[Gender and cardiovascular diseases : Why we need gender medicine].
Gender medicine is concerned with the question of why diseases are expressed differently in the genders. It takes differences between men and women into account, which are often neglected by traditional medicine. Sex differences can also be found in cardiovascular diseases; therefore, risk factors for cardiovascular diseases have a different significance depending on the sex. Diabetic diseases tend to promote the occurrence of coronary heart disease (CHD) more strongly in women than in men. Myocardial infarctions affect women 10 years later than men and young women are often treated too late, possibly because myocardial infarction is consider to be a "male disease". The number of cases of coronary syndrome is significantly increasing, particularly in young women. Some of the diseases which predominantly occur in women are takotsubo cardiomyopathy, microcirculation disorders and spontaneous coronary artery dissection. Pharmacological treatment of CHD is principally the same in men and women but attention must be paid to differences in the pharmacokinetics of important drugs. Coronary dilatation has comparable effects in both men and women but more complications occur in women. Cardiac failure with impaired left ventricular systolic function affects more men than women in the Western world but the opposite is true for cardiac failure with preserved left ventricular ejection fraction. Hypertrophic and dilatative cardiomyopathies are more frequent in men. Many of the drugs used to treat cardiac failure have different actions in men and women. Too little attention is paid to the pharmacokinetics and pharmacodynamics in women when testing active agents; however, awareness of the differences that need to be considered is growing.


Oxidized dextran as crosslinker for chitosan cryogel scaffolds and formation of polyelectrolyte complexes between chitosan and gelatin.
Macroporous scaffolds composed of chitosan and using oxidized dextran as a crosslinker are produced through cryogelation. Introducing gelatin as a third component into the structure results in the formation of mesopores in the pore walls, which are not seen if gelatin is excluded. The mesoporous structure is explained by the formation of polyelectrolyte complexes between chitosan and gelatin before crosslinking takes place. The scaffolds exhibit highly elastic properties withstanding compressions up to 60%. The in vitro biocompatibility of the cryogels is evaluated using fibroblasts from a mouse cell line (L929) and it is seen that the cells adhere and proliferate on the scaffolds. The mesoporous structure seems to have a positive effect on proliferation.


Chemotherapy improves thymoma-associated graft-versus-host-disease-like erythroderma.
Graft-versus-host-disease (GVHD) with erythroderma can rarely occur in the context of thymoma and is associated with a poor prognosis due to an increased risk of infection-related death. The present study describes a case of a 50-year-old man with malignant thymoma who developed sepsis in addition to skin manifestations similar to that seen in GVHD. This patient experienced marked improvement in skin lesions in response to steroids and combination chemotherapy with carboplatin and paclitaxel, with subsequent resolution of infection. The present study describes the clinical course of this patient, followed by a review of pertinent reports of thymoma associated with GVHD with particular focus on the efficacy of treatment strategies.


Influence of steroids on the hypothalamic corticotropin-releasing factor and preproenkephalin mRNA responses to stress.
We have used in situ hybridization histochemistry to investigate the influence of both circulating corticosteroids and the stress paradigm of i.p. hypertonic saline on the levels of mRNAs encoding corticotropin-releasing factor (CRF) and preproenkephalin in parvocellular neurons of the rat hypothalamus. Stress increased both CRF and preproenkephalin mRNAs, whereas adrenalectomy increased only CRF mRNA. After adrenalectomy, even when CRF mRNA had reached peak levels, stress still further increased CRF mRNA and caused an exaggerated rise in preproenkephalin mRNA. Dexamethasone administration in the fast or intermediate-feedback time domains had no effect on CRF or preproenkephalin mRNA responses to stress; however, when administered over a longer period of time in the slow-feedback time domain dexamethasone reduced basal CRF mRNA levels and the stress-stimulated levels of CRF and preproenkephalin mRNA. These results show that different stimuli to the parvocellular paraventricular hypothalamus differentially regulate CRF transcript levels. Furthermore, in spite of the lack of any detectable effect of changes in circulating glucocorticoid levels on basal levels of preproenkephalin mRNA, glucocorticoids markedly alter the preproenkephalin mRNA response to stress.


Dissociations between behavioural recovery and restoration of vestibular activity in the unilabyrinthectomized guinea-pig.
1. In the guinea-pig, a unilateral labyrinthectomy induces postural disturbances and an ocular nystagmus which abate or disappear over time. These behavioural changes are accompanied by an initial collapse and a subsequent restoration of the spontaneous activity in the neurones of the ipsilateral vestibular nuclei. Recently, it has been shown that the vestibular neuronal activity remained collapsed over at least 10 h whereas its restoration was complete 1 week after the lesion. The aims of this study were to determine when restoration of spontaneous activity in the partially deafferented vestibular neurones started and to compare the time courses of the behavioural and neuronal recoveries in guinea-pigs that had undergone a unilateral labyrinthectomy. 2. Neuronal discharge measurements were made using chronic extracellular recording of single unit activity. After a left labyrinthectomy, electrodes, were placed on the site of the destroyed labyrinth to enable stimulation of the left vestibular nerve. Behavioural measurements included chronic recording of eye movements by the scleral search coli technique. After a left labyrinthectomy, lateral deviation of the head, twisting of the head, and eye velocity of the slow phases of the nystagmus were measured. 3. The neuronal activity of the rostral part of the vestibular nuclear complex on the lesioned side was recorded in alert guinea-pigs over 4 h recording sessions between 12 and 72 h after the lesion. 4. The criterion used to select vestibular neurones for analysis was their recruitment by an electric shock on the vestibular nerve. In addition, in order to explore a uniform population, we focused on neurones recruited at monosynaptic latencies (0.85-1.15 ms). 5. For each recording period, the mean resting rate was calculated animal by animal and the grand mean of these individual resting rate means was calculated. Previously, a decline in the grand mean resting rate from 35.8 +/- 6.0 spikes s-1 (control state) to 7.1 +/- 4.2 spikes s-1 during the first 4 h after labyrinthectomy has been shown. In the present study, the first sign of recovery was observed during the 12-16 h recording period when the resting rate grand mean increased to 16.3 +/- 3.9 spikes s-1. This grand mean activity did not change significantly during the following 12 h. Thereafter, restoration of neuronal activity improved and was complete 1 week after the lesion. 6. Although the abatement of the vestibular symptoms roughly paralleled the restoration of neuronal activity in the vestibular nuclei, some discrepancies between the time courses of both phenomena emerged. An important step in postural recovery (the animals managed to stand up) and a major part of the abatement of the nystagmus occurred before the recovery of vestibular neuronal activity. In addition, lateral deviation of the head disappeared while restoration of the neuronal activity was incomplete, but significant head twisting was still evident when vestibular resting rates had recovered completely. 7. We conclude that restoration of neuronal activity in the ipsilateral vestibular nuclei starts 12 h after the lesion and that restoration of neuronal activity in the ipsilateral vestibular nuclei is not the only mechanism underlying behavioural vestibular compensation.


The protective influence of the locus ceruleus on the blood-brain barrier.
The functions of the putative noradrenergic innervation of cerebral microvessels from the nucleus locus ceruleus remain ambiguous. Although most evidence indicates that such innervation does not have a major role in the control of cerebral blood flow, there are increasing indications that it modulates transport and permeability functions of the blood-brain barrier. In this study we investigated the effect of unilateral chemical lesioning of the locus ceruleus on the leakage of radioiodinated human serum albumin across the blood-brain barrier. Experiments were performed in awake and restrained rats under steady-state conditions and during drug-induced systemic arterial hypertension, and in anesthetized and paralyzed rats during bicuculline-induced seizures. Both hypertension and seizures are known to be associated with increased leakage of macromolecules across the blood-brain barrier. Albumin leakage into norepinephrine-depleted forebrain structures ipsilateral to the locus ceruleus lesion was compared with that of the contralateral side. There were no side-to-side differences in blood-brain barrier permeability to albumin under steady-state conditions, the stress of restraint, or angiotensin-induced hypertension, or after isoproterenol administration. Norepinephrine-induced hypertension and seizures, however, caused significant increases in albumin leakage into forebrain structures ipsilateral to the lesion. These results suggest that noradrenergic innervation of cerebral microvessels from the locus ceruleus helps preserve the integrity of the blood-brain barrier during pathophysiological states associated with hypertension and increased circulating catecholamines.


Biological features, distribution, and conservation of the near-threatened Gangetic leaf fish Nandus nandus (Hamilton, 1822): A review.
Nandus nandus (Hamilton, 1822) is a small indigenous species (SIS) and commercially important food fish found in Bangladesh, India, Nepal, Pakistan, Myanmar, and Thailand. Concerns have arisen due to the gradual decline in its abundance, reflected by poor catches and limited availability of this species in local markets. Habitat loss and overexploitation pose significant threats to this species, leading to its classification as near threatened by the IUCN Bangladesh. Despite the absence of dedicated conservation efforts for N. nandus in Indian subcontinent, this study aims to investigate the species' biology, ecology, distribution within the country and globally, as well as its threats, conservation strategies, and research needs. Additionally, a proposed conservation framework for this near-threatened species is presented, which can be adapted for implementation in other nations facing similar challenges.


FBXO5 acts as a novel prognostic biomarker for patients with cervical cancer.
Background: Cervical cancer (CC) remains one of the most common and deadly malignancies in women worldwide. FBXO5, a protein-coding gene, is highly expressed in a variety of primary tumors and promotes tumor progression, however, its role and prognostic value in CC remain largely unknown. Methods: A key differential gene, FBXO5, was screened according to WGCNA based on immunohistochemical assays of clinical samples, multiple analyses of the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, including survival analysis, tumor mutational burden, GO, KEGG, tumor immune infiltration, and chemotherapeutic drug sensitivity, to explore the expression and prognostic value of FBXO5 in CC. The migration and invasiveness of cervical cancer cells following FBXO5 knockdown and overexpression were examined using wound healing and transwell assays, and the viability of cancer cells was assessed using CCK8 and EdU assays. Results: FBXO5 was discovered to be substantially expressed in CC tissues using data from our CC cohort and the TCGA database, and a survival analysis indicated FBXO5 as a predictive factor for poor overall survival in CC patients. In vitro, CC cells were more inclined to proliferate, migrate, and invade when FBXO5 was upregulated as opposed to when it was knocked down.


