Intake of vitamin B12 in relation to vitamin B12 status in groups susceptible to deficiency: a systematic review.
To systematically review the evidence for whether habitual or different levels of experimental intake of vitamin B12 from diet and supplements is sufficient to ensure adequate B12 status in groups most susceptible to vitamin B12 deficiency. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Scopus up to 21 May 2021, for intervention studies, prospective cohort studies and case-control studies assessing B12 intake from diet and/or supplements in relation to B12 status (s/p-B12, holotranscobalamin, methylmalonic acid, homocysteine or breastmilk B12). Cross-sectional studies were eligible for studies conducted during pregnancy and lactation. Included populations were children (0-18 years), young adults (18-35 years), pregnant or lactating women, older adults (≥65 years) and vegans or vegetarians. Study selection, data extraction and risk of bias assessment were conducted by two assessors independently. The evidence was synthesized qualitatively and classified according to the World Cancer Research Fund. The searches yielded 4855 articles of which 89 were assessed in full text and 18 included. Three studies were conducted during pregnancy and three during lactation or infancy - all observational. Eight studies were conducted among older adults; most were interventions among B12-deficient participants. Four studies were eligible for vegetarian and vegans, all interventions. The strength of evidence that habitual B12 intake or an intake in line with the current Nordic recommended intake (RI) is sufficient to ensure adequate status was considered Limited - no conclusion for all included populations. Evidence is insufficient to assess if or which level of B12 intake is sufficient to maintain adequate status for all included populations. Population-based cohort studies and low-to-moderate dose interventions that address this question are highly warranted.


Prefabrication and prelamination strategies for the reconstruction of complex defects of trachea and larynx.
Complex tracheal and laryngeal defects can be reconstructed using prelamination and prefabrication techniques. Three clinical situations are described in detail in the article. In short segment restenosis defects within scarred surroundings, we restore the fibrocartilaginous defect with a radial forearm fascia flap prelaminated with buccal mucosa or cartilage. This provides a newly vascularized inner lining to the tracheal defect and restores the tubular convexity. For long segment defects we need a technique that can withstand respiratory forces. We use a heterotopic prefabrication strategy to vascularize a tracheal allograft wrapped in forearm fascia. Chimerism is created by replacing donor respiratory epithelium with buccal mucosa of the recipient. After orthotopic transfer, this chimerism allows immunosuppression to be tapered and stopped when bronchoscopy shows mucosal integrity of the new trachea, since the recipient epithelium replaces the allogeneic inner tracheal lining by means of a chronic rejection process. A distinct situation occurs after resection of a unilateral larynx tumor, which usually results in a total laryngectomy with loss of both vocal cords, since reconstruction of the hemilarynx is considered too complex. First, we prefabricate a nearby four-ring autologous tracheal segment using radial forearm fascia. In a second stage, this orthotopically vascularized trachea restores the laryngeal structure with the aim to conserve one vocal cord and thus speech. Orthotopic and heterotopic prelamination and prefabrication strategies offer efficient and reproducible solutions for the restoration of challenging short and long segment tracheal defects, as well as unilateral laryngeal defects. The series in this review article are based on previous studies and case reports. The level of evidence is III-"Study of nonconsecutive patients, without a universally applied gold standard: case-control study".


De novo supernumerary ring chromosome 7: first report of a non-mosaic patient and review of the literature.
The present authors report the case of a 12-year-old-boy with a de novo, non-mosaic supernumerary ring chromosome 7 associated with significant developmental delay and speech difficulty. A review of the literature identified a total of 18 cases with ring chromosomes 7 who can be classified into two groups: (1) patients with a cell line that has 47 chromosomes with a small supernumerary ring chromosome 7 resulting in partial trisomy; and (2) individuals had a cell line with a large ring chromosome replacing one of the normal chromosomes 7 resulting in partial monosomy. A comparison of clinical features in the two groups of patients showed several common features such as growth and mental retardation, and facial dysmorphism, including, ear and eye anomalies. However, patients with partial trisomy have speech difficulty as a distinguishing feature, while patients with partial monosomy have skin lesions as a cardinal feature. All the published cases of ring chromosome 7, irrespective whether they are supernumerary or normal modal number, are mosaics except for one. The present subject is the first case of a de novo, non-mosaic supernumerary ring chromosome 7.


Action of adenosine on energy metabolism and on glucose-6-phosphate dehydrogenase in rat brains.
The Warburg method was used to study the action of adenosine on several phases of rat cerebral cortex metabolism, using cortex slices or homogenates. In the presence of exogenous glucose in vitro, oxygen consumption and lactate production are not affected by adenosine in sections. In vivo, there is an increase of oxygen consumption and of lactate production but which are not significant. Adenosine may activate metabolic pathways, since the observed metabolic changes remain constant during the period of activity of adenosine (30 to 60 min) and disappear concomitantly with adenosine. The action of adenosine is much more evident in sections from the brains of injected animals, where the increase of lactate production becomes significant. This suggests that in this case adenosine favors a better utilization of glycogen via an activation of adenylate cyclase. The increased activity of G-6-PDH was observed in vitro but was not significant in vivo. These observations were confirmed with homogenates from the in vivo series by the significant decrease of inorganic phosphate levels, consistent with an increased formation of nucleotide phosphates. The increased cerebral glucose concentration is perhaps a result of increased blood glucose levels, in turn resulting from the known depression of insulin release by adenosine, or from a preferential utilization of glycogen, resulting from the activation of adenylate cyclase.


Flavonoid compounds from Pyrus communis L. flowers.
Five flavonoid glycosides: kaempferol 3-O-beta-D-glucopyranoside (IV), isorhamnetin 3-O-beta-D-glucopyranoside (V), isorhamnetin 3-O-beta-D-(6''-O-alpha-L-rhamnopyranosyl)-glucopyranoside (VIII), 8-methoxykaempferol 3-O-beta-D-(2''-O-alpha-D-glucopyranosyl)-glucopyranoside (VI), 8-methoxykaempferol 3-O-beta-D-(2''-O-alpha-L-rhamnopyranosyl)-glucopyranoside (VII) and chlorogenic acid (IX) were isolated from the flowers naturally growing Pyrus communis L. They were identified by chemical and spectroscopic methods.


Risk Profiles for Care Dependency: Cross-Sectional Findings of a Population-Based Cohort Study in Germany.
Background: Rising life expectancy in Western societies is accompanied by a rising incidence of care dependency (CD) among older people. Objective: The aim of the study was to examine which health-related and social determinants were associated with CD. Method: We used cross-sectional data from the first follow-up (N = 1,699) of a prospective, population-based cohort study of older participants (≥70 years). CD was assessed if participants required substantial assistance in at least two activities of daily living for 90+ minutes daily. Multivariate logistic regressions were applied. Results: Participants' mean age was 82 years; 18.9% were care-dependent. CD was significantly associated with older age, urinary incontinence, stroke, falls, cancer, diabetes, education level, having no partner, limited mobility, and limited physical activity. Discussion: Our research highlights the importance of promoting mobility, even in care-dependent people. Further research should investigate the role of partnership in terms of the prevention and delay of CD.


[Pharmacotherapy of cough].
The optimal approach to the treatment of cough consists, first, in determination of its precise cause. Treatment should be directed at the specific etiology or the pathophysiologic mechanism responsible for cough. The outcome of specific treatment is almost always successful. However, there are also situations in which the cause of cough is unknown or in which the cough does not serve any useful purpose but prevents rest and sleep. In such cases symptomatic treatment with antitussives may be indicated. Centrally acting antitussives such as opium alkaloids, dextromethorphan and noscapine are the most effective drugs. The indication for expectorants lacks scientifically based support.


A polymer film modified sensor for voltammetric determination of uric acid in the presence of ascorbic Acid and its application in urine.
A novel uric acid electrochemical sensor was fabricated by electropolymerization on glassy carbon electrode (GCE) with 4-(2-pyridylazo)-resorcinol (PAR) and its electrochemical property was investigated through cyclic voltammetry. The effect of film thickness on the oxidation response was also studied by electropolymerized scan times. The voltammetric behavior of uric acid (UA) was studied with the poly PAR modified GCE. The modified GCE was used to electrochemically detect the individual of UA and the mixture of UA and ascorbic acid (AA) by cyclic voltammetry (CV) or differential pulse voltammetry (DPV) method. For the ternary mixture containing UA and AA, the two compounds can well be separated from each other at a scan rate of 100 mV s(-1) with a potential difference of 345 mV in DPV between UA and AA. The peak currents of UA oxidation increase linearly with the concentration in ranges of 1.0x10(-8)-5.0x10(-5) mol l(-1), and the detection limits (S/N=3) was 1.0x10(-9) mol l(-1). This method was successfully applied to the determination of uric acid in human urine samples.


Development, implementation, and evaluation of a geriatric nurse education program.
Substantial gaps exist between the number of older adults requiring competent geriatric care and the number of nurses able to provide it. The purpose of this study was to develop, implement, and evaluate a geriatric nurse education program to ensure nurses meet the needs of the increasing elderly population. Establishing partnerships between individuals in academia and those in a clinical practice was imperative in the development of the program. Content for the program was created with the assistance of a geriatric nursing consultant and approved by the State Nurses Association. The program was piloted with 18 participating nurses. Using paired ttests, pretests and posttests revealed significant improvements in the level of knowledge and attitudes toward older adults. As a result of the program, participants showed improved attitudes toward and increased knowledge of older adults' needs, and further program development and dissemination are planned nationally and abroad.


The Outcomes and Impact Scale - Revised: the psychometric properties of a scale assessing the impact of service provision.
The Outcomes and Impact Scale - Revised (O&IS-R) was developed to measure the impact of service provision on adults with disability. The aim of this research was to explore the psychometric properties of the scale following a recent revision. Adults with disability and/or their carers or support workers participated in the research. Participants were recruited across Australia using a range of strategies and completed the scale in relation to a service or support that they nominated. Two forms of the scale were developed (easy and standard English), which could be completed in hardcopy or via a bespoke website. The O&IS-R demonstrated good internal consistency and alternate form reliability. Factor analysis of the scale revealed one factor that clearly corresponded to the whole of life construct that the scale was designed to measure and, in general, participants with disability and staff understood the intent or purpose of the survey. All domains except the spiritual and political domain were considered to be relevant service outcomes. Some changes to wording were suggested to improve clarity. The O&IS-R is a psychometrically sound scale that can be used in service and research settings to measure the impact of services and supports.


