Continuous Detection of Increasing Concentrations of Thrombin Employing a Label-Free Photonic Crystal Aptasensor.
Thrombin generation is a complex and finely regulated pathway that provokes dynamical changes of thrombin concentration in blood when a vascular injury occurs. In order to characterize the initiation phase of such process, when thrombin concentration is in the nmol/L range, a label-free optical aptasensor is proposed here. This aptasensor combines a 1D photonic crystal structure consisting of a silicon corrugated waveguide with thrombin binding aptamers on its surface as bioreceptors. As a result, this aptasensor has been demonstrated to specifically detect thrombin concentrations ranging from 270 pmol/L to 27 nmol/L with an estimated detection limit of 33.5 pmol/L and a response time of ~2 min. Furthermore, it has also been demonstrated that this aptasensor is able to continuously respond to consecutive increasing concentrations of thrombin and to detect binding events as they occur. All these features make this aptasensor a good candidate to continuously study how thrombin concentration progressively increases during the initiation phase of the coagulation cascade.


Formaldehyde activity on historical glass objects in museum microclimate.
Degradation of some cultural heritage monuments has been caused by interaction with the closest environment (micro-climate). Amount of separate compounds is very small and because of it, this fact becomes neglected. Time and temperature can induce their activity finally causing deterioration. In this category organic compounds can be interpreted as one of museum show - case element. This statement has been improved by testing glass objects and their suitable sensors (model glasses). Destructive activity of formaldehyde on historical glasses belonging to the XVIII-th c. objects with totally different compositions has been confirmed by carried out experiments. For historical material which is very limited, sensor glass method has been applied. Sensors are prepared on the base of results of chemical analyses of original glass chemical analyses and melted on laboratory scale (according to historical data). Induced corrosion for sensor supports knowledge about deterioration process in real micro-environmental conditions. The following testing methods were used: scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), optical interferometer (OI), inductively couple plasma (ICP).


Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK.
Constitutive overexpression and activation of NPM-ALK fusion protein [t(2:5)(p23;q35)] is a key oncogenic event that drives the survival and proliferation of anaplastic large-cell lymphomas (ALCLs). We have identified a highly potent and selective small-molecule ALK inhibitor, NVP-TAE684, which blocked the growth of ALCL-derived and ALK-dependent cell lines with IC(50) values between 2 and 10 nM. NVP-TAE684 treatment resulted in a rapid and sustained inhibition of phosphorylation of NPM-ALK and its downstream effectors and subsequent induction of apoptosis and cell cycle arrest. In vivo, NVP-TAE684 suppressed lymphomagenesis in two independent models of ALK-positive ALCL and induced regression of established Karpas-299 lymphomas. NVP-TAE684 also induced down-regulation of CD30 expression, suggesting that CD30 may be used as a biomarker of therapeutic NPM-ALK kinase activity inhibition.


A Pattern-Based Approach Combining Tumor Morphology on MRI With Distinct Signal Patterns on Diffusion-Weighted Imaging to Assess Response of Rectal Tumors After Chemoradiotherapy.
Diffusion-weighted imaging is increasingly used in rectal cancer MRI to assess response after chemoradiotherapy. Certain pitfalls (eg, artefacts) may hamper diffusion-MRI assessment, leading to suboptimal diagnostic performance. Combining diffusion-weighted MRI with the underlying morphology on standard (T2-weighted) MRI may help overcome these pitfalls. The purpose of this study was to evaluate the diagnostic performance of a pattern-based approach combining tumor morphology on T2-weighted MRI with distinct diffusion-weighted imaging signal patterns to assess response after chemoradiotherapy in rectal cancer. Response to chemoradiotherapy was scored according to 4 patterns: 1) cases with either a clear residual mass with corresponding high-diffusion signal (A+) or completely normalized wall without diffusion signal (A-); 2) cases with circular and/or irregular fibrosis with (B+) or without (B-) small foci of diffusion signal scattered throughout the fibrosis; 3) cases with semicircular fibrosis with (C+) or without (C-) high diffusion signal at the inner margin of the fibrosis; and 4) polypoid tumors showing regression of the polyp and fibrosis at the site of the stalk with (D+) or without (D-) focal high-diffusion signal in the stalk. A total of 75 cases were rescored by an independent second reader to study interobserver variations. Standard of reference was histopathology or long-term outcome. The study was conducted at a single tertiary referral center. A total of 222 patients with locally advanced rectal cancer undergoing chemoradiotherapy were included. Diagnostic performance to discriminate between a complete response and residual tumor was measured. The pattern-based approach resulted in a sensitivity of 94%, specificity of 77%, positive predictive value of 88%, negative predictive value of 87%, and overall accuracy of 88% to differentiate between tumor versus complete response. Accuracies per pattern were 100% (A), 74% (B), 86% (C), and 92% (D). Interobserver agreement was good (κ = 0.75). The study included no comparison with routine (nonpattern) diffusion-MRI assessment. A pattern-based approach combining tumor morphology with distinct diffusion-weighted imaging patterns results in good diagnostic performance to assess response. See Video Abstract at http://links.lww.com/DCR/A433.


Studies on the development of DNA vaccine against Cysticercus cellulosae infection and its efficacy.
DNA vaccine against Cysticercus cellulosae infection was developed and its efficacy was tested. A pair of primers specific to antigen B gene of C. cellulosae was designed which amplified the gene successfully with RT-PCR. The gene was ligated to PV93 vector, and the recombinant of antigen B gene and PV93 was transformed to JM83 cells. The transformed JM83 cells were cultured in a large scale and the plasmid purified. Based on the recombinant plasmid. a DNA vaccine was developed and used to vaccinate two groups of experimental pigs. In each group, there was a routine vaccine, an enhanced vaccine and a control group. Groups 1 and 2 were challenged at 4 months and at 14 days post vaccination respectively with eggs of Taenia solium. The antibody response was also tested with ELISA. The results suggested that all animals vaccinated AgB gene DNA vaccine, no matter by routine or enhanced vaccine, their antibodies reached maximum peak 23 days post vaccination and decreased gradually. When the animals were challenged 4 months after vaccination, they had strong immunity and the parasites decrease rates were 91.2% and 93.1% respectively. When pigs vaccinated with AgB gene DNA vaccine were challenged 14 days post vaccination with 18,000 eggs/pig. The animals showed strong immunity and the parasite decrease rates were 99.5% and 84.9% respectively. However at that time, the antibodies did not reach the peak. While in the control group, the number of C. cellulosae was as many as 2,500. It was concluded that the pigs vaccinated with DNA vaccine had strong immunity against infection of eggs of T. solium.


The Reciprocity Team: Development of an Interprofessional Research Collaboration.
The purpose of this article is to articulate and provide detail about an interprofessional research collaboration at a public university in a rural area of western United States. This interprofessional research collaboration was organized to explore infant and maternal reciprocity. As a part of the organization and process portion of the collaborative effort, the authors identify the unique attributes of their collaboration. Additionally, barriers to collaborative research are presented, with opportunities and recommendations made to support existing and future interprofessional collaborative efforts for basic science scholars, clinicians, and educators in health-related professions.


Effect of quiescence on integrin alpha5beta1 expression in human retinal pigment epithelium.
The retinal pigment epithelium (RPE) is differentiated and mitotically inactive in the normal eye, but several pathologies such as proliferative vitreoretinopathy (PVR) cause RPE cells to dedifferentiate and resume proliferation. Integrins, a family of cell surface glycoproteins that mediate cell proliferation and differentiation, are thought to play fundamental roles in PVR. The aim of this study was to evaluate protein expression and gene regulation of the integrin alpha5 subunit in proliferating and quiescent RPE cells. Protein expression was studied in situ by immunohistochemistry and in vitro at different cell confluences by immunoprecipitation. Semi-quantitative RT-PCR and transient transfections were used to determine whether increasing cell confluence also affected alpha5 subunit mRNA levels and promoter activity, respectively. We demonstrated that the integrin alpha5 subunit is present at the RPE cell surface both in situ and in vitro, and that alpha5 protein level is influenced by confluence. Levels of integrin alpha5 transcripts are similar for sub-confluent and confluent cells, and a small increase in the promoter activity was observed between sub-confluent and confluent cells. However, both the integrin alpha5 subunit transcript and the alpha5 promoter activity decreased when cells reached post-confluence. We demonstrated that cell confluence affected protein and gene expression of the integrin alpha5 subunit. Proliferating RPE cells expressed high levels of both the alpha5 protein and mRNA transcripts and showed a high promoter activity. However, when cells reached quiescence, alpha5 gene expression was substantially reduced and RPE cells expressed little alpha5 protein at their cell surface.


Patterns Exploration on Patterns of Empirical Herbal Formula of Chinese Medicine by Association Rules.
In this study, we use association rules to explore the latent rules and patterns of prescribing and adjusting the ingredients of herbal decoctions based on empirical herbal formula of Chinese Medicine (CM). The consideration and development of CM prescriptions based on the knowledge of CM doctors are analyzed. The study contained three stages. The first stage is to identify the chief symptoms to a specific empirical herbal formula, which can serve as the key indication for herb addition and cancellation. The second stage is to conduct a case study on the empirical CM herbal formula for insomnia. Doctors will add extra ingredients or cancel some of them by CM syndrome diagnosis. The last stage of the study is to divide the observed cases into the effective group and ineffective group based on the assessed clinical effect by doctors. The patterns during the diagnosis and treatment are selected by the applied algorithm and the relations between clinical symptoms or indications and herb choosing principles will be selected by the association rules algorithm. Totally 40 patients were observed in this study: 28 patients were considered effective after treatment and the remaining 12 were ineffective. 206 patterns related to clinical indications of Chinese Medicine were checked and screened with each observed case. In the analysis of the effective group, we used the algorithm of association rules to select combinations between 28 herbal adjustment strategies of the empirical herbal formula and the 190 patterns of individual clinical manifestations. During this stage, 11 common patterns were eliminated and 5 major symptoms for insomnia remained. 12 association rules were identified which included 5 herbal adjustment strategies. The association rules method is an effective algorithm to explore the latent relations between clinical indications and herbal adjustment strategies for the study on empirical herbal formulas.


A Novel Clinical Tool for the Management of Taste Changes in Patients With Chronic Kidney Disease: The Chronic Kidney Disease Taste Plate.
Taste alteration is a common, but poorly understood, symptom in end-stage kidney disease. The pathophysiology of taste alteration is complex; to date, management has been largely empirical. As our understanding of pathophysiology grows so does the evidence base for its management. This article introduces a clinical tool-the CKD Taste Plate-to assist clinicians in directing management to the underlying pathophysiology of taste alterations in chronic kidney disease.


