[Delayed diagnosis of alpha-1 antitrypsin deficiency].
Alpha-1 antitrypsin deficiency (AAT-D) is a genetic disease, relatively common in populations of European ancestry. AAT-D remains undiagnosed in many patients, and there are often long delays between the onset of respiratory symptoms and diagnosis. AAT-D can be readily diagnosed by measurement of the serum or plasma protein level, which should be confirmed by assessing the genotype or protein phenotype when AAT levels are below the normal range. Close monitoring for the development or progression of lung disease or liver disease is required, and can improve the prognosis. We show the case of a 69 year old woman with recurrent respiratory infections and asthma symptoms. The serum levels of AAT were below the normal range, and ZZ genotype was confirmed. The delayed diagnosis of our patient seems to emphasize the need to remind the doctors about AAT-D, frequently associated with asthma or COPD symptoms.


IL-16 inhibition of CD3-dependent lymphocyte activation and proliferation.
We have recently described the cDNA and predicted protein structure of a natural soluble CD4 ligand, IL-16. IL-16 is chemotactic for CD4+ T cells and induces functional IL-2 receptors in CD4+ T cells. The binding of IL-16 to CD4 results in activation of p56(lck), whose adaptor function is essential for the chemotactic response. Subsequently, increases in intracellular Ca2+ and phosphatidylinositol 1,4,5-trisphosphate occur, as does translocation of protein kinase C from cytosol to membrane. Because of the similarities between these signals and functions and those noted for the CD4 ligand HIV-1 gp120, we investigated the potential regulatory effects of IL-16 on CD3/TCR-mediated lymphocyte activation. Preincubation of human T cells with IL-16 up to 24 h before activation with plate-bound anti-CD3 Abs reduced T cell activation by 80%, as monitored by IL-2R expression and [3H]thymidine uptake. If IL-16 was added following anti-CD3 activation, no suppression was noted. The suppressive effects of preincubation with IL-16 were not rescued by the addition of rIL-2 and were not the result of priming for anti-CD3-induced apoptosis. In addition, IL-16 had no effect on surface expression of CD3 or CD4. However, IL-16 did reduce the magnitude of the anti-CD3-induced intracellular Ca2+ increase. These studies indicate that while the interaction of CD4 with its natural ligand, IL-16, results in Ag-independent chemotaxis and IL-2R expression, this pro-inflammatory state is associated with subsequent transient inhibition of responsiveness via the CD3/TCR complex.


Long-Term Survival With Tafamidis in Patients With Transthyretin Amyloid Cardiomyopathy.
Tafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial). Patients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same tafamidis dose or, if previously treated with placebo, randomized (2:1) to tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to tafamidis in the LTE. Median follow-up was 58.5 months in the continuous tafamidis group (n=176) and 57.1 months in the placebo to tafamidis group (n=177). There were 79 (44.9%) deaths with continuous tafamidis and 111 (62.7%) with placebo to tafamidis (hazard ratio, 0.59 [95% CI, 0.44-0.79]; P<0.001). Mortality was also reduced in the continuous tafamidis (versus placebo to tafamidis) subgroups of: variant transthyretin amyloidosis (0.57 [0.33-0.99]; P=0.05) and wild-type transthyretin amyloidosis (0.61 [0.43-0.87]; P=0.006); and baseline New York Heart Association class I and II (0.56 [0.38-0.82]; P=0.003) and class III (0.65 [0.41-1.01]; P=0.06). In the LTE, patients initially treated with tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01994889 and NCT02791230.