[Diagnostic strategy of the liver and bile ducts].
The diagnosis of gallbladder and liver diseases depends primarily on noninvasive techniques (ultrasound and computer tomogram). Gallstones can be detected by ultrasonography in more than 90% of such patients and this is a sufficient indication for operation. The preoperative diagnosis of stones of the biliary tract by sonography is however, unreliable. Even a preoperative endoscopic retrograde cholangio-pancreaticography cannot justify foregoing an intraoperative cholangiogram. Detection of metastasis is still a problem in the diagnosis of liver tumors. Further developments in computed tomogram and scintigram techniques, however, promise improvements.


Dietary homogenization and spatial distributions of carbon, nitrogen, and sulfur isotope ratios in human hair in South Korea.
Dietary homogenization has progressed worldwide due to westernization and the globalization of food production systems. We investigated dietary heterogeneity in South Korea by examining the spatial distribution of carbon (C), nitrogen (N), and sulfur (S) isotope ratios using 264 human hair samples. Overall, variation in isotope values was small, indicating low dietary heterogeneity. We detected differences in δ13C, δ15N, and δ34S values between administrative provinces and metropolitan cities; inter-regional differences were typically < 1 ‰. Values of δ34S were significantly lower in hair samples from inland regions relative to those from coastal locations, and a similar pattern was observed in δ15N values. Understanding geographic variation in δ34S and δ15N values in human hair is useful for provenancing humans in South Korea.


Gender differences in attitudes toward alcohol, tobacco, and other drugs.
A number of differences exist between men and women in use patterns and risk factors for substance abuse. In recent years these differences have received increased attention; however, gender-related attitudes toward substance abuse need additional study. This study examines gender-related differences in beliefs about the causes of the abuse of alcohol, tobacco, and other drugs; the power of various substances of abuse; the prevalence of substance use; and the effectiveness of various interventions. Women were more likely to attribute causality to biological or environmental factors, to perceive drugs as more powerful, to perceive a higher incidence of substance abuse, and to believe prevention and treatment were more effective. Therefore, prevention, assessment, and treatment programs should be designed differently for women than for men.


A durable response to programmed cell death 1 blockade in a multidrug-resistant recurrent ovarian cancer patient with HLA-B44 supertype: A case report.
Relapsed/refractory ovarian cancer, especially platinum resistance recurrence, remains a major therapeutic challenge. Here, we present the case of a patient with recurrent ovarian clear cell carcinoma (OCCC) who failed to respond to multiline chemotherapy and target therapy but achieved an immune complete response (iCR) with programmed cell death 1 (PD-1) inhibitor treatment. The overall survival (OS) was 59 months, and the recurrence-free survival (RFS) was 34 months after immunotherapy, which was counting. Meantime, molecular testing results revealed that traditional biomarkers for immunotherapy, including PD-L1 expression, microsatellite instability (MSI), and tumor mutational burden (TMB), were negative. HLA-B44 (B*18:01) supertype was confirmed by sequence-based HLA typing. This case raises the possibility that ovarian cancer patients with multidrug resistance may still benefit from PD-1 inhibitor therapy, even if PD-L1 pathology is negative.


ipRGCs: possible causation accounts for the higher prevalence of sleep disorders in glaucoma patients.
Sleep accounts for a third of one's lifetime, partial or complete deprivation of sleep could elicit sever disorders of body function. Previous studies have reported the higher prevalence of sleep disorders in glaucoma patients, but the definite mechanism for this phenomenon is unknown. On the other hand, it is well known by us that the intrinsically photosensitive retinal ganglion cells (ipRGCs) serve additional ocular functions, called non-image-forming (NIF) functions, in the regulation of circadian rhythm, melatonin secretion, sleep, mood and others. Specifically, ipRGCs can directly or indirectly innervate the central areas such as suprachiasmatic nucleus (SCN), downstream pineal gland (the origin of melatonin), sleep and wake-inducing centers and mood regulation areas, making NIF functions of ipRGCs relate to sleep. The more interesting thing is that previous research showed glaucoma not only affected visual functions such as the degeneration of classical retinal ganglion cells (RGCs), but also affected ipRGCs. Therefore, we hypothesize that higher prevalence of sleep disorders in glaucoma patients maybe result from the underlying glaucomatous injuries of ipRGCs leading to the abnormalities of diverse NIF functions corresponding to sleep.


A low-cost, highly functional, emergency use ventilator for the COVID-19 crisis.
Respiratory failure complicates most critically ill patients with COVID-19 and is characterized by heterogeneous pulmonary parenchymal involvement, profound hypoxemia and pulmonary vascular injury. The high incidence of COVID-19 related respiratory failure has exposed critical shortages in the supply of mechanical ventilators, and providers with the necessary skills to treat. Traditional mass-produced ventilators rely on an internal compressor and mixer to moderate and control the gas mixture delivered to a patient. However, the current emergency has energized the pursuit of alternative designs, enabling greater flexibility in supply chain, manufacturing, storage, and maintenance considerations. To achieve this, we hypothesized that using the medical gasses and flow interruption strategy would allow for a high performance, low cost, functional ventilator. A low-cost ventilator designed and built-in accordance with the Emergency Use guidance from the US Food and Drug Administration (FDA) is presented wherein pressurized medical grade gases enter the ventilator and time limited flow interruption determines the ventilator rate and tidal volume. This simple strategy obviates the need for many components needed in traditional ventilators, thereby dramatically shortening the time from storage to clinical deployment, increasing reliability, while still providing life-saving ventilatory support. The overall design philosophy and its applicability in this new crisis is described, followed by both bench top and animal testing results used to confirm the precision, safety and reliability of this low cost and novel approach to mechanical ventilation. The ventilator meets and exceeds the critical requirements included in the FDA emergency use guidelines. The ventilator has received emergency use authorization from the FDA.


Infliximab treatment in psoriatic arthritis: our experience.
The aim of this work was to give clinical practice recommendations on the use of tumour necrosis factor blocking agents in psoriatic arthritis, underlining the pathogenetic mechanism of this condition and its articular and dermatologic manifestations. We retrace the stages leading to the therapeutic indications of biological agents that are presently used in the treatment of psoriatic arthritis: Entanercept, Adalimumab, Infliximab. We also report our personal experience describing an emblematic case of a patient with psoriatic arthritis in which a decisive regression of joint/skin involvement was obtained with Infliximab treatment.


Direct measurement of the spatial-spectral structure of waveguided parametric down-conversion.
We present a study of the propagation of higher-order spatial modes in a waveguided parametric down-conversion photon-pair source. Observing the multimode photon-pair spectrum from a periodically poled KTiOPO(4) waveguide allowed us to isolate individual spatial modes through their distinctive spectral properties. We have measured directly the spatial distribution of each mode of the photon pairs, confirming the findings of our waveguide model, and demonstrated by coincidence measurements that the total parity of the modes is conserved in the nonlinear interaction. Furthermore, we show that we can combine the advantages of a waveguide source with the potential to generate spatially entangled photon pairs as in bulk-crystal down-converters.


Adsorption and desorption characteristics of adlay bran free phenolics on macroporous resins.
In this study, the adsorption and desorption characteristics of six macroporous resins including XAD-7HP, XAD-16, HP-20, HP-2MGL, SP-207 and SP-825 for enrichment of adlay bran free phenolics were studied. XAD-16, SP-207 and SP-825 were chosen for further study due to their strong adsorption and desorption capacities. XAD-16, SP-207 and SP-825 had similar phenolics adsorption/desorption behaviors. Pseudo-second-order kinetics model and Freundlich isotherm model were suitable for describing the whole exothermic and physical adsorption processes of adlay bran free phenolics on XAD-16, SP-207 and SP-825. After treatment with gradient elution on XAD-16 resin column, the free phenolics were mostly enriched (from 89.61 to 1015.26mg/100g) in 50% ethanol fraction. The oxygen radical absorbance capacity of 50% ethanol fraction was eight times higher than that of the crude extract. Therefore, the production of highly concentrated phenolics might expand the application of adlay bran used as a bioactive ingredient in functional food.


Unilateral "vanishing psoas": an anatomic variant.
We report five patients found to have obvious asymmetry of the psoas muscles on abdominal computed tomography (CT) examination. In all five patients, the upper portion of the psoas muscle was normal, but the lower portion was significantly reduced in size. In no patient was there neurological or other disease that might explain this finding. No patient exhibited signs or symptoms secondary to psoas asymmetry. Asymmetry of the psoas musculature is apparently a benign anatomical variant that may be recognized on CT examination and must be differentiated from pathological conditions.


Plasma protein adsorption patterns on emulsions for parenteral administration: establishment of a protocol for two-dimensional polyacrylamide electrophoresis.
The two-dimensional polyacrylamide electrophoresis (2-D PAGE) of the plasma protein adsorption pattern previously established for polymeric nanoparticles was modified and transferred to oil in water emulsions for intravenous administration. The emulsions were incubated with citrated plasma, and separation from excess plasma was performed by centrifugation under optimized conditions: 15000 g and three washing steps with 0.05 M phosphate buffer, pH 7.4. With this sample preparation, coalescence of droplets could be avoided and an unchanged surface area maintained, in addition the phosphate buffer minimized artificial IgG adsorption. Critical factors affecting sensitivity were contamination of the sample by oil residues and the use of thiourea in the immobilized pH gradients. Changes in the protein adsorption pattern caused by altered surface properties of the emulsion (i.e. adsorbed Poloxamer 407) were detectable when applying the optimized protocol. Knowledge of the protein adsorption patterns and their correlation to in vivo behavior opens the perspective for the development of intravenous emulsions for controlled drug delivery.


Multizone and transition zone photorefractive keratectomy for high myopia.
Variations in ablation profile may alter the stability of refraction and cause adverse effects in photorefractive keratectomy. We compared the benefits of multizone and transition zone ablation in the treatment of high and extreme myopia. A scanning excimer laser system, Nidek EC-5000 was used with three-zone treatment and our results were compared retrospectively with results obtained in a group with a conventional ablation profile using a transition zone. Six-month follow-up data were available for 65 eyes with a transition zone and 46 eyes with three-zone treatment. Postoperative mean (+/- SD) healing time was 2.98 days (+/- 0.12) and 3.02 days (+/- 0.15) and night vision disturbances were 16% and 11.5% respectively, (p > 0.05). Refractive regression was also similar in the two groups; uncorrected visual acuity of 20/40 or better was 90.77% and 89.14%. At 6 months postoperatively, the mean (+/- SD) corneal clarity score was 0.61 (+/- 0.29) in the transition zone group, and 0.51 (+/- 0.07) in the multizone group (p < 0.05). No discernible differences between treatments were found in either epithelial healing or refractive outcome, such as regression, between the groups. Corneal haze was less in eyes treated with three-zone ablation.


