Implication of RAF and RKIP genes in urinary bladder cancer.
RKIP has been shown to regulate the RAS-RAF-MEK-ERK kinase cascade acting as modulator of apoptosis and metastasis in prostate cancer. Our goal was to examine the expression of the RAF (A-RAF, B-RAF and RAF-1) and RKIP genes in urinary bladder cancer. Microarray analysis and qPCR was employed to investigate the expression of RAF and RKIP, in 30 patients with transitional cell carcinoma (TCC) of the urinary bladder vs. the corresponding levels of adjacent normal tissue. Computational analysis was also performed on Gene Expression Omnibus (GEO) datasets, to unravel differences in the expression of RAF or RKIP between tumor and control samples, and between superficial and muscle invasive tumors. Microarray analysis revealed >2-fold expression of BRAF and RKIP in T2, T3, grade III tumors vs. controls. B-RAF over-expression was verified by qPCR in pT1, grade III tumors vs. their normal counterparts (p = 0.016). qPCR revealed a significant RKIP reduction in TCC vs. normal tissue (p = 0.002 and p < 0.001 for T1, grade II and Ta-T1, grade III, respectively); All RAF genes were positively correlated among each other (A-RAF/B-RAF, p = 0.003; A-RAF/RAF-1, p < 0.001; B-RAF/RAF-1, p = 0.050), whereas B-RAF was negatively correlated with RKIP in TCC (p = 0.050). Further computational analysis revealed different expression profiles for the genes of interest, among muscle invasive carcinomas, superficial TCCs, cystectomy specimens and normal tissue. The reduced RKIP mRNA levels in TCC and the elevated levels of B-RAF in pT1, grade III tumors vs. normal tissue, corroborate that these genes are involved in the pathogenesis of urinary bladder cancer.


Phenylephrine protects cardiomyocytes from starvation-induced apoptosis by increasing glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is known to be a "housekeeping" protein; studies in non-cardiomyocytic cells have shown that GAPDH plays pro-apoptotic role by translocating from cytoplasm to the nucleus or to the mitochondria. However, the cardiovascular roles of GAPDH are unknown. We observed that phenylephrine (PE) (100 µM) protected against serum and glucose starvation -induced apoptosis in neonatal rat cardiac myocytes as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and mitochondrial membrane potential depolarization. GAPDH glycolysis activity was positively correlated with the antiapoptotic action of PE. GAPDH activity inhibition blunted PE-induced protection of the mitochondrial membrane potential and cardiomyocytes. PE-induced Bcl-2 protein increase, Bax mitochondrial decrease and inhibition of cytochrome C release and Caspase 3 activation, as well as ROS production were blunted by GAPDH activity inhibition. Moreover, GAPDH overexpression provided protection against starvation-induced cardiomyocyte apoptosis in vitro and ischemia-induced cardiac infarction in vivo. Inhibition of Akt prevented PE-induced GAPDH activity increase and cardiomyocytes protection. In conclusion, the present study provides the first direct evidence of an antiapoptotic role of GAPDH in PE-induced cardiomyocytes protection; GAPDH activity elevation mainly affects the mitochondria-induced apoptosis.


Effects of the antioestrogen, ICI 164,384, on oestrogen induced RNAs in MCF-7 cells.
The effects of ICI 164,384 on the expression of six oestrogen-regulated RNAs (pNR-1, pNR-2, pNR-13, pNR-17, pNR-25 and pNR-100) and the 46 kDa secreted protein were measured in MCF-7 cells. In marked contrast to tamoxifen, an antioestrogen commonly used in the treatment of breast cancer, ICI 164,384 administered alone had little or no effect on the RNAs or protein. ICI 164,384 completely inhibited the induction of the RNAs and 46 kDa protein by oestradiol. Although ICI 164,384 has an affinity for the human oestrogen receptor only slightly less than that of oestradiol, half maximal inhibition of oestradiol action was attained with between a 50 and 150-fold molar excess of ICI 164,384. The pNR-1 RNA is induced by tamoxifen but this induction was abolished by ICI 164,384. Thus, ICI 164,384 acts as a potent antioestrogen for the regulation of the expression of specific oestrogen-responsive genes in human breast cancer cells.


Exploring the psychometric properties of a tripartite model of risk perception (TRIRISK) in a general U.S. population sample.
Risk perceptions are key constructs in some theories of health behavior. A tripartite model of risk perception, the TRIRISK model, was developed to assess deliberative, affective, and experiential components of risk perception. The current paper attempts to replicate the factor structure of the TRIRISK measure for cancer and extend the structure to respiratory illness. Participants 18 or older were recruited using an address-based sample in New York State to participate in a Web-based survey. We employed the TRIRISK questionnaire with respect to cancer and respiratory illness. Confirmatory Factor Analyses were conducted in Mplus to validate the TRIRISK model in our sample. TRIRISK model fit across demographic and behavioral groups was tested using multiple-group models. Of the 704 people included in the analysis, the mean age of participants was 46.9, the majority reported being female (58.5%), and most were White (81.7%). For cancer and respiratory illness, items loaded on the respective constructs as expected. Overall, the TRIRISK model framework fits well across differing subgroups, suggesting that this is a valid model of risk perception to use in a general population sample. These results provide further evidence that the TRIRISK model is a good model to use for risk perceptions in tobacco control research. The TRIRISK model can be used to communicate risk to encourage positive health behaviors among most sociodemographic groups.


Additional inhibitors of rat serum acute phase alpha 2-macroglobulin levels. Effect of 6-mercaptopurine and some lipoxygenase and cyclo-oxygenase inhibitors.
With the use of a previously described electroimmunoassay, 4 more compounds were found to depress acute phase alpha 2-macroglobulin levels in rat serum following the injection of turpentine. The compounds, meclofenamic acid, dextropropoxyphene, 5,8,11,14-eicosatetraynoic acid and 6-mercaptopurine are thus grouped with a variety of anti-inflammatory agents, cyclo-oxygenase inhibitors, hypolipidaemics and colchicine, all of which share the property of reducing the concentration of alpha 2-macroglobulin in rat serum. Compounds with immunosuppressant properties, namely amethopterin, azathioprine, cyclophosphamide and 5-fluorouracil, the steroids, betamethasone and dexamethasone, the lipoxygenase inhibitor, nordihydroguaiaretic acid, and MK477, a compound said to stimulate prostaglandin synthesis, did not reduce serum levels of the acute phase protein. 6-Mercaptopurine, a compound known to show anti-inflammatory properties in some systems, proved to be the strongest inhibitor found so far. The rat acute phase protein electroimmunoassay may thus be an effective screen for detecting a new class of anti-inflammatory agents. Knowledge of the mechanisms of action of drugs that depress rat serum alpha 2-macroglobulin concentrations may promote understanding of the control of acute phase protein production by the liver.


A rare disease mimicking lung cancer.
We present an interesting case of a 34 year old gentleman with bilateral FDG avid lesions in the apex of the lung. He presented with a two month history of cough, fever and hemoptysis. A contrast enhanced CT scan showed a spiculated lesion in the right upper lobe. A CT guided biopsy was done which was suggestive of an inflammatory lesion. He was started empirically on anti tubercular therapy, but his symptoms did not subside. A PET CT scan was done, which showed the lesion to be FDG avid. A repeat biopsy was done and again it was reported as an inflammatory infiltrate. He was then referred to our center for a surgical biopsy. We repeated a PET scan and were surprised to find another lesion in the apex of the opposite lung. The case was discussed with our interventional pulmonogy team and an EBUS guided biopsy of the lesion was done. On microbiological analysis the specimen was found to be positive for Nocardia.


Recombinant interferon-alpha, but not interferon-gamma is effective therapy for essential thrombocythemia.
Recombinant interferon-gamma with a starting dose of 0.5 mg 3x/week subcutaneously, was administered to 6 patients with essential thrombocythemia (median platelet count 1172 X 10(9)/l, range 602-1564). Four of the patients had received alkylating agents previously. Hematological remission, defined as a decrease in platelet counts to less than or equal to 350 X 10(9)/l, was observed in none of these patients. Subsequently 4 of these 6 patients, supplemented by 2 others were treated with interferon-alpha 2c at a dose of 5 X 10(6) U daily subcutaneously. Five patients showed hematological remission. In case of hematological remission the interferon-alpha doses was reduced to 5 X an thereafter to 3 X weekly 5 X 10(6) U. During an observation period ranging from 12-41 weeks platelet counts remained normal in all patients. Side-effects were mild and consisted of fever, myalgias, malaise and itching occurring mainly during the first month of treatment. No dose adaptation was required. The patients treated previously with interferon-gamma experienced the side effects from this drug less tolerably than those from the alpha-compound. These observations suggest that recombinant interferon-alpha may be an effective drug in treating essential thrombocythemia resulting in a sustained response.


The South African national health insurance: a revolution in health-care delivery!
A brief overview of the Green Paper on the National Health Insurance (NHI) policy of South Africa is presented. It describes the intention of the NHI to ensure equity, address the inequalities presented by the current private and public health system and present an ambitious plan to change the face of the South African health care system over the next fourteen years. It provides the context of the currents system that provides the case for the change. It also provides some detail on the structure of the proposed new Re-engineered Primary Health Care system as well as the future financing of this bold new health care system for South Africa. The challenge will be in its implementation.


Effects of restricted feeding on the light-induced body weight change and locomotor activity in the Djungarian hamster.
To investigate the role of food intake in seasonal body weight changes in the Djungarian hamster, we divided animals, which had minimum body weights after 18 wk in SD, into ad-lib feeding and restricted feeding groups under a long day (LD) and a short day (SD) photoperiods. In the ad-lib feeding groups, body weight and food intake increased in parallel after 3 wk under LD and after 6-7 wk in SD because of photorefractoriness. In the restricted feeding groups, almost all animals moved around furiously (food-seeking activity) when they came to consume all the food provided at 2-3 wk of the treatment in LD and after several weeks in SD with the initiation of photorefractoriness, and ended up with death. In the restricted feeding groups, body weight increase was not observed. The furious food-seeking activity in the restricted groups and the increase of body weight specific food intake (food intake/body weight) in the ad-lib feeding groups might reflect the increased requirement for food. This increase of requirement for food seems to be one of the critical factors regulating the seasonal body weight change.