Learning Heterogeneous Hidden Markov Random Fields.
Hidden Markov random fields (HMRFs) are conventionally assumed to be homogeneous in the sense that the potential functions are invariant across different sites. However in some biological applications, it is desirable to make HMRFs heterogeneous, especially when there exists some background knowledge about how the potential functions vary. We formally define heterogeneous HMRFs and propose an EM algorithm whose M-step combines a contrastive divergence learner with a kernel smoothing step to incorporate the background knowledge. Simulations show that our algorithm is effective for learning heterogeneous HMRFs and outperforms alternative binning methods. We learn a heterogeneous HMRF in a real-world study.


A linkage disequilibrium-based approach to selecting disease-associated rare variants.
Rare variants have increasingly been cited as major contributors in the disease etiology of several complex disorders. Recently, several approaches have been proposed for analyzing the association of rare variants with disease. These approaches include collapsing rare variants, summing rare variant test statistics within a particular locus to improve power, and selecting a subset of rare variants for association testing, e.g., the step-up approach. We found that (a) if the variants being pooled are in linkage disequilibrium, the standard step-up method of selecting the best subset of variants results in loss of power compared to a model that pools all rare variants and (b) if the variants are in linkage equilibrium, performing a subset selection using step-based selection methods results in a gain of power of association compared to a model that pools all rare variants. Therefore, we propose an approach to selecting the best subset of variants to include in the model that is based on the linkage disequilibrium pattern among the rare variants. The proposed linkage disequilibrium-based variant selection model is flexible and borrows strength from the model that pools all rare variants when the rare variants are in linkage disequilibrium and from step-based selection methods when the variants are in linkage equilibrium. We performed simulations under three different realistic scenarios based on: (1) the HapMap3 dataset of the DRD2 gene, and CHRNA3/A5/B4 gene cluster (2) the block structure of linkage disequilibrium, and (3) linkage equilibrium. We proposed a permutation-based approach to control the type 1 error rate. The power comparisons after controlling the type 1 error show that the proposed linkage disequilibrium-based subset selection approach is an attractive alternative method for subset selection of rare variants.


Low dimensional representation of face space by face-selective inferior temporal neurons.
The representation of visual objects in primate brain is distributed and multiple neurons are involved in encoding each object. One way to understand the neural basis of object representation is to estimate the number of neural dimensions that are needed for veridical representation of object categories. In this study, the characteristics of the match between physical-shape and neural representational spaces in monkey inferior temporal (IT) cortex were evaluated. Specifically, we examined how the number of neural dimensions, stimulus behavioral saliency and stimulus category selectivity of neurons affected the correlation between shape and neural representational spaces in IT cortex. Single-unit recordings from monkey IT cortex revealed that there was a significant match between face space and its neural representation at lower neural dimensions, whereas the optimal match for the non-face objects was observed at higher neural dimensions. There was a statistically significant match between the face and neural spaces only in the face-selective neurons, whereas a significant match was observed for non-face objects in all neurons regardless of their category selectivity. Interestingly, the face neurons showed a higher match for the non-face objects than for the faces at higher neural dimensions. The optimal representation of face space in the responses of the face neurons was a low dimensional map that emerged early (~150 ms post-stimulus onset) and was followed by a high dimensional and relatively late (~300 ms) map for the non-face stimuli. These results support a multiplexing function for the face neurons in the representation of very similar shape spaces, but with different dimensionality and timing scales.


High-energy-resolution angle-resolved inverse-photoelectron spectroscopy apparatus for damage-free measurements of conduction band structures of functional materials.
The energy band structure of the conduction band (energy-momentum relation of electrons) is crucial to understanding the electron transport of crystalline materials. In this paper, we describe an angle-resolved low-energy inverse photoelectron spectroscopy (AR-LEIPS) apparatus that examines the conduction band structures of materials sensitive to the electron beam, such as organic semiconductors and organic-inorganic hybrid perovskites. The principle of this apparatus is based on AR inverse photoelectron spectroscopy. To minimize radiation damage and improve energy resolution, we employed our previous approach used in LEIPS [H. Yoshida, Chem. Phys. Lett. 539-540, 180 (2012)]. We obtained an overall energy resolution of 0.23 eV with a momentum resolution of 0.9 nm-1 at the electron kinetic energy of 2 eV or higher.


[The coordinated effect of the excessive protein and cholesterin intake on inducing rat myocardial fibrosis and its mechanism].
To investigate the coordinated role and its mechanism of the high protein and hypercholesterol intake on inducing rat myocardial fibrosis. The tissue level of the collagen in left ventricule, the concentrations of the plasma and the cardiac tissue angiotensin II (Ang II) and Aldosterone (Ald), the serum concentration of nitrite (NO2-), in the Wistar rats on diet which adding 20% protein or/and 100 mg/d cholesterin in the rat standard foods for 8 weeks, were measured by the colorimetric analysis of the hydroxyproline, by the radioimmunoassay, and by the assay of Griess, respectively. 1.69 times left ventricular collagen contents, 0.7 times plasma concentrations of total cholesterin, 1.5 times levels of the plasma Ang II and 1 time myocardial ald contents were higher, and the serum NO2- concentration was significant lower, in the rats of the high protein and hypercholesterol intake than in the rats of the high protein intake. That 0.48 times left ventricular collagen contents, 0.23 times plasma Ang II in the high protein and hypercholesterol intake rats were higher than in the high cholesterin intake rats. The excessive protein and cholesterin intake can induce the coordinated effect on developing the myocardial fibrosis of rats. And the mechanism of the fibrosis in rat left ventricule maybe result with the activation of RAAS and the endothelial injury.


Effects of various imidazole ligands on heme conformation in endothelial nitric oxide synthase.
We have evaluated the influence of a series of substituted imidazoles on the heme structure of endothelial nitric oxide synthase (eNOS). Optical, MCD, and EPR spectra reveal widely differing effects on heme spin state and geometry. 1-Substituted imidazoles always yield low-spin heme complexes, but the size of the 2- and 4-substituent influences their structural effects on the heme. Methyl substituents lead to low-spin complexes while the bulky phenyl group yields high-spin complexes. The only exception to this behavior is provided by 2-aminoimidazole. Although this compound has three functional groups which can serve as an axial ligand to the heme, its binding to eNOS leads to a pure high-spin complex. This result can only be interpreted as due to a direct binding of 2-aminoimidazole to the guanidine binding subdomain of L-arginine. MCD spectra also imply that an O-ligand is present in the low-spin resting eNOS, while EPR data reveal the presence of two low-spin heme complexes in resting eNOS and its imidazole complexes. EPR also distinguishes four different high-spin forms of eNOS generated by different imidazole analogues. This series of ligands promises to be useful in probing the subtle structural difference among the active sites of three NOS isozymes and in developing selective inhibitors to these important enzymes.


Hepatic metabolic effects of Curcuma longa extract supplement in high-fructose and saturated fat fed rats.
The metabolic effects of an oral supplementation with a Curcuma longa extract, at a dose nutritionally relevant with common human use, on hepatic metabolism in rats fed a high fructose and saturated fatty acid (HFS) diet was evaluated. High-resolution magic-angle spinning NMR and GC/MS in combination with multivariate analysis have been employed to characterize the NMR metabolite profiles and fatty acid composition of liver tissue respectively. The results showed a clear discrimination between HFS groups and controls involving metabolites such as glucose, glycogen, amino acids, acetate, choline, lysophosphatidylcholine, phosphatidylethanolamine, and β-hydroxybutyrate as well as an increase of MUFAs and a decrease of n-6 and n-3 PUFAs. Although the administration of CL did not counteract deleterious effects of the HFS diet, some metabolites, namely some n-6 PUFA and n-3 PUFA, and betaine were found to increase significantly in liver samples from rats having received extract of curcuma compared to those fed the HFS diet alone. This result suggests that curcuminoids may affect the transmethylation pathway and/or osmotic regulation. CL extract supplementation in rats appears to increase some of the natural defences preventing the development of fatty liver by acting on the choline metabolism to increase fat export from the liver.


Paediatric Posttraumatic Cyst-Like Lesions: A Report of Two Cases and Review of the Literature.
Posttraumatic cyst-like lesions are a rare finding after greenstick fractures in children. These asymptomatic, cystic lesions become radiologically apparent 2-4 months after the initial trauma. Conventional radiographs typically show nonexpansile, well-circumscribed lesions in the cortex, proximal to the fracture site. It is important to recognize them as benign to prevent unnecessary concern and additional imaging or invasive diagnostic procedures. No treatment is indicated, as they eventually resolve spontaneously in 1 to 3 years. The two cases of posttraumatic cyst-like lesions after paediatric forearm fractures are presented.


RSRC1 suppresses gastric cancer cell proliferation and migration by regulating PTEN expression.
Arginine/serine‑rich coiled coil 1 (RSRC1) is a gene which plays a significant role in the constitutive and alternative splicing of mRNA and transcriptional regulation. It has been implicated in various neurological disorders, as well as in cancer. However, its role in gastric cancer (GC) remains unknown. Thus, the present study aimed to investigate the role of RSRC1 in GC. RSRC1 expression in GC tissues was determined by RT‑qPCR and immunohistochemical staining. The effects of RSRC1 on cell proliferation and migration were detected using a Cell Counting Kit‑8 assay, 5‑ethynyl‑2'‑deoxyuridine (EdU) incorporation assay and a Transwell migration assay. Western blot analysis and RT‑qPCR were used to explore the molecular mechanisms of of action of RSRC1 in GC. The results indicated that RSRC1 expression was downregulated in GC tissues compared to paired normal tissues and the reduced expression of RSRC1 was shown to contribute to a poor prognosis of patients with GC. RSRC1 knockdown promoted the proliferation and migration of GC cells. In addition, the knockdown of RSRC1 decreased the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a potent tumor suppressor gene controlling cellular growth and viability. On the whole, the findings of the present study indicate that RSRC1 functions as a tumor suppressor gene in GC and that it may exert its effects by regulating PTEN expression.