A new family of human histone deacetylases related to Saccharomyces cerevisiae HDA1p.
Histone deacetylases are the catalytic subunits of multiprotein complexes that are targeted to specific promoters through their interaction with sequence-specific DNA-binding factors. We have cloned and characterized a new human cDNA, HDAC-A, with homology to the yeast HDA1 family of histone deacetylases. Analysis of the predicted amino acid sequence of HDAC-A revealed an open reading frame of 967 amino acids containing two domains: a NH2-terminal domain with no homology to known proteins and a COOH-terminal domain with homology to known histone deacetylases (42% similarity to RPD3, 60% similarity to HDA1). Three additional human cDNAs with high homology to HDAC-A were identified in sequence data bases, indicating that HDAC-A itself is a member of a new family of human histone deacetylases. The mRNA encoding HDAC-A was differentially expressed in a variety of human tissues. The expressed protein, HDAC-Ap, exhibited histone deacetylase activity and this activity mapped to the COOH-terminal region (amino acids 495-967) with homology to HDA1p. In immunoprecipitation experiments, HDAC-A interacted specifically with several cellular proteins, indicating that it might be part of a larger multiprotein complex.


Prevalence of Upper Respiratory Tract Infections Before, During, and After the COVID-19 Pandemic in Germany: A Cross-Sectional Study of 2 167 453 Outpatients.
Although the burden of the COVID-19 pandemic on global healthcare systems is declining, long-term sequelae such as long COVID syndrome and other disease dynamics not primarily associated with COVID-19 remain a challenge. Recent data suggest that the incidence of non-COVID upper respiratory tract infections (URTI) is increasing sharply in the post-pandemic period, but there is a lack of real-world data from Germany in this respect. This cross-sectional study evaluated the number of patients with a diagnosis of URTI from the Disease Analyzer database (IQVIA) between January 2019 and December 2022. The number of UTRI diagnoses per practice and the duration of sick leave per patient were compared over time. A total of 1 872 935 individuals (1 403 907 patients from general practices (GP) and 469 028 patients from pediatric offices) were included, 48% of whom were female. The number of URTI patients per practice was significantly higher in 2022 than in 2019 (732 vs 464, 58%, P < .001), and this was observed for both women (56%, P < .001) and men (60%, P < .001). The post-pandemic increase in the number of URTI diagnoses correlated with age and was highest in the age group between 18 and 30 years (22%, P < .001) and lowest in older patients >70 years (3%). In pediatric patients (<18 years), the increase was highest in the age group ≤5 years (89%). Both the number of patients per practice on sick leave due to URTI (184 vs 92) and the average duration of sick leave (+2 days) increased from 2019 to 2022. Our data suggest a dramatic increase in the incidence of URTI among all demographic subgroups in Germany between 2019 and 2022, which was associated with a tremendous impact on socioeconomic variables such as the frequency or duration of sick leave. These data could be of great importance in current pandemic management and the management of future pandemics.


[Sequelae of cholecystectomy].
The removal of the gallbladder is followed by a number of compensatory changes, which in most cases do not result in clinical symptoms: the loss of the pressure reservoir for the bile, the duodenogastric reflux with a subsequent increase in gastric pH and helicobacter infections as well as alterations in bile metabolism. An increased incidence of colon carcinoma has been suggested to be caused by cholecystectomy. However, this might also be due to cholelithiasis. Abdominal symptoms widely regarded as postcholecystectomy syndrome are often due to functional disorders of the gastrointestinal tract and the unrelated to the loss of the gallbladder. Therefore, the expression postcholecystectomy syndrome is imprecise and should not be used in the future. Changes affecting the bile ducts such as sphincter Oddi dyskinesia, stones and stenoses are rare and treatment by endoscopic interventions is generally successful.


Chloroplast Preproteins Bind to the Dimer Interface of the Toc159 Receptor during Import.
Most chloroplast proteins are synthesized in the cytosol as higher molecular weight preproteins and imported via the translocons in the outer (TOC) and inner (TIC) envelope membranes of chloroplasts. Toc159 functions as a primary receptor and directly binds preproteins through its dimeric GTPase domain. As a first step toward a molecular understanding of how Toc159 mediates preprotein import, we mapped the preprotein-binding regions on the Toc159 GTPase domain (Toc159G) of pea (Pisum sativum) using cleavage by bound preproteins conjugated with the artificial protease FeBABE and cysteine-cysteine cross-linking. Our results show that residues at the dimer interface and the switch II region of Toc159G are in close proximity to preproteins. The mature portion of preproteins was observed preferentially at the dimer interface, whereas the transit peptide was found at both regions equally. Chloroplasts from transgenic plants expressing engineered Toc159 with a cysteine placed at the dimer interface showed increased cross-linking to bound preproteins. Our data suggest that, during preprotein import, the Toc159G dimer disengages and the dimer interface contacts translocating preproteins, which is consistent with a model in which conformational changes induced by dimer-monomer conversion in Toc159 play a direct role in facilitating preprotein import.


Chronic hepatitis C: latest treatment options.
The most common chronic bloodborne infection in the United States, hepatitis C virus (HCV) is the most frequent reason for liver transplantation. Unfortunately, most infected individuals don't realize they're HCV positive and only discover the disease after severe liver damage has occurred. Here, update your knowledge on the epidemiology, transmission and risk factors, diagnosis, clinical presentation, and management of chronic HCV. Insight on counseling and quality of life issues for infected patients is also included.


In vitro enzymatic treatment and carbon dioxide laser beam irradiation of morphologic cartilage specimens.
To determine the role of the main cartilage components in the internal system of interlocked stresses and to clarify the effect of laser beam irradiation on cartilage. Control and experimental series. Rabbit ear cartilage. Rabbit ear cartilage strips incubated in collagenase and hyaluronidase enzyme solutions for specific periods were examined, and the observed changes in shape, strength, and elasticity were recorded, as well as the effect of carbon dioxide laser irradiation. Laser-pretreated cartilage strips were also incubated in the enzyme solutions to determine whether the laser-provoked changes were susceptible to enzymatic action. All cartilage pieces were examined by light and electron microscopy. Collagenase-treated cartilage strips gradually lost their interlocked stresses, while hyaluronidase-treated strips mostly maintained their shape and their physical characteristics. Hyaluronidase-incubated cartilage strips altered their shape when they were laser treated. Collagenase-treated cartilages did not modify their shape when they were laser treated. Laser-pretreated cartilage pieces lost their new form in collagenase solutions but kept their laser-evoked shape when put in hyaluronidase solutions. The macroscopic observations combined with light and electron microscopy findings argue for the distinct role of the collagen network in morphologic cartilage shape and tensile strength preservation and provide a probable mechanism of cartilage transformation owing to carbon dioxide laser irradiation.


Psychophysical and electrophysiological aerial audiograms of a Steller sea lion (Eumetopias jubatus).
A within-subject comparison of auditory steady-state response (ASSR) and psychophysical measurements of aerial hearing sensitivity was conducted with an individual of the largest otariid species, the Steller sea lion. Psychophysical methods were used to obtain an unmasked aerial audiogram at 13 frequencies, spanning a range of 0.125-34 kHz. The subject had a hearing range (frequencies audible at 60 dB(rms) re 20 microPa) of about 0.250-30 kHz, and a region of best hearing sensitivity from 5-14.1 kHz. The psychophysical aerial audiogram of this Steller sea lion was remarkably similar to aerial audiograms previously obtained for California sea lions and northern fur seals, suggesting that the otariid pinnipeds form a functional hearing group. ASSR thresholds, measured at frequencies of 1, 2, 5, 10, 20, and 32 kHz, were elevated relative to corresponding psychophysical thresholds, ranging from +1 dB at 20 kHz, to +31 dB at 1 kHz. The ASSR audiogram accurately predicted the subject's high-frequency cutoff, and provided a reasonable estimate of hearing sensitivity at frequencies above 2 kHz. In testing situations where psychophysical methods are not possible, ASSR methods may provide an objective and efficient estimate of behavioral hearing sensitivity in otariid pinnipeds.


Amplification and sequencing of Brachyspira spp. specific portions of nox using paraffin-embedded tissue samples from clinical colitis in Austrian pigs shows frequent solitary presence of Brachyspiramurdochii.
Brachyspira infections are significant causes of enterocolitis in pigs. In order to differentiate pathogenic species (Brachyspira (Br.) hyodysenteriae, Brachyspira pilosicoli) from less pathogenic or non-pathogenic species (Brachyspira intermedia, Brachyspira innocens, Brachyspira murdochii) in paraffin-embedded tissue samples a polymerase chain reaction (PCR) protocol allowing identification of Brachyspira at species level in archival material was developed. This approach was complemented by sequencing of the PCR amplification products. All seven cases presented with clinical and morphological Brachyspira-associated enterocolitis. Br. hyodysenteriae was not identified in any of the cases, while Br. pilosicoli was identified in a single case in conjunction with Br. murdochii. One case each was found positive for Br. innocens and Br. intermedia. Interestingly, the majority of cases presented as single or double infections with Br. murdochii. In some of the pigs other pathogens, like porcine circovirus-2 or Lawsonia intracellularis were present. These observations point at the possibility that under certain conditions even Brachyspira species of low pathogenicity can multiplicate extensively and lead to Brachyspira-associated enterocolitis.


[A clinical report of partially debonded adhesion fixed metal splint repaired with adhesion-mechanically fixed metal splint].
The patient was 60-year-old male whose chief complaint was esthetic problem due to median diastema. After orthodontic treatment, an adhesion-fixed metal splint was placed to retain 3-3. After 11 months, the metal retainer on 3 partially debonded. The retainer on 3 was removed and 3 was connected to 4 with an adhesion-mechanically fixed metal splint. Six months later, 3 was separated from 2+2 and connected to 4 5 with the conventional crown restoration. The prognosis is good. This result is attributed to the decrease of splint length and the application of the adhesion-mechanical retainer. These seemed to increase the rigidity and prevent deformation of the splint, thus reducing tensile or shear stress applied to the adhesion interface and improving the bonding durability. This clinical case suggested that the range of splinting and design of retainer affect the durability of adhesion-fixed metal splints.


