Comparison of histomorphometry and microradiography of different implant designs to assess primary implant stability.
To contribute toward optimizing the long-term stability of dental implants. Our working hypothesis was that the degrees of immediate implant-bone contact, and hence of primary stability, would demonstrably differ between implant systems due to their different external geometries and thread designs (macro-design). This demonstration was provided in a bovine model (ex vivo) by employing and comparing histomorphometry and microradiography as evaluation methods. A total of 120 implants, representing six different implant thread designs, were inserted following the recommended surgical protocol in ribs of freshly slaughtered cattle. Twenty specimens of implants with surrounding bone were prepared per system and were divided into two equally sized groups of 60 specimens for analysis by either histomorphometry or micro-computed tomography. Data were analyzed by Mann-Whitney U test (P ≤ .05). One of the implant systems, featuring a slight tapered external geometry and a progressive thread design, consistently revealed the most favorable bone-implant contacts in both histomorphometric and microradiographic evaluations. Overall, consistently higher values of bone-implant contact were obtained with the microradiographic than the histomorphometric approach, and this difference reached statistical significance in three of the six implant systems tested. Progressive threads offering a bone-condensing effect can significantly help to maximize implant-bone contact percentages. Compared to histomorphometry, microradiography is likewise a suitable method to evaluate bone-implant contact, offering the additional benefits of being noninvasive and less time consuming.


Conidiobolus coronatus infection treated with ketoconazole.
We describe a case of subcutaneous zygomycosis caused by Conidiobolus coronatus of six years' duration. Following treatment failure using potassium iodide, the patient responded with ketoconazole therapy. She remained well three years following therapy. Brazilian cases of subcutaneous infections caused by C coronatus and Basidiobolus ranarum are reviewed.


Transport and metabolism in legume-rhizobia symbioses.
Symbiotic nitrogen fixation by rhizobia in legume root nodules injects approximately 40 million tonnes of nitrogen into agricultural systems each year. In exchange for reduced nitrogen from the bacteria, the plant provides rhizobia with reduced carbon and all the essential nutrients required for bacterial metabolism. Symbiotic nitrogen fixation requires exquisite integration of plant and bacterial metabolism. Central to this integration are transporters of both the plant and the rhizobia, which transfer elements and compounds across various plant membranes and the two bacterial membranes. Here we review current knowledge of legume and rhizobial transport and metabolism as they relate to symbiotic nitrogen fixation. Although all legume-rhizobia symbioses have many metabolic features in common, there are also interesting differences between them, which show that evolution has solved metabolic problems in different ways to achieve effective symbiosis in different systems.


Ceruloplasmin correlates with immune infiltration and serves as a prognostic biomarker in breast cancer.
Breast-invasive carcinoma (BRCA) is the most frequent and malignant tumor in females. Ceruloplasmin (CP) is a multifunctional molecule involved in iron metabolism, but its expression profile, prognostic potential and relationship with immune cell infiltration in BRCA are unknown. Ceruloplasmin mRNA and protein expression was significantly decreased in BRCA patients according to the Oncomine, UALCAN, GEPIA and TCGA databases. Ceruloplasmin expression was strongly correlated with various clinicopathological features of BRCA patients. BRCA patients with high ceruloplasmin expression exhibited shorter survival times than those with low ceruloplasmin expression based on the Kaplan-Meier plotter and PrognoScan databases. GO and KEGG analyses and GSEA revealed a strong correlation between ceruloplasmin and various immune-related pathways. Ceruloplasmin expression was significantly associated with the infiltration of immune cells into tumor sites by analyzing the TIMER and CIBERSORT. Additionally, ceruloplasmin was positively correlated with immune checkpoints in BRCA. These findings suggest that low ceruloplasmin expression correlates with a favorable prognosis and tumor immune cell infiltration in BRCA patients. Ceruloplasmin may serve as a therapeutic target and predict the efficacy of immunotherapy for BRCA.


The Ross operation - a feasible and safe option in the setting of a bicuspid aortic valve?
The Ross operation in the setting of a bicuspid aortic valve (BAV) remains controversial. Using data from the German Ross Registry, we sought to investigate the effect of the presence of a BAV on autograft function and diameters over time after the Ross operation compared with the presence of a tricuspid aortic valve (TAV). A total of 1277 patients (mean age 42.2 + or - 15.3 years) with intra-operatively documented aortic valve morphology during the Ross operation were analysed in the present study (sub-coronary technique, n=648, root replacement technique, n=629 patients). A BAV was present in 70.9% of patients. Clinical and echocardiographic follow-up was performed preoperatively and at pre-specified intervals (mean follow-up 5.7 + or - 3.8 years, 6806 patient-years). Hierarchical multilevel modelling techniques were used for the statistical analysis of serial measurements and comparisons among groups. Initial neo-aortic regurgitation was lower in the BAV group (0.52 vs 0.62 aortic insufficiency (AI) grades, p=0.008), whereas the annual increase of it did not differ among groups. In both surgical techniques, no significant development of neo-aortic regurgitation (<0.02 AI grades per year) could be detected. Initial aortic annulus and sinus dimensions did not differ in the presence of a BAV. However, BAV patients developed a higher degree of annulus and sinus dilatation over time (0.20mm per year vs 0.06 mm per year, p=0.003; 0.24 vs 0.11 mm per year, p=0.013). This effect persisted when allowing for the two different surgical techniques. Baseline sinotubular junction (STJ) diameters did not differ among groups and annual increase thereof was similar (29.15 mm vs 28.9 mm, p=0.69; 0.44 mm vs 0.35 mm, p=0.15). For the observed time period, postoperative neo-aortic regurgitation after the Ross procedure did not differ between patients with a BAV or a TAV. Root dimensions, although clinically not relevant, increased in both valve entities supporting surgical reinforcement strategies. We cannot consider a BAV as a contraindication for the Ross operation.


[The clinical, pathological features and expression of Ki-67 and COX-2 in severe reflux esophagitis and Barrett's esophagus].
To study the clinical, pathological features of severe reflux esophagitis (SRE) and Barrett's esophagus (BE) and search for expression and significance of Ki-67 and COX-2 in their tissues. Both SRE (n = 15) and BE (n = 25) cases were retrospectively analyzed for clinical manifestations, endoscopic findings and pathological features. The expression levels of Ki-67 and COX-2 of esophageal epithelium in the two groups were compared with that of normal esophageal (NE) epithelium (n = 10) by immunoperoxidase staining. It was found that the positivity and staining intensity of Ki-67 expression in SRE and BE were higher than those in normal esophageal epithelium (P<0.01), but there were no statistical differences between these two groups (P>0.05); COX-2 was selectively expressed in some BE epithelium, but not in SRE and normal esophageal epithelium. There were intensified Ki-67 expressions in the epithelium of SRE and BE, which could help us to evaluate the prognosis of gastroesophageal reflux disease (GERD) patients clinically by surveillance of Ki-67. COX-2 was selectively expressed in BE epithelium, so COX-2 inhibitors may have the potential for treatment of BE and for chemoprevention of its malignant change.


[Serum immunoglobulins in cardiovascular pathology].
The authors measured as a routine IgA, IgG and IgM serum immunoglobulins in a hundred subjects free from any cardiac or hypertensive disease, in 51 patients with coronary heart disease in in 50 hypertensive subjects. They found that in 2% of the normal subjects and in 28% of the coronary heart disease or hypertension, the level of one of the three serum immunoglobulins was outside the following limits: IgA 100 to 480 mg/100 ml, IgG 500 to 1900 mg/100 ml and IgM 45 to 380 mg/100 ml. The 2 normal subjects and 12% of the patients with coronary heart disease or hypertension presented an abnormally low level of one of the immunoglobulins, while an abnormally high level was observed in 16% of the subjects with coronary heart disease or hypertension. The abnormal serum levels may concern any class of immunoglobulin and persist in the case of some patients with coronary heart disease several years after the acute ischemic incident.


The parasitic hematophagous worm Haemonchus contortus inhibits human platelet aggregation and adhesion: partial purification of a platelet inhibitor.
Blood sucking parasites elaborate mechanisms to counteract the hemostatic system of their victim. Haemonchus contortus worms use several mechanisms directed against the normal platelet hemostatic function. Platelet adhesion onto collagen and fibrinogen, and the ristocetin-mediated interaction of von Willebrand Factor with glycoprotein (GP) Ib were inhibited by the protein extract of adult worms. Also platelet aggregation induced by collagen, thrombin, ADP, ristocetin or A23187 was inhibited. Although we obtained evidence for interference with fibrinogen binding to GPIIb/IIIa, the strongest inhibition was seen when the agonists collagen or thrombin were used. A small multisubunit inhibitor of collagen-induced platelet aggregation was partially purified using anion exchange chromatography, gel filtration and RP-HPLC. The inhibitor has a pI between 4 and 6.5, elutes with a molecular weight of 23,800 Da after gel filtration, and is part of the elaborate broad-spectrum antiplatelet activity that results in the potent synergistic anti-hemostatic cocktail produced by H. contortus.


Involvement of distal airways in a chronic model of experimental asthma.
Bronchial asthma is characterized by chronic airway inflammation and airway remodelling which occurs in both proximal and distal airways. These changes are associated with development of airway hyper-responsiveness and airflow limitation. This study was aimed to analyse whether chronic inhalative allergen challenges in mice lead to morphological and physiological changes comparable with this phenotype. For this purpose, BALB/c mice were systemically sensitized to ovalbumin (OVA) followed by aerosol allergen challenges on 2 consecutive days per week for 12 weeks. In chronically challenged mice, tissue inflammation in proximal as well as distal airways was observed with a predominance of lymphocytes within the cellular infiltrate. In contrast, inflammation in the airway lumen decreased over time. These changes were associated by a shift in bronchoalveolar lavage-cytokine levels from IL-4, IL-5 and TNF-alpha production (during the acute phase) towards markedly increased levels of TGF-beta during the chronic phase. Goblet cell hyperplasia and subepithelial fibrosis occurred throughout the airway tree. In terms of lung function, chronically challenged mice developed persistent bronchial hyper-responsiveness and progressive airflow limitation. Six weeks after OVA aerosol discontinuation, airway inflammation still persisted although lung function was normalized. These data indicate that our model of chronic aerosol allergen challenges leads to a phenotype of experimental asthma with participation of distal airways and persistence of inflammation thereby resembling many morphological and physiological aspects of human bronchial asthma.