Guillain-Barré syndrome coexisting with pericarditis or nephrotic syndrome after influenza vaccination.
A 68-year-old woman and a 72-year-old man presented with distal weakness of the limbs and numbness following an influenza vaccination within 2 weeks. Moreover, Guillain-Barré syndrome (GBS) was diagnosed in two patients. Pericarditis was diagnosed in the first patient who also had precordial chest pain with referral to trapezius ridge, and nephrotic syndrome, was observed in the second patient who had leg edema and proteinuria. The relationship among GBS, pericarditis and nephrotic syndrome after an influenza vaccination is discussed.


Isolation of foamy viruses from peripheral blood lymphocytes.
The isolation of a retrovirus from peripheral blood lymphocytes/monocytes can be a difficult task, requiring the fulfillment of three essential parameters. First, this viral agent must infect such cells in vivo. Second, these circulating cells should harbor wild-type proviruses. Finally, the viral agent has to express, at least when these cells are cultured in vitro, the structural proteins necessary for the production of viral particles. Foamy viruses (FVs), also known as spumaviruses, are complex retroviruses whose genomic organization has been known since the cloning of the prototypic primate foamy virus type 1. These retroviruses infect most cell lines in culture, but circulating lymphocytes seem to represent their major reservoir in vivo. FV infection leads to the formation of multinucleated giant cells, resulting from the fusion of adjacent infected cells, which present multiple vacuoles giving the monolayer culture a foam aspect. These two features, combined with electron microscopy studies, have helped investigators in their attempt to isolate new FVs. These viruses were described and isolated from different animal species, mostly in nonhuman primates. Here we present the successive steps leading to the isolation of the equine foamy virus from peripheral blood lymphocytes of infected horses.


Fatal Interstitial Pneumonia Associated with Bovine Coronavirus in Cows from Southern Italy.
An outbreak of winter dysentery, complicated by severe respiratory syndrome, occurred in January 2020 in a high production dairy cow herd located in a hilly area of the Calabria region. Of the 52 animals belonging to the farm, 5 (9.6%) died with severe respiratory distress, death occurring 3-4 days after the appearance of the respiratory signs (caught and gasping breath). Microbiological analysis revealed absence of pathogenic bacteria whilst Real-time PCR identified the presence of RNA from Bovine Coronavirus (BCoV) in several organs: lungs, small intestine (jejunum), mediastinal lymph nodes, liver and placenta. BCoV was therefore hypothesized to play a role in the lethal pulmonary infection. Like the other CoVs, BCoV is able to cause different syndromes. Its role in calf diarrhea and in mild respiratory disease is well known: we report instead the involvement of this virus in a severe and fatal respiratory disorder, with symptoms and disease evolution resembling those of Severe Acute Respiratory Syndromes (SARS).


Pd-containing magnetic periodic mesoporous organosilica nanocomposite as an efficient and highly recoverable catalyst.
A novel magnetic ionic liquid based periodic mesoporous organosilica supported palladium (Fe3O4@SiO2@IL-PMO/Pd) nanocomposite is synthesized, characterized and its catalytic performance is investigated in the Heck reaction. The Fe3O4@SiO2@IL-PMO/Pd nanocatalyst was characterized using FT-IR, PXRD, SEM, TEM, VSM, TG, nitrogen-sorption and EDX analyses. This nanocomposite was effectively employed as catalyst in the Heck reaction to give corresponding arylalkenes in high yield. The recovery test was performed to study the catalyst stability and durability under applied conditions.


Subgrouping Factors Influencing Migraine Intensity in Women: A Semi-automatic Methodology Based on Machine Learning and Information Geometry.
Migraine is a heterogeneous condition with multiple clinical manifestations. Machine learning algorithms permit the identification of population groups, providing analytical advantages over other modeling techniques. The aim of this study was to analyze critical features that permit the differentiation of subgroups of patients with migraine according to the intensity and frequency of attacks by using machine learning algorithms. Sixty-seven women with migraine participated. Clinical features of migraine, related disability (Migraine Disability Assessment Scale), anxiety/depressive levels (Hospital Anxiety and Depression Scale), anxiety state/trait levels (State-Trait Anxiety Inventory), and pressure pain thresholds (PPTs) over the temporalis, neck, second metacarpal, and tibialis anterior were collected. Physical examination included the flexion-rotation test, cervical range of cervical motion, forward head position while sitting and standing, passive accessory intervertebral movements (PAIVMs) with headache reproduction, and joint positioning sense error. Subgrouping was based on machine learning algorithms by using the nearest neighbors algorithm, multisource variability assessment, and random forest model. For migraine intensity, group 2 (women with a regular migraine headache intensity score of 7 on an 11-point Numeric Pain Rating Scale [where 0 = no pain and 10 = maximum pain]) were younger and had lower joint positioning sense error in cervical rotation, greater cervical mobility in rotation and flexion, lower flexion-rotation test scores, positive PAIVMs reproducing migraine, normal PPTs over the tibialis anterior, shorter migraine history, and lower cranio-vertebral angles while standing than the remaining migraine intensity subgroups. The most discriminative variable was the flexion-rotation test score of the symptomatic side. For migraine frequency, no model was able to identify differences between groups (ie, patients with episodic or chronic migraine). A subgroup of women with migraine who had common migraine intensity was identified with machine learning algorithms.


The accuracy of measuring condylion location.
In locating condylion (Co), clinicians have used cephalograms in maximum mandibular opening to provide a clearer image of the condyle. The purpose of this study was to evaluate the accuracy of identifying condylin on a sample of open and closed mouth cephalograms of 20 patients. Five orthodontists traced each mandibular outline and located condylion and the tip of the mandibular incisor (I). The incisor tip was assumed to be relatively interpretable and served as an internal control. The differences between the open and closed positions in the horizontal and vertical components of condylion relative to the mandibular plane or in the length Co-Gn were not statistically significant. The absolute deviation around condylion was significantly different (p = 0.007), but the average absolute deviation of condylion in the open position was only 0.5 mm less than condylion in the closed position. Statistically significant differences also occurred in the means of the vertical component of the incisor tip (p = 0.002), the length Gn-I (p = 0.006), and the absolute deviation of incisor tip (p = 0.004). These results indicate that the open mouth method does not significantly change the location of condylion. It does increase the accuracy of landmark identification, but this increased accuracy on the average is not clinically significant.


Natural killer cell heterogeneity: cellular dysfunction and significance in HIV-1 immuno-pathogenesis.
Natural killer (NK) cells are innate immune effectors that provide first line of defence against viruses. Human NK cells are heterogeneous in nature, and their functions rely on a dynamic balance between germ-line-encoded activating and inhibitory receptors. HIV-1 infection results in altered NK cell receptor repertoire and impaired effector functions including the ability to lyse virus-infected cells and secretion of antiviral cytokine IFN-γ. Over the last decade, additional NK cell subset-specific molecules have been identified, leading to emergence of a more complex cellular diversity than previously thought. Herein, we discuss NK cell subset redistribution, altered receptor repertoire and influence of interaction of polymorphic leucocyte antigen (HLA) and killer cell immunoglobulin-like receptors (KIR) on HIV-1 disease progression.


Prevalence and molecular characterization of occult hepatitis B virus in pregnant women from Gondar, Ethiopia.
The greatest risk of chronic hepatitis B (CHB) is from mother-to-child transmission. Approximately 20% of individuals in sub-Saharan Africa are hepatitis B virus (HBV) surface antigen-positive (HBsAg+), but the prevalence of occult hepatitis B (OHB) is unknown. Aim: This study investigated CHB and OHB prevalence and viral variants in a cohort of pregnant women in Gondor, Ethiopia. Patients were prospectively recruited from the University of Gondar Hospital (N = 200; median age 27 [inter-quartile range] 8.3y) from March through June 2016. Data were collected using an investigator-administered questionnaire. Plasma was tested for HBsAg and HBV core antibody (anti-HBc), and HBV genotype and presence of HBV variants (ie, vaccine escape mutants [VEMs]) were determined by polymerase chain reaction, Sanger sequencing, and phylogenetic analysis. Of women tested, 1% (2/200) were HBsAg+; 26.8% (47/182) of HBsAg-negative patients were anti-HBc+, of whom 37/47 (78.7%) had detectable HBV DNA. The overall rate of OHB was 20.3%. Both HBsAg+ cases were HBV genotype D, and 36/37 (97.3%) of OHB individuals were genotype D. None carried VEM, but both HBsAg+ cases and 32/37 (86.5%) of the OHB cases showed lamivudine-resistant mutations. Twenty-seven percent of pregnant women in this cohort showed evidence of CHB or prior HBV exposure (ie, HBsAg+ or anti-HBc+) and clinically relevant HBV variants. Data from this single-centre study suggests high HBV prevalence, reinforcing the World Health Organization's recommendation for universal prenatal HBV screening and infant vaccination.


Lumican is down-regulated in cells expressing endoglin. Evidence for an inverse correlationship between Endoglin and Lumican expression.
Endoglin (CD105) is a homodimeric membrane glycoprotein, which acts as a TGF-beta coreceptor in the vasculature and plays an important role in cardiovascular development and vascular remodelling. To isolate putative genes regulated by endoglin expression, a PCR-based RNA fingerprinting technique was carried out. Myoblasts stably transfected with endoglin showed a decrease in the expression of lumican both at the RNA and protein levels. Lumican is a proteoglycan of the extracellular matrix, belonging to the SLRP (Small Leucine-Rich Repeat Proteoglycans) family. Lumican down-regulation by endoglin appeared to be controlled, at least in part, at the transcriptional level, as indicated by RT-PCR, and transient transfection experiments using a lumican promoter reporter based vector. This inverse correlation between endoglin and lumican expression was substantiated by immunohistochemical staining of vessels from human tissues. Thus, cells belonging to the high endothelia, such as tonsil, express a large amount of endoglin, and the lumican content of their matrix is considerably reduced. Conversely, in resting endothelia, such as that of large vessels, the expression of endoglin is reduced whereas the amount of lumican is greatly increased. The inverse regulation in the expression of endoglin and lumican was also evident after TGF-beta treatments since endoglin was up-regulated, whereas lumican was down-regulated by this cytokine. This report describes for the first time a relationship between endoglin and lumican expression.