Medicinal herb use among asthmatic patients attending a specialty care facility in Trinidad.
There is an increasing prevalence of asthma in the Caribbean and patients remain non-compliant to therapy despite the development of guidelines for management and prevention. Some patients may self-medicate with medicinal herbs for symptomatic relief, as there is a long tradition of use for a variety of ailments. The study assessed the prevalence of use and the factors affecting the decision to use herbs in asthmatic patients attending a public specialty care clinic in Trinidad. A descriptive, cross-sectional study was conducted at the Chest Clinic in Trinidad using a de novo, pilot-tested, researcher-administered questionnaire between June and July 2003. Fifty-eight out of 191 patients (30.4%) reported using herbal remedies for symptomatic relief. Gender, age, ethnicity, and asthma severity did not influence the decision to use herbs; however, 62.5% of patients with tertiary level schooling used herbs, p = 0.025. Thirty-four of these 58 patients (58.6%) obtained herbs from their backyards or the supermarket; only 14 patients (24.1%) obtained herbs from an herbalist, herbal shop or pharmacy. Relatives and friends were the sole source of information for most patients (70.7%), and only 10.3% consulted an herbalist. Ginger, garlic, aloes, shandileer, wild onion, pepper and black sage were the most commonly used herbs. Among patients attending the Chest Clinic in Trinidad the use of herbal remedies in asthma is relatively common on the advice of relatives and friends. It is therefore becoming imperative for healthcare providers to become more knowledgeable on this modality and to keep abreast with the latest developments.


Airway inflammation in children and adolescents with bronchiolitis obliterans.
Airway inflammation plays a major role in the progression of chronic lung diseases. The features of airway inflammation are not well defined among patients with cases of bronchiolitis obliterans (BO) that began in childhood. To investigate the sputum cell and cytokine profiles of stable cases of BO regarding lung function and the involvement of small airway disease (SAD). Twenty patients with BO (median age=14.5, range=7-23years) and 22 healthy controls (median age=16.5years, range=7-24years) were investigated. Lung function parameters and bronchial reversibility testing as well as sputum cell and cytokine profiles (IL-1β, IL-6, IL-8, TNF-α, IL-5, IFN-γ, and NFκB regulation) were analysed using quantitative RT-PCR and cytometric bead assay (CBA) in induced sputum. Patients with BO had significantly lower lung function values, including FVC, forced expiratory volume (FEV1), the Tiffeneau index (FEV1/VC), and MEF25, but increased functional residual capacity (RV/TLC) values. Bronchial reversibility was found in five patients (25%). Moreover, airway inflammation (as indicated by total cells, neutrophils, IL-1β, IL-6, IL-8, TNF-α, and NFκB) was significantly increased among patients with BO compared with controls. BO is predominantly a neutrophilic disease of the small bronchioles featuring elevated levels of pro-inflammatory cytokines leading to tissue remodelling and fibrosis of the small airways. Future therapies for patients with BO should more efficiently target the small airways.


[Aftermaths of lesions of coronary arteries in Kawasaki disease].
Kawasaki disease, also known as cutaneous-mucous-glandular mucocutaneous glandular syndrome, is acute systemic vasculitis of small-to-medium calibre arteries, frequently involving coronary arteries, affect almost exceptionally children, with reports concerning cases of Kawasaki syndrome in 20-to-30-year-old adults being extremely rare. The most serious manifestation of Kawasaki disease is coronaritis and formation of coronary artery aneurysms. The dynamics of the formed coronary aneurysms and, consequently, the fate of patients may be different. Thrombosis of an aneurysm in the early period of the disease and stenosing of the affected coronary artery later on present possible complications of Kawasaki disease and potential causes of myocardial infection in young adults. Increased risk of coronary artery thromboses in Kawasaki disease is conditioned by a decrease in velocity of blood flow and its turbulent pattern in the aneurysms, endothelial dysfunction due to currently existing or endured coronaritis and thrombocytosis typical of this pathology. Predisposing factors of coronary artery stenosing are unfavourable haemodynamic conditions appearing at the sites of the "entry" and "exit" of the aneurysm. Described herein are two case reports of myocardial infarction, one of which being a complication of an acute case of Kawasaki disease in a 29-year-old patient, with the second one being a consequence of coronary artery stenosing in a 25-year-old patient who had endured Kawasaki disease in his childhood.