The Dual Diverse Dynamic Reversible Effects of Ankaferd Blood Stopper on EPCR and PAI-1 Inside Vascular Endothelial Cells With and Without LPS Challenge.
Ankaferd blood stopper (ABS) is comprised of a mixture of the plants Thymus vulgaris, Glycyrrhiza glabra, Vitis vinifera, Alpinia officinarum, and Urtica dioica. ABS is used as a topical hemostatic agent due to its antihemorrhagic effect, yet its hemostatic mechanism of action remains to be investigated. ABS does not affect the levels of coagulation factors II, V, VII, VIII, IX, X, XI and XII. The aim of this study was to investigate the effects of ABS on endothelium and immune response. As such, we evaluated changes in endothelial cell protein C receptor (EPCR) and plasminogen activator inhibitor type-1 (PAI-1) expression inside human umbilical vein endothelial cells (HUVECs) in the presence and absence of lipopolysaccharides (LPSs). We exposed HUVECs to 10 μL and 100 μL of ABS for 5 min, 25 min, 50 min, 6 h, and 24 h. Additionally, 10 μg mL-1 of LPS was administered for 1 h to observe the effects of LPS challenge on HUVECs, and then the cells were treated with ABS for 5 min, 25 min, 50 min, and 6 h to observe the effects of ABS on HUVECs. Total RNA was isolated from HUVECs and then the level of expression of EPCR and PAI-1 mRNA was measured. Cells were microscopically observed to arise from the surface and adhere to each other following the administration of ABS to HUVECs. Additionally, after 24 h the cells had normal growth and physiology, which suggests that the adhesive cellular effects of ABS might be reversible. ABS had a negative effect on EPCR and PAI-1 expression; the effect in response to 100 µL was greater than that to 10 µL. EPCR and PAI-1 expression increased over time in response to LPS and 10 µL of ABS. EPCR and PAI-1 expression was very low during the first hour of exposure to LPS and 100 µL of ABS, but after 6 h increased to levels similar to those observed in response to LPS and 10 µL of ABS. It was observed that ABS had dual diverse dynamic reversible effects on EPCR and PAI-1 expression in HUVECs, which were dependent on dose and concentration. ABS might play a role in numerous cellular mechanisms, in addition to having hemostatic effects. None declared.


Celiac disease: From genetics to epigenetics.
Celiac disease (CeD) is a multifactorial autoimmune disorder spread worldwide. The exposure to gluten, a protein found in cereals like wheat, barley and rye, is the main environmental factor involved in its pathogenesis. Even if the genetic predisposition represented by HLA-DQ2 or HLA-DQ8 haplotypes is widely recognised as mandatory for CeD development, it is not enough to explain the total predisposition for the disease. Furthermore, the onset of CeD comprehend a wide spectrum of symptoms, that often leads to a delay in CeD diagnosis. To overcome this deficiency and help detecting people with increased risk for CeD, also clarifying CeD traits linked to disease familiarity, different studies have tried to make light on other predisposing elements. These were in many cases genetic variants shared with other autoimmune diseases. Since inherited traits can be regulated by epigenetic modifications, also induced by environmental factors, the most recent studies focused on the potential involvement of epigenetics in CeD. Epigenetic factors can in fact modulate gene expression with many mechanisms, generating more or less stable changes in gene expression without affecting the DNA sequence. Here we analyze the different epigenetic modifications in CeD, in particular DNA methylation, histone modifications, non-coding RNAs and RNA methylation. Special attention is dedicated to the additional predispositions to CeD, the involvement of epigenetics in developing CeD complications, the pathogenic pathways modulated by epigenetic factors such as microRNAs and the potential use of epigenetic profiling as biomarker to discriminate different classes of patients.


The Arabinose 5-Phosphate Isomerase KdsD Is Required for Virulence in Burkholderia pseudomallei.
Burkholderia pseudomallei is the causative agent of melioidosis, which is endemic primarily in Southeast Asia and northern Australia but is increasingly being seen in other tropical and subtropical regions of the world. Melioidosis is associated with high morbidity and mortality rates, which is mediated by the wide range of virulence factors encoded by B. pseudomallei. These virulence determinants include surface polysaccharides such as lipopolysaccharide (LPS) and capsular polysaccharides (CPS). Here, we investigated a predicted arabinose-5-phosphate isomerase (API) similar to KdsD in B. pseudomallei strain K96243. KdsD is required for the production of the highly conserved 3-deoxy-d-manno-octulosonic acid (Kdo), a key sugar in the core region of LPS. Recombinant KdsD was expressed and purified, and API activity was determined. Although a putative API paralogue (KpsF) is also predicted to be encoded, the deletion of kdsD resulted in growth defects, loss of motility, reduced survival in RAW 264.7 murine macrophages, and attenuation in a BALB/c mouse model of melioidosis. Suppressor mutations were observed during a phenotypic screen for motility, revealing single nucleotide polymorphisms or indels located in the poorly understood CPS type IV cluster. Crucially, suppressor mutations did not result in reversion of attenuation in vivo. This study demonstrates the importance of KdsD for B. pseudomallei virulence and highlights further the complex nature of the polysaccharides it produces. IMPORTANCE The intrinsic resistance of B. pseudomallei to many antibiotics complicates treatment. This opportunistic pathogen possesses a wide range of virulence factors, resulting in severe and potentially fatal disease. Virulence factors as targets for drug development offer an alternative approach to combat pathogenic bacteria. Prior to initiating early drug discovery approaches, it is important to demonstrate that disruption of the target gene will prevent the development of disease. This study highlights the fact that KdsD is crucial for virulence of B. pseudomallei in an animal model of infection and provides supportive phenotypic characterization that builds a foundation for future therapeutic development.


A randomized trial of empirical antibiotic therapy with one of four beta-lactam antibiotics in combination with netilmicin in febrile neutropenic patients.
Over a two year period 174 evaluable episodes of fever in neutropenic patients were treated in a randomized study comparing four beta-lactam antibiotics, each given in combination with netilmicin. Exclusions included episodes due to viral or fungal infection, and trial violations. Most patients were receiving treatment for leukaemia, including 18% undergoing bone marrow transplantation. The overall response rate (EORTC criteria) was 66%, ranging from 56% for cefoperazone to 76% for mezlocillin. Microbial documentation was obtained in 31% of episodes; Gram-positive isolates were most frequent but Pseudomonas aeruginosa was found in 18 patients. In patients with microbiologically documented infection 70% improved, overall--from 40% with cefoperazone to 80% with piperacillin (P less than 0.05). Nephrotoxicity was seen in 6.7% and was associated with severe documented sepsis. Hypokalaemia was seen in 29% and was most marked in patients receiving ticarcillin. Rashes occurred in 6.6% overall, with no difference between the groups. Ototoxicity, shown by serial audiograms, was seen in 4.7% of patients. No evidence of vestibular dysfunction was seen in 62 patients studied. Of thirteen deaths due to the primary infection, seven were caused by Ps. aeruginosa and five by fungi.


Cy5-conjugated hybridization-sensitive fluorescent oligonucleotides for ratiometric analysis of nuclear poly(A)+ RNA.
Subnuclear poly(A)(+) RNA localization in living mammalian cells was visualized by ratiometric analysis using hybridization-sensitive fluorescent oligonucleotide probes. Probes were oligonucleotides, which contained a Cy5 fluorescent dye at the strand end and a thiazole orange double-labeled nucleotide inside strand. A ratiometric analysis using poly(A)-targeting probes revealed a distribution of the probe itself as red fluorescence and localization of the target RNA sequence in cell nuclei as green fluorescence. The fluorescence of the subnuclear poly(A)(+) RNA hybridized with the poly(A)-targeting probes was observed as puncta in interchromatin areas.


Guidelines for establishing a maternal serum alpha-fetoprotein screening program.
Maternal serum alpha-fetoprotein (MSAFP) screening of all pregnant women between 15 and 20 weeks gestational age is generally recognized as a standard of care in current obstetric practice. There are many factors to consider when deciding to establish MSAFP testing as an in-house procedure versus ship-out testing by a reference laboratory at fee-for-service cost. In this report, we review clinical and analytical aspects of MSAFP testing, along with appropriate guidelines for establishing an on-site MSAFP screening program.


Pulmonary embolism in acute medicine: a case-based review incorporating latest guidelines in the COVID-19 era.
Pulmonary embolism remains an important cause of morbidity and mortality in the UK, particularly following the outbreak of the novel coronavirus 2019 (COVID-19), where those infected have an increased prevalence of venous thromboembolic events. The pathophysiology in COVID-19 patients is thought to relate to a thromboinflammatory state within the pulmonary vasculature, triggered by the infection, but other risk factors such as reduced mobility, prolonged immobilisation and dehydration are likely to contribute. Several societies have released comprehensive guidelines emphasising the importance of risk stratification in patients with acute pulmonary embolism. They advocate the use of clinically validated risk scores in conjunction with biochemical and imaging results. Patients with mild disease can now be managed in the outpatient setting and with newly developed therapies, such as catheter-directed thrombolysis, becoming available in more centres, treatment options for those with more severe disease are also expanding. This article presents four theoretical but realistic cases, each diagnosed with acute pulmonary embolism, but differing in levels of severity. These demonstrate how the guidelines can be applied in a clinical setting, with particular focus on risk stratification and management.


Evolutionary dynamics in financial markets with heterogeneities in investment strategies and reference points.
In nature and human societies, the effects of homogeneous and heterogeneous characteristics on the evolution of collective behaviors are quite different from each other. By incorporating pair pattern strategies and reference point strategies into an agent-based model, we have investigated the effects of homogeneous and heterogeneous investment strategies and reference points on price movement. In the market flooded with the investors with homogeneous investment strategies or homogeneous reference points, large price fluctuations occur. In the market flooded with the investors with heterogeneous investment strategies or heterogeneous reference points, moderate price fluctuations occur. The coexistence of different kinds of investment strategies can not only refrain from the occurrence of large price fluctuations but also the occurrence of no-trading states. The present model reveals that the coexistence of heterogeneous populations, whether they are the individuals with heterogeneous investment strategies or heterogeneous reference points of stock prices, is an important factor for the stability of the stock market.


