Capture and Direct Amplification of DNA on Chitosan Microparticles in a Single PCR-Optimal Solution.
While nucleic acid amplification tests have great potential as tools for rapid diagnostics, complicated sample preparation requirements inhibit their use in near-patient diagnostics and low-resource-setting applications. Recent advancements in nucleic acid purification have leveraged pH-modulated charge switching polymers to reduce the number of steps required for sample preparation. The polycation chitosan (pKa 6.4) has been used to efficiently purify DNA by binding nucleic acids in acidic buffers and then eluting them at a pH higher than 8.0. Though it is an improvement over conventional methods, this multistep procedure has not transformed the application of nucleic acid amplification assays. Here we describe a simpler approach using magnetic chitosan microparticles that interact with DNA in a manner that has not been reported before. The microparticles capture DNA at a pH optimal for PCR (8.5) just as efficiently as at low pH. Importantly, the captured DNA is still accessible by polymerase, enabling direct amplification from the microparticles. We demonstrate quantitative PCR from DNA captured on the microparticles, thus eliminating nearly all of the sample preparation steps. We anticipate that this new streamlined method for preparing DNA for amplification will greatly expand the diagnostic applications of nucleic acid amplification tests.


Formative Evaluation and Learning Achievement in Epidemiology for Preclinical Medical Students.
Teaching epidemiology and biostatistics is a challenge for medical teachers. Formative evaluation has been shown to improve the learning outcomes in various medical subjects. However, the effectiveness of formative evaluation in the subject of epidemiology has yet to be clearly demonstrated. The aim of this study is to investigate the association between formative evaluation and learning outcomes of medical students. We retrospectively reviewed the prospectively collected learning data of 266 third-year medical students who were enrolled in an epidemiology course in 2016. All learning data and outcomes were analyzed. Nearly all students (97.4%) attended the formative evaluation. Learning outcomes were deemed unsatisfactory in 9.8% of cases. Multivariate analysis revealed that gender, the students' medical training program, laboratory attendance, and the amount of calculation students do during the formative examination were factors that were associated with learning outcomes. The formative evaluation was effective at improving learning outcomes in the subject of epidemiology. The parameters indicated that the attention of the medical students, such as laboratory attendance, and the amount of calculation done during the formative examination, were associated with learning outcomes.


Synergy between von Hippel-Lindau and P53 contributes to chemosensitivity of clear cell renal cell carcinoma.
The von Hippel-Lindau tumor suppressor (VHL; E3 ubiquitin ligase gene) is frequently mutated or undetectable in clear cell renal cell carcinoma (CCRCC), and therefore these tumors are highly resistant to chemotherapeutic agents, including adriamycin (ADM) and sunitinib. A mutation in the tumor protein p53 (TP53) also leads to chemoresistance in tumors; however, in CCRCC, TP53 is frequently functional, yet the tumors remain highly insensitive to chemotherapy. This indicates the possibility of a synergistic effect of VHL and P53 in CCRCC. The present study aimed to detect the chemosensitivity of CCRCC. The expression of VHL in the MZ1257 cell line sensitized these cells to ADM and sunitinib, and a knockdown of VHL in the ACHN cells increased their chemoresistance. To confirm that VHL and P53 are both required for chemosensitivity, VHL and P53 were co‑expressed in 786‑O cells. The results of the functional antagonist assay (which assessed the IC50 values, i.e. the half maximal inhibitory concentration) confirmed that VHL and P53 act in synergy to promote chemosensitivity. Cell cycle arrest was measured by propidium iodide staining following treatment with ADM or sunitinib. Further analysis indicated that co‑expression of VHL and P53 inhibited cell proliferation by completely inhibiting the cell cycle at the G0/G1 phase, and promoted apoptosis following treatment with ADM or sunitinib. These findings demonstrated that VHL and P53 act synergistically in the regulation of cell proliferation and apoptosis in CCRCC. Overall, VHL and P53 have important roles in the regulation of cell proliferation and apoptosis in CCRCC. Furthermore, the regulatory role of VHL is dependant on the activation P53.


The action and safety of ketoconazole: a brief literature review.
A great number of human diseases can be attributed in some way to the effects of fungi, and consequently have long been recognized as important to the dermatologist and mycologist. However, not in all spheres of medicine are fungi significant in the diagnosis and treatment of disease. Fungi are biochemically similar to the host since they are eukaryotic. Thus, it is difficult to synthesize agents that will destroy the pathogenic organism and not harm the patient. Ketoconazole, an imidazole, was the first broad-spectrum, oral antifungal drug to be used in clinical medicine. Selected publications on the pharmacology, comparative efficacy in treatment, toxicity and safety of ketoconazole are briefly reviewed. In addition, new areas of research being undertaken for the azole derivatives are surveyed.


Pharyngeal pouch: link with reflux and oesophageal dysmotility.
Twenty patients aged 56-92 years who underwent surgical correction of pharyngeal pouches at Queen Alexandra Hospital, Portsmouth were asked to fill in a detailed questionnaire. They were then interviewed and barium swallow studies performed from 3 months to 4 years post-operatively. Nineteen patients in the sample were found to have reflux and 20 had dysmotility. These findings suggest that pharyngeal pouches are not a purely localized inco-ordination of the cricopharyngeal sphincter but are associated with a generalized oesophageal muscle dysfunction.


Towards peptide formation inside the channels of a new divinylaniline-bridged periodic mesoporous organosilica.
The first synthesis of a new highly ordered divinylaniline-bridged periodic mesoporous organosilica (PMO) with crystal-like pore walls and further chemical modification of the amino groups on the inner surface of the product by a peptide formation reaction with a chiral amino acid are reported.


[Characteristics of surface runoff pollution of Shanghai urban area].
Sampling and monitoring of surface runoff in Shanghai urban area were carried out during rainy seasons from 2003 to 2005, and pollutographs of COD, BOD5, SS, NH4+ -N, TP and TN of 56 rainfall events from 19 sampling sites were analyzed. Discharge processes of runoff pollutants during rain events and relationships of the processes with rainfall characters were discussed, and event mean concentrations (EMCs) were calculated. Probability distribution of EMCs and correlation between EMCs and rain characters were analyzed. Medium event mean concentrations of pollutants in surface runoff of Shanghai urban area are: COD 205, BOD5 68, SS 185, NH4+ -N 3.14,TP 0.40, TN 7.23 (mg/L), which are much higher than those in Paris urban area. The ratio of BOD5 to COD is 0.37, which is very high for surface runoff compared with that of large cities of developed countries. Results show that impervious surface pollution is serious in Shanghai urban area and some measures must be taken to improve urban water environment quality except stormwater separation.


Aligned carbon nanotubes for high-efficiency Schottky solar cells.
The development of low-cost and high-efficiency silicon Schottky solar cells has drawn considerable interest in recent years. A facial approach for the fabrication of carbon nanotube-silicon (CNT-Si) Schottky solar cells by using aligned double-walled CNTs drawn from a CNT array is demonstrated. The aligned CNTs help to form high CNT-Si junction density and provide efficient charge-transport paths. The power conversion efficiency (PCE) reaches 10.5%, which is higher than that of solar cells fabricated using pristine and random CNT networks. Furthermore, the cell fabrication is scalable, and the solar cells fabricated in one batch show very small PCE fluctuations.


▼Romosozumab for osteoporosis.
Generic name: Romosozumab Brand name: Evenity Formulation: 105 mg solution for injection in a pre-filled pen Market Authorisation holder: UCB Pharma Limited Indication: treatment of severe osteoporosis in postmenopausal women at high risk of fracture Dose: 210 mg romosozumab (administered as two subcutaneous injections of 105 mg each) once a month for 12 months. It is recommended that patients begin antiresorptive therapy after completing treatment with romosozumab. Cost: £427.75 for two pre-filled pens each containing 105 mg romosozumab Classification: Prescription only medicine (POM) subject to additional monitoring (▼).


Acid Chlorides as Formal Carbon Dianion Linchpin Reagents in the Aluminum Chloride-Mediated Dieckmann Cyclization of Dicarboxylic Acids.
The development of acid chlorides as formal dianion linchpin reagents that enable access to cyclic 2-alkyl- and 2-acyl-1,3-alkanediones from dicarboxylic acids is described herein. Mechanistic experiments relying on 13C-labeling studies confirm the role of acid chlorides as carbon dianion linchpin reagents and have led to a revised reaction mechanism for the aluminum(III)-mediated Dieckmann cyclization of dicarboxylic acids with acid chlorides.


Hydrogen sensing with Ni-doped TiO2 nanotubes.
Doping with other elements is one of the efficient ways to modify the physical and chemical properties of TiO2 nanomaterials. In the present work, Ni-doped TiO2 nanotubes were fabricated through anodic oxidation of NiTi alloy and further annealing treatment. The hydrogen sensing properties of the nanotube sensor were investigated. It was found that the Ni-doped TiO2 nanotubes were sensitive to an atmosphere of 1,000 ppm hydrogen, showing a good response at both room temperature and elevated temperatures. A First-Principle simulation revealed that, in comparison with pure anatase TiO2 oxide, Ni doping in the TiO2 oxide could result in a decreased bandgap. When the oxide sensor adsorbed a certain amount of hydrogen the bandgap increased and the acceptor impurity levels was generated, which resulted in a change of the sensor resistance.


Myo4p is a monomeric myosin with motility uniquely adapted to transport mRNA.
The yeast Saccharomyces cerevisiae uses two class V myosins to transport cellular material into the bud: Myo2p moves secretory vesicles and organelles, whereas Myo4p transports mRNA. To understand how Myo2p and Myo4p are adapted to transport physically distinct cargos, we characterize Myo2p and Myo4p in yeast extracts, purify active Myo2p and Myo4p from yeast lysates, and analyze their motility. We find several striking differences between Myo2p and Myo4p. First, Myo2p forms a dimer, whereas Myo4p is a monomer. Second, Myo4p generates higher actin filament velocity at lower motor density. Third, single molecules of Myo2p are weakly processive, whereas individual Myo4p motors are nonprocessive. Finally, Myo4p self-assembles into multi-motor complexes capable of processive motility. We show that the unique motility of Myo4p is not due to its motor domain and that the motor domain of Myo2p can transport ASH1 mRNA in vivo. Our results suggest that the oligomeric state of Myo4p is important for its motility and ability to transport mRNA.