Towards design principles for optimal transport networks.
We investigate the navigation problem in lattices with long-range connections and subject to a cost constraint. Our network is built from a regular two-dimensional (d=2) square lattice to be improved by adding long-range connections (shortcuts) with probability P(ij) approximately r(ij)(-alpha), where r(ij) is the Manhattan distance between sites i and j, and alpha is a variable exponent. We introduce a cost constraint on the total length of the additional links and find optimal transport in the system for alpha=d+1 established here for d=1 and d=2. Remarkably, this condition remains optimal, regardless of the strategy used for navigation, being based on local or global knowledge of the network structure, in sharp contrast with the results obtained for unconstrained navigation using global or local information, where the optimal conditions are alpha=0 and alpha=d, respectively. The validity of our results is supported by data on the U.S. airport network.


A kinetic study of the rat liver adenosine kinase reverse reaction.
Adenosine kinase is an enzyme catalyzing the reaction: adenosine + ATP --> AMP + ADP. We studied some biochemical properties not hitherto investigated and demonstrated that the reaction can be easily reversed when coupled with adenosine deaminase, which transforms adenosine into inosine and ammonia. The overall reaction is: AMP + ADP --> ATP + inosine + NH(3). The exoergonic ADA reaction shifts the equilibrium and fills the energy gap necessary for synthesis of ATP. This reaction could be used by cells under particular conditions of energy deficiency and, together with myokinase activity, may help to restore physiological ATP levels.


Pantoea Species Bacteremia in a Child With Sickle Cell Disease: Looking for a Culprit.
Pantoea agglomerans has been classically associated with cellulitis or synovitis secondary to penetrating trauma by vegetation. It is an infrequent cause of systemic infections. We describe the case of a 5-year-old girl with sickle cell disease with P. agglomerans bacteremia and review its potential causes.


Characterization of delta 9 acyl-lipid desaturase homologues from Arabidopsis thaliana.
Two cDNAs, ADS1 and ADS2, were isolated from Arabidopsis. These cDNAs encoded proteins homologous to delta 9 acyl-lipid desaturases of cyanobacteria and acyl-CoA desaturases of yeast and mammals. The expression of ADS1 and ADS2 was organ-dependent. Cold temperature up-regulated the ADS2 expression, whereas it down-regulated the ADS1 expression.


Ileocolic junction resection in dogs and cats: 18 cases.
There is limited veterinary literature about dogs or cats with ileocolic junction resection and its long-term follow-up. To evaluate the long-term outcome in a cohort of dogs and cats that underwent resection of the ileocolic junction without extensive (≥50%) small or large bowel resection. Medical records of dogs and cats that had the ileocolic junction resected were reviewed. Follow-up information was obtained either by telephone interview or e-mail correspondence with the referring veterinary surgeons. Nine dogs and nine cats were included. The most common cause of ileocolic junction resection was intussusception in dogs (5/9) and neoplasia in cats (6/9). Two dogs with ileocolic junction lymphoma died postoperatively. Only 2 of 15 animals, for which long-term follow-up information was available, had soft stools. However, three dogs with suspected chronic enteropathy required long-term treatment with hypoallergenic diets alone or in combination with medical treatment to avoid the development of diarrhoea. Four of 6 cats with ileocolic junction neoplasia were euthanised as a consequence of progressive disease. Dogs and cats undergoing ileocolic junction resection and surviving the perioperative period may have a good long-term outcome with mild or absent clinical signs but long-term medical management may be required.


Placental basement membrane proteins are required for effective cytotrophoblast invasion in a three-dimensional bioprinted placenta model.
Fetal cytotrophoblast invasion of maternal decidual vasculature is necessary to normal pregnancy. In preeclampsia, there is shallow invasion and abnormal remodeling of the uterine vasculature that lead to significant maternal and perinatal morbidity and mortality. The placental basement membrane (BM) proteins (e.g., laminin and collagen) has been implicated in the development of placenta while the level of laminin is significantly lower in preeclampsia. However, there are very limited studies, if any, on the effect of extracellular matrix (ECM) microenvironment on the invasion of cytotrophoblast. In this study, we hypothesized that placental BM proteins are required for effective cytotrophoblast invasion. Using proteomics, we found that more than 80% of ECM proteins in placental basal plate (pECM) were BM proteins. In addition to upregulating expressions of MMP2 (1.5-fold) and MMP9 (6.3-fold), pECM significantly increased the motility rates of cytotrophoblasts by 13-fold (from 5.60 ± 0.95 to 75.5 ± 21.8 µm/day) to achieve an effective invasion rate that was comparable to in vivo results. Treatments with PI3K inhibitors completely removed the pECM-enhanced invasive phenotypes and genotypes of cytotrophoblasts, suggesting its dominant role in cytotrophoblast-ECM interactions. Our results described, for the first time, the substantial effects of the ECM microenvironment on regulating cytotrophoblast invasion, an area that is less investigated but appear to be critical in the pathogenesis of preeclampsia. Moreover, the approach presented in this work that fabricates organ models with organ-specific ECM can be an attractive option to screen and develop novel therapeutics and biomarkers not only in preeclampsia but also other diseases such as cancer metastasis. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1476-1487, 2018.


Overexpression of 5-HT1B receptor in dorsal raphe nucleus using Herpes Simplex Virus gene transfer increases anxiety behavior after inescapable stress.
5-HT(1B) autoreceptors have been implicated in animal models of stress and are regulated selectively by serotonin-selective reuptake inhibitors such as fluoxetine. These terminal autoreceptors regulate serotonin release from dorsal raphe nucleus (DRN) projections throughout rat forebrain. However, it has not been previously possible to manipulate 5-HT(1B) autoreceptor activity selectively without also changing 5-HT(1B) activity in other neurons mediating different behavioral responses. Therefore, we have developed a viral-mediated gene transfer strategy to express hemagglutinin-tagged 5-HT(1B) and manipulate these autoreceptors in DRN. Green fluorescent protein (GFP) was coexpressed from a separate transcriptional unit on the same amplicon to assist in monitoring infection and expression. We confirmed the expression and biological activity of both transgenic proteins in vitro. When injected directly into DRN using stereotaxic procedure, HA-5-HT(1B) receptors were expressed in serotonergic neurons and translocated to the forebrain. The effect of DRN expression of HA-5-HT(1B) on stress-induced behaviors was compared with control rats that received GFP-only amplicons. There was no change in immobility in the forced swim test. However, HA-5-HT(1B) expression significantly reduced entrances into the central region of an open-field arena after water-restraint stress without altering overall locomotor activity, but not in the absence of stress exposure. HA-5-HT(1B) expression also reduced entries into the open arms of the elevated plus maze after water restraint. Because these tests are sensitive to increases in anxiety-like behavior, our results suggest that overactivity of 5-HT(1B) autoreceptors in DRN neurons may be an important mediator of pathological responses to stressful events.


The Role of Philanthropic Funding in Building Research Evidence to Support an Aging Population: A Case Study from Ireland.
This case study examines the role of philanthropic funding in building capacity for aging research in Ireland, and how this investment has addressed the lack of evidence to support planning for an aging population. The funding has supported a range of initiatives including the national longitudinal study on aging (TILDA), the creation of three professorships/chairs, and the establishment of four new research centers. Important potential outcomes are emerging across other domains including research-informed policy development and the generation of health benefits. The efforts of academic researchers to ensure that their findings are readily accessible to end users and to forge robust working relationships with all stakeholders have helped to enhance the use of research findings. Overall, philanthropy has played a pivotal role in building capacity, infrastructure, and expertise in academic settings in Ireland. Moreover, this work provides an excellent example of how such efforts can begin to inform effective planning and service provision.


Is iron deficiency modulating physical activity in COPD?
There is evidence that iron plays a key role in the adequate functioning of skeletal muscle. While it has been demonstrated that nonanemic iron deficiency (NAID) affects exercise tolerance and response to exercise training in patients with COPD, the impact on daily physical activities (DPAs) remains unknown. Eighteen COPD patients with NAID (ferritin <100 ng/mL or ferritin 100-299 ng/mL with a transferrin saturation <20%) and 18 COPD patients without this abnormality, matched for age, gender, and the degree of airflow limitation (control group), were enrolled to the study. The primary outcome was the level of DPA assessed by accelerometers. Patients were (mean [SD]) 66 (7) years and were mostly male (70%) and former smokers (52%). Their forced expiratory volume at 1 second was 41 (16)% predicted, carbon monoxide diffusing capacity was 47 (14)% predicted and oxygen arterial pressure reached 70 (11) mmHg. DPA and the number of steps per day were lower in NAID COPD patients compared with controls (physical activity level 1.39 vs 1.59, P<0.05; and 4,402 vs 6,975 steps/day, P<0.05, respectively). The percentage of patients with increased time spent sitting per day (>6 hours) was higher in patients with NAID compared with controls (73% vs 37%, P<0.05). In addition, the percentage of patients doing moderate to vigorous physical activity per day (>3 metabolic equivalents of task, at least 30 minutes) was lower in this group (66% vs 100%, P<0.05). The presence of iron deficiency was associated with reduced DPA in COPD patients. Further studies are needed to evaluate iron reposition and their impact on the level of physical activity in these patients.