[Syndrome X, at the crossroads of metabolic and cardiovascular diseases].
The relationships between metabolic disorders and cardiovascular diseases are very strong. Hypercholesterolaemia and diabetes mellitus, for instance, are well-known risk factors. The multifaceted metabolic syndrome or syndrome X, originally described by Reaven in 1988, comprises several abnormalities which are associated to insulin resistance and compensatory hyperinsulinaemia. Syndrome X results in an increased vascular risk by at least two mechanisms. On the one hand, it favours atherosclerosis and is associated to angiographic lesions, especially in the coronary arteries. On the other hand, it is associated to endothelial dysfunction which may contribute to myocardial ischaemia even in presence of angiographically normal arteries, a phenomenon named also syndrome X by the cardiologists. Thus, metabolic syndrome X and cardiological syndrome X are very close and syndrome X may be considered as a crossing between metabolic disorders and cardiovascular diseases.


Synthesis of polymer-bound 4-acetoxy-3-phenylbenzaldehyde derivatives: applications in solid-phase organic synthesis.
Aminomethyl polystyrene resin was reacted with 4-(5'-formyl-2'-hydroxyphenyl)benzoic acid and 4-(5'-formyl-2'-hydroxyphenyl)phenyl propionic acid, respectively, in the presence of 1-hydroxybenzotriazole and 1,3-diisopropylcarbodiimide to yield polymer-bound benzaldehydes. The phenolic group in resins was acetylated with acetic anhydride to afford two polymer-bound 4-acetoxybenzaldehydes. The reductive amination of polymer-bound linkers by amines and sodium triacetoxyborohydride, followed by sulfonylation with arylsulfonyl chloride derivatives in the presence of pyridine and the cleavage with TFA/DCM/H2O, produced pure sulfonamides.


Stable Surface Modification of Mesenchymal Stem Cells Using the Avidin-Biotin Complex Technique.
Mesenchymal stem cells (MSCs) hold promise in cell-based therapies because of their strong tissue repair ability and immunosuppressive effects; however, the therapeutic efficacy of transplanted MSCs is limited due to low survival rates and short-term functioning after transplantation. While the functionalization of MSCs is an ideal way to solve these problems, conventional cell functionalization methods have disadvantages such as cell damage, changes in cellular characteristics, and short-term modification. This unit describes a technique for MSC functionalization by surface modification via the avidin-biotin complex (ABC). This technique provides long-term modification MSC surfaces with biotinylated compounds. This easy method of MSC functionalization will support effective MSC-based therapy. © 2018 by John Wiley & Sons, Inc.


Genotypic and Phenotypic Characterization of the O-Linked Protein Glycosylation System Reveals High Glycan Diversity in Paired Meningococcal Carriage Isolates.
Species within the genus Neisseria display significant glycan diversity associated with the O-linked protein glycosylation (pgl) systems due to phase variation and polymorphic genes and gene content. The aim of this study was to examine in detail the pgl genotype and glycosylation phenotype in meningococcal isolates and the changes occurring during short-term asymptomatic carriage. Paired meningococcal isolates derived from 50 asymptomatic meningococcal carriers, taken about 2 months apart, were analyzed with whole-genome sequencing. The O-linked protein glycosylation genes were characterized in detail using the Genome Comparator tool at the https://pubmlst.org/ database. Immunoblotting with glycan-specific antibodies (Abs) was used to investigate the protein glycosylation phenotype. All major pgl locus polymorphisms identified in Neisseria meningitidis to date were present in our isolate collection, with the variable presence of pglG and pglH, both in combination with either pglB or pglB2 We identified significant changes and diversity in the pgl genotype and/or glycan phenotype in 96% of the paired isolates. There was also a high degree of glycan microheterogeneity, in which different variants of glycan structures were found at a given glycoprotein. The main mechanism responsible for the observed differences was phase-variable expression of the involved glycosyltransferases and the O-acetyltransferase. To our knowledge, this is the first characterization of the pgl genotype and glycosylation phenotype in a larger strain collection. This report thus provides important insight into glycan diversity in N. meningitidis and into the phase variability changes that influence the expressed glycoform repertoire during meningococcal carriage.IMPORTANCE Bacterial meningitis is a serious global health problem, and one of the major causative organisms is Neisseria meningitidis, which is also a common commensal in the upper respiratory tract of healthy humans. In bacteria, numerous loci involved in biosynthesis of surface-exposed antigenic structures that are involved in the interaction between bacteria and host are frequently subjected to homologous recombination and phase variation. These mechanisms are well described in Neisseria, and phase variation provides the ability to change these structures reversibly in response to the environment. Protein glycosylation systems are becoming widely identified in bacteria, and yet little is known about the mechanisms and evolutionary forces influencing glycan composition during carriage and disease.


Immunological changes in mesothelioma patients and their experimental detection.
It is common knowledge that asbestos exposure causes asbestos-related diseases such as asbestosis, lung cancer and malignant mesothelioma (MM) not only in people who have handled asbestos in the work environment, but also in residents living near factories that handle asbestos. These facts have been an enormous medical and social problem in Japan since the summer of 2005. We focused on the immunological effects of asbestos and silica on the human immune system. In this brief review, we present immunological changes in patients with MM and outline their experimental detection. For example, there is over-expression of bcl-2 in CD4+ peripheral T-cells, high plasma concentrations of interleukin (IL)-10 and transforming growth factor (TGF)-ß, and multiple over-representation of T cell receptor (TcR)-Vß in peripheral CD3+ T-cells found in MM patients. We also detail an experimental long-term exposure T-cell model. Analysis of the immunological effects of asbestos may help our understanding of the biological effects of asbestos.


Low heart rate variability is not caused by typical neuroleptics in schizophrenia patients.
Both elevated cardiovascular mortality and low cardio-vagal (parasympathetic) heart rate variability (HRV)--a risk factor for postmyocardial infarction--are reported in schizophrenia (SZ). Since a number of medications have strong effects of cardiac conductivity, we thought it important to examine if typical neuroleptic medications might also affect HRV. We examined cardiac vagal activity during both neuroleptic treatment and a drug-free condition in seven SZ patients who were participating in a pilot double-blind, crossover study of placebo and haloperidol treatment. Twenty-four-hour Holter electrocardiograms were analyzed for high frequency HRV, quantitated as the percent of successive normal interbeat intervals greater than 50 milliseconds (PNN50), which is a good index of parasympathetic cardiac modulation. The patients showed unchanged PNN50 (8.4+/-9.5 versus 8.3+/-10.5; t=.22, df=6, P=.5) between the haloperidol treatment and drug-free conditions. Despite the elapsed time, change in medication, and altered clinical state, the PNN50s were highly correlated (Spearman r=.98, P=.000). SAPS positive symptom scores declined with treatment from 12.8+/-6.5 to 8.5+/-3.5; paired t=3.26: df=6; P=.01. PNN50s were significantly associated with positive (r=-.86, df=6, P=.012) and negative symptom scores (r=-.87, df=6, P=.01). We found low cardiovagal modulation in medication-free SZ patients that was associated with core SZ symptoms and was unchanged by haloperidol and benztropine treatment. The reduced HRV in SZ patients at baseline may render them at greater cardiovascular risk than healthy subjects when treated with medications having strong cardiovascular effects.


Biologic data of Macaca mulatta, Macaca fascicularis, and Saimiri sciureus used for research at the Fiocruz primate center.
Physiological parameters of laboratory animals used for biomedical research is crucial for following several experimental procedures. With the intent to establish baseline biologic parameters for non-human primates held in closed colonies, hematological and morphometric data of captive monkeys were determined. Data of clinically healthy rhesus macaques (Macaca mulatta), cynomolgus monkeys (Macaca fascicularis), and squirrel monkeys (Saimiri sciureus) were collected over a period of five years. Animals were separated according to sex and divided into five age groups. Hematological data were compared with those in the literature by Student's t test. Discrepancies with significance levels of 0.1, 1 or 5% were found in the hematological studies. Growth curves showed that the sexual dimorphism of rhesus monkeys appeared at an age of four years. In earlier ages, the differences between sexes could not be distinguished (p < 0.05). Sexual dimorphism in both squirrel monkeys and cynomolgus monkeys occurred at an age of about 32 months. Data presented in this paper could be useful for comparative studies using primates under similar conditions.


Combining Electronic and Steric Effects To Generate Hindered Propargylic Alcohols in High Enantiomeric Excess.
Tethered ruthenium-TsDPEN complexes have been applied to the catalysis of the asymmetric transfer hydrogenation of a range of aryl/acetylenic ketones. The introduction of an ortho- substituent to the aryl ring of the substrate results in a reversal of the enantioselectivity, while the introduction of two o-fluoro substituents results in an improvement to the reduction enantioselectivity, as does the replacement of a phenyl ring on the alkyne with a trimethylsilyl group. These effects are rationalized as resulting from a change in the steric properties of the aryl ring and the electronic properties of the alkyne which, when matched in the reduction transition state, combine within a "window" of substrate/catalyst matching to generate products of high ee.


Unilateral Stimulation of Subthalamic Nucleus Does Not Affect Inhibitory Control.
Despite the relevance of inhibitory control in shaping our behavior its neural substrates are still hotly debated. In this regard, it has been suggested that inhibitory control relies upon a right-lateralized network which involves the right subthalamic nucleus (STN). To assess the role of STN, we took advantage of a relatively rare model, i.e., advanced Parkinson's patients who received unilateral deep-brain stimulation (DBS) of the STN either of the left (n = 10) or of the right (n = 10) hemisphere. We gave them a stop-signal reaching task, and we compared patients' performance in two experimental conditions, DBS-ON and DBS-OFF. In addition, we also tested 22 age-matched healthy participants. As expected, we found that inhibitory control is impaired in Parkinson's patients with respect to healthy participants. However, neither reactive nor proactive inhibition is improved when either the right or the left DBS is active. We interpreted these findings in light of the fact that previous studies, exploiting exactly the same task, have shown that only bilateral STN DBS restores a near-normal inhibitory control. Thus, although null results have to be interpreted with caution, our current findings confirm that the right STN does not play a key role in suppressing pending actions. However, on the ground of previous studies, it is very likely that this subcortical structure is part of the brain network subserving inhibition but to implement this executive function both subthalamic nuclei must be simultaneously active. Our findings are of significance to other researchers studying the effects of STN DBS on key executive functions, such as impulsivity and inhibition and they are also of clinical relevance for determining the therapeutic benefits of STN DBS as they suggest that, at least as far as inhibitory control is concerned, it is better to implant DBS bilaterally than unilaterally.


