Secondary product glucosyltransferase and putative glucosyltransferase expression during Citrus paradisi (c.v. Duncan) growth and development.
Flavonoids are secondary metabolites that have significant roles in plant defense and human nutrition. Glucosyltransferases (GTs) catalyze the transfer of sugars from high energy sugar donors to other substrates. Several different secondary product GTs exist in the tissues of grapefruit making it a model plant for studying their structure and function. The goal of this investigation was to determine the expression patterns of seven putative secondary product GTs during grapefruit growth and development by quantifying mRNA expression levels in the roots, stems, leaves, flowers, and mature fruit to establish whether the genes are expressed constitutively or if one or more could be expressed in a tissue specific manner and/or developmentally regulated. Six growth stages were defined from which RNA was extracted, and expression levels were quantified by standardized densitometry of gene-specific RT-PCR products. Results show that there were variable degrees of PGT expression in different tissues and at different developmental stages. These results add to the growing knowledge base of dynamics of expression and potential regulation of secondary metabolism in Citrus paradisi.


The effect of vagotomy and hydrocortisone administration on pulmonary surfactant activity in adult albino rats.
The role of vagus and hydrocortisone in the regulation of lung surfactant was studied in adult albino rats. Dynamic surface tension and phospholipid content were measured in the lung wash for estimating surfactant activity. The results indicate that vagotomy significantly decreases the surfactant activity whereas hydrocortisone does not alter it. But when hydrocortisone was administered prior to vagotomy it could prevent the decrease in surfactant activity. Thus it is concluded the regulation of lung surfactant in the adult lung is mainly by vagus nerve and hydrocortisone as such has no role but in the absence of vagal regulation hydrocortisone could maintain normal lung surfactant activity.


Changes in Skeletal Tumor Activity on (18)F-choline PET/CT in Patients Receiving (223)Radium Radionuclide Therapy for Metastatic Prostate Cancer.
Radium-223 dichloride is an alpha-emitting radiopharmaceutical shown to prolong survival in patients with castrate-resistant prostate cancer (CRPC) and symptomatic skeletal metastases. This report describes in two patients the acute changes in bone metastatic activity detected by F-18 choline PET/CT imaging midway during treatment with radium-223 dichloride. In addition to visual and standardized uptake value analysis, changes in the whole-body tumor burden were quantified by measuring the difference in net metabolically active tumor volume (MATV) and total lesion activity (TLA) between pre- and mid-treatment PET scans. After the third dose of radium-223 dichloride, near-total disappearance of abnormal skeletal activity was observed in one case (net MATV change from 260.7 to 0.8 cc; net TLA change from 510.7 to 2.1), while a heterogeneous tumor response was observed in the other (net MATV change from 272.2 to 241.3 cc; net TLA change from 987.1 to 779.4). Corresponding normalization and persistent elevation in serum alkaline phosphatase levels were observed in these cases, respectively. Further research is needed to determine the predictive value of serial F-18 choline PET/CT imaging in patients receiving radium-223 dichloride for CRPC.


Inhibition of VCAM-1 expression in the arterial wall is shared by structurally different antioxidants that reduce early atherosclerosis in NZW rabbits.
We previously established that probucol decreases basal expression of VCAM-1 in the aorta of WHHL rabbits and inhibits the up-regulation of VCAM-1 expression that normally accompanies atherogenesis. To determine whether this effect is shared by other antioxidants in vivo, we now investigated whether a structurally unrelated antioxidant, vitamin E, also inhibits arterial VCAM-1 expression and whether the degree of VCAM-1 inhibition correlates with the reduction of atherosclerosis or the antioxidant protection of LDL. Atherogenesis and VCAM-1 mRNA and protein were determined in four groups of NZW rabbits (n = 6;-8) fed 0.5% cholesterol alone or supplemented with 0.1% vitamin E, a low dose (0.04;-0.075%) of probucol yielding the same degree of antioxidant protection of plasma LDL as vitamin E, or a high dose (0.5%) of probucol, and in normocholesterolemic rabbits. After 81 days, extensive atherosclerosis and a greater than 4-fold up-regulation of VCAM-1 mRNA was seen in rabbits on high cholesterol diet, mostly in the intima. Treatment with vitamin E, high-dose probucol, and low-dose probucol significantly decreased VCAM-1 mRNA by 49.0, 74.9, and 57. 5%, respectively, and reduced atherosclerosis in adjacent segments of the thoracic aorta to a similar degree as reported by previous studies. Immunocytochemistry confirmed that lesions of antioxidant-treated animals also contained less VCAM-1 protein. Neither the degree of VCAM-1 inhibition nor the extent of atherosclerosis correlated with the degree of antioxidant protection of plasma LDL.In summary, treatment with structurally unrelated antioxidants conveyed different degrees of antioxidant protection to plasma LDL but significantly reduced VCAM-1 expression in vivo and inhibited atherogenesis. This is consistent with the assumption that antiatherogenic effects of antioxidants may in part be mediated by interference with oxidation-dependent intracellular signaling.


Aspherical liquid crystal lenses based on a variable transmission electrode.
In this work, a technique to generate aspherical liquid crystal lenses with positive and negative optical power is experimentally demonstrated. The main enabling element is a micro-metric electrode with variable spatial size. This produces a decreasing resistance towards the lens centre that generates the desired voltage/phase profiles. Then, the voltage is homogeneously distributed across the active area of the lens by micro-metric concentric electrodes. As it is demonstrated, the phase shift can be controlled with voltages from 0 to 4.5 VRMS. As a result, parabolic profiles are obtained both for negative and positive optical powers. Furthermore, this approach avoids some disadvantages of previous techniques; parabolic profiles can be obtained with only one lithographic step and one or two voltage sources. Other complex aspherical profiles could be fabricated using the same technique, such as elliptical or hyperbolic ones.


[What do Norwegian media communicate about back pain?].
Mass media influence peoples' attitudes and conduct. We set out to investigate what Norwegian mass media write about back pain and whether this information is in accordance with national interdisciplinary guidelines for low back pain (published in 2002). Quantitative content analysis of 495 news stories from Norwegian newspapers and magazines published in 2001-03 and 2005-06. Most publications were about a single case. Risk factors for low back pain, examinations, treatment and prevention were frequent topics. No publication was in direct disagreement with the clinical guidelines. Dependent on the media type, 44 to 62 % of the publications supported the guidelines' main messages of regaining daily normal activities, including work and exercises, as soon as possible. Norwegian mass media communicate evidence-based information about low back pain to a large extent. We regard these media as collaborators in the communication of important recommendations in guidelines about low back pain.


An analytical study of the neurosecretory cells of the brain of the mature larvae and diapause pupae of Amsacta collaris Hampson (Lepidoptera: Arctiidae) under different temperature regimes.
The neurosecretory cells (NSCs) of the brain of the mature larvae and 3 months old diapause pupae of Amsacta collaris Hampson (Lepidopera: arctiidae) have been studied under different temperature regimes (0, 7, 18, 37, and 42 degrees C), using paraldehyde fuchsin and performic acid resorcin fuchsin staining techniques. The 0 degree C is fatal to the larvae, and at 7 degrees C, within 24 h the quantity of NSM reduced considerably in all the subtypes of A-cells; activity started 3rd day onwards, and on 5th day, the A1-cells appeared loaded with NSM, the A2-cells moderately filled, but no change in A3-cells was observed. At 0 degree C, within 48 h or chilling, the NSCs of diapause pupae (DP) revealed a moderate amount of NSM with numerous, large vacuoles in the A1-cells and in some insects, the cells appeared gigantic in form; the A2- and A3-cells were moderately filled with NSM. After 1 week of chilling, at 0 degree C, the A1-cells appeared almost empty. The A1-cells of DP-kept at 7 degrees C and 18 degrees C respectively, discharged quickly all the previously stored NSM, within 2 days, hence appeared poorly filled. 3rd day onwards, a gradual increase in NSM was observed. After 15 days, a moderate amount of NSM in A1-, a large amount in A3-, and increased amount in A2-cells of the medial and lateral groups was observed. The 37 degrees C appeared to be the most suitable temperature at which all the cells show maximum activity in mature larvae and DP both, and contain a moderate amount of NSM in them. At 42 degrees C, the A1-cells in larvae and DP contain a moderate amount of NSM, A2-cells of the medial group a poor, and A2-cells of the lateral group, a depleted amount of NSM, the A3-cells, however, appeared heavily loaded. Later, the NSM decreased gradually in all the subtypes of A-cells. On 15th day, at 42 degrees C the A1-cells in DP revealed depletion of NSM, the A2-cells become totally inactive and lack NSM; the A3-cells a poor amount of NSM in them. The significance of these changes at different temperature regimes is discussed.


Guidance of neurite outgrowth on aligned electrospun polypyrrole/poly(styrene-beta-isobutylene-beta-styrene) fiber platforms.
The purpose of this work was to investigate the potential biomedical application of novel aligned electrospun polypyrrole (PPy)/poly(styrene-beta-isobutylene-beta-styrene) (SIBS) fibers. After successfully aligning the electroactive PPy/SIBS fibers based on our modified electrospinning method, we demonstrated that neurite outgrowth from PC12 cells could be highly orientated parallel to the aligned PPy/SIBS fibers. Physical interactions between the nerve cells and PPy/SIBS fibers through filopodia "sensing" were observed using atomic force microscopy. These observations indicate a role of contact guidance as a mechanism for the observed alignment. This work highlights the capacity for electroactive PPy/SIBS fibers to support and guide nerve cell differentiation through topographic cues, which is a highly desirable characteristic in medical implants for neurological applications.


Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function.
Contrast MRI enhancement patterns in several pathophysiologies resulting from ischemic myocardial injury are controversial or have not been investigated. We compared contrast enhancement in acute infarction (AI), after severe but reversible ischemic injury (RII), and in chronic infarction. In dogs, a large coronary artery was occluded to study AI and/or chronic infarction (n = 18), and a second coronary artery was chronically instrumented with a reversible hydraulic occluder and Doppler flowmeter to study RII (n = 8). At 3 days after surgery, cine MRI revealed reduced wall thickening in AI (5+/-6% versus 33+/-6% in normal, P<0.001). In RII, wall thickening before, during, and after inflation of the occluder for 15 minutes was 35+/-5%, 1+/-8%, and 21+/-10% and Doppler flow was 19.8+/-5.3, 0.2+/-0.5, and 56.3+/-17.7 (peak hyperemia) cm/s, respectively, confirming occlusion, transient ischemia, and reperfusion. Gd-DTPA-enhanced MR images acquired 30 minutes after contrast revealed hyperenhancement of AI (294+/-96% of normal, P<0.001) but not of RII (98+/-6% of normal, P = NS). Eight weeks later, the chronically infarcted region again hyperenhanced (253+/-54% of normal, n = 8, P<0.001). High-resolution (0.5 x 0.5 x 0.5 mm) ex vivo MRI demonstrated that the spatial extent of hyperenhancement was the same as the spatial extent of myocyte necrosis with and without reperfusion at 1 day (R = 0.99, P<0.001) and 3 days (R = 0.99, P<0.001) and collagenous scar at 8 weeks (R = 0.97, P<0.001). In the pathophysiologies investigated, contrast MRI distinguishes between reversible and irreversible ischemic injury independent of wall motion and infarct age.