Therapeutic cancer vaccination against mutant calreticulin in myeloproliferative neoplasms induces expansion of specific T cells in the periphery but specific T cells fail to enrich in the bone marrow.
Therapeutic cancer vaccination against mutant calreticulin (CALR) in patients with CALR-mutant (CALRmut) myeloproliferative neoplasms (MPN) induces strong T-cell responses against mutant CALR yet fails to demonstrate clinical activity. Infiltration of tumor specific T cells into the tumor microenvironment is needed to attain a clinical response to therapeutic cancer vaccination. Determine if CALRmut specific T cells isolated from vaccinated patients enrich in the bone marrow upon completion of vaccination and explore possible explanations for the lack of enrichment. CALRmut specific T cells from four of ten vaccinated patients were expanded, enriched, and analyzed by T-cell receptor sequencing (TCRSeq). The TCRs identified were used as fingerprints of CALRmut specific T cells. Bone marrow aspirations from the four patients were acquired at baseline and at the end of trial. T cells were enriched from the bone marrow aspirations and analyzed by TCRSeq to identify the presence and fraction of CALRmut specific T cells at the two different time points. In silico calculations were performed to calculate the ratio between transformed cells and effector cells in patients with CALRmut MPN. The fraction of CALRmut specific T cells in the bone marrow did not increase upon completion of the vaccination trial. In general, the T cell repertoire in the bone marrow remains relatively constant through the vaccination trial. The enriched and expanded CALRmut specific T cells recognize peripheral blood autologous CALRmut cells. In silico analyses demonstrate a high imbalance in the fraction of CALRmut cells and CALRmut specific effector T-cells in peripheral blood. CALRmut specific T cells do not enrich in the bone marrow after therapeutic cancer peptide vaccination against mutant CALR. The specific T cells recognize autologous peripheral blood derived CALRmut cells. In silico analyses demonstrate a high imbalance between the number of transformed cells and CALRmut specific effector T-cells in the periphery. We suggest that the high burden of transformed cells in the periphery compared to the number of effector cells could impact the ability of specific T cells to enrich in the bone marrow.


Primary chronic cold agglutinin disease: an update on pathogenesis, clinical features and therapy.
Chronic cold agglutinin disease (CAD) is a subgroup of autoimmune hemolytic anemia. Primary CAD has traditionally been defined by the absence of any underlying or associated disease. The results of therapy with corticosteroids, alkylating agents and interferon-alpha have been poor. Cold reactive immunoglobulins against erythrocyte surface antigens are essential to pathogenesis of CAD. These cold agglutinins are monoclonal, usually IgMkappa autoantibodies with heavy chain variable regions encoded by the V(H)4-34 gene segment. By flowcytometric and immunohistochemical assessments, a monoclonal CD20+kappa+B-lymphocyte population has been demonstrated in the bone marrow of 90% of the patients, and lymphoplasmacytic lymphoma is a frequent finding. Novel attempts at treatment for primary CAD have mostly been directed against the clonal B-lymphocytes. Phase 2 studies have shown that therapy with the chimeric anti-CD20 antibody rituximab produced partial response rates of more than 50% and occasional complete responses. Median response duration, however, was only 11 months. In this review, we discuss the clinical and pathogenetic features of primary CAD, emphasizing the more recent data on its close association with clonal lymphoproliferative bone marrow disorders and implications for therapy. We also review the management and outline some perspectives on new therapy modalities.


Bumba, a replacement name for Maraca Pérez-Miles, 2005 and Bumbalennoni, a new tarantula species from western Amazonia (Araneae, Theraphosidae, Theraphosinae).
We propose the name Bumba as a new name for Maraca, preoccupied by Maraca Hebard, 1926 (Orthoptera). We describe and illustrate Bumbalennoni, a new theraphosid species from Caxiuanã, Pará, Brazil. This species differs from the other species of the genus in the extremely reduced keel on male palpal organ and in the higher number of labial and maxillary cuspules. Females additionally differ in the spermathecal morphology. As a consequence of the name replacement, three new combinations are established.


Effect of heating rate on evaporative heat loss in the microwave-exposed mouse.
Male CBA/J mice were administered heat loads of 0-28 J X g-1 at specific absorption rates (SARs) of either 47 or 93 W X kg-1 by exposure to 2,450-MHz microwave radiation at an ambient temperature of 30 degrees C while evaporative heat loss (EHL) was continuously monitored with dew-point hygrometry. At an SAR of 47 W X kg-1 a threshold heat load of 10.5 J X g-1 had to be exceeded before EHL increased. An approximate doubling of SAR to 93 W X kg-1 reduced the threshold to 5.2 J X g-1. Above threshold the slopes of the regression lines were 1.15 and 0.929 for the low- and high-SAR groups, respectively. Thus the difference in threshold and not slope attributes to the significant increase in EHL when mice are exposed at a high SAR (P less than 0.02). In separate experiments a SAR of 47 W X kg-1 raised the deep body temperature of anesthetized mice at a rate of 0.026 degrees C X s-1, whereas 93 W X kg-1 raised temperature at 0.049 degrees C X s-1. Hence the sensitivity of the EHL mode of heat dissipation is directly proportional to the rate of heat absorption and to the rate of rise in body temperature. These data contradict the notion that mammals have control over whole-body heat exchange only (i.e., thermoregulation) but instead indicate that the EHL system is highly responsive to the rate of heat absorption (i.e., temperature regulation).


Ethyl (2E)-2-(2H-1,3-benzodioxol-5-yl-methyl-idene)-4-chloro-3-oxobutano-ate.
In the title compound, C(14)H(13)ClO(5), the five-membered ring is in an envelope conformation with the methyl-ene C-atom being the flap. The conformation about the C=C double bond [1.341 (2) Å] is E. The chloro-propan-2-one residue is approximately orthogonal to the remaining mol-ecule [dihedral angle = 88.03 (6)°]. In the crystal, the mol-ecules associate via C-H⋯O inter-actions, involving both carbonyl-O atoms, giving rise to an undulating two-dimensional array in the ac plane.


Sandwich-cultured hepatocytes: utility for in vitro exploration of hepatobiliary drug disposition and drug-induced hepatotoxicity.
The sandwich-cultured hepatocyte (SCH) model has become an invaluable in vitro tool for studying hepatic drug transport, metabolism, biliary excretion and toxicity. The relevant expression of many hepatocyte-specific functions together with the in vivo-like morphology favor SCHs over other preclinical models for evaluating hepatobiliary drug disposition and drug-induced hepatotoxicity. In this review, the authors highlight recommended procedures required for reproducibly culturing hepatocytes in sandwich configuration. It also provides an overview of the SCH model characteristics as a function of culture time. Lastly, the article presents a summary of the most prominent applications of the SCH model, including hepatic drug clearance prediction, drug-drug interaction potential and drug-induced hepatotoxicity. When human (cryopreserved) hepatocytes are used to establish sandwich cultures, the model appears particularly valuable to quantitatively investigate clinically relevant mechanisms related to in vivo hepatobiliary drug disposition and hepatotoxicity. Nonetheless, the SCH model would largely benefit from better insight into the fundamental cell signaling mechanisms that are critical for long-term in vitro maintenance of the hepatocytic phenotype. Studies systematically exploring improved cell culture conditions (e.g., co-cultures or extracellular matrix modifications), as well as in vitro work identifying key transcription factors involved in hepatocyte differentiation are currently emerging.


[Effect of smoking on weight and cardiopulmonary capacities in young athletes].
The aim of the study was to determine wether smokers practising sports have reduced weight, if recuperation time after moderate exercise and maximal aerobic power were lowered. Thousand young soldiers [50 smokers (S), 50 no smokers (NS)] averaging 24 years in age were studied. The subjects performed to exhaustion on Ruffier test, then a maximal exercise with Cooper test. Several biometrical and physiological parameters were evaluated: weight (W), percent of body fat (PBF), body mass index (BMI), maximal oxygen uptake (VO2 max) and recuperation index (RI). Kinetics of heart rate (HR) were studied for 7 min considering time constant (1 min) and delay for recovery. The smokers showed significant differences for W (p < 0.001), PBF (p < 0.05), VO2 max (p < 0.01) and recuperation index (p < 0.001). Maximal aerobic power were 45.8 +/- 2.7 and 50.3 +/- 3.2 ml/kg/min for S and NS, and RI were 7.5 +/- 0.9 (S) and 5.0 +/- 1 (NS). figure 1 shows that HR recovery of S has generally two components: the first was fast, the second was a slone none. The smokers who presented a great dependence to tobacco smoking had a significant lower RI (p < 0.001) as those subjects with little tobacco dependence (Table 5). The smokers had lower values of VO2 max, and there exists a tobacco dependence difference. Recuperation time for the aerobically well trained S subjects was more rapid during the lactic phase. Note that correlations obtained between the VO2 max and RI were significant (r = - 0.788; p < 0.05). The smokers and no smokers differences are discussed with reference to nicotinemia effects and the sympathetic-parasympathetic unbatance of influences. The comparison of smokers groups concerning cardiovascular data led to suppose that there exists a tobacco dependence difference in regards of the catecholaminergic sensitivity. In conclusion, this study showed that smoker practising a physical activity have a reduced weight, a higher recuperation time and an anaerobic limitation influenced by the state of tobacco dependence.


A review of the renin-angiotensin system in the normal heart.
This review describes the vascular and cardiac tissue renin-angiotensin system (RAS), a so-called autocrine hormonal system as opposed to the circulating endocrine system. The existence of this autocrine system is suggested by the persistence of elevated concentrations of angiotensin II (Ang II) following binephrectomy. There is considerable evidence to support the concept of an autocrine RAS, but the functional aspects of such a system remain controversial: (a) Cultured endothelial cells from blood vessels can, for example, synthesize renin, but angiotensinogen messenger RNA (mRNA) is only present in perivascular adipocytes. (b) In the myocardium, there are obviously problems raised depending on the animal species considered: only rats apparently lack ventricular RAS, but tissue RAS is present in their atrial and conducting tissue system. In other species such as rabbit, the situation is quite different. In addition to the inotropic effect of Ang II, it has recently been demonstrated that this substance may determine the expression of the cardiac genome (oncogenes).


Optimization of pressurized liquid extraction (PLE) of dioxin-furans and dioxin-like PCBs from environmental samples.
Pressurized liquid extraction (PLE) applying three extraction cycles, temperature and pressure, improved the efficiency of solvent extraction when compared with the classical Soxhlet extraction. Polychlorinated-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and dioxin-like PCBs (coplanar polychlorinated biphenyls (Co-PCBs)) in two Certified Reference Materials [DX-1 (sediment) and BCR 529 (soil)] and in two contaminated environmental samples (sediment and soil) were extracted by ASE and Soxhlet methods. Unlike data previously reported by other authors, results demonstrated that ASE using n-hexane as solvent and three extraction cycles, 12.4 MPa (1800 psi) and 150 degrees C achieves similar recovery results than the classical Soxhlet extraction for PCDFs and Co-PCBs, and better recovery results for PCDDs. ASE extraction, performed in less time and with less solvent proved to be, under optimized conditions, an excellent extraction technique for the simultaneous analysis of PCDD/PCDFs and Co-PCBs from environmental samples. Such fast analytical methodology, having the best cost-efficiency ratio, will improve the control and will provide more information about the occurrence of dioxins and the levels of toxicity and thereby will contribute to increase human health.