BCL6 modulation of acute lymphoblastic leukemia response to chemotherapy.
The bone marrow niche has a significant impact on acute lymphoblastic leukemia (ALL) cell phenotype. Of clinical relevance is the frequency with which quiescent leukemic cells, in this niche, survive treatment and contribute to relapse. This study suggests that marrow microenvironment regulation of BCL6 in ALL is one factor that may be involved in the transition between proliferative and quiescent states of ALL cells. Utilizing ALL cell lines, and primary patient tumor cells we observed that tumor cell BCL6 protein abundance is decreased in the presence of primary human bone marrow stromal cells (BMSC) and osteoblasts (HOB). Chemical inhibition, or shRNA knockdown, of BCL6 in ALL cells resulted in diminished ALL proliferation. As many chemotherapy regimens require tumor cell proliferation for optimal efficacy, we investigated the consequences of constitutive BCL6 expression in leukemic cells during co-culture with BMSC or HOB. Forced chronic expression of BCL6 during co-culture with BMSC or HOB sensitized the tumor to chemotherapy induced cell death. Combination treatment of caffeine, which increases BCL6 expression in ALL cells, with chemotherapy extended the event free survival of mice. These data suggest that BCL6 is one factor, modulated by microenvironment derived cues that may contribute to regulation of ALL therapeutic response.


Amyotrophic lateral sclerosis - cell based therapy and novel therapeutic development.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, characterized by the predominant loss of motor neurons (MNs) in primary motor cortex, the brainstem, and the spinal cord, causing premature death in most cases. Minimal delay of pathological development by available medicine has prompted the search for novel therapeutic treatments to cure ALS. Cell-based therapy has been proposed as an ultimate source for regeneration of MNs. Recent completion of non-autologous fetal spinal stem cell transplant to ALS patients brought renewed hope for further human trials to cure the disease. Autologous somatic stem cell-based human trials are now in track to reveal the outcome of the ongoing trials. Furthermore, induced pluripotent stem cell (iPSC)-based ALS disease drug screen and autologous cell transplant options will broaden therapeutic options. In this review paper, we discuss recent accomplishments in cell transplant treatment for ALS and future options with iPSC technology.


Long-Term Progression-Free Survival in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer Patient Treated With Crizotinib.
Lung cancer is the second most common cancer worldwide. Non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) gene rearrangements constitutes 3-5%. Crizotinib was approved for the first-line therapy of advanced ALK-positive NSCLC patients. We present a female patient with advanced ALK-positive NSCLC who was kept on crizotinib as first-line therapy and showed progression-free survival (PFS) of 48 months despite the data suggesting that the majority of patients on crizotinib show relapse within 1 year. Further studies should focus on the molecular and biological factors and the possible effect of the long-term use of this drug.


Modelling the endothelial blood-CNS barriers: a method for the production of robust in vitro models of the rat blood-brain barrier and blood-spinal cord barrier.
Modelling the blood-CNS barriers of the brain and spinal cord in vitro continues to provide a considerable challenge for research studying the passage of large and small molecules in and out of the central nervous system, both within the context of basic biology and for pharmaceutical drug discovery. Although there has been considerable success over the previous two decades in establishing useful in vitro primary endothelial cell cultures from the blood-CNS barriers, no model fully mimics the high electrical resistance, low paracellular permeability and selective influx/efflux characteristics of the in vivo situation. Furthermore, such primary-derived cultures are typically labour-intensive and generate low yields of cells, limiting scope for experimental work. We thus aimed to establish protocols for the high yield isolation and culture of endothelial cells from both rat brain and spinal cord. Our aim was to optimise in vitro conditions for inducing phenotypic characteristics in these cells that were reminiscent of the in vivo situation, such that they developed into tight endothelial barriers suitable for performing investigative biology and permeability studies. Brain and spinal cord tissue was taken from the same rats and used to specifically isolate endothelial cells to reconstitute as in vitro blood-CNS barrier models. Isolated endothelial cells were cultured to expand the cellular yield and then passaged onto cell culture inserts for further investigation. Cell culture conditions were optimised using commercially available reagents and the resulting barrier-forming endothelial monolayers were characterised by functional permeability experiments and in vitro phenotyping by immunocytochemistry and western blotting. Using a combination of modified handling techniques and cell culture conditions, we have established and optimised a protocol for the in vitro culture of brain and, for the first time in rat, spinal cord endothelial cells. High yields of both CNS endothelial cell types can be obtained, and these can be passaged onto large numbers of cell culture inserts for in vitro permeability studies. The passaged brain and spinal cord endothelial cells are pure and express endothelial markers, tight junction proteins and intracellular transport machinery. Further, both models exhibit tight, functional barrier characteristics that are discriminating against large and small molecules in permeability assays and show functional expression of the pharmaceutically important P-gp efflux transporter. Our techniques allow the provision of high yields of robust sister cultures of endothelial cells that accurately model the blood-CNS barriers in vitro. These models are ideally suited for use in studying the biology of the blood-brain barrier and blood-spinal cord barrier in vitro and for pre-clinical drug discovery.