Excess infections due to antimicrobial resistance: the "Attributable Fraction".
Antimicrobial use causes a transient decrease in an individual's resistance to colonization by noncommensal bacteria ("competitive effect") and increases the likelihood of infection upon exposure to a foodborne pathogen. The additional "selective effect" of antimicrobial resistance results in a >3-fold increase in vulnerability to infection by an antimicrobial-resistant pathogen among individuals receiving antimicrobial therapy for unrelated reasons. Combining the increase in vulnerability to infection with the prevalence of taking an antimicrobial agent, it is possible to estimate the attributable fraction, or the number of excess infections that occurred as a result of the unrelated use of an antimicrobial agent to which the pathogen was resistant. Calculations based on estimates of the annual infection rates and attributable fractions of infections with nontyphoidal Salmonella and Campylobacter jejuni suggest that resistance to antimicrobial agents results annually in an additional 29,379 nontyphoidal Salmonella infections, leading to 342 hospitalizations and 12 deaths, and an additional 17,668 C. jejuni infections, leading to 95 hospitalizations.


Minimizing opioid use after acute major trauma.
Results of an initiative at an academic medical center to reduce prescription opioid use in patients with acute traumatic injuries are reported. In 2014, the University of Kentucky Hospital trauma service implemented a pain management strategy consisting of patient and provider education emphasizing the use of nonopioid analgesics to minimize opioid use without compromising analgesia effectiveness. To assess the impact of the initiative, a retrospective analysis of data on cohorts of patients admitted with acute trauma before (n = 489) and after (n = 424) project implementation was conducted. The primary endpoint was opioid use (prescribed daily milligram morphine equivalents [MME]) at discharge. Secondary endpoints included inpatient opioid and alternative analgesic use, pain control, ileus development, length of stay, and discharge disposition. Compared with the preintervention cohort, the postintervention cohort had a lower median daily discharge MME overall (45 MME versus 90 MME, p < 0.001); after stratification of MME data by baseline opioid use, this finding held true only for patients with no opioid prescription at admission. Although utilization of gabapentinoids, skeletal muscle relaxants, and clonidine increased during the postintervention period, inpatient opioid use did not differ significantly in the 2 cohorts. Utilization of both nonsteroidal antiinflammatory drugs and acetaminophen was lower in the postintervention cohort versus the preintervention cohort. Targeted provider and patient education on minimizing opioid use was associated with a reduction in MME on discharge from the hospital after traumatic injury.


Mapping patterns of c-fos expression in the central nervous system after seizure.
A dramatic and specific induction of c-fos was observed in identifiable neuronal populations in vivo after administration of the convulsant Metrazole. This effect was time- and dose-dependent and was abolished by prior treatment with the anticonvulsant drugs diazepam or pentobarbital. About 60 minutes after administration of Metrazole, c-fos messenger RNA reached a maximum and declined to basal levels after 180 minutes. A further decrease below that in normal brain was observed before a return to basal levels after 16 hours. While Metrazole still elicited seizures during this period, reinduction of c-fos was largely refractory. At 90 minutes, c-fos protein was observed in the nuclei of neurons in the dentate gyrus, and in the pyriform and cingulate cortices. Subsequently, c-fos protein appeared throughout the cortex, hippocampus, and limbic system. Thus, seizure activity results in increased c-fos gene expression in particular subsets of neurons.


The effects of cryosolvents on DOPC-β-sitosterol bilayers determined from molecular dynamics simulations.
Polyhydroxylated alcohols and DMSO are common cryosolvents that can damage cell membranes at sufficiently high concentrations. The interaction of representative plant cell membranes composed of mixed 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)-β-sitosterol bilayers, at a range of compositions, with a variety of cryosolvent molecules (DMSO, propylene glycol, ethylene glycol, glycerol, and methanol) has been investigated using molecular dynamics simulations. All the cryosolvents cause the bilayers to thin and become disordered; however, DMSO and propylene glycol have a greater disordering effect on the bilayer. Propylene glycol is shown to have the ability to cause the formation of pores in pure DOPC bilayers in a manner similar to that previously shown for DMSO. As the concentration of β-sitosterol within the bilayer increases, the membranes become more resistant to the deleterious effects of the cryosolvents. All three polyhydroxylated species are observed to form hydrogen bonds to multiple phospholipid molecules, effectively acting as cross-linkers, with glycerol being the most effective cross-linker. Increases in the concentration of β-sitosterol reduce overall hydrogen bonding of the bilayer with the cryosolvents as well as cross-linking, with glycerol and ethylene glycol being the most affected. The ability of all of these cryosolvents to affect the integrity of cell membranes appears to be the result of the balance of their ability to disorder lipid bilayers, to diffuse across them, and to interact with the lipid head groups.


[Decision analysis: application of a diagnostic and therapeutic strategy in cases of bronchial carcinoma].
Faced with a constant development of new methods of treatment and diagnosis, the clinician does not always have an easy task: the multiplicity of options available makes it difficult to take decisions guaranteeing both maximum safety of diagnosis with a reasonable number of examinations. In relation to this problem the respective places of CT scanning, mediastinoscopy and exploratory thoracotomy in the search for metastatic mediastinal adenopathy in the course of the local and regional assessment of a bronchial carcinoma are considered. In this situation the general principles of decision analysis can be contemplated: the characteristics of the test (sensibility and specificity), the prevalence of the disease and Bayes theorem and the concept of utility. The consequences flowing from this approach are analysed.


A taxonomy of hospitals participating in Medicare accountable care organizations.
Medicare was an early innovator of accountable care organizations (ACOs), establishing the Medicare Shared Savings Program (MSSP) and Pioneer programs in 2012-2013. Existing research has documented that ACOs bring together an array of health providers with hospitals serving as important participants. Hospitals vary markedly in their service structure and organizational capabilities, and thus, one would expect hospital ACO participants to vary in these regards. Our research identifies hospital subgroups that share certain capabilities and competencies. Such research, in conjunction with existing ACO research, provides deeper understanding of the structure and operation of these organizations. Given that Medicare was an initiator of the ACO concept, our findings provide a baseline to track the evolution of ACO hospitals over time. Hierarchical clustering methods are used in separate analyses of MSSP and Pioneer ACO hospitals. Hospitals participating in ACOs with 2012-2013 start dates are identified through multiple sources. Study data come from the Centers for Medicare and Medicaid Services, American Hospital Association, and Health Information and Management Systems Society. Five-cluster solutions were developed separately for the MSSP and Pioneer hospital samples. Both the MSSP and Pioneer taxonomies had several clusters with high levels of health information technology capabilities. Also distinct clusters with strong physician linkages were present. We examined Pioneer ACO hospitals that subsequently left the program and found that they commonly had low levels of ambulatory care services or health information technology. Distinct subgroups of hospitals exist in both the MSSP and Pioneer programs, suggesting that individual hospitals serve different roles within an ACO. Health information technology and physician linkages appear to be particularly important features in ACO hospitals. ACOs need to consider not only geographic and service mix when selecting hospital participants but also their vertical integration features and management competencies.


Plasma concentrations during repeated intravenous and oral methyl-proscillaridin application in man.
The aim of this study was to establish data on the plasma levels of the glycoside derivative methyl-proscillaridin (MP) following repeated intravenous and oral doses. The study was carried out on healthy male volunteers. Each received 0.5 mg of MP daily at 8 a.m. for 7 days. 6 volunteers received the drug i.v., 6 p.o. as tablets and 5 p.o. as elixir. Plasma glycoside concentrations were measured utilizing a 86Rb-erythrocyte assay. The mean plasma concentrations on the 6th and 7th days of application were: 752.9 (Sx = 303.5) pg/ml for the i.v. route, 432.9 (Sx = 115.5) pg/ml for the tablets and 473.1 (Sx = 321.5) pg/ml for the elixir. The mean ratio between plasma concentrations with tablets and i.v. injection averaged 63%. It is concluded that the therapeutic activity of oral MP is about 60 to 70% that of the i.v. application.


A Real-Time Skin Dose Tracking System for Biplane Neuro-Interventional Procedures.
A biplane dose-tracking system (Biplane-DTS) that provides a real-time display of the skin-dose distribution on a 3D-patient graphic during neuro-interventional fluoroscopic procedures was developed. Biplane-DTS calculates patient skin dose using geometry and exposure information for the two gantries of the imaging system acquired from the digital system bus. The dose is calculated for individual points on the patient graphic surface for each exposure pulse and cumulative dose for both x-ray tubes is displayed as color maps on a split screen showing frontal and lateral projections of a 3D-humanoid graphic. Overall peak skin dose (PSD), FOV-PSD and current dose rates for the two gantries are also displayed. Biplane-DTS uses calibration files of mR/mAs for the frontal and lateral tubes measured with and without the table in the beam at the entrance surface of a 20 cm thick PMMA phantom placed 15 cm tube-side of the isocenter. For neuro-imaging, conversion factors are applied as a function of entrance field area to scale the calculated dose to that measured with a Phantom Laboratory head phantom which contains a human skull to account for differences in backscatter between PMMA and the human head. The software incorporates inverse-square correction to each point on the skin and corrects for angulation of the beam through the table. Dose calculated by Biplane DTS and values measured by a 6-cc ionization chamber placed on the head phantom at multiple points agree within a range of -3% to +7% with a standard deviation for all points of less than 3%.


High flow priapism following the insertion of an inflatable penile prosthesis mimicking autoinflation: a case report.
Penile prosthesis implantation is a surgical option for erectile dysfunction when other treatments fail or the patient prefers implantation. Although penile prosthesis is generally considered safe and effective, various complications have been reported in the literature. High-flow priapism, resulting from an arteriovenous fistula between the cavernosal artery and the corpora cavernosa, is a rare complication after penile prosthesis implantation. Managing the condition as autoinflation may lead to unfortunate complications. A 54-year-old male patient underwent a penile prosthesis implantation due to erectile dysfunction lasting for 5 years. Doppler ultrasound revealed arterial insufficiency that was refractory to oral and intracavernosal treatments. A 3-piece inflatable penile prosthesis (Coloplast - Titan) was implanted through a midline penoscrotal incision without any complications. The patient reported uncontrolled tumescence after activating the device, which led us to suspect autoinflation. The final diagnosis was high-flow priapism due to an arteriovenous fistula in the cavernosal artery. The patient was given an antiandrogenic medication and the prosthesis was deflated for 3 months. The fistula closed without any additional intervention. High-flow priapism is a rare but potential complication of penile prosthesis implantation. Careful evaluation and management of patients' symptoms are necessary for diagnosing and treating this condition. This case highlights the importance of considering high-flow priapism as a potential cause of uncontrolled tumescence after penile prosthesis implantation and the possibility of successful non-surgical management.