Linkage disequilibrium and haplotype analysis in German Friedreich ataxia families.
The main mutation causing Friedreich ataxia (FRDA) is the expansion of a GAA repeat localized within the intron between exon 1 and exon 2 of the gene X25. This expansion has been observed in 98% of FRDA chromosomes. To analyze frequencies of markers tightly linked to the Friedreich ataxia gene and to investigate wheter a limited number of ancestral chromosomes are shared by German FRDA families, a detailed analysis employing nine polymorphic markers was performed. We found strong linkage disequilibria and association of FRDA expansions with a few haplotypes. FRDA haplotypes differ significantly from control haplotypes. Our results confirm that GAA repeat expansions in intron 1 of the frataxin gene are limited to a few chromosomes and indicate an obvious founder effect in German patients. Based on these analyses, we estimate a minimum age of the mutation of 107 generations.


Air quality-related health damages of food.
Agriculture is a major contributor to air pollution, the largest environmental risk factor for mortality in the United States and worldwide. It is largely unknown, however, how individual foods or entire diets affect human health via poor air quality. We show how food production negatively impacts human health by increasing atmospheric fine particulate matter (PM2.5), and we identify ways to reduce these negative impacts of agriculture. We quantify the air quality-related health damages attributable to 95 agricultural commodities and 67 final food products, which encompass >99% of agricultural production in the United States. Agricultural production in the United States results in 17,900 annual air quality-related deaths, 15,900 of which are from food production. Of those, 80% are attributable to animal-based foods, both directly from animal production and indirectly from growing animal feed. On-farm interventions can reduce PM2.5-related mortality by 50%, including improved livestock waste management and fertilizer application practices that reduce emissions of ammonia, a secondary PM2.5 precursor, and improved crop and animal production practices that reduce primary PM2.5 emissions from tillage, field burning, livestock dust, and machinery. Dietary shifts toward more plant-based foods that maintain protein intake and other nutritional needs could reduce agricultural air quality-related mortality by 68 to 83%. In sum, improved livestock and fertilization practices, and dietary shifts could greatly decrease the health impacts of agriculture caused by its contribution to reduced air quality.


Targeting CAMKK2 and SOC Channels as a Novel Therapeutic Approach for Sensitizing Acute Promyelocytic Leukemia Cells to All-Trans Retinoic Acid.
Calcium ions (Ca2+) play important and diverse roles in the regulation of autophagy, cell death and differentiation. Here, we investigated the impact of Ca2+ in regulating acute promyelocytic leukemia (APL) cell fate in response to the anti-cancer agent all-trans retinoic acid (ATRA). We observed that ATRA promotes calcium entry through store-operated calcium (SOC) channels into acute promyelocytic leukemia (APL) cells. This response is associated with changes in the expression profiles of ORAI1 and STIM1, two proteins involved in SOC channels activation, as well as with a significant upregulation of several key proteins associated to calcium signaling. Moreover, ATRA treatment of APL cells led to a significant activation of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) and its downstream effector AMP-activated protein kinase (AMPK), linking Ca2+ signaling to autophagy. Pharmacological inhibition of SOC channels and CAMKK2 enhanced ATRA-induced cell differentiation and death. Altogether, our results unravel an ATRA-elicited signaling pathway that involves SOC channels/CAMKK2 activation, induction of autophagy, inhibition of cellular differentiation and suppression of cell death. We suggest that SOC channels and CAMKK2 may constitute novel drug targets for potentiating the anti-cancer effect of ATRA in APL patients.


A galerkin/neural-network-based design of guaranteed cost control for nonlinear distributed parameter systems.
This paper presents a Galerkin/neural-network- based guaranteed cost control (GCC) design for a class of parabolic partial differential equation (PDE) systems with unknown nonlinearities. A parabolic PDE system typically involves a spatial differential operator with eigenspectrum that can be partitioned into a finite-dimensional slow one and an infinite-dimensional stable fast complement. Motivated by this, in the proposed control scheme, Galerkin method is initially applied to the PDE system to derive an ordinary differential equation (ODE) system with unknown nonlinearities, which accurately describes the dynamics of the dominant (slow) modes of the PDE system. The resulting nonlinear ODE system is subsequently parameterized by a multilayer neural network (MNN) with one-hidden layer and zero bias terms. Then, based on the neural model and a Lure-type Lyapunov function, a linear modal feedback controller is developed to stabilize the closed-loop PDE system and provide an upper bound for the quadratic cost function associated with the finite-dimensional slow system for all admissible approximation errors of the network. The outcome of the GCC problem is formulated as a linear matrix inequality (LMI) problem. Moreover, by using the existing LMI optimization technique, a suboptimal guaranteed cost controller in the sense of minimizing the cost bound is obtained. Finally, the proposed design method is applied to the control of the temperature profile of a catalytic rod.


Improving ascertainment of sudden cardiac death in patients with end stage renal disease.
Data collected by the US Renal Data System (USRDS) identify sudden cardiac death (SCD) as the leading cause of death among hemodialysis patients. However, evidence suggests that clinical events captured on the USRDS death notification form may be inaccurate. A new method for classifying SCD was recently developed to enhance the accuracy of SCD classification. This study examined the performance characteristics of this refined definition using a cohort of hemodialysis patients who experienced a witnessed SCD as the reference standard. This is a retrospective cohort study of 363 patients who experienced a witnessed SCD in US Gambro (DaVita) outpatient dialysis clinics. Sensitivity of SCD defined by death notification forms and SCD defined using additional administrative sources was compared. Clinical data recorded near time of death were also examined. Existing USRDS death notification forms reported 70.8% of witnessed SCD as "cardiac arrest/cause unknown" or "arrhythmia." The refined definition significantly improved identification to 83.8% of witnessed SCD events (P<0.001). Verified SCD cases that were not identified by either definition were more likely to be reported on the death notification form as death due to myocardial infarction, hyperkalemia, sepsis, malignancy, or unknown cause. Compared with the death notification form alone, the refined SCD definition significantly improves the sensitivity of reporting of witnessed SCD occurring within outpatient hemodialysis clinics. More accurate reporting of cardiac events by clinicians and refinements to existing death notification forms may further improve recognition and understanding of SCD.


Pregnancy-related changes in the mouse oviduct and uterus revealed by differential binding of fluoresceinated lectins.
The binding of 20 fluorescein isothiocyanate (FITC)-labeled lectins to various portions of the pregnant and non-pregnant murine oviduct and uterus was studied by fluorescence microscopy. Five lectins (from Ricinus communis (RCA-I), Maclura pomifera (MPA), Triticum vulgare (wheat germ-WGA), Bauhinia purpurea (BPA), and Ulex europeus (UEA-I] reacted differentially with the epithelium of pregnant as compared with the non-pregnant uterus. The binding of RCA-I, MPA and WGA delineated pregnancy-related changes in the distal oviduct and colliculus tubaris. WGA recognized also pregnancy related changes in the proximal oviduct. The reactivity of the remaining 15 lectins did not distinguish the pregnant and non-pregnant oviduct and uterus, although some of them served to identify specific components of the mouse genital tract. Thus, Soybean lectin (SBA) reacted almost exclusively with the colliculus tubaris. UEA-I alone reacted exclusively with the epithelium of the non-pregnant uterus. RCA-II reacted preferentially with the epithelium of the oviduct and uterus as compared with its weak reactivity with the stroma. Two lectins (from Pisum sativum and Lens culinaris) reacted selectively with stromal cells of the uterus and oviduct. Present data indicate that the differential binding properties of these FITC-labeled lectins can be exploited to identify certain components of the mouse oviduct and uterus and to indicate changes in the cell surface and/or cytoplasm in these structures during pregnancy.


Functional studies in the human submandibular duct cell line, HSG-PA, suggest a second salivary gland receptor subtype for nucleotides.
Extracellular nucleotides, acting through P2 purinoceptors, have been implicated in the regulation of ion transporting epithelia, including salivary gland acini. Multiple P2 purinoceptor subtypes have been suggested, including P2X, P2Y and P2U (or nucleotide) subtypes, as well as the P2Z subtype found in rat parotid acinar cells. We investigated responses to ATP, ATP analogs and UTP in transformed human submandibular gland duct cells (HSG-PA), in order to compare duct cell purinoreceptors with those in acinar cells. ATP, UTP and some ATP analogs increased, with different potencies, inositol phosphate accumulation, calcium mobilization and potassium efflux. Nucleotide-stimulated calcium mobilization occurred in the absence of, but was enhanced by, extracellular calcium, and maximal potassium efflux required extracellular calcium. UTP and ATP demonstrated equal potencies of about 1 microM and similar efficacies in eliciting these responses, and identical rank orders of potency for stimulating calcium mobilization and potassium efflux were obtained: UTP = ATP greater than ATP gamma S greater than ADP greater than ADP beta S, with alpha,beta-methylene-ATP and 2-methylthio-ATP having little or no effect. Agents reported to block nucleotide effects in parotid acini were ineffective in HSG-PA cells, and experiments in Mg(++)- and Ca(++)-free medium did not indicate that a form of ATP other than MgATP was the active species at the HSG-PA purinoceptor. The extracellular nucleotide effects were not altered by pertussis toxin. These results indicate the presence of a P2U or nucleotide receptor subtype in HSG-PA submandibular duct cells distinguishable from the P2Z purinoceptor of rat parotid acinar cells, suggesting involvement of multiple nucleotide receptor subtypes in salivary gland regulation.


