Mechanics of graphyne crumpling.
The recent capability of synthesizing large-scale crumpled graphene-related 2D materials has motivated intensive efforts to boost its promising applications in electronics, energy storage, composites and biomedicine. As deformation of graphene-related 2D materials can strongly affect their properties and the performance of graphene-based devices and materials, it is highly desirable to attain subtle control of reversible wrinkling and crumpling of graphene. Graphyne, a 2D lattice of sp(2)- and sp(1)-hybridized carbons similar to graphene, has remained unexplored with respect to its crumpling behavior. Here we employ molecular dynamics simulation to explore the behavior of graphynes under geometric confinement across various temperatures, sizes, and crumpling rates and compare them to graphene under the same conditions, with a focus on the mechanical stabilizing mechanisms and properties of the crumpled structures. The lower density of graphynes creates less deformation-induced bending energy than graphene; as such the graphynes exhibit a markedly increased propensity for stable crumpling. It is also shown that the crumpled 2D carbon materials demonstrate the hardness and bulk modulus of an equivalent magnitude with crumpled graphene, with the most important behavior-determining factor being the number of linking sp(1)-hybridized carbons in the material. Our results show that irrespective of the initial geometry and crumpling rate, the final structures present intriguing and useful properties which can be incorporated into crumpled graphene structures.


Unified Mechanism of Oxygen Atom Transfer and Hydrogen Atom Transfer Reactions with a Triflic Acid-Bound Nonheme Manganese(IV)-Oxo Complex via Outer-Sphere Electron Transfer.
Outer-sphere electron transfer from styrene, thioanisole, and toluene derivatives to a triflic acid (HOTf)-bound nonheme Mn(IV)-oxo complex, [(N4Py)MnIV(O)]2+-(HOTf)2 (N4Py = N, N-bis(2-pyridylmethyl)- N-bis(2-pyridyl)methylamine), has been shown to be the rate-determining step of different types of redox reactions such as epoxidation, sulfoxidation, and hydroxylation of styrene, thioanisole, and toluene derivatives, respectively, by [(N4Py)MnIV(O)]2+-(HOTf)2. The rate constants of HOTf-promoted epoxidation of all styrene derivatives with [(N4Py)MnIV(O)]2+ and electron transfer from electron donors to [(N4Py)MnV(O)]2+ exhibit a remarkably unified correlation with the driving force of outer-sphere electron transfer in light of the Marcus theory of electron transfer. The same electron-transfer driving force dependence is observed in the oxygen atom transfer from [(N4Py)MnIV(O)]2+-(HOTf)2 to thioanisole derivatives as well as in the hydrogen atom transfer from toluene derivatives to [(N4Py)MnIV(O)]2+-(HOTf)2. Thus, mechanisms of oxygen atom transfer (epoxidation and sulfoxidation) reactions of styrene and thioanisole derivatives and hydrogen atom transfer (hydroxylation) reactions of toluene derivatives by [(N4Py)MnIV(O)]2+-(HOTf)2 have been unified for the first time as the same reaction pathway via outer-sphere electron transfer, followed by the fast bond-forming step, which exhibits the singly unified electron-transfer driving force dependence of the rate constants as outer-sphere electron-transfer reactions. In the case of the epoxidation of cis-stilbene by [(N4Py)MnIV(O)]2+-(HOTf)2, the isomerization of cis-stilbene radical cation to trans-stilbene radical cation occurs after outer-sphere electron transfer from cis-stilbene to [(N4Py)MnIV(O)]2+-(HOTf)2 to yield trans-stilbene oxide selectively, which is also taken as evidence for the occurrence of electron transfer in the acid-catalyzed epoxidation.


Probing the Monophyly of the Sphaeropleales (Chlorophyceae) Using Data From Five Genes.
Molecular phylogenetic analyses have had a major impact on the classification of the green algal class Chlorophyceae, corroborating some previous evolutionary hypotheses, but primarily promoting new interpretations of morphological evolution. One set of morphological traits that feature prominently in green algal systematics is the absolute orientation of the flagellar apparatus in motile cells, which correlates strongly with taxonomic classes and orders. The order Sphaeropleales includes diverse green algae sharing the directly opposite (DO) flagellar apparatus orientation of their biflagellate motile cells. However, algae across sphaeroplealean families differ in specific components of the DO flagellar apparatus, and molecular phylogenetic studies often have failed to provide strong support for the monophyly of the order. To test the monophyly of Sphaeropleales and of taxa with the DO flagellar apparatus, we conducted a molecular phylogenetic study of 16 accessions representing all known families and diverse affiliated lineages within the order, with data from four plastid genes (psaA, psaB, psbC, rbcL) and one nuclear ribosomal gene (18S). Although single-gene analyses varied in topology and support values, analysis of combined data strongly supported a monophyletic Sphaeropleales. Our results also corroborated previous phylogenetic hypotheses that were based on chloroplast genome data from relatively few taxa. Specifically, our data resolved Volvocales, algae possessing predominantly biflagellate motile cells with clockwise (CW) flagellar orientation, as the monophyletic sister lineage to Sphaeropleales, and an alliance of Chaetopeltidales, Chaetophorales, and Oedogoniales, orders having multiflagellate motile cells with distinct flagellar orientations involving the DO and CW forms.