The phosphoinositide 3-kinase pathway is crucial for the growth of canine mast cell tumors.
Mast cell tumors (MCTs) are the most common tumors in dogs, accounting for 16-21% of cutaneous tumors. Although several small molecule inhibitors, including imatinib mesylate, have been used for the treatment of MCTs, the response rate remains less than 50%. In this study, the effects of different selective signal inhibitors on MCT cell growth were evaluated using 4 different cell lines derived from dogs. We found that the phosphoinositide 3-kinase (PI3K) signaling pathway is crucial for the proliferation of MCT cells in the presence or absence of c-kit gene mutations. Here, we propose a novel therapeutic strategy to target the PI3K pathway for the treatment of canine MCTs.


Quantum Griffiths phase in the weak itinerant ferromagnetic alloy Ni(1-x)V(x).
We present magnetization (M) data of the d-metal alloy Ni(1-x)V(x) at vanadium concentrations close to x(c) approximately = 11.4% where the onset of long-range ferromagnetic (FM) order is suppressed to zero temperature. Above x(c), the temperature (T) and magnetic field (H) dependencies of the magnetization are best described by simple nonuniversal power laws. The exponents of M/H approximately T(-gamma) and M approximately H(alpha) are related by 1-gamma = alpha for wide temperature (10 < T < or = 300 K) and field (H < or = 5 T) ranges. gamma is strongly x dependent, decreasing from 1 at x approximately = x(c) to gamma < 0.1 for x = 15%. This behavior is not compatible with either classical or quantum critical behavior in a clean 3D FM. Instead it closely follows the predictions for a quantum Griffiths phase associated with a quantum phase transition in a disordered metal. Deviations at the lowest temperatures hint at a freezing of large clusters and the onset of a cluster glass phase.


Nifedipine-sensitive blood pressure component in hypertensive models characterized by high activity of either sympathetic nervous system or renin-angiotensin system.
High blood pressure (BP) of spontaneously hypertensive rats (SHR) is maintained by enhanced activity of sympathetic nervous system (SNS), whereas that of Ren-2 transgenic rats (Ren-2 TGR) by increased activity of renin-angiotensin system (RAS). However, both types of hypertension are effectively attenuated by chronic blockade of L-type voltage-dependent calcium channel (L-VDCC). The aim of our study was to evaluate whether the magnitude of BP response elicited by acute nifedipine administration is proportional to the alterations of particular vasoactive systems (SNS, RAS, NO) known to modulate L-VDCC activity. We therefore studied these relationships not only in SHR, in which mean arterial pressure was modified in a wide range of 100-210 mm Hg by chronic antihypertensive treatment (captopril or hydralazine) or its withdrawal, but also in rats with augmented RAS activity such as homozygous Ren-2 TGR, pertussis toxin-treated SHR or L-NAME-treated SHR. In all studied groups the magnitude of BP response to nifedipine was proportional to actual BP level and it closely correlated with BP changes induced by acute combined blockade of RAS and SNS. BP response to nifedipine is also closely related to the degree of relative NO deficiency. This was true for both SNS- and RAS-dependent forms of genetic hypertension, suggesting common mechanisms responsible for enhanced L-VDCC opening and/or their upregulation in hypertensive animals. In conclusions, BP response to nifedipine is proportional to the vasoconstrictor activity exerted by both SNS and RAS, indicating a key importance of these two pressor systems for actual L-VDCC opening necessary for BP maintenance.


Ceruloplasmin and Alpha-1-Acid Glycoprotein, but not C-Reactive Protein, Correlate With Serum Ferritin During Various Postpartum/Lactation Periods in Congolese Females.
Background: Serum ferritin usually correlates positively with acute phase proteins (APPs), but limited information is available on this association during various postpartum/lactation periods. The objective of this study was to assess the association between serum ferritin and APPs in Congolese females during different postpartum/lactation periods. Methods: Serum ferritin, C-reactive protein (CRP), alpha-1-acid glycoprotein (AGP), ceruloplasmin (Cp), and transferrin saturation (TS) were measured during various postpartum/lactation periods (0.5 to 6, 6.1 to 12, 12.1 to 18, and 18.1 to 24 months) in 131 Congolese females aged 15 to 45 years. Results: Mean serum ferritin concentrations were lower in females in the 0.5- to 6-month postpartum/lactation subgroup than in the other 3 subgroups (P<0.05). Mean concentrations of hemoglobin, APPs, and TS were not different among the 4 subgroups. While serum ferritin concentrations correlated with Cp (r=0.514) and AGP (r=0.795) during the 0.5- to 6-month and the 6.1- to 12-month postpartum/lactation periods, respectively (P<0.05), they did not correlate with CRP. Multiple regression analysis suggested that Cp explained 25% of serum ferritin variance in the 0.5- to 6-month postpartum/lactation period (39.3% at 0.5 to 4 months) and AGP explained 60.5% of the variance in the 6.1- to 12-month period (3.7% at 0.5 to 4 months). CRP explained <5% of the serum ferritin variance at these postpartum/lactation periods. APPs explained ≤15.1% of serum ferritin variance at postpartum/lactation periods >12 months. Conclusion: Data suggest that the association between serum ferritin and inflammation is dependent on APP type and lactation time. This association may affect the diagnosis of iron deficiency in lactating females. The positive association between serum ferritin and Cp at 0.5 to 6 months postpartum may be necessary to increase liver iron release and erythropoiesis after childbirth.


Electronic and Optical Properties of van der Waals Heterostructures Based on Two-Dimensional Perovskite (PEA)2PbI4 and Black Phosphorus.
Combining two-dimensional (2D) perovskites with other 2D materials to form a van der Waals (vdW) heterostructure has emerged as an intriguing way of designing electronic and optoelectronic devices. The structural, electronic, and optical properties of the 2D (PEA)2PbI4/black phosphorus (BP) [PEA:(C4H9NH3)+] vdW heterostructure have been investigated using first-principles calculations. We found that the (PEA)2PbI4/BP heterostructure shows a high stability at room temperature. It is demonstrated that the (PEA)2PbI4/BP heterostructure exhibits a type-I band arrangement with high carrier mobility. Moreover, the band gap and band offset of (PEA)2PbI4/BP can be effectively modulated by an external electric field, and a transition from semiconductor to metal is observed. The band edges of (PEA)2PbI4 and BP in the (PEA)2PbI4/BP heterostructure, which show significant changes with the external electric field, provide further support. Furthermore, the BP layers can enhance the light absorption of the (PEA)2PbI4/BP heterostructures. Our results indicate that the 2D perovskite and BP vdW heterostructures are competitive candidates for the application of low-dimensional photovoltaic and optoelectronic devices.


Simulation Study on Molecular Behavior of Rhamnolipids and Biobased Zwitterionic Surfactants at the Oil/Water Interface: Effect of Rhamnose Moiety Structures.
Molecular behavior of rhamnolipid mixed with a biobased zwitterionic surfactant at an n-hexadecane/water interface has been studied, and the effects of a rhamnose moiety and composition are evaluated. Results showed that rhamnolipid abundantly interacts with biobased surfactant EAB by means of hydrophobic interactions between aliphatic tails and electrostatic interactions between headgroups, including the attractive interaction between COO- of rhamnolipids and N+ of biobased surfactants and the repulsive interaction between COO- of both surfactants. Dirhamnolipid has a larger number of bound Na+ and a more stable bound structure of COO- ∼ Na+, which screens the repulsive interaction between two kinds of surfactants and shows a more homogeneous distribution with biobased surfactants. The interfacial tension between n-hexadecane and water has been synergistically reduced by dirhamnolipids mixed with biobased surfactants at a higher molar ratio of biobased surfactants. Monorhamnolipids show a strengthened interaction with N+ of biobased surfactants and a more stable hydrogen bond with water relative to that of dirhamnolipids, and there is no synergistic effect in lowering the interfacial tension for the mixture of monorhamnolipids and biobased surfactants. The present work provides details of the molecular behavior of biosurfactant rhamnolipids mixed with biobased surfactants and obtains the key factor in affecting the interfacial properties of the binary system.


[The ZZP Questionnaire. Reliability of a new resource utilization measure].
Data to determine the resource utilization of care recipients need to be reliable and the items that are measured need to be useful. In 2006, the Dutch Ministry of Health and Welfare has mandated all nursing homes and homes for the elderly to measure the Resource Utilization of all residents with the ZZP Questionnaire. Are the data resulting from this measurement reliable and is each of the 54 items of the ZZP Questionnaire useful? To answer this we tested the reliability of the data in a nursing home and a home for the elderly in two wards each. For 122 residents questionnaires were completed such that the inter- and intra-rater reliability of the answers could be assessed. Ten of the 54 items in the questionnaire showed insufficient inter rater reliability (<0.40) on the weighted Cohen kappa and another sixteen moderate (0.40 - 0.60). On the intra rater reliability test seven items had an insufficient kappa and another fifteen moderate. Besides, ten clusters of items could be formed with in-cluster Spearman correlation rates of .75 or higher. From the results of the reliability tests and the item intercorrelation rates we concluded that a substantial number of items needs to be improved and that in the ZZP Questionnaire 15 of the 54 items appear to be redundant on statistical grounds.


Label-free Mass Cytometry for Unveiling Cellular Metabolic Heterogeneity.
Comprehensive analysis of single-cell metabolites is critical since differences in cellular chemical compositions give rise to specialized biological functions. Herein, we propose a label-free mass cytometry by coupling flow cytometry to ESI-MS (named CyESI-MS) for high-coverage and high-throughput detection of cellular metabolites. Cells in suspension were isolated, online extracted by sheath fluid, and lysed during gas-assisted electrospray, followed by real-time MS analysis. Hundreds of metabolites, including nucleotides, amino acids, peptides, carbohydrates, fatty acyls, glycerolipids, glycerophospholipids, and sphingolipids, were detected and identified from one single cell. Discrimination of four types of cancer cell lines and even three subtypes of breast cancer cells was readily achieved using their distinct metabolic profiles. Furthermore, we screened out 102 characteristic ions from 615 detected peak signals for distinguishing breast cancer cell subtypes and identified 40 characteristic molecules which exhibited significant differences among these subtypes and would be potential metabolic markers for clinical diagnosis. CyESI-MS is expected to be a new-generation mass cytometry for studying cell heterogeneity on the metabolic level.