Short and long term variability of indices from the single and multiple breath nitrogen test.
We have studied the short and long term variabilities of indices derived from the single and multiple breath nitrogen tests in adolescents aged 12-18 years. In 333 boys and girls, up to 10 measurements were performed at half-year intervals; in 39 of them four measurements were also made at 10 min intervals. The standard deviations of the residual volume and the height of phase IV were roughly proportional to the magnitude of these indices, and so were best expressed by coefficients of variation, of which the means were 8% and 37% respectively. The measurement error in residual volume (RV) was small (1.4 to 1.9%) when compared to 'real' biological variability (8.9%). The variabilities of other tests were not correlated with their magnitude. Using autocorrelation coefficients, short term variability could be approximated from longitudinal data for the vital capacity (VC) and RV, but less well for other indices. The between-to-within variance ratios were rather low in the 39 healthy pupils. Based on these findings, RV and VC appear to be indices with a potentially good predictive value for lung volume assessment or for detecting abnormal lung growth in longitudinal studies of adolescents.


Racial differences in legal socialization models across adolescence and emerging adulthood.
White and non-White adolescents report different experiences in the legal system. This disparity impacts their evaluations of, and attitudes toward, legal authorities such that non-White and older adolescents tend to perceive the legal system more negatively. Yet, many researchers assume that the process of legal socialization, which involves internalizing norms and information about the law and the legal system, is universal for all ages and races. We hypothesized that legal socialization models would change over the course of adolescent development and would differ by race. We used data from two longitudinal studies to examine racial differences in the integrated legal socialization model in early, middle, and late adolescence. Study 1 included 140 young adolescents (59% White, 41% non-White), and Study 2 included 296 midadolescents (82% White, 18% non-White) followed into late adolescence/emerging adulthood. Study 1 identified differences in the integrated legal socialization model for young White and non-White adolescents. Normative status predicted rule-violating behavior for White participants, whereas no predictors or mediators related to rule-violating behavior for non-White participants. In Study 2, legal and moral reasoning during midadolescence became relevant in the model for both groups. Enforcement status predicted rule-violating behavior for non-White youth, whereas normative status continued to predict rule-violating behavior for White youth. In late adolescence/emerging adulthood, differences in the model shifted toward the relation between reasoning and legal attitudes. Our findings suggest that legal socialization is a developmental process occurring and changing throughout adolescence and that this developmental process differs for White and non-White youth. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Humoral immune responses to Pneumocystis jirovecii antigens in HIV-infected and uninfected young children with pneumocystis pneumonia.
Humoral immune responses in human immunodeficiency virus (HIV)-infected and uninfected children with Pneumocystis pneumonia (PcP) are poorly understood. Consecutive children hospitalized with acute pneumonia, tachypnea, and hypoxia in South Africa were investigated for PcP, which was diagnosed by real-time polymerase chain reaction on lower respiratory tract specimens. Serum antibody responses to recombinant fragments of the carboxyl terminus of Pneumocystis jirovecii major surface glycoprotein (MsgC) were analyzed. 149 children were enrolled of whom 96 (64%) were HIV-infected. PcP occurred in 69 (72%) of HIV-infected and 14 (26%) of HIV-uninfected children. HIV-infected children with PcP had significantly decreased IgG antibodies to MsgC compared to HIV-infected patients without PcP, but had similar IgM antibodies. In contrast, HIV-uninfected children with PcP showed no change in IgG antibodies to MsgC, but had significantly increased IgM antibodies compared to HIV-uninfected children without PCP. Age was an independent predictor of high IgG antibodies, whereas PcP was a predictor of low IgG antibodies and high IgM antibodies. IgG and IgM antibody levels to the most closely related MsgC fragments were predictors of survival from PcP. Young HIV-infected children with PcP have significantly impaired humoral immune responses to MsgC, whereas HIV-uninfected children with PcP can develop active humoral immune responses. The children also exhibit a complex relationship between specific host factors and antibody levels to MsgC fragments that may be related to survival from PcP.


[Effect of hyaluronic acid chitosan-based microemulsion on the permeability of blood brain barrier in mice].
To study the effect of hyaluronic acid chitosan-based microemulsion (HAC-ME) on the permeability of blood brain barrier( BBB) by using Evans blue (EB) as the indicator. A formamide extraction-ultraviolet spectrophotometry method was employed to determine the concentrations of EB in each of the tissues. The in vivo distribution of HAC-ME groups containing EB in mice and the fluorescence intensity and diffusion domain of brain slices were all studied. Contrasting to the common microemulsion (ME), HAC-ME at the lower concentration of HAC (<5 mg x mL(-1)) could further improve the transporting of EB across the BBB while EB concentration in other tissues decreased, and Tmax was delayed about 30 min. HAC-ME could facilitate the transporting of EB across the BBB and it was concentration dependent. While the brain targeting absorptive capability of HAC-ME was enhanced.


Pyrolysis characteristics and kinetics analysis of oil sludge with CaO additive.
In the process of exploitation, transportation and refining of high-sulfur crude oil, a large number of oil sludge (OS) with high sulfur content is produced. Pyrolysis has been proved to be an effective method for OS disposal, but for solid waste with high sulfur content, lots of sulfur-containing gases will be released during thermal disposal. The addition of calcium oxide in pyrolysis process is an economical and effective way to capture sulfur-containing gases. In order to understand the pyrolysis process of OS with CaO, a thermogravimetric analyser was used to conduct pyrolysis experiments of OS with different Ca/S molar ratios (0, 1, 2 and 3) at different heating rates (10°C/min, 20°C/min, 30°C/min and 40°C/min). The results showed that with the increase of CaO addition the derivative thermogravimetric curves showed a gentle trend. In addition, new weight loss peaks were occurred at 700-900°C and after 1100°C, which were the decomposition of calcium carbonate and calcium sulfate, respectively. The kinetic parameters were solved by Friedman, FWO, and Starink methods, and the results were similar, with an average activation energies (E) value of 214 kJ/mol. The change trend of the activation energy was followed by an increase and then a decrease corresponding to the change of energy demand for the reaction. The calculated average values of ΔH, ΔG and ΔS were about 207, 447 and -0.3250 kJ/mol, respectively. When the conversion rate was 0.5, the thermodynamic parameters reached their maximum values.


Prognostic significance of apoptosis in squamous cell carcinoma of oral cavity with special reference to TNM stage, histological grade and survival.
Apoptotic count was assessed in 38 cases of squamous cell carcinoma of oral cavity by light microscopy and correlated with TNM stage, histological grade and survival. A direct correlation with the TNM stage (p = 0.0166) and an inverse correlation with the histological grade (p = 0.03) was found, however no correlation was found with the survival. Apoptotic count was significantly different between well and moderately differentiated carcinoma (p = 0.347) and well and poorly differentiated carcinoma (p = 0.0190). Thus apoptotic count may have prognostic value particularly in combination with staging and histological grade.


Some biochemical parameters of blood plasma of turkey-hens following administration of 1,2,4-triasole derivative.
The present study involved 180 slaughter turkey-hens of heavy Big-6 type divided into four groups (in triplicate repetition for 15 birds). All the birds were fed with the same standard full-dose mixtures in 5-stage system. The turkey-hens of groups I, II and III were given 1,2,4-triasole derivative (3-(2-pyridil)-4-phenyl-1,2,4-triasole-5-carboxylic acid), which has antibacterial, antifungal and immunomodulating properties, in amount of 50, 75 and 100 microg per 1 dm3 of water. Group IV--control was given water without the additive. The 1,2,4-triasole derivative was given to drinking water, starting from the first day of bird's life and for the whole rearing period. The present results of biochemical analysis of blood plasma showed that addition of examined substance significantly reduced concentration of protein, glucose, triglycerides and uric acid as compared to control. It was stated that tested 1,2,4-triasole derivative elevated the level of HDL fraction percentage and alkaline phosphatase activity in blood plasma.


The aftermath of the Merck's HIV vaccine trial.
The recently released results of the Merck's Phase IIb "test-of concept" vaccine trials have shown no protection from HIV-1 infection in the vaccinated group compared with a control group vaccinated with placebo. The study was designed to test the Merck's MRKAd5 trivalent candidate vaccine. The vaccine formulation was expected to stimulate a HIV-specific T cell immune response and to either prevent infection, or to reduce the levels of the viral load in vaccinated subjects. Upon the first evaluation of the interim data, the independent Data and Safety Monitoring Board (DSMB) underscored no protection from HIV-1 infection in the vaccine-inoculated volunteers compared with the control group; accordingly, the vaccine trial was stopped. This disappointing outcome warrants a critical analysis of the current vaccine studies and calls for a renewed effort toward a rational design of novel immunogens to be tested in large primate trials.


The CVC removal distress syndrome: an unappreciated complication of central venous catheter removal.
The removal of a central venous catheter (CVC) can be complicated by rare but potentially life-threatening neurocardiopulmonary distress. The clinical courses of eight patients who had CVC removal complications are reviewed. Seven patients had catheter removal from the right internal jugular vein, and one from the right subclavian vein. The complications occurred after complete removal of the catheter (four patients), after guidewire replacement for catheter change (three patients), and after detachment of the hemostasis side port of the Swan introducer during sheath removal (one patient). Each of them had more than one complication. The major complications were: neurologic paresis or coma (four patients), respiratory failure (four patients), and shock (two patients). One patient died of pulmonary sepsis. The overall mortality rate was 12.5 per cent. Guidelines for safe removal of central venous catheters are proposed. Possible mechanisms of the complications are discussed. We refer to the observed complications as the CVC removal distress syndrome.