Isoflurane and Sevoflurane Induce Cognitive Impairment in Neonatal Rats by Inhibiting Neural Stem Cell Development Through Microglial Activation, Neuroinflammation, and Suppression of VEGFR2 Signaling Pathway.
Inhaled anesthetics are known to induce neurotoxicity in the developing brains of rodents, although the mechanisms are not well understood. The aim of this study was to elucidate the molecular mechanisms underlying anesthetics-induced neurodevelopmental toxicity by VEGF receptor 2 (VEGFR2) through the interaction between microglia and neural stem cells (NSCs) in postnatal day 7 (P7) rats. Cognitive function of P7 rats exposed to isoflurane and sevoflurane were assessed using Morris Water Maze and T maze tests. We also evaluated the expression levels of NSC biomarkers (Nestin and Sox2), microglia biomarker (CD11b or or IBA1), pro-inflammatory cytokines (IL-6 and TNF-α), and VEGFR2 using western blotting and immunohistochemistry in the brains of control and anesthesia-treated rats. We found spatial learning and working memory was impaired 2 weeks after anesthetics exposure in rats. Isoflurane induced stronger and more prolonged neurotoxicity than sevoflurane. However, cognitive functions were recovered 6 weeks after anesthesia. Isoflurane and sevoflurane decreased the levels of Nestin, Sox2, and p-VEGFR2, activated microglia, decreased the number of NSCs and reduced neurogenesis and the proliferation of NSCs, and increased the levels of IL-6, TNF-α, and CD11b. Our results suggested that isoflurane and sevoflurane induced cognitive impairment in rats by inhibiting NSC development and neurogenesis via microglial activation, neuroinflammation, and suppression of VEGFR2 signaling pathway.


[Pseudoxanthoma elasticum (Grönblad-Strandberg syndrome) and rheumatoid arthritis].
A 72-year-old woman, not previously known to have coronary heart disease, was admitted to hospital with an acute anterior wall myocardial infarction. The history revealed that, when about 40 years of age, a coarse skin-fold and yellowish-white xanthoma-like efflorescences had been noted around her umbilicus, the inguinal regions and axillae. These changes subsequently developed into a pathognomonic picture of pseudoxanthoma elasticum (PE), which was a significant factor in the myocardial infarction. At the age of 69 years, rheumatoid arthritis (RA), stage II after Steinbrocker, had been diagnosed on the basis of morning stiffness, symmetrical arthritis in more than three joint regions and the radiological appearance of narrowed joint spaces with erosions. Different pathological mechanisms of PE and RA change the connective tissue metabolism, thus affecting the same target tissue, but there is no known connection between the two diseases.