Parent Evaluation of Developmental Status (PEDS) in screening: The Thai experience.
Parent Evaluation of Developmental Status (PEDS) is a feasible developmental screening tool but it is not commonly used in Thailand. To examine the potential of PEDS as a screening tool, PEDS was implemented in well-child visits to identify the prevalence of developmental problems, characteristic parental concerns and comments, and to compare it with pediatrician developmental evaluation using Parent Evaluation of Developmental Status: Developmental Milestones, assessment level (PEDS: DM-AL). Participants were 266 children at the 9, 18 and 30 month health checkups as well as their parents. The PEDS questionnaire (Thai version) was first used for parents, and then the children were evaluated by pediatricians using PEDS: DM-AL. Using PEDS, 12% and 34% of children were classified as high and moderate risk for developmental and social-emotion disorders. The most common concerns were behavioral problems, social-emotion problems and expressive language. On PEDS: DM-AL, 24% of children had delay in at least one domain of development. When PEDS screening was compared with PEDS: DM-AL, being in the PEDS high-risk group had 27.7% sensitivity and 93.0% specificity. If being in the moderate or high-risk group was used instead, the sensitivity was enhanced to 67.7%, with 60.7% specificity. Implementation of PEDS in well-child visits could enhance early detection of developmental problems, but many Thai parents were unable to mention their concerns about delayed abilities in the correct PEDS question. Therefore, to ensure higher sensitivity, criteria for referral should be adjusted and a second stage developmental evaluation may be incorporated with PEDS.


Characterization of four Phyllanthus species using liquid chromatography coupled to tandem mass spectrometry.
This paper reports a comparison of four Phyllanthus species (P. amarus, P. stipulatus, P. niruri and P. tenellus), commonly known as stone breaker, by the characterization of the chemical profile of their aqueous extracts. Such characterization was carried out using liquid chromatography coupled to ion trap tandem mass spectrometry (LC-IT-MS(n)) under reversed-phase gradient elution mode. The results of MS/MS and MS(3) on-line experiments, using the electrospray ionization source in the positive and negative mode, are extensively discussed. Furthermore, quercetin-3-O-β-d-glucuronopyranoside was isolated in multimilligram scale from the aqueous extract of P. stipulatus and characterized by mass spectrometry and NMR. Although it is an unusual flavonol in natural products, LC-IT-MS(n) experiments showed it to be present also in P. amarus.


Cytochrome P450 CYP307A1/Spook: a regulator for ecdysone synthesis in insects.
The prothoracic gland (PG) has essential roles in synthesizing and secreting a steroid hormone called ecdysone that is critical for molting and metamorphosis of insects. However, little is known about the genes controlling ecdysteroidogenesis in the PG. To identify genes functioning in the PG of the silkworm, Bombyx mori, we used differential display PCR and focused on a cytochrome P450 gene designated Cyp307a1. Its expression level positively correlates with a change in the hemolymph ecdysteroid titer. In addition, Drosophila Cyp307a1 is encoded in the spook locus, one of the Halloween mutant family members showing a low ecdysone titer in vivo, suggesting that Cyp307a1 is involved in ecdysone synthesis. While Drosophila Cyp307a1 is expressed in the early embryos and adult ovaries, the expression is not observed in the PGs of embryos or third instar larvae. These results suggest a difference in the ecdysone synthesis pathways during larval development in these insects.


[11C]tropanyl benzilate-binding to muscarinic cholinergic receptors: methodology and kinetic modeling alternatives.
Quantitative estimation of cerebral muscarinic receptors was investigated with the use of the antagonist [11C]tropanyl benzilate ([11C]TRB) and positron emission tomography (PET). Kinetic modeling alternatives were examined with the goal of identifying an analysis method providing stable receptor measures, yet avoiding biases from inappropriate reductions in model complexity. Dynamic PET scans were performed on six young normal volunteers. Several modeling approaches yielding relative receptor density measures were evaluated: (a) a single "late" scan using relative tracer concentration values; (b) a slope estimate from graphic analysis (Patlak plot); (c) a two-compartment, two-parameter model (transport and total ligand distribution volume); (d) a three-compartment, two-parameter model using the free+nonspecific distribution volume, DV', fixed to the cerebellar value; (e) an early scan for transport, a fixed value for DV', and a single late scan for the binding rate constant; and (f) a three-compartment, three-parameter model. Both computer simulations and PET scan results indicate all methods provide receptor density index measures with the same rank order as in vitro measures. Oversimplified approaches (methods 1 and 2) yield a more highly nonlinear relation between the estimated receptor density index and the known receptor density than do methods retaining greater model complexity (methods 3-6). However, noise propagation into the receptor measure is greater for the more complex methods. Reliable receptor density information can be obtained from kinetic [11C]TRB PET studies, with methods 3-5 providing the most appropriate levels of model complexity for estimates of relative muscarinic receptor density.


Gastric cancer following highly selective vagotomy.
A case of gastric cancer occurring seven years after a highly selective vagotomy is described. This operation may not be the appropriate choice for the surgical treatment of gastric ulcers and H2 blockers should be used with caution in these patients.


[Genetic causes of mental retardation].
Mental retardation (MR) is defined as congenital or early onset lifelong impairment of cognitive and adaptive functioning (IQ < 70). It effects approximately 3% of the Western population. The causes are heterogenous. Numerical or structural chromosome abnormalities are responsible for 10-20% of the mild cases (MMR) and 40% of the severe cases (SMR). Among them Down syndrome represents the most frequent chromosome aberration and the most frequent defined MR syndrome. Gonosomal aberrations do not coincide with MR, as long as only one gonosome is lost or gained. Nearly all unbalanced structural autosomal aberrations cause SMR. Recent studies suggested that sub-microscopic chromosomal microdeletions or subtelomeric rearrangements account for approximately 10% of the undiagnosed cases. They represent a group of newly defined disorders. Single gene mutations are responsible for > 1200 known syndromal conditions with MR. But only few causative genes have been identified as yet. However, an increasing number of genes causing X-linked mental retardation (XLMR) have been localized and cloned, namely 38 genes of the 136 known syndromic conditions and 19 for the non-syndromic conditions. XLMR explains the 20 % excess of males over females. Despite the increasing knowledge about the causes of MR, about half of the cases remain undiagnosed. Guidelines for the diagnostic procedure in children with MR have been proposed.


Endovascular management of superior mesenteric artery pseudoaneurysm and fistula.
The uncommon presentation of an arterioportal fistula (APF) involving the superior mesenteric artery (SMA) associated with a pseudoaneurysm represents a therapeutic challenge. We present the case of a 24-year-old female admitted to the hospital after multiple gunshot wounds to the abdomen; the patient underwent multiple surgeries and, in the process, developed a SMA pseudoaneurysm and fistula. The vascular interventional radiology team was consulted for treatment of the pseudoaneurysm and fistula. A covered stent was inserted percutaneously to exclude the APF and the pseudoaneurysm in a single procedure. The patient returned to our service after 21 months for a follow-up CT scan, which demonstrated the stent and the distal vasculature to be patent.


Triad role of hepcidin, ferroportin, and Nrf2 in cardiac iron metabolism: From health to disease.
Iron is an essential trace element required for several vital physiological and developmental processes, including erythropoiesis, bone, and neuronal development. Iron metabolism and oxygen homeostasis are interlinked to perform a vital role in the functionality of the heart. The metabolic machinery of the heart utilizes almost 90 % of oxygen through the electron transport chain. To handle this tremendous level of oxygen, the iron metabolism in the heart is utmost crucial. Iron availability to the heart is therefore tightly regulated by (i) the hepcidin/ferroportin axis, which controls dietary iron absorption, storage, and recycling, and (ii) iron regulatory proteins 1 and 2 (IRP1/2) via hypoxia inducible factor 1 (HIF1) pathway. Despite iron being vital to the heart, recent investigations have demonstrated that iron imbalance is a common manifestation in conditions of heart failure (HF), since free iron readily transforms between Fe2+ and Fe3+via the Fenton reaction, leading to reactive oxygen species (ROS) production and oxidative damage. Therefore, to combat iron-mediated oxidative stress, targeting Nrf2/ARE antioxidant signaling is rational. The involvement of Nrf2 in regulating several genes engaged in heme synthesis, iron storage, and iron export is beginning to be uncovered. Consequently, it is possible that Nrf2/hepcidin/ferroportin might act as an epicenter connecting iron metabolism to redox alterations. However, the mechanism bridging the two remains obscure. In this review, we tried to summarize the contemporary insight of how cardiomyocytes regulate intracellular iron levels and discussed the mechanisms linking cardiac dysfunction with iron imbalance. Further, we emphasized the impact of Nrf2 on the interplay between systemic/cardiac iron control in the context of heart disease, particularly in myocardial ischemia and HF.


Ecology and extent of freshwater browning - What we know and what should be studied next in the context of global change.
Water browning or brownification refers to increasing water color, often related to increasing dissolved organic matter (DOM) and carbon (DOC) content in freshwaters. Browning has been recognized as a significant physicochemical phenomenon altering boreal lakes, but our understanding of its ecological consequences in different freshwater habitats and regions is limited. Here, we review the consequences of browning on different freshwater habitats, food webs and aquatic-terrestrial habitat coupling. We examine global trends of browning and DOM/DOC, and the use of remote sensing as a tool to investigate browning from local to global scales. Studies have focused on lakes and rivers while seldom addressing effects at the catchment scale. Other freshwater habitats such as small and temporary waterbodies have been overlooked, making the study of the entire network of the catchment incomplete. While past research investigated the response of primary producers, aquatic invertebrates and fishes, the effects of browning on macrophytes, invasive species, and food webs have been understudied. Research has focused on freshwater habitats without considering the fluxes between aquatic and terrestrial habitats. We highlight the importance of understanding how the changes in one habitat may cascade to another. Browning is a broader phenomenon than the heretofore concentration on the boreal region. Overall, we propose that future studies improve the ecological understanding of browning through the following research actions: 1) increasing our knowledge of ecological processes of browning in other wetland types than lakes and rivers, 2) assessing the impact of browning on aquatic food webs at multiple scales, 3) examining the effects of browning on aquatic-terrestrial habitat coupling, 4) expanding our knowledge of browning from the local to global scale, and 5) using remote sensing to examine browning and its ecological consequences.


Malignant rhabdoid tumour of the uterus: an immunohistochemical and ultrastructural study.
Malignant rhabdoid tumours (MRTs) are highly aggressive neoplasms which most frequently occur in the kidney of young children. Several cases of primary MRT occurring in extra-renal sites have been reported, particularly in the soft tissues. We report a case of primary MRT of the uterus, a very rare site for this neoplasm, with morphological, immunohistochemical and ultrastructural features corresponding to restrictive morphological criteria for MRT. The possible differential diagnoses were considered.