The prognostic significance of intracerebral haematoma as shown on CT scanning after aneurysmal subarachnoid haemorrhage.
In a prospective study of 1076 consecutive patients with aneurysmal subarachnoid haemorrhage (SAH), CT was carried out in 815 patients. CT visible intracerebral haematoma (ICH) was found in 42.6% of the 815 patients. There were no differences in age, pre-existing hypertension or sex between patients with or without ICH. Patients with ICH were in poorer clinical condition on admission, and had a poorer mental outcome and a higher mortality at the 2-year follow-up examination compared with patients without ICH. Of the 491 operated patients, there were in every group according to the clinical condition on admission fewer patients with a normal mental outcome and more fatal cases if an ICH was present after aneurysm rupture. This indicates that the acute brain dysfunction from SAH complicated by ICH is more likely to be followed by permanent cerebral damage compared to the corresponding acute cerebral dysfunction from SAH without ICH.


The incidence of post-transplant cancer among kidney transplant recipients is associated with the level of tacrolimus exposure during the first year after transplantation.
Immunosuppressive therapy plays a major role in the development of post-transplant cancer. In this nested case-control study of kidney transplant recipients (KTRs), we investigated whether the incidence of post-transplant cancer is associated with the level of tacrolimus exposure over time. We screened the Rabin Medical Center database for adults who received kidney transplants between 2001 and 2014 and developed post-transplant cancer (excluding basal and squamous cell skin cancers). They were matched against KTRs without cancer. All patients received a maintenance immunosuppressive treatment with tacrolimus, mycophenolate mofetil and corticosteroids. The degree of exposure to tacrolimus was estimated as the time-weighted average (tTWA) value of tacrolimus blood levels. The tTWA was calculated as the area under the curve divided by time at 1, 6, and 12 months after transplantation and at time of cancer diagnosis. Thirty-two cases were matched against 64 controls. tTWA values above 11 ng/mL at 6 and 12 months after transplantation were associated with odds ratio (OR) of 3.1 (95% CI 1.1-9) and 11.7 (95% CI = 1.3-106), respectively, for post-transplant cancer; and with OR of 5.2 (95% CI 1.3-20.5) and 14.1 (95% CI = 1.5-134.3), respectively, for cancer diagnosed more than 3 years after transplantation. Exposure to a tacrolimus time-weighted average level above 11 ng/mL at 6 or 12 months after kidney transplantation is associated with an increased risk of developing cancer.


One-step purification of vitronectin from human plasma by affinity chromatography on phage-displayed peptides.
A novel affinity purification method for rapid isolation of vitronectin (VN) from human plasma is described. Recently we have used phage display technology to obtain clones expressing peptides with high binding activity for VN. The isolated "strong VN binders" were covalently coupled to CNBr-activated Sepharose. Human plasma was applied to the column and bound VN was eluted using 0.5 M acetic acid, giving purity exceeding 90%. The developed method is a convenient alternative to conventional antibody-antigen affinity chromatography techniques for purification of VN, as it offers low ligand cost, is rapid and ensures good protein recovery from human plasma.


Improving the physical health of people living with mental illness in Australia and New Zealand.
People diagnosed with mental illness have relatively poor physical health and die earlier than their counterparts in the general population. People living with mental illness in rural Australia have three times the risk of premature death than the total population. This article reviews recent international, Australian and New Zealand research, identifies the increased risk of early death of people living with mental health issues in rural settings and looks at the need for policy and practice responses. The 'Equally Well' national initiatives are described in Australia and New Zealand, which seek to systematically address this inequity as a matter of priority. Finally, it argues for co-design and consumer participation in policy development, program implementation and research. Improved understanding of the perspectives and priorities of people with experience of mental illness is vital if change is to be fully realised.


[Pharmacological bases of the treatment of cardiac insufficiency].
Congestive heart failure is a complex physiopathological state where both myocardial hypo-contraction and excessive peripheral vasoconstriction lead to lower cardiac output. The increase in cytosolic calcium concentration triggers the contractile processus. Digitalis inhibits the Na+/K+ ATPase enzyme and indirectly increases intracellular calcium concentration. beta 1 agonists increase the synthesis of cAMP-dependent protein kinase and hence the recruitment of new receptor-operated calcium channels which increase the calcium influx and the mobilization from its intracellular storage sites. Vascular smooth muscle contraction occurs with calcium influx into the cell resulting from various receptor activation. In congestive heart failure, activation of the sympathetic nervous system and of the renin-angiotensin system leads to neurohumoral-induced peripheral vasoconstriction. Renal effects of angiotensin II and aldosterone are responsible for sodium and water retention. alpha 1-blocking agents are drugs that block competitively the catecholamines effects on vascular receptors. Angiotensin I-converting-enzyme inhibitors block the formation of the key-element of the system: angiotensin II. Both alpha 1-blocking agents and converting-enzyme inhibitors show vasodilatator effects and acutely improve hemodynamic status of patients with congestive heart failure. Converting-enzyme inhibitors exhibit specific improvement of intrarenal hemodynamics and do not induced sodium and water retention in longterm therapy.


"Experience-sharing" as an antidote to dependence-making behavior of general practitioners.
This article explores how group-dynamic interventions can be used to teach health professionals to counter impulses to make clients dependent on them. The basic assumption, derived from Kohut's work on narcissism, is that dependence-making behavior is connected with deep-rooted feelings of insufficiency resulting from a defective autonomy. A part of the standard Dutch General Practice (GP) training program, experience-sharing in groups of 12 GP trainees, offers opportunities to explore these feelings. The format of this experience-sharing (well-defined boundaries, minimal structure, facilitating leaders) often evokes behavior in which the peculiarities of the dependence-making behavior of the GP's vis-à-vis patients are mirrored: that is, dependent behavior. In order to analyze and influence this behavior, use can be made of Levine's model of group psychotherapy, which focuses on enhancing autonomy. In this paper we show, by means of four group cases, how Levine's framework can be used to enhance autonomy, lessen dependence, and thus diminish the tendency of GP's toward dependence-making behavior.


Selective monitoring of 3 out of 50,000 protein vibrations.
An important group in a large protein, which is the phosphate group that transiently binds to the Ca2+ transporting ATPase (Ca2+-ATPase) of the sarcoplasmic reticulum membrane, is selectively observed with IR spectroscopy. The three phosphate stretching vibrations stand out from the 50,000 protein vibrations in an isotope exchange experiment where oxygen exchange at the phosphate group is catalyzed by the Ca2+-ATPase.


Sampling properties of random graphs: the degree distribution.
We discuss two sampling schemes for selecting random subnets from a network, random sampling and connectivity dependent sampling, and investigate how the degree distribution of a node in the network is affected by the two types of sampling. Here we derive a necessary and sufficient condition that guarantees that the degree distributions of the subnet and the true network belong to the same family of probability distributions. For completely random sampling of nodes we find that this condition is satisfied by classical random graphs; for the vast majority of networks this condition will, however, not be met. We furthermore discuss the case where the probability of sampling a node depends on the degree of a node and we find that even classical random graphs are no longer closed under this sampling regime. We conclude by relating the results to real Eschericia coli protein interaction network data.


Immunoblot typing of oxacillin-resistant Staphylococcus aureus clinical isolates.
Recently an immunoblotting system was developed for typing oxacillin-resistant Staphylococcus aureus. Oxacillin-resistant S. aureus (ORSA) isolates recovered during a 4-month period from premature new-borns division of University Hospital of Pavia, with several antimicrobial susceptibility patterns, were evaluated with this typing scheme. Immunoblotting was found to be a useful method with good reproducibility and the ORSA strains isolated at our institution were differentiated in two major groups of organisms clinically and epidemiologically related. Furthermore immunoblot typing showed same specific correlations with susceptibility patterns of ORSA isolates studied.


Clinical Significance of Preoperative Thrombin Time in Patients with Esophageal Squamous Cell Carcinoma following Surgical Resection.
Noninvasive tools for the prognosis of ESCC are urgently needed. To this end, serum coagulation tests have been researched in some cancers, but the prognostic value of the TT in ESCC has not been described. The levels of pre-treatment serum coagulation markers (including the PT, APTT, PTA, INR, fibrinogen level, TT and PLT) were retrospectively analyzed in 204 patients with ESCC who underwent surgical resection at our department and in 200 healthy controls, and the two groups were compared. The prognostic significance of the coagulation tests was then determined with univariate and multivariate cox hazard analyses in patients with ESCC. Compared with those in normal controls, the PT, APTT, and fibrinogen levels were significantly increased, whereas the TT values significantly decreased in the 204 ESCC patients. The TT directly correlated with the 5-year survival rate, not only in the entire ESCC cohort (p = 0.023) but also in the subgroups stratified according to the T and N classifications and metastasis. Conversely, the other tests were not independent prognostic factors for ESCC. Of the clotting markers, the TT inversely correlated with the fibrinogen level (p = 0.005). The 5-year survival was shorter in ESCC patients exhibiting decreased pre-treatment TT values. Thus, the serum TT may be a clinical prognostic factor for ESCC patients.


Contrast Media Administration in Coronary Computed Tomography Angiography - A Systematic Review.
Background Various different injection parameters influence enhancement of the coronary arteries. There is no consensus in the literature regarding the optimal contrast media (CM) injection protocol. The aim of this study is to provide an update on the effect of different CM injection parameters on the coronary attenuation in coronary computed tomographic angiography (CCTA). Method Studies published between January 2001 and May 2014 identified by Pubmed, Embase and MEDLINE were evaluated. Using predefined inclusion criteria and a data extraction form, the content of each eligible study was assessed. Initially, 2551 potential studies were identified. After applying our criteria, 36 studies were found to be eligible. Studies were systematically assessed for quality based on the validated Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-II checklist. Results Extracted data proved to be heterogeneous and often incomplete. The injection protocol and outcome of the included publications were very diverse and results are difficult to compare. Based on the extracted data, it remains unclear which of the injection parameters is the most important determinant for adequate attenuation. It is likely that one parameter which combines multiple parameters (e. g. IDR) will be the most suitable determinant of coronary attenuation in CCTA protocols. Conclusion Research should be directed towards determining the influence of different injection parameters and defining individualized optimal IDRs tailored to patient-related factors (ideally in large randomized trials). Key points · This systematic review provides insight into decisive factors on coronary attenuation.. · Different and contradicting outcomes are reported on coronary attenuation in CCTA.. · One parameter combining multiple parameters (IDR) is likely decisive in coronary attenuation.. · Research should aim at defining individualized optimal IDRs tailored to individual factors.. · Future directions should be tailored towards the influence of different injection parameters.. Citation Format · Mihl C, Maas M, Turek J et al. Contrast Media Administration in Coronary Computed Tomography Angiography - A Systematic Review. Fortschr Röntgenstr 2017; 189: 312 - 325.