Realities and challenges of breastfeeding policy in the context of HIV: a qualitative study on community perspectives on facilitators and barriers related to breastfeeding among HIV positive mothers in Baringo County, Kenya.
Although recent policies have sought to increase the rates of exclusive breastfeeding (EBF) and continued breastfeeding for HIV exposed infants, few programs have considered the multiple social and cultural barriers to the practice. Therefore, to generate evidence for exclusive and continued breastfeeding policies in Kenya, we examined community perspectives on the facilitators and barriers in adherence to EBF for the HIV positive mothers. Qualitative research was conducted in Koibatek, a sub-County in Baringo County Kenya, in August 2014 among 205 respondents. A total of 14 focus group discussions (n = 177), 14 In-depth Interviews and 16 key informant interviews were conducted. Transcribed data was analyzed thematically. NVivo version 10.0 computer qualitative software program was used to manage and facilitate the analysis. Facilitators to exclusive breastfeeding were perceived to include counselling at the health facility, desire to have a healthy baby, use of antiretroviral drugs and health benefits associated with breastmilk. Barriers to EBF included poor dissemination of policies, knowledge gap, misinterpretation of EBF, inadequate counselling, attitude of mother and health workers due to fear of vertical HIV transmission, stigma related to misconception and misinformation that EBF is only compulsory for HIV positive mothers, stigma related to HIV and disclosure, social pressure, lack of male involvement, cultural practices and traditions, employment, food insecurity. There are multiple facilitators and barriers of optimal breastfeeding that needs a holistic approach to interventions aimed at achieving elimination of mother to child transmission. Extension of infant feeding support in the context of HIV to the community while building on existing interventions such as the Baby Friendly Community Initiative is key to providing confidential support services for the additional needs faced by HIV positive mothers.


High dose chemotherapy without hematopoietic cell support for the treatment of refractory lymphoma.
Conventional dose combination chemotherapy for patients with relapsed or refractory lymphoma is rarely curative. High dose chemotherapy followed by hematopoietic progenitor cell transplant (HPCT) has a clearly defined role in patients who have first relapsed after standard CHOP chemotherapy for lymphoma. However, the role of HPCT is less well defined for patients with chemo-resistant, or chemo-refractory disease. Sixteen patients (15 Non-Hodgkin's, 1 Hodgkin's Disease) were entered into a phase II study to determine if a dose intensive induction regimen in heavily pre-treated refractory lymphoma patients could permit further consolidation with HPCT. The primary endpoints were survival, response, toxicity, and resource utilization. The regimen consisted of continuous infusion etoposide 1 or 2 gm/m2/72 hours, idarubicin 12 mg/m2/d for 3 days followed by cytarabine 2 gm/m2/72 hours on days 8, 9, and 10 (VIC). Fifteen patients were evaluable for objective response. The overall response rate was 53% with 7 patients achieving a partial response and 1 patient achieving a complete response. Of the 8 responders, 6 patients subsequently received high dose chemotherapy followed by HPCT (4 autologous, 2 allogeneic). The median survival was 176 days for the non-responders contrasted with 722 days for the responders. The average duration of hospitalization was 38 days. Toxicity was mainfest primarily as mucositis with a median grade of 3 among the first 13 patients, and a median grade of 2 in three subsequent patients who received an etoposide dose of 1 gm/m2/72 hours. All patients had an episode of neutropenic fever and 5 patients developed clinically significant pneumonitis during therapy. The VIC regimen is active in the treatment of chemo-refractory lymphoma with clinically significant differences in survival for patients who respond to therapy. Further modifications to the regimen could include the addition of a topoisomerase I inhibitor for synergy with etoposide, and using VIC as part of a tandem transplant regimen where response to VIC would allow further therapy with a myeloablative induction followed by HPCT.


Role of maspin in tumor metastasis and angiogenesis.
Cancer is one of the leading causes of mortality in developed countries such as the USA. In 1998, there were more than 280,000 and 250,000 cancer related deaths in males and females, respectively. In males, lung and prostate cancers accounted for almost half of these deaths, whereas in females, lung and breast cancers were the leading causes of cancer mortalities. Therefore, the study of cancer has been of the utmost importance to patients, doctors, and researchers alike. A variety of cellular processes occur in the precancerous cells that contribute to the development and progression to cancer. Not surprisingly, all of these cellular processes have been targeted for anticancer therapy. A novel serpin, maspin, has demonstrated a robust effect on a variety of these cancer progression steps. A number of studies have shown that maspin inhibits angiogenesis and tumor cell growth and invasion both in vitro and in vivo. In addition, maspin promotes cell adhesion to the basement membrane and extracellular matrix components. Efforts underway to understand the molecular mechanisms involved in the diverse functions influenced by maspin have yielded promising results and shed light on the cancer pathways.