Human cytomegalovirus binding to human monocytes induces immunoregulatory gene expression.
To continue our investigation of the cellular events that occur following human CMV (HCMV) infection, we focused on the regulation of cellular activation following viral binding to human monocytes. First, we showed that viral binding induced a number of immunoregulatory genes (IL-1beta, A20, NF-kappaB-p105/p50, and IkappaBalpha) in unactivated monocytes and that neutralizing Abs to the major HCMV glycoproteins, gB (UL55) and gH (UL75), inhibited the induction of these genes. Next, we demonstrated that these viral ligands directly up-regulated monocyte gene expression upon their binding to their appropriate cellular receptors. We then investigated if HCMV binding also resulted in the translation and secretion of cytokines. Our results showed that HCMV binding to monocytes resulted in the production and release of IL-1beta protein. Because these induced gene products have NF-kappaB sites in their promoter regions, we next examined whether there was an up-regulation of nuclear NF-kappaB levels. These experiments showed that, in fact, NF-kappaB was translocated to the nucleus following viral binding or purified viral ligand binding. Changes in IkappaBalpha levels correlated with the changes in NF-kappaB translocation. Lastly, we demonstrated that p38 kinase activity played a central role in IL-1beta production and that it was rapidly up-regulated following infection. These results support our hypothesis that HCMV initiates a signal transduction pathway that leads to monocyte activation and pinpoints a potential mechanism whereby HCMV infection of monocytes can result in profound pathogenesis, especially in chronic inflammatory-type conditions.


Gender differences in gastric cancer incidence in elderly former drinkers.
Although numerous studies have been done on gastric cancer and alcohol consumption, results from these studies are inconsistent. We conducted a population-based, prospective cohort study to establish a relationship between alcohol and gastric cancer according to gender. The cohort consisted of elderly (>64 years of age) subjects at the baseline of 1993-1998. Baseline information was surveyed using a self-administered questionnaire. Gastric cancers were identified by the National Cancer Registry. Cox proportional hazards models were used to calculate relative risks with 95% confidence intervals. A follow up of 116,997.1 person-years of the 13,396 subjects revealed 151 newly diagnosed gastric cancers (80 men and 71 women). The risk of gastric cancer was higher by a factor of three among female former drinkers (adjusted relative risk 2.85 [95% confidence interval 1.11-7.32]) compared to current and nondrinkers. Female former drinkers showed greater alcohol consumption than current drinkers (36.5g/week vs. 16.4g/week; P<.0001) and a longer duration of alcohol consumption than did current drinkers (24.5 years vs. 18.46 years; P<.0001). Female subjects with more than 110g of weekly alcohol consumption had an increased risk of developing gastric cancer (adjusted relative risk 2.23 [95% confidence interval 0.79-6.29]), although the result was statistically insignificant. No relationship was observed for male subjects. The relationship between alcohol and gastric cancer differs according to gender. Alcohol consumption may increase the risk of gastric cancer in women, and the risk elevation may persist for several years after drinking ceases.


ANDALE Pittsburgh: results of a promotora-led, home-based intervention to promote a healthy weight in Latino preschool children.
Latino preschool children have higher rates of obesity than preschool children from other racial/ethnic groups; however, few effective, culturally appropriate interventions exist targeting this group. The purpose of this study was to test the feasibility of a 10-week, promotora-mediated, home-based intervention to promote a healthy weight in Latino preschool children. Trained promotoras (community health workers) delivered 10, 90-min weekly interactive and tailored sessions to Latino families living in Allegheny County. Participants were recruited through promotoras' own social networks and community gatherings, flyers, and word of mouth. Primary outcome measures included child body mass index (BMI) z-score and percentile. Secondary outcome measures included child objectively measured physical activity and dietary intake, and the home social and physical environment (e.g., parent health behaviors, parent self-efficacy, parental support, physical activity equipment in the home). The final analysis sample included 49 of 51 participants who completed both baseline and follow-up assessments. Participants included mothers (33.5 ± 6.1 years old) and their preschool-aged children who were primarily 1st generation immigrants from Mexico (65%). The primary analyses of BMI percentile and z-score showed no change post-intervention. However, there was a significant decrease in child BMI percentile for overweight and obese children from baseline to follow-up (p < .05). We also saw significant pre/post increases in child daily fruit and vegetable intake, and parent moderate-to-vigorous physical activity, fruit and vegetable servings per day, and self-efficacy; and significant decreases in child saturated fat and added-sugar intake, and child and parent screen time (p's < .05). Despite the short duration of the intervention and follow-up, this pilot study showed promising effects of a promotora-mediated intervention to promote a healthy weight in Latino preschool children.


Group 12 dihalides: structural predilections from gases to solids.
Connections between the structures of Group 12 dihalides in their vapor and crystal phases are sought and discussed. The molecular structures of all monomers and dimers (MX(2): M=Zn, Cd, Hg and X=F, Cl, Br, I) were calculated at the density functional B3PW91 and MP2 computational levels. All the monomers are linear, with the mercury dihalide molecules having shorter bonds than their cadmium analogues; the ZnX(2) and CdX(2) structures are similar. The shorter Hg-X distances are traced back to relativistic effects. For the dimers, many possible geometrical arrangements were considered. The zinc and cadmium dihalide dimers have the usual D(2h)-symmetry geometry, whereas the mercury dihalide dimers are loosely-bound units with C(2h) symmetry. The origins of this C(2h) structure are discussed from different points of view, including frontier orbital interactions. The crystals of Group 12 dihalides span a wide range of structure types, from three-dimensional extended solids to molecular crystals. There is an obvious connection between the structures and characteristics of monomers, their dimers, and the crystals they form. The similarities as well as startling differences from the Group 2 dihalides are analyzed.


In vivo evidence for a novel pathway of vitamin D₃ metabolism initiated by P450scc and modified by CYP27B1.
We define previously unrecognized in vivo pathways of vitamin D(3) (D3) metabolism generating novel D3-hydroxyderivatives different from 25-hydroxyvitamin D(3) [25(OH)D3] and 1,25(OH)(2)D3. Their novel products include 20-hydroxyvitamin D(3) [20(OH)D3], 22(OH)D3, 20,23(OH)(2)D3, 20,22(OH)(2)D3, 1,20(OH)(2)D3, 1,20,23(OH)(3)D3, and 17,20,23(OH)(3)D3 and were produced by placenta, adrenal glands, and epidermal keratinocytes. We detected the predominant metabolite [20(OH)D3] in human serum with a relative concentration ∼20 times lower than 25(OH)D3. Use of inhibitors and studies performed with isolated mitochondria and purified enzymes demonstrated involvement of the steroidogenic enzyme cytochrome P450scc (CYP11A1) as well as CYP27B1 (1α-hydroxylase). In placenta and adrenal glands with high CYP11A1 expression, the predominant pathway was D3 → 20(OH)D3 → 20,23(OH)(2)D3 → 17,20,23(OH)(3)D3 with further 1α-hydroxylation, and minor pathways were D3 → 25(OH)D3 → 1,25(OH)(2)D3 and D3 → 22(OH)D3 → 20,22(OH)(2)D3. In epidermal keratinocytes, we observed higher proportions of 22(OH)D3 and 20,22(OH)(2)D3. We also detected endogenous production of 20(OH)D3, 22(OH) D3, 20,23(OH)(2)D3, 20,22(OH)(2)D3, and 17,20,23(OH)(3)D3 by immortalized human keratinocytes. Thus, we provide in vivo evidence for novel pathways of D3 metabolism initiated by CYP11A1, with the product profile showing organ/cell type specificity and being modified by CYP27B1 activity. These findings define the pathway intermediates as natural products/endogenous bioregulators and break the current dogma that vitamin D is solely activated through the sequence D3 → 25(OH)D3 → 1,25(OH)(2)D3.


The identification and description of critical thinking behaviors in the practice of clinical laboratory science, Part 1: Design, implementation, evaluation, and results of a national survey.
The ability to think critically has been identified as a pivotal attribute of health care professionals. The purpose of this study was to identify and describe critical thinking (CT) behaviors and observable events resulting from CT, important in the practice of clinical laboratory science. Medical, educational, and psychological literature related to the many behaviors characterized under the CT rubric has been focused by an operationalized definition positing CT to be a metaprocess that facilitates learning by interlinking the more basic processes associated with different learning orientations: behaviorist, cognitivist, humanist, and situated/contextual learning. A total of 65 CT behaviors were identified through a process including discovery (expert interviews, a focus group with practitioners) and refinement (literature comparisons, expert rankings/reviews, pilot survey). CT behaviors were characterized further through a national survey of practitioners (n = 1,571, > 50% of time in bench work). Using a 6-point scale, practitioners ranked the importance of the CT behaviors. Important CT behaviors were characterized as being not only cognitive in nature, but also behavioral, affective, and situated/contextual. These findings suggest a stronger relationship between CT behaviors and all aspects of practice than previously reported. Given that these behaviors span all learning domains, findings support the metaprocess view of CT. Implications are that CT behaviors cannot be learned or taught, apart from a discipline-related practice setting. This study contributes to learning theory related to transfer and how learning occurs and to literature describing survey methodology. It also provides a basis for measurement of CT in practice settings.


Targeting the Wnt signaling pathway in colorectal cancer.
The treatment of patients with advanced colorectal cancer still remains challenging, and identification of new target molecules and therapeutic avenues remains a priority. The great majority of colorectal cancers have mutations in one of two genes involved in the Wnt signaling pathway: the adenomatous polyposis coli (APC) and β-catenin (CTNNB1) genes. Up to now, however, no therapeutics for targeting this pathway have been established. This review article begins with a brief summary of Wnt signaling from the viewpoints of genetics, cancer stem cell biology, and drug development. We then overview current attempts to develop drugs directed at various components of the Wnt signaling pathway. APC is a tumor suppressor, and therefore only downstream signal transducers of the APC protein can be considered as targets for pharmaceutical intervention. TRAF2 and NCK-interacting protein kinase (TNIK) was identified as the most downstream regulator of Wnt signaling by two independent research groups, and several classes of small-molecule inhibitors targeting this protein kinase have been developed. TNIK is a multifunctional protein with actions that extend beyond Wnt signaling regulation. Such TNIK inhibitors are expected to have a large variety of clinical applications.