Rat intestinal brush border membrane peptidases. I. Solubilization, purification, and physicochemical properties of two different forms of the enzyme.
Two brush border peptidases have been isolated from the particulate fraction of the rat intestinal mucosa and purified to homogeneity as judged by polyacrylamide gel electrophoresis, starch gel electrophoresis, isoelectric focusing, and double immunodiffusion. For convenience, the peptidases have been designated peptidase F (fast) and S (slow) on the basis of their anodic mobilities. The isoelectric point of peptidase F was 4.76 and of peptidase S, 5.10. Both enzymes are glycoproteins. The amino acid compositions of the two peptidases are similar. The same carbohydrates are found in both enzymes, but there are differences in the molar concentrations of individual sugars. Peptidase S has greater concentrations of mannose and galactose and of hexosamines than peptidase F, while sialic acid is slightly greater in peptidase F. Carbohydrate accounted for approximately 19% and 23% of the weight of peptidases F and S, respectively. Estimates of the molecular weights of both enzymes by gel filtration gave values of 280,000. Electrophoresis of the enzymes under denaturing conditions on sodium dodecyl sulfate polyacrylamide gels indicated that each enzyme is a dimer consisting of two subunits of equal molecular weight, 140,000.


[Evaluation of shunt therapy in normal pressure hydrocephalus-surgical results in neurological conditions (author's transl)].
This presentation is a study of 18 patients diagnosed as having normal pressure hydrocephalus and treated by CSF diversion procedures. Pre- and postoperative neurological conditions of these patients were evaluated, compared, and analysed. There were 56% of males and 44% of females and the number of patients under 60 and over 61 were equal. The histories and clinical findings in all suggested a diagnosis of normal pressure hydrocephalus. In 12, the two thirds of patients, showed progressive intellectual deterioration, ataxic gait and/or incontinence following subarachnoid hemorrhage. Similar neurological features were preceded by craniocerebral trauma in one, megadolichobasilar artery in one and superior sagittal sinus thrombosis in one. Three cases were idiopathic. 169Yb cisternography, transfer test of radioisotope to blood, angiography and in some cases pneumoencephalography were performed in the usual manner to confirm the diagnosis. Attempts have been made to correlate the surgical results with the ages of patients, the duration of symtoms, and the causes of hydrocephalus. Neurological symptoms were divided into three groups. Group "A" is composed of mental deterioration, lack of spontaneity and willingness, mutism and disorientation, groups "B" includes gait disturbance and group "C" incontinence. The results of surgical treatment were analyzed according to the three groups of symptoms not only in the percentage of cases who improved but also in the time interval from the time of shunting to the appearance of operative results. The results are as follows. The good surgical improvements were achieved in the cases of under 70 years old, in the case of NPH of known causes, such as subarachnoid hemorrhage, craniocerebral trauma, and in the cases operated on within three months after the onset of symptoms. Recovery of "A" symtoms was achieved not only sooner after the operation but also in more cases than those of "B" and "C" symptoms. The correlation was analyzed between the duration or symptoms and time interval after the shunting and the appearance of operative results. Although no correlation was obtained in "A" symptoms, the sooner was shunting performed, the earlier appeared the operative results in "B" and "C" symptoms. In conclusion, it appeared from the results of the present study, that in addition to the integration of the results of different examinations such as isotope cisternography, air study and angiography, the combination of the patient data such as ages, duration of symptoms and the cause of hydrocephalus are essential in selecting the patients for shunting operation. If the diagnosis of normal pressure hydrocephalus is confirmed and surgical improvement is predicted, the patient should be shunted as soon as possible to obtain a good surgical results especially in mental symptoms, which is the important factor in performing rehabilitation therapy.


Autophagy and Hallmarks of Cancer.
Autophagy is a catabolic program that is responsible for the degradation of dysfunctional or unnecessary proteins and organelles to maintain cellular homeostasis. Mechanistically, it involves the formation of double-membrane autophagosomes that sequester cytoplasmic material and deliver it to lysosomes for degradation. Eventually, the material is recycled back to the cytoplasm. Abnormalities of autophagy often lead to human diseases, such as neurodegeneration and cancer. In the case of cancer, increasing evidence has revealed the paradoxical roles of autophagy in both tumor inhibition and tumor promotion. Here, we summarize the context-dependent role of autophagy and its complicated molecular mechanisms in the hallmarks of cancer. Moreover, we discuss how therapeutics targeting autophagy can counter malignant transformation and tumor progression. Overall, the findings of studies discussed here shed new light on exploiting the complicated mechanisms of the autophagic machinery and relevant small-molecule modulators as potential antitumor agents to improve therapeutic outcomes.


Detection of Pneumocystis carinii in respiratory specimens by PCR-solution hybridization enzyme-linked immunoassay.
By using a recently developed PCR-solution hybridization enzyme-linked assay (PCR-SHELA), we investigated Pneumocystis carinii in bronchoalveolar lavage fluid samples and induced sputa of patients with pneumocystosis. In detecting P. carinii, PCR-SHELA proved more sensitive than immunofluorescence staining or a single PCR and significantly more diagnostically specific than a nested PCR. Our data suggest that PCR-SHELA could be used to detect P. carinii organisms in respiratory samples, particularly in patients with uncertain diagnoses.


Structural characterization of the voltage-sensor domain and voltage-gated K+-channel proteins vectorially oriented within a single bilayer membrane at the solid/vapor and solid/liquid interfaces via neutron interferometry.
The voltage-sensor domain (VSD) is a modular four-helix bundle component that confers voltage sensitivity to voltage-gated cation channels in biological membranes. Despite extensive biophysical studies and the recent availability of X-ray crystal structures for a few voltage-gated potassium (Kv) channels and a voltage-gate sodium (Nav) channel, a complete understanding of the cooperative mechanism of electromechanical coupling, interconverting the closed-to-open states (i.e., nonconducting to cation conducting) remains undetermined. Moreover, the function of these domains is highly dependent on the physical-chemical properties of the surrounding lipid membrane environment. The basis for this work was provided by a recent structural study of the VSD from a prokaryotic Kv-channel vectorially oriented within a single phospholipid (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)) membrane investigated by X-ray interferometry at the solid/moist He (or solid/vapor) and solid/liquid interfaces, thus achieving partial to full hydration, respectively (Gupta et al. Phys. Rev. E2011, 84, 031911-1-15). Here, we utilize neutron interferometry to characterize this system in substantially greater structural detail at the submolecular level, due to its inherent advantages arising from solvent contrast variation coupled with the deuteration of selected submolecular membrane components, especially important for the membrane at the solid/liquid interface. We demonstrate the unique vectorial orientation of the VSD and the retention of its molecular conformation manifest in the asymmetric profile structure of the protein within the profile structure of this single bilayer membrane system. We definitively characterize the asymmetric phospholipid bilayer solvating the lateral surfaces of the VSD protein within the membrane. The profile structures of both the VSD protein and phospholipid bilayer depend upon the hydration state of the membrane. We also determine the distribution of water and exchangeable hydrogen throughout the profile structure of both the VSD itself and the VSD:POPC membrane. These two experimentally determined water and exchangeable hydrogen distribution profiles are in good agreement with molecular dynamics simulations of the VSD protein vectorially oriented within a fully hydrated POPC bilayer membrane, supporting the existence of the VSD's water pore. This approach was extended to the full-length Kv-channel (KvAP) at a solid/liquid interface, providing the separate profile structures of the KvAP protein and the POPC bilayer within the reconstituted KvAP:POPC membrane.


Molecular Identification and Virulence of Four Strains of Entomopathogenic Fungi Against the Whitefly, Bemisia tabaci (Hemiptera: Aleyrodidae).
The whitefly, Bemisia tabaci (Gennadius), is a key pest of many economically important crops grown in the field and in greenhouses throughout the world. Because entomopathogenic fungi (EPF) are potential biological control agents for B. tabaci, however, minimal research has been conducted on using fungal strains to control B. tabaci. In this study, four EPF strains were isolated and identified as Lecanicillium attenuatum (Zare & Gams) JL-003, Beauveria bassiana Balsamo (Vuillemin) JL-005, Lecanicillium longisporum (Petch) JL-006, and Akanthomyces lecanii (Zimmerman) JL-007, based on rDNA-ITS sequence analysis. In comparing the virulence of the four fungi against the different life stages (i.e., eggs, 1st-, 2nd-, 3rd-, 4th-instar nymphs, and adults) of B. tabaci the mortality of B. tabaci decreased and LT50 values increased as the conidia concentration decreased in a series of conidia concentrations (1 × 105, 106, 107, and 108 conidia/mL). The fungal strains L. attenuatum JL-003 (LC50: 1.31 × 106) and B. bassiana JL-005 (LC50: 0.92 × 106) were found to be more effective than L. longisporum JL-006 (LC50: 4.97 × 107) and A. lecanii JL-007 (LC50: 6.46 × 106). Fourth-instar nymphs, eggs, and adult stages of B. tabaci were less susceptible to all fungal strains compared to 1st-, 2nd-, and 3rd-instar nymphs. The virulence of L. attenuatum, which was tested for the first time on B. tabaci, was found to be more toxic to early-stage nymphs. Our data will be useful in biological control programs that are considering using EPF against B. tabaci.