Cytogenetic changes during the early stages of liver carcinogenesis in Chinese hamster: an in vivo--in vitro comparison.
Cytogenetic changes were investigated during the early stages of hepatic adenocarcinoma development in Chinese hamsters injected with a single dose of dimethylnitrosamine (DMN). An in vivo-in vitro comparison was made from 7 to 35 weeks after injection. A partial hepatectomy was used to stimulate mitosis for in vivo analysis, and the excised liver, grown to the primary culture stage, was used for chromosome analysis in vitro. Aneuploidy, tetraploidy, and chromosome aberrations increased significantly in the hepatic cells of DMN-treated animals in vivo, with no significant change over the 7- to 35-week period. No differences, however, could be detected between the primary cultures of control and DMN-treated animals because of an inherent tendency for all cultures to develop aneuploid stem lines at an early stage in culture. A preferential involvement of chromosome #6 in the single trisomic state was demonstrated in vitro and to a minor extent in vivo. The relevance of increased aneuploidy in early carcinogenesis and the differences between the in vivo and in vitro results are discussed.


2-Chloro-2'-deoxyadenosine inhibits DNA repair synthesis and potentiates UVC cytotoxicity in chronic lymphocytic leukemia B lymphocytes.
2-Chloro-2'-deoxyadenosine (CdA) is a deoxyadenosine analogue which targets enzymes involved in DNA synthesis, and hence might interfere with the resynthesis step of DNA repair. We tested this hypothesis in resting B cell chronic lymphocytic leukemia (B-CLL) lymphocytes, after firstly characterizing unscheduled DNA synthesis occurring in these cells. We observed that the spontaneous incorporation of [methyl-3H]thymidine (dThd) into DNA of B-CLL cells was not completely inhibitable by hydroxyurea (HU) which blocks DNA replication. In addition, in the presence of HU, dThd incorporation could be upregulated by UVC radiation or DNA alkylation, without re-entry of the cells into S phase. CdA was found to inhibit both spontaneous and upregulated DNA synthesis in B-CLL cells. Phosphorylation of CdA was essential to exert this effect. We finally observed a strong synergistic cytotoxicity between UV light and CdA, which was correlated with activation of caspase-3 and high molecular weight DNA fragmentation, two markers of apoptosis. Taken together, these observations indicate that in B-CLL cells CdA inhibits unscheduled DNA synthesis which represents the polymerizing step of a repair process responsive to DNA aggression. Inhibition of this process by CdA, together with a combined activation of the apoptotic proteolytic cascade by CdA and UV, may explain their synergistic cytotoxicity.


Editor's Choice - Volume-Outcome Relationships in Elective Abdominal Aortic Aneurysm Surgery: Analysis of the UK Hospital Episodes Statistics Database for the Getting It Right First Time (GIRFT) Programme.
To investigate whether a volume-outcome relationship exists for elective abdominal aortic aneurysm (AAA) surgery conducted within the National Health Service (NHS) in England. This was an analysis of administrative data. Data were extracted from the Hospital Episodes Statistics database for England from April 2011 to March 2019 for all adult admissions for elective infrarenal AAA surgery. Data were extracted for the NHS trust and surgeon undertaking the procedure, the surgical technique used (open or endovascular), the financial year of admission, length of hospital and critical care stay during the procedure and subsequent emergency re-admissions (primary outcome) and deaths within 30 days. Multilevel modelling was used to adjust for hierarchy and confounding. A dataset of 31 829 procedures (8867 open, 22 962 endovascular) was extracted. For open surgery, lower trust annual volume was associated with higher 30 day emergency re-admission rates and higher 30 day mortality. For open surgery, lower surgeon annual volume was associated with higher 30 day mortality and length of hospital stay greater than the median. For endovascular surgery, lower surgeon annual volume was associated with not having an overnight stay in critical care. None of the other volume-outcome relationships investigated was significant. For elective infrarenal AAA surgery in the UK NHS, there was strong evidence of a volume-outcome relationship for open surgery. However, evidence for a volume-outcome relationship is dependent on the specific procedure undertaken and the outcome of interest.


Older age and higher body mass index are independent risk factors for tendon healing in small- to medium-sized rotator cuff tears.
Many previous research efforts have been made to identify prognostic factors for rotator cuff healing. However, majority of these studies were conducted with heterogeneous cohorts consisted of different tear characteristics. Healing properties of a rotator cuff tear may differ depending on tear characteristics such as tear size or fatty infiltration. Therefore, studies with subgroups confined by these variables may reflect more accurate results. This study aims to investigate predictive factors for rotator cuff healing in a subgroup with small- to medium-sized tears without significant fatty infiltration. This retrospective case-control study was conducted with 94 patients with small- to medium-sized rotator cuff tears. Mean age of patients was 56.0 ± 9.0 years and mean follow-up duration was 38.3 ± 8.1 months. Post-operative magnetic resonance imaging assessment showed that there were 75 (79.8%) successfully healed repairs and 19 (20.2%) healing failures. Age, gender, hand dominancy, body mass index (BMI), smoking habit, diabetes, corticosteroid injection, baseline clinical status, duration of surgery and biceps procedure were variables evaluated as predictive factors. Both study groups showed significant improvement from baseline regarding clinical outcome measures (p < 0.05). However, successfully healed patients had significantly higher post-operative functional scores and lower pain scores (p < 0.05). The univariate analysis revealed that healing was significantly affected by age (p = 0.004), BMI (p = 0.01) and diabetes (p = 0.03). In the multivariate analysis, age (p = 0.02) and BMI (p = 0.02) were found to be significant independent factors for healing. Cutoff values for oldest age and highest BMI were 63 years and 28.1 kg/m2, respectively, for a successful healing according to receiver-operating characteristic curve analysis. Healing failure after rotator cuff repair in small- to medium-sized tears is associated with poorer outcomes. Age and BMI are independent predictive factors for healing. A successful repair is more likely in patients younger than 63 years and with BMI less than 28.1 kg/m2. Surgeons should consider this information during risk assessment, decision making and patient counselling. Level III.


Loss of functional peroxisomes leads to increased mitochondrial biogenesis and reduced autophagy that preserve mitochondrial function.
Peroxisomes are essential for mitochondrial health, as the absence of peroxisomes leads to altered mitochondria. However, it is unclear whether the changes in mitochondria are a function of preserving cellular function or a response to cellular damage caused by the absence of peroxisomes. To address this, we developed conditional hepatocyte-specific Pex16 deficient (Pex16 KO) mice that develop peroxisome loss and subjected them to a low-protein diet to induce metabolic stress. Loss of PEX16 in hepatocytes led to increased biogenesis of small mitochondria and reduced autophagy flux but with preserved capacity for respiration and ATP capacity. Metabolic stress induced by low protein feeding led to mitochondrial dysfunction in Pex16 KO mice and impaired biogenesis. Activation of PPARα partially corrected these mitochondrial disturbances, despite the absence of peroxisomes. The findings of this study demonstrate that the absence of peroxisomes in hepatocytes results in a concerted effort to preserve mitochondrial function, including increased mitochondrial biogenesis, altered morphology, and modified autophagy activity. Our study underscores the relationship between peroxisomes and mitochondria in regulating the hepatic metabolic responses to nutritional stressors.


Sickness absence due to mandatory COVID-19 certificates in the workplace.
As vaccines for COVID-19 became available, many countries introduced an obligation in 2021 for employees to prove their COVID-19 status at work, known in Germany as the 3G rule (vaccinated, recovered, tested). In view of the controversial debate, there was concern that employees might try to avoid providing mandatory COVID-19 certificates by taking sick leave. The aim of this study was to investigate whether mandatory COVID-19 tests in the workplace led to such an evasive response. For an empirical panel analysis, we collected data from official sources and combined aggregated health insurance data on sick leave, epidemiological data on laboratory-confirmed COVID-19 infections, and vaccination rates for the German states from September 2021 to January 2022. We used a regional panel data analysis to estimate the impact of the mandatory COVID-19 certificates at the workplace on workers' sick leave. The regional vaccination rate reflected differences in treatment intensity. This study contributes to the limited evidence on the potential impact of introducing mandatory COVID-19 certificates at the workplace on sickness absence rates. In fact, our results showed that after controlling for infection rates, a one percentage point lower vaccination rate led to a 0.021 percentage point increase in the sickness absence rate when the 3G rule came into effect. This effect was measured with high statistical precision. In addition, in robustness checks, we controlled for a number of other possible influencing factors that may have affected sickness behaviours, such as time-varying labour market situations. However, the results remained robust. The results of our empirical panel analysis implied that mandatory COVID-19 certificates in the workplace led to evasive responses and to additional days of sick leave of a relevant magnitude. Testing obligations were meant to help contain the epidemic. However, when introducing controversial obligations, it is important to consider evasive responses and to design the rules appropriately and communicate them convincingly.


Effect of salinity on molecular characterization of dissolved organic matter using ESI FT-ICR MS.
Solid-phase extraction (SPE) coupled with negative-ion Electrospray ionization (ESI) Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) has been widely used for molecular characterization of dissolved organic matter (DOM). However, little attention has paid to test whether the salinity of the sample and the presence of chloride ions in water samples affect the molecular composition of DOM extracted by SPE (SPE-DOM). In this study, one natural organic matter standard and several natural waters were selected to investigate how salinity affects the molecular composition of SPE-DOM and the selectivity of chloride ion adducts formation with respect to the molecular structure of SPE-DOM in negative ion ESI FT-ICR MS analysis. The results show that the molecular composition of SPE-DOM varied in a sample made by different salinity; and the variation pattern of DOM composition was different among different water samples under the treatment of consistent salinity gradients. The chloride ions can't be completely removed from cartridges in conventional SPE, thus leading organic compounds in SPE-DOM to form [M+Cl]‾ adducts when performing ESI FT-ICR MS analysis. In addition, the molecules with high H/C and low O/C ratios were likely to form [M+Cl]‾ ions. The relative abundance of [M+Cl]‾ ions could increase with the increase of salinity. These results are instructive to guide the pretreatment and molecular characterization of DOM in water samples with different salinity. Overall, we proposed a modification to the SPE to minimum reduce the formation of chloride ion adducts during the isolation of DOM.