Synthesis, Characterization and Crystal Structures of Schiff Base Copper Complexes with Urease Inhibitory Activity.
Urease inhibitors can inhibit the decomposition rate of urea, and decrease the air pollution caused by ammonia. In this paper, four new copper(II) complexes [CuL(ONO2)]n (1), [Cu2L2(μ1,3-N3)2] (2), [CuBrL] (3), and [CuClL] (4), where L = 5-bromo-2-(((2-methylamino)ethyl)imino)methyl)phenolate, have been synthesized and characterized. The complexes were characterized by elemental analyses, IR and UV-Vis spectroscopy, molar conductivity, and single crystal X-ray diffraction. X-ray analysis reveals that Cu atoms in complexes 1 and 2 are in square pyramidal coordination, and those in complexes 3 and 4 are in square planar coordination. The molecules of the complexes are linked through hydrogen bonds and π···π interactions. The inhibitory effects of the complexes on Jack bean urease were studied, which showed that the complexes have effective activity on urease.


Clinical and pathological changes in the knee after accidental chlorhexidine irrigation during arthroscopy. Case reports and review of the literature.
We describe six knees in five patients, referred to us after accidental irrigation with chlorhexidine 1% in aqueous solution during arthroscopy. All six knees developed persisting pain, swelling and crepitus with loss of range of movement. Radiographs showed loss of joint space in all three compartments due to extensive chondrolysis, with many loose bodies and synovitis. Histological examination showed partial necrosis of the cartilage, with slight non-specific inflammation and fibrosis of synovial specimens. Care is needed in checking irrigation fluids, and these should have a distinctive colour.


COVID-19-related headache and sinonasal inflammation: A longitudinal study analysing the role of acute rhinosinusitis and ICHD-3 classification difficulties in SARS-CoV-2 infection.
The genesis of headache in coronavirus disease 2019 (COVID-19) is currently unclear and the multitude of disease symptoms often further hinders locating the source of pain. Interestingly, many subjects with COVID-19 have symptoms of acute rhinosinusitis. The relation between nasal symptoms and headache in SARS-CoV-2 infection remains unknown. This bi-center longitudinal study evaluated symptoms in consecutive COVID-19 patients in the participating practices. The first assessment was performed during the initial consultation after infection confirmation. That was followed up by a second consultation after a median 9 days. 130 patients were included in the study (80 women, 50 men; mean age 46.9 years). Headache was highly prevalent at the first visit (72%) and significantly associated with acute rhinosinusitis symptoms. The odds ratio for headache in subjects with rhinosinusitis was 3.5. Headache could be attributed to systemic viral infection in 96% and to acute rhinosinusitis in 51% of cases according to 3rd edition of the International Classification of Headache Disorders. Criterium C.3 (exacerbation of headache by pressure applied over paranasal sinuses) and C.4 (ipsilaterality of headache and sinusitis) had low sensitivity in headache attributed to acute rhinosinusitis. Nasal inflammation is associated with headache in COVID-19, although the pain mechanism lies probably in a systemic reaction to the virus. 3rd edition of the International Classification of Headache Disorders criteria for headache attributed to acute rhinosinusitis need adjusting to the current understanding of acute sinonasal infection.


Orbitofrontal and hippocampal contributions to memory for face-name associations: the rewarding power of a smile.
Memory processes can be enhanced by reward, and social signals such a smiling face can be rewarding to humans. Using event-related functional MRI (fMRI), we investigated the rewarding effect of a simple smile during the encoding and retrieval of face-name associations. During encoding, participants viewed smiling or neutral faces, each paired with a name, and during retrieval, only names were presented, and participants retrieved the associated facial expressions. Successful memory activity of face-name associations was identified by comparing remembered vs. forgotten trials during both encoding and retrieval, and the effect of a smile was identified by comparing successful memory trials for smiling vs. neutral faces. The study yielded three main findings. First, behavioral results showed that the retrieval of face-name associations was more accurate and faster for smiling than neutral faces. Second, the orbitofrontal cortex and the hippocampus showed successful encoding and retrieval activations, which were greater for smiling than neutral faces. Third, functional connectivity between the orbitofrontal cortex and the hippocampus during successful encoding and retrieval was stronger for smiling than neutral faces. As a part of the reward system, the orbitofrontal cortex may modulate memory processes of face-name associations mediated by the hippocampus. Interestingly, the effect of a smile during retrieval was found even though only names were presented as retrieval cues, suggesting that the effect was mediated by face imagery. Taken together, the results demonstrate how rewarding social signals from a smiling face can enhance relational memory for face-name associations.