Bovine thyroglobulin gene polymorphisms and their association with sexual precocity in Guzerat bulls.
Puberty is a stage of sexual development determined by the interaction of environmental factors and genetic mechanisms. Among them, thyroid function plays a key role in sexual development and spermatogenic function and is under the control of several genes, including the well-described thyroglobulin gene (TG). Previous reports have shown genetic association between thyroid function and selected single nucleotide polymorphisms (SNPs) in taurine cattle. Therefore, the identification of genetic mechanisms involved in the regulation of this trait can assist with the selection for early pubertal bulls, thus improving genetic progress in livestock breeding. The aim of this study was to validate the association between TG SNPs and age at puberty in zebuine bulls. Three SNPs (rs110406764, rs109662686, rs109057985) were genotyped in 159 Guzerat animals using SEQUENOM technology. Results showed a significant association (p < .05) between the studied SNPs and puberty age, in agreement with our previous reports in a taurine breed. Interestingly, allele frequencies were different from those already reported, being GAT the most favourable allele for age at puberty in Guzerat (94.4 days lower). Overall, our findings corroborate previous reports and reinforce the importance of genetic influence in the regulation of sexual development and puberty through a thyroid pathway in zebuine cattle.


Profile and repair success of vesico-vaginal fistula in Lahore.
To describe the profile of patients with vesico-vaginal fistula (VVF) and success rate of the surgery. Descriptive study. Sir Ganga Ram Hospital and Ghurki Trust Hospital, Lahore, between 1998 and 2002. patients and All patients diagnosed as cases of vesico-vaginal fistula were included in the study. Those patients, who had previous unsuccessful surgery for vesico-vaginal repair, whether done in the hospital or outside, were also included. Their demographic profile and repair success was determined. Out of 2570 gynaecological admissions, 14 women had vesico-vaginal fistulae showing the prevalence of 0.55 / 100 gynaecological admissions. Obstetrical cause was found in 71.4% of the cases. The mean age of the patients was 34.85 +/- 6.3 years (range 25-45) with parity varying from 0-9 (median 4). The position of majority of the fistulas (57.2%) was high (vault, juxta-cervical). Success rate of the surgery in the study was 85.7%. Majority of the repairs (78.6%) were done through vaginal route. The most common cause of vesico-vaginal fistula in this study was obstetrical, either prolonged labour or caesarean hysterectomy. Although the success rate of repair was high, yet the attempt should be focussed on prevention.


[Fast Discrimination of Drugs by Improved Projection Algorithm Based on Raman Spectroscopy].
The projection algorithm used in mixture analysis to determine whether there is unknown disturbance existing in grey system can not accurately identify different samples and similar samples at the same time when it is used in the identification of drugs, because of the insufficient criteria. In the present study, one of its criteria for whether the size of measurement error of testing sample is at a limited level is improved for whether the size and distribution of measurement error is equal and similar between testing sample and standard sample. By testing 6 kinds of normal drugs (including BAYER Aspirin Enteric-coated Tablets, TYLENOL Acetaminophen Sustained Release Tablets, BAYER Compound Paracetamol Tablets(II), HUAZHONG Compound Vitamin C, HUAZHONG Vitamin B and MADINGLIN Demperidone Tablets) and 3 kinds of similar drugs of aspirin (including BAYER Aspirin Enteric-coated Tablets, Shanghai SINE Aspirin Enteric-coated Tablets and Bamyl Aspirin Effervescent Tablets), it was found that the un-improved projection algorithm directly used in discrimination of drugs shows poor performance with many problems existing, however, the improved projection algorithm can discriminate different drugs and similar drugs with accuracy up to 100%. The improved projection algorithm can be a universal, accurate and reliable automated pharmaceutical identification algorithm and can provide a reference for the study on identification of substance.


Calcium-sensitive MRI contrast agents based on superparamagnetic iron oxide nanoparticles and calmodulin.
We describe a family of calcium indicators for magnetic resonance imaging (MRI), formed by combining a powerful iron oxide nanoparticle-based contrast mechanism with the versatile calcium-sensing protein calmodulin and its targets. Calcium-dependent protein-protein interactions drive particle clustering and produce up to 5-fold changes in T2 relaxivity, an indication of the sensors' potency. A variant based on conjugates of wild-type calmodulin and the peptide M13 reports concentration changes near 1 microM Ca(2+), suitable for detection of elevated intracellular calcium levels. The midpoint and cooperativity of the response can be tuned by mutating the protein domains that actuate the sensor. Robust MRI signal changes are achieved even at nanomolar particle concentrations (<1 microM in calmodulin) that are unlikely to buffer calcium levels. When combined with technologies for cellular delivery of nanoparticulate agents, these sensors and their derivatives may be useful for functional molecular imaging of biological signaling networks in live, opaque specimens.


Neuropsychological correlates of schizotypy: a systematic review and meta-analysis of cross-sectional studies.
Cognitive deficits can precede the onset of psychotic episodes and predict the onset of the illness in individuals with schizotypy traits. In some studies, high levels of schizotypy were associated with impairments in memory, attention, executive functions, and verbal fluency. This review provides a more comprehensive understanding of cognitive impairments related to schizoytpy. A systematic review of "schizotypy and neuropsychological measures" was conducted, and it retrieved 67 studies. All papers with case-control design showing means and standard deviations from neuropsychological measures were included in a meta-analysis (n = 40). A comparison between our finding and another metaanalysis with patients with schizophrenia-spectrum disorders [Fatouros-Bergman, H., Cervenka, S., Flyckt, L., Edman, G., & Farde, L. (2014). Meta-analysis of cognitive performance in drugnaive patients with schizophrenia. Schizophrenia Research. doi: 10.1016/j.schres.2014.06.034 ] was performed to study the similarities on the MATRICS domains between the two disorders. We found evidence of worse functioning of verbal and visual-spatial working memory, and of language in people with schizotypy or with schizotypal traits. Working memory deficit is present in both schizotypy and schizophrenia with larger effect sizes compared to other domains. Working memory deficit might be a cognitive marker of the risk of psychosis. Interventions targeting cognitive deficits early may be crucial to the prevention of psychosis.


Simultaneous Fluorescein Angiography and Spectral Domain Optical Coherence Tomography Correlate Retinal Thickness Changes to Vascular Abnormalities in an In Vivo Mouse Model of Retinopathy of Prematurity.
Retinopathy of prematurity (ROP) is a condition of abnormal retinal vascular development (RVD) in premature infants. Fluorescein angiography (FA) has depicted phases (early, mid, late, and mature) of RVD in oxygen-induced retinopathy (OIR) mice. We sought to establish the relationship between retinal structural and vascular changes using simultaneous FA and spectral domain optical coherence tomography (SD-OCT). 63 mice were exposed to 77% oxygen at postnatal day 7 (P7) for 5 days, while 63 mice remained in room air (RA). Total retinal thickness (TRT), inner retinal thickness (IRT), and outer retinal thickness (ORT) were calculated at early (P19), mid (P24), late (P32), and mature (P47) phases of RVD. TRT was reduced in OIR (162.66 ± 17.75 μm, n = 13) compared to RA mice at P19 (197.57 ± 3.49 μm, n = 14), P24, P32, and P49 (P < 0.0001). ORT was similar in RA and OIR mice at all ages (P > 0.05). IRT was reduced in OIR (71.60 ± 17.14 μm) compared to RA (103.07 ± 3.47 μm) mice at P19 and all ages (P < 0.0001). We have shown the spatial and temporal relationship between retinal structure and vascular development in OIR. Significant inner retinal thinning in OIR mice persisted despite revascularization of the capillary network; further studies will elucidate its functional implications in ROP.


Analysis of absorbed dose in radioimmunotherapy with 177Lu-trastuzumab using two different imaging scenarios: a pilot study.
Internal organ dosimetry is an important procedure to demonstrate the reliable application of 177Lu-trastuzumab radioimmunotherapy for human epidermal growth factor receptor-positive metastatic breast cancers. We are reporting the first human dosimetry study for 177Lu-trastuzumab. Another objective of our study was to calculate and compare the absorbed doses for normal organs and tumor lesions in patients before radioimmunotherapy with 177Lu-trastuzumab using two different imaging scenarios. Eleven patients (48.27 ± 8.95 years) with a history of metastatic breast cancer were included in the study. Postadministration of 177Lu-trastuzumab (351.09 ± 23.89 MBq/2 mg), acquisition was performed using planar and hybrid imaging scenarios at 4, 24, 72 and 168 h. Single-photon emission computed tomography/computed tomography imaging was performed at 72 h postinjection. Acquired images were processed using Dosimetry Toolkit software for the estimation of normalized cumulated activity in organs and tumor lesions. OLINDA/EXM 2.0 software was used for absorbed dose calculation in both scenarios. Significant difference in normalized cumulated activity and the absorbed dose is noted between two imaging scenarios for the organs and tumor lesions (P < 0.05). Mean absorbed dose (mGy/MBq) estimated from heart, lungs, liver, spleen, kidney, adrenal, pancreas and colon using planar and hybrid scenarios were 0.81 ± 0.19 and 0.63 ± 0.17; 0.75 ± 0.13 and 0.32 ± 0.06; 1.26 ± 0.25 and 1.01 ± 0.17; 0.68 ± 0.22 and 0.53 ± 0.16; 0.91 ± 0.3 and 0.69 ± 0.24; 0.18 ± 0.04 and 0.11 ± 0.02; 0.25 ± 0.22 and 0.09 ± 0.02 and 0.75 ± 0.61 and 0.44 ± 0.28, respectively. On the basis of our dosimetric evaluation, we concluded that radioimmunotherapy with 177Lu-trastuzumab is well tolerated to be implemented in routine clinical practice against HER2 positive metastatic breast cancer. Liver is the main critical organ at risk. Hybrid scenario demonstrated significantly lower absorbed doses in organs and tumors compared to the multiplanar method.


Advanced Silicon Chemistry in Australia: Forming Strong Links with Asia.
This paper details Australian commercial and academic silicon research. Areas of interest include silicon metal, polysiloxane polymers, copolymers, cyclics, emulsions, microemulsions, silanes, silane coupling agents, sol-gel chemistry and water-treatments, porous silicon, polysiloxane degradation, silicon hydrogel contact lenses, silanolate synthesis, siloxane interfacial polymerisation, hydrosilylation, polysiloxane electrolytes for lithium ion batteries, silanes for PBX materials, octafunctionalized polyhedral oligomeric silsesquioxanes (POSS), POSS hybrids, sol-gel hydrogenation catalysts, silane modification of silica, sol-gel energy storage, silicate grout stabilisation, GeoPolymer concretes, aerogel insulating foams, "Phaco-Ersatz" Accommodating Gel-Intraocular Lens technologies. Strong collaborative opportunities, in silicon, with Asia, exist with organisations such as: 1) The Asian Silicon Society and 2) The Agency for the Assessment and Application of Technology (BPPT) Indonesia.