Long-term corticosteroid-induced chronic glaucoma model produced by intracameral injection of dexamethasone-loaded PLGA microspheres.
To evaluate a new chronic glaucoma model produced by intracameral injection of dexamethasone-loaded poly lactic-co-glycolic acid microspheres (Dex-PLGA-Ms) over six months. Healthy rats received two injections (at baseline and Week 4) of Dex-PLGA-Ms into the anterior chamber of the right eye. Clinical signs and intraocular pressure (IOP) were weekly recorded. The structure of the retina and optic nerve was in vivo evaluated using optical coherence tomography (OCT) every two weeks and functionally using dark- and light-adapted electroretinography at 0-12-24 weeks. Histological studies were also performed. IOP progressively increased up to hypertension (23.22 ± 3.63 mmHg) in both eyes but did so later in left eyes. OCT quantified a decrease in full-thickness retina posterior pole (R), retinal-nerve-fiber layer (RNFL), and ganglion-cell layer (GCL) thickness up to 24 weeks. Right eyes showed higher neuroretinal thickness loss up to week 8. RNFL experienced the highest percentage thickness loss at the inferior-superior axis, while in GCL the inner sectors of the horizontal axis (Nasal-Temporal) suffered the greatest decrease in thickness. Retinal ganglion cell, photoreceptor, and intermediate cell functionality decreased over time. Increased deposition of collagen IV was also found in zonular fibers and the ciliary body. This work shows the usefulness of drug delivery systems, not to treat pathology but to induce it. Only two injections of Dex-PLGA-Ms in the anterior chamber of rat eyes were enough to progressively create ocular hypertension and subsequent functional and structural neuroretinal degeneration, at least over 6 months.


Biotransformation of 3-amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]butyl}quinazolin-4(3H)-one (TZB-30878), a novel 5-hydroxytryptamine (5-HT)1A agonist/5-HT3 antagonist, in human hepatic cytochrome P450 enzymes.
3-Amino-5,6,7,8-tetrahydro-2-{4-[4-(quinolin-2-yl)piperazin-1-yl]-butyl}quinazolin-4(3H)-one (TZB-30878), a novel 5-hydroxytryptamine (5-HT)(1A) agonist/5-HT(3) antagonist, is currently under development for the treatment of irritable bowel syndrome. The objective of this investigation was to obtain information on the biotransformation of TZB-30878. This compound has quinazoline, piperazine, and quinoline rings. Metabolites of [quinazoline-2-(14)C]TZB-30878 were determined using radio high-performance liquid chromatography on samples obtained after incubation with human hepatic microsomes. Eight metabolites were detected in the microsomal incubation mixture, and their structures were proposed by mass spectrometry techniques using TZB-30878 and two stable labeled TZB-30878 analogs, [quinoline-deuterium (D)(6)]TZB-30878 and [piperazin-D(8)]TZB-30878. Liquid chromatography/tandem mass spectrometry analyses suggested that the eight metabolites consisted of a cyclic metabolite (M6), four hydroxylated metabolites (M1, M2, M3, and M4) (three on quinoline ring and one on quinazoline ring), a deaminated metabolite (M5), and two metabolites (M7 and M8) that were presumably intermediates leading to the formation of the cyclic metabolite M6. Hydroxylation sites in the quinoline and quinazoline rings were predicted by electron density calculations and confirmed by comparison with authentic standards. To the best of our knowledge, N-deamination by microsomes leading to the formation of M5 appears to be novel. In addition, in vitro experiments in human liver microsomes with cytochrome P450 (P450)-specific inhibitors revealed that CYP3A4 was the major enzyme responsible for the metabolism of TZB-30878. Other P450 enzymes, such as a CYP2D6, played a minor role in its metabolism.