Computer-aided design and manufacturing of surgical templates and their clinical applications: a review.
The surgical template is a guide aimed at directing the implant placement, tumor resection, osteotomy and bone repositioning. Using it, preoperative planning can be transferred to the actual surgical site, and the precision, safety and reliability of the surgery can be improved. However, the actual workflow of the surgical template design and manufacturing is quite complicated before the final clinical application. The major goal of the paper is to provide a comprehensive reference source of the current and future development of the template design and manufacturing for relevant researchers. Expert commentary: This paper aims to present a review of the necessary procedures in the template-guided surgery including the image processing, 3D visualization, preoperative planning, surgical guide design and manufacturing. In addition, the template-guided clinical applications for various kinds of surgeries are reviewed, and it demonstrated that the precision of the surgery has been improved compared with the non-guided operations.


Short boys treated with growth hormone show normal progression of testicular size and achieve normal serum testosterone concentrations.
To determine whether there is evidence for impaired testicular function at final height in short boys treated with growth hormone (GH) during their childhood and adolescence. The analysis was restricted to males who had isolated GH deficiency or idiopathic short stature, and who were included in the Swedish National Registry and the Swedish GH trials. The subjects had to have been treated with GH for at least 4 years; the treatment had to have been started prepubertally, given for at least one year before the onset of puberty and the subjects had to have reached final height. One hundred and eleven boys fulfilled the criteria. Testicular volumes were determined by orchidometer in each boy when GH treatment was started and at final height. Samples for testosterone measurements were collected from 77 boys at final height, and were measured by RIA. Each subject had normal testicular size (15 ml or more) and for those in whom concentrations were determined, serum testosterone levels and diurnal rhythm were normal. The results of our survey do not show evidence of testicular impairment following GH therapy.


Anchored Cu single atoms on porous g-C3N4 for superior photocatalytic H2 evolution from water splitting.
One of the most promising strategies for producing hydrogen is photocatalytic water splitting, in which the photocatalyst is a key component. Among many semiconductor photocatalysts, g-C3N4 has attracted great attention due to its narrow band gap, excellent stability and low cost. However, practical application is limited by its poor intrinsic activity. In this work, a high-performance porous g-C3N4 (PCN) photocatalyst with anchored Cu single atoms (CuSAs) was synthesized by a one-step co-heating approach. The obtained Cu1.5-PCN displays an excellent hydrogen evolution rate (HER) of 2142.4 μmol h-1 g-1 under visible light (=420 nm), which is around 15 and 109 times higher than those of PCN and bulk g-C3N4, respectively. In addition, it also shows good stability during H2 evolution. The results of experimental research and DFT simulations indicate that the single Cu ions formed bonds with the N-ring and these remain stable. Meanwhile, the special electronic structure of the Cu-N charge bridge extends the light absorption band to the visible-light region (380-700 nm). This high-performance and low-cost photocatalyst has great potential in solar energy conversion.


Bed-blocking. Acute distress.
A study of bed occupancy in 21 hospitals over the past two years showed an average of 29 per cent of patients no longer needed acute care. Two-thirds of this group had been in hospital for more than 28 days. About a fifth of this group were under 65. The main reasons for delayed discharges were waits for social services assessment or home-care packages.


Constrained regularization: hybrid method for multivariate calibration.
We present a hybrid multivariate calibration method, constrained regularization (CR), and demonstrate its utility via numerical simulations and experimental Raman spectra. In this new method, multivariate calibration is treated as an inverse problem in which an optimal balance between model complexity and noise rejection is achieved with the inclusion of prior information in the form of a spectral constraint. A key feature is that the constraint is incorporated in a flexible manner, allowing the minimization algorithm to arrive at the optimal solution. We demonstrate that CR, when used with an appropriate constraint, is superior to methods without prior information, such as partial least-squares, and is less susceptible to spurious correlations. In addition, we show that CR is more robust than methods in which the constraint is rigidly incorporated, such as hybrid linear analysis, when the exact spectrum of the analyte of interest as it appears in the sample is not available. This situation can occur as a result of experimental or sample variations and often arises in complex or turbid samples such as biological tissues.


Vascular compromise and hemodynamics in pulmonary arterial hypertension: model predictions.
A previously validated computer model of the normal pulmonary circulation is adapted to simulate pulmonary arterial hypertension (PAH) in humans. Model predictions are used to explore the suitability of currently accepted criteria for diagnosing PAH by correlating hemodynamic data with the degree of vascular compromise (disease severity). Model predictions demonstrate a hyperbolic relationship between vascular compromise, mean pulmonary artery pressure (PAPm) and pulmonary vascular resistance (PVR). PAPm and PVR change very little from disease initiation until a vascular compromise of 65% to 70% (surface area of 0.35 to 0.3 of baseline, respectively) is reached. Following that, further compromise is associated with a steep rise in PAPm and PVR. The relationship between vascular compromise and hemodynamics may explain the relative stability of cardiac output early in this disease process and, therefore, the lack of symptoms. It also explains the rapid deterioration following diagnosis if the disease remains untreated. Model predictions demonstrate the inadequacy of the current hemodynamic criteria for diagnosing PAH over a wide range of left atrial pressure and cardiac output combinations and for early detection of disease. The model provides an alternative approach to diagnosing PAH by translating hemodynamic data to degree of vascular compromise.


Neural tube defects by NUAK1 and NUAK2 double mutation.
NUAK1 and NUAK2, members of the AMP-activated protein kinase family of serine/threonine kinases, are prominently expressed in neuroectoderm, but their functions in neurulation have not been elucidated. NUAK1 and NUAK2 double mutants exhibited exencephaly, facial clefting, and spina bifida. Median hinge point was formed, but dorsolateral hinge point formation was not apparent in cranial neural plate; neither apical constriction nor apico-basal elongation took place efficiently in the double mutants during the 5-10-somite stages. Concomitantly, the apical concentration of phosphorylated myosin light chain 2, F-actin, and cortactin was insignificant, and development of acetylated α-tubulin-positive microtubules was poor. However, the distribution of F-actin, cortactin, Shroom3, Rho, myosin heavy chain IIB, phosphorylated myosin light chain 2, α-tubulin, γ-tubulin, or acetylated α-tubulin was apparently normal in the double mutant neuroepithelia at the 5-somite stage. NUAK1 and NUAK2 complementarily function in the apical constriction and apico-basal elongation that associate with the dorsolateral hinge point formation in cephalic neural plate during the 5- to 10-somite stages. In the double mutant neural plate, phosphorylated myosin light chain 2, F-actin, and cortactin did not concentrate efficiently in apical surfaces, and acetylated α-tubulin-positive microtubules did not develop significantly.


Multi-Image Blind Super-Resolution of 3D Scenes.
We address the problem of estimating the latent high-resolution (HR) image of a 3D scene from a set of non-uniformly motion blurred low-resolution (LR) images captured in the burst mode using a hand-held camera. Existing blind super-resolution (SR) techniques that account for motion blur are restricted to fronto-parallel planar scenes. We initially develop an SR motion blur model to explain the image formation process in 3D scenes. We then use this model to solve for the three unknowns-the camera trajectories, the depth map of the scene, and the latent HR image. We first compute the global HR camera motion corresponding to each LR observation from patches lying on a reference depth layer in the input images. Using the estimated trajectories, we compute the latent HR image and the underlying depth map iteratively using an alternating minimization framework. Experiments on synthetic and real data reveal that our proposed method outperforms the state-of-the-art techniques by a significant margin.


Autoimmune hepatitis after liver transplantation and other lessons of self-intolerance.
Autoimmune hepatitis has been described as recurrent or de novo disease after transplantation. The legitimacy of these diagnoses and the bases for their occurrence are unknown. To better understand these aspects of allograft dysfunction, the purported pathogenic mechanisms of classical autoimmune hepatitis were reviewed and extrapolated to recurrent and de novo disease after transplantation. Loss of self-tolerance may relate to defects in the negative selection of autoreactive immunocytes and the clonal expansion of promiscuous lymphocytes that are cross-reactive to homologous antigens (molecular mimicry). Repopulation of the allograft with recipient antigen-presenting cells and the presence of primed promiscuous cytotoxic T cells within the recipient are likely factors for recurrent disease. Targets may be the same peptides that triggered the original disease, donor-derived class II antigens of the major histocompatibility complex, or homologous antigens associated with unidentified hepatotrophic viruses. De novo disease is probably due to similar mechanisms, but its predilection for children suggests that thymic dysfunction associated with cyclosporine treatment may be a factor. Corticosteroid therapy is effective in each condition. In conclusion, recurrent and de novo autoimmune hepatitis after transplantation are examples of self-intolerance. The mechanisms that perturb immunologic homeostasis in this human model of the classical disease must be studied more rigorously.


Relevance of chromatin features in the progression of esophageal epithelial severe dysplasia.
Since 1983, a long-term clinical trial of esophageal carcinoma chemoprevention has been conducted in a high-risk area in China. From this study, 25 esophageal severe dysplasia patients without therapy were selected for analysis. After 5-year follow-ups, 14 cases progressed to esophageal carcinoma, while the other 11 cases remained stable. Three Papanicolaou's smears were used for each case, including one from the esophageal cytological examination at the beginning, two from the re-examinations three and five years later respectively. About 100 visually normal intermediate cells were randomly collected per slide by high resolution image analysis. More than 100 features (morphologic, densitometric, textural) were extracted. The classifications were made by means of stepwise linear discriminate analysis at the single cell level as on the specimen level using up to ten features. In all three comparisons of patients with progression and with regression at time of diagnosis, three years after diagnosis and five years later, the correct cell classification rates were about 70%. The subsequent specimen classifications by means of the a posteriori probability (APOP) distribution of the cells in each case led to 80% correct classification. All selected features reflected the chromatin structure of nuclei. The result demonstrated that the chromatin structures of esophageal epithelial cells in severely dysplasic patients are different between cases with and without progression. These results suggest the possibility of the application of image analysis in the clinical trials to find the dysplasia patients with higher risk of progression, in order to reduce the number of patients for therapy.


[Treatment of the acute graft versus host skin reaction with cyclosporin and PUVA].
Acute graft-versus-host reaction is usually managed by immunosuppressive therapy, and cyclosporin is one drug of choice. In some patients, cyclosporin alone cannot always control the evolution. The use of other immunosuppressive drugs could be considered but their toxicity and side-effects are such that a vital risk is introduced for the patient. Conversely, when the disease primarily affects the skin, photochemotherapy (PUVA) associated with cyclosporin appears to be effective and safe.