The Independent Value of Neutrophil to Lymphocyte Ratio in Gouty Arthritis: A Narrative Review.
Since the incidence of gouty arthritis (GA) exhibits yearly increases, accurate assessment and early treatment have significant values for improving disease conditions and monitoring prognosis. Neutrophil to lymphocyte ratio (NLR) is a common indicator in blood routine, which has the characteristics of easy access and low cost. In recent years, NLR has been proven to be an effective indicator for guiding the diagnosis, treatment, and prognosis of various diseases. Moreover, NLR has varying degrees of relationship with various inflammatory biomarkers, which can affect and reflect the inflammatory response in the body. This paper reviews the independent value of NLR for GA and its underlying molecular pathological mechanisms, intending to contribute to the further application of NLR.


Overexpression of phosphoprotein enriched in astrocytes 15 reverses the damage induced by propofol in hippocampal neurons.
Propofol is a general anesthetic used in surgical operations. Phosphoprotein enriched in astrocytes 15(PEA15) was initially identified in astrocytes. The present study examined the role of PEA15 in the damage induced by propofol in hippocampal neurons. A model of hippocampal neuron damage was established using 50 µmol/l propofol. Cell viability, proliferation and apoptosis of hippocampal neurons were tested by Cell Counting Kit‑8 and flow cytometry. Western blotting and reverse transcription‑quantitative polymerase chain reaction analysis were performed to measure the expression levels of PEA15, and additional factors involved in apoptosis or in the signaling pathway downstream of PEA15. The present results suggested that propofol significantly decreased PEA15 expression levels in hippocampal neurons. Furthermore, overexpression of PEA15 significantly increased the cell viability and cell proliferation of cells treated with propofol. Additionally, PEA15 overexpression decreased apoptosis, which was promoted by propofol. Treatment with propofol significantly decreased the protein expression levels of pro‑caspase‑3, B‑cell lymphoma-2, phosphorylated extracellular signal‑regulated kinases (ERK)1/2, ribosomal S6 kinase 2 (RSK2) and phosphorylated cAMP responsive element binding protein 1 (CREB1). However, propofol upregulated active caspase‑3 and Bax expression levels. Notably, PEA15 overexpression was able to reverse the effects of propofol. Collectively, overexpression of PEA15 was able to attenuate the neurotoxicity of propofol in rat hippocampal neurons by increasing proliferation and repressing apoptosis via upregulation of the ERK‑CREB‑RSK2 signaling pathway.


Health insurers' financial performance and quality improvement expenditures in the Affordable Care Act's second year.
The Affordable Care Act requires health insurers to rebate any amounts less than 80%-85% of their premiums that they fail to spend on medical claims or quality improvement. This study uses the new comprehensive reporting under this law to examine changes in insurers' financial performance and differences in their quality improvement expenditures. In the ACA's second year (2012), insurers' median medical loss ratios continued to increase and their median administrative cost ratios dropped, producing moderate operating margins in the group markets but a small operating loss in the individual market, at the median. For-profit insurers showed larger changes, in general, than did nonprofits. For quality improvement, insurers reported spending a significantly greater amount per member in their government plans than they did on their self-insured members, with spending on commercial insurance being in between these two extremes. The magnitude and source of these differences varied by corporate ownership.


Ordered Assembly of DNA on Topological Insulator Bi2Se3 and Octadecylamine for a Sensitive Biosensor.
Controlling the assembly of DNA in order on a suitable electrode surface is of great significance for biosensors and disease diagnosis, but it is full of challenges. In this work, we creatively assembled DNA on the surface of octadecylamine (ODA)-modified topological insulator (Tls) Bi2Se3 and developed an electrochemical biosensor to detect biomarker DNA of coronavirus disease 2019 (COVID-19). A high-quality Bi2Se3 sheet was obtained from a single crystal synthesized in our lab. A uniform ODA layer was coated in argon by chemical vapor deposition (CVD). We observed and analyzed the assembly and mechanism of single-strand DNA (ssDNA) and double-strand DNA (dsDNA) on the Bi2Se3 surface through atomic force microscopy (AFM) and molecular dynamics (MD) simulations. The electrochemical signal revealed that the biosensor based on the DNA/ODA/Bi2Se3 electrode has a wide linear detection range from 1.0 × 10-12 to 1.0 × 10-8 M, with the limit of detection as low as 5 × 10-13 M. Bi2Se3 has robust surface states and improves the electrochemical signal-to-noise ratio, while the uniform ODA layer guides high-density ordered DNA, enhancing the sensitivity of the biosensor. Our work demonstrates that the ordered DNA/ODA/Bi2Se3 electrode surface has great application potential in the field of biosensing and disease diagnosis.


Histiocytosis and a leukaemoid response. A case report.
A patient with all the clinical signs of Letterer-Siwe disease is reported. The patient was unusual in that he had a severe leukaemoid reaction. To our knowledge, only 2 similar patients with reticulo-endotheliosis, histiocytic skin infiltration and leukaemoid reaction have been reported. It is possible that the disorder may represent a variant of the histiocytic proliferative disorders, characterized by both histiocytic and myeloid hyperplasia, and is thus similar to myelomonocytic leukaemia. However, it differs from the latter condition in that there is proliferation of monocytes and granulocytes in soft tissues rather than in the blood.


Correlation between a quantitative anti-SARS-CoV-2 IgG ELISA and neutralization activity.
In the current COVID-19 pandemic, a better understanding of the relationship between merely binding and functionally neutralizing antibodies is necessary to characterize protective antiviral immunity following infection or vaccination. This study analyzes the level of correlation between the novel quantitative EUROIMMUN Anti-SARS-CoV-2 QuantiVac ELISA (IgG) and a microneutralization assay. A panel of 123 plasma samples from a COVID-19 outbreak study population, preselected by semiquantitative anti-SARS-CoV-2 IgG testing, was used to assess the relationship between the novel quantitative ELISA (IgG) and a microneutralization assay. Binding IgG targeting the S1 antigen was detected in 106 (86.2%) samples using the QuantiVac ELISA, while 89 (72.4%) samples showed neutralizing antibody activity. Spearman's correlation analysis demonstrated a strong positive relationship between anti-S1 IgG levels and neutralizing antibody titers (rs = 0.819, p < 0.0001). High and low anti-S1 IgG levels were associated with a positive predictive value of 72.0% for high-titer neutralizing antibodies and a negative predictive value of 90.8% for low-titer neutralizing antibodies, respectively. These results substantiate the implementation of the QuantiVac ELISA to assess protective immunity following infection or vaccination.


Postoperative mitral leaflet rupture in an infant with Loeys-Dietz syndrome.
This report describes an infantile case of Loeys-Dietz syndrome (LDS) with spontaneous mitral leaflet rupture. The patient was diagnosed with a type B interruption of the aortic arch. Bilateral pulmonary artery banding was performed 5 days after birth. On the 53rd day, intra-cardiac repair was performed without valvuloplasty. Although the operation was successful, mitral regurgitation deteriorated at 4 weeks after operation. On the 88th day, a mitral valvuloplasty was performed and a severely ruptured anterior leaflet was observed. Seven days after valvuloplasty, the mitral valve insufficiency again worsened and a fourth operation was performed. Two tears were observed in the anterior and posterior mitral valve leaflets, and a mitral valve replacement was required. Subsequently, the patient was diagnosed with LDS according to gene mutational status. LDS is known to have a poor prognosis with cardiovascular complications, but valve rupture has not been previously reported in other cases.


Entrainment of a spatially extended nonlinear structure under selective forcing.
The response of a nonlinear state to a variable forcing periodic in space is studied in an extended dynamical system consisting of a liquid crystal layer driven to convection. Both the statics and the dynamics of the entrainment and the locking effects are analyzed. The dynamics of the evolution are controlled by topological singularities that allow a diffusion of the phase. The mechanisms involved are related to the role of the defects in systems undergoing spontaneous symmetry breakings.


The Impact of Body Mass Index on Outcomes Following Open Sub-Pectoralis Major Biceps Tenodesis.
Traditionally, biceps tenotomy has been recommended for obese, older, and less active patient populations, while tenodesis is preferred in younger, thinner, and more active individuals. In an effort to better understand the impact obesity has on the surgical management of long head of the biceps tendinopathy, the current study analyzed the effect body mass index had on surgical outcomes following open subpectoralis major biceps tenodesis. Patients who underwent biceps tenodesis between June 2006 and December 2013 were identified from our institution's surgical database. They were then contacted to assess their functional outcomes using validated outcome measures. Comparisons were made between the outcomes seen in obese patients (BMI ≥ 30) and non-obese patients (BMI < 30) with subgroup analyses looking at gender, age, and length of follow-up. One hundred and twenty-two patients completed a follow-up assessment with a mean follow-up of 29.3 months. The non-obese cohort was composed of 84 patients with a mean BMI of 25.8. The obese cohort was composed of 38 patients with a mean BMI of 33.4. No significant difference was noted to be present with respect to postoperative outcome measures. Regression analysis with BMI as an independent variable demonstrated poor correlation with outcome measures. The results of the current study support open subpectoralis biceps tenodesis as an acceptable option for the treatment of LHB pathology irrespective of the treated patient's body mass index. Both obese and non-obese patients demonstrated low postoperative DASH scores and high Oxford Shoulder scores.


Automated image registration of cerebral digital subtraction angiography.
Our aim is to automatically align digital subtraction angiography (DSA) series, recorded before and after endovascular thrombectomy. Such alignment may enable quantification of procedural success. Firstly, we examine the inherent limitations for image registration, caused by the projective characteristics of DSA imaging, in a representative set of image pairs from thrombectomy procedures. Secondly, we develop and assess various image registration methods (SIFT, ORB). We assess these methods using manually annotated point correspondences for thrombectomy image pairs. Linear transformations that account for scale differences are effective in aligning DSA sequences. Two anatomical landmarks can be reliably identified for registration using a U-net. Point-based registration using SIFT and ORB proves to be most effective for DSA registration and are applicable to recordings for all patient sub-types. Image-based techniques are less effective and did not refine the results of the best point-based registration method. We developed and assessed an automated image registration approach for cerebral DSA sequences, recorded before and after endovascular thrombectomy. Accurate results were obtained for approximately 85% of our image pairs.