Barrett's esophagus and β-carotene therapy: symptomatic improvement in GERD and enhanced HSP70 expression in esophageal mucosa.
Epidemiological studies suggest a protective role for β-carotene with several malignancies. Esophageal adenocarcinoma frequently arises from Barrett's esophagus (BE). We postulated that β-carotene therapy maybe protective in BE. We conducted a prospective study in which 25 mg of β-carotene was administered daily for six-months to six patients. Each patient underwent upper endoscopy before and after therapy and multiple mucosal biopsies were obtained. Additionally, patients completed a gastroesophageal reflux disease (GERD) symptoms questionnaire before and after therapy and severity score was calculated. To study the effect of β-carotene at molecular level, tissue extracts of the esophageal mucosal biopsy were subjected to assessment of heat-shock protein 70 (HSP70). A significant (p<0.05) reduction in mean GERD symptoms severity score from 7.0±2.4 to 2.7±1.7 following β-carotene therapy was noted. Measurement of Barrett's segment also revealed a significant reduction in mean length after therapy. In fact, two patients had complete disappearance of intestinal metaplasia. Furthermore, marked enhancement of HSP70 expression was demonstrated in biopsy specimens from Barrett's epithelium in four cases that were tested. Long- term β-carotene therapy realizes amelioration of GERD symptoms along with restitution of the histological and molecular changes in esophageal mucosa of patients with BE, associated with concurrent increase in mucosal HSP70 expression.


Organized assemblies of colloids formed at the poles of micrometer-sized droplets of liquid crystal.
We report on the formation of organized assemblies of 1 μm-in-diameter colloids (polystyrene (PS)) at the poles of water-dispersed droplets (diameters 7-20 μm) of nematic liquid crystal (LC). For 4-cyano-4'-pentylbiphenyl droplets decorated with two to five PS colloids, we found 32 distinct arrangements of the colloids to form at the boojums of bipolar droplet configurations. Significantly, all but one of these configurations (a ring comprised of five PS colloids) could be mapped onto a local (non-close packed) hexagonal lattice. To provide insight into the origin of the hexagonal lattice, we investigated planar aqueous-LC interfaces, and found that organized assemblies of PS colloids did not form at these interfaces. Experiments involving the addition of salts revealed that a repulsive interaction of electrostatic origin prevented formation of assemblies at planar interfaces, and that regions of high splay near the poles of the LC droplets generated cohesive interactions between colloids that could overcome the repulsion. Support for this interpretation was obtained from a model that included (i) a long-range attraction between adsorbed colloids and the boojum due to the increasing rate of strain (splay) of LC near the boojum (splay attraction), (ii) an attractive inter-colloid interaction that reflects the quadrupolar symmetry of the strain in the LC around the colloids, and (iii) electrostatic repulsion between colloids. The model predicts that electrostatic repulsion between colloids can lead to a ∼1000kBT energy barrier at planar interfaces of LC films, and that the repulsive interaction can be overcome by splay attraction of the colloids to the boojums of the LC droplets. Overall, the results reported in this paper advance our understanding of the directed assembly of colloids at interfaces of LC droplets.


Global intracoronary infusion of allogeneic cardiosphere-derived cells improves ventricular function and stimulates endogenous myocyte regeneration throughout the heart in swine with hibernating myocardium.
Cardiosphere-derived cells (CDCs) improve ventricular function and reduce fibrotic volume when administered via an infarct-related artery using the "stop-flow" technique. Unfortunately, myocyte loss and dysfunction occur globally in many patients with ischemic and non-ischemic cardiomyopathy, necessitating an approach to distribute CDCs throughout the entire heart. We therefore determined whether global intracoronary infusion of CDCs under continuous flow improves contractile function and stimulates new myocyte formation. Swine with hibernating myocardium from a chronic LAD occlusion were studied 3-months after instrumentation (n = 25). CDCs isolated from myocardial biopsies were infused into each major coronary artery (∼ 33 × 10(6) icCDCs). Global icCDC infusion was safe and while ∼ 3% of injected CDCs were retained, they did not affect ventricular function or myocyte proliferation in normal animals. In contrast, four-weeks after icCDCs were administered to animals with hibernating myocardium, %LADWT increased from 23 ± 6 to 51 ± 5% (p<0.01). In diseased hearts, myocyte proliferation (phospho-histone-H3) increased in hibernating and remote regions with a concomitant increase in myocyte nuclear density. These effects were accompanied by reductions in myocyte diameter consistent with new myocyte formation. Only rare myocytes arose from sex-mismatched donor CDCs. Global icCDC infusion under continuous flow is feasible and improves contractile function, regresses myocyte cellular hypertrophy and increases myocyte proliferation in diseased but not normal hearts. New myocytes arising via differentiation of injected cells are rare, implicating stimulation of endogenous myocyte regeneration as the primary mechanism of repair.


Plasma oxylipin profiles reflect Parkinson's disease stage.
Derivatives of polyunsaturated fatty acids (PUFAs), also known as oxylipins, are key participants in regulating inflammation. Neuroinflammation is involved in many neurodegenerative diseases, including Parkinson's disease. The development of ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) facilitated the study of oxylipins on a system level, i.e., the analysis of oxylipin profiles. We analyzed oxylipin profiles in the blood plasma of 36 healthy volunteers (HC) and 73 patients with Parkinson's disease (PD), divided into early (L\M, 29 patients) or advanced (H, 44 patients) stages based on the Hoehn and Yahr scale. Among the 40 oxylipins detected, we observed a decrease in the concentration of arachidonic acid (AA) and AA derivatives, including anandamide (AEA) and Leukotriene E4 (LTE4), and an increase in the concentration of hydroxyeicosatetraenoic acids 19-HETE and 12-HETE (PD vs HC). Correlation analysis of gender, age of PD onset, and disease stages revealed 20 compounds the concentration of which changed depending on disease stage. Comparison of the acquired oxylipin profiles to openly available PD patient brain transcriptome datasets showed that plasma oxylipins do not appear to directly reflect changes in brain metabolism at different disease stages. However, both the L\M and H stages are characterized by their own oxylipin profiles - in patients with the H stage oxylipin synthesis is increased, while in patients with L\M stages oxylipin synthesis decreases compared to HC. This suggests that different therapeutic approaches may be more effective for patients at early versus late stages of PD.


Exploitation of in situ generated sugar-based olefin keto-nitrones: synthesis of carbocycles, heterocycles, and nucleoside derivatives.
Application of intramolecular 1,3-dipolar nitrone cycloaddition reaction on carbohydrate-derived precursors containing an olefin functionality at C-1 or C-3 or C-5 and a nitrone moiety at C-2 or C-3 as appropriate has resulted in the formation of structurally new cycloaddition products containing furanose-fused oxepane, thiepane, azepane, cyclopentane, cycloheptane, tetrahydrofuran, and pyranose-fused tetrahydrofuran rings. The structure and stereochemistry of these products have been characterized by spectral as well as single-crystal X-ray analyses. Two of the compounds have been transformed to the bicyclic nucleoside derivatives applying Vorbrüggen reaction conditions.


"You get stuck in it": Young people's accounts of attempting to quit non-medical tramadol use.
Aim: Non-medical use of tramadol and other prescription opioid use has become a great concern in many countries, including Sweden. This study examines key components in young people's accounts of attempting to quit drugs, focusing on non-medical use of tramadol. Methods: Repeated qualitative interviews were conducted with 12 individuals aged 19-24 years with experiences of problems related to non-medical tramadol use. The analysis used the concepts of autonomy, competence, and relatedness from self-determination theory. Results: Three themes emerged from the young people's accounts: (1) quitting initiated by parents and professionals; (2) being willing, but unable; and (3) between ambivalence and determination. These themes demonstrate conflicting emotions towards drug use along with a significant external pressure to quit, but also difficulties in quitting due to experiences of dependence, withdrawal symptoms, and mental health issues. For most participants, however, an increasing autonomous will and ability to abstain from drugs gradually developed, with the support from trusted relationships with professionals, family, and friends playing a crucial role. Conclusion: The process of trying to quit non-medical tramadol use can be challenging and involve a complex interaction between willingness and capability, where external influence can be either facilitating or hindering. This study highlights the importance of taking into account young people's own perspectives in treatment efforts, where trust is a key component.


[Musculoskeletal rehabilitation and bone. locomotive syndrome].
In accordance with the increase of elderly population in Japan, the number of the elderly requiring care services is also increasing. Musculoskeletal conditions account for 24% of the causes for requiring care services. These backgrounds lead to the advocacy of the term "Locomotive Syndrome" by the Japanese Orthopaedic Association in 2007. This means such conditions that an elderly person necessitates or is at risk of necessitating care services due to the decreased ambulation caused mainly by aging-related musculoskeletal disorders, and judged with seven check items at this point of time. This syndrome requires intervention with exercise training, and two kinds of "Locomotion Trainings" are recommended as easily performable ones at home.


Differences in molecular features of triple-negative breast cancers based on the age at diagnosis.
Although the proportion of triple-negative breast cancers (TNBCs) diagnosed among older women is low, the number of TNBC cases is substantial because of the high incidence of breast cancer after the age of 65 years. The molecular features of TNBC in this age group have not been well described. This study examined a population-based cohort of women with stage I to III TNBC diagnosed between the ages of 25 and 91 years with the PAM50 gene expression subtyping assay. The concordance between the TNBC classification by immunohistochemistry and the gene expression classification by PAM50, the expression of individual genes, and 5-year recurrence and breast cancer mortality in older women (≥65 years old) and younger women (<50 years old) was assessed. The molecular subtype distribution in TNBC was significantly different according to the age at diagnosis. TNBC was more likely to be classified as basal-like in women younger than 50 years (sensitivity, 0.91; 95% confidence interval, 0.77-0.97) than women 65 years old or older (sensitivity, 0.72; 95% confidence interval, 0.48-0.87); 35% of clinical TNBC cases in the latter group were the human epidermal growth factor receptor 2 (HER2)-enriched subtype by molecular classification. Older women with TNBC also had significantly higher expression of ERBB2 and lower expression of all 10 proliferation-associated genes tested (P < .01). The risk of breast cancer death within 5 years was significantly higher in women with TNBC in comparison with women with hormone receptor-positive cancers in all age groups. This study revealed differences in molecular subtypes among clinical TNBC cases based on patient age. A potentially targetable HER2-enriched group raises the possible need for intrinsic subtyping in older women with TNBC.


Treating maladaptive grief and posttraumatic stress symptoms in orphaned children in Tanzania: group-based trauma-focused cognitive-behavioral therapy.
This study was designed to test the feasibility and child clinical outcomes for group-based trauma-focused cognitive behavior therapy (TF-CBT) for orphaned children in Tanzania. There were 64 children with at least mild symptoms of grief and/or traumatic stress and their guardians who participated in this open trial. The TF-CBT for Child Traumatic Grief protocol was adapted for use with a group, resulting in 12 weekly sessions for children and guardians separately with conjoint activities and 3 individual visits with child and guardian. Using a task-sharing approach, the intervention was delivered by lay counselors with no prior mental health experience. Primary child outcomes assessed were symptoms of grief and posttraumatic stress (PTS); secondary outcomes included symptoms of depression and overall behavioral adjustment. All assessments were conducted pretreatment, posttreatment, and 3 and 12 months after the end of treatment. Results showed improved scores on all outcomes posttreatment, sustained at 3 and 12 months. Effect sizes (Cohen's d) for baseline to posttreatment were 1.36 for child reported grief symptoms, 1.87 for child-reported PTS, and 1.15 for guardian report of child PTS.