Combining a Deconvolution and a Universal Library Search Algorithm for the Nontarget Analysis of Data-Independent Acquisition Mode Liquid Chromatography-High-Resolution Mass Spectrometry Results.
Nontarget analysis is considered one of the most comprehensive tools for the identification of unknown compounds in a complex sample analyzed via liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Due to the complexity of the data generated via LC-HRMS, the data-dependent acquisition mode, which produces the MS2 spectra of a limited number of the precursor ions, has been one of the most common approaches used during nontarget screening. However, data-independent acquisition mode produces highly complex spectra that require proper deconvolution and library search algorithms. We have developed a deconvolution algorithm and a universal library search algorithm (ULSA) for the analysis of complex spectra generated via data-independent acquisition. These algorithms were validated and tested using both semisynthetic and real environmental data. A total of 6000 randomly selected spectra from MassBank were introduced across the total ion chromatograms of 15 sludge extracts at three levels of background complexity for the validation of the algorithms via semisynthetic data. The deconvolution algorithm successfully extracted more than 60% of the added ions in the analytical signal for 95% of processed spectra (i.e., 3 complexity levels multiplied by 6000 spectra). The ULSA ranked the correct spectra among the top three for more than 95% of cases. We further tested the algorithms with 5 wastewater effluent extracts for 59 artificial unknown analytes (i.e., their presence or absence was confirmed via target analysis). These algorithms did not produce any cases of false identifications while correctly identifying ∼70% of the total inquiries. The implications, capabilities, and the limitations of both algorithms are further discussed.


Bile duct-duodenal fistula caused by AIDS/HIV-associated tuberculosis.
Although infrequent, digestive fistulae in HIV/AIDS patients have been reported throughout the digestive tract from the esophagus to the anus, with predominance of esophageal fistulae. AIDS/HIV-associated opportunistic infections may invade the digestive system and lead to fistula formation. Tuberculosis is the most common infection associated with these esophageal fistulae. We report here one case of bile duct-duodenal fistula in a female AIDS patient with associated abdominal Mycobacterium tuberculosis infection compromising lymph nodes of the hepatic pedicle where the fistula was found. According to the reviewed literature, this is the third case of bile duct-duodenal fistula associated with abdominal tuberculosis in AIDS patient, and the first where both the fistula and the tuberculosis infection were diagnosed at laparotomy for acute abdomen. Whether the AIDS patient with abdominal pain needs or not a laparotomy to treat an infectious disease is often a difficult matter for the surgeon to decide, as most of the times appropriate medical treatment will bring more benefit.


Case report on the analysis of single nucleotide polymorphisms of the serotonergic pathway and array-based comparative genomic hybridisation of a suicide victim.
Slovenia, with its population of 2 million, has one of the highest suicide rates in Europe (around 30 per 100,000). It has been determined by twin studies that up to 45% of the variance in suicidal ideation and behaviour may be attributable to genetic variables. In the present paper we report on a case of a male suicide victim. Before the psychological autopsy was performed we genotyped this person for 15 genetic polymorphisms of the serotonergic pathway, since molecular-genetic studies of neurotransmitters from brain and blood samples of suicide victims have shown that the serotonergic system might be implicated in suicide. This case report evaluated by psychological autopsy and serotoninergic gene polymorphisms determination indicates the influence of genetic and environmental factors contributing to the suicidal behaviour of the individual person. Probably the interplay between genes and stressful events jut before suicide, together with mental disorder lead to suicide in the case described.


Cost-effectiveness Analysis for Genotyping before Allopurinol Treatment to Prevent Severe Cutaneous Adverse Drug Reactions.
Patients with an HLA-B*58:01 allele have an increased risk of developing severe cutaneous adverse drug reactions (SCAR) when treated with allopurinol. Although one-off pharmacogenetic testing may prevent life-threatening adverse drug reactions, testing prior to allopurinol initiation incurs additional costs. The study objective was to evaluate the cost-effectiveness of HLA-B*58:01 screening compared with using other available urate-lowering agents (ULA). A decision-analytical model was used to compare direct medical costs and effectiveness [including lifetime saved, quality-adjusted life-yrs (QALY) gained] in treating new patients with the following options: (1) genetic screening followed by allopurinol prescribing for noncarriers of HLA-B*58:01, (2) prescribing benzbromarone without screening, (3) prescribing febuxostat without screening, and (4) prescribing allopurinol without screening. A 1-year time frame and third-party payer perspective were modeled for both the entire cohort (base-case) and for the subgroup of patients with chronic kidney disease (CKD). The incremental cost-effectiveness ratio of genetic screening prior to ULA therapy was estimated as New Taiwan (NT) $234,610 (US$7508) per QALY gained in the base-case cohort. For patients with CKD, it was estimated as NT$230,925 (US$7390) per QALY. The study results were sensitive to the probability of benzbromarone/febuxostat-related hypersensitivity, and a negative predicted value of genotyping. HLA-B*58:01 screening gave good value for money in preventing allopurinol-induced SCAR in patients indicated for ULA therapy. In addition to the costs of genotyping, it is important to monitor ULA safety closely in adopting HLA-B*58:01 screening in practice.


Influence of tablet hardness and hydrophobicity on the adhesive properties of an acrylic resin copolymer.
The adhesive properties--including the force of adhesion, elongation at adhesive failure, the modulus of adhesion, and the adhesive toughness--of an acrylic resin copolymer were determined using the butt adhesion technique. Flat-faced tablets containing up to 30% hydrogenated castor oil were coated with an aqueous dispersion of Eudragit L30D-55. Using data obtained from a Chatillon digital force gauge attached to a motorized test stand, force-deflection profiles, similar to stress-strain curves generated in the tensile testing of free films, were constructed. The surface characteristics of the tablets significantly influenced polymer-substrate interaction. The force of adhesion, the elongation at adhesive failure, and the adhesive toughness decreased as the surface of the tablet became more hydrophobic through the addition of wax to the tablet formulation. Lower adhesive properties were found with increasing tablet hardness, due to a decrease in the effective area of contact between the film coating and the tablet surface. Increased polymer loading resulted in stronger adhesion, indicating a relationship between the mechanical and adhesive properties of the polymer. The present study demonstrated that the area under the force-deflection profile in conjunction with the force of adhesion was more representative of the adhesive properties of the polymer.


Tsukamurella pulmonis bloodstream infection identified by secA1 gene sequencing.
Recurrent bloodstream infections caused by a Gram-positive bacterium affected an immunocompromised child. Tsukamurella pulmonis was the microorganism identified by secA1 gene sequencing. Antibiotic treatment in combination with removal of the subcutaneous port healed the patient.


Correlation between trimester of fetal wastage and anti-cardiolipin antibody titer.
The existence of circulating lupus anticoagulant and anti-cardiolipin antibodies (ACA) has been reported to be associated with recurrent fetal loss. We used an enzyme-linked immunosorbent assay (ELISA) for detection of ACA in plasma samples from 104 women with a history of recurrent fetal loss. The normal range of the ACA level was defined as less than 6 GPL (IgG anti-cardiolipin) units (n = 100 normal plasma samples). Nine women (9.7%) were positive for ACA. The population was divided into two groups on the basis of medical history, and analysis revealed that 42.8% (3/7) of the group of patients with at least one fetal loss in the second or third trimester were positive for ACA; their mean ACA titer was 34 GPL units.


Recent insight into the correlation of SREBP-mediated lipid metabolism and innate immune response
Fatty acids are essential nutrients that contribute to several intracellular functions. Fatty acid synthesis and oxidation are known to be regulated by sterol regulatory element-binding proteins (SREBPs), which play a pivotal role in the regulation of cellular triglyceride synthesis and cholesterol biogenesis. Recent studies point to a multifunctional role of SREBPs in the pathogenesis of metabolic diseases, such as obesity, type II diabetes and cancer as well as in immune responses. Notably, fatty acid metabolic intermediates are involved in energy homeostasis and pathophysiological conditions. In particular, intracellular fatty acid metabolism affects an inflammatory response, thereby influencing metabolic diseases. The objective of this review is to summarize the recent advances in our understanding of the dual role of SREBPs in both lipid metabolism and inflammation-mediated metabolic diseases.


High-Fidelity, Hyper-Accurate, and Evolved Mutants Rewire Atomic Level Communication in CRISPR-Cas9.
The Cas9-HF1, HypaCas9, and evoCas9 variants of the Cas9 endonuclease are critical tools to mitigate off-target effects in the application of CRISPR-Cas9 technology. The mechanisms by which mutations in the Rec3 domain mediate specificity in these variants are poorly understood. Here, solution NMR and molecular dynamics simulations establish the structural and dynamic effects of high-specificity mutations in Rec3, and how they propagate the allosteric signal of Cas9. We reveal conserved structural changes and peculiar dynamic differences at regions of Rec3 that interface with the RNA:DNA hybrid, transducing chemical signals from Rec3 to the catalytic HNH domain. The variants remodel the communication sourcing from the Rec3 α-helix 37, previously shown to sense target DNA complementarity, either directly or allosterically. This mechanism increases communication between the DNA mismatch recognition helix and the HNH active site, shedding light on the structure and dynamics underlying Cas9 specificity and providing insight for future engineering principles.


Structures and comparative characterization of biosynthetic gene clusters for cyanosporasides, enediyne-derived natural products from marine actinomycetes.
Cyanosporasides are marine bacterial natural products containing a chlorinated cyclopenta[a]indene core of suspected enediyne polyketide biosynthetic origin. Herein, we report the isolation and characterization of novel cyanosporasides C-F (3-6) from the marine actinomycetes Salinispora pacifica CNS-143 and Streptomyces sp. CNT-179, highlighted by the unprecedented C-2' N-acetylcysteamine functionalized hexose group of 6. Cloning, sequencing, and mutagenesis of homologous ~50 kb cyanosporaside biosynthetic gene clusters from both bacteria afforded the first genetic evidence supporting cyanosporaside's enediyne, and thereby p-benzyne biradical, biosynthetic origin and revealed the molecular basis for nitrile and glycosyl functionalization. This study provides new opportunities for bioengineering of enediyne derivatives and expands the structural diversity afforded by enediyne gene clusters.


Coil embolization of a tuboovarian anastomosis before uterine artery embolization to prevent nontarget particle embolization of the ovary.
Uterine artery embolization (UAE) is being used more frequently as a primary treatment for uterine leiomyoma. Performing UAE in women who desire future fertility is controversial because of the risks of premature menopause and the undetermined effects on pregnancy. The etiology of ovarian failure after UAE is not yet clearly defined, but one of the leading possibilities is nontarget embolization of the ovaries. In this case report, the authors describe a technique of selective coil embolization of a uterine artery-to-ovarian artery communication before UAE performed specifically to protect the ovary from nontarget embolization.