Training-Induced Muscle Fatigue with a Powered Lower-Limb Exoskeleton: A Preliminary Study on Healthy Subjects.
Powered lower-limb exoskeletons represent a promising technology for helping the upright stance and gait of people with lower-body paralysis or severe paresis from spinal cord injury. The powered lower-limb exoskeleton assistance can reduce the development of lower-limb muscular fatigue as a risk factor for spasticity. Therefore, measuring powered lower-limb exoskeleton training-induced fatigue is relevant to guiding and improving such technology's development. In this preliminary study, thirty healthy subjects (age 23.2 ± 2.7 years) performed three motor tasks: (i) walking overground (WO), (ii) treadmill walking (WT), (iii) standing and sitting (STS) in three separate exoskeleton-based training sessions of 60 min each. The changes in the production of lower-limb maximal voluntary isometric contraction (MVIC) were assessed for knee and ankle dorsiflexion and extension before and after the three exoskeleton-based trained motor tasks. The MVIC forces decreased significantly after the three trained motor tasks except for the ankle dorsiflexion. However, no significant interaction was found between time (before-, and after-training) and the training sessions except for the knee flexion, where significant fatigue was induced by WO and WT trained motor tasks. The results of this study pose the basis to generate data useful for a better approach to the exoskeleton-based training. The STS task leads to a lower level of muscular fatigue, especially for the knee flexor muscles.


Deep vein thrombosis related to environment (Review).
The first-time venous thromboembolism (VTE) is less frequent than other thrombotic events, however, both the pulmonary embolism (PE) and the deep vein thrombosis (DVT) show a frequent morbidity. Many factors play as risk situations in determining VTE, and the air exposure to the fine and ultrafine particulate matter (PM) as PM10, PM2.5, PM0.1 is considered. Epidemiological studies have supported this association although both the effective burden of the association and the mechanisms are to date unclear. The PM concentrations and the exposure time are notable as emerging factors. Interestingly, the seasonal climate variations resulted as effective risk factor for appearance of VTE or DVT. There is a need to ameliorate the environment by reducing the air pollution at global scale.


A Life Outside.
How do the morphologies of organisms affect their physical interactions with the environment and other organisms? My research in marine systems couples field studies of the physical habitats, life history strategies, and ecological interactions of organisms with laboratory analyses of their biomechanics. Here, I review how we pursued answers to three questions about marine organisms: (a) how benthic organisms withstand and utilize the water moving around them, (b) how the interaction between swimming and turbulent ambient water flow affects where small organisms go, and (c) how hairy appendages catch food and odors. I also discuss the importance of different types of mentors, the roadblocks for women in science when I started my career, the challenges and delights of interdisciplinary research, and my quest to understand how I see the world as a dyslexic. Expected final online publication date for the Annual Review of Marine Science, Volume 16 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.


Supervisor leadership in relation to resident job satisfaction.
Research from outside the medical field shows that leadership behaviours influence job satisfaction. Whether the same is true for the medical training setting needs to be explored. The aim of this study was to investigate the influence of residents' overall appreciation of their supervisor's leadership and observation of specific supervisor leadership behaviours on job satisfaction. We invited residents (N = 117) to rate how often they observed certain task and relation-oriented leadership behaviours in their supervisor and overall appreciation of their supervisor's leadership. Furthermore, they rated their satisfaction with 13 different aspects of their jobs on a 10-point scale. Using exploratory factor analysis we identified four factors covering different types of job satisfaction aspects: personal growth, autonomy, affective, and instrumental job satisfaction aspects. Influence of overall appreciation for supervisor leadership and observation of certain leadership behaviours on these job satisfaction factors were analysed using multiple regression analyses. The affective aspects of job satisfaction were positively influenced by overall appreciation of leadership (B = 0.792, p = 0.017), observation of specific instructions (B = 0.972, p = 0.008) and two-way communication (B = 1.376, p = 0.008) and negatively by mutual decision-making (B = -1.285, p = 0.007). No effects were found for the other three factors of job satisfaction. We recommend that supervisors become more aware of whether and how their behaviours influence residents' job satisfaction. Especially providing specific instructions and using two-way communication seem important to help residents deal with their insecurities and to offer them support.


Implications of radiation microdosimetry for accelerator-based boron neutron capture therapy: a radiobiological perspective.
Boron neutron capture therapy (BNCT) has great potential to selectively destroy cancer cells while sparing surrounding normal cells. The basic concept of BNCT was developed in the 1930s, but it has not yet been commonly used in clinical practice, even though there is now a large number of experimental and translational studies demonstrating its marked therapeutic potential. With the development of neutron accelerators that can be installed in medical institutions, accelerator-based BNCT is expected to become available at several medical institutes around the world in the near future. In this commentary, from the point of view of radiation microdosimetry, we discuss the biological effects of BNCT, especially the underlying mechanisms of compound biological effectiveness. Radiobiological perspectives provide insight into the effectiveness of BNCT in creating a synergy effect in the field of clinical oncology.


Neuropharmacology of buspirone.
Buspirone is a clinically effective anxiolytic with a unique structure and pharmacology which distinguishes it from the benzodiazepines. It has been termed anxioselective because it lacks anticonvulsant, sedative, or muscle-relaxant properties. Preclinical evidence suggests it lacks potential for abuse or physical dependence and interacts minimally with CNS depressants such as alcohol. Rather than working through traditional benzodiazepine mechanisms, buspirone affects diverse aspects of the brain's neurochemical circuitry. For example, it exerts potent influences on the nigrostriatal and mesolimbic dopamine systems, the dorsal raphe serotonergic system, and the locus coeruleus noradrenergic system. Although without direct receptor interaction, potentiation of cholinergically mediated behavior and involvement with GABAergic neurotransmission have also been demonstrated.


Genome sequence comparisons of serial multi-drug-resistant Mycobacterium tuberculosis isolates over 21 years of infection in a single patient.
We report a case of chronic pulmonary multi-drug-resistant tuberculosis. Despite 14 years of treatment, Mycobacterium tuberculosis was persistently isolated from sputum. Following treatment cessation the patient remained well, although M. tuberculosis was isolated from sputum for a further 8 years. Genome sequencing of eight serial M. tuberculosis isolates cultured between 1991 and 2011 revealed 17 mutations (0.8 mutations per genome year- 1). Eight of these were persisting mutations and only two mutations were detected in the 7 years following cessation of treatment in 2004. In four isolates there were mixed alleles, suggesting the likely presence of bacterial subpopulations. The initial 1991 isolate demonstrated genotypic resistance to isoniazid (katG W91R), rifampicin (rpoB S531L), ethambutol (embB M306V), streptomycin (gidB L16R), quinolones (gyrA S95T) and P-aminosalicylic acid (thyA T202A). Subsequent resistance mutations developed for pyrazinamide (pncA I31F) and ethionamide (ethA frameshift). Such information might have been instructive when developing a treatment regimen. In retrospect and with the benefit of high-resolution genomic hindsight we were able to determine that the patient received only one or two active anti-tuberculous agents for most of their treatment. Additionally, mutations in bacA and Rv2326c were detected, which may have contributed to the persistent but mild disease course. BacA is likely to be associated with maintenance of chronic infection and Rv2326c with a decreased bacterial metabolic state. These results expand our understanding of M. tuberculosis evolution during human infection and underline the link between antibiotic resistance and clinical persistence.


[THE INFLUENCE OF DELTA SLEEP-INDUCING PEPTIDE ON FUNCTIONAL STATE OF RATS HEPATOCYTES IN FOOT-SHOCK STRESS].
The effect of delta sleep-inducing peptide (DSIP) intraperitoneal injection in the doses of 40, 120, 360, and 1080 mcg/kg b. w. on lipid peroxidation and functional hepatocyte state in Wistar male rats subjected to acute and chronic electrical foot-shock stress was investigated. It was observed that 120 mcg/kg peptide normalized the elevation of malondialdehyde (MDA) level in the liver homogenate caused by acute foot-shock stress and also significantly decreased catalase activity in all investigated doses. In serum the injection of DSIP up to 40 mcg/kg increased aminotransferase activity. Peptide in all doses provided the normalization of protein synthetic hepatocyte function, increased catalase and superoxide dismutase activity in chronic stress. In addition malondialdehyde content in the liver homogenate was significantly decreased in the dose of 40 mcg/kg and in other cases it was significantly increased against the background of the common antioxidative activity reduction. The stress-induced increase in serum alanine aminotransferase activity was normalized by peptide administration in the doses of 120, 360, and 1080 mcg/kg.


Well-coupled graphene and Pd-based bimetallic nanocrystals nanocomposites for electrocatalytic oxygen reduction reaction.
In this paper, a series of well-coupled graphene (G) and MPd3 (M = Fe, Cu, Ag, Au, Cr, Mo, W) nanocrystals nanocomposites (G-MPd3 NCPs) have been synthesized via a versatile electrostatic assembly and hydrogen reduction strategy, i.e., sequential assembly of coordination anions and cations on excess cationic polymer modified graphene oxide to form composite precursors and then thermal treating under H2/Ar gases atmosphere. In those NCPs, the MPd3 components are uniform and smaller than 10 nm, which are well anchored on G with "naked" or "clean" surfaces. By adjusting reaction temperature, the interplay of MPd3 nanocrystals and G can be well-controlled. Below 700 °C, no sintering phenomena are observed, indicating the unprecedented dispersion and stability effect of G for MPd3 nanocrystals. All the obtained NCPs can be directly used to catalyze oxygen reduction reaction in alkaline media. Compared with single component, monometallic, and some reported non-Pt catalysts, greatly enhanced electrocatalytic performances are observed in those NCPs due to strong synergistic or coupling of their constituents. Among them, G-FePd3 NCPs exhibit the highest catalytic activity, but their current density needs to be improved compared with G-CrPd3, G-MoPd3, and G-WPd3 ones. This work not only provides a general strategy for fabricating well-coupled G-MPd3 NCPs but also paves the way for future designing multicomponent NCPs with multiple interfaces to apply in alkaline fuel cells.


Novel Treatment of a Malignant Peripheral Nerve Sheath Tumor of the Median Nerve.
Malignant peripheral nerve sheath tumors are rare, associated with a poor prognosis and uncertainty regarding the appropriate management. We report a novel oncologic and reconstructive treatment of a young patient with a malignant peripheral nerve sheath tumor of the median nerve of the left hand. The patient underwent a wide local excision, an opponensplasty, a nerve reconstruction by nerve allografts followed by brachytherapy treatment. Two years later, the patient remains disease free with preserved function of her hand.