Very late stent thrombosis associated with multiple stent fractures and peri-stent aneurysm formation after sirolimus-eluting stent implantation.
Previous randomized trials have shown that drug-eluting stents (DES) are superior to bare-metal stents in reducing the need for target lesion revascularization, but safety issues with DES have recently been raised. We report a rare case of very late stent thrombosis 35 months after sirolimus-eluting stent implantation associated with delayed 5-segment stent fractures and peri-stent aneurysm formation.


[Effect of micro-injection angiotensin II into subfornical organ in rats on Na+, K(+)-ATPase activity in proximal tubules].
To investigate the effect of micro-injection Ang II into the subfornical organ (SFO) on the proximal tubules (PT) Na+, K(+)-ATPase activity in rats and its mechanism. SFO in SD rats was administrated respectively with Ang II (20 ng), or losartan (5 microg) and AngII (20 ng) successively. The levels of serum EDLS and plasm AngII were assessed with radioimmunoassay (RIA). The PT segments were microdissected freehand and their Na+, K(+)-ATPase activities were assessed by liquid scintillation counter (LSC). The serum EDLS levels increased significantly compared with a CSF group after SFO administration with Ang II; The Na+, K(+)-ATPase activities in PT segments decreased significantly at 30 min and 60 min after SFO administration with Ang II. There was a negative linear correlation between serum EDLS level and the Na+, K(+)-ATPase activity of PT segments in rats administrated with Ang II (r = -0.938). Inhibition of the Na+, K(+)-ATPase activity in PT as a result of administration of Ang II in SFO is mediated by AT1 receptors. The increase in EDLS release may play an important role in this inhibition.


Actin-related protein 5 functions as a novel modulator of MyoD and MyoG in skeletal muscle and in rhabdomyosarcoma.
Myogenic regulatory factors (MRFs) are pivotal transcription factors in myogenic differentiation. MyoD commits cells to the skeletal muscle lineage by inducing myogenic genes through recruitment of chromatin remodelers to its target loci. This study showed that actin-related protein 5 (Arp5) acts as an inhibitory regulator of MyoD and MyoG by binding to their cysteine-rich (CR) region, which overlaps with the region essential for their epigenetic functions. Arp5 expression was faint in skeletal muscle tissues. Excessive Arp5 in mouse hind limbs caused skeletal muscle fiber atrophy. Further, Arp5 overexpression in myoblasts inhibited myotube formation by diminishing myogenic gene expression, whereas Arp5 depletion augmented myogenic gene expression. Arp5 disturbed MyoD-mediated chromatin remodeling through competition with the three-amino-acid-loop-extension-class homeodomain transcription factors the Pbx1-Meis1 heterodimer for binding to the CR region. This antimyogenic function was independent of the INO80 chromatin remodeling complex, although Arp5 is an important component of that. In rhabdomyosarcoma (RMS) cells, Arp5 expression was significantly higher than in normal myoblasts and skeletal muscle tissue, probably contributing to MyoD and MyoG activity dysregulation. Arp5 depletion in RMS partially restored myogenic properties while inhibiting tumorigenic properties. Thus, Arp5 is a novel modulator of MRFs in skeletal muscle differentiation.


Changes in regulation of human monocyte proteins in response to IgG from patients with antiphospholipid syndrome.
The effects of immunoglobulin G (IgG) from patients with the antiphospholipid syndrome (APS) upon monocyte activation have not been fully characterized. We carried out a comprehensive proteomic analysis of human monocytes treated with IgG from patients with different manifestations of the APS. Using 2-dimensional differential gel electrophoresis (2D DiGE), 4 of the most significantly regulated proteins (vimentin [VIM], zinc finger CCH domain-containing protein 18, CAP Gly domain-containing linker protein 2, and myeloperoxidase) were differentially regulated in monocytes treated with thrombotic or obstetric APS IgG, compared with healthy control (HC) IgG. These findings were confirmed by comparing monocytes isolated from APS patients and HC. Anti-VIM antibodies (AVAs) were significantly increased in 11 of 27 patients (40.7%) with APS. VIM expression on HC monocytes was stimulated more strongly by APS IgG from patients with higher-avidity serum AVA. We further characterized the proteome of thrombotic APS IgG-treated monocytes using a label-free proteomics technique. Of 12 proteins identified with the most confidence, 2 overlapped with 2D DiGE and many possessed immune response, cytoskeletal, coagulation, and signal transduction functions which are all relevant to APS and may therefore provide potential new therapeutic targets of this disease.


Solid-state dye-sensitized TiO(2) solar cells based on a sensitizer covalently wired to a hole conducting polymer.
We report on the molecular wiring efficiency of a ruthenium polypyridine complex acting as a sensitizer connected to a poly(3-hexyl)thiophene chain acting as hole transporting material. We have developed an efficient synthetic strategy to covalently connect via an ethanyl spacer a regioregular poly(3-hexyl)thiophene chain to a ruthenium complex. Solid-state dye-sensitized solar cells were prepared either with the latter system or with a similar ruthenium sensitizer but lacking the polymer chain (reference system). The comparison of the photocurrent-photovoltage characteristics of the cells recorded under AM1.5 indicates a two fold improvement of the overall photoconversion efficiencies when the sensitizer is grafted to the hole transporting material (eta = 0.27%) relative to the reference system (eta = 0.13%). The higher photovoltaic performance can be attributed to the better diffusion-like propagation of the holes from the sensitizer to the counter electrode through the covalently linked polythiophene chain.


The role of cytochromes p450 and aldo-keto reductases in prognosis of breast carcinoma patients.
Metabolism of anticancer drugs affects their antitumor effects. This study has investigated the associations of gene expression of enzymes metabolizing anticancer drugs with therapy response and survival of breast carcinoma patients. Gene expression of 13 aldo-keto reductases (AKRs), carbonyl reductase 1, and 10 cytochromes P450 (CYPs) was assessed using quantitative real-time polymerase chain reaction in tumors and paired adjacent nonneoplastic tissues from 68 posttreatment breast carcinoma patients. Eleven candidate genes were then evaluated in an independent series of 50 pretreatment patients. Protein expression of the most significant genes was confirmed by immunoblotting. AKR1A1 was significantly overexpressed and AKR1C1-4, KCNAB1, CYP2C19, CYP3A4, and CYP3A5 downregulated in tumors compared with control nonneoplastic tissues after correction for multiple testing. Significant association of CYP2B6 transcript levels in tumors with expression of hormonal receptors was found in the posttreatment set and replicated in the pretreatment set of patients. Significantly higher intratumoral levels of AKR1C1, AKR1C2, or CYP2W1 were found in responders to neoadjuvant chemotherapy compared with nonresponders. Patients with high AKR7A3 or CYP2B6 levels in the pretreatment set had significantly longer disease-free survival than patients with low levels. Protein products of AKR1C1, AKR1C2, AKR7A3, CYP3A4, and carbonyl reductase (CBR1) were found in tumors and those of AKR1C1, AKR7A3, and CBR1 correlated with their transcript levels. Small interfering RNA-directed knockdown of AKR1C2 or vector-mediated upregulation of CYP3A4 in MDA-MB-231 model cell line had no effect on cell proliferation after paclitaxel treatment in vitro. Prognostic and predictive roles of drug-metabolizing enzymes strikingly differ between posttreatment and pretreatment breast carcinoma patients. Mechanisms of action of AKR1C2, AKR7A3, CYP2B6, CYP3A4, and CBR1 should continue to be further followed in breast carcinoma patients and models.


Effects of Visual Game Experience on Auditory Processing Speed.
Games are one of the fastest growing and most exciting forms of entertainment. Whether casual mobile game playing has a cognitive, physiological, or behavioral effect on players whose game use is not pathological is unknown. Here we explored whether preattentive auditory processing is linked to the behavioral inhibition system (BIS) in frequent and infrequent game players. A total of 74 subjects who were enrolled in our study were divided into two groups, 40 subjects were frequent gamers and 34 subjects were age-, gender-, IQ-, and education-matched infrequent gamers. All participants underwent a passive auditory oddball paradigm and completed the behavioral inhibition/behavioral activation system scales. The mismatch negativity (MMN) latency was shorter for the frequent gamers relative to the infrequent gamers, whereas no difference in MMN amplitude was found between groups. MMN amplitude was negatively associated with the degree of behavioral inhibition in the frequent and infrequent gaming group. We also found that those who frequently play games show an enhanced processing speed, which could be an effect of game practice. Greater behavioral inhibition induces increased vigilance, and this may have enhanced the MMN amplitude in the infrequent gamers. This differential pattern of correlations suggests that differences in the BIS could lead to different approaches to auditory information processing.


Pleasure: The missing link in the regulation of sleep.
Although largely unrecognized by sleep scholars, sleeping is a pleasure. This report aims first, to fill the gap: sleep, like food, water and sex, is a primary reinforcer. The levels of extracellular mesolimbic dopamine show circadian oscillations and mark the "wanting" for pro-homeostatic stimuli. Further, the dopamine levels decrease during waking and are replenished during sleep, in opposition to sleep propensity. The wanting of sleep, therefore, may explain the homeostatic and circadian regulation of sleep. Accordingly, sleep onset occurs when the displeasure of excessive waking is maximal, coinciding with the minimal levels of mesolimbic dopamine. Reciprocally, sleep ends after having replenished the limbic dopamine levels. Given the direct relation between waking and mesolimbic dopamine, sleep must serve primarily to gain an efficient waking. Pleasant sleep (i.e. emotional sleep), can only exist in animals capable of feeling emotions. Therefore, although sleep-like states have been described in invertebrates and primitive vertebrates, the association sleep-pleasure clearly marks a difference between the sleep of homeothermic vertebrates and cool blooded animals.