Postnatal depression in Japanese women. Detecting the early onset of postnatal depression by closely monitoring the postpartum mood.
The terminology and definition of mood disturbance during the early postpartum period has yet to be clearly elucidated among clinical practitioners. Criteria for maternity blues have not been well established, and it may overlap with the beginning of a postnatal depression. The aims of the present study, are firstly to survey the symptomatic features of mood disturbance in the very early postpartum period and secondary, to develop a guideline for detecting and predicting postnatal depression during the same period using a simple screening technique. Eighty-eight mothers recruited from a maternity ward for the prospective study completed the whole protocol. Two methods were used to survey the symptomatic features of mood disturbance; (1) interview and (2) self-report questionnaires. The interviews were carried out twice. At three weeks postpartum, the Schedule for Affective Disorder and Schizophrenia (SADS)/Research Diagnostic Criteria was administered, together with an interview of the symptoms of "maternity blues". The SADS interview was re-administered at three months postnatally. Two self-report questionnaires addressing mood disturbance were administered: (1) Maternity Blues Scale; (Stein, 1980). (2) Edinburgh Postnatal Depression Scale (EPDS; Cox et al., 1987). The Maternity Blues Scale was administered on the first five consecutive postnatal days. The EPDS was administered on the fifth day, one month and three months postnatally. In addition, the Life Event Scale (Burgha et al., 1985) was also administered at one month postnatally. Obstetric notes were also examined. At the first interview, 12 mothers were diagnosed with postnatal depression and 10 of these had their onset within one week. At the second interview three additional mothers were newly diagnosed with depression. In all mothers, depression was detected at one month using the EPDS, with a cut-off of 8/9. The EPDS scores on the fifth postnatal day were also higher in the depressed mothers and could detect early onset of postnatal depression. The use of the EPDS during the early postnatal days, can be a simple and useful screening instrument for the onset of early postnatal depression.


TFP5, a Peptide Derived from Cdk5 Activator p35, Protects Pancreatic β Cells from Glucose Toxicity.
We studied the effect of TFP5 on MIN6 cells (cultured mouse islet β cells) treated with different concentrations of glucose (5 or 25 mM). The results were verified in C57BL/6J mice (control; n=12) and db/db mice with type 2 diabetes mellitus (n=12). To synthesize TFP5, peptide p5 (a derivative of p35 protein, activator of cyclin-dependent kinase 5, Cdk5) was conjugated with a FITC tag at the N-terminus and an 11-amino acid TAT protein transduction domain at the C-terminus. TFP5 was employed to inhibit Cdk5 activity and then to evaluate its efficiency in treating experimental type 2 diabetes mellitus. TFP5 effectively inhibited the pathological hyperactivity of Cdk5, enhanced insulin secretion, and protected pancreatic β cells from apoptosis in vitro and in vivo. In addition, TFP5 inhibited inflammation in pancreatic islets by reducing the expression of inflammatory cytokines TGF-β1, TNFα, and IL-1β. These novel data indicates that TFP5 is a promising candidate for treatment of type 2 diabetes mellitus.


The contribution of chronic diseases to the prevalence of dependence among older people in Latin America, China and India: a 10/66 Dementia Research Group population-based survey.
The number of older people is set to increase dramatically worldwide. Demographic changes are likely to result in the rise of age-related chronic diseases which largely contribute to years lived with a disability and future dependence. However dependence is much less studied although intrinsically linked to disability. We investigated the prevalence and correlates of dependence among older people from middle income countries. A one-phase cross-sectional survey was carried out at 11 sites in seven countries (urban sites in Cuba, Venezuela, and Dominican Republic, urban and rural sites in Peru, Mexico, China and India). All those aged 65 years and over living in geographically defined catchment areas were eligible. In all, 15,022 interviews were completed with an informant interview for each participant. The full 10/66 Dementia Research Group survey protocol was applied, including ascertainment of depression, dementia, physical impairments and self-reported diagnoses. Dependence was interviewer-rated based on a key informant's responses to a set of open-ended questions on the participant's needs for care. We estimated the prevalence of dependence and the independent contribution of underlying health conditions. Site-specific prevalence ratios were meta-analysed, and population attributable prevalence fractions (PAPF) calculated. The prevalence of dependence increased with age at all sites, with a tendency for the prevalence to be lower in men than in women. Age-standardised prevalence was lower in all sites than in the USA. Other than in rural China, dementia made the largest independent contribution to dependence, with a median PAPF of 34% (range 23%-59%). Other substantial contributors were limb impairment (9%, 1%-46%), stroke (8%, 2%-17%), and depression (8%, 1%-27%). The demographic and health transitions will lead to large and rapid increases in the numbers of dependent older people particularly in middle income countries (MIC). The prevention and control of chronic neurological and neuropsychiatric diseases and the development of long-term care policies and plans should be urgent priorities.


Effect of Vibronic Coupling on Correlated Triplet Pair Formation in the Singlet Fission Process of Linked Tetracene Dimers.
Tetracene-based singlet fission (SF) materials show application prospects as triplet sensitizers in organic optoelectronics. SF involves internal conversion from photoexcited singlet states 1(S1S0) to correlated triplet pair states 1(T1T1). We derive an expression for the internal conversion rate on the basis of the Fermi golden rule with an artificial Lorentzian broadening. The internal conversion rate depends on the interstate vibronic couplings (VCs) and energy difference (ΔESF) between 1(S1S0) and 1(T1T1). Therefore, understanding the interplay between interstate VCs and ΔESF is necessary to reveal how the structure-property relationship affects the SF efficiency. Here, we propose a method to quantitatively analyze interstate VCs between 1(S1S0) and 1(T1T1). We apply this method to SF in ortho-, meta-, and para-bis(ethynyltetracenyl)benzene and identify an effect of interstate VCs on the 1(T1T1) formation rate. The interstate VCs of the meta dimer are remarkably weak, which reasonably explains the experimentally obtained slow 1(T1T1) formation rate. The weak VCs result from a very small overlap density between 1(S1S0) and 1(T1T1) of the meta dimer. Furthermore, we investigate structure-dependence of the 1(T1T1) formation rate of the para dimer and find that the para dimer shows large VCs and small ΔESF when the rotational angle between the two tetracene units is large, which leads to the faster 1(T1T1) formation rate than those of the ortho and meta dimers. The rotation of the tetracene units is the origin of the experimentally observed fast 1(T1T1) formation rate of the para dimer.


Knockdown of RAGE inhibits growth and invasion of gastric cancer cells.
The receptor for advanced glycation endproducts (RAGE) is an oncogenic trans-membranous receptor, which is overexpressed in multiple human cancers. However, the role of RAGE in gastric cancer is still elusive. In this study, we investigated the expression and molecular mechanisms of RAGE in gastric cancer cells. Forty cases of gastric cancer and corresponding adjacent non-cancerous tissues (ANCT) were collected, and the expression of RAGE was assessed using immunohistochemistry (IHC) in biopsy samples. Furthermore, RAGE signaling was blocked by constructed recombinant small hairpin RNA lentiviral vector (Lv-shRAGE) used to transfect into human gastric cancer SGC-7901 cells. The expression of AKT, proliferating cell nuclear antigen (PCNA) and matrix metallopeptidase-2 (MMP-2) was detected by Real-time PCR and Western blot assays. Cell proliferative activities and invasive capability were respectively determined by MTT and Transwell assays. Cell apoptosis and cycle distribution were analyzed by flow cytometry. As a consequence, RAGE was found highly expressed in cancer tissues compared with the ANCT (70.0% vs 45.0%, P=0.039), and correlated with lymph node metastases (P=0.026). Knockdown of RAGE reduced cell proliferation and invasion of gastric cancer with decreased expression of AKT, PCNA and MMP-2, and induced cell apoptosis and cycle arrest. Altogether, upregulation of RAGE expression is associated with lymph node metastases of gastric cancer, and blockade of RAGE signaling suppresses growth and invasion of gastric cancer cells through AKT pathway, suggesting that RAGE may represent a potential therapeutic target for this aggressive malignancy.


Candida albicans has a cell-associated ferric-reductase activity which is regulated in response to levels of iron and copper.
For survival, pathogenic organisms such as Candida albicans must possess an efficient mechanism for acquiring iron in the iron-restricted environment of the human body. C. albicans can use iron from a variety of sources found within the host. However, it is not clear how biologically active ferrous iron is obtained from these sources. One strategy adopted by some organisms is to reduce iron extracellularly and then specifically transport the ferrous iron into the cell. We have shown that clinical isolates of C. albicans do have a cell-associated ferric-reductase activity. The determination of ferric-reductase activity of cells growing exponentially in either low- or high-iron media over a period of time indicated that C. albicans reductase activity is induced when in low-iron conditions. Moreover, we have demonstrated that C. albicans reductase activity is also regulated in response to the growth phase of the culture, with induction occurring upon exit from stationary phase and maximal levels being reached in early exponential stage irrespective of the iron content of the medium. These results suggest that C. albicans reductase activity is regulated in a very similar manner to the Saccharomyces cerevisiae ferric-reductase. Iron reduction and uptake in S. cerevisiae are closely connected to copper reduction, and possibly copper uptake. In this report we show that iron and copper reduction also appear to be linked in C. albicans. The ferric-reductase activity is negatively regulated by copper. Moreover, quantitative cupric-reductase assays indicated that C. albicans is capable of reducing copper and that this cupric-reductase activity is negatively regulated by both iron and copper. This is the first report that C. albicans has an iron- and copper-mediated ferri-reductase activity.


A method for the in vivo measurement of zebrafish tissue neutrophil lifespan.
Neutrophil function is thought to be regulated, in large part, by limitation of lifespan by apoptosis. A number of studies suggest that circulating neutrophils have a half-life of approximately 6 hours, although contradictory evidence exists. Measuring tissue neutrophil lifespan, however, is more problematic. It is thought that tissue neutrophils survive longer, perhaps with a half-life in the order of 3-5 days, but this has never been directly measured. Zebrafish are an emerging model organism, with several advantages for the study of vertebrate immunity. In zebrafish, neutrophils constitutively assume tissue locations allowing their direct study in vivo. Using a transgenic approach, neutrophils were labelled with a photoconvertible pigment, Kaede. Photoconversion parameters were optimised and the stability of the Kaede confirmed. Individual neutrophils were photoconverted by scanning a confocal 405 nm laser specifically over each cell and their survival monitored for 48 hours, revealing an in vivo half-life for zebrafish tissue neutrophils of around 120 hours (117.7 hrs, 95% CI 95.67-157.8). Laser energy did not extend neutrophil lifespan, and we conclude that this represents a lower bound for the lifespan of a resting tissue neutrophil in the developing zebrafish larva. This is the first direct measurement of the lifespan of an in vivo tissue neutrophil.