Diagnostic accuracy of magnetic resonance angiography for internal carotid artery disease: a systematic review and meta-analysis.
Accurate diagnosis of the degree of internal carotid artery (ICA) stenosis is needed for decisions regarding optimal stroke prevention. Noninvasive magnetic resonance angiography (MRA) is being proposed and used as a replacement for the gold standard, intra-arterial angiography. Our purpose was to perform a systematic review and diagnostic meta-analysis to determine the sensitivity and specificity of time-of-flight (TOF) MRA and contrast-enhanced (CE) MRA for the detection of (1) high-grade (> or = 70% to 99%) ICA stenoses; (2) ICA occlusions; (3) moderately severe (50% to 69%) ICA stenoses; and (4) compare the overall accuracy of the 2 MRA techniques. The medical literature on MRA and the diagnosis of ICA steno-occlusive disease was reviewed through the PubMed, EMBASE, and SCOPUS databases. All publication years were included through to November 2006. Studies were eligible for inclusion if they compared the accuracy of TOF or CE MRA for the detection of ICA disease against intra-arterial angiography and reported sufficient data. The overall sensitivity of TOF MRA for the detection of > or = 70% to 99% ICA stenoses was 91.2% (95% CI: 88.9% to 93.1%) with a specificity of 88.3% (86.7% to 89.7%), whereas the sensitivity of CE MRA was 94.6% (92.4% to 96.4%) with a specificity of 91.9% (90.3% to 93.4%). For the detection of ICA occlusions, the sensitivity of TOF MRA was 94.5% (91.2% to 96.8%) and the specificity was 99.3% (98.9% to 99.6%), whereas the sensitivity and specificity values for CE MRA were 99.4% (96.8% to 100%) and 99.6% (99.2% to 99.9%), respectively. For moderately severe (50% to 69%) stenoses, TOF MRA had a sensitivity of only 37.9% (29.3% to 47.1%) and a specificity of 92.1% (89.6% to 94.1%); for CE MRA, the pooled sensitivity value was somewhat better at 65.9% (57.0% to 74.0%), whereas the specificity was 93.5% (91.3% to 95.3%). TOF MRA and CE MRA showed high accuracy for the detection of high-grade ICA stenoses and occlusions with CE MRA having the edge over TOF MRA, but had only poor (TOF MRA) to fair (CE MRA) sensitivity for the detection of moderately severe stenoses.


An Efficient Signature Based on Necroptosis-Related Genes for Prognosis of Patients With Pancreatic Cancer.
Pancreatic cancer (PCa) is a highly lethal and aggressive disease, characterized by high mortality rates. Although necroptosis plays a vital role in tumor progression, cancer metastasis, prognosis of cancer patients, necroptosis-related gene (NRG) sets have rarely been analyzed in PCa. Therefore, definition of novel necroptosis-related prognostic markers for PCa patients is urgently needed. Here, we screened 159 NRGs and identified 132 differentially expressed NRGs in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) cohorts. Next, we employed univariate and multivariate Cox proportional regression models to establish a prognostic-related NRG signature comprising five NRGs that could stratify patients into high-risk and low-risk groups. Results from survival analysis showed that patients in the high-risk had dramatically shorter overall survival (OS) rates compared with their low-risk counterparts. Results from univariate and multivariate Cox regression analysis further confirmed the independent prognostic value of the established necroptosis-related signature, and the area under receiver (AUC) of the operating curve (ROC) for 1-, 3-, 5-years was 0.72, 0.74, and 0.75, respectively. Finally, we validated the signature efficacy using an independent cohort from the Gene Expression Omnibus (GEO) database. The ROC curve confirmed the predictive capacity of the five-gene signature. Furthermore, we validated expression of the signature proteins using the Human Protein Atlas (HPA) database. In conclusion, we successfully constructed a novel necroptosis-related signature for prognosis of patients with pancreatic cancer.


The effects of social structure and sex-biased transmission on macroparasite infection.
Mathematical models of disease dynamics tend to assume that individuals within a population mix at random and so transmission is random, and yet, in reality social structure creates heterogeneous contact patterns. We investigated the effect of heterogeneity in host contact patterns on potential macroparasite transmission by first quantifying the level of assortativity in a socially structured wild rodent population (Apodemus flavicollis) with respect to the directly-transmitted macroparasitic helminth, Heligmosomoides polygyrus. We found the population to be disassortatively mixed (i.e. male mice mixing with female mice more often than same sex mixing) at a constant level over time. The macroparasite H. polygyrus has previously been shown to exhibit male-biased transmission so we used a Susceptible-Infected (SI) mathematical model to simulate the effect of increasing strengths of male-biased transmission on the prevalence of the macroparasite using empirically-derived transmission networks. When transmission was equal between the sexes the model predicted macroparasite prevalence to be 73% and infection was male biased (82% of infection in the male mice). With a male-bias in transmission ten times that of the females, the expected macroparasite prevalence was 50% and was equally prevalent in both sexes, results that both most closely resembled empirical dynamics. As such, disassortative mixing alone did not produce macroparasite dynamics analogous to those from empirical observations; a strong male-bias in transmission was also required. We discuss the relevance of our results in the context of network models for transmission dynamics and control.