Molecular Recognition Regulates Coordination Structure of Single-Atom Sites.
Coordination engineering for single-atom sites has drawn increasing attention, yet its chemical synthesis remains a tough issue, especially for tailorable coordination structures. Herein, a molecular recognition strategy is proposed to fabricate single-atom sites with regulable local coordination structures. Specifically, a heteroatom-containing ligand serves as the guest molecule to induce coordination interaction with the metal-containing host, precisely settling the heteroatoms into the local structure of single-atom sites. As a proof of concept, thiophene is selected as the guest molecule, and sulfur atoms are successfully introduced into the local coordination structure of iron single-atom sites. Ultrahigh oxygen reduction electrocatalytic activity is achieved with a half-wave potential of 0.93 V versus reversible hydrogen electrode. Furthermore, the strategy possesses excellent universality towards diversified types of single-atom sites. This work makes breakthroughs in the fabrication of single-atom sites and affords new opportunities in structural regulation at the atomic level.


Membrane Phase Transitions in Lipid-Wrapped Nanoparticles.
A Landau theory is constructed for the gel/fluid transition of a lipid bilayer wrapped around a spherical nanoparticle (lipid-wrapped nanoparticle, LNP). The bilayer is regarded as a regular solution of gel and fluid lipids with distinct inter- and intralayer interactions plus the interaction of the core with the inner layer. It is required that both the inner and the outer surfaces of the bilayer are perfectly covered with lipids, with the gel and fluid lipids having different areas/lipid. The equilibrium state is found by minimizing the free energy as a function of the fractions of fluid lipids in the inner and outer layers. The transition has been studied extensively for lamellar membranes in the thermodynamic limit. LNP have significant curvature and are not in the thermodynamic limit. The increase of the gel energy with curvature, identified in our previous work as its most important effect, is included. The focus of the paper is the dependence of the transition on the core radius, R, controlling curvature, and the core-lipid interaction. With decreasing R, trends found in experiment are reproduced in a model calculation: (1) decrease of the transition temperature, Tm, (2) decoupling of the transitions in the inner and outer layers, and (3) possibility of lower Tm in the inner layer. The disruption of gel packing by curvature and the interaction of the core with the inner layer are highlighted as the most important determinants of deviation from bulk behavior.


Mammography-guided stereotactic fine needle aspiration cytology of breast lesions.
The purpose of the present study was to evaluate the efficacy of mammographic guided stereotactic fine needle aspiration cytology in 136 patients with breast lesions including mammographic features, cytomorphological findings and nuclear grading in malignant cases. Majority of the cases were predictable correctly by combination of the three modalities of diagnosis viz, clinical examination, mammography and cytology.


A facile and sensitive method for quantification of cyclic nucleotide monophosphates in mammalian organs: basal levels of eight cNMPs and identification of 2',3'-cIMP.
A sensitive, versatile and economical method to extract and quantify cyclic nucleotide monophosphates (cNMPs) using LC-MS/MS, including both 3',5'-cNMPs and 2',3'-cNMPs, in mammalian tissues and cellular systems has been developed. Problems, such as matrix effects from complex biological samples, are addressed and have been optimized. This protocol allows for comparison of multiple cNMPs in the same system and was used to examine the relationship between tissue levels of cNMPs in a panel of rat organs. In addition, the study reports the first identification and quantification of 2',3'-cIMP. The developed method will allow for quantification of cNMPs levels in cells and tissues with varying disease states, which will provide insight into the role(s) and interplay of cNMP signalling pathways.


A case of thalamic abscess treated by endoscopic surgery.
We report about a 7-year-old female child with cyanotic heart disease whose thalamic abscess was successfully treated by endoscope-assisted abscess drainage. Endoscopic aspiration of thalamic abscess appears to be a safe and effective method of treatment for deep-seated abscesses, as direct visualization of the abscess cavity is possible and the completeness of evacuation can be assessed.


Assessment of left ventricular ejection fraction by four different methods using 99mTc tetrofosmin gated SPECT in patients with small hearts: correlation with gated blood pool.
To compare the currently available gated SPECT software programs, quantitative gated SPECT (QGS), Emory Cardiac Toolbox (ECTb), Left Ventricular Global Thickening Fraction (LVGTF), and the recently developed Layer of Maximum Count (LMC) method with equilibrium Gated Blood Pool (GBP) scintigraphy in calculating the ejection fraction in patients with small hearts. Twenty patients with small hearts (end diastolic volume <85 ml) were collected for the study. Gated myocardial perfusion SPECT and planar GBP were performed for all patients. The four methods QGS, ECTb, and LVGTF and LMC were used for volumes estimation and ejection fraction calculation. ANOVA analysis revealed significant differences among the methods in ejection fraction estimation (P<0.0001). The mean ejection fraction by GBP was significantly overestimated by QGS and ECTb and LVGTF (P<0.0001, P<0.0001 and P=0.006, respectively). The mean ejection fraction by GBP was not significantly different from that by the LMC method (P=0.213). Ejection fraction measurements by QGS and ECTb yielded moderate correlation with GBP values (r=0.588, P=0.006; and r=0.564, P=0.010, respectively). The ejection fraction by the LMC method was marginally correlated but LVGTF showed a non-significant correlation with GBP (r=0.438, P=0.053; and r=0.155, P=0.515, respectively). Agreement analysis for ejection fraction estimation by QGS and ECTb demonstrated a non-significant correlation between the difference and the mean. The LMC method showed a non-significant trend to decrease the difference with GBP as the mean increased. However, the LVGTF method significantly increased the difference as the mean increased. The currently available gated SPECT methods have moderate to poor correlations in addition to wide agreement limits with gated blood pool studies in patients with small hearts. Improvement of these methods to achieve better results in such patients is recommended. The newly developed LMC method yielded better results in the group with small hearts but with low interchangeability with GBP studies.


[Comparison of methods for evaluating the nephrotoxicity of cisplatin].
The BUN, serum creatinine, creatinine clearance and the urinary excretion of leucine aminopeptidase (LAP), alkaline phosphatase (ALP), beta 2-microglobulin (beta-m), and N-acetyl-beta-glucosaminidase (NAG), were measured in 21 gynecological cancer patients treated with CAPF (CPA + ADM + CDDP + 5-FU) to evaluate the sensitivity of these indices to renal tubular damage. After receiving CDDP almost all patients displayed an increase in excretion of beta-m but no urinary enzyme activities. However, NAG index (NAG activity/urinary creatinine) rose markedly in all patients. We concluded that NAG index is a valuable method in providing sensitive indices for detecting renal tubular damage caused by CDDP.


Functional analysis of MSH6 mutations linked to kindreds with putative hereditary non-polyposis colorectal cancer syndrome.
To date, five mismatch-repair (MMR) genes, MLH1, MSH2, MSH6, MSH3 and PMS2, are known to be involved in human MMR function. Two of those, MLH1 and MSH2, are further the most common susceptibility genes for hereditary non-polyposis colorectal cancer (HNPCC), while MSH3 and PMS2 are seldom (PMS2) or not at all (MSH3 ) reported to be involved in HNPCC. Despite the increasing number of MSH6 germline mutations, their pathogenicity remains questionable, because the mutations are mainly linked to putative HNPCC families lacking the typical clinical and molecular characteristics of the syndrome, such as early age at onset and high microsatellite instability (MSI). High MSI is a consequence of MMR defect, and the pathogenicity of germline mutations in HNPCC is thus linked to malfunction of MMR. To address the question of whether and how MSH6 mutations cause susceptibility to HNPCC, we studied heterodimerization of four MSH6 variants with MSH2, and the functionality of these MutSalpha complexes in an in vitro MMR assay. All mutations occurred in putative HNPCC patients. Irrespective of the type or the site of the amino acid substitutions, all the variants repaired G.T mismatches to A.T as wild-type MSH6 protein. However, the MSH6 protein carrying a mutation in the MSH2/MSH6 interaction region was poorly expressed, suggesting problems in its stability. Our results are clinically relevant, since they demonstrate that under the stable in vitro conditions, when the amounts of the proteins are adequate for repair, the tested MSH6 mutations do not affect repair function. Consequently, while the typical HNPCC syndrome is associated with problems in repair reaction, the pathogenicity of mutations in putative HNPCC families may be linked to other biochemical events.


Prevalence and Determinants of Burnout Among Palliative Care Clinicians in Saudi Arabia.
Palliative care is in dire necessity than ever before due to aging populations and the prevalence of cancer and other chronic diseases associated with aging. To assess the prevalence and risk factors associated with burnout among palliative care clinicians in Saudi Arabia. A cross-sectional study conducted in 2018 covering all palliative care centers of Saudi Arabia and included 44 palliative care physicians (26 males and 18 females). The level of burnout was measured using Maslach Burnout Inventory's (MBI) 22 point scale questionnaire which assesses emotional exhaustion, depersonalization, and reduced personal accomplishment, the three dimensions of burnout syndrome. Pearson correlation and binary logistic analysis were performed using SPSS to find out factors influencing burnout considering P-value of <0.05 as significant. Eight participants (18.2%) had experienced emotional exhaustion and 11 (25%) had experienced depersonalization and detachment, and reduced personal accomplishment, each. Job title and availability of some administrative departments, supporting health care staff, and pain relief medications have shown significant impact of level of burnout. However, the prevalence of the burnout dimensions did not differ significantly according to the palliative care physicians' other characteristics. This is amongst the first survey to assess the prevalence of burnout among palliative care physicians in Saudi Arabia. Although, some variables have shown significantly high level in the burnout domains, yet, the overall prevalence of burnout is low among palliative care physicians in Saudi Arabia. The availability of hospitals services such as administrative departments, supporting health care staff, and pain relief drugs have shown significant impact on burnout.


Drying of a charge-stabilized colloidal suspension in situ monitored by vertical small-angle X-ray scattering.
We report a first application of vertical small-angle X-ray scattering to investigate the drying process of a colloidal suspension by overcoming gravity related restrictions. From the observation of the drying behavior of charge-stabilized colloidal silica in situ, we find the solidification of the colloidal particles exhibits an initial ordering, followed by a sudden aggregation when they overcome an electrostatic energy barrier. The aggregation can be driven not only by capillary pressure but also by thermal motion of the particles. The dominating contribution is determined by the magnitude of the energy barrier at the transition, which significantly decreases during drying due to an increased ionic strength.