Investigation of Avian Influenza Viruses (H9N2-H5nx) in Pigeons during Highly Pathogenic Avian Influenza Outbreaks in Iran, in 2016.
Avian influenza (AI) virus (H9N2 and H5 subtypes) infections in birds cause major concerns around the world. The majority of the avian species, such as domestic, pet, and wild birds, are natural and experimental hosts of avian influenza viruses. There are global concerns about members of the Columbidae family, namely pigeons or doves, for their role as the potential interspecies bridge in influenza A viruses ecology. The acquired scientific data in this regard is still not clear since there are doubts about whether or not they transmit viruses between susceptible populations, and spread viruses among farms during outbreaks. To monitor H5 and H9 influenza virus infection status in the rural, backyard, and domestic birds, an annual active surveillance program was performed from September to October 2016. In December 2016, an outbreak of highly pathogenic avian influenza (HPAI) virus subtype H5N8 was detected in a layer farm in Tehran province, Iran. The present research was conducted to study H9N2 or H5 infections in pigeons within HPAI H5N8 2016 outbreaks and annual national AI surveillance in Iran. For this purpose, cloacal swabs and tissue samples (trachea, lung, brain, liver, heart, pancreas, and cecal tonsil) were collected and examined by real-time reverse transcription-polymerase chain reaction (RT-PCR) method and virus isolation. Results of the tests performed on the swab and tissue samples were negative for H5 nor H9N2 viruses. The samples in real-time RT-PCR that after three passages still showed negative results in HA and molecular tests were considered negative. Moreover, the Newcastle disease virus was isolated in most of the samples taken from dead pigeons, after inoculation in embryonated chicken eggs.


The association of serum prolidase activity with the presence and severity of coronary artery disease.
Prolidase is a cytosolic exopeptidase that cleaves iminodipeptides with carboxy-terminal proline or hydroxyproline and plays major role in collagen turnover. Collagen is the essential content in atherosclerotic plaque playing a key role in the stability/instability of and progression of coronary artery disease (CAD). Consequently, in this study we sought to determine serum prolidase activity and markers of oxidative stress such as lipid hydroperoxide and total free sulfhydryl in CAD. We have evaluated 199 patients with CAD and 122 control cases with clinical, electrocardiographic, and laboratory investigation. We have measured serum prolidase activity and serum total free sulfhydryl levels spectrophotometrically. Serum lipid hydroperoxide levels were determined with ferrous ion oxidation-xylenol orange method. We assessed the association of serum prolidase activity with the presence and severity of CAD and clinical characteristics, and laboratory parameters. Serum prolidase activity (52.5+/-5.6 vs. 46.7+/-5.1 U/l, respectively, P<0.001) and serum lipid hydroperoxide levels were significantly increased in patients with CAD compared with control cases whereas, serum total free sulfhydryl levels were significantly decreased in patients with CAD compared with control cases. Serum prolidase activity and total free sulfhydryl levels were independent predictors of the presence of CAD [(chi=75.532, ss=0.212, P=0.003) and (chi=25.969, ss=-30.486, P=0.019), respectively] and Gensini score [(beta=0.276, P<0.001) and (beta=-0.274, P<0.001), respectively]. Independent predictors of serum prolidase activity were serum high-density lipoprotein cholesterol (beta=-0.138, P=0.023) and urea levels (beta=0.146, P=0.036), and Gensini score (beta=0.317, P<0.001). Findings of this study have shown that serum prolidase activity is significantly associated with the presence and severity of CAD, and elevated serum prolidase activity might be an independent predictor of coronary atherosclerosis.


Hepatitis C virus vaccine candidates inducing protective neutralizing antibodies.
With more than 150 million chronically infected people, hepatitis C virus (HCV) remains a substantial global health burden. Direct-acting antivirals have dramatically improved viral cure. However, limited access to therapy, late stage detection of infection and re-infection following cure illustrate the need for a vaccine for global control of infection. Vaccines with induction of neutralizing antibodies (nAbs) have been shown to protect successfully against infections by multiple viruses and are currently developed for HCV. Areas covered: Here we review the progress towards the development of vaccines aiming to confer protection against chronic HCV infection by inducing broadly nAbs. The understanding or viral immune evasion in infected patients, the development of novel model systems and the recent structural characterization of viral envelope glycoprotein E2 has markedly advanced our understanding of the molecular mechanisms of virus neutralization with the concomitant development of several vaccine candidates. Expert commentary: While HCV vaccine development remains challenged by the high viral diversity and immune evasion, marked progress in HCV research has advanced vaccine design. Several vaccine candidates have shown robust induction of nAbs in animal models and humans. Randomized clinical trials are the next step to assess their clinical efficacy for protection against chronic infection.


Ethnic differences in long-term improvement of angina following revascularization or medical management: a comparison between south Asians and white Europeans.
It is not known whether there are disparities in morbidity outcomes between south Asians and whites with established coronary disease. Six-year prospective cohort study to determine whether improvement of angina symptoms differs between 196 south Asians and 1508 whites following revascularization or medical management. 43.9% of south Asians reported improvement in angina at 6 years compared with 60.3% of whites (age-adjusted OR 0.56, 95% CI 0.41-0.76, adjusted for diabetes, hypertension, smoking, number of diseased vessels, left ventricular function and social class OR 0.59, 95% CI 0.41-0.85). Similar proportions of whites and south Asians underwent percutaneous coronary intervention (PCI) (19.6% versus 19.9%) and coronary artery bypass surgery (CABG) (32.8% versus 30.1%). South Asians were less likely to report improved angina after PCI (OR 0.19, 95% CI 0.06-0.56) or CABG (OR 0.36, 95% CI 0.17-0.74). There was less evidence of ethnic differences in angina improvement when treatment was medical (OR 0.87, 95% CI 0.48-1.57). South Asians were less likely to experience long-term improvements in angina than whites after receipt of revascularization. Further research is needed to identify why these ethnic groups differ in symptomatic prognosis following revascularization for coronary disease and how these differences may be mitigated.


Highly efficient visible-light-induced photocatalytic activity of nanostructured AgI/TiO2 photocatalyst.
Nanostructured AgI/TiO(2) photocatalyst was synthesized by a feasible approach with AgNO(3), LiI, and Ti(OBu)(4) and characterized by X-ray diffraction, transmission electron microscopy, angle-dependent X-ray photoelectron spectroscopy, diffusive reflectance UV-vis spectroscopy, Raman spectroscopy, photoluminescence, and the Brunauer-Emmett-Teller technique. The results of characterization reveal that the nanostructured AgI/TiO(2) has a novel core/shell/shell nanostructure of AgI/Ag-I(2)/TiO(2). Compared with TiO(2) (P25) supported AgI, the formation of the nanostructure results in substantial shifting of the absorption edge of AgI to red, enhancement of the absorption intensity, and the appearance of a strong tail absorption above 490 nm, which is assigned to the absorption of I(2) and Ag. Photocatalytic tests show that the nanostructured AgI/TiO(2) photocatalyst exhibited very high visible-light-induced photocatalytic activity for the photodegradation of crystal violet and 4-chlorophenol, which is 4 and 6 times higher than that of P25 titania supported AgI, respectively. The highly efficient visible-light-induced photocatalytic activity of the nanostructured AgI/TiO(2) is attributed to its strong absorption in the visible region and low recombination rate of the electron-hole pair due to the synergetic effect among the components of AgI, Ag, I(20, and TiO(2) in the nanostructured AgI/TiO(2).


A-MYB (MYBL1) transcription factor is a master regulator of male meiosis.
The transcriptional regulation of mammalian meiosis is poorly characterized, owing to few genetic and ex vivo models. From a genetic screen, we identify the transcription factor MYBL1 as a male-specific master regulator of several crucial meiotic processes. Spermatocytes bearing a novel separation-of-function allele (Mybl1(repro9)) had subtle defects in autosome synapsis in pachynema, a high incidence of unsynapsed sex chromosomes, incomplete double-strand break repair on synapsed pachytene chromosomes and a lack of crossing over. MYBL1 protein appears in pachynema, and its mutation caused specific alterations in expression of diverse genes, including some translated postmeiotically. These data, coupled with chromatin immunoprecipitation (ChIP-chip) experiments and bioinformatic analysis of promoters, identified direct targets of MYBL1 regulation. The results reveal that MYBL1 is a master regulator of meiotic genes that are involved in multiple processes in spermatocytes, particularly those required for cell cycle progression through pachynema.


Obtusifolin suppresses phthalate esters-induced breast cancer bone metastasis by targeting parathyroid hormone-related protein.
This study is the first to demonstrate that parathyroid hormone-related protein (PTHrP), produced by human breast cancer cells after exposure to phthalate esters, contributes to bone metastasis by increasing osteoclastogenesis. This is also the first to reveal that obtusifolin reverses phthalate esters-mediated bone resorption. Human breast cancer cells were treated with dibutyl phthalate (DBP), harvested in conditioned medium, and cultured to osteoblasts or osteoclasts. Cultures of osteoblasts with DBP-MDA-MB-231-CM increased the osteoclastogenesis activator RANKL (receptor activator of nuclear factor κ-B ligand) and M-CSF (macrophage colony-stimulating factor). PTHrP was secreted in MDA-MB-231 cells. DBP-MDA-MB-231-CM reduced osteoblasts to produce osteoprotegerin, an osteoclastogenesis inhibitor, while DBP mediated PTHrP up-regulation, increasing IL-8 secretion in MDA-MB-231 and contributing to breast cancer-mediated osteoclast differentiation and bone resorption. Obtusifolin, a major bioactive compound present in Cassia tora L., suppressed phthalate esters-mediated bone resorption. Therefore, obtusifolin may be a novel anti-breast-cancer bone metastasis agent.


Noise-enhanced stability in fluctuating metastable states.
We derive general equations for the nonlinear relaxation time of Brownian diffusion in randomly switching potential with a sink. For piece-wise linear dichotomously fluctuating potential with metastable state, we obtain the exact average lifetime as a function of the potential parameters and the noise intensity. Our result is valid for arbitrary white noise intensity and for arbitrary fluctuation rate of the potential. We find noise enhanced stability phenomenon in the system investigated: The average lifetime of the metastable state is greater than the time obtained in the absence of additive white noise. We obtain the parameter region of the fluctuating potential where the effect can be observed. The system investigated also exhibits a maximum of the lifetime as a function of the fluctuation rate of the potential.