Weight Decay With Tailored Adam on Scale-Invariant Weights for Better Generalization.
Weight decay (WD) is a fundamental and practical regularization technique in improving generalization of current deep learning models. However, it is observed that the WD does not work effectively for an adaptive optimization algorithm (such as Adam), as it works for SGD. Specifically, the solution found by Adam with the WD often generalizes unsatisfactorily. Though efforts have been made to mitigate this issue, the reason for such deficiency is still vague. In this article, we first show that when using the Adam optimizer, the weight norm increases very fast along with the training procedure, which is in contrast to SGD where the weight norm increases relatively slower and tends to converge. The fast increase of weight norm is adverse to WD; in consequence, the Adam optimizer will lose efficacy in finding solution that generalizes well. To resolve this problem, we propose to tailor Adam by introducing a regularization term on the adaptive learning rate, such that it is friendly to WD. Meanwhile, we introduce first moment on the WD to further enhance the regularization effect. We show that the proposed method is able to find solution with small norm and generalizes better than SGD. We test the proposed method on general image classification and fine-grained image classification tasks with different networks. Experimental results on all these cases substantiate the effectiveness of the proposed method in help improving the generalization. Specifically, the proposed method improves the test accuracy of Adam by a large margin and even improves the performance of SGD by 0.84% on CIFAR 10 and 1.03 % on CIFAR 100 with ResNet-50. The code of this article is public available at xxx.


Facile fabrication of hollow polymer microspheres through the phase-inversion method.
This letter reports a novel, facile method of fabricating hollow polymer microspheres based on the phase-inversion method. In this approach, when hydrophobic chlorinated polypropylene was grafted with methyl methacrylate, butyl acrylate, and acrylic acid via free-radical polymerization and then neutralized by triethylamine and gradually diluted with deionized water, phase inversion happened, directly yielding hollow polymer microspheres. SEM, TEM, and optical images confirmed the hollow structure. A formation mechanism of the hollow polymer microspheres was proposed.


Analysis of membrane microdomain-associated proteins in the insular cortex of post-mortem human brain.
Membrane microdomains (MM) are membrane rafts within the cell membrane enriched in cholesterol and glycosphingolipids that have been implicated in the trafficking and sorting of membrane proteins, secretory and endocytotic pathways, and signal transduction. To date, MM have not been characterised in the human brain. We reason that by identifying MM in the normal human cortex, we may better understand the molecular mechanisms of human brain dysfunction. To characterize the protein composition of MM in the human brain, we have carried out a comprehensive proteomic analysis of detergent resistant membranes (DRMs) associated proteins derived from human postmortem insular cortex using 1-DE separation prior to LC coupled to MS/MS or GeLC-MS/MS. Eighty five proteins were identified including 57 unique to human brain cortex DRMs (by comparison with DRM proteins reported in other cell types). High levels of signal transduction, cell adhesion, cell transport and cell trafficking proteins were identified including synaptic proteins such as synapsin II and synaptic vesicle membrane protein, mitochondrial proteins such as ATPase subunits and metabolic enzymes such as malate dehydrogenase. This data will facilitate our understanding of protein expression changes within membranes in candidate brain regions in human brain diseases such as schizophrenia, bipolar disorder and other psychiatric and neurodegenerative disorders.


Pathogenesis of Trypanosoma brucei infection in deer mice (Peromyscus maniculatus). Ultrastructural pathology of the spleen, liver, heart, and kidney.
Trypanosoma brucei EATRO 110 infection of the deer mice (Peromyscus maniculatus) produced moderate to marked lesions in the spleen, liver, heart, and kidney seven to ten weeks after infection. Splenic lesions consisted of marked splenomegaly, with infected spleens weighing 25.9 times control spleens. Transmission electron microscopy of the sinuses and Billroth's cords of the splenic red pulp demonstrated an increased cellularity with greater contact between cells due partly to proliferation of macrophages, transformed lymphocytes and plasma cells and partly to accelerated erythropoiesis with increases in the numbers of rubricytes and reticulocytes. Erythrocytes also were present in large numbers, and erythroclasis was accelerated. Hepatic lesions consisted of necrosis of few hepatocytes, proliferation and hypertrophy of Kupffer's cells which exhibited increased phagocytosis--particularly of erythrocytes, as well as perivascular cuffs consisting of lymphocytes, plasma cells and macrophages. Myocarditis was marked and was characterized by degeneration of myocardial fibers with decreases in mitochondrial size and myofibril contents and fragmentation of some degenerating fibers, and was accompanied by accumulation of inflammatory cells including lymphocytes, transformed lymphocytes, plasma cells, and macrophages between the myocardial fibers. Renal lesions consisted of severe glomerulonephritis characterized by deposition of electron dense material along the basement membrane and in the mesangium of the glomerular tufts, and less frequently beneath the basement membrane and visceral epithelium of the Bowman's capsule and within the peritubular vessels. Neutrophils with fewer macrophages and lymphocytes invaded the glomeruli.(ABSTRACT TRUNCATED AT 250 WORDS)


A toxicological review of the ethylene glycol series: Commonalities and differences in toxicity and modes of action.
This review summarizes the hazards, exposure and risk that are associated with ethylene glycols (EGs) in their intended applications. Ethylene glycol (EG; CAS RN 107-21-1) and its related oligomers include mono-, di-, tri-, tetra-, and penta-EG. All of the EGs are quickly and extensively absorbed following ingestion and inhalation, but not by the dermal route. Metabolism involves oxidation to the mono- and dicarboxylic acids. Elimination is primarily through the urine as the parent compound or the monoacid, and, in the case of EG, also as exhaled carbon dioxide. All EGs exert acute toxicity in a similar manner, characterized by CNS depression and metabolic acidosis in humans and rodents; the larger molecules being proportionally less acutely toxic on a strict mg/kg basis. Species differences exist in the metabolism and distribution of toxic metabolites, particularly with the formation of glycolic acids and oxalates (OX) from EG and diethylene glycol (DEG); OX are not formed to a significant degree in higher ethylene glycols. Among rodents, rats are more sensitive than mice, and males more sensitive than females to the acute and repeated-dose toxicity of EG. The metabolic formation of glycolic acid (GA), diglycolic acid (DGA), and OX are associated with nephrotoxicity in humans and rodents following single and repeated exposures. However, physiological and metabolic differences in the rate of formation of GA, DGA and OX and their distribution result in EG and DEG causing embryotoxicity in rats, but not rabbits. This rodent-specific sensitivity indicates that EG and its higher oligomers are not anticipated to be embryotoxic in humans at environmentally relevant doses. None of the compounds present developmental toxicity concerns at doses that do not also cause significant maternal toxicity, nor do any of the EGs cause adverse effects on fertility. The EGs are neither genotoxic nor carcinogenic. A read-across matrix is presented, which considers the common and distinct toxicological properties of each compound. It is concluded that EGs pose no risk to human health as a result of their intended use patterns.


The effect of insulin on the leg and splanchnic balance of glucose and gluconeogenic substrates after cardiac surgery.
The effect of insulin and glucose infusion on the leg and splanchnic balance of glucose and the gluconeogenic substrates lactate, pyruvate, alanine and glycerol was studied in 13 patients directly after cardiac surgery. Insulin was infused continuously at a rate of 1.0 Unit/kg/hr during 1 hour. Sixteen patients served as a control group and received no insulin and glucose infusion. A significant increase in arterial lactate concentration in both the control group (from 1.40 +/- 0.19 to 1.68 +/- 0.24 mmol/l p less than 0.01) and the insulin group (from 1.58 +/- 0.27 to 2.07 +/- 0.22 mmol/l, p less than 0.05) was observed. The arterial pyruvate concentration was significantly increased (from 0.075 +/- 0.019 to 0.105 +/- 0.021 mmol/l, p less than 0.01) and glycerol was significantly decreased (from 0.15 +/- 0.03 to 0.12 +/- 0.03 mmol/l, p less than 0.05) during the insulin and glucose infusion. The alanine concentration was unchanged in both groups. Insulin and glucose infusion was followed by an increased leg uptake of glucose (from 0.15 +/- 0.14 to 1.06 +/- 0.16 mmol/min/100 ml, p less than 0.05), and by a changed splanchnic glucose balance (from -8.2 +/- 2.8 to +4.0 +/- 1.2 mmol/kg/min, p less than 0.01). A net leg release and at the same time a net splanchnic uptake of all gluconeogenic substrates was observed. The insulin and glucose infusion did not significantly change either the splanchnic balance or the leg balance of the gluconeogenic substrates.


Cytotoxic and apoptotic activities of black widow spiderling extract against HeLa cells.
Black widow spiders contain toxic components not only in the venom glands but also in other parts of the spider body, including the legs and abdomen. Additionally, both the eggs and newborn spiderlings of the black widow spider contain venom. It is important to investigate their potential effects on cancer cells. In the present study, the effects of newborn black widow spiderling extract on human HeLa cells were evaluated in vitro. When applied at different concentrations, the total extract decreased HeLa cell viability in a dose-dependent manner, with an IC50 value of 158 µg/ml. Flow cytometry indicated that treatment of HeLa cells with the total extract of the spiderlings induced apoptosis in HeLa cells in a dose-dependent manner and led to cell cycle arrest in the S-phase. Additionally, application of the total extract at different concentrations increased apoptosis-related caspase 3 activity in a dose-dependent manner. HeLa cells treated with the total extract appeared to be morphologically changed, exhibiting membrane blebbing, nuclear fragmentation and condensation of chromatin. Further separation and activity screening demonstrated that the cytotoxic and apoptotic activities of the total extract were attributable mainly to its high molecular mass proteins, one of which was purified and characterized to determine its anti-tumor activities on HeLa cells. The results of the present study therefore have expanded understanding regarding the effect of spider toxins on cancer cells and suggested that components of black widow spiderlings may be developed as a promising novel agent to treat cancer.


Paraneurons in the gills and airways of fishes.
This chapter describes the distributional patterns of the neuroendocrine cells in the respiratory surfaces of fishes and their bioactive secretions which are compared with similar elements in higher vertebrates. The neuroendocrine cells in the airways of fishes differentiate as solitary and clustered cells, but the clusters are not converted into neuroepithelial bodies which are reported in terrestrial vertebrates. The dipnoan fish Protopterus has innervated neuroendocrine cells in the pneumatic duct region. In Polypterus and Amia the lungs have neuroendocrine cells that are apparently not innervated. Two types of neuroendocrine cells are found in the gill of teleost fishes. These cells are very different by their location, structure and immunohistochemistry. Advanced studies on functional morphology of neuroendocrine cells in fish airways are still necessary to increase our understanding of their multifunctional role in the gill area.