Pymetrozine is hydroxylated by CYP6CM1, a cytochrome P450 conferring neonicotinoid resistance in Bemisia tabaci.
Resistance to neonicotinoid insecticides such as imidacloprid in the cotton whitefly, Bemisia tabaci, is linked to its hydroxylation by constitutively overexpressed CYP6CM1, a cytochrome P450 enzyme. Here, an investigation was conducted to establish whether CYP6CM1 functionally expressed in Sf9 cells also detoxifies pymetrozine, a selective homopteran feeding blocker known to be cross-resistant to neonicotinoids in whiteflies. Incubation of pymetrozine with functionally expressed Bemisia CYP6CM1 and subsequent LC-MS/MS analysis revealed a rapid formation of two pymetrozine metabolites by hydroxylation of its heterocyclic 1,2,4-triazine ring system. Enzyme kinetics revealed a Km value of 5.9 ± 0.3 µM and a time-dependent depletion of pymetrozine. The known cross-resistance between imidacloprid, other neonicotinoid insecticides and pymetrozine in B. tabaci is most likely conferred by the very same detoxification mechanism, i.e. a monooxygenase-based hydroxylation mechanism linked to the overexpression of CYP6CM1. These insecticide chemistries should not be alternated in whitefly resistance management strategies.


Temporal and spatial factors influencing Systena frontalis (Coleoptera: Chrysomelidae) behavior in Virginia nurseries.
Ornamental plant production in eastern Virginia nurseries have been greatly impacted by Systena frontalis (F.), also known as the red-headed flea beetle. With the advent of S. frontalis as a prevalent pest in the past 2 decades, baseline phenology and behavior are currently understudied within Virginia nurseries. This pest is costly to control due to insecticide expenses and loss of saleable plants. In 2021 and 2022, populations of this insect were monitored at 2 commercial nurseries in eastern Virginia in order to better understand their temporal and spatial population dynamics. Patterns that emerged indicated S. frontalis could have up to 3 generations in eastern Virginia, with peaks of adult abundance in June, late July, and late August to early September. Phenylethyl alcohol was tested as an adult attractant lure, but it was found to be ineffective under nursery conditions. Diel monitoring demonstrated these adults were most active from 1100 to 1500 h. Severity of defoliation at the leaf level increased linearly with increased density of adults, where 5 individuals defoliated up to 4% of any Hydrangea paniculata cv. 'Limelight' leaf in 1 wk under greenhouse conditions. Timing of scouting and insecticide sprays according to the adult activity peaks of the day and across the season may allow reduction in overall insecticide usage.


Differentiation of Murine C2C12 Myoblasts Strongly Reduces the Effects of Myostatin on Intracellular Signaling.
Alongside in vivo models, a simpler and more mechanistic approach is required to study the effects of myostatin on skeletal muscle because myostatin is an important negative regulator of muscle size. In this study, myostatin was administered to murine (C2C12) and human (CHQ) myoblasts and myotubes. Canonical and noncanonical signaling downstream to myostatin, related ligands, and their receptor were analyzed. The effects of tumorkines were analyzed after coculture of C2C12 and colon cancer-C26 cells. The effects of myostatin on canonical and noncanonical signaling were strongly reduced in C2C12 cells after differentiation. This may be explained by increased follistatin, an endogenous blocker of myostatin and altered expression of activin receptor ligands. In contrast, CHQ cells were equally responsive to myostatin, and follistatin remained unaltered. Both myostatin administration and the coculture stimulated pathways associated with inflammation, especially in C2C12 cells. In conclusion, the effects of myostatin on intracellular signaling may be cell line- or organism-specific, and C2C12 myotubes seem to be a nonoptimal in vitro model for investigating the effects of myostatin on canonical and noncanonical signaling in skeletal muscle. This may be due to altered expression of activin receptor ligands and their regulators during muscle cell differentiation.


Evaluation and Improvement of Employee Performance with respect to Health, Safety, and Environment (HSE) Factors: A Case of Complex Transport Construction Project.
Risk control in complex transport construction is complicated due to the dangerous nature of high variation and unpredictability. Most of the current research analysis focuses on the health, safety, and environment (HSE) risk assessment and employee performance evaluation, which neglects the impact of HSE risks on employee performance. Consequently, this research develops a framework to evaluate employee performance and identify key factors affecting performance. The employee performance indicators and HSE indicators are established by reviewing related literature. Using data from questionnaires, an artificial neural network- (ANN-) based model of employee activity effectiveness is then developed to evaluate employee performance. Sensitivity analysis is implemented to determine the key factors affecting employee performance. The Hong Kong-Zhuhai-Macau Bridge, a large-scale cross-sea channel project, is taken as a case study for validation. The model results show that the employees are satisfied with the effect of HSE management in general, but the psychological stress they perceive becomes large. The indicators of risk control and employee participation positively impact employee performance, while job satisfaction has a negative impact on performance. These findings indicate that operators should pay more attention to employees' psychological perception of work and form a standardized process management and control plan to prevent cumbersome processes from increasing employees' workload. This study helps construction systems and managers to identify the areas of strengths and weaknesses in their HSE management. The research only focuses on the impact of HSE risks on managers' performance in the complex transport construction project. In the future, further engineering projects and employee performance in composite scenarios can be investigated to improve the overall productivity.


[Preliminary assessment of habitat of juvenile Collichthys lucidus in the Yangtze estuary].
To evaluate the choice preference of fish habitat in the Yangtze estuary, juvenile Collichthys lucidus which is the dominant species in spring was selected. The 4 indicator factors, including abundance of Pseudograpsus albus, salinity, substrate type and water depth, were selected from 19 environmental factors. Then, the indices of the habitat suitability curves of the 4 indicator factors were established, and the HSI of juvenile C. lucidus at each site was calculated. The results indicated that HSI was almost more than 0.5 in North Branch, and less than 0.2 in South Branch. It showed that the North Branch of Yangtze estuary was the main nursery area of C. lucidus. The most suitable growth sector was the area with salinity more than 14, mean grain size of substrate less than 29 μm and water depth 2 to 5 m, which was consistent with the distribution of HSI. The study demonstrated that biological factors could be characterized by the response of juvenile C. lucidus to the environment. Chemical oxygen demand, ammonium nitrogen, total phosphorus and volatile phenol did not have significant correlation with the fish abundance, with which nitrite nitrogen, nitrate nitrogen and total nitrogen had significant positive correlation. It suggested that the eutrophication of the survey area had not damaged the habitat of C. lucidus. However, copper ion and cadmium ion had significant negative correlation with the fish abundance, which indicated that the heavy metal pollution had harmed the growth and distribution of juvenile C. lucidus. It was inferred that the heavy metal pollution was the restrictive factor influencing the fish habitat in Yangtze estuary.


Isolated adenocarcinoma of the nipple.
A 47-year-old female presented with a 1-year history of 'eczematous change' to the right nipple. Bilateral mammography and ultrasound were entirely normal. Free hand biopsy demonstrated invasive adenocarcinoma of the nipple. The patient underwent a right-sided central segmentectomy and sentinel node biopsy. Histology demonstrated that the nipple was almost completely replaced by an invasive ductal carcinoma with a maximum diameter of 13 mm. Invasion of the underlying breast tissue was to a depth of 3 mm. A single sentinel lymph node demonstrated metastatic carcinoma. Her oestrogen receptor status was positive while HER-2 status was negative. The patient subsequently underwent right-sided axillary node clearance to level three nodes. All 17 nodes in the specimen were found to be within normal limits. She is scheduled to undergo radiotherapy, chemotherapy and hormonal treatment.


Characterization of liver zonation-like transcriptomic patterns in HLCs derived from hiPSCs in a microfluidic biochip environment.
The liver zonation is an important phenomenon characterized by a gradient of several functions along the liver acinus. However, this gradient remains difficult to reproduce in in-vitro conditions, making the obtention of an in-vitro method to recapitulate the liver zonation a challenging issue. In this study, we evaluated the spatial evolution of the transcriptome profile of human induced pluripotent stem cells (hiPSCs) differentiated toward hepatocytes-like cells (HLCs) phenotype in a microfluidic biochip environment. Cells collected at the inlet of the biochip, where the oxygen concentration is higher, were identified by the expression of genes involved in metabolic pathways related to cellular reorganization and cell proliferation. Cells collected in the middle and at the outlet of the biochips, where oxygen concentrations are lower, were characterized by the upregulation of genes involved in cellular detoxification processes (CYP450), PPAR signaling or arginine biosynthesis. A subset of 16 transcription factors (TFs) was extracted and identified as upstream regulators to HNF1A and PPARA. These TFs are also known as regulators to target genes engaged in the Wnt/βcatenin pathway, in the TGFβ/BMP/SMAD signaling, in the transition between epithelial mesenchymal transition (EMT) and mesenchymal epithelial transition (MET), in the homeostasis of lipids, bile acids and carbohydrates homeostasis, in drug metabolism, in the estrogen processing and in the oxidative stress response. Overall, the analysis allowed to confirm a partial zonation-like pattern in hiPSCs-derived HLCs in the microfluidic biochip environment. These results provide important insights into the reproduction of liver zonation in-vitro for a better understanding of the phenomenon.


Chemotherapy and radiotherapy in Hodgkin's lymphoma: joining in or splitting up?
Radiotherapy is very effective in local control of Hodgkin's lymphoma. Unfortunately, long-term survivors exhibit an excess of life-threatening radiation-related late side effects. Consequently, there have been calls to cease the use of radiation in the primary treatment of Hodgkin's lymphoma, although there is also support for the judicious use of combined modality treatment. Most patients treated for Hodgkin's lymphoma are being cured with modern approaches. Recent publications confirm the superior efficacy of combined modality treatment over chemotherapy alone, but the initial gain in cure rate may be outweighed by late deaths due to various treatment-related diseases. Many patients may already be cured by chemotherapy alone. Classical risk factors can be used to distinguish favourable and unfavourable subgroups of patients with Hodgkin's lymphoma, but these risk factors cannot predict outcome in individual cases. A simple test to predict the likelihood of cure in individual patients would be of great benefit. Fluoro-deoxyglucose-PET scan investigation holds this promise. The present review deals with the role of radiation therapy in the treatment of Hodgkin's lymphoma.


A lysosome targetable fluorescent probe for endogenous imaging of hydrogen peroxide in living cells.
A lysosome targetable naphthalimide based fluorescent probe (LyNC) has been designed and synthesized which detects hydrogen peroxide (H2O2) with high selectivity and sensitivity in brain tissues and in living nematodes among various ROS/RNS tested. Further, the probe LyNC was successfully employed in exogenous and endogenous imaging of H2O2 in living cell lines.