What is the contribution of different cognitive biases and stressful childhood events to the presence and number of previous depressive episodes?
Negative cognitive biases as well as stressful childhood events are well-known risk factors for depression. Few studies have compared the association of different types of biases and events with depression. The current study examined whether different cognitive biases and stressful childhood events variables were associated with depression and recurrence. Three types of childhood events were assessed in 83 never-depressed and 337 formerly depressed individuals: trauma within the family, trauma outside the family, and adverse events. Furthermore, after a sad mood induction procedure, participants executed a Dot Probe task (selective attentional bias), an Emotional Stroop task (attentional interference bias) and an incidental learning task (memory bias). The association of these measures with case status and recurrence status (one or multiple past episodes) was examined. Negative memory bias and traumatic childhood events within the family were associated with case status, whereas none of the bias measures or childhood events variables were associated with recurrence status. The results indicate that memory bias as well as the experience of aggression and/or abuse within the family during childhood are independently associated with depression. Biases and stressful childhood events did not offer differentiation between individuals with one or multiple past episodes.


Rapid and reproducible surveillance for ventilator-associated pneumonia.
The complexity and subjectivity of ventilator-associated pneumonia (VAP) surveillance limit its value in assessing and comparing quality of care for ventilated patients. A simpler, more quantitative VAP definition may increase utility. We streamlined the Centers for Disease Control and Prevention definition of VAP to increase objectivity and efficiency. Qualitative criteria were replaced with quantitative criteria, and changes in ventilator settings were used to screen patients for worsening oxygenation. We retrospectively compared surveillance time, reproducibility, and outcomes for streamlined versus conventional surveillance among medical and surgical patients on mechanical ventilation in 3 university hospitals. Application of the streamlined definition was faster (mean 3.5 minutes vs 39.0 minutes per patient) and more objective (interrater reliability κ 0.79 vs 0.45) than the conventional definition. On multivariate analysis, the streamlined definition predicted increases in ventilator days (6.5 days [95% CI, 4.1-10.0] vs 6.4 days [95% CI, 4.7-8.6]), intensive care days (5.6 days [95% CI, 3.2-8.9] vs 6.2 days [95% CI, 4.6-8.2]), and hospital mortality (odds ratio [OR] 0.84 [95% CI, 0.31-2.29] vs OR 0.69 [95% CI, 0.30-1.55]) as effectively as conventional surveillance. The conventional definition was a marginally superior predictor of increased hospital days (5.2 days [95% CI, 3.4-7.6] vs 2.1 days [95% CI, -0.5-5.6]). A streamlined version of the VAP definition was faster, more objective, and predicted patients' outcomes almost as effectively as the conventional definition. VAP surveillance using the streamlined method may facilitate more objective and efficient quality assessment for ventilated patients.


Kinetics of human cone photopigments explained with a Rushton-Henry model.
Densitrometric measurements of the regeneration of cone visual photopigments have shown effects that cannot be explained by the existing quantitative models. Regeneration from a fully bleached state seems to depend on how this state has been reached and the shape of the regeneration curve cannot be produced by a first order reaction. Rushton and Henry (1968) proposed a store of 11-cis-retinal to explain rapid regeneration after a short bleach. We elaborated this idea into a quantitative model. Regeneration after three different bleach histories and steady state behaviour of the pigments was measured using the Utrecht densitometer. The Rushton-Henry model gives a good fit to the data and is clearly superior to the classical Rushton model in describing densitometric measurements.


[Expression of BP1 gene in adult acute leukemia].
To explore the expression of beta protein 1 (BP1) gene in adult acute leukemia (AL) and its relationship with acute leukemia. Expression of BP1 gene mRNA was detected in 70 adult AL, 10 normal controls and HEL cell line, by reverse transcriptase-polymerase chain reaction (RT-PCR). No detectable BP1 gene was found in peripheral blood or bone marrow cells of normal controls and 20 acute myeloid leukemia (AML) in complete remission (CR) stage. BP1 gene was highly expressed in HEL cell line, 57% (20/35) of AML and 80% (8/10) of AML-M(5) cases. BP1 gene could not be detected in adult acute lymphoid leukemia. BP1 gene was highly expressed in AML. It might be used as a molecular marker of AML.


Correlation between spontaneous metastatic potential and type I collagenolytic activity in a human pancreatic cancer cell line (SUIT-2) and sublines.
A human pancreatic cancer cell line (SUIT-2) and four sublines cloned in vitro (S2-007, S2-013, S2-020 and S2-028) were inoculated into nude mice for assessment of metastatic potentials. After 16 weeks of subcutaneous injection, the parent SUIT-2 line metastasized to the lungs and lymph nodes in three of six mice. S2-007 cells presented the highest metastatic potential in pulmonary (5/6) and lymph node (2/6) metastases among the four sublines. No metastasis was found in S2-028. The incidence of spontaneous pulmonary metastasis was correlated with that of pulmonary colonization after intravenous (i.v.) injection of cell clusters (r = 0.87, P = 0.056). Pulmonary colonization potential using single cells, however, did not always reflect a spontaneous metastatic ability. Type I collagenolytic activity in serum-free conditioned media of these cells was correlated effectively with the incidence of spontaneous pulmonary metastasis (r = 0.92, P = 0.026) and pulmonary colonization after i.v. injection of cell clusters (r = 0.95, P = 0.013). Thus, type I collagenolytic activity may possibly be essential to spontaneous cancer metastasis.


IVF-induced pregnancy and early motherhood among women with a history of severe eating disorders.
There is a higher prevalence of eating disorders among women seeking in vitro fertilization (IVF). Women with a history of eating disorders may be particularly vulnerable to eating disorder relapse during IVF, pregnancy, and early motherhood. The experience of these women during this process has hardly been studied scientifically, despite its high clinical relevance. The overall aim of this study is to describe how women with a history of eating disorders experience the process of becoming a mother through IVF, pregnancy, and the postpartum period. We recruited women with a history of severe anorexia nervosa who had undergone IVF (n = 7) at public family health centers in Norway. Semi-openly, the participants were interviewed extensively first during pregnancy, and then 6 months after birth. The 14 narratives were analyzed using interpretative phenomenological analyses (IPA). All participants were required to complete the Eating Disorder Examination Questionnaire (EDE-Q) and were diagnosed (DSM-5) by using the Eating Disorder Examination (EDE), during both pregnancy and postpartum. All participants experienced a relapse of an eating disorder during IVF. They perceived IVF, pregnancy, and early motherhood to be overwhelming, confusing, a source of severe loss of control, and a source of body alienation. There were four core phenomena that were reported that were strikingly similar across all participants: "anxiousness and fear," "shame and guilt," "sexual maladjustment," and "non-disclosure of eating problems." These phenomena persisted continuously throughout IVF, pregnancy, and motherhood. Women with a history of severe eating disorders are highly susceptible to relapse when undergoing IVF, pregnancy, and early motherhood. The process of IVF is experienced as extremely demanding and provoking. There is evidence that eating problems, purging, over-exercising, anxiousness and fear, shame and guilt, sexual maladjustment, and non-disclosure of eating problems continue throughout IVF, pregnancy, and the early years of motherhood. Therefore, it is necessary for healthcare workers providing services to women undergoing IVF to be attentive and intervene when they suspect a history of eating disorders.


Transient pseudo-Duane syndrome after lateral orbital trauma.
Duane syndrome is a dysinnervation disorder that frequently involves secondary anomalous eye movement, in particular, ocular retraction and the narrowing of the palpebral fissure on the adduction. Pseudo-Duane syndrome is caused by a mechanical restriction that produces clinical findings similar to those of Duane syndrome. Most patients with pseudo-Duane syndrome have restrictive pathologies on the medial side of the globe, such as entrapment of the medial rectus muscle. We report the case of a 44-year-old man with pseudo-Duane syndrome in whom we identified a lateral orbital wall fracture and entrapment of the soft tissue surrounding the lateral rectus muscle by computed tomography. To the best of our knowledge, this etiology of pseudo-Duane syndrome has not been previously reported.


Microcarrier cell culture: new methods for research-scale application.
A positive-charge-carrying, dextran microsphere has been developed which serves as an excellent surface for the attachment and growth of anchorage-dependent cells in microcarrier culture. With standard cell culture media, saturation cell concentrations in excess of 4 X 10(6) cells/ml are routinely obtained for secondary chicken embryo fibroblasts or normal diploid human fibroblasts. The use of microcarriers reduces the time, expense, and apparatus complexity required for the routine propagation of anchorage-dependent cells.


Improved regional activity quantitation in nuclear medicine using a new approach to correct for tissue partial volume and spillover effects.
We have developed a new method of compensating for effects of partial volume and spillover in dual-modality imaging. The approach requires segmentation of just a few tissue types within a small volume-of-interest (VOI) surrounding a lesion; the algorithm estimates simultaneously, from projection data, the activity concentration within each segmented tissue inside the VOI. Measured emission projections were fitted to the sum of resolution-blurred projections of each such tissue, scaled by its unknown activity concentration, plus a global background contribution obtained by reprojection through the reconstructed image volume outside the VOI. The method was evaluated using multiple-pinhole μSPECT data simulated for the MOBY mouse phantom containing two spherical lung tumors and one liver tumor, as well as using multiple-bead phantom data acquired on μSPECT and μCT scanners. Each VOI in the simulation study was 4.8 mm (12 voxels) cubed and, depending on location, contained up to four tissues (tumor, liver, heart, lung) with different values of relative (99m)Tc concentration. All tumor activity estimates achieved bias after ∼ 15 ordered-subsets expectation maximization (OSEM) iterations (×10 subsets) , with better than 8% precision ( ≤ 25% greater than the Cramer-Rao lower bound). The projection-based fitting approach also outperformed three standardized uptake value (SUV)-like metrics, one of which was corrected for count spillover. In the bead phantom experiment, the mean ± standard deviation of the bias of VOI estimates of bead concentration were 0.9±9.5%, comparable to those of a perturbation geometric transfer matrix (pGTM) approach (-5.4±8.6%); however, VOI estimates were more stable with increasing iteration number than pGTM estimates, even in the presence of substantial axial misalignment between μCT and μSPECT image volumes.