Broadened optical absorption, enhanced photoelectric conversion and ultrafast carrier dynamics of N, P co-doped carbon dots.
Carbon dots (CDs) have attracted extensive attention for their unique properties and promising applications in many fields. Many efforts have been made to improve the optical and physicochemical properties of CDs using an atomic doping strategy; however, the photoelectric properties of CD-based devices have been less studied and the photocurrent density is far from satisfactory for practical operation. Deep understanding of the doping effects on the electronic structure and photophysical properties of CDs is fundamental and essential for effectively improving the optical and photoelectrical performance of CD-based devices. Here, we have synthesized nitrogen (N) and phosphorus (P) co-doped CDs (N, P-CDs) through a one-step hydrothermal approach, and systematically investigated the effects of P-dopants on the improved optical and photoelectric properties of N, P-CDs. The introduction of P atoms into N-CDs significantly changes the electronic structure and extends the absorption spectral region, enhancing the light-harvesting ability of N, P-CDs. Meanwhile, the regulated carrier dynamics have been investigated using time-resolved fluorescence and transient absorption spectroscopy. We found that the carrier recombination was decreased with introducing P atoms, and the photogenerated electrons in the higher excited states could be efficiently transferred to the lowest excited state. Moreover, the photocurrent density of N, P-CDs was increased by twelve times compared with that of N-CDs. Therefore, the effective doping of P atoms can significantly regulate the electronic structure, optical properties, carrier dynamics and photoelectric conversion of N, P-CDs. The achieved broadband light-harvesting, good photoelectric properties and photostability of the as-prepared N, P-CDs demonstrate an important example of P-doping to improve the optical and photoelectrical properties of CD-based devices.


Role of Lipid Rafts in Pathogen-Host Interaction - A Mini Review.
Lipid rafts, also known as microdomains, are important components of cell membranes and are enriched in cholesterol, glycophospholipids and receptors. They are involved in various essential cellular processes, including endocytosis, exocytosis and cellular signaling. Receptors are concentrated at lipid rafts, through which cellular signaling can be transmitted. Pathogens exploit these signaling mechanisms to enter cells, proliferate and egress. However, lipid rafts also play an important role in initiating antimicrobial responses by sensing pathogens via clustered pathogen-sensing receptors and triggering downstream signaling events such as programmed cell death or cytokine production for pathogen clearance. In this review, we discuss how both host and pathogens use lipid rafts and associated proteins in an arms race to survive. Special attention is given to the involvement of the major vault protein, the main constituent of a ribonucleoprotein complex, which is enriched in lipid rafts upon infection with vaccinia virus.


Insights into the microbiological and virulence characteristics of bacteria in orthopaedic implant infections: A study from Pakistan.
The exponential increase in the prevalence of multidrug resistant bacteria has resulted in limiting surgical treatment options globally, potentially causing biofilm-related complications, implant failure, and severe consequences. This study aims to isolate and characterize bacteria from post-surgical orthopaedic implant infections and screening for multiple antibiotic resistance. A cross-sectional study was conducted, involving isolation of forty-four dominant pathogenic bacterial isolates from 16 infected implant samples from across Islamabad and Rawalpindi. Out of forty-four, 38% cocci and 61% bacilli were obtained. Approximately 90% of isolates showed multiple antibiotic resistance (MAR) index of more than 0.2. Eleven strains were identified via 16S rRNA gene sequencing as Pseudomonas aeruginosa, Bacillus spp., Planococcus chinensis, Staphylococcus, Escherichia coli and Enterobacter cloacae. The bacterial strain E. coli MB641 showed sensitivity to Polymyxin only, and was resistant to all other antibiotics used. Maximum biofilm forming ability 0.532 ± 0.06, 0.55 ± 0.01 and 0.557 ± 0.07 was observed in Pseudomonas aeruginosa MB663, Pseudomonas aeruginosa MB664 and Bacillus spp. MB647 respectively after 24 hours of incubation. EPS production of bacterial strains was assessed, the polysaccharides and protein content of EPS were found to be in the range of 11-32 μg/ml and 2-10 μg/ml, respectively. Fourier transform infrared spectroscopic analysis of EPS showed the presence of carbohydrates, proteins, alkyl halides, and nucleic acids. X-ray diffraction analysis revealed crystalline structure of EPS extracted from biofilm forming bacteria. These findings suggest a high prevalence of antibiotic-resistant bacteria in orthopaedic implant-associated surgeries, highlighting the urgent need for ongoing monitoring and microorganism testing in infected implants.


Lymphokine-activated killer (LAK) cell phenomenon in cluster headache. "In vitro" activation by recombinant interleukin-2.
Previous studies showed that the Natural Killer (NK) activity of peripheral blood lymphocytes (PBL) from cluster headache (CH) patients is lower than that of controls. This decreased activity seems to be independent of the cluster period. beta-interferon has been shown to be more effective in increasing NK activity when incubated with PBL from CH patients, than with PBL from control donors. Lymphokine-Activated Killer (LAK) cells can be generated by incubation of human PBL in recombinant Interleukin-2 (rIL-2). This phenomenon was studied in 10 CH patients and 8 healthy volunteers. PBL were activated to LAK cells by "in vitro" incubation for 72 hours in Control Medium containing rIL-2 (1000 I.U./ml). A four hour Chromium 51 release was used to measure LAK Cell Killing of K562 target cells. The released radioactivity was measured in a gamma scintillation counter. The CH patients showed a marked increase of LAK generation compared to control subjects. This effect seems to be augmented during the cluster period.


Transient variations in the systolic pulsations in amplitude of intracranial echoes: their artifactual origin.
Variations in the amplitude of intracranial echoes that synchronize with systole are caused by movement of the reflecting interfaces. These movements result from propagation of the arterial pulse through the brain and vary with the arterial pulse pressure and the distance through the vascular tree for which the pulse propagates before being completely attenuated; this distance varies with the degree of arteriolar dilatation. The interpretation of such systolic fluctuations in echo amplitudes is subject to a number of limitations, and their recording is also subject to artifactual variations, usually resulting from the relative motion of the signal with respect to a fixed gate. Transient variation in the systolic fluctuations of echo amplitudes, as a result of various stimuli, can be recorded by a fixed gate but not simultaneously by a tracking gate. They would therefore appear to be artifactual and not indicative of regional changes in cerebral blood flow, which in any case would cause motion and amplitude changes in interfaces that were not confined to the region involved.


Highly Efficient Lithium Recovery from Pre-Synthesized Chlorine-Ion-Intercalated LiAl-Layered Double Hydroxides via a Mild Solution Chemistry Process.
Lithium extraction from salt lake brine is critical for satisfying the increasing demand of a variety of lithium products. We report lithium recovery from pre-synthesized LiAl-layered double hydroxides (LDHs) via a mild solution reaction. Lithium ions were released from solid LiAl-LDHs to obtain a lithium-bearing solution. The LiAl-LDHs phase was gradually transformed into a predominantly Al(OH)3 phase with lithium recovery to the aqueous solution. The lithium recovery percentage and the concentration of the lithium-bearing solution were dependent on the crystallinity of LiAl-LDHs, the initial concentration of the LiAl-LDHs-1 slurry, the reaction temperature, and the reaction time. Under optimized conditions, the lithium recovery reached 86.2% and the Li+ concentration in the filtrate is 141.6 mg/L. Interestingly, no aluminum ions were detected in the filtrate after solid-liquid separation with high crystallinity LiAl-LDHs, which indicated the complete separation of lithium and aluminum in the liquid and solid phases, respectively. The 27Al NMR spectra of the solid products indicate that lithium recovery from the lattice vacancies of LiAl-LDHs affects the AlO6 coordination in an octahedral configuration of the ordered Al(OH)3 phase. The XPS O 1s spectra show that the Oad peak intensity increased and the OL peak intensity decreased with the increasing lithium recovery, which indicated that the Al-OH bond was gradually formed and the metal-oxygen-metal bond was broken.


[Effects of cisapride on intestinal bacterial and endotoxin translocation in cirrhotic rats].
To further investigate the effects of cisapride on intestinal bacterial overgrowth (IBO), bacterial and endotoxin translocation, intestinal transit and permeability in cirrhotic rats. 25 normal control rats, 25 cirrhotic rats, 20 cirrhotic rats received saline, and 20 cirrhotic rats treated with cisapride were included in the study. All animals were assessed with many variables including bacterial and endotoxin translocation, IBO, intestinal transit and permeability. Bacterial translocation was found in 48%(12/25) cirrhotic rats and none of control rats. Among the 20 rats with IBO, there were 11 rats with bacterial translocation (BT) while only one rats occurred BT out of the 5 rats without IBO. Cirrhotic rats with IBO had a significantly higher rate of endotoxin translocation, higher intestinal permeability and longer intestinal transit than those without IBO. BT of a specific organism was always associated with IBO of that organism. Compared with the placebo group, cisapride-treated rats had lower rates of bacterial and endotoxin translocation and IBO, which had close relationship with shorter intestinal transit and lower permeability. Endotoxin and bacterial translocation in cirrhotic rats may be the result of IBO and higher permeability. IBO may be the result of longer transit. Cisapride which can accelerate intestinal transit and improve intestinal permeability is helpful in preventing and treating intestinal bacterial and endotoxin translocation.


Development and validation of a nomogram for predicting cancer-specific survival in patients with Wilms' tumor.
Purpose: The objective of this study was to develop and validate a nomogram for predicting the cancer-specific survival (CSS) in patients with Wilms' tumor (WT). Methods: Patients with WT diagnosed between 2002 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were divided randomly into training and validation cohorts in this study. Multivariate Cox regression analysis was used to screen variables. A Cox proportional-hazards regression model and a nomogram were constructed based on variables that significantly affected the CSS in the training cohort. The nomogram for distinguishing and predicting the CSS was evaluated using the concordance index (C-index), the area under the time-dependent receiver operating characteristic curve (AUC), and calibration plots. Results: In total, 1631 patients from the SEER database were enrolled, with 1141 categorized into the training cohort and 490 into the validation cohort. All significant variables associated with CSS-age, the number of examined lymph nodes, SEER stage, and tumor size-were included in the nomogram. The C-index values of the nomogram in the training and validation cohorts were 0.746 and 0.703, respectively. The 3-, 5-, and 10-year AUCs were 0.755, 0.749, and 0.724, respectively, in the training cohort, and 0.718, 0.707, and 0.718 in the validation cohort. The calibration plots indicated the nomogram could accurately predict the 3-, 5-, and 10-year CSS. Conclusions: We have developed and validated the first nomogram for predicting the survival of WT patients. The nomogram is a reliable tool for distinguishing and predicting the CSS in patients with WT. Information provided by the nomogram may help to improve the clinical practices related to WT.


Patients' and health care professionals' views of complications after elective surgery.
In this study, which is a part of a clinical-epidemiological study of post-operative complications, the Project Peri-operative Risk (PROPER), patients' and health professionals' perceptions of complications during the patients' stay in hospital are analysed. Five hundred and ten patients admitted for elective (= planned) surgery and attending a pre-operative outpatient clinic set up for this project were seen pre-operatively and then monitored closely during and after surgery. Three months after having been operated on, they were sent a postal questionnaire in which they were asked to indicate whether they had suffered post-operative complications and to evaluate the care process. The incidence of complications reported by patients and staff was similar, but there were large differences at the individual level. Two-thirds of the staff-reported complications were not reported by the patients and vice versa. Patients generally classified complications as more severe than the staff did. Patients' evaluation of the care process was clearly related to reported complications. Most dissatisfied were those patients who reported complications not reported by the staff, and the most satisfied were those who had complications according to the staff but no complications according to themselves. The implication of these findings is discussed.