Role of chloride channels in regulating the volume of acinar cells of the rabbit superior lacrimal gland.
To characterize the outward chloride currents (Cl(OR)) in single acinar cells isolated from the rabbit superior lacrimal gland (RSLG) to investigate the hypothesis that Cl(OR) may have a role in regulating the volume of RSLG acini. Cl(OR) was characterized by using patch-clamp electrophysiology. Confocal microscopy was used to measure intracellular calcium concentration ([Ca(2+)](i)) and cell volume. Cell volume was altered by superfusing the cells with a hyposmotic solution. The Cl(OR) current contributed 33% of total membrane conductance. With normal osmotic conditions, the Cl(OR) current was activated by [Ca(2+)](i) with an EC(50) of 10(-8) M. A decrease in intracellular pH from 7.4 to 6.8 totally inhibited Cl(OR) current activity. Continuous superfusion of hyposmotic solution caused (1) an increase in cell volume that peaked within 4 minutes and gradually returned to baseline levels after 12 minutes, (2) an increase in [Ca(2+)](i) that peaked between 6 and 8 minutes and gradually returned to baseline levels after 15 minutes, and (3) an increase the Cl(OR) current that peaked within 6 minutes after commencement of perfusion and quickly returned to baseline levels. The Cl(OR) current appears to be triggered by an increase in cell volume and then deactivates within the period of raised [Ca(2+)](i) during hyposmotic stress, suggesting that Cl(OR) may be an initiating event for volume homeostasis. This effect would be important during RSLG tear secretion, which usually involves cell volume changes and is accompanied by intracellular pH changes in the presence of the raised [Ca(2+)](i) to support secretion.


Hemoglobin NYU, a delta chain variant, alpha 2 delta 2 lys.
A minor hemoglobin (Hb) component with the electrophoretic properties of the delta-chain variant Hb A(2') was encountered in two unrelated families of Russian-Jewish ancestry. This minor component, designated Hb NYU, was shown to result from the substitution of lysine for asparagine at delta(12). We have confirmed studies of others that hemoglobin A(2') isolated from the hemoglobin of some African subjects, results from the replacement of the normal glycine at delta(16) by arginine. Thus for interpretations of the incidence of delta-chain variants in different populations, electrophoretic data are not sufficient. In members of one of the families in the present study, the visual estimations of normal Hb A(2) and of Hb NYU on starch-gel electrophoretic patterns suggested the presence of delta-thalassemia. In hemolysates of one of the heterozygotes for Hb NYU, hemoglobin A(2) was not demonstrable with starch-gel electrophoretic methods but was readily recovered by column chromatography in approximately the amounts expected for delta-chain heterozygotes.


Antifouling (Bio)materials for Electrochemical (Bio)sensing.
(Bio)fouling processes arising from nonspecific adsorption of biological materials (mainly proteins but also cells and oligonucleotides), reaction products of neurotransmitters oxidation, and precipitation/polymerization of phenolic compounds, have detrimental effects on reliable electrochemical (bio)sensing of relevant analytes and markers either directly or after prolonged incubation in rich-proteins samples or at extreme pH values. Therefore, the design of antifouling (bio)sensing interfaces capable to minimize these undesired processes is a substantial outstanding challenge in electrochemical biosensing. For this purpose, efficient antifouling strategies involving the use of carbon materials, metallic nanoparticles, catalytic redox couples, nanoporous electrodes, electrochemical activation, and (bio)materials have been proposed so far. In this article, biomaterial-based strategies involving polymers, hydrogels, peptides, and thiolated self-assembled monolayers are reviewed and critically discussed. The reported strategies have been shown to be successful to overcome (bio)fouling in a diverse range of relevant practical applications. We highlight recent examples for the reliable sensing of particularly fouling analytes and direct/continuous operation in complex biofluids or harsh environments. Opportunities, unmet challenges, and future prospects in this field are also pointed out.


Intrinsic Electric Field-Induced Properties in Janus MoSSe van der Waals Structures.
Focusing on two-dimensional (2D) Janus MoSSe monolayers, we show that simultaneously existing in-plane and out-of-plane intrinsic electric fields cause Zeeman- and Rashba-type spin splitting, respectively. In MoSSe van der Waals (vdW) structures, intrinsic electric field results in a large interlayer band offset. Therefore, large interlayer band offset, being the driving force for interlayer excitons, endows ultralong lifetimes to excitons and might dissociate excitons into free carriers. In comparison to its parent structure (i.e., MoS2), MoSSe vdW structures are rather appealing for new concepts in light-electricity interconversion. In addition, the Rashba effects could be tuned by changing the interlayer distances due to the competition between the intralayer and interlayer electric field. Due to the large band offset, valley polarization relaxation is markedly reduced, promising enhanced valley polarization and ultralong valley lifetimes. As a result, MoSSe vdW structures harbor strong valley-contrasting physics, making them competitive systems to their parent structures.


[Asymptomatic uterine rupture after two spontaneous vaginal deliveries following prior cesarean section].
We present the case of an almost asymptomatic uterine rupture after two consecutive vaginal deliveries after a prior cesarean delivery (first child). Uterine rupture is rare even after a prior cesarean delivery, permitting a trial of labor after a cesarean delivery in spite of the increased risk of uterine rupture. Vaginal birth after previous cesarean delivery, however, demands a cautious approach. Appropriate recommendations have been published by the ACOG and the 'AG fOr fetomaternale Medizin' (a branch of the German Society of Obstetrics and Gynaecology). In our case diagnosis was made by an vaginal ultrasound examination 7.5 weeks after an uncomplicated vaginal delivery. An additional MRI examination did not result in substantial extra information. For that reason it will be indicated only in exceptional cases. To answer the question whether a vaginal ultrasound examination should routinely be offered after an uncomplicated vaginal delivery with a prior cesarean delivery in the history to preclude uterine rupture further studies are necessary.


Non-specific and DNP--erythrocyte rosette formation after contact sensitization with DNCB.
DNA--guinea-pig erythrocyte rosette-forming cells (RFC), as found after contact sensitization of guinea-pigs with DNCB, were shown to be highly sensitive to pretreatment with cyclophosphamide or X-irradiation, which suggests that these cells are B cells. The finding was confirmed by rosette-blocking experiments using an anti-immunoglobulin serum. It has already been shown that they are not directly related to antibody production. Possibly they represent precursors of antibody-producing cells. An increase in rosette formation, using non-antigenically related erythrocytes, was shown to parallel development of cell-mediated immunity (CMI) in the lymph nodes. These non-specifically induced RFC were also found to be B cells. Data were obtained which make it improbable that either proliferation or influx of B cells during development of CMI plays a major role in this increase. An alternative mechanism is suggested, while a possible role for these non-specifically induced RC is proposed.


Radiation Response Prediction Model Based on Integrated Clinical and Genomic Data Analysis.
The value of the genomic profiling by targeted gene-sequencing on radiation therapy response prediction was evaluated through integrated analysis including clinical information. Radiation response prediction model was constructed based on the analyzed findings. Patients who had the tumor sequenced using institutional cancer panel after informed consent and received radiotherapy for the measurable disease served as the target cohort. Patients with irradiated tumor locally controlled for more than 6 months after radiotherapy were defined as the durable local control (DLC) group, otherwise, non-durable local control (NDLC) group. Significant genomic factors and domain knowledge were used to develop the Bayesian Network model to predict radiotherapy response. Altogether, 88 patients were collected for analysis. Of those, 41 (43.6%) and 47 (54.4%) patients were classified as the NDLC and DLC group, respectively. Somatic mutations of NOTCH2 and BCL were enriched in the NDLC group, whereas, mutations of CHEK2, MSH2, and NOTCH1 were more frequently found in the DLC group. Altered DNA repair pathway was associated with better local failure-free survival (hazard ratio, 0.40; 95% confidence interval, 0.19 to 0.86; p=0.014). Smoking somatic signature was found more frequently in the DLC group. Area under the receiver operating characteristic curve of the Bayesian network model predicting probability of 6-month local control was 0.83. Durable radiation response was associated with alterations of DNA repair pathway and smoking somatic signature. Bayesian network model could provide helpful insights for high precision radiotherapy. However, these findings should be verified in prospective cohort for further individualization.


Eye-tracking laser Doppler velocimeter stabilized in two dimensions: principle, design, and construction.
We developed an eye-tracking laser Doppler velocimeter to minimize eye-movement artifacts in the study of ocular hemodynamics in humans. The instrument compensates for both horizontal and vertical eye motions by using galvanometer mirrors controlled by a dual-Purkinje eye tracker. The performance of the instrument is demonstrated in a preliminary study of retinal arterial blood velocity in a normal subject. The subject's fixation point was adjusted manually to oscillate through a 2.3-deg span at 0.3 Hz. In spite of this motion the pulsatile velocity waveform of the heart cycle could be continuously recorded. Without eye tracking the velocity waveform was lost after the initiation of movement.


Heat stroke : a review of cooling methods.
The prognosis of heat stroke in patients is directly related to the degree of hyperthermia and its duration. Therefore, the most important feature in the treatment of heat stroke is rapid cooling. Several cooling methods have been presented in the literature including immersion in water at different temperatures, evaporative cooling, ice pack application, pharmacological treatment and invasive techniques. This article describes the various cooling techniques in terms of efficacy, availability, adverse effects and mortality rate. Data suggest that cooling should be initiated immediately at time of collapse and should be based on feasible field measures including ice or tepid water (1-16 degrees C), which are readily available. In the emergency department, management should be matched to the patient's age and medical background and include immersion in ice water (1-5 degrees C) or evaporative cooling.


Evaluation of patency following revision technique of high-velocity arteriovenous fistula.
The objective of this study is to report our experience with surgical revision of dialysis access-induced ischemia syndrome. Between January 2005 and July 2013, 1254 patients underwent arteriovenous fistula operation, and 86 of them [53 males, mean age: 55 ± 25 (range: 25 to 75) years; 33 females, mean age: 50 ± 20 (range: 30 to 70) years] subsequently developed steal syndrome. These patients were treated with arterial pressure-controlled polytetrafluoroethylene banding or constriction with polypropylene suturing technique. Patients were followed in the outpatient clinic at regular intervals. Symptoms were not relieved during the first 15 days in 4 patients; therefore, reintervention was performed. Thrombosis occurred in one patient after reintervention. No early or late complications were detected in other patients, and fistulae were suitable for hemodialysis. Patency rates at 6 and 12 months were 96% and 92%, respectively, and thrombosis rates were 7% and 9%. There was no hospital mortality in our study, but one patient died from unrelated causes and two other patients quit follow-up after 6 months. We think that arterial pressure-controlled surgical revision is an effective and safe technique in patients with fistula-related hand ischemia.