Effect of up to 3 years of high-dose lansoprazole on Barrett's esophagus.
Barrett's esophagus is a metaplastic condition resulting from gastroesophageal reflux disease. Previous medical and surgical therapies have failed to predictably eradicate Barrett's. The objective of this study was to assess the impact of long-term, high-dose lansoprazole, a proton pump inhibitor, on Barrett's esophagus. Patients with Barrett's esophagus at least 3 cm long and with specialized columnar epithelium were treated with 60 mg of lansoprazole each morning. Every 6 months, patients had standardized symptomatic, laboratory, and endoscopic assessment. The length of Barrett's esophagus was measured, photo-documented, and biopsied. Twenty-seven patients with Barrett's esophagus have been treated an average of 2.9 yr. Symptoms improved (70%, 19 patients), and erosive esophagitis healed (100%, 13 patients), but there was no significant reduction in the length of Barrett's epithelium (mean length at baseline 5.7 cm, final visit 5.3 cm). However, by the final visit, 20 of 26 patients (77%) had squamous islands: two unchanged in size, six with increased surface area, and 12 newly developed on therapy. Initially, mean fasting gastrin levels rose significantly but then plateaued after 1 month of therapy. Of 10 patients with gastrin levels for 18 months or longer, only one had a level > or = 400 pg/ml. Lansoprazole 60 mg for up to 3 yr was safe and effective in controlling symptoms and esophagitis. The impact on the extent of Barrett's esophagus over this time interval was manifested by the extension and development of squamous islands.


URG4 overexpression is correlated with cervical cancer progression and poor prognosis in patients with early-stage cervical cancer.
Upregulator of cell proliferation 4 (URG4) has been implicated in the oncogenesis of certain cancers. However, the correlation between URG4 expression and clinicopathological significance in human cancer remains unclear. Therefore, this study investigated its expression and clinicopathological significance in cervical cancer patients. URG4 expression was examined using quantitative PCR (qPCR) and western blotting in normal cervical epithelial cells, cervical cancer cells, and eight matched pairs of cervical cancer tissues and adjacent noncancerous tissues from the same patient. In addition, immunohistochemistry (IHC) was used to examine URG4 expression in paraffin-embedded tissues from 167 cervical cancer patients (FIGO stages Ib1-IIa2). Statistical analyses were performed to evaluate associations between URG4 expression and prognostic and diagnostic factors. URG4 was significantly upregulated in the cervical cancer cell lines and tissues compared with the normal cells and adjacent noncancerous cervical tissues. IHC revealed high URG4 expression in 59 out of the 167 (35.13%) cervical cancer specimens. Its expression was significantly correlated with clinical stage (P < 0.0001), tumour size (P = 0.012), T classification (P = 0.023), lymph node metastasis (P = 0.001) and vaginal involvement (P = 0.002). Patients with high URG4 expression, particularly those who received concurrent chemotherapy and radiotherapy (P < 0.0001), showed a shorter overall survival (OS) and disease-free survival (DFS) compared to those with the low expression of this protein. Multivariate analysis revealed that URG4 expression is an independent prognostic factor for cervical cancer patients. Our results demonstrated that elevated URG4 protein expression is associated with a poor outcome in patients with early-stage cervical cancer. URG4 may be a novel prognostic marker and therapeutic target for the treatment of cervical cancer.


The adverse effects of sorafenib in patients with advanced cancers.
Sorafenib is the first multi-kinase inhibitor (TKI) approved for the treatment of advanced hepatocellular cancer (HCC) and metastatic renal cell cancer (RCC) and is increasingly being used to treat patients with well-differentiated radioiodine-resistant thyroid cancer (DTC). Sorafenib demonstrates targeted activity on several families of receptor and non-receptor tyrosine kinases that are involved in angiogenesis, tumour growth and metastatic progression of cancer. Sorafenib treatment results in long-term efficacy and low incidence of life-threatening toxicities. Although sorafenib has demonstrated many benefits in patients, the adverse effects cannot be ignored. The most common treatment-related toxicities include diarrhoea, fatigue, hand-foot skin reaction and hypertension. Most of these toxicities are considered mild to moderate and manageable to varying degrees; however, cardiovascular events might lead to death. In this MiniReview, we summarize the adverse effects of sorafenib that commonly occur in patients with advanced cancers.


Different pharmacological properties of the optical isomers of MN9202, a novel 1,4-dihydropyridine Ca+ channel modulator, in rat ventricular myocytes.
1. We have shown previously that 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid pentyl methyl ester (MN9202), a new 1,4-dihydropyridine Ca(2+) channel modulator, has significant hypotensive effects and favourable pharmacokinetic characteristics. As a chiral molecule, MN9202 has two optical isomers. The aim of the present study was to evaluate the pharmacological properties of the two enantiomers. 2. The two enantiomers, S-(-)- and R-(+)-MN9202, were obtained by HPLC. At 1 micromol/L, both racemic MN9202 and S-(-)-MN9202 decreased the contractility of rat ventricular myocytes by 54.0 and 64.4%, respectively, compared with control, whereas R-(+)-MN9202 enhanced cell shortening by 10.1%. At 1 micromol/L, racemic MN9202 markedly reduced calcium transient (CaT) and L-type Ca(2+) channel current (I(Ca,L)) by 60.0 and 50.7%, respectively, whereas the reductions in CaT and I(Ca,L) produced by 1 micromol/L S-(-)-MN9202 were greater still (62.2 and 65.7%, respectively). In contrast, 1 micromol/L R-(+)-MN9202 increased CaT and I(Ca,L) by 11.4 and 10.6%, respectively. Furthermore, findings from kinetics studies of I(Ca,L) revealed that the steady state inactivation curve of I(Ca,L) was shifted towards a hyperpolarizing potential by S-(-)-MN9202, but towards a depolarizing potential by R-(+)-MN9202. These results demonstrate different effects of R-(+)-MN9202 and S-(-)-MN9202. 3. In conclusion, the findings of the present study suggest that the chirality of MN9202 results in opposing pharmacological properties of its two enantiomers: S-(-)-MN9202 may be responsible for the therapeutic effects of racemic MN9202, whereas R-(+)-MN9202 contributes to it unwanted effects. The findings of the present study also indicate that MN9202 may be used as a new probe with which to investigate the structure-function relationships of Ca(2+) channels.


Assembly of bacteriophage lambda terminase into a viral DNA maturation and packaging machine.
Terminase enzymes are common to complex double-stranded DNA viruses and function to package viral DNA into the capsid. We recently demonstrated that the bacteriophage lambda terminase gpA and gpNu1 proteins assemble into a stable heterotrimer with a molar ratio gpA1/gpNu1(2). This terminase protomer possesses DNA maturation and packaging activities that are dependent on the E. coli integration host factor protein (IHF). Here, we show that the protomer further assembles into a homogeneous tetramer of protomers of composition (gpA1/gpNu1(2))4. Electron microscopy shows that the tetramer forms a ring structure large enough to encircle duplex DNA. In contrast to the heterotrimer, the ring tetramer can mature and package viral DNA in the absence of IHF. We propose that IHF induced bending of viral DNA facilitates the assembly of four terminase protomers into a ring tetramer that represents the catalytically competent DNA maturation and packaging complex in vivo. This work provides, for the first time, insight into the functional assembly state of a viral DNA packaging motor.


Gorlin-Goltz syndrome.
A 12 years old girl was presented with bilateral swellings on angle and body of mandible. On general physical examination, there were polydactyly and papular lesions on arm. Histopathology of mandibular lesions revealed odontogenic keratocysts. Marsupialization of the cysts followed by enucleation was done. The patient was reviewed every six months and there was no recurrence at the end of two years.


Proofreading DNA: recognition of aberrant DNA termini by the Klenow fragment of DNA polymerase I.
Fluorescence depolarization decays were measured for 5-dimethylaminonaphthalene-1-sulfonyl (dansyl) probes attached internally to 17-mer.27-mer oligonucleotides bound to Klenow fragment of DNA polymerase I. The time-resolved motions of the dansyl probes were sensitive indicators of DNA-protein contacts, showing that the protein binds to DNA with two footprints, corresponding to primer termini at either the polymerase or 3'-5' exonuclease sites. We examined complexes of Klenow fragment with DNAs containing various base mismatches. Single mismatches at the primer terminus caused a 3- to 4-fold increase in the equilibrium partitioning of DNA into the exonuclease site; the largest effects were observed for purine-purine mismatches. Two or more consecutive G.G mismatches caused the DNA to bind exclusively at the exonuclease site, with a partitioning constant at least 250-fold greater than that of the corresponding matched DNA sequence. Internal single mismatches produced larger effects than the same mismatch at the primer terminus, with a delta delta G relative to the matched sequence of -1.1 to -1.3 kcal/mol for mismatches located 2, 3, or 4 bases from the primer terminus. Although part of the observed effects may be attributed to the increased melting capacity of the DNA, it appears that the polymerase site also promotes movement of DNA into the exonuclease site by rejecting aberrant primer termini. These effects suggest that the polymerase and exonuclease sites act together to recognize specific errors that distort the primer terminus, such as frameshifts, in addition to proofreading misincorporated bases.


Serious safety events: Getting to Zero™.
To advance the goal of Getting to Zero and eliminating preventable harm, ASHRM is providing guidance for defining, investigating, and measuring serious safety events. The first step in this process is the recommendation for a common and standardized definition. A common definition for a serious safety event facilitates timely detection, rapid action, and future prevention. This paper outlines that definition, provides a skill-based model for investigation, and explains a clear plan for how to conduct the investigation. A measurement system is described to determine the frequency of SSEs and comparison methods to determine events prevented, potential lives saved, and methods to demonstrate financial loss control. These methods and approach are consistent with ASHRM's core values and mission, which is safe and trusted healthcare.


[Measurements of prostatic acid phosphatase and prostate specific antigen by fully automated enzyme immunoassay system--its analytical and clinical evaluation].
Analytical and clinical evaluations were made on the measurement of prostatic acid phosphatase (PAP) and prostate specific antigen (PA) by a fully automated enzyme immunoassay system. Results concerning reproducibility, recovery and sensitivity were good. PAP values by this method correlated well with those obtained by radioimmunoassay. PA values by this method were higher than those obtained by other enzyme immunoassays, although the correlation coefficient was high. PAP, PA and gamma-Seminoprotein (gamma-Sm), another prostatic tumor marker, were all poorly correlated to one another. Normal upper value, 2 SD of 720 healthy males was 1.2 ng/ml for PAP, and 3.7 ng/ml for PA. Positive ratios of these tests in 31 patients with prostatic carcinoma were high at advanced stages, and low at early stages. ROC (receiver operating characteristics) curve analysis on patients with prostatic carcinoma and benign prostatic hypertrophy indicated that PAP and PA were more effective than gamma-Sm for the differential diagnosis of prostatic carcinoma, and that the clinical cut off was 2.0 ng/ml for PAP, 7.4 ng/ml for PA and 4.0 ng/ml for gamma-Sm.