Diabetes self-management arrangements in Europe: a realist review to facilitate a project implemented in six countries.
Self-management of long term conditions can promote quality of life whilst delivering benefits to the financing of health care systems. However, rarely are the meso-level influences, likely to be of direct relevance to these desired outcomes, systematically explored. No specific international guidelines exist suggesting the features of the most appropriate structure and organisation of health care systems within which to situate self-management approaches and practices. This review aimed to identify the quantitative literature with regard to diabetes self-management arrangements currently in place within the health care systems of six countries (The United Kingdom, The Netherlands, Norway, Spain, Bulgaria, and Greece) and explore how these are integrated into the broader health care and welfare systems in each country. The methodology for a realist review was followed. Publications of interest dating from 2000 to 2013 were identified through appropriate MeSH terms by a systematic search in six bibliographic databases. A search diary was maintained and the studies were assessed for their quality and risk of bias. Following the multi-step search strategy, 56 studies were included in the final review (the majority from the UK) reporting design methods and findings on 21 interventions and programmes for diabetes and chronic disease self-management. Most (11/21, 52%) of the interventions were designed to fit within the context of primary care. The majority (11/21, 52%) highlighted behavioural change as an important goal. Finally, some (5/21, 24%) referred explicitly to Internet-based tools. This review is based on results which are derived from a total of at least 5,500 individuals residing in the six participating countries. It indicates a policy shift towards patient-centred self-management of diabetes in a primary care context. The professional role of diabetes specialist nurses, the need for multidisciplinary approaches and a focus on patient education emerge as fundamental principles in the design of relevant programmes. Socio-economic circumstances are relevant to the capacity to self-manage and suggest that any gains and progress will be hard to maintain during economic austerity. This realist review should be interpreted within the wider context of a whole systems approach regarding self-care support and chronic illness management.


Association Between Targeted HER-2 Therapy and Breast Reconstruction Outcomes: A Propensity Score-Matched Analysis.
Current treatment for HER-2+ breast cancer includes chemotherapy and targeted HER-2 therapy with trastuzumab and/or pertuzumab. Evidence is lacking on the safety of breast reconstructive operations in these patients. We hypothesized that targeted HER-2 therapy was not associated with post-mastectomy reconstructive outcomes. Women receiving chemotherapy and post-mastectomy reconstruction at Duke University Medical Center from 2006 to 2016 were retrospectively identified. Patients receiving targeted HER-2 therapy with trastuzumab and/or pertuzumab within 6 weeks before breast reconstruction were propensity score-matched 1:1 to patients who did not receive targeted HER-2 therapy, based on the following factors: age, obesity, diabetes, tobacco use, receipt of neoadjuvant chemotherapy, chemotherapy regimen, and radiation therapy. Primary study outcomes included the occurrence of hematoma, seroma, infection, wound breakdown, mastectomy skin flap necrosis, and postoperative flap thrombosis. A total of 481 women were identified, resulting in 107 propensity score-matched pairs. Administration of combined trastuzumab and pertuzumab therapy before breast reconstruction was independently associated with increased risk of postoperative wound breakdown requiring operative intervention for closure, compared with patients not undergoing targeted HER-2 therapy (odds ratio 65.29; 95% CI 1.63 to 2,611.50; p = 0.03). In addition, larger tumor size (2 to 5 cm) was significantly associated with a reduced risk of postoperative wound breakdown, compared with smaller tumors (<2 cm) (odds ratio 0.41; 95% CI 0.19 to 0.87; p = 0.02). Single-agent targeted HER-2 therapy with trastuzumab was not significantly associated with reconstructive complications. Our study suggests that trastuzumab therapy in conjunction with breast reconstructive operation is not associated with reconstructive complications, and breast reconstruction does not need to be delayed due to the administration of trastuzumab. Future studies are needed to evaluate the impact of pertuzumab on surgical outcomes.


R&D in Vaccines Targeting Neglected Diseases: An Exploratory Case Study Considering Funding for Preventive Tuberculosis Vaccine Development from 2007 to 2014.
Based on an exploratory case study regarding the types of institutions funding the research and development to obtain new tuberculosis vaccines, this article intends to provoke discussion regarding the provision of new vaccines targeting neglected disease. Although our findings and discussion are mainly relevant to the case presented here, some aspects are more generally applicable, especially regarding the dynamics of development in vaccines to prevent neglected diseases. Taking into account the dynamics of innovation currently seen at work in the vaccine sector, a highly concentrated market dominated by few multinational pharmaceutical companies, we feel that global PDP models can play an important role throughout the vaccine development cycle. In addition, the authors call attention to issues surrounding the coordination of actors and resources in the research, development, manufacturing, and distribution processes of vaccine products arising from PDP involvement.


[Differential diagnosis of central bronchial cancer and tuberculosis of the lungs].
Although the X-ray pattern of central cancer of upper lobular bronchus is sometimes very similar to that of tuberculosis of the lungs, a correct diagnosis can be established at a relatively early stage, if specific differences in the patterns are interpreted adequately with a due consideration of peculiarities of the clinical picture. Segment localization is of no practical value in differential diagnosis between cancer and tuberculosis of the lung. This purpose can be effectively served by bronchoscopy. A single bronchoscopy may verify diagnosis in as many as 77% of cases. Since carcinoma of upper lobular bronchus has a tendency to peribronchial growth, the results of a single bronchoscopy are inclusive in 23% and double bronchoscopy--in 10% of cases.


Hierarchical exploratory factor analyses of the Woodcock-Johnson IV Full Test Battery: Implications for CHC application in school psychology.
The Woodcock-Johnson (fourth edition; WJ IV; Schrank, McGrew, & Mather, 2014a) was recently redeveloped and retains its linkage to Cattell-Horn-Carroll theory (CHC). Independent reviews (e.g., Canivez, 2017) and investigations (Dombrowski, McGill, & Canivez, 2017) of the structure of the WJ IV full test battery and WJ IV Cognitive have suggested the need for additional factor analytic exploration. Accordingly, the present study used principal axis factoring (PAF) followed by the Schmid and Leiman (SL; Schmid & Leiman, 1957) procedure with the 2 school-aged correlation matrices from the normative sample to determine the degree to which the WJ IV total battery structure could be replicated. Although 7 factors emerged across the 9 to 19 age range, the pattern of subtests loadings did not fully cohere with the structure presented in the Technical Manual, most notably for the academic fluency subtests. Also, the Fluid Reasoning (Gf) and Quantitative Reasoning (Gq) subtests coalesced to form a combined factor rather than 2 separate factors and the Long Term Retrieval (Gltr) subtests aligned with a variety of different factors. The results of this study indicated that the general intelligence factor variance far exceeded the variance attributed to the lower-order CHC factors. The combination of subtest migration and nominal total/common variance of the CHC lower-order factors suggests caution when interpreting the myriad CHC-related indices when making high stakes decisions. Implications for clinical practice are discussed. (PsycINFO Database Record


Usual intake of meat in Australians: secondary analysis of the 2011-12 National Nutrition and Physical Activity Survey using the NCI method.
Global public health recommendations advise limiting the intake of red and processed meats. There is a need for more comprehensive information on meat consumption in Australia, specifically usual intake of meat from a nationally representative sample. The aim of this study was to use the National Cancer Institute (NCI) method to examine usual meat intakes in the 2011-12 National Nutrition and Physical Activity Survey (NNPAS). This was a secondary analysis of the cross-sectional 2011-12 NNPAS, which contains observations for 12 153 respondents (9341 adults and 2812 children/adolescents). Usual consumption of all meat, red and processed meats was calculated using the NCI method. Consumption of meat was explored by age and gender groups, as well as by household type. Amongst adults and children/adolescents, consumption of all meat was significantly higher in males (adults: 187.1 g day-1 ; children/adolescents: 125.0 g day-1 ) than females (adults: 125.5 g day-1 ; children/adolescents: 95.4 g day-1 ). Similar patterns were observed for red (males: adults 85.5 g day-1 , children/adolescents 42.9 g day-1 ; females: adults 57.1 g day-1 , children/adolescents 34.9 g day-1 ) and processed meat, although intakes of processed meats in children and adolescents (males: 26.5 g day-1 ; females: 16.8 g day-1 ) were found to be similar to those of adults aged ≥19 years (males: 28.3 g day-1 ; females: 15.3 g day-1 ). Patterns of meat consumption across household types appeared to differ between genders. The present study suggests that Australians are likely to be exceeding population recommendations for meat intakes, with differing patterns observed across gender and household types. These findings highlight a need for targeted dietetic and population strategies aimed at promoting a healthy consumption of meats within the Australian population.


Unpredictable Effects of the Genetic Background of Transgenic Lines in Physiological Quantitative Traits.
Physiology, fitness and disease phenotypes are complex traits exhibiting continuous variation in natural populations. To understand complex trait gene functions transgenic lines of undefined genetic background are often combined to assess quantitative phenotypes ignoring the impact of genetic polymorphisms. Here, we used inbred wild-type strains of the Drosophila Genetics Reference Panel to assess the phenotypic variation of six physiological and fitness traits, namely, female fecundity, survival and intestinal mitosis upon oral infection, defecation rate and fecal pH upon oral infection, and terminal tracheal cell branching in hypoxia. We found continuous variation in the approximately 150 strains tested for each trait, with extreme values differing by more than four standard deviations for all traits. In addition, we assessed the effects of commonly used Drosophila UAS-RNAi transgenic strains and their backcrossed isogenized counterparts, in the same traits plus baseline intestinal mitosis and tracheal branching in normoxia, in heterozygous conditions, when only half of the genetic background was different among strains. We tested 20 non-isogenic strains (10 KK and 10 GD) from the Vienna Drosophila Resource Center and their isogenized counterparts without Gal4 induction. Survival upon infection and female fecundity exhibited differences in 50% and 40% of the tested isogenic vs. non-isogenic pairs, respectively, whereas all other traits were affected in only 10-25% of the cases. When 11 isogenic and their corresponding non-isogenic UAS-RNAi lines were expressed ubiquitously with Gal4, 4 isogenic vs. non-isogenic pairs exhibited differences in survival to infection. Furthermore, when a single UAS-RNAi line was crossed with the same Gal4 transgene inserted in different genetic backgrounds, the quantitative variations observed were unpredictable on the basis of pure line performance. Thus, irrespective of the trait of interest, the genetic background of commonly used transgenic strains needs to be considered carefully during experimentation.