Combined Gadolinium and Boron Neutron Capture Therapies for Eradication of Head-and-Neck Tumor Using Gd10B6 Nanoparticles under MRI/CT Image Guidance.
Eradication of head-and-neck (H&N) tumors is very difficult and challenging because of the characteristic feature of frequent recurrence and the difficulty in killing cancer stem cells. Neutron capture therapy (NCT) is emerging as a noninvasive potential modality for treatments of various types of tumors. Herein, we report that 98.5% 10B-enriched anti-EGFR-Gd10B6 nanoparticles can not only deliver large doses of 158 μg 10B/g tumor tissues as well as 56.8 μg 157Gd/g tumor tissues with a very high tumor-to-blood (T/B) 10B ratio of 4.18, but also exert very effective CT/MRI image-guided combined GdBNCT effects on killing cancer stem cells and eradication of recurrent head-and-neck (H&N) tumors. This leads to a long average half-lifespan of 81 days for H&N tumor-bearing mice, which is a record-making result, and surpasses the best result reported in the literature using combined radiotherapy and T cell-mediated immunotherapy (70 d).


Circulating Tumor Cells as Cancer Biomarkers in the Clinic.
It is believed that the development of metastatic cancer requires the presence of circulating tumor cells (CTCs) , which are found in a patient's circulation as rare abnormal cells comingled with billions of the normal red and white blood cells. The systems developed for detection of CTCs have brought progress to cancer treatment. The molecular characterization of CTCs can aid in the development of new drugs, and their presence during treatment can help clinicians determine the prognosis of the patient. Studies have been carried out in patients early in the disease course, with only primary tumors, and the role of CTCs in prognosis seems to be as important as it is in patients with metastatic disease. The published studies on CTCs have focused on their prognostic significance, their utility in real-time monitoring of therapies, the identification of therapeutic and resistance targets, and understanding the process of metastasis . The analysis of CTCs during the early stages, as a "liquid biopsy," helps to monitor patients at different points in the disease course, including minimal residual disease, providing valuable information about the very early assessment of treatment effectiveness. Finally, CTCs can be used to screen patients with family histories of cancer or with diseases that can lead to the development of cancer. With standard protocols, this easily obtained and practical tool can be used to prevent the growth and spread of cancer. In this chapter, we review some important aspects of CTCs , surveying the disease aspects where these cells have been investigated.


Biological properties of different type carbon particles in vitro study on primary culture of endothelial cells.
Carbon powders have extended surface of carbon layers, which is of significant biomedical importance since the powders are employed to cover implants material. Carbon Powder Particles are produced by different methods: by a detonation method, by RF PACVD (Radio Frequency Plasma Activated Chemical Vapour Deposition) or MW/RF PCVD (Microwave/Radio Frequency Plasma Activated Chemical Vapour Deposition) and others. Our previous data showed that Carbon Powder Particles may act as antioxidant and/or anti-inflammatory factor. However the mechanism of such behavior has been not fully understood. The aim of the work was tested influence carbon powders manufactured by Radio Frequency Plasma Activated Chemical Vapour Deposition RFPACVD method and detonation method on selected parameters of human endothelial cells, which play a crucial role in the regulation of the circulation and vascular wall homeostasis. Graphite powder was used as a control substance. Endothelial cells are actively involved in a wide variety of processes e.g., inflammatory responses to a different type of stimuli (ILs, TNF-alpha) or regulating vasomotor tone via production of vasorelaxants and vasocontrictors. Biological activation is dependent on the type and quantity of chemical bonds on the surface of the powders. The effect of powders on the proliferation of HUVECs (Human Umbilical Vein Endothelial Cells) was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) reduction assay. We found decreased cell proliferation after 72 h treatment with graphite as well as Carbon Powder Particles.


Fusion of the SEC31L1 and ALK genes in an inflammatory myofibroblastic tumor.
Inflammatory myofibroblastic tumor (IMT) is a neoplasm composed of myofibroblastic spindle cells and infiltrating inflammatory cells. Cytogenetic analyses have revealed that a subgroup of IMT, in particular among children and young adults, harbors clonal chromosomal rearrangements involving chromosome band 2p23. Further, molecular genetic studies have shown that these rearrangements target the ALK gene, serving as the 3'-partner in fusion genes with various translocation partners. In the present study, we describe the finding of a novel SEC31L1/ALK fusion gene in an intraabdominal IMT of a young man. G-band analysis revealed a translocation t(2;4)(p23;q21) and subsequent fluorescence in situ hybridization with locus-specific probes strongly indicated disruption of the ALK locus on chromosome 2. Immunostaining with monoclonal mouse anti-human CD246 ALK Protein showed diffuse cytoplasmic positivity. Using reverse primers for the ALK-gene, we could, by 5'-RACE methodology, amplify a single 1.2 kb fragment. Sequence analysis showed that the fragment was a hybrid cDNA product in which nt 3012 of SEC31L1 (NM_016211), located in band 4q21, was fused in-frame to nt 4080 of ALK (NM_004304). RT-PCR with two sets of primer pairs specific for SEC31L1 and ALK amplified two transcripts, which at sequencing corresponded to two types of chimeric SEC31L1/ALK transcripts. In the long, type I, transcript nt 3012 of SEC31L1 (NM_016211) was fused in-frame to nt 4080 of ALK. In the short, type II, transcript nt 2670 of SEC31L1 was fused in-frame to nt 4080 of ALK. Genomic PCR and subsequent sequencing showed that the breakpoints were located in intron 23 of SEC31L1 and intron 20 of ALK.


Update on anesthetic complications of robotic thoracic surgery.
In the last decade, there has been increasing use of the da Vinci® robot surgical system to perform minimally invasive thoracic surgery. The robotic technology can be applied for surgery of the lungs, mediastinum, and esophagus. A number of case reports have been shown steep learning curve, and promising surgical outcome with this new technology. However, anesthesia management of the robotic thoracic surgery can be complex and requires further education. For example, most of the cases require sufficient lung collapse in order to provide adequate surgical field. In addition, a unique operative setting, such as patient positioning and capnothorax can make anesthesia management further challenging. Hence, anesthesiologists should have better awareness of adverse events or complications related to the robotic surgery to accomplish successful anesthesia management. This review will focus on the potential complications of robotic thoracic surgery involving the lungs, mediastinum and esophagus.


Disentangling health information appraisal competence: Results from an interdisciplinary scoping review and online consultation among Swiss stakeholders.
The ability to critically appraise health information-often referred to as critical health literacy-is recognized as a crucial component of health literacy. Yet to date, it is not clear what specific abilities are needed to adequately accomplish this task, thereby hindering both its assessment and the development and evaluation of related interventions. By systematically building on past research, this study aimed to operationally define the concept of health information appraisal competence. We systematically searched five scholarly databases to identify the conceptualizations and operational definitions of information appraisal in different disciplines. The resulting operationalization was subsequently validated through an online consultation exercise among 85 Swiss stakeholders. Ninety-four publications were included in the review to the point of saturation. We extracted 646 skills, attitudes, and knowledge for health information appraisal. We then collated overlapping or duplicate statements, which produced a list of 43 unique statements belonging to six emergent themes or core competences: (1) basic competence, (2) predisposition, (3) identification competence, (4) critical evaluation competence, (5) selection competence, and (6) application competence. The consultation exercise enriched the operationalization of some of the core competences and confirmed the importance of all competences. Most skills, attitudes, and knowledge, however, were assigned low feasibility by the stakeholders. This study was the first attempt to systematically operationalize health information appraisal competence. From a theoretical perspective, it sheds light on an understudied, health literacy domain, thus contributing to clarity around the concept. From a practical perspective, it provides a strong theoretical basis for the development of a tool to measure health information appraisal competence. This could be used routinely as a screening tool, as an outcome measure for public health interventions, or to identify citizens who are most at risk. Furthermore, it will provide support for the development of future interventions to build health information appraisal competence in the population.


Impact of protein D-containing pneumococcal conjugate vaccines on non-typeable Haemophilus influenzae acute otitis media and carriage.
Protein D-containing vaccines may decrease acute otitis media (AOM) burden and nasopharyngeal carriage of non-typeable Haemophilus influenzae (NTHi). Protein D-containing pneumococcal conjugate vaccine PHiD-CV (Synflorix, GSK Vaccines) elicits robust immune responses against protein D. However, the phase III Clinical Otitis Media and PneumoniA Study (COMPAS), assessing PHiD-CV efficacy against various pneumococcal diseases, was not powered to demonstrate efficacy against NTHi; only trends of protective efficacy against NTHi AOM in children were shown. Areas covered: This review aims to consider all evidence available to date from pre-clinical and clinical phase III studies together with further evidence emerging from post-marketing studies since PHiD-CV has been introduced into routine clinical practice worldwide, to better describe the clinical utility of protein D in preventing AOM due to NTHi and its impact on NTHi nasopharyngeal carriage. Expert commentary: Protein D is an effective carrier protein in conjugate vaccines and evidence gathered from pre-clinical, clinical and observational studies suggest that it also elicits immune response that can help to reduce the burden of AOM due to NTHi. There remains a need to develop improved vaccines for prevention of NTHi disease, which could be achieved by combining protein D with other antigens.