Probabilistic kinetic model of slow oxidation of low-density lipoprotein: I. Theory.
The microscopic probabilistic model has been introduced to explain the kinetics of very slow oxidation of low-density lipoprotein (LDL) from human plasma. The LDL oxidation, carried out in very unfavorable conditions, is assumed to be initiated by the traces of the transition-metal ions associated with the lipoprotein. The substrates for the metal-ion attack are alpha-tocopherol and the pre-formed lipid hydroperoxide. The theory assumes oscillation of the metal ions and alpha-tocopherol from the oxidized to the reduced states. In this model alpha-tocopherol acts as a pro-oxidant. The entire oxidation process consists of rare bursts of events in individual LDL particles. The reactions within the particles are treated in terms of probabilities of individual active species to participate in a specified reaction. The circular flow of the radical reactions could be visualized as circular flow of microscopic probabilities. The empirical, macroscopic quantities are quantitatively related with the microscopic probabilities, determined by a set of five adjustable parameters. The differential equations describing the initial radical generation rate and the rates of change of concentration of oxygen, hydroperoxide, co-antioxidant and trapped radicals in an LDL system are numerically solved in a finite difference approach.


Obstructive Sleep Apnea-Induced Hypertension: Role of the Gut Microbiota.
Obstructive sleep apnea (OSA) is a significant risk factor for systemic hypertension and other cardiovascular diseases. While this relationship has been firmly established, a detailed understanding of how OSA leads to hypertension is lacking. This review will examine the emerging idea that the gut microbiota plays a role in the development of hypertension, including that associated with OSA. Disruption of the normal composition of the gut microbiota, termed dysbiosis, has been identified in a number of metabolic and cardiovascular diseases, including diabetes, obesity, and atherosclerosis. Recently, a number of studies have demonstrated gut dysbiosis in various animal models of hypertension as well as in hypertensive patients. Evidence is now emerging that gut dysbiosis plays a causal role in the development of OSA-induced hypertension. In this review, we will examine the evidence that gut dysbiosis plays a role in OSA-induced hypertension. We will discuss potential mechanisms linking OSA to gut dysbiosis, examine how gut dysbiosis may be linked to hypertension, and highlight how this understanding may be utilized for the development of future therapeutics.


Improving pulmonary perfusion assessment by dynamic contrast-enhanced computed tomography in an experimental lung injury model.
Pulmonary perfusion has been poorly characterized in acute respiratory distress syndrome (ARDS). Optimizing protocols to measure pulmonary blood flow (PBF) via dynamic contrast-enhanced (DCE) computed tomography (CT) could improve understanding of how ARDS alters pulmonary perfusion. In this study, comparative evaluations of injection protocols and tracer-kinetic analysis models were performed based on DCE-CT data measured in ventilated pigs with and without lung injury. Ten Yorkshire pigs (five with lung injury, five healthy) were anesthetized, intubated, and mechanically ventilated; lung injury was induced by bronchial hydrochloric acid instillation. Each DCE-CT scan was obtained during a 30-s end-expiratory breath-hold. Reproducibility of PBF measurements was evaluated in three pigs. In eight pigs, undiluted and diluted Isovue-370 were separately injected to evaluate the effect of contrast viscosity on estimated PBF values. PBF was estimated with the peak-enhancement and the steepest-slope approach. Total-lung PBF was estimated in two healthy pigs to compare with cardiac output measured invasively by thermodilution in the pulmonary artery. Repeated measurements in the same animals yielded a good reproducibility of computed PBF maps. Injecting diluted isovue-370 resulted in smaller contrast-time curves in the pulmonary artery (P < 0.01) and vein (P < 0.01) without substantially diminishing peak signal intensity (P = 0.46 in the pulmonary artery) compared with the pure contrast agent since its viscosity is closer to that of blood. As compared with the peak-enhancement model, PBF values estimated by the steepest-slope model with diluted contrast were much closer to the cardiac output (R2 = 0.82) as compared with the peak-enhancement model. DCE-CT using the steepest-slope model and diluted contrast agent provided reliable quantitative estimates of PBF.NEW & NOTEWORTHY Dynamic contrast-enhanced CT using a lower-viscosity contrast agent in combination with tracer-kinetic analysis by the steepest-slope model improves pulmonary blood flow measurements and assessment of regional distributions of lung perfusion.


Basement membrane surfaces and perivascular compartments in normal human brain and glial tumours. A scanning electron microscope study.
The relationship of perivascular tissues to arteries and veins in normal brain and glial tumors were investigated by light microscopy and by scanning and transmission electron microscopy. Vessels and perivascular tissues were separated through various planes by careful tearing of fixed tissue blocks of brain and tumour. Mirror surfaces of torn blocks were examined by scanning electron microscopy and the identity of the vessels and other structure confirmed by transmission electron microscopy. Perivascular glial basement membranes remained adherent to arterial adventitia in both normal brain and in tumour so that the torn surface around the vessel exposed perivascular glial processes attached to the vessel walls. A clear plane of separation of perivascular glial basement membrane from the adventitia of veins was achieved in glial tumours. Mirror surfaces showed the smooth undulating sheet of basement membrane separated from the fine fibrillary connective tissue of the vessel wall. Tears in the basement membrane revealed the perivascular glial processes. The structure of the perivascular basement membrane is discussed in relation to its role as an attachment site for perivascular glial and as an impedence to inflammatory cell migration into brain parenchyma.


Microarray analysis in rat liver slices correctly predicts in vivo hepatotoxicity.
The microarray technology, developed for the simultaneous analysis of a large number of genes, may be useful for the detection of toxicity in an early stage of the development of new drugs. The effect of different hepatotoxins was analyzed at the gene expression level in the rat liver both in vivo and in vitro. As in vitro model system the precision-cut liver slice model was used, in which all liver cell types are present in their natural architecture. This is important since drug-induced toxicity often is a multi-cellular process involving not only hepatocytes but also other cell types such as Kupffer and stellate cells. As model toxic compounds lipopolysaccharide (LPS, inducing inflammation), paracetamol (necrosis), carbon tetrachloride (CCl(4), fibrosis and necrosis) and gliotoxin (apoptosis) were used. The aim of this study was to validate the rat liver slice system as in vitro model system for drug-induced toxicity studies. The results of the microarray studies show that the in vitro profiles of gene expression cluster per compound and incubation time, and when analyzed in a commercial gene expression database, can predict the toxicity and pathology observed in vivo. Each toxic compound induces a specific pattern of gene expression changes. In addition, some common genes were up- or down-regulated with all toxic compounds. These data show that the rat liver slice system can be an appropriate tool for the prediction of multi-cellular liver toxicity. The same experiments and analyses are currently performed for the prediction of human specific toxicity using human liver slices.


Low-Risk Myelodysplastic Syndrome Revisited: Morphological, Autoimmune, and Molecular Features as Predictors of Outcome in a Single Center Experience.
Low-risk myelodysplastic syndromes (LR-MDS) are a very heterogeneous disease, with extremely variable clinical features and outcome. Therapeutic strategies are still limited and mainly consist of erythropoiesis-stimulating agents (ESAs) and transfusion support. The contribution of molecular lesions and of autoimmune phenomena to pathogenesis and clinical course, including leukemic evolution, is a field of open investigation. We analyzed data from a cohort of 226 patients with LR-MDS followed at our center in the last 20 years, focusing on morphological, immunological (antiplatelets and anti-erythrocyte autoantibodies, anti-erythroblast antibodies), and molecular features. Hypoplastic bone marrow was found in 7% of the cases correlating with younger age, deeper cytopenia, lower dysplasia, and worse response to ESAs. A marker of autoimmunity was observed in 46% of the tested cases, who were younger, were less frequent dysplastic changes, and responded better to ESAs and steroids. Finally, 68% of the tested cases displayed at least one somatic mutation, most commonly SF3B1, TET2, ASXL1, and SRSF2, associated with older age, presence of neutropenia, and lower response to ESAs. Leukemic evolution (2.2%) was associated with presence of somatic mutations, and survival was favorably related to response to ESAs and transfusion independence. Overall, granular evaluation and re-evaluation are pivotal in LR-MDS patients to optimize clinical management.


Clinical Evaluation of Nuclear Imaging Agents in Breast Cancer.
Precision medicine is the customization of therapy for specific groups of patients using genetic or molecular profiling. Noninvasive imaging is one strategy for molecular profiling and is the focus of this review. The combination of imaging and therapy for precision medicine gave rise to the field of theranostics. In breast cancer, the detection and quantification of therapeutic targets can help assess their heterogeneity, especially in metastatic disease, and may help guide clinical decisions for targeted treatments. Positron emission tomography (PET) or single-photon emission tomography (SPECT) imaging has the potential to play an important role in the molecular profiling of therapeutic targets in vivo for the selection of patients who are likely to respond to corresponding targeted therapy. In this review, we discuss the state-of-the-art nuclear imaging agents in clinical research for breast cancer. We reviewed 17 clinical studies on PET or SPECT agents that target 10 different receptors in breast cancer. We also discuss the limitations of the study designs and of the imaging agents in these studies. Finally, we offer our perspective on which imaging agents have the highest potential to be used in clinical practice in the future.


Kainic acid may enhance hippocampal NO generation of awake rats in a seizure stage-related fashion.
Temporal changes in kainate-induced seizure activity and hippocampal NO generation were evaluated simultaneously in conscious rats by using in vivo microdialysis and by determining the concentrations of nitrite and nitrate in perfusates. Intraperitoneal injection of kainic acid produced 'wet dog shake', focal seizure of the limbs and neck, hypersalivation, or generalized convulsion. These behavioral changes peaked at 120 min after the drug challenge and lasted for about 100 min. In contrast, the concentrations of NO metabolites, nitrite and nitrate, in the hippocampal perfusates increased rapidly and reached a plateau level at 40 min after the injection, and the level remained high for over 220 min. The increase was more marked in animals presenting severe seizures than those presenting mild ones. Pre-treatment with 25 mg/kg N(G)-nitro-L-arginine methyl ester promoted the severity of kainate-induced seizures, but it suppressed the increase in NO metabolites. These results suggest that kainic acid enhances hippocampal NO generation in a severity-related manner of the induced seizures. The enhanced NO generation upon kainate challenge appears mainly to be involved in seizure suppression.