Separation and localization of the four cysteine-949 residues in human alpha 2-macroglobulin using fluorescence energy transfer.
By use of the intermediate form (I-form) [Gettins, Crews, & Cunningham (1989) Biochemistry 28, 5613-5618], alpha 2-macroglobulin can be specifically labeled with fluorescent probes in a manner that allows the determination of the topology of the four thiol ester derived Cys949 residues within this large tetrameric protease inhibitor. Freshly prepared I-form alpha 2-macroglobulin was reacted with 5-[[2-[(iodoacetyl)-amino]ethyl]amino]naphthalene-1-sulfonate (1,5-I-AEDANS) to produce alpha 2-macroglobulin specifically and stoichiometrically labeled with 1,5-AEDANS (donor) at the two Cys949 SH groups in the first protease interaction site. Upon subsequent reaction of this labeled species with chymotrypsin, the remaining two bait regions and thiol ester linkages were opened, generating two free SH groups on the two Cys949 residues in the second protease interaction site. These SH groups were specifically and stiochiometrically labeled with 5-(iodoacetamido)fluorescein (acceptor). Fluorescence energy transfer from donor to acceptor results in 82% loss of AEDANS fluorescence intensity. By use of an R0(2/3) value of 43.5 A, calculated from the spectral parameters of this system, an R(2/3) separation between donor and acceptor of 33.9 A was calculated. From fluorescence anisotropy measurements of both donor and acceptor attached to alpha 2-macroglobulin, upper and lower limits on the separation of 43.4 and 26.1 A, respectively, were calculated. These separations, small in the context of the alpha 2-macroglobulin tetramer, which has approximate dimensions of 190 x 90 x 90 A, severely restrict the possible locations of the four Cys949 residues.(ABSTRACT TRUNCATED AT 250 WORDS)


Causes and consequences of adult laryngotracheal stenosis.
Laryngotracheal stenosis (LTS) is largely considered a structural entity, defined on anatomic terms (i.e., percent stenosis, distance from vocal folds, overall length). This has significant implications for identifying at-risk populations, devising systems-based preventive strategies, and promoting patient-centered treatment. The present study was undertaken to test the hypothesis that LTS is heterogeneous with regard to etiology, natural history, and clinical outcome. Retrospective cohort study of consecutive adult tracheal stenosis patients from 1998 to 2013. Subjects diagnosed with laryngotracheal stenosis (ICD-9: 478.74, 519.19) between January 1, 1998, and January 1, 2013, were identified. Patient characteristics (age, gender, race, follow-up duration) and comorbidities were extracted. Records were reviewed for etiology of stenosis, treatment approach, and surgical dates. Stenosis morphology was derived from intraoperative measurements. The presence of tracheostomy at last follow-up was recorded. One hundred and fifty patients met inclusion criteria. A total of 54.7% had an iatrogenic etiology, followed by idiopathic (18.5%), autoimmune (18.5%), and traumatic (8%). Tracheostomy dependence differed based on etiology (P < 0.001). Significantly more patients with iatrogenic (66%) and autoimmune (54%) etiologies remained tracheostomy-dependent compared to traumatic (33%) or idiopathic (0%) groups. On multivariate regression analysis, each additional point on Charlson Comorbidity Index was associated with a 67% increased odds of tracheostomy dependence (odds ratio 1.67; 95% confidence interval 1.04-2.69; P = 0.04). Laryngotracheal stenosis is not a homogeneous clinical entity. It has multiple distinct etiologies that demonstrate disparate rates of long-term tracheostomy dependence. Understanding the mechanism of injury and contribution of comorbid illnesses is critical to systems-based preventive strategies and patient-centered treatment. 4.


A new species of nucleo-cytoplasmic large DNA virus (NCLDV) associated with mortalities in Manitoba lake sturgeon Acipenser fulvescens.
A newly discovered virus, Namao virus, associated with morbidity and mortality, was detected among juvenile lake sturgeon Acipenser fulvescens being propagated by a conservation stocking program for this endangered species in Manitoba, Canada. The outbreaks resulted in cumulative mortalities of 62 to 99.6% among progeny of wild Winnipeg River or Nelson River lake sturgeon and occurred at 2 geographically separate facilities. Namao virus was detected in almost 94% of the moribund or dead lake sturgeon according to a conventional polymerase chain reaction (cPCR) test that is based upon amplification of a 219 bp fragment of the virus major capsid protein (MCP). The virus itself was large (242 to 282 nm) and icosahedral-shaped with 2 capsids and a condensed bar-shaped core. It was found in virus factories within the host cell cytoplasm and displayed a tropism for the integument. Namao virus caused cellular changes characterized by enlarged eosinophilic epithelial cells in the gills and skin. Samples suspected of containing Namao virus did not have cytopathic effects on primary lake sturgeon or established white sturgeon cell lines. However, viral nucleic acid was detected in the former after prolonged incubation periods. Using primers designed from conserved regions of the MCP from NCLDVs, an estimated 95 to 96% of the Namao virus MCP open reading frame was captured. Phylogenetic analysis using the MCP of Namao virus and 27 other NCLDVs suggested that Namao virus and white sturgeon iridovirus share a common evolutionary past and might be members of the family Mimiviridae or a new, as yet unrecognized, virus family.


Dermatologic care of sexual and gender minority/LGBTQIA youth, Part I: An update for the dermatologist on providing inclusive care.
Sexual and gender minority (SGM) persons, including lesbian, gay, bisexual, transgender/gender diverse, questioning/queer, intersex, and asexual (LGBTQIA) individuals, represent a historically underserved population within the field of medicine, though their unique health needs are increasingly recognized. Unfortunately, our understanding of these needs as they relate to dermatology is still nascent, particularly with respect to children and adolescents. This two-part review will discuss the dermatologic care of SGM youth, with Part 1 providing practical advice for dermatologists seeking to provide more culturally mindful and accessible care for SGM children and adolescents. A more comprehensive understanding of the psychosocial and physical needs of SGM youth will allow dermatologists to more actively and compassionately care for this health disparity population.


Molecular diagnosis of Rett syndrome.
In 1999, mutations in the MECP2 gene were identified as the primary cause of Rett syndrome. MECP2 mutations can be found in 70% to 80% of all clinically defined Rett syndrome cases; in classic Rett syndrome, this frequency is even higher. In most cases, missense and nonsense mutations affecting functionally important domains can be found. Additionally, a hot spot for small deletions has been defined, and several gross rearrangements have also been described. Among female individuals with Rett syndrome, the spectrum of clinical phenotypes is broad, but most fulfill the diagnostic criteria. In contrast, male individuals with mutations in the MECP2 gene are rare, and only a minority have clinical symptoms resembling Rett syndrome.


Newly Synthesized Anticancer Purine Derivatives Inhibiting p-EIF4E Using Surface-Modified Lipid Nanovesicles.
Translation of mRNA is one of the processes adopted by cancer cells to maintain survival via phosphorylated (p)-eIF4E overexpression. Once p-eIF4E binds to the cap structure of mRNA, it advocates a nonstop translation process. In this regard, 15 new-based GMP analogs were synthesized to target eIF4E and restrain its binding to cap mRNA. The compounds were tested against three types of cancer cell lines: Caco-2, HepG-2, MCF-7, and normal kidney cells (Vero cells). Most of the compounds showed high potency against breast cancer cells (MCF-7), characterized by the highest cancer type for overexpression of p-eIF4E. Compound 4b was found to be the most active against three cell lines, colon (Caco-2), hepatic (HepG-2), and breast (MCF-7), with positive IC50 values of 31.40, 27.15, and 21.71 μM, respectively. Then, chitosan-coated niosomes loaded with compound 4b (Cs/4b-NSs) were developed (as kinetically enhanced molecules) to improve the anticancer effects further. The prepared Cs/4b-NSs showed pronounced cytotoxicity compared to the free 4b against Caco2, Hepg2, and MCF-7 with IC50 values of 16.15, 26.66, and 6.90 μM, respectively. Then, the expression of both the phosphorylated and nonphosphorylated western blot techniques was conducted on MCF-7 cells treated with the most active compounds (based on the obtained IC50 values) to determine the total protein expression of both eIF4E and p-eIF4e. Interestingly, the selected most active compounds displayed 35.8-40.7% inhibition of p-eIF4E expression when evaluated on MCF-7 compared to Ribavirin (positive control). CS/4b-NSs showed the best inhibition (40.7%). The findings of the present joint in silico molecular docking, simulation dynamic studies, and experimental investigation suggest the potential use of niosomal nanovesicles as a promising nanocarrier for the targeted delivery of the newly synthesized compound 4b to eukaryotic initiation factor 4E. These outcomes support the possible use of Cs/4b-NSs in targeted cancer therapy.


MTM program increased statin use.
Educating physicians about statins resulted in more physicians prescribing the drugs and saved money by averting major coronary events, according to a study of an MTM program


Plasma Homocysteine Concentration is Associated with the Expression Level of Folate Receptor 3.
Folic acid and folate receptors (FOLRs) play an important role in the downregulation of homocysteine (Hcy), a risk factor of Alzheimer's disease, thrombosis, neuropsychiatric illness and fractures. While several studies have reported that FOLR1 and FOLR2 import folic acid into cells, the role of FOLR3 remains unknown. In this study, we evaluated the impact of FOLR3 on the metabolism of Hcy alongside its protective effect against homocysteine-induced neurotoxicity. To reveal the role of FOLR3, we constructed FOLR3-overexpressed HEK293 cells (FOLR3+ cells) and evaluated cell growth, folic acid intake and Hcy-induced neurotoxicity. Subjects with a high expression of FOLR3 exhibited low levels of plasma homocysteine. The ectopic expression of FOLR3 enhanced cell growth, and the enhanced effect was neutralised by folic acid-deficient media. The Western blot analysis revealed that FOLR3 is secreted into cell supernatant. The folic acid intake of FOLR3+ cells was higher than that of wild-type cells. Supernatant from FOLR3+ cells showed a protective effect on Hcy-induced cytotoxicity. FOLR3 expression in plasma is negatively correlated with plasma homocysteine. Our study emphasizes the role of FOLR3 in the intake of folic acid into cells on the one hand and its protective role in Hcy-induced cytotoxicity on the other.