Pushing the detection limit of infrared spectroscopy for structural analysis of dilute protein samples.
Fourier-transform infrared spectroscopy is a powerful and versatile tool to investigate the structure and dynamics of proteins in solution. The intrinsically low extinction coefficient of the amide I mode, the main structure-related oscillator, together with the high infrared absorptivity of aqueous media, requires that proteins are studied at high concentrations (>10 mg L(-1)). This may represent a challenge in the study of aggregation-prone proteins and peptides, and questions the significance of structural data obtained for proteins physiologically existing at much lower concentrations. Here we describe the development of a simple experimental approach that increases the detection limit of protein structure analysis by infrared spectroscopy. Our approach relies on custom-made filters to isolate the amide I region (1700-1600 cm(-1)) from irrelevant spectral regions. The sensitivity of the instrument is then increased by background attenuation, an approach consisting in the use of a neutral density filter, such as a non-scattering metal grid, to attentuate the intensity of the background spectrum. When the filters and grid are combined, a 2.4-fold improvement in the noise level can be obtained. We have successfully tested this approach using a highly diluted solution of pyruvate kinase in deuterated medium (0.2% w/v), and found that it provides spectra of a quality comparable to those recorded with a 10-fold higher protein concentration.


A unified noise analysis for iterative image estimation.
Iterative image estimation methods have been widely used in emission tomography. Accurate estimation of the uncertainty of the reconstructed images is essential for quantitative applications. While both iteration-based noise analysis and fixed-point noise analysis have been developed, current iteration-based results are limited to only a few algorithms that have an explicit multiplicative update equation and some may not converge to the fixed-point result. This paper presents a theoretical noise analysis that is applicable to a wide range of preconditioned gradient-type algorithms. Under a certain condition, the proposed method does not require an explicit expression of the preconditioner. By deriving the fixed-point expression from the iteration-based result, we show that the proposed iteration-based noise analysis is consistent with fixed-point analysis. Examples in emission tomography and transmission tomography are shown. The results are validated using Monte Carlo simulations.


A case report of haemorrhagic-aneurismal bone cyst of the mandible.
Haemorrhagic-aneurismal bone cysts (HABCs) are quite rare, benign, non-neoplastic, expansive, and vascular locally destructive lesions. They are generally considered sequelae of an earlier trauma causing an overflow of blood into the bone. HABCs are classified as pseudocysts and they should be differentiated from true cysts because their treatment is different. Since few of these cysts involve subjective symptoms, most are discovered accidentally during radiography, while a sure diagnosis is likely to be obtained only during surgery, on discovery of a non-epithelialised cavity. Here, we report a typical case of a haemorrhagic-mandibular cyst in a 13-year-old girl, which was treated by opening the cavity and scraping its walls following diagnostic arteriography and post-operative transcutaneous intralesional embolization. No further complications were recorded in the post-operative period, although the convalescence lasted for a time longer than expected, because of anemia. No further surgery was performed. She has been disease-free for two years. Evaluation of intralesional blood flow is important for HABCs because of the hemorrhagic risk in surgery. Embolization seems to be a useful procedure in the treatment of HABCs and could be tried as the treatment modality in the standard protocol for the treatment of HABCs.


Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use.
Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared with conventional dose guidelines. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration at steady state) and implement a simple model-based tool for the initial dosing of busulfan in children undergoing hematopoietic cell transplantation. Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone hematopoietic cell transplantation with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the nonlinear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model. Modeling of busulfan time-concentration data indicates that busulfan clearance displays nonlinearity in children, decreasing up to approximately 20% between the concentrations of 250-2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan clearance were actual body weight and age. The percentage of individuals achieving a therapeutic concentration at steady state was significantly higher in subjects receiving initial doses based on the population PK model (81%) than in historical controls dosed on conventional guidelines (52%) (P = 0.02). When compared with the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults.


Commentary: one strategy for building public trust in changing times.
Major health care reforms are being debated in the United States. While these debates address issues of access and cost, the systems-based problems of patient safety, continuous quality improvement, and an integrated approach to continuing professional development (CPD) remain traditional opportunities for the profession to directly improve health care and maintain professional accountability. Such challenges can be addressed independently of proposed reforms and offer an opportunity for the profession to build greater public trust. Given recent evidence questioning many assumptions behind individually focused CPD, and as physicians' work shifts into group and team contexts, it is an opportune time to address better CPD strategies within emerging group and team settings.The first strategic change requires a focus on managing the development of the individual physician's educational growth into a systems-oriented approach based on better information and feedback within groups of practitioners and health care teams. Second, the renewal of the linked visions of professional collegiality and accountability with professional regulation needs to be seen as a collective responsibility across key organizations within the profession's normal accountability framework. Thus, the professional colleges, certifying boards, and regulatory authorities need to collaborate with the CDP community in refocusing their collective activities to promote the profession's traditional role of improving the quality of care and maintaining the public's trust in these times of intense policy debate.