Near-Infrared Photoimmunotherapy Targeting Prostate Cancer with Prostate-Specific Membrane Antigen (PSMA) Antibody.
Prostate-specific membrane antigen (PSMA) is a membrane protein that is overexpressed manifold in prostate cancer and provides an attractive target for molecular therapy. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photoabsorber conjugate (APC). Here, we describe the efficacy of NIR-PIT, using a fully human IgG1 anti-PSMA monoclonal antibody (mAb), conjugated to the photoabsorber, IR700DX, in a PSMA-expressing PC3 prostate cancer cell line. Anti-PSMA-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR light in vitro In the in vivo study, anti-PSMA-IR700 showed high tumor accumulation and high tumor-background ratio. Tumor-bearing mice were separated into 4 groups: (i) no treatment; (ii) 100 μg of anti-PSMA-IR700 i.v.; (iii) NIR light exposure; (iv) 100 μg of anti-PSMA-IR700 i.v., NIR light exposure was administered. These were performed every week for up to 3 weeks. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other control groups (P < 0.001), and significantly prolonged survival was achieved (P < 0.0001 vs. other control groups). More than two thirds of tumors were cured with NIR-PIT. In conclusion, the anti-PSMA antibody is suitable as an APC for NIR-PIT. Furthermore, NIR-PIT with the anti-PSMA-IR700 antibody is a promising candidate of the treatment of PSMA-expressing tumors and could be readily translated to humans.Implications: NIR-infrared photoimmunotherapy (NIR-PIT) using a fully human anti-PSMA-IR700 conjugate showed potential therapeutic effects against a PSMA-expressing prostate cancer that is readily translated to humans. Mol Cancer Res; 15(9); 1153-62. ©2017 AACR.


Perfectionism moderates stereotype threat effects on STEM majors' academic performance.
Using a randomized, between-subjects experimental design, we tested hypotheses that self-critical perfectionism would moderate the effects of subtle stereotype threat (ST) for women and students in underrepresented racial/ethnic groups who are pursuing traditional degrees in science, technology, engineering, or math (STEM). A diverse sample of freshmen students (N = 294) was recruited from 2 major universities. Students were blocked by gender and race/ethnicity and randomly assigned to experience subtle ST or no ST. Participants in the subtle ST condition were primed to consider their gender, race, and ethnicity prior to completing measures of science self-efficacy. Those in the control condition completed the measures without such priming. Controlling for prior academic performance and university context, ST priming significantly interacted (a) with self-critical perfectionism to predict coping self-efficacy scores and (b) with race/ethnicity to predict end-of-semester STEM grades. A 3-way interaction of ST priming, sex, and self-critical perfectionism also predicted students' grades in courses wherein women and men were more proportionally represented. The Sex × Self-Critical Perfectionism interaction was not significant for those in the ST group but was for those in the control group. Men in the control group had higher grade-point averages (GPAs) at low levels of self-critical perfectionism than they had at higher levels of perfectionism. In contrast, women had lower GPAs when self-critical perfectionism was low, but their GPAs were higher when self-critical perfectionism was high. The findings are discussed in terms of their implications for self-efficacy and performance in the pursuit of a STEM major.


Combination of radiotherapy and targeted therapy for melanoma brain metastases: a systematic review.
Radiotherapy is a mainstay of efficient treatment of brain metastases from solid tumors. Immunotherapy has improved the survival of metastatic cancer patients across many tumor types. However, targeted therapy is a feasible alternative for patients unable to continue immunotherapy or with poor outcomes of immunotherapy. The combination of radiotherapy and targeted therapy for the treatment of brain metastases has a strong theoretical underpinning, but data on the efficacy and safety of this combination is still limited. A systematic search of PubMed, Embase, Web of Science and the Cochrane library database was conducted. Eleven studies were included for a total of 316 patients. Median OS was about 6.2-17.8 months from radiotherapy. Weighted survival and local control at 1 and 2 years were correlated (50.1 and 17.8%, 90.7 and 14.7% at 1 and 2 year, respectively). Radiotherapy given before or concurrently to targeted therapy provided the best effect on the outcome. For patients with brain metastases from cutaneous melanoma, the addition of concurrent targeted therapy to brain radiotherapy can increase survival and provide long-term control.


Age-dependent immune responses in COVID-19-mediated liver injury: focus on cytokines.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is potentially pathogenic and causes severe symptoms; in addition to respiratory syndromes, patients might experience other severe conditions such as digestive complications and liver complications injury. The abnormality in the liver is manifested by hepatobiliary dysfunction and enzymatic elevation, which is associated with morbidity and mortality. The direct cytopathic effect, immune dysfunction, cytokine storm, and adverse effects of therapeutic regimens have a crucial role in the severity of liver injury. According to aging and immune system alterations, cytokine patterns may also change in the elderly. Moreover, hyperproduction of cytokines in the inflammatory response to SARS-CoV-2 can lead to multi-organ dysfunction. The mortality rate in elderly patients, particularly those with other comorbidities, is also higher than in adults. Although the pathogenic effect of SARS-CoV-2 on the liver has been widely studied, the impact of age and immune-mediated responses at different ages remain unclear. This review discusses the association between immune system responses in coronavirus disease 2019 (COVID-19) patients of different ages and liver injury, focusing on cytokine alterations.


Associations between Korean Adolescents' Sexual Orientation and Suicidal Ideation, Plans, Attempts, and Medically Serious Attempts.
Despite growing interest in the public health of sexual minority, youth around the world due to the high rates of suicidal ideation and attempts in this population, few studies on the sexual orientation of Korean adolescents have been conducted. Therefore, this study investigated the relationship between the sexual orientation of Korean adolescents and their suicide-related behavior. Raw data from the tenth Korea Youth Risk Behavior Web-based Survey were analyzed by logistic regression analysis. The sample consisted of 3603 adolescents who provided selected demographic variables and reported on their experience of sexual intercourse with the same or the opposite sex, along with lifestyle and suicide-related behaviors. Rates of suicidal ideation, plans, attempts, and medically serious attempts were higher in both homosexual and bisexual than heterosexual groups. Suicidal ideation (odds ratio 95% confidence interval: 1.09-2.08), suicidal plans (odds ratio 95% confidence interval: 1.01-2.09), and suicide attempts (odds ratio 95% confidence interval: 1.28-2.88) had the strongest associations with homosexuality after multivariate adjustment. In contrast, bisexuality was only significantly associated with suicidal attempts (odds ratio 95% confidence interval: 1.01-2.97) after multivariate adjustment. Effective suicide prevention interventions are required for homosexual and bisexual adolescents, in the form of targeted programs to improve their mental health status and ability to cope with stress.


Synthesis and identification of GZD856 as an orally bioavailable Bcr-AblT315I inhibitor overcoming acquired imatinib resistance.
Bcr-AblT315I induced drug resistance remains a major challenge to chronic myelogenous leukemia (CML) treatment. Herein, we reported GZD856 as a novel orally bioavailable Bcr-AblT315I inhibitor, which strongly suppressed the kinase activities of both native Bcr-Abl and the T315I mutant with IC50 values of 19.9 and 15.4 nM, and potently inhibited proliferation of corresponding K562, Ba/F3WT and Ba/F3T315I cells with IC50 values of 2.2, 0.64 and 10.8 nM. Furthermore, GZD856 potently suppressed tumor growth in mouse bearing xenograft K562 and Ba/F3 cells expressing Bcr-AblT315I. Thus, GZD856 may serve as a promising lead for the development of Bcr-Abl inhibitors overcoming acquired imatinib resistance.


Comparative effects of diltiazem and glycerol trinitrate on isolated ureter and coronary artery of the dog.
Effects of diltiazem on isolated ureter and coronary artery of the dog were compared with those of glycerol trinitrate (GTN). Diltiazem (DZ) (10(-9)-10(-6) M) decreased the force and frequency of ureteral rhythmic contractions evoked by potassium or phenylephrine in a concentration-dependent manner, and relaxed potassium-contracted coronary artery strips. The dose dependence of the inhibitory effects of diltiazem was similar on the ureter and coronary artery. GTN (10(-7)-10(-5) M) also showed similar inhibitory effects, but these were more pronounced on the coronary artery than on the ureter.


[New knowledge about Creutzfeldt-Jakob disease can yield therapeutic possibilities].
Creutzfeldt-Jakob disease (CJD) is a rare neurological disease which is always terminal, often within months. The disease attracted attention in the 1990 s, when reports appeared about people acquiring the disease by eating meat from cattle infected with BSE (bovine spongiform encephalopathy). Recent progress within research on CJD has raised hopes about finding a treatment. The most promising results of this research are presented. The review is based on articles (and references in them) identified through non-systematic searches in PubMed. CJD is a disease that emerges when the cellular form of the prion protein PrPC is transformed into the disease-associated PrPSc. Transgenic mice that did not express PrPC did not develop clinical signs of the disease after being exposed to prions. Both administration of antibodies towards PrPC and use of RNA interference technique to reduce PrPC gene expression increased the survival time in mice. Pentosan polysulphate (a drug against interstitial cystitis) infused intraventriculary in mice, prolonged the incubation time from 51 to 123 days. The drug has been tested in patients with CJD with promising results with respect to survival time. New treatment modalities have shown results that raise hopes about finding curative treatment in the future.


Sarcolipin deletion exacerbates soleus muscle atrophy and weakness in phospholamban overexpressing mice.
Sarcolipin (SLN) and phospholamban (PLN) are two small proteins that regulate the sarco(endo)plasmic reticulum Ca2+-ATPase pumps. In a recent study, we discovered that Pln overexpression (PlnOE) in slow-twitch type I skeletal muscle fibers drastically impaired SERCA function and caused a centronuclear myopathy-like phenotype, severe muscle atrophy and weakness, and an 8 to 9-fold upregulation of SLN protein in the soleus muscles. Here, we sought to determine the physiological role of SLN upregulation, and based on its role as a SERCA inhibitor, we hypothesized that it would represent a maladaptive response that contributes to the SERCA dysfunction and the overall myopathy observed in the PlnOE mice. To this end, we crossed Sln-null (SlnKO) mice with PlnOE mice to generate a PlnOE/SlnKO mouse colony and assessed SERCA function, CNM pathology, in vitro contractility, muscle mass, calcineurin signaling, daily activity and food intake, and proteolytic enzyme activity. Our results indicate that genetic deletion of Sln did not improve SERCA function nor rescue the CNM phenotype, but did result in exacerbated muscle atrophy and weakness, due to a failure to induce type II fiber compensatory hypertrophy and a reduction in total myofiber count. Mechanistically, our findings suggest that impaired calcineurin activation and resultant decreased expression of stabilin-2, and/or impaired autophagic signaling could be involved. Future studies should examine these possibilities. In conclusion, our study demonstrates the importance of SLN upregulation in combating muscle myopathy in the PlnOE mice, and since SLN is upregulated across several myopathies, our findings may reveal SLN as a novel and universal therapeutic target.