Rate of arterial occlusion in patients with acute ischemic stroke.
Computed tomographic angiography (CTA) was invented more than 20 years ago, but only gained acceptance recently, thanks to advancements in the computer technology. It can demonstrate areas of arterial stenosis or occlusion with accuracy nearly that of digital subtraction angiography (DSA). It is also able to clearly illustrate calcification, which is more difficult to define on magnetic resonance angiography and is not clearly depicted on DSA. Our retrospective study attempted to clarify the rate of occlusion or stenosis in the patients with acute ischemic stroke. Over the period of 7 months, 93 consecutive patients were admitted with acute ischemic stroke. Fifty-six patients underwent CTA and were included in this study. Most of the patients were admitted after 6 hours following onset of symptoms. There were 28 men and 28 women, and 80.4% of the cohort was of African-American origin. The majority of strokes were attributed to small-vessel disease (25/56). The rest of the cases were deemed secondary to atheroembolism (15/56), cardioembolism (9/56) or of unclear etiology (7/56). In 24 (42.9%) patients, CTA failed to reveal any abnormalities of the cerebrovascular tree. CTA demonstrated arterial occlusion in ten (17.9%) patients and stenosis of extracranial or intracranial arteries on the symptomatic side in 22 (39.2%) patients. There was very good correlation between CTA and ultrasound techniques (carotid duplex and transcranial Doppler). CTA was superior in demonstrating distal intracranial stenosis. Overall, CTA is an extremely valuable and fast way to emergently evaluate the cerebrovascular anatomy, making it very useful for pre-thrombolysis evaluation of patients with ischemic stroke.


Contrasting selective patterns across the segmented genome of bluetongue virus in a global reassortment hotspot.
For segmented viruses, rapid genomic and phenotypic changes can occur through the process of reassortment, whereby co-infecting strains exchange entire segments creating novel progeny virus genotypes. However, for many viruses with segmented genomes, this process and its effect on transmission dynamics remain poorly understood. Here, we assessed the consequences of reassortment for selection on viral diversity through time using bluetongue virus (BTV), a segmented arbovirus that is the causative agent of a major disease of ruminants. We analysed ninety-two BTV genomes isolated across four decades from India, where BTV diversity, and thus opportunities for reassortment, are among the highest in the world. Our results point to frequent reassortment and segment turnover, some of which appear to be driven by selective sweeps and serial hitchhiking. Particularly, we found evidence for a recent selective sweep affecting segment 5 and its encoded NS1 protein that has allowed a single variant to essentially invade the full range of BTV genomic backgrounds and serotypes currently circulating in India. In contrast, diversifying selection was found to play an important role in maintaining genetic diversity in genes encoding outer surface proteins involved in virus interactions (VP2 and VP5, encoded by segments 2 and 6, respectively). Our results support the role of reassortment in driving rapid phenotypic change in segmented viruses and generate testable hypotheses for in vitro experiments aiming at understanding the specific mechanisms underlying differences in fitness and selection across viral genomes.


Hepatitis C virus infection in Irish drug users and prisoners - a scoping review.
Hepatitis C infection is a major public health concern globally. In Ireland, like other European countries, people who use drugs (PWUD) and prisoners carry a larger HCV disease burden than the general population. Recent advances in HCV management have made HCV elimination across Europe a realistic goal. Engaging these two marginalised and underserved populations remains a challenge. The aim of this review was to map key findings and identify gaps in the literature (published and unpublished) on HCV infection in Irish PWUD and prisoners. A scoping review guided by the methodological framework set out by Levac and colleagues (based on previous work by Arksey & O'Malley). A total of 58 studies were identified and divided into the following categories; Epidemiology, Guidelines and Policy, Treatment Outcomes, HCV-related Health Issues and qualitative research reporting on Patients' and Health Providers' Experiences. This review identified significantly higher rates of HCV infection among Irish prisoners and PWUD than the general population. There are high levels of undiagnosed and untreated HCV infection in both groups. There is poor engagement by Irish PWUD with HCV services and barriers have been identified. Prison hepatology nurse services have a positive impact on treatment uptake and outcomes. Identified gaps in the literature include; lack of accurate epidemiological data on incident infection, untreated chronic HCV infection particularly in PWUD living outside Dublin and those not engaged with OST. Ireland like other European countries has high levels of undiagnosed and untreated HCV infection. Collecting, synthesising and identifying gaps in the available literature is timely and will inform national HCV screening, treatment and prevention strategies.


Inner Profile Measurement for Pipes Using Penetration Testing.
Penetration testing has been used to measure material properties for over fifty years. Currently, it is under-utilised as a contemporary scientific and engineering tool for investigating the condition of pipes whose inner surface has been exposed to chemical attack. We describe the design, development and calibration of a portable probe which uses a penetrative strain gauge load cell to measure where the semi-solid surface starts and stops within a pipe. We also describe the results of field tests of the probe in concrete sewers, affected by internal corrosion, where the probe proved to be a fast and reliable method for collecting pipe profile information. The results indicate significant benefit in the use of penetrometers to perform concrete sewer condition assessment.


Liposomes labeled with biotin and horseradish peroxidase: a probe for the enhanced amplification of antigen--antibody or oligonucleotide--DNA sensing processes by the precipitation of an insoluble product on electrodes.
Liposomes labeled with biotin and the enzyme horseradish peroxidase (HRP) are used as a probe to amplify the sensing of antigen-antibody interactions or oligonucleotide-DNA binding. The HRP-biocatalyzed oxidation of 4-chloro-1-naphthol (1) in the presence of H2O2, and the precipitation of the insoluble product 2 on electrode supports, are used as an amplification route for the sensing processes. The anti-dinitrophenyl antibody (DNP-Ab) is sensed by a dinitrophenyl-L-cysteine antigen monolayer associated with an Au electrode. A biotinylated anti-IgG-antibody (Fc-specific) is linked to the antigen-DNP-Ab complex, and the biotin-labeled HRP-liposomes associate with the assembly through an avidin bridge. The biocatalyzed precipitation of 2 on the electrode increases the electron-transfer resistances at the electrode-solution interface or the electrode resistance itself. The binding events of the different proteins on the electrode and the biocatalyzed precipitation of 2 on the conductive support are followed by Faradaic impedance spectroscopy or constant-current chronopotentiometry. DNP-Ab concentrations as low as 1 x 10(-11) g x mL(-1) can be detected by this method. The labeled liposomes were also used for the amplified detection of DNA 3. The oligonucleotide 4, complementary to a part of the target DNA 3 that is a model nucleic acid sequence for the Tay-Sachs genetic disorder, is assembled on an Au electrode. Hybridization of the analyte 3 followed by the association of the biotin-tagged oligonucleotide 5 yields a three-component double-stranded assembly. Sensing of the analyte 3 is amplified by the association of avidin, the labeled liposomes, and the subsequent biocatalyzed precipitation of 2 on the electrodes. The DNA 3 is detected with a sensitivity that corresponds to 6.5 x 10(-13) M. Faradaic impedance spectroscopy and chronopotentiometry were employed to follow the stepwise assembly of the systems and the electronic transduction of the detection of the analyte DNA 3.


Use of a polymeric implant system to assess the neurotoxicity of subacute exposure to 2,2',5,5'-tetrachlorobiphenyl-4-ol, a human metabolite of PCB 52, in male adolescent rats.
Polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that ubiquitously exist in the environment. PCB exposure has been linked to cancer and multi-system toxicity, including endocrine disruption, immune inhibition, and reproductive and neurotoxicity. 2,2',5,5'-Tetrachlorobiphenyl (PCB 52) is one of the most frequently detected congeners in the environment and human blood. The hydroxylated metabolites of PCB 52 may also be neurotoxic, especially for children whose brains are still developing. However, it is challenging to discern the contribution of these metabolites to PCB neurotoxicity because the metabolism of PCB is species-dependent. In this study, we evaluated the subacute neurotoxicity of a human-relevant metabolite, 2,2',5,5'-tetrachlorobiphenyl-4-ol (4-52), on male adolescent Sprague Dawley rats, via a novel polymeric implant drug delivery system grafted subcutaneously, at total loading concentrations ranging from 0%, 1%, 5%, and 10% of the implant (w/w) for 28 days. Y-maze, hole board test, open field test, and elevated plus maze were performed on exposure days 24-28 to assess their locomotor activity, and exploratory and anxiety-like behavior. 4-52 and other possible hydroxylated metabolites in serum and vital tissues were quantified using gas chromatography with tandem mass spectrometry (GC-MS/MS). Our results demonstrate the sustained release of 4-52 from the polymeric implants into the systemic circulation in serum and tissues. Dihydroxylated and dechlorinated metabolites were detected in serum and tissues, depending on the dose and tissue type. No statistically significant changes were observed in the neurobehavioral tasks across all exposure groups. The results demonstrate that subcutaneous polymeric implants provide a straightforward method to expose rats to phenolic PCB metabolites to study neurotoxic outcomes, e.g., in memory, anxiety, and exploratory behaviors.


Real-time and label-free detection of the prostate-specific antigen in human serum by a polycrystalline silicon nanowire field-effect transistor biosensor.
In this research, we used a polycrystalline silicon nanowire field-effect transistor (poly-Si NWFET) as a biosensor that employs the sidewall spacer technique instead of an expensive electron beam lithography method. When compared with commercial semiconductor processes, the sidewall spacer technique has the advantages of simplicity and low cost. In this study, we employed a novel poly-Si NWFET device for real-time, label-free, and ultrahigh-sensitivity detection of prostate-specific antigen (PSA) in human serum. Since serum proteome is very complex containing high levels of salts and other interfering compounds, we hereby developed a standard operating procedure for real-sample pretreatment to keep a proper pH value and ionic strength of the desalted serum and also utilized Tween 20 to serve as the passivation agent by surface modification on the NWFET to reduce nonspecific binding for medical diagnostic applications. We first modified 3-aminopropyltriethoxysilane on the surface of a poly-Si nanowire device followed by glutaraldehyde functionalization, and the PSA antibodies were immobilized on the aldehyde terminal. While PSA was prepared in the buffers to maintain an appropriate pH value and ionic strength, the results indicated that the sensor could detect trace PSA at less than 5 fg/mL in a microfluidic channel. The novel poly-Si NWFET is developed as a diagnostic platform for monitoring prostate cancer and predicting the risk of early biochemical relapse.