Dimerization or oligomerization of the actin-like FtsA protein enhances the integrity of the cytokinetic Z ring.
In bacteria, the actin-like FtsA protein interacts with the tubulin-like FtsZ protein, helping to assemble the cytokinetic Z ring, anchor it to the cytoplasmic membrane and recruit other essential divisome proteins. FtsA also interacts with itself, but it is not clear whether this self-interaction is required for its full functionality. Here we describe new dominant negative missense mutations in Escherichia coli ftsA that specifically inhibit FtsA homodimerization and simultaneously cause disruption of Z rings. The negative effects of one mutation, M71A, were suppressed by altering levels of certain division proteins or by additional mutations in ftsA that promote increased integrity of the Z ring. Remarkably, when FtsA, FtsA-M71A, and other mutants of FtsA that compromise self-interaction were connected in a tandem repeat, they were at least partially functional and suppressed defects of an ftsZ84(ts) mutation. This gain of function by FtsA tandems further suggested that FtsA monomers cause deleterious interactions with FtsZ and that increased dimerization or oligomerization of FtsA enhances its ability to promote Z-ring integrity. Therefore, we propose that FtsZ assembly is regulated by the extent of FtsA oligomerization.


[Percutaneous alcoholization of the small hepatocarcinoma].
Percutaneous ethanol injection (PEI) under ultrasound guidance is a new therapeutic possibility for patients with small hepatocellular carcinoma (HCC). In our series, 51 patients with a total of 72 lesions were treated (tumor size 0.8-5.0 cm). No significant complications occurred after 745 treatments. Forty patients presented complete remission, as no evidence of residual HCC was revealed during the follow-up (mean 18 months). Ten patients with lesions larger than 3.5 cm and one with lesion less than 3 cm presented partial remission (80-90% of necrosis). The cumulative survival rates at 1, 2 and 3 years (Kaplan-Meier method) were 100%, 89% and 58%. The survival rates for patients carrier of single lesion were 100%, 94% and 71% respectively. In comparison with the survival curves of untreated and surgically treated patients, PEI seems to be the better treatment for operable HCC smaller than 3 cm, and for lesions smaller than 5 cm in patients with surgical risk.


Biomimetic six-axis robots replicate human cardiac papillary muscle motion: pioneering the next generation of biomechanical heart simulator technology.
Papillary muscles serve as attachment points for chordae tendineae which anchor and position mitral valve leaflets for proper coaptation. As the ventricle contracts, the papillary muscles translate and rotate, impacting chordae and leaflet kinematics; this motion can be significantly affected in a diseased heart. In ex vivo heart simulation, an explanted valve is subjected to physiologic conditions and can be adapted to mimic a disease state, thus providing a valuable tool to quantitatively analyse biomechanics and optimize surgical valve repair. However, without the inclusion of papillary muscle motion, current simulators are limited in their ability to accurately replicate cardiac biomechanics. We developed and implemented image-guided papillary muscle (IPM) robots to mimic the precise motion of papillary muscles. The IPM robotic system was designed with six degrees of freedom to fully capture the native motion. Mathematical analysis was used to avoid singularity conditions, and a supercomputing cluster enabled the calculation of the system's reachable workspace. The IPM robots were implemented in our heart simulator with motion prescribed by high-resolution human computed tomography images, revealing that papillary muscle motion significantly impacts the chordae force profile. Our IPM robotic system represents a significant advancement for ex vivo simulation, enabling more reliable cardiac simulations and repair optimizations.


The ability of magnetic field sensors to monitor feeding in three domestic herbivores.
The rate at which animals ingest food is a fundamental part of animal ecology although it is rarely quantified, with recently-developed animal-attached tags providing a potentially viable approach. However, to date, these methods lack clarity in differentiating various eating behaviours, such as 'chewing' from 'biting'. The aims of this study were to examine the use of inter-mandibular angle sensors (IMASENs), to quantify grazing behaviour in herbivores including cattle (Bos taurus), sheep (Ovis aries) and pygmy goats (Capra aegagrus hircus) eating different foodstuffs. Specifically, we aimed to: (1) quantify jaw movements of each species and determine differences between biting and chewing; (2) assess whether different food types can be discerned from jaw movements; and (3) determine whether species-specific differences in jaw movements can be detected. Subjects were filmed while consuming concentrate, hay, grass and browse to allow comparison of observed and IMASEN-recorded jaw movements. This study shows that IMASENs can accurately detect jaw movements of feeding herbivores, and, based on the rate of jaw movements, can classify biting (taking new material into the mouth) from chewing (masticating material already in the mouth). The biting behaviours associated with concentrate pellets could be identified easily as these occurred at the fastest rate for all species. However, the rates of chewing different food items were more difficult to discern from one another. Comparison of chew:bite ratios of the various food types eaten by each species showed no differences. Species differences could be identified using bite and chew rates. Cattle consistently displayed slower bite and chew rates to sheep and pygmy goats when feeding, while sheep and pygmy goats showed similar bite and chew rates when feeding on concentrate pellets. Species-specific differences in chew:bite ratios were not identified. Magnetometry has the potential to record quantitative aspects of foraging such as the feeding duration, food handling time and food type. This is of major importance for researchers interested in both captive (e.g., agricultural productivity) and wild animal foraging dynamics as it can provide quantitative data with minimal observer interference.