Phase behavior of lipid-based lyotropic liquid crystals in presence of colloidal nanoparticles.
We have investigated the microstructure and phase behavior of monoglyceride-based lyotropic liquid crystals in the presence of hydrophilic silica colloidal particles of size comparable to or slightly exceeding the repeat units of the different liquid crystalline phases. Using small angle X-ray scattering (SAXS) and differential scanning calorimetry (DSC), we compare the structural properties of the neat mesophases with those of the systems containing silica colloidal particles. It is found that the colloidal particles always macrophase separate in inverse bicontinuous cubic phases of gyroid (Ia3d) and double diamond (Pn3m) symmetries. SAXS data for the inverse columnar hexagonal phase (H(II)) and lamellar phase (L(α)) suggest that a low volume fraction of the nanoparticles can be accommodated within the mesophases, but that at concentrations above a given threshold, the particles do macrophase separate also in these systems. The behavior is interpreted in terms of the enthalpic and entropic interactions of the nanoparticles with the lamellar and hexagonal phases, and we propose that, in the low concentration limit, the nanoparticles are acting as point defects within the mesophases and, upon further increase in concentration, initiate nucleation of nanoparticles clusters, leading to a macroscopic phase separation.


Presurgical neoadjuvant targeted molecular therapy for kidney cancer with concomitant vena cava tumor embolus: A clinical study.
The present study aimed to investigate presurgical neoadjuvant targeted therapy for patients with kidney cancer and vena cava tumor embolus, in order to examine its indications, therapeutic effects and optimal timing of surgery. Between June 2009 and June 2014, 12 patients from The People's Liberation Army General Hospital (Beijing, China) were diagnosed with kidney cancer with superior vena cava tumor embolus, and received presurgical neoadjuvant targeted therapy (sorafenib 400 mg twice a day or sunitinib 50 mg/day) for a median of 13.3 weeks. Patients included 8 males and 4 females, with a median age of 49.8 years. Kidney cancer was present on the left side in 3 patients and in the right side in 9 patients. The median tumor embolus length was 9.7 cm (range, 6.5-14.0 cm). Tumor embolus levels II, III and IV, classified by the Mayo Clinic standard, were observed in 2, 6 and 4 patients, respectively. Median treatment time and average targeted therapy discontinuation time were observed to be longer in sunitinib-treated patients compared with sorafenib-treated patients. In total, 2 patients in the present study had partial remission (PR) and 8 patients had stable disease (SD); for tumor embolus, 4 patients had PR and 8 patients had SD. Tumor embolus length decreased by a median value of 18.7% (range, 0.0-42.1%) or 1.8 cm (range, 0.1-5.2 cm). Tumor diameter decreased by a median value of 8.6% (range, 0.0-38.9%) or 0.7 cm (range, 0.0-3.5 cm). The level of the tumor thrombus, classified by the Mayo Clinic standard, was observed to decrease following sunitinib treatment, including two cases downgraded from tumor thrombus level IV to II, one case from level IV to III and two cases from level III to II. Presurgical neoadjuvant targeted molecular therapy may have the potential to reduce the tumor stage of patients, as well as decreasing the surgical difficulty for radical nephrectomy.


Microcephaly with simplified gyral pattern, epilepsy and permanent neonatal diabetes syndrome (MEDS). A new patient and review of the literature.
Microcephaly with simplified gyration, epilepsy and permanent neonatal diabetes syndrome (MEDS) is a recently described, autosomal recessive-inherited syndrome. We report the case of an infant presenting with lethargy at age five weeks and clinical findings of persistent hyperglycaemia and microcephaly with simplified gyration, suggestive of MEDS. The diagnosis was confirmed by the detection of a known c.233 T > C mutation in the IER3IP1 gene. Only eight cases of MEDS have been reported in the literature. We reviewed these with the aim of better delineating their clinical manifestations, which should allow earlier and more accurate diagnosis and genetic counseling.


Discovery of a Human Testis-specific Protein Complex TEX101-DPEP3 and Selection of Its Disrupting Antibodies.
TEX101 is a testis-specific protein expressed exclusively in male germ cells and is a validated biomarker of male infertility. Studies in mice suggest that TEX101 is a cell-surface chaperone which regulates, through protein-protein interactions, the maturation of proteins involved in spermatozoa transit and oocyte binding. Male TEX101-null mice are sterile. Here, we identified by co-immunoprecipitation-mass spectrometry the interactome of human TEX101 in testicular tissues and spermatozoa. The testis-specific cell-surface dipeptidase 3 (DPEP3) emerged as the top hit. We further validated the TEX101-DPEP3 complex by using hybrid immunoassays. Combinations of antibodies recognizing different epitopes of TEX101 and DPEP3 facilitated development of a simple immunoassay to screen for disruptors of TEX101-DPEP3 complex. As a proof-of-a-concept, we demonstrated that anti-TEX101 antibody T4 disrupted the native TEX101-DPEP3 complex. Disrupting antibodies may be used to study the human TEX101-DPEP3 complex, and to develop modulators for male fertility.


Importance of plasma membrane dynamics in chemical-induced carcinogenesis.
In the last decade, a lot of patents have been filled regarding molecular biology and functions of cellular membranes. The membrane bilayer model has evolved from a static, passive, homogeneous barrier to a highly dynamic, asymmetric, heterogeneous structure composed of distinct domains. Changes in membrane fluidity and composition of microdomains have been proven to be involved in the regulation of many important physiological signaling pathways. Recently, several xenobiotics, including various drugs and environmental pollutants, have been reported to change plasma membrane characteristics, thereby altering cell physiology. Interestingly, it has been suggested that a cross talk between chemical-induced cellular membrane effects and DNA damages may be important for the final mutation outcome of genotoxic chemicals. Thus, effects on plasma membrane remodeling may give additional mechanistic explanations to how certain chemicals exert their carcinogenic effect. With respect to such effects, recent patents suggest to focus on plasma membrane and its components like caveolin-1 for cancer screening and chemotherapy. Here, we review the effects of environmental toxicants on cellular plasma membrane structure and function, and further describe possible implication for health and disease.


Effects of prolactin on the morphology of cultured rat granulosa cells.
Morphological changes were correlated with biochemical data induced by prolactin (PRL) in cultured rat granulosa cells from large preovulatory follicles. Biochemical results indicated that PRL exerted a significant dose-dependent inhibition in gonadotrophin-induced secretion of progesterone and 17 beta-oestradiol. PRL alone failed to affect basal steroidogenic secretion. In parallel morphological experiments, using phase-contrast microscopy, untreated and 100 ng/ml PRL-treated cells appeared as a monolayer of flattened, fibroblast-like cells. Upon exposure to 0.4 IU/ml human chorionic gonadotrophin (hCG), aggregates of rounded, epithelioid-shaped cells were formed. The addition of PRL to hCG in the same doses minimized the changes induced by hCG. Similarly, electron microscopy of untreated and PRL-treated cultures revealed flat cells devoid of microvilli, with evenly dispersed microfilaments. The addition of hCG caused rounding of the cells and was accompanied by the appearance of microvilli and by pronounced steroid-producing organelles. Bundles of microfilaments were noted at the cell periphery. PRL added to hCG caused a reduction of the hCG effects, and the cell morphology was intermediate to that seen in untreated and hCG-treated cultures. The finding that PRL can prevent or minimize morphological changes caused by hCG in rat cultured granulosa cells correlates with the biochemical changes induced by PRL, and supports the concept that PRL is a modulator of gonadotrophic action in the ovary.


Evidence-based evaluation of three imaging methods for the temporomandibular disc.
To review the literature and evaluate the evidence for the diagnostic outcome of arthrography, computed tomography (CT) and magnetic resonance imaging (MRI) in the assessment of temporomandibular joint (TMJ) disc position. A literature search from 1978 to 1994 was conducted. Data on sensitivity, specificity, predictive values and likelihood ratios were collected and, if not available, calculated for each imaging method. Measures of observer performance were also recorded. In total, more than 400 publications were retrieved on imaging of TMJ disc position, 219 on arthrography, 99 on CT and 147 on MRI, with a marked decrease in recent years. The majority of the publications (54%) presented series of patients. The diagnostic outcome cold be obtained from only 7% of the studies and the observer performance from only two of these. Arthrography had the highest diagnostic outcome for the diagnosis of anterior disc position; sensitivity 0.90, specificity 0.80, positive predictive value 0.88 and negative predictive value 0.82. Corresponding figures for CT were 0.66, 0.68, 0.66 and 0.74 and for MRI 0.86, 0.63, 0.67 and 0.83. The diagnostic outcomes expressed as the likelihood ratios for positive test outcome were 4.5 for arthrography, 2.3 for MRI and 2.1 for CT. The outcomes in diagnosing sideways and rotational displacements were higher for MRI (sensitivity 0.81, specificity 0.87, positive predictive value 0.82, negative predictive value 0.88) than for arthrography (0.64, 0.83, 0.70, 0.79). The likelihood ratios were 6.2 for MRI and 3.8 for arthrography. The interobserver performance ranged between moderate to substantial for arthrography and was almost perfect for MRI. Based on current evidence on the diagnostic outcome, MRI seems to be the method of choice for diagnosing TMJ disc position. Arthrography has a higher diagnostic outcome for anterior disc position but the disadvantage of being an invasive method. We suggest that the quality of the evidence should be improved and that an analysis of the impact of the imaging methods on patient treatment should be performed.


Attachment of an electron-withdrawing fluorophore to a cryptand for modulation of fluorescence signaling.
The laterally nonsymmetric aza cryptand synthesized by condensing tris(2-aminoethyl)amine (tren) with tris[2-[(3-(oxomethyl)phenyl)oxy]ethyl]mine readily forms mononuclear inclusion complexes with both transition- and main-group-metal ions. The fluorophore 7-nitrobenz-2-oxa-1,3-diazole is attached to one of the secondary amines, to give an integrated fluorophore-receptor configuration. The fluorophoric system does not show any appreciable emission when excited due to an efficient photoinduced intramolecular electron transfer (PET) from the nitrogen lone pair. When a metal ion enters the cavity, the PET is blocked, causing recovery of fluorescence; Cd(II) gives the highest quantum yield. The fluorophore, with pi-accepting ability, drastically alters the binding property of the cryptand. With perchlorate or tetrafluoroborate salts of Cd(II), the metal ion enters the cavity, causing recovery of fluorescence. However, in the presence of coordinating ions such as Cl-, N3-, and SCN-, the metal ion comes out of the cavity, causing PET to take place once again, and the fluorescence is lost. Thus, translocation of Cd(II) between the inside and outside of the cryptand cavity can lead to a reversible fluorescence on/off situation.