Honokiol induces apoptosis in human lymphoid leukemia Molt 4B cells.
The exposure of human lymphoid leukemia Molt 4B cells to honokiol led to both growth inhibition and the induction of apoptosis. Morphological change showing apoptotic bodies was observed in the cells treated with honokiol. The fragmentation by honokiol of DNA to oligonucleosomal-sized fragments that are characteristics of apoptosis was observed to be concentration- and time-dependent. These findings suggest that growth inhibition by honokiol of Molt 4B cells results from the induction of apoptosis in the cells.


Clinical efficacy of transforaminal endoscopic lumbar discectomy for lumbar degenerative diseases: A minimum 6-year follow-up.
Transforaminal Endoscopic Lumbar Discectomy (TELD) is widely applied for lumbar degenerative disease (LDDs) and satisfactory short-term outcomes have been achieved. However, the mid-term and long-term follow-up of this technique is still lacking. To retrospectively analyze the mid-term clinical efficacy of TELD for single-level LDD and its effect on intervertebral disc degeneration with a minimum of 6-year follow-up. 64 patients with single-level LDDs (lumbar disc herniation, lumbar spinal stenosis) who underwent TELD under local anesthesia in our department from December 2014 to December 2015 were observed. Visual analog scale (VAS), Japanese Orthopaedic Association evaluation treatment (JOA) score and Oswestry Disability Index (ODI) were calculated and compared before operation, 3 months after operation, 6 months after operation, 1 year after operation and at the last follow-up. Disc Height (DH), disc range of motion (ROM) and disc degeneration on standard lumbar lateral radiographs before operation and at the last follow-up were determined. Recurrence rate and operation-related complications during follow-up were recorded. 64 cases were followed up for 6.4 ± 0.1 years. There were no complications such as infection, epidural hematoma and nerve root injury. 1 patient (1.67%) was found to have dural rupture and cauda equina hernia during the operation. There were significant differences in VAS, JOA, ODI between preoperative and postoperative 3 months, 6 months, 1 year and last follow-up (P < 0 01), VAS, JOA, ODI at 3 months after operation were different from 6 months after operation (P < 0 05), and there were significant differences compared with preoperative, 1 year after operation and last follow up (P < 0 01). VAS, JOA and ODI at 6 months after operation were significantly different from those before operation (P < 0.01), but not significantly different from those at 1 year after operation and the last follow-up (P > 0.05). There was no significant difference in DH, ROM and the Pfirrmann grade of intervertebral disc preoperative and the last follow-up. During the follow-up period, 3 patients (4.69%) were recurrent, 13 patients (20.31%) had various degrees of postoperative dysesthesia (POD), and 3 patients (4.69%) had various degrees of muscle weakness. TELD has a satisfactory mid-term efficacy, and has no significant effect on the DH, the stability of the intervertebral disc space, or on intervertebral disc degeneration. However, as expected, TELD was associated with some complications including recurrent disc herniation and POD.


The Rx to ease a community's burdens. A Detroit hospital helps low-income patients obtain prescription medication.
St. John Hospital and Medical Center found itself with an increasing volume of indigent and low-income patients who had few or no resources with which to purchase prescription medications. With funding cutbacks in various federal, state, and local programs, the hospital's pharmaceutical resources had diminished to the point at which it could only occasionally meet a patient's needs. The Indigent Pharmaceutical Fund was established in 1992. Once a staff member from the hospital's Social Work and Discharge Planning Department has exhausted all patient or community resources, he or she requests assistance for a patient. In the first year of operation, the fund assisted 278 patients at a cost of just under $5,000.


A mixed-methods analysis of patient safety incidents involving opioid substitution treatment with methadone or buprenorphine in community-based care in England and Wales.
Opioid substitution treatment is used in many countries as an effective harm minimization strategy. There is a need for more information about patient safety incidents and the resulting harm relating to this treatment. We aimed to characterize patient safety incidents involving opioid substitution treatment with methadone or buprenorphine in community-based care by: (i) identifying the sources and nature of harm and (ii) describing and interpreting themes to identify priorities to focus future improvement work. Mixed-methods study examining patient safety incident reports involving opioid substitution treatment with either methadone or buprenorphine in community-based care. Data submitted between 2005 and 2015 from the National Reporting and Learning System (NRLS), a national repository of patient safety incident reports from across England and Wales. A total of 2284 reports were identified involving patients receiving community-based opioid substitution treatment. Incident type, contributory factors, incident outcome and severity of harm. Analysis involved data coding, processing and iterative generation of data summaries using descriptive statistical and thematic analysis. Most risks of harm from opioid substitution treatment came from failure in one of four processes of care delivery: prescribing opioid substitution (n = 151); supervised dispensing (n = 248); non-supervised dispensing (n = 318); and monitoring and communication (n = 1544). Most incidents resulting in harm involved supervised or non-supervised dispensing (n = 91 of 127, 72%). Staff- (e.g. slips during task execution, not following protocols) and organization-related (e.g. poor working conditions or poor continuity of care between services) contributory factors were identified for more than half of incidents. Risks of harm in delivering opioid substitute treatment in England and Wales appear to arise out of failures in four processes: prescribing opioid substitution, supervised dispensing, non-supervised dispensing and monitoring and communication.


Effect of greater trochanteric epiphysiodesis after femoral varus osteotomy for lateral pillar classification B and B/C border Legg-Calvé-Perthes disease: A retrospective observational study.
This is a retrospective observational study. Greater trochanteric epiphysiodesis (GTE) has been recommended to prevent Trendelenburg gait and limitation of the hip joint motion due to trochanteric overgrowth after femoral varus osteotomy (FVO) in Legg-Calvé-Perthes disease (LCPD). However, capital femoral physeal arrest frequently occurs in patients with severe disease (lateral pillar C), so GTE might not be as effective in these patients. The aim of this study was to compare trochanteric growth inhibition due to GTE after FVO between 2 age groups (<8 or >8 years) in patients with lateral pillar B and B/C border LCPD and evaluate the effectiveness of GTE compared with the normal, unaffected hip.This study included 19 children with lateral pillar B and B/C border LCPD in 1 leg who underwent FVO followed by GTE. Of the 19 children, 9 underwent GTE before the age of 8 years and 10 underwent GTE after 8 years of age. On radiographs taken at the immediate postoperative period and at skeletal maturity, the articulo-trochanteric distance (ATD), center-trochanteric distance (CTD), and neck-shaft angle (NSA) were compared between the 2 age groups. The amount of correction was compared between groups. The contralateral, unaffected hip was used as a control for trochanteric growth. The patients were clinically evaluated with Iowa hip score at the final follow-up.There was no significant difference between the 2 age groups in terms of time to GTE, length of follow-up, or lateral pillar classification. In the affected hip, the amount of correction of the ATD, CTD, and NSA was significantly greater in patients < 8 years than in patients > 8 years. However, in the unaffected hip, the change in the ATD, CTD, and NSA did not differ significantly between the 2 groups.We suggest that FVO followed by GTE for lateral pillar B and B/C border LCPD in patients under the age of 8 years can affect growth of the greater trochanter. However, effective growth inhibition due to GTE was not achieved after 8 years of age.


Emergence of a floral colour polymorphism by pollinator-mediated overdominance.
Maintenance of polymorphism by overdominance (heterozygote advantage) is a fundamental concept in evolutionary biology. In most examples known in nature, overdominance is a result of homozygotes suffering from deleterious effects. Here we show that overdominance maintains a non-deleterious polymorphism with black, red and white floral morphs in the Alpine orchid Gymnadenia rhellicani. Phenotypic, metabolomic and transcriptomic analyses reveal that the morphs differ solely in cyanidin pigments, which are linked to differential expression of an anthocyanidin synthase (ANS) gene. This expression difference is caused by a premature stop codon in an ANS-regulating R2R3-MYB transcription factor, which is heterozygous in the red colour morph. Furthermore, field observations show that bee and fly pollinators have opposite colour preferences; this results in higher fitness (seed set) of the heterozygous morph without deleterious effects in either homozygous morph. Together, these findings demonstrate that genuine overdominance exists in nature.


Detection of Lysosomal Exocytosis in Platelets by Flow Cytometry.
Flow cytometry is a method that allows high throughput analysis of individual cells in suspension. By inclusion of fluorescently labelled antibodies, it is possible to analyze the abundance of one or more surface antigens, such as LAMP-1, without prior lysis of cells. Here we describe the special considerations required for the investigation of lysosomal exocytosis from platelets analyzed with flow cytometry.


Pathological survivin expression links viral infections with pathogenesis of erosive rheumatoid arthritis.
Rheumatoid arthritis (RA) is an inflammatory joint disease leading to cartilage and bone destruction. Insufficient apoptosis in the inflamed RA synovium along with accumulation of highly differentiated B- and T-lymphocytes as well as invasive growth of macrophages and fibroblasts is among the major mechanisms supporting joint destruction. We have recently shown that circulating survivin, an apoptosis inhibitor tightly bound to tumorigenesis, is an independent predictor of development and progression of joint destruction in RA. In this review we discuss the possible connectivity between viral infection, leading to interferon (IFN)-alpha production, survivin expression, and subsequent joint inflammation. The role of IFN-alpha and the involvement of IFN transcription factors and phosphoinositide-3-kinase signalling as essential modulators of arthritogenic process are discussed in the context of survivin.


Effects of prolonged incubation of rat peritoneal mast cells with compound 48/80.
Rat peritoneal mast cells (MC) co-cultured on a monolayer of 3T3 fibroblasts (MC/3T3) were continuously exposed to compound 48/80 for 14 days. As early as 2 days following continuous exposure to compound 48/80, the MC/3T3 appeared as a heterogeneous population, with various MC appearing partially or fully degranulated or intact; this morphological pattern continued throughout the duration of the experiment. MC/3T3 remained functionally active as demonstrated by their ability to secrete histamine 15 min after each replacement with fresh medium containing compound 48/80, although this capacity diminished towards the end of the 14-day experiment. Concomitant with the histamine release, a significant increase in cellular histamine pools was observed. When MC/3T3 continuously exposed to compound 48/80 for 7 or 14 days were acutely challenged with anti-IgE antibodies, they were able to secrete histamine and prostaglandin D2 in amounts similar to those produced by control MC. In contrast, when these cells were challenged on day 7 or 14 with a higher dose of compound 48/80 or with substance P, the release of histamine was partially inhibited. Our results indicate that continuous in vitro exposure to compound 48/80, and the resulting MC degranulation product histamine, does not adversely affect the ability of MC/3T3 to synthesize histamine and to respond to activation stimuli of a related secretagogue for 7 days and a non-related one for at least 14 days.