An effective method of pruning support vector machine classifiers.
Support vector machine (SVM) classifiers often contain many SVs, which lead to high computational cost at runtime and potential overfitting. In this paper, a practical and effective method of pruning SVM classifiers is systematically developed. The kernel row vectors, with one-to-one correspondence to the SVs, are first organized into clusters. The pruning work is divided into two phases. In the first phase, orthogonal projections (OPs) are performed to find kernel row vectors that can be approximated by the others. In the second phase, the previously found vectors are removed, and crosswise propagations, which simply utilize the coefficients of OPs, are implemented within each cluster. The method circumvents the problem of explicitly discerning SVs in the high-dimensional feature space as the SVM formulation does, and does not involve local minima. With different parameters, 3000 experiments were run on the LibSVM software platform. After pruning 42% of the SVs, the average change in classification accuracy was only - 0.7%, and the average computation time for removing one SV was 0.006 of the training time. In some scenarios, over 90% of the SVs were pruned with less than 0.1% reduction in classification accuracy. The experiments demonstrate the existence of large numbers of superabundant SVs in trained SVMs, and suggest a synergistic use of training and pruning in practice. Many SVMs already used in applications could be upgraded by pruning nearly half of their SVs.


Control of lambda repressor synthesis.
Direct measurements of the intracellular level of lambda repressor have been made by a DNA-filter assay and a radioimmune assay. Transcription of cI, the structural gene for repressor, appears to initiate at two different promoters, prm and pre. Promoter pre is activated during the establishment of lysogeny by the action of cII and cIII proteins at the DNA site cY. Phage mutated in cII, cIII, or cY do not make a normal burst of repressor after infection and do not efficiently lysogenize the cell. Cro product stops repressor synthesis midway in the infective cycle. Promoter prm maintains the repressor level in established lysogens. Delection mapping places it very near the right operator (Or). Prm is activated by repressor bound to the right operator. In the absence of cII or cIII protein, repressor synthesis requires active repressor and only proceeds on genomes able to bind repressor at Or.


Study of efficient catalytic electrode for hydrogen evolution reaction from seawater based on low tortuosity corn straw cellulose biochar/Mo2C with porous channels.
Porosity and channel structure has important effects on the performance of hydrogen evolution reaction (HER) of nanostructured electrocatalysts in acid solution and seawater. Mesopore usually helps to enhance the reaction kinetics and mass transfer, while the macroporous channel structure also affects the electrocatalyst. Traditional graphene materials do not have such structure. Therefore, this paper designs a method to synthesize Mo2C composite nanomaterial in situ on corn straw biochar, inspires by the natural channel structure of conducting water, salt and organic matter in plants. Characteristic characterization shows that the material also has a large number of mesoporous and vertical distribution of large porous channel structure, through the decrease of tortuosity and porosity, ensure the catalyst surface electrolyte transport and hydrogen timely escape, alleviate the process of metal ion precipitation blocking pore channel, so as to improve the rate of hydrogen evolution reaction. The results shows that the overpotential of the catalyst was 48 mV and 251 mV under 10 mA cm-2 acidic electrolyte and simulated seawater electrolyte, respectively. This method provides new ideas for the design of efficient electrocatalysts for seawater decomposition, then the HER performance in alkaline and neutral environments needs to be further explored.


Toward atomic-scale bright-field electron tomography for the study of fullerene-like nanostructures.
We present the advancement of electron tomography for three-dimensional structure reconstruction of fullerene-like particles toward atomic-scale resolution. The three-dimensional reconstruction of nested molybdenum disulfide nanooctahedra is achieved by the combination of low voltage operation of the electron microscope with aberration-corrected phase contrast imaging. The method enables the study of defects and irregularities in the three-dimensional structure of individual fullerene-like particles on the scale of 2-3 A. Control over shape, size, and atomic architecture is a key issue in synthesis and design of functional nanoparticles. Transmission electron microscopy (TEM) is the primary technique to characterize materials down to the atomic level, albeit the images are two-dimensional projections of the studied objects. Recent advancements in aberration-corrected TEM have demonstrated single atom sensitivity for light elements at subångström resolution. Yet, the resolution of tomographic schemes for three-dimensional structure reconstruction has not surpassed 1 nm3, preventing it from becoming a powerful tool for characterization in the physical sciences on the atomic scale. Here we demonstrate that negative spherical aberration imaging at low acceleration voltage enables tomography down to the atomic scale at reduced radiation damage. First experimental data on the three-dimensional reconstruction of nested molybdenum disulfide nanooctahedra is presented. The method is applicable to the analysis of the atomic architecture of a wide range of nanostructures where strong electron channeling is absent, in particular to carbon fullerenes and inorganic fullerenes.