Hemodialysis trends in time, 1989 to 1998, independent of dose and outcome.
The 1989 Morbidity, Mortality, and Prescription of Dialysis Symposium (Dallas, TX) deeply modified the way of prescribing and delivering hemodialysis (HD) in the United States, as elsewhere. Among strategies emerging for end-stage renal disease treatment improvement, increasing the delivered dose has been the central issue, whereas the session time effect has remained an unsettled question. The purpose of this article is to analyze the trends in HD session time over the last decade in Tassin, France, and elsewhere and their relationship to outcome, independent of dialysis dose. The published data indicate that in the United States, there has been an increase in session time. Outside the United States, where session time had been somewhat longer, there has been either no change or a decrease in time without apparent ill effects. The dialysis dose, as measured by the urea Kt/V, has increased everywhere because improved technology allows for efficient toxin removal within a very short dialysis session. In Tassin, a recent limited experience of high-dose shortened dialysis did not show a significant short-term survival difference, but an impaired control of blood pressure (BP) and nutrition. Thus far, the highest HD long-term survival rates have been reported by the groups that used the largest doses and the longer times of HD. Effects of dose and time are, at this point, impossible to disentangle. A longer dialysis time improves extracellular volume (ECV) and BP control and decreases cardiovascular mortality. Shortening the HD session leads to impaired control of BP and increasing cardiovascular morbidity (by far the first cause of mortality on HD). In the future, the length of dialysis session should be governed by the demand of BP control.


Using visual speech at the cocktail-party: CNV evidence for early speech extraction in younger and older adults.
The comprehension of spoken language benefits from visual speech information. One reason for this is the temporal lead of mouth and lip movements over the onset of acoustic speech utterance. Here, we investigated EEG event-related potentials preceding acoustic speech, focusing on a fronto-central contingent negative variation (CNV) prior to the onset of acoustic speech. We explored influences of expectation and visual speech content as well as age-related differences. In a multi-talker two-alternative speech discrimination task, younger and older subjects responded to short words presented simultaneously to competing speech under free-field conditions. Subjects were always presented with audiovisual speech stimuli, while the modality containing the task-relevant information was modulated in a block-wise fashion. Thus, task-relevant speech information was either available as audio-visually congruent stimuli or only in the visual (visual-valid) or the auditory (auditory-valid) modality. Subjects were instructed to fixate a pre-specified position in the left or right hemispace. In each task block, task-relevant stimuli appeared either at the pre-specified position (standard trials, 80%) or at a rare deviant position (20%). Target words were recognized faster and more accurately when visual speech information was available. The CNV prior to the acoustic speech onset was more pronounced with visual-informative than with visually non-informative speech. Especially in the younger group, a less pronounced CNV occurred with purely visual speech in deviant trials, that is, when a task-irrelevant speech stimulus appeared instead of the expected target stimulus. The results indicate that processes preceding the onset of acoustic speech are modulated by expectations and visual speech content, while age differences are rather small.


Thermodiffusion of ions in nanoconfined aqueous electrolytes.
Understanding of thermal effects on ion transport in porous media is very important for environmental applications. The movement of ions along a temperature gradient is named thermophoresis or thermodiffusion. In nanoporous media, where the interaction of ions with solid-liquid interfaces has a significant influence on their migration, the theoretical understanding of thermodiffusion is still incomplete. Herein, we present experimental results for the thermodiffusion of cations in saturated nanoporous silica by the through-diffusion method. Both the experimental data and theoretical analysis indicate that the temperature-induced polarization of surface charges strongly influences ionic transport. Stated simply, the electric field in a liquid electrolyte confined in nanopores changes when the applied temperature gradients are altered, thereby affecting the motion of the nanoconfined ionic species. By applying an external temperature field, the gradient of the surface charge density leads to the charged aqueous species exhibiting strong temperature gradient-dependent electrophoretic mobility. When the thickness of the electrical double layer is comparable to the size of the nanopores, the theory used herein indicates that this kind of nonisothermal ionic mobility is up to one order of magnitude larger than classical thermophoretic mobility. This study improves the understanding of the underlying mechanisms that govern the transport of ions in nanoporous media, which could set the stage for diffusional metamaterials induced by specific thermal fields.


A quantitative polymerase chain reaction method for the detection in avian faeces of salmonellas carrying the spvR gene.
A quick, semi-quantitative method of detecting Salmonella species which contain the virulence plasmid has been developed using the polymerase chain reaction (PCR). A pair of primers have been synthesized encompassing a 500 bp fragment of the spvR virulence gene. Competitor DNA consisting of the spvR gene with a 94 bp deletion situated between the primer recognition sequences, was cloned into a plasmid vector. Co-amplification of the 'unknown' target salmonella DNA with known quantities of competitor DNA in the same reaction tube gave PCR products of 500 and 406 bp respectively. Visual assessment of the ratio of the two products on ethidium bromide stained agarose gels provided an estimate of the approximate number of salmonella cells present in avian faeces. The technique could be applied to detect quantifiably any non-host DNA in clinical samples if a suitable DNA sequence for primer construction is available.


A process evaluation: does recruitment for an exercise program through ethnically specific channels and key figures contribute to its reach and receptivity in ethnic minority mothers?
Ethnic minority women from low-income countries who live in high-income countries are more physically inactive than ethnic majority women in those countries. At the same time, they can be harder to reach with health promotion programs. Targeting recruitment channels and execution to ethnic groups could increase reach and receptivity to program participation. We explored using ethnically specific channels and key figures to reach Ghanaian, Antillean, and Surinamese mothers with an invitation for an exercise program, and subsequently, to determine the mothers' receptivity and participation. We conducted a mixed methods process evaluation in Amsterdam, The Netherlands. To recruit mothers, we employed ethnically specific community organizations and ethnically matched key figures as recruiters over Dutch health educators. Reach and participation were measured using reply cards and the attendance records from the exercise programs. Observations were made of the recruitment process. We interviewed 14 key figures and 32 mothers to respond to the recruitment channel and recruiter used. Content analysis was used to analyze qualitative data. Recruitment through ethnically specific community channels was successful among Ghanaian mothers, but less so among Antillean and Surinamese mothers. The more close-knit an ethnic community was, retaining their own culture and having poorer comprehension of the Dutch language, the more likely we were to reach mothers through ethnically specific organizations. Furthermore, we found that using ethnically matched recruiters resulted in higher receptivity to the program and, among the Ghanaian mothers in particular, in greater participation. This was because the ethnically matched recruiter was a familiar, trusted person, a translator, and a motivator who was enthusiastic, encouraging, and able to adapt her message (targeting/tailoring). Using a health expert was preferred in order to increase the credibility and professionalism of the recruitment. Recruitment for an exercise program through ethnically specific organizations seems to contribute to its reach, particularly in close-knit, highly organized ethnic communities with limited fluency in the local language. Using ethnically matched recruiters as motivator, translator, and trusted person seems to enhance receptivity of a health promotion program. An expert is likely to be needed for effective information delivery.


Genome Editing in Livestock, Complicity, and the Technological Fix Objection.
Genome editing in livestock could potentially be used in ways that help resolve some of the most urgent and serious global problems pertaining to livestock, including animal suffering, pollution, antimicrobial resistance, and the spread of infectious disease. But despite this potential, some may object to pursuing it, not because genome editing is wrong in and of itself, but because it is the wrong kind of solution to the problems it addresses: it is merely a 'technological fix' to a complex societal problem. Yet though this objection might have wide intuitive appeal, it is often not clear what, exactly, the moral problem is supposed to be. The aim of this paper is to formulate and shed some light on the 'technological fix objection' to genome editing in livestock. I suggest that three concerns may underlie it, make implicit assumptions underlying the concerns explicit, and cast some doubt on several of these assumptions, at least as they apply to the use of genome editing to produce pigs resistant to the Porcine Reproductive and Respiratory Syndrome and hornless dairy cattle. I then suggest that the third, and most important, concern could be framed as a concern about complicity in factory farming. I suggest ways to evaluate this concern, and to reduce or offset any complicity in factory farming. Thinking of genome editing's contribution to factory farming in terms of complicity, may, I suggest, tie it more explicitly and strongly to the wider obligations that come with pursuing it, including the cessation of factory farming, thereby addressing the concern that technological fixes focus only on a narrow problem.


Bcl-2 inhibits cell death of serum-free mouse embryo cells caused by epidermal growth factor deprivation.
SFME cells are brain-derived neural precursor cells that are acutely dependent on epidermal growth factor (EGF) for survival, undergoing apoptosis within 24 h after EGF withdrawal. Because the expression of the protooncogene bcl-2 inhibits apoptosis induced by the withdrawal of interleukins or nerve growth factor in some growth factor-dependent haematopoietic or neuronal cell cultures, we examined the effect of Bcl-2 expression on cell death of SFME cells in the absence of EGF. SFME cells expressing human Bcl-2 showed prolonged survival when deprived of EGF compared to control cells not expressing Bcl-2. A significant fraction of Bcl-2-expressing cells remained viable for 4 days in the absence of EGF and resumed proliferation upon readdition of EGF to the cultures. These results suggest that apoptosis induced by EGF withdrawal in SFME cells may share common mechanisms with other growth factor-related apoptotic systems.


Strong lymphoproliferative suppressive function of PLT clones specific for SB-like antigens.
From a total of 37 different priming combinations between donors matched for HLA-A,B, and/or Dw/DR, but mismatched for SB, antigens, T cell clones strongly restimulated with concordance for SB specificities were isolated from only two. Most of the alloproliferative (PLT) clones obtained were restimulated by determinants not correlated with any currently known HLA product. Nonetheless, their stimulation was inhibited by a monoclonal antibody TU 39, which preferentially blocks stimulation by SB-, rather than by Dw/DR-associated determinants. Despite having an OKT4+, OKT-, Leu8- phenotype, and secreting Interleukin-2 after contact with stimulatory cells, these clones strongly suppressed proliferative responses of cloned PLT reagents as well as unprimed lymphocytes in mixed leukocyte cultures. They may thus represent a novel type of immunoregulatory T cell, stimulated by SB-related antigens, which despite their "helper/inducer" phenotype are able directly to suppress lymphoproliferative responses.


Characterization of ASKP1240, a fully human antibody targeting human CD40 with potent immunosuppressive effects.
Blocking the CD40-CD154 interaction is reported to be effective for transplantation management and autoimmune disease models in rodents and nonhuman primates. However, clinical trials with anti-CD154 mAbs were halted because of high incidence of thromboembolic complications. Thus, we generated and characterized a fully human anti-CD40 mAb ASKP1240, as an alternative to anti-CD154 mAb. In vitro ASKP1240 concentration-dependently inhibited human peripheral blood mononuclear cell proliferation induced by soluble CD154. In addition, ASKP1240 did not destabilize platelet thrombi under physiological high shear conditions while mouse anti-human CD154 mAb (mu5C8) did. And ASKP1240 itself did not activate platelet and endothelial cells. In vivo administration of ASKP1240 (1 or 10 mg/kg, intravenously) to cynomolgus monkeys, weekly for 3 weeks, significantly attenuated both delayed-type hypersensitivity and specific antibody formation evoked by tetanus toxoid. The immunosuppressive effect was well correlated with the CD40 receptor saturation. Thus, these results suggest that ASKP1240 is immunosuppressive but not prothromboembolic, and as such appears to be a promising therapeutic candidate for the management of solid organ transplant rejection and autoimmune diseases therapy.