Contrast perception as a visual heuristic in the formulation of referential expressions.
We hypothesize that contrast perception works as a visual heuristic, such that when speakers perceive a significant degree of contrast in a visual context, they tend to produce the corresponding adjective to describe a referent. The contrast perception heuristic supports efficient audience design, allowing speakers to produce referential expressions with minimum expenditure of cognitive resources, while facilitating the listener's visual search for the referent. We tested the perceptual contrast hypothesis in three language-production experiments. Experiment 1 revealed that speakers overspecify color adjectives in polychrome displays, whereas in monochrome displays they overspecified other properties that were contrastive. Further support for the contrast perception hypothesis comes from a re-analysis of previous work, which confirmed that color contrast elicits color overspecification when detected in a given display, but not when detected across monochrome trials. Experiment 2 revealed that even atypical colors (which are often overspecified) are only mentioned if there is color contrast. In Experiment 3, participants named a target color faster in monochrome than in polychrome displays, suggesting that the effect of color contrast is not analogous to ease of production. We conclude that the tendency to overspecify color in polychrome displays is not a bottom-up effect driven by the visual salience of color as a property, but possibly a learned communicative strategy. We discuss the implications of our account for pragmatic theories of referential communication and models of audience design, challenging the view that overspecification is a form of egocentric behavior.


A least angle regression model for the prediction of canonical and non-canonical miRNA-mRNA interactions.
microRNAs (miRNAs) are short non-coding RNAs with regulatory functions in various biological processes including cell differentiation, development and oncogenic transformation. They can bind to mRNA transcripts of protein-coding genes and repress their translation or lead to mRNA degradation. Conversely, the transcription of miRNAs is regulated by proteins including transcription factors, co-factors, and messenger molecules in signaling pathways, yielding a bidirectional regulatory network of gene and miRNA expression. We describe here a least angle regression approach for uncovering the functional interplay of gene and miRNA regulation based on paired gene and miRNA expression profiles. First, we show that gene expression profiles can indeed be reconstructed from the expression profiles of miRNAs predicted to be regulating the specific gene. Second, we propose a two-step model where in the first step, sequence information is used to constrain the possible set of regulating miRNAs and in the second step, this constraint is relaxed to find regulating miRNAs that do not rely on perfect seed binding. Finally, a bidirectional network comprised of miRNAs regulating genes and genes regulating miRNAs is built from our previous regulatory predictions. After applying the method to a human cancer cell line data set, an analysis of the underlying network reveals miRNAs known to be associated with cancer when dysregulated are predictors of genes with functions in apoptosis. Among the predicted and newly identified targets that lack a classical miRNA seed binding site of a specific oncomir, miR-19b-1, we found an over-representation of genes with functions in apoptosis, which is in accordance with the previous finding that this miRNA is the key oncogenic factor in the mir-17-92 cluster. In addition, we found genes involved in DNA recombination and repair that underline its importance in maintaining the integrity of the cell.


A method of outdoor housing dairy calves in pairs using individual calf hutches.
Interest in housing dairy calves in groups is currently growing. Group housing using individual calf hutches, a resource already available in most dairy farms in North America, could provide a novel housing method that can be a simple way to implement group housing on farm. The main objective of this study was to determine whether pair housing dairy calves in hutches outdoors would result in similar weight gain and milk intake compared with individual housing in hutches. The study was designed to avoid competition for resources (including milk and solid feed, teat, bucket, outdoor space, and hutch) to test a setup that has the potential to maximize performance and calf growth. Secondary objectives were to document how calves in both treatments use their environment in terms of time spent and behaviors performed in each area, how paired calves interact, and the time they spend together. Single calves (n = 6/season) were housed in 1 hutch with an attached outdoor environment; paired calves (n = 6 pairs/season) were given twice the resources. Calves were fed up to 16 L/d of milk replacer. Daily milk intake and weekly weight gains were recorded. Behavioral observations were recorded live once per week for 5 (summer) or 4 (winter) nonconsecutive periods. Paired and single calves had similar weight gain (averaging from 1.1 to 1.3 kg/d across trials) and milk intake (averaging from 11.1 to 13.7 kg/d across trials), showing no difference in performance between treatments. Low occurrences of cross sucking (averaging from 0.1 to 0.4 bouts/h of observation per pen across trials) and displacements at the teat (0.8 to 1.4 bouts/h of observation per pen across trials) were found. All calves altered their behavior in some way to accommodate companions; paired calves were seen interacting and spending time together (i.e., lying in the same hutch), and in the summer trial single calves spent less time lying inside the hutch than paired calves, presumably to have visual access to other calves. The solution of mixed indoor and outdoor housing environments tested as part of this study showed that calves make use of all spaces provided to them in winter and in summer conditions while maintaining good performance. Housing calves in pairs using individual hutches can be a suitable alternative to housing calves individually in hutches outdoors.


Multiple isoforms of mitochondrial glutathione S-transferases and their differential induction under oxidative stress.
The mitochondrial respiratory chain, which consumes approx. 85-90% of the oxygen utilized by cells, is a major source of reactive oxygen species (ROS). Mitochondrial genetic and biosynthetic systems are highly susceptible to ROS toxicity. Intramitochondrial glutathione (GSH) is a major defence against ROS. In the present study, we have investigated the nature of the glutathione S-transferase (GST) pool in mouse liver mitochondria, and have purified three distinct forms of GST: GSTA1-1 and GSTA4-4 of the Alpha family, and GSTM1-1 belonging to the Mu family. The mitochondrial localization of these multiple GSTs was confirmed using a combination of immunoblot analysis, protease protection assay, enzyme activity, N-terminal amino acid sequencing, peptide mapping and confocal immunofluorescence analysis. Additionally, exogenously added 4-hydroxynonenal (HNE), a reactive byproduct of lipid peroxidation, to COS cells differentially affected the cytosolic and mitochondrial GSH pools in a dose- and time-dependent manner. Our results show that HNE-mediated mitochondrial oxidative stress caused a decrease in the GSH pool, increased membrane lipid peroxidation, and increased levels of GSTs, glutathione peroxidase and Hsp70 (heat-shock protein 70). The HNE-induced oxidative stress persisted for longer in the mitochondrial compartment, where the recovery of GSH pool was slower than in the cytosolic compartment. Our study, for the first time, demonstrates the presence in mitochondria of multiple forms of GSTs that show molecular properties similar to those of their cytosolic counterparts. Our results suggest that mitochondrial GSTs may play an important role in defence against chemical and oxidative stress.


Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia.
Preeclampsia is a hypertensive disorder of pregnancy in which patients develop profound sensitivity to vasopressors, such as angiotensin II, and is associated with substantial morbidity for the mother and fetus. Enhanced vasoconstrictor sensitivity and elevations in soluble fms-like tyrosine kinase 1 (sFLT1), a circulating antiangiogenic protein, precede clinical signs and symptoms of preeclampsia. Here, we report that overexpression of sFlt1 in pregnant mice induced angiotensin II sensitivity and hypertension by impairing endothelial nitric oxide synthase (eNOS) phosphorylation and promoting oxidative stress in the vasculature. Administration of the NOS inhibitor l-NAME to pregnant mice recapitulated the angiotensin sensitivity and oxidative stress observed with sFlt1 overexpression. Sildenafil, an FDA-approved phosphodiesterase 5 inhibitor that enhances NO signaling, reversed sFlt1-induced hypertension and angiotensin II sensitivity in the preeclampsia mouse model. Sildenafil treatment also improved uterine blood flow, decreased uterine vascular resistance, and improved fetal weights in comparison with untreated sFlt1-expressing mice. Finally, sFLT1 protein expression inversely correlated with reductions in eNOS phosphorylation in placental tissue of human preeclampsia patients. These data support the concept that endothelial dysfunction due to high circulating sFLT1 may be the primary event leading to enhanced vasoconstrictor sensitivity that is characteristic of preeclampsia and suggest that targeting sFLT1-induced pathways may be an avenue for treating preeclampsia and improving fetal outcomes.


Organ preservation in success of cadaver transplants.
The long-term function of 110 cadaver kidney transplants preserved by hypothermic perfusion was compared with that of 79 fresh cadaver kidneys. The one-month failure rate was 4 percent in the perfused kidneys in contrast to a 32 percent one-month failure rate reported by one cooperative group. These data were again confirmed in a prospective, paired study comparing perfused and fresh cadaver kidneys from the same donor. Thus, perfusion of kidneys was not harmful for cadaver transplantation. In fact, of 83 first cadaver transplants, less than 30 percent of perfused kidneys failed in the first year. There appears to be no evidence supporting the idea that bloodless hypothermic perfusion permanently damages human kidneys or increases the chances of rejection.


The novel anticytomegalovirus compound AIC246 (Letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase.
Human cytomegalovirus (HCMV) remains the leading viral cause of birth defects and life-threatening disease in transplant recipients. All approved antiviral drugs target the viral DNA polymerase and are associated with severe toxicity issues and the emergence of drug resistance. Attempts to discover improved anti-HCMV drugs led to the identification of the small-molecular-weight compound AIC246 (Letermovir). AIC246 exhibits outstanding anti-HCMV activity in vitro and in vivo and currently is undergoing a clinical phase IIb trial. The initial mode-of-action studies suggested that the drug acts late in the HCMV replication cycle via a mechanism distinct from that of polymerase inhibitors. Here, we extend our mode-of-action analyses and report that AIC246 blocks viral replication without inhibiting the synthesis of progeny HCMV DNA or viral proteins. The genotyping of mutant viruses that escaped AIC246 inhibition uncovered distinct point mutations in the UL56 subunit of the viral terminase complex. Marker transfer analyses confirmed that these mutations were sufficient to mediate AIC246 resistance. The mapping of drug resistance to open reading frame UL56 suggests that viral DNA processing and/or packaging is targeted by AIC246. In line with this, we demonstrate that AIC246 affects the formation of proper unit-length genomes from viral DNA concatemers and interferes with virion maturation. However, since AIC246-resistant viruses do not exhibit cross-resistance to previously published terminase inhibitors, our data suggest that AIC246 interferes with HCMV DNA cleavage/packaging via a molecular mechanism that is distinct from that of other compound classes known to target the viral terminase.