Regulatory Forum Opinion Piece*: Use and Utility of Animal Models of Disease for Nonclinical Safety Assessment: A Pharmaceutical Industry Survey.
An Innovation and Quality (IQ) Consortium focus group conducted a cross-company survey to evaluate current practices and perceptions around the use of animal models of disease (AMDs) in nonclinical safety assessment of molecules in clinical development. The IQ Consortium group is an organization of pharmaceutical and biotechnology companies with the mission of advancing science and technology. The survey queried the utilization of AMDs during drug discovery in which drug candidates are evaluated in efficacy models and limited short-duration non-Good Laboratory Practices (GLP) toxicology testing and during drug development in which drug candidates are evaluated in GLP toxicology studies. The survey determined that the majority of companies used AMDs during drug discovery primarily as a means for proactively assessing potential nonclinical safety issues prior to the conduct of toxicology studies, followed closely by the use of AMDs to better understand toxicities associated with exaggerated pharmacology in traditional toxicology models or to derisk issues when the target is only expressed in the disease state. In contrast, the survey results indicated that the use of AMDs in development is infrequent, being used primarily to investigate nonclinical safety issues associated with targets expressed only in disease states and/or in response to requests from global regulatory authorities.


Tracheal Narrowing and Its Impact on Anesthesia Care in Patients With Morquio A (Mucopolysaccharidosis Type IVA): An Observational Study.
Recently, tracheal narrowing has been recognized as a significant comorbid condition in patients with Morquio A, also known as mucopolysaccharidosis IVA. We studied a large cohort of patients with Morquio A to describe the extent of their tracheal narrowing and its relationship to airway management during anesthesia care. This is an observational study, collecting data retrospectively, of a cohort of patients with Morquio A. Ninety-two patients with Morquio A syndrome were enrolled, among whom 44 patients had their airway evaluated by computed tomography angiography and had undergone an anesthetic within a year of the evaluation. Our hypothesis was that the tracheal narrowing as evaluated by computed tomography angiography increases with age in patients with Morquio A. The primary aim of the study was to examine the degree of tracheal narrowing in patients with Morquio A and describe the difficulties encountered during airway management, thus increasing awareness of both the tracheal narrowing and airway management difficulties in this patient population. In addition, the degree of tracheal narrowing was evaluated for its association with age or spirometry parameters using Spearman's rank correlation. Analysis of variance followed by the Bonferroni test was used to further examine the age-based differences in tracheal narrowing for the 3 age groups: 1 to 10 years, 11 to 20 years, and >21 years. Patient age showed a positive correlation with tracheal narrowing ( rs= 0.415; 95% confidence interval [95% CI], 0.138-0.691; P = .005) with older patients having greater narrowing of the trachea. Among spirometry parameters, FEF25%-75% showed an inverse correlation with tracheal narrowing as follows: FEF25%-75% versus tracheal narrowing: ( rs = -0.467; 95% CI, -0.877 to -0.057; P = .007). During anesthetic care, significant airway management difficulties were encountered, including cancelation of surgical procedures, awake intubation using flexible bronchoscope, and failed video laryngoscopy attempts. Clinically significant tracheal narrowing was present in patients with Morquio A, and the degree of such narrowing likely contributed to the difficulty with airway management during their anesthetic care. Tracheal narrowing worsens with age, but the progression appears to slow down after 20 years of age. In addition to tracheal narrowing, spirometry values of FEF25%-75% may be helpful in the overall evaluation of the airway in patients with Morquio A.


Perceived injustice: a risk factor for problematic pain outcomes.
Emerging research suggests that perceptions of injustice after musculoskeletal injury can have a significant impact on a number of pain-related outcomes. The purpose of this paper is to review evidence linking perceptions of injustice to adverse pain outcomes. For the purposes of this paper, perceived injustice is defined as an appraisal cognition comprising elements of the severity of loss consequent to injury ("Most people don't understand how severe my condition is"), blame ("I am suffering because of someone else's negligence"), a sense of unfairness ("It all seems so unfair"), and irreparability of loss ("My life will never be the same"). Cross-sectional studies show that high scores on perceptions of injustice are correlated with pain catastrophizing, fear of movement, and depression. Prospective studies show that high scores on perceived injustice are a prognostic indicator of poor rehabilitation outcomes and prolonged work disability. Research shows that perceptions of injustice interfere not only with physical recovery after injury, but perceptions of injustice also impact negatively on recovery of the mental health problems that might arise subsequent to traumatic injury. Although research has yet to address the process by which perceptions of injustice impact on pain-related outcomes systematically; possible mechanisms include attentional disengagement difficulties, emotional distress, maladaptive coping, heightened displays of pain behavior, anger, and revenge motives. Perceived injustice appears to be associated with problematic health and mental health recovery trajectories after the onset of a pain condition. Future directions for research and treatment are addressed.


Contractile properties of esophageal striated muscle: comparison with cardiac and skeletal muscles in rats.
The external muscle layer of the mammalian esophagus consists of striated muscles. We investigated the contractile properties of esophageal striated muscle by comparison with those of skeletal and cardiac muscles. Electrical field stimulation with single pulses evoked twitch-like contractile responses in esophageal muscle, similar to those in skeletal muscle in duration and similar to those in cardiac muscle in amplitude. The contractions of esophageal muscle were not affected by an inhibitor of gap junctions. Contractile responses induced by high potassium or caffeine in esophageal muscle were analogous to those in skeletal muscle. High-frequency stimulation induced a transient summation of contractions followed by sustained contractions with amplitudes similar to those of twitch-like contractions, although a large summation was observed in skeletal muscle. The results demonstrate that esophageal muscle has properties similar but not identical to those of skeletal muscle and that some specific properties may be beneficial for esophageal peristalsis.


Correlation of Etest and Neo-Sensitabs diffusion assays on Mueller-Hinton-methylene blue agar with broth microdilution reference method (CLSI-M27-A2) for testing susceptibilities of Cryptococcus neoformans to amphotericin B and fluconazole.
Cryptococcus neoformans causes disseminated infection in 7-8% of HIV positive patients admitted to Hospital F. J. Muñiz in Buenos Aires. Meningoencephalitis is the most frequent clinical manifestation and is one of the main causes of death in those patients with AIDS. The standard treatment for this mycosis consists of amphotericin B followed by fluconazole until two successive cultures of CFS are negative. Although resistance to these drugs is infrequent, minimal inhibitory concentrations (MIC) of some antifungals can be high. Since it is important to know the susceptibility levels of this fungus to the antifungal drugs usually employed in our institution, we analyzed the susceptibility test results of C. neoformans with two diffusion methods (Etest and NeoSensitabs tablets) employing Mueller-Hinton agar with 2% glucose and 0.5 microg/ml methylene blue. These results were compared with MICs obtained through the use of the broth microdilution reference method (CLSI). Results showed good agreement with the reference method, with no very major errors and only two major errors for fluconazole using NeoSensitabs tablets. For all the above mentioned, we confirm the usefulness of Mueller-Hinton agar to evaluate C. neoformans susceptibility to amphotericin B and fluconazole with these two agar diffusion methods.


Some effects of random dose measurement errors on analyses of atomic bomb survivor data.
The effects of random dose measurement errors on analyses of atomic bomb survivor data are described and quantified for several analytical procedures. It is found that the ways in which measurement error is most likely to mislead are through downward bias in the estimated regression coefficients and through distortion of the shape of the dose-response curve. The magnitude of the bias and the power for testing the hypothesis of no effect are evaluated for several dose treatments including the use of grouped and ungrouped data, analyses with and without substituting 600 rad for estimated doses exceeding this value, and analyses which exclude doses exceeding 200 rad. The calculations are based on a model in which the error distributions are assumed to be log normal with standard deviations that are 0, 30, and 50%, respectively, of the true dose values. Results are limited to a dose-response function which is linear on total dose. It is found that the commonly applied practice of substituting 600 rad for doses exceeding this value definitely reduces bias in the presence of error. Restricting analyses to doses less than 200 rad reduces bias even more but at the price of considerable loss of power. Both the bias and the power for analyses based on grouped data are very close to the respective bias and power with ungrouped data.


Large-scale Health Information Database and Privacy Protection.
Japan was once progressive in the digitalization of healthcare fields but unfortunately has fallen behind in terms of the secondary use of data for public interest. There has recently been a trend to establish large-scale health databases in the nation, and a conflict between data use for public interest and privacy protection has surfaced as this trend has progressed. Databases for health insurance claims or for specific health checkups and guidance services were created according to the law that aims to ensure healthcare for the elderly; however, there is no mention in the act about using these databases for public interest in general. Thus, an initiative for such use must proceed carefully and attentively. The PMDA projects that collect a large amount of medical record information from large hospitals and the health database development project that the Ministry of Health, Labour and Welfare (MHLW) is working on will soon begin to operate according to a general consensus; however, the validity of this consensus can be questioned if issues of anonymity arise. The likelihood that researchers conducting a study for public interest would intentionally invade the privacy of their subjects is slim. However, patients could develop a sense of distrust about their data being used since legal requirements are ambiguous. Nevertheless, without using patients' medical records for public interest, progress in medicine will grind to a halt. Proper legislation that is clear for both researchers and patients will therefore be highly desirable. A revision of the Act on the Protection of Personal Information is currently in progress. In reality, however, privacy is not something that laws alone can protect; it will also require guidelines and self-discipline. We now live in an information capitalization age. I will introduce the trends in legal reform regarding healthcare information and discuss some basics to help people properly face the issue of health big data and privacy protection with a sense of ownership.


Knowledge, skills and attitudes of rural and remote psychologists.
To develop a list of knowledge, skills and attitudes (KSAs, components of competencies) considered required or desirable by rural and remote psychologists for rural and remote psychology practice. Semi-structured qualitative telephone interviews. Data were analysed thematically. Rural and remote regions of South Australia. Nine registered psychologists living and working in rural and remote South Australia (as defined by ARIA++ classification categories excluding Highly Accessible communities). All participants were women. Seven competencies were identified, relating to two broad themes: 'Professional Isolation' (competencies arising from being the sole psychologist or one of few in the community); and 'rural life' (competencies relating to the need to manage features of the rural context). The seven competencies (managing professional development, supervision, the lack of other services, dual relationships, visibility, confidentiality and appreciation of the rural context) encompassed a number of corresponding and overlapping KSAs. Personality characteristics, including autonomy, resilience and confidence were also identified as important for working in rural areas. Competencies and KSAs identified were consistent with issues identified in previous research for rural and remote psychologists and other health professionals. The present study contributes by providing a comprehensive checklist of KSAs for rural practice identified by rural psychologists. With further development, the competencies outlined could be used in conjunction with rural placements as part of competency-based training.