Probability of target recollection varies with target-lure relatedness under the dual process signal detection model.
The ROC function plots hit and false alarm rates against one another. For item recognition the z-transformed ROC (Z-ROC) function is typically linear with slope less than one. The Dual Process Signal Detection (DPSD) and Unequal Variance Signal Detection (UVSD) models see the slope as reflecting the ratio of the lure and target evidence standard deviations. The DPSD model in addition sees the slope as co-varying with estimates of target recollection probability (R). This follows because the slope decreases with increases in the target evidence standard deviation which in turn increases with increases in the numbers of high evidence recollection items. However our results suggest that the lure evidence standard deviation, and thus the Z-ROC slope, can vary with factors seemingly unrelated to target recollection, posing problems for DPSD estimates of R. In word recognition the standard deviation of lure confidence ratings and the slope of the z-ROC function were larger with semantically related than unrelated lures. When the data for related and unrelated lures were fit separately, the standard two-parameter DPSD model, implausibly, set R lower for related than unrelated lures. The UVSD model, more plausibly, set the lure evidence standard deviation larger for related than unrelated lures.


RhoA/ROCK-dependent moesin phosphorylation regulates AGE-induced endothelial cellular response.
The role of advanced glycation end products (AGEs) in the development of diabetes, especially diabetic complications, has been emphasized in many reports. Accumulation of AGEs in the vasculature triggers a series of morphological and functional changes in endothelial cells (ECs) and induces an increase of endothelial permeability. This study was to investigate the involvement of RhoA/ROCK-dependent moesin phosphorylation in endothelial abnormalities induced by AGEs. Using human dermal microvascular endothelial cells (HMVECs), the effects of human serum albumin modified-AGEs (AGE-HSA) on the endothelium were assessed by measuring monolayer permeability and staining of F-actin in HMVECs. Activations of RhoA and ROCK were determined by a luminescence-based assay and immunoblotting. Transfection of recombinant adenovirus that was dominant negative for RhoA (RhoA N19) was done to down-regulate RhoA expression, while adenovirus with constitutively activated RhoA (RhoA L63) was transfected to cause overexpression of RhoA in HMVECs. H-1152 was employed to specifically block activation of ROCK. Co-immunoprecipitation was used to further confirm the interaction of ROCK and its downstream target moesin. To identify AGE/ROCK-induced phosphorylation site in moesin, two mutants pcDNA3/HA-moesinT(558A) and pcDNA3/HA-moesinT(558D) were applied in endothelial cells. The results showed that AGE-HSA increased the permeability of HMVEC monolayer and triggered the formation of F-actin-positive stress fibers. AGE-HSA enhanced RhoA activity as well as phosphorylation of ROCK in a time- and dose-dependent manner. Down-regulation of RhoA expression with RhoA N19 transfection abolished these AGE-induced changes, while transfection of RhoA L63 reproduced the AGE-evoked changes. H-1152 attenuated the AGE-induced alteration in monolayer permeability and cytoskeleton. The results also confirmed the AGE-induced direct interaction of ROCK and moesin. Thr558 was further identified as the phosphorylating site of moesin in AGE-evoked endothelial responses. These results confirm the involvement of RhoA/ROCK pathway and subsequent moesin Thr558 phosphorylation in AGE-mediated endothelial dysfunction.


Interactions between a cavitation bubble and solidification front under the effects of ultrasound: Experiments and lattice Boltzmann modeling.
The phenomena of melting and dendritic fragmentation are captured by using an in-situ device during the ultrasound-assisted solidification of a succinonitrile-acetone (SCN-ACE) alloy. The experimental results show that the dendrite arms detach from primary trunk due to the melting of the solid phase, which is caused by a moving ultrasound cavitation bubble. To quantify the interactions between the ultrasound cavitation bubble and the solidification front, a coupled lattice Boltzmann (LB) model is developed for describing the fields of temperature, flow, and solid fraction, and their interactions. The multi-relaxation-time (MRT) scheme is applied in the LB model to calculate the liquid-gas flow field, while the Bhatnagar-Gross-Krook (BGK) equation is executed to simulate the evolution of temperature. The kinetics of solidification and melting are calculated according to the lever rule based on the SCN-ACE phase diagram. After the validation of the LB model by an analytical model, the morphologies of the cavitation bubble and solidification front are simulated. It is revealed that the solidification interface melts due to the increase of the temperature nearby the cavitation bubble in ultrasonic field. The simulated morphologies of the cavitation bubble and solidification front are compared well with the experimental micrograph. Quantitative investigations are carried out for analyzing the melting rate of the solidification front under different conditions. The simulated data obtained from LB modeling and theoretical predictions reasonably accord with the experimental results, demonstrating that the larger the ultrasonic intensity, the faster the melting rate. The present study not only reveals the evolution of the solidification front shape caused by the cavitation bubbles, which is invisible in the ultrasound-assisted solidification process of practical alloys, but also reproduces the complex interactions among the temperature field, acoustic streaming, and multi-phase flows.


Upfront Small Bowel Resection for Small Bowel Neuroendocrine Tumors With Synchronous Metastases: A Propensity-score Matched Comparative Population-based Analysis.
We examined the impact of upfront small bowel resection (USBR) for metastatic small bowel neuroendocrine (SB-NET) compared to nonoperative management (NOM) on long-term healthcare utilization and survival outcomes. The role of early resection of the primary tumor in metastatic SB-NET remains controversial. Conflicting data exist regarding its clinical and survival benefits. This is a population-based retrospective matched comparative cohort study of adults diagnosed with synchronous metastatic SB-NET between 2001 and 2017 in Ontario. USBR was defined as resection within 6 months of diagnosis. Primary outcomes were subsequent unplanned acute care admissions and small bowel-related surgery. Secondary outcome was overall survival. USBR and NOM patients were matched 2:1 using a propensity-score. We used time-to-event analyses with cumulative incidencefunctions and univariate Andersen-Gill regression for primary outcomes. E value methods assessed the potential for residual confounding. Of 1000 patients identified, 785 had USBR. The matched cohort included 348 patients with USBR and 174 with NOM. Patients with USBR had lower 3-year risk of subsequent admissions (72.6% vs 86.4%, P < 0.001) than those with NOM, with hazard ratio 0.72 (95% confidence interval 0.570.91). USBR was associated with lower risk of subsequent small bowel-related surgery (15.4% vs 40.3%, P < 0.001), with hazard ratio 0.44 (95% confidence interval 0.29-0.67). E -values indicated it was unlikely that the observed risk estimates could be explained by an unmeasured confounder. Sensitivity analysis excluding emergent resections to define USBR did not alter the results. USBR for SB-NETs in the presence of metastatic disease was associated with better patient-oriented outcomes of decreased subsequent admissions and interventions, compared to NOM. USBR should be considered for metastatic SB-NETs.


Evaluation of platelet parameters, coagulation markers, antiphospholipid syndrome, and thyroid function in palestinian women with recurrent pregnancy loss.
Multiple etiologies contribute to recurrent pregnancy loss (RPL) including immunological, endocrine, anatomical, genetic and infection but more than 50% of cases remain unexplained. Evidences of thrombotic and inflammatory processes were observed at maternal-fetal interface and considered pathological findings in most RPL cases including unexplained cases. This study aimed to evaluate the association between RPL and several risk factors: platelet parameters, coagulation factors, antiphospholipid syndrome, and thyroid function. This is an unmatched case-control study that included 100 RPL and 100 control women. Anthropometric and health data were collected and a gynecologist examined participants to assure fitting the inclusion criteria. Platelet parameters [including Mean Platelet Mass (MPM), Concentration (MPC) and Volume (MPV)] and ratios (MPV/Platelet, MPC/Platelet, MPM/Platelet, Platelet/Mononuclear cells), coagulation markers [Protein C (PC), Protein S (PS), Antithrombin III, D-dimer], antiphospholipid antibodies [Anti-phospholipid (APA), Anti-cardiolipin (ACA) and anti-B2-glycoprotein 1], Lupus anticoagulant, Antinuclear antibodies, and thyroid function (Thyroid stimulating hormone and anti-thyroid peroxidase) were measured. Mean ages of cases and controls at marriage were 22.5 years for both, and their current ages were 29.4 and 33.0, respectively. 92% of cases and 99% of controls aged blow 30 years at marriage. 75% of cases have 3-4 miscarriages and 9% have ≥ 7 miscarriages. Our results indicated significantly lower male/female age ratio (p = .019), PC (p = .036) and PS (p = .025) in cases compared to controls. Plasma D-dimer (p = .020) and antiphospholipid antibodies [ACA (IgM and IgG), APA (IgM)] were significantly higher in cases compared to controls. No significant differences were observed between cases and controls concerning APA (IgG), anti-B2-glycoprotein 1 (IgM and IgG), Lupus anticoagulant, Antinuclear antibodies, platelet parameters, thyroid markers, family history of miscarriage, consanguineous marriage, and other health data. This is the first study that investigated the association between platelet, coagulation, antiphospholipid, autoimmune and thyroid parameters, and RPL in Palestinian women. Significant associations between male/female age ratio, PC, PS, D-dimer, ACA (IgM, IgG), APA (IgM) and RPL were observed. These markers could be used in evaluating RPL. These findings confirm the heterogeneous nature of RPL and emphasize the need for further studies to find out risk factors for RPL.


New combinations for six species belonging to Cryptotympanini Handlirsch (Hemiptera: Cicadidae), former members of the genus Tibicen Latreille, 1825.
The generic status of several species formerly placed in the genus Tibicen is reconsidered based on the recent erection of new genera as well as historical evidence. Subsolanus Moulds, 2015 syn. nov. is shown to be a junior synonym of Auritibicen Lee, 2015. Six species are reassigned from Tibicen to appropriate genera based on morphological characteristics.