Cardiovascular health in young adulthood and structural brain MRI in midlife: The CARDIA study.
To examine the association between the American Heart Association (AHA) Life's Simple 7 (LS7) metric and brain structure. We determined cardiovascular health (CVH) according to the AHA LS7, assigning 0, 1, or 2 points for meeting poor, intermediate, or ideal criteria for the 7 components (range 0-14) at baseline (aged 18-30 years in 1985-1986) and year 25 follow-up examination for 518 participants of the Coronary Artery Risk Development in Young Adults (CARDIA) brain MRI substudy. Visit-based CVH score and average score was assessed in relation to percent of intracranial volume of normal tissue of the whole brain, gray matter, and white matter, and abnormal tissue volume of white matter at year 25 using multivariable linear, logistic, and quantile regression, after adjustment for age, sex, race, field center, educational attainment, and alcohol consumption. Mean percentage of whole brain volume, normal gray matter, and normal white matter was 81.3% (±2.5), 42.9% (±2.0), and 38.4% (±2.0). Greater CVH score at baseline (per each additional point at year 0: 0.1%, 95% confidence limits 0.01-0.3; p < 0.05) and average CVH score were associated with greater percentage of whole brain volume (per each additional point in average score: 0.2%, 95% confidence limits 0.04-0.3; p < 0.05). Visit-based or average CVH score was not significantly associated with normal gray or white matter volume or abnormal white matter volume. Maintaining ideal levels of cardiovascular health, determined by the LS7, in young adulthood is associated with greater whole brain volume in middle age but not regional differences in structure.


Plasma concentrations of praziquantel after oral administration of single and multiple doses in loggerhead sea turtles (Caretta caretta).
To determine the pharmacokinetics of praziquantel following single and multiple oral dosing in loggerhead sea turtles. 12 healthy juvenile loggerhead sea turtles. Praziquantel was administered orally as a single dose (25 and 50 mg/kg) to 2 groups of turtles; a multiple-dose study was then performed in which 6 turtles received 3 doses of praziquantel (25 mg/kg, PO) at 3-hour intervals. Blood samples were collected from all turtles before and at intervals after drug administration for assessment of plasma praziquantel concentrations. Pharmacokinetic analyses included maximum observed plasma concentration (Cmax), time to maximum concentration (Tmax), area under the plasma praziquantel concentration-time curve, and mean residence time (MRTt). Large interanimal variability in plasma praziquantel concentrations was observed for all dosages. One turtle that received 50 mg of praziquantel/kg developed skin lesions within 48 hours of administration. After administration of 25 or 50 mg of praziquantel/kg, mean plasma concentrations were below the limit of quantification after 24 hours. In the multiple-dose group of turtles, mean plasma concentration was 90 ng/mL at the last sampling time-point (48 hours after the first of 3 doses). In the single-dose study, mean Cmax and Tmax with dose were not significantly different between doses. After administration of multiple doses of praziquantel, only MRTt was significantly increased, compared with values after administration of a single 25-mg dose. Oral administration of 25 mg of praziquantel/kg 3 times at 3-hour intervals may be appropriate for treatment of loggerhead sea turtles with spirorchidiasis.


Evaluation of an Accelerated Chemoradiotherapy Protocol for Oropharyngeal Squamous Cell Carcinoma in 5 Cats and 3 Dogs.
Accelerated radiation therapy protocols address the specific biology of aggressive oropharyngeal squamous cell carcinoma and this approach was applied in 5 feline and 3 canine oropharyngeal squamous cell carcinoma patients where surgery was not possible (4/5 feline and 2/3 canine cases) or was declined (1/5 feline and 1/3 canine cases). A protocol using 14 fractions of 3.5 Gy over 9-days, combined with carboplatin chemotherapy as a radiosensitiser (total dose 180 mg/m2 in feline and 300 mg/m2 in canine cases) resulted in a complete tumor response in most cases (4/5 feline and 3/3 canine cases) with acceptable acute and long-term side effects. Results achieved in feline cases correspond with published data where these specific radiotherapy protocols were employed. A complete response and long-term survival (> 2-years) was achieved in all canine patients. Although no standardized chemoradiotherapy protocols currently exist, this therapeutic approach can be a useful addition for the management of oropharyngeal squamous cell carcinoma of cats and dogs when the goals of treatment include maximizing tumor control while maintaining function and quality of life.


A statistical mechanical analysis of postural sway using non-Gaussian FARIMA stochastic models.
In this paper, postural sway is modeled using a fractional autoregressive integrated moving average (FARIMA) family of models: the center-of-pressure (COP) motion is viewed in terms of a self-similar, anti-persistent random-walk process, obtained by fractionally summating non-Gaussian random variables, whose correlation structure for small time lags is shaped by a linear time-invariant low-pass filter. The model parameters are: the strength of the stochastic driving, e.g., the root mean square (rms) value of the time-difference COP motion; the DC gain, damping ratio and natural frequency of the filter; the Hurst exponent, which measures the random-walk antipersistence magnitude. In the proposed modeling procedure, a graphical estimator for determining the Hurst exponent is cascaded to a method for matching autoregressive (AR) models to fractionally difference COP motion via higher order cumulants. The effect of the presence or absence of vision on the model parameter values is discussed with regard to data from experiments on healthy young adults.