Cross-sectional Use Patterns and Characteristics of Premium Versus Non-Premium Cigar Smokers in the United States, 2010-2019.
Few studies have addressed the use patterns and characteristics of the past 30 days of premium versus non-premium cigar smokers. We pooled 10 years of data from the National Survey on Drug Use and Health (NSDUH; 2010-2019) to evaluate use patterns and demographic and tobacco use characteristics of premium and non-premium cigar smokers ages 12 years and older in the U.S. cigar-type was manually coded as premium or non-premium according to the brand used most often. Between 2010 and 2019, 4.7% (95% CI = 4.6-4.8) of individuals aged 12 and older currently smoked cigars (past-30-day use). Smoking premium cigars (0.9% [95% CI = 0.8-0.9]) was less prevalent than smoking non-premium cigars (3.0% [95% CI = 2.9-3.1]). Although current non-premium cigar smoking prevalence steadily declined over the years, current premium cigar smoking prevalence remained stable. Premium cigar smokers were more likely to be older (≥25 years), male, non-Hispanic white, heterosexual, college educated, living in a large metro area, and to have income above 200% of the poverty threshold compared to non-premium users (p < .05). Additionally, past-30-day premium cigar smokers were less likely than non-premium users to initiate cigar smoking before the age of 18 years, smoke cigars frequently or daily, smoke cigarettes, or use marijuana (p < .05). Overall, premium cigar smoking is less prevalent than non-premium cigar smoking, especially among populations such as youth, racial/ethnic and sexual minorities, and low socioeconomic individuals. Premium cigar smokers tend to smoke infrequently and initiate cigars later in life compared with non-premium smokers. Study results can inform recommendations for regulating premium cigars. This study found that between 2010 and 2019, there are meaningful differences in the use patterns and characteristics of past-30-day premium versus non-premium cigar smokers in the United States. Premium cigars comprise a small share of the market compared to other cigar types and are less likely to be used by youth and other tobacco control priority groups (eg, racial/ethnic minorities and individuals with low socioeconomic statuses) that bear a disproportionate burden of risk and harm from using tobacco products. Additionally, most premium cigar users smoke them only occasionally. However, it is important to continue to monitor premium cigar use, as these patterns could shift because of factors like changes in marketing practices, consumer awareness, and product prices. Tobacco policy changes may also alter the patterns and trends of premium cigar use over time. A greater, more comprehensive understanding of premium cigars' physical characteristics, patterns of use, user perceptions, tobacco industry marketing strategies, and health effects will together help to inform cigar-related regulations.


Mitochondria as a Cellular Hub in Infection and Inflammation.
Mitochondria are the energy center of the cell. They are found in the cell cytoplasm as dynamic networks where they adapt energy production based on the cell's needs. They are also at the center of the proinflammatory response and have essential roles in the response against pathogenic infections. Mitochondria are a major site for production of Reactive Oxygen Species (ROS; or free radicals), which are essential to fight infection. However, excessive and uncontrolled production can become deleterious to the cell, leading to mitochondrial and tissue damage. Pathogens exploit the role of mitochondria during infection by affecting the oxidative phosphorylation mechanism (OXPHOS), mitochondrial network and disrupting the communication between the nucleus and the mitochondria. The role of mitochondria in these biological processes makes these organelle good targets for the development of therapeutic strategies. In this review, we presented a summary of the endosymbiotic origin of mitochondria and their involvement in the pathogen response, as well as the potential promising mitochondrial targets for the fight against infectious diseases and chronic inflammatory diseases.


The role of feedback from the vocal organ. I. Maintenance of stereotypical vocalizations by adult zebra finches.
The stereotypical vocal patterns of adult male zebra finches (Poephila guttata) were examined before and after elimination of auditory feedback and/or feedback from the vocal organ (the syrinx). Elimination of auditory feedback was accomplished via bilateral removal of the cochleae, whereas feedback from the syrinx was eliminated by cutting hypoglossal afferent fibers while leaving hypoglossal efferents intact. Very little or no disruption of song was observed in birds which underwent deafening as well as unilateral deafferentation of the syrinx. Control experiments showed that the minor deficits observed were not attributable to lesion of pulmonary fibers in the descending branch of the vagus. There was also little deficit in song behavior of birds that were deafened and subjected to bilateral deafferentation of the syrinx. These results are consistent with the hypothesis that stable song patterns in adult passerine birds are not dependent on peripheral sources of feedback, but may be governed by a learned central control program.


PEGMA/MMA copolymer graftings: generation, protein resistance, and a hydrophobic domain.
We synthesized various graft copolymer films of poly(ethylene glycol) methacrylate (PEGMA) and methyl methacrylate (MMA) on silicon to examine the dependency of protein-surface interactions on grafting composition. We optimized atom transfer radical polymerizations to achieve film thicknesses from 25 to 100 nm depending on the monomer mole fractions, and analyzed the resulting surfaces by X-ray photoelectron spectroscopy (XPS), ellipsometry, contact angle measurements, and atomic force microscopy (AFM). As determined by XPS, the stoichiometric ratios of copolymer graftings correlated with the concentrations of provided monomer solutions. However, we found an unexpected and pronounced hydrophobic domain on copolymer films with a molar amount of 10-40% PEGMA, as indicated by advancing contact angles of up to 90 degrees . Nevertheless, a breakdown of the protein-repelling character was only observed for a fraction of 15% PEGMA and lower, far in the hydrophobic domain. Investigation of the structural basis of this exceptional wettability by high-resolution AFM demonstrated the independence of this property from morphological features.


The isolation of 2,3-oxidosqualene from the liver of rats treated with 1-dodecylimidazole, a novel hypocholesterolaemic agent.
1. Non-saponifiable lipid from the livers of rats treated with 1-dodecylimidazole contained an unidentified compound that was not present in the livers from untreated animals. 2. Treated rats had lower serum cholesterol concentrations than control rats. 3. 1-Dodecylimidazole, when added to rat liver slices, inhibited the incorporation of [1-(14)C]acetate and [2-(14)C]mevalonate into digitonin-precipitable sterols and resulted in the accumulation of a labelled compound, which was chromatographically identical with the unknown compound described in 1 above. 4. Rats treated with 1-dodecylimidazole incorporated less [(14)C]mevalonate into liver digitonin-precipitable sterols than untreated animals and accumulated the unknown compound as a labelled intermediate. 5. The unknown intermediate had the same chromatographic properties, n.m.r. and mass spectra as authentic 2,3-oxidosqualene. 6. The identity of the intermediate as 2,3-oxidosqualene was further established by showing that it was incorporated into sterols by rat liver homogenates under anaerobic conditions. In addition, incubation of [(14)C]squalene with rat liver homogenates resulted in trapping of the radioactivity by the added intermediate. 7. It is suggested that the hypocholesterolaemic activity of 1-dodecylimidazole results in part from the inhibition of cholesterol biosynthesis at the level of 2,3-oxidosqualene sterol cyclase.


Edge Preserving and Multi-Scale Contextual Neural Network for Salient Object Detection.
In this paper, we propose a novel edge preserving and multi-scale contextual neural network for salient object detection. The proposed framework is aiming to address two limits of the existing CNN based methods. First, region-based CNN methods lack sufficient context to accurately locate salient object since they deal with each region independently. Second, pixel-based CNN methods suffer from blurry boundaries due to the presence of convolutional and pooling layers. Motivated by these, we first propose an end-to-end edge-preserved neural network based on Fast R-CNN framework (named RegionNet) to efficiently generate saliency map with sharp object boundaries. Later, to further improve it, multi-scale spatial context is attached to RegionNet to consider the relationship between regions and the global scenes. Furthermore, our method can be generally applied to RGB-D saliency detection by depth refinement. The proposed framework achieves both clear detection boundary and multi-scale contextual robustness simultaneously for the first time, and thus achieves an optimized performance. Experiments on six RGB and two RGB-D benchmark datasets demonstrate that the proposed method achieves state-of-the-art performance.In this paper, we propose a novel edge preserving and multi-scale contextual neural network for salient object detection. The proposed framework is aiming to address two limits of the existing CNN based methods. First, region-based CNN methods lack sufficient context to accurately locate salient object since they deal with each region independently. Second, pixel-based CNN methods suffer from blurry boundaries due to the presence of convolutional and pooling layers. Motivated by these, we first propose an end-to-end edge-preserved neural network based on Fast R-CNN framework (named RegionNet) to efficiently generate saliency map with sharp object boundaries. Later, to further improve it, multi-scale spatial context is attached to RegionNet to consider the relationship between regions and the global scenes. Furthermore, our method can be generally applied to RGB-D saliency detection by depth refinement. The proposed framework achieves both clear detection boundary and multi-scale contextual robustness simultaneously for the first time, and thus achieves an optimized performance. Experiments on six RGB and two RGB-D benchmark datasets demonstrate that the proposed method achieves state-of-the-art performance.


Factors associated with prescription drug expenditures among children: an analysis of the Medical Expenditure Panel survey.
Pharmaceutical costs have reached 14% of total health care costs in the United States and continue to rise. Many studies have looked at factors that influence utilization of hospital and ambulatory care services in the pediatric population. This study examines the factors that influence utilization of prescription drugs in the pediatric population. Data from the 1996 Medical Expenditure Panel Survey (MEPS) were used in the analysis. A 2-part multivariate regression analysis was conducted using pediatric (ages 0-17) prescription drug expenditures as the dependent variable. Independent variables were constructed using demographic variables, socioeconomic variables, health status, and medical conditions. Black children are less likely than white children to use any prescription drug (odds ratio: 0.67). Similarly, uninsured children are less likely than privately insured children to use any prescription drug (odds ratio: 0.62). Among children who had any prescription drug expenditure in 1996, children who are black, Asian, and Hispanic had lower prescription drug expenditures than children who are white. Children who are uninsured had lower expenditures than children who are privately insured. Children in near-poor families had lower prescription drug expenditures than those in high-income families, even after controlling for insurance status. Children who are covered by Medicaid had comparable prescription drug expenditures to children who are covered by private insurance. Socioeconomic characteristics such as race, insurance status, and family income levels had significant impact on pediatric prescription drug expenditures, even after controlling for the influences of health status and medical conditions.