Extracorporeal irradiation of tumorous calvaria: a case series.
OBJECT When intracranial tumors invade the overlying skull, gross resection typically includes removal of the involved bone. Methods used to repair the resulting structural defect in the cranium include artificial prostheses, allogeneic bone grafts, and autoclaving the autologous graft. The authors have previously reported a case involving high-dose extracorporeal ionizing radiation to treat the tumorous calvaria intraoperatively, followed by reimplantation of the treated bone flap. In this paper the authors report the long-term follow-up of that case, as well as results of using extracorporeal irradiation of tumorous calvaria (EITC) for an additional 20 patients treated similarly. METHODS The decision to undergo EITC was typically anticipated preoperatively, but determined intraoperatively, if upon inspection the bone flap was invaded by tumor. The bone flap was then delivered to the radiation oncology department, where a total dose of 120 Gy was delivered, using a clinical linear accelerator, over a period of approximately 15 minutes. After the intracranial tumor resection was completed, the irradiated craniotomy bone flap was reimplanted and the wound was closed in a standard fashion. A retrospective review of patients who had undergone EITC was performed for evidence of calvarial tumor recurrence or other complications. RESULTS Since the originally reported case, 20 additional patients have received EITC during craniotomy for invasive tumors. Eighteen (86%) of 21 patients were diagnosed with meningioma: 12 (67%) with WHO Grade I, 5 (28%) with WHO Grade II, and 1 with WHO Grade III (6%). The remaining 3 patients presented with dural-based B-cell lymphoma with extensive adjacent bone invasion (n = 2) and metastatic adenocarcinoma of the lung (n = 1). Follow-up of the 21 patients ranged from 1 to 132 months, with a mean of 41 months and a median of 23 months. No patients have experienced tumor recurrence, infection associated with the treated calvaria, or evidence of bone flap resorption. CONCLUSIONS Calvaria reconstructions represent an important component in structural and cosmetic outcome following craniectomy for tumorous bone. The authors' long-term experience with EITC has been excellent with no local tumor recurrence or complications. Therefore, EITC represents an excellent and efficient option for cranial reconstruction in such patients.


New insights into the biological and clinical significance of fecal calprotectin in inflammatory bowel disease.
Nowadays, calprotectin, a cytoplasmatic protein, released by activated neutrophilic polymorphonuclear cells (PMN) and/or monocytes-macrophages (MØ), is considered a good indicator of inflammation in several diseases. Accordingly, fecal calprotectin represents a good predictor of clinical relapse in ulcerative colitis (UC) patients, whereas conflicting results have been reported in Crohn's disease (CD) patients. In our study, in 76 IBD patients (29 CD and 47 UC) fecal calprotectin has been evaluated by a commercial ELISA kit. Results demonstrate that levels of this protein in the stool are significantly more elevated in active CD and UC patients than in normal volunteers. In quiescent CD and UC a trend to higher levels of calprotectin than in the normal counterpart is, however, evident. These data suggest that a low-grade inflammation of the intestinal wall is always present in CD and UC patients, which may predict a clinical relapse risk. In the same group of patients calprotectin levels also were analyzed according to sex and age. A trend to higher values of calprotectin was present in male patients with active or quiescent CD than in their female counterparts. Only in UC patients in remission a trend to calprotectin increase was more marked in the male group than in the female counterpart. When CD and UC patients were divided up according to age, calprotectin positivity peaked between 30-39 years in active CD patients, while in quiescent CD maximum positivity was between 40 and 49 years. However, in both active and quiescent UC patients, calprotectin positivity increased with age. The more precocious detectability of fecal calprotectin in CD patients, as a marker of intestinal mucosa inflammation, may be related to the different histopathology of the two diseases (CD versus UC). However, reduced PMN and/or MØ trafficking from peripheral blood to intestinal mucosa with age by effects of chronic treatment should not be ignored in CD patients.


From the roots of parasitology: Hippocrates' first scientific observations in helminthology.
Although knowledge of intestinal parasites predates Hippocrates, the Hippocratic Corpus provides the first scientific observations about the clinical perception and treatment of helminthic diseases. These observations follow the scientific principles of Hippocrates, the father of modern medicine, who relied on knowledge and observation. This article is based on a systematic study of the Hippocratic texts, and presents observations on diseases caused by intestinal parasites with respect to regularity of appearance, patient age, symptoms, and treatment. Three types of helminths are described: "helmins strongyle" (roundworm), "helmins plateia" (flatworm), and "ascaris" (which corresponds to Enterobius vermicularis). Helminthic diseases primarily appear during childhood, well after teething. The described systemic symptoms include weakness, sickness, discomfort, tiredness, anorexia, and emotional instability; gastrointestinal symptoms include change in bowel movements, vomiting, and colic pain in the epigastrium. We identified several accounts of cases of helminthic diseases in the Hippocratic texts. Of particular interest are the descriptions of a helminth emerging from a fistula in the navel region and the surgical treatment of helminthic diseases, reinforced by being described on a dedicatory inscription at the Asclepion in Epidaurus. We finally encountered the use of powerful purgatives as antihelminthics, which have been widely used, even into the 21st century.


Optimizing and evaluating biomarker combinations as trial-level general surrogates.
We extend the method proposed in a recent work by the Authors for trial-level general surrogate evaluation to allow combinations of biomarkers and provide a procedure for finding the "best" combination of biomarkers based on the absolute prediction error summary of surrogate quality. We use a nonparametric Bayesian model that allows us to select an optimal subset of biomarkers without having to consider a large number of explicit model specifications for that subset. This dramatically reduces the number of model comparisons needed. Given the model's flexibility, complex nonlinear relationships can be fit when enough data are available. We evaluate the operating characteristics of our proposed method in simulations designed to be similar to our motivating example. We use our method to compare and evaluate combinations of biomarkers as trial-level general surrogates for the pentavalent rotavirus vaccine RotaTeq™ (RV5) (Merck & Co, Inc, Kenilworth, New Jersey, USA), finding that the same single biomarker identified in our previously published analysis is likely the optimal subset.


New insights in the genetics of isolated hypogonadotropic hypogonadism.
Isolated gonadotropic deficiency or isolated hypogonadotropic hypogonadism is defined as a low sexual hormone secretion by the gonads associated with low LH and FSH plasma levels. Kallmann syndrome is defined as a congenital isolated gonadotropic deficiency associated with anosmia whereas the phenotype of the idiopathic form is limited to the gonadotropic axis. For several years, it has been known that mutations of the KAL-1 gene or loss-of-function mutations of GnRH receptor did not explain all familial cases of isolated gonadotropic deficiency with or without anosmia. Thus the existence of other genes playing a major role in the physiology of the gonadotropic axis was highly suggested. In 2003, fibroblast growth factor receptor 1 (FGFR1) and GPR54 were shown to be two of these genes. FGFR1 loss-of-function mutations were reported in Kallmann syndrome whereas inactivating mutations of GPR54 were described in the idiopathic form of the gonadotropic deficiency. These genetic studies have opened up a new chapter in the physiology and the pharmacology of the gonadotropic axis.


No support for dual process accounts of human affective learning in simple Pavlovian conditioning.
Dual process accounts of affective learning state that the learning of likes and dislikes reflects a learning mechanism that is distinct from the one reflected in expectancy learning, the learning of signal relationships, and has different empirical characteristics. Affective learning, for example, is said not to be affected by: (a) extinction training; (b) occasion setting; (c) cue competition; and (d) awareness of the CS-US contingencies. These predictions were tested in a series of experiments that employed simple Pavlovian conditioning procedures. Neutral visual pictures of geometric shapes, or tactile conditional stimuli (CS) were paired with aversive electrotactile unconditional stimuli (US). Dependent measures were physiological (skin conductance, blink startle modulation) or verbal (US expectancy, on-line and off-line ratings of CS pleasantness). Different combinations of these dependent measures were employed across different experiments in an attempt to assess affective and expectancy learning simultaneously. Changes in CS pleasantness as indexed by ratings or blink startle modulation were readily observed. However, contrary to the predictions from dual-process accounts, results indicated that acquired CS unpleasantness is subject to extinction, occasion setting, cue competition, and not found in absence of CS-US contingency awareness.


Three-dimensional subwavelength imaging by a photonic-crystal flat lens using negative refraction at microwave frequencies.
We experimentally demonstrate subwavelength resolution imaging at microwave frequencies by a three-dimensional (3D) photonic-crystal flat lens using full 3D negative refraction. The photonic crystal was fabricated in a layer-by-layer process. A subwavelength pinhole source and a dipole detector were employed for the measurement. By point-by-point scanning, we obtained the image of the pinhole source shown in both amplitude and phase, which demonstrated the imaging mechanism and subwavelength feature size in all three dimensions. An image of two pinhole sources with subwavelength spacing showed two resolved spots, which further verified subwavelength resolution.


Measuring the quality of medical care. A clinical method.
We outline the implementation of a new method of measuring the quality of medical care that counts cases of unnecessary disease and disability and unnecessary untimely deaths. First of all, conditions are listed in which the occurrence of a single case of disease or disability or a single untimely death would justify asking, "Why did it happen?" Secondly, we have selected conditions in which critical increases in rates of disease, disability, or untimely death could serve as indexes of the quality of care. Finally, broad categories of illness are noted in which redefinition and intensive study might reveal characteristics that could serve as indexes of health. We describe how these inth of the general population and the effects of economic, political, and other environmental factors upon it, and to evaluate the quality of medical care provided both within and without the hospital to maintain health and to prevent and treat disease.


The relationships among depression, pain, and masticatory functioning in temporomandibular disorder patients.
To evaluate the effect of comorbid depression and pain on an early biopsychosocial intervention for acute temporomandibular disorder (TMD) patients. Depressed (either current or lifetime; n=32) or nondepressed (n=31) acute TMD patients received a biopsychosocial intervention, and were evaluated at preintervention and again 12 months postintervention by Characteristic Pain Intensity, the Beck Depression Inventory, and a masticatory function test. Findings revealed that both depressed and nondepressed patients reported comparable pain decreases at 12 months postintervention. Moreover, there were no significant differences between patient groups in masticatory function. With appropriate early biopsychosocial intervention, acute TMD patients, regardless of the presence or absence of vulnerability to depression symptomatology, can be effectively treated.


Microbial cellulose as a specialty chemical.
Microbial polysaccharides are extensively used commercially as gelling or suspending agents, as protective colloids or as thickening agents. Until recently, microbial cellulose producing systems such as Acetobacter xylinum, had been used largely as model systems for the study of cellulose biosynthesis. Current advances in molecular biology and biochemical engineering promise to usher microbial cellulose into the specialty chemical market. This review will highlight some of the recent progress made in our understanding of microbial cellulose biochemistry and biosynthesis, describe some of its inherent virtues and identify current unique applications of this versatile biopolymer.