Validity and Reliability of the Quality of Life in Epilepsy Inventory (QOLIE-31) for Turkey.
The purpose of this study was to evaluate reliability and validity of the 31-item Quality of Life in Epilepsy Inventory (QOLIE-31) in Turkish epileptic patients. This study was performed methodologically. To standardize the inventory, using a standard "forward-backward" translation and cultural adaptation procedure the English version of the QOLIE-31 was translated to Turkish. Language equivalence of the scale was provided. The opinions of experts were considered regarding the content validity of the scale. Reliability of the scale was determined with the test-retest reliability, item-total correlation and internal consistency analysis. For the construct validity, QOLIE-31 was compared with Nottingham Health Profile (NHP) scale and pre validity was determined. One hundred and forty-eight epileptic patients (62 females, 86 males), with a mean age of 32.5 (SD: 10.71) years were enrolled in the study. Content Validity Index of instrument was .85. Alpha reliability was .91. Item-total correlations were between .46 and .74 (p=.001). The mean score for the quality of life of epileptic patients was found to be moderate level (56.4; SD: 17.3). The mean score of Seizure Worry subscale was the lowest (48.9, SD: 29.82), while social function subscale (60.1, SD: 20.12) was found to be highest. As expected, correlations between QOLIE-31 and NHP subscales were fairly strong, particularly between those subscales with close or interdependent content. Thus, Emotional Well-Being correlated with NHP Emotional Reactions, Social Isolation and Pain; Social Function with NHP Social Isolation and Physical Mobility; Seizure Worry with NHP Social Isolation and Emotional Reactions; and Cognitive Function with NHP Energy, Emotional Reactions and Pain. The Turkish version of the QOLIE-31 questionnaire has good structural characteristics, is a reliable and valid instrument and can be used for measuring the effect of epilepsy on the quality of life.


Fourier transform infrared spectroscopic signature of blood plasma in the progression of breast cancer with simultaneous metastasis to lungs.
Despite advanced diagnostic techniques used for detecting cancer, this disease still remains a leading cause of death in the developed world. What is more, the greatest danger for patients is not related with growing of tumor but rather with metastasis of cancer cells to the distant organs. In this study, Fourier transform infrared (FTIR) spectroscopy was used to track chemical changes in blood plasma to find spectral markers of metastatic breast cancer during the disease progression. Plasma samples were taken 1-5 weeks after orthotropic inoculation of 4T1 metastatic breast cancer cells to mice. The earliest changes detected by FTIR spectroscopy in plasma were correlated with unsaturation of phospholipids and secondary structures of proteins that appeared 2 and 3 weeks, respectively, after 4T1 cells inoculation (micrometastatic phase). Significant alternations in the content and structure of lipids and carbohydrates were identified in plasma at the later stages (macrometastatic phase). When large primary tumors in breast and macrometastases in lung were developed, all bands in FTIR spectra significantly differed from those at earlier phases of the cancer progression. In conclusion, we showed that each phase of the breast cancer progression and its pulmonary metastasis can be characterized by a specific panel of spectral markers.


Antioxidant and Anti-Inflammatory Activity and Cytotoxicity of Ethanol Extracts from Rhynchosia nulubilis Cultivated with Ganoderma lucidum Mycelium.
In this study, in order to verify the use of mycelium as a new functional material, Rhynchosia nulubilis was cultivated with Ganoderma lucidum mycelium, and the biological activity of the culture extract was evaluated. Measurements of the 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt radical scavenging activity showed that the ethanol extract from Rhynchosia nulubilis cultivated with Ganoderma lucidum mycelium (RNGM) had significantly higher radical scavenging activity compared to the ethanol extract from Rhynchosia nulubilis (RN). The growth inhibition rate of RNGM against HeLa cells was 93.93% at 400 μg/mL in the 3-(4,5-dimethylthiazol-2-yl)-2,5-dimethyl tetrazolium assay. RNGM effectively decreased nitric oxide production in lipopolysaccharide-treated RAW264.7 macrophage cells. The total polyphenol, total flavonoid, and the β-glucan contents of RNGM were higher than those of RN. These results demonstrated that increased total polyphenols, flavonoids, and β-glucan of Rhynchosia nulubilis during cultivation with the Ganoderma lucidum mycelium could increase the antioxidant and anti-inflammatory activity and cytotoxicity of cancer cells.


Sex-determined antigens in rats detected by bone marrow transplantation but not skin grafting.
Skin grafting in untreated rats and bone marrow transplantation into minimally immunosuppressed recipients have been used to investigate histocompatibility differences associated with the Y chromosome. Male skin survived for upwards of 120 days with no sign of rejection when grafted into female rats in circumstances where male bone marrow was rejected. Y chromosome-associated antigens were only detected with skin grafting by prior exposure of the female rats to male cells. It is concluded that bone marrow grafting into minimally immunosuppressed recipients may provide a more sensitive index of minor histocompatibility differences than skin grafting. The need to recognise donor cells in recipients prepared for bone marrow grafting with cytotoxic chemicals is emphasized.


Spontaneous resolution of invasive cerebral aspergillosis following partial resection in a medically untreated infant.
Invasive craniocerebral aspergillosis, often encountered in an immunocompromised setting, is almost uniformly fatal despite radical surgical and medical management, and is frequently a necropsy finding. The authors report a unique, self-resolving clinical course of this aggressive infection in a 10-month-old infant. The infant was brought to the emergency services in altered sensorium with a 1-week history of left-sided hemiparesis, excessive irritability, and vomiting. An MRI study of the brain revealed multiple, heterogeneously enhancing lesions in the right cerebral hemisphere with mass effect. The largest lesion in the frontotemporal cortical and subcortical regions was decompressed on an emergent basis. Histopathological findings were suggestive of invasive aspergillosis, although there was no evidence of the infection in the lungs or paranasal sinuses. Computed tomography-guided aspiration of the remaining lesions and follow-up antifungal therapy were recommended. The parents, however, requested discharge without further treatment. The child was seen at a follow-up visit 3 years later without having received any antifungal treatment. Imaging showed resolution of the infection and features of Dyke-Davidoff-Masson syndrome (cerebral hemiatrophy). This report of invasive cerebral aspergillosis resolving without medical therapy is the first of its kind. Its clinicoradiological aspects are discussed in light of previously reported cases.


Targeted therapies in non-small cell lung cancer.
Chemotherapy now has an established role in the treatment of non-small cell lung cancer, with randomised evidence supporting a survival benefit in both advanced disease and the adjuvant setting. The availability of newer cytotoxic agents has not led to further improvement in outcome, and novel approaches a re needed. Growth factor-mediated signalling pathways are frequently subverted in human cancers, so that physiological processes become abnormally regulated by oncogene products such as epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). Drugs targeting EGFR and VEGF have already demonstrated improved survival compared with standard of care in lung cancer, and the evidence supporting the use of these and related agents is reviewed here. These newer agents are in general cytostatic rather than cytotoxic, so that clinical benefit can be associated with stable disease rather than with disease response alone, and the impact of this on imaging modalities used to assess response in trials and clinical practice is discussed.


[Current status of urinary cytology in the evaluation of bladder neoplasms].
Urine cytology is a reliable method for identification and follow up of the patients who develop high-grade urothelial carcinoma. Reactive changes of superficial and intermediate urothelial cells cytologically often mimic low grade urothelial carcinoma. This is the cause of relatively high number of false positive and false negative results. Diagnostic accuracy can be improved introducing different procedures for material handling namely cytospin and liquid based cytology and new diagnostic protocols such as FISH for chromosomal aberrations or mRNA and miRNA analysis. Most recently Next Generation Sequencing for DNA analysis was applied. Availability of clinical information improves the diagnostic accuracy and shortens the time to diagnosis.


[Acute management of spinal injuries. The thoracic and lumbar spine, conservative and functional therapy].
Fractures of the thoracic spine are commonly treated functionally. In the thoracolumbar and lumbar region compression fractures with angulation can be treated by closed reduction and casting according to the Boehler method. Yet, stable fractures with minor deformities may be treated with advantage by early weight bearing. Primarily unstable thoracic and lumbar vertebra fractures gradually become stable with increasing fracture healing and may also be treated functionally but with prolonged bed rest of 6-12 weeks. Thus open reduction and internal fixation achieve better anatomical alignment and also allow early mobilisation and ambulation. They are therefore recently favoured.


Simultaneous Quantification of Gallic Acid, Bergenin, Epicatechin, Epicatechin Gallate, Isoquercitrin, and Quercetin-3-Rhamnoside in Rat Plasma by LC-MS/MS Method and Its Application to Pharmacokinetics after Oral Administration of Ardisia japonica Extract.
Ardisia japonica is a well-known traditional Chinese medicinal herb used as a diuretic, for treating cough and for stopping uterine bleeding. A simple, sensitive, and reliable LC-MS/MS method was developed to determine six active compounds in rat plasma and this method was further applied to the pharmacokinetic study of these compounds after oral administration of Ardisia japonica extract. Acetonitrile was used to precipitate the protein in the plasma samples. Using acetonitrile and formic acid aqueous solution (0.05%) as the mobile phase, the separation of the six compounds and internal standards was achieved at a flow rate of 300 μL min-1 on an Eclipse plus C18 column at an elution time of 16 min. A tandem mass spectrometer having an electrospray ionization (ESI) source was used in the detection of the analytes and internal standards using multiple reactions monitoring (MRM) in the negative ionization mode. The LLOQ was 2, 2, 4, 2, 1, and 0.4 ng mL-1 for gallic acid, bergenin, epicatechin, epicatechin gallate, isoquercitrin, and quercetin-3-rhamnoside, respectively. The validated method was applied to the pharmacokinetic study of gallic acid, bergenin, and quercetin-3-rhamnoside in rat plasma after oral administration of A. japonica extract to rats.