Ethics in Evaluating a Sociotechnical Intervention With Socially Isolated Older Adults.
The purpose of this article is to consider how ethical principles can inform the effective design and implementation of technology-based interventions that aim to promote the well-being of socially isolated older adults. We evaluated a new iPad application with small groups of older adults. In this article, we reflect on the ethical issues encountered at each stage of the research process. Drawing on the ethical principles of beneficence, research merit and integrity, justice, and respect, we identify key issues to consider in the future design and implementation of social isolation interventions that use new technologies. Key issues include (a) providing sufficient support to facilitate ongoing social interactions, (b) managing older adults' expectations, (c) providing encouragement without coercion, and (d) responding to individual needs. We conclude that it is important to report on ethical challenges incurred when evaluating social isolation interventions to inform future research in this important area.


Tuning SpyTag-SpyCatcher mutant pairs toward orthogonal reactivity encryption.
Genetically encoded covalent peptide tagging technology, such as the SpyTag-SpyCatcher reaction, has emerged as a unique way to do chemistry with proteins. Herein, we report the reactivity engineering of SpyTag-SpyCatcher mutant pairs and show that distinct reactivity can be encrypted for the same reaction based on protein sequences of high similarity. Valuable features, including high selectivity, inverse temperature dependence and (nearly) orthogonal reactivity, could be achieved based on as few as three mutations. This demonstrates the robustness of the SpyTag-SpyCatcher reaction and the plasticity of its sequence specificity, pointing to a family of engineered protein chemistry tools.


The development of the human spleen. Ultrastructural studies in fetuses from the 14th to 24th week of gestation.
Splenic tissue of human fetuses from the 14th to the 24th week of gestation (menstrual age) were investigated by light- and electron microscopy to describe the development of the red and white pulp in close relationship to the differentiation of the vascular tree. Special interest is focussed on the differentiation of the T-cell- and the B-cell regions and their specific stationary cells. The preliminary stage, here called the "primary vascular reticulum," lasts up to the 14th gestational week (gw). Numerous erythrocytes, normoblasts and macrophages are seen among a network of mesenchymal cells and argyrophilic fibers. Hematopoiesis, especially erythropoiesis, can be recognized. The characteristic organ structure becomes established during the subsequent transformation stage of the fetal spleen, beginning with the 15th gw. Splenic lobules begin to form during the 15th to 17th gw. They consist of a central artery, surrounded by a sheath of lightly stained stationary cells which resemble myofibroblasts. At the periphery of these lobules the red pulp forms. Initially mobile cells are distributed throughout the reticulum. Soon they begin to accumulate in the venous sinuses, which develop from lacunae among the reticular network and come into contact with the venous system. The endothelial wall of these sinuses remains discontinuous, confirming the theory of the "open" vascularization of the spleen. The development of the larger veins is correlated with the differentiation of the splenic trabeculae. The development of the white pulp is correlated with the stage of lymphoid colonization within the spleen, beginning around the 18th gw. An accumulation of lymphocytes around the central arteries can be recognized during the 19th and 20th gw. These lymphoid cells show morphological and immunohistochemical characteristics of T-precursor cells. Within the now assembling periarterial lymphoid sheath (PALS) a few precursors of interdigitating cells (IDC) are recognizable, giving evidence for the differentiation of the T-cell region. Around the 23rd gw the assemblage of primary follicles is discernible at the periphery of the PALS. Precursors of the follicular dendritic reticulum cell (FDRC), the specific stationary cell of the B-cell region, have been recognized. This observation leads to the conclusion that the small primary follicles represent the beginning formation of the B-cell region. The significance of the vascular system for the differentiation of the specific splenic organization is discussed.


Misoprostol clinical pharmacology. Establishment of activity in man.
Misoprostol has been evaluated in healthy subjects for both antisecretory and pharmacological activity. Doses used were determined initially from acute and chronic tolerance testing in healthy subjects. In the single dosage range of 50-200 micrograms, misoprostol inhibits gastric acid secretion in a dose-related manner both in the basal state and after stimuli such as histamine and standard test meals. The 200 micrograms dose differs significantly from placebo as an antisecretory agent. A preliminary study in six subjects suggested that the 400 micrograms dose does not produce a substantial increase in activity over the 200 micrograms dose. Furthermore, side-effects such as diarrhea and abdominal cramps appear to be dose related. The antisecretory action of misoprostol is maximal one hour after drug administration and is negligible after 4-5 hours. These factors have until now dictated a 50-200 micrograms q.i.d. dosing regimen for misoprostol in clinical trials against peptic ulcer. Misoprostol does not significantly affect platelet function in terms of ADP-, collagen- and thrombin-induced platelet aggregation. Measurements of FEV1, vital capacity, and peak expiratory flow rate have revealed that misoprostol has no significant bronchodilating or bronchoconstricting effect. Studies of endocrine function revealed only a slight rise within the normal range in serum cortisol in women.


The Parkinson's disease-linked protein TMEM230 is required for Rab8a-mediated secretory vesicle trafficking and retromer trafficking.
TMEM230 is a newly identified Parkinson's disease (PD) gene encoding a transmembrane protein whose cellular and pathogenic roles remain largely unknown. Here, we demonstrate that loss of TMEM230 disrupts retromer cargo CI-M6PR (cation-independent mannose 6-phosphate receptor) trafficking and autophagic cargo degradation rates. TMEM230 depletion further inhibits extracellular secretion of the autophagic cargo p62 and immature lysosomal hydrolases in Golgi-derived vesicles leading to their intracellular accumulation, and is specifically mediated by loss of the small GTPase Rab8a. Importantly, PD-linked TMEM230 variants also induce retromer mislocalization, defective cargo trafficking, and impaired autophagy. Finally, we show that knockdown of another PD gene, LRRK2, which phosphorylates Rab8a, similarly impairs retromer trafficking, secretory autophagy and Golgi-derived vesicle secretion, thus demonstrating converging roles of two PD genes TMEM230 and LRRK2 on Rab8a function, and suggesting that retromer and secretory dysfunction play an important role in PD pathogenesis.


[The count of urine corpuscles using automated analyzer Iris IQ 200 TM].
The volume of urine of high power field of analyzer Iris IQ 200 TM was identified according standard of stabilizing erythrocytes and amounted up to 0.18 mkl. The amount of urine corpuscles detected by analyzer in this volume corresponds to amount of urine corpuscles under microscopy of sediment often times concentrated urine at thickness of preparation in 0.1 mm, under microscope with objective x40 and ocular 10/18. The count of corpuscles by analyzer in 1 mkl of urine is the most objective and convenient technique for quantitative evaluation of urine corpuscles.


[Diseases and causes of death of outstanding creative and scientific figures of XVII-XX centuries].
The article reviewed the literature which analyzes clinical symptoms and causes of some creative and scientific figures of XVII-XX centuries. A conclusion has been made that there are not enough works with professional retrospective investigation of somatic diseases and causes of death of ukrainain outstanding cultural and scientific people in today's national medical literature.


Self-organized perturbations enhance class IV behavior and 1/f power spectrum in elementary cellular automata.
In this paper, we propose a new class of cellular automata based on the modification of its state space. It is introduced to model a computation which is exposed to an environment. We formalized the computation as extension and projection processes of its state space and resulting misidentifications of the state. This is motivated to embed the role of an environment into the system itself, which naturally induces self-organized internal perturbations rather than the usual external perturbations. Implementing this structure into the elementary cellular automata, we characterized its effect by means of input entropy and power spectral analysis. As a result, the cellular automata with this structure showed robust class IV behavior and a 1/f power spectrum in a wide range of rule space comparative to the notion of the edge of chaos.


Laboratory Monitoring of Non-Vitamin K Antagonist Oral Anticoagulant Use in Patients With Atrial Fibrillation: A Review.
The non-vitamin K antagonist oral anticoagulants (NOACs) apixaban, dabigatran, edoxaban, and rivaroxaban are administered in fixed doses without anticoagulant monitoring. Randomized trials show that unmonitored NOAC therapy is at least as effective as and safer than dose-adjusted warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. Subgroup analyses indicate that plasma drug levels or anticoagulant activity of the NOACs predict stroke and bleeding. This review examines the historical basis for anticoagulant monitoring, discusses methods to measure and interpret drug levels, and critically assesses the role of routine laboratory monitoring in the management of NOAC therapy. The predictable anticoagulant response of NOACs has provided the pharmacological basis for their administration in fixed doses without routine coagulation monitoring. Although it is possible to accurately measure NOAC drug levels, within-patient variability complicates interpretation of these results. Furthermore, patient characteristics, such as age and renal function, confound the association between NOAC drug levels and clinical outcomes. Information is lacking on the optimal drug level in particular patient groups (eg, elderly, the renally impaired, and those with high bleeding risk), the appropriate dose adjustment to achieve expected levels, and whether routine laboratory monitoring and dose adjustment will improve clinical outcomes. A benefit of a management strategy that incorporates routine therapeutic drug monitoring and dose adjustment over current standard-of-care metrics without such monitoring remains unproven. Robust evidence from patients with atrial fibrillation randomized to NOACs or warfarin demonstrates that unmonitored NOAC therapy is at least as effective and safe as monitored warfarin, with lower rates of intracranial hemorrhage and reduced mortality. Further research is required to determine whether routine laboratory monitoring might provide a net benefit for patients. Until such data are available, clinicians should continue to prescribe NOACs in fixed doses without routine monitoring.


Thoracic endometriosis syndrome at University of Ilorin Teaching Hospital.
Endometriosis is defined as the presence of endometrial tissue (stroma and functional glands) outside the uterine cavity in women of reproductive age. Ectopic sites are frequently located in the pelvis; extrapelvic sites have been reported in the gastrointestinal tract and thoracic cavity. Thoracic manifestation of endometriosis constitutes thoracic endometriosis syndrome (TES). To examine the presentation pattern and outcome of in the management of TES. This study is a retrospective review of medical records of patients diagnosed with endometriosis at the University of Ilorin Teaching Hospital over a 3.5-year period from January 2014 to June 2017. A total of 21 patients presented with endometriosis, of whom 8 (38.1%) presented with TES. The most common variety of TES was catamenial pleural effusion (CPE) accounting for 75%, followed by catamenial chest pain (37.5%). Two patients (25%) each presented with catamenial pneumothorax and catamenial haemoptysis, while 1 (12.5%) had catamenial surgical emphysema. Closed thoracostomy tube drainage plus chemical pleurodesis was the most frequent intervention technique, accounting for 62.5%. TES remains an uncommon entity, despite being the most common extrapelvic manifestation of endometriosis. CPE appeared to be the most common variant of TES in our environment. Currently available treatment options need to be improved, and more use made of video-assisted thoracoscopic surgery.