Muscarinic therapies in Alzheimer's disease; from palliative treatments to disease modification.
Cholinergic therapies for Alzheimer's disease (AD) have been developed following painstaking neuropathological and neurochemical studies. Drugs based upon this approach are in development and it is hoped that these compounds will be of some use as palliative therapy. However, increasing evidence from molecular biology suggests that increasing cholinergic neurotransmission might not only alter cognition but also modify disease progression. The evidence that muscarinic-induced increases in protein kinase C activity favourably alter amyloid precursor protein metabolism and tau phosphorylation is reviewed. A unifying hypothesis of AD pathogenesis brings together plaque and tangle formation, suggesting that cholinergic therapies in development may have far-reaching implications as treatments for AD. (Int J Psych Clin Pract 1997; 1: 15-20).


A structured literature review on the role of mindfulness, mindful eating and intuitive eating in changing eating behaviours: effectiveness and associated potential mechanisms.
The role of mindfulness, mindful eating and a newer concept of intuitive eating in modulating eating habits is an area of increasing interest. In this structured literature review, a summary of the current evidence is presented, together with details of interventions undertaken and the tools to measure outcomes. It is broad in scope given the emerging evidence base in this area. The review yielded sixty-eight publications: twenty-three interventions in obese/overweight populations; twenty-nine interventions in normal-weight populations; sixteen observational studies, three of which were carried out in overweight/obese populations. Mindfulness-based approaches appear most effective in addressing binge eating, emotional eating and eating in response to external cues. There is a lack of compelling evidence for the effectiveness of mindfulness and mindful eating in weight management. Mindfulness-based approaches may prevent weight gain. Reduced food intake was seen in some of the studies in overweight and obese populations, but this was less apparent in the studies in normal-weight populations. The evidence base for intuitive eating is limited to date and further research is needed to examine its potential in altering eating behaviours. Mindfulness appears to work by an increased awareness of internal, rather than external, cues to eat. Mindfulness and mindful eating have the potential to address problematic eating behaviours and the challenges many face with controlling their food intake. Encouraging a mindful eating approach would seem to be a positive message to be included in general weight management advice to the public.


Mechanism of Low Chemical Agent Adsorption by High Pressure for Hydraulic Fracturing-Assisted Oil Displacement Technology: A Study of Molecular Dynamics Combined with Laboratory Experiments.
This study investigates the influence of physical parameters such as porosity, permeability, pore-throat radius, and specific surface area/volume on the adsorption capacity of surfactants in the pore surface of reservoirs. In the meantime, the hydraulic fracturing-assisted oil displacement (HFAD) technique can effectively improve the permeability and porosity of pores in the reservoir, which may affect the adsorption capacity of surfactants in low-permeability reservoirs. This may help to reduce the adsorption loss of surfactants in low-permeability reservoirs. Based on physical simulation methods, dynamic adsorption experiments were conducted to clarify the dynamic saturation adsorption capacity effect of high-pressure and low-pressure displacement agents by the HFAD technique. In addition, the molecular dynamics simulation method was used to study the effect of high-pressure conditions of HFAD on the adsorption capacity of surfactants on weakly lipophilic silica walls. Under the condition of high injection pressure by the HFAD technique, the fluid flow velocity and the initial kinetic energy of molecules increase, while the absolute value of the electrostatic potential energy in the system decreases. In addition, the van der Waals potential energy increases. In other words, the smaller the gravitational attraction experienced by the surfactant molecules during adsorption, the greater the repulsive force. Under the dual action of electrostatic force and van der Waals forces, the absolute values of the adsorption energy and the free energy decrease. The adsorption capacity of the surfactant molecules is weakened. Moreover, the decrease in adsorption capacity has little effect on the improvement of wettability, indicating that the adsorption of the surfactant reduced by HFAD technology is mostly ineffective adsorption.


X-ray microanalysis of synchronized HeLa S3 cells infected with Vaccinia virus.
X-ray microanalysis has been used to study changes in concentration of P, S, Cl Na and K in synchronized HeLa S3 cells in g1 phase infected with Vaccinia virus. No dramatic redistribution of elements between nucleus and cytoplasm was demonstrated during the first 6 h post-infection, during which time viral shut-off of host protein synthesis occurred. [Cl] increased relative to [Na] and [K] during the first 3 h post-infection. The magnitude and direction of change in [K] and [Na] (from approximately 10 cells/analysis) was compared with data previously obtained by flame photometry (from approximately 10(6) cells/analysis) and found to be remarkably parallel.


Affective Prosody Perception and the Relation to Social Competence in Autistic and Typically Developing Children.
Individuals diagnosed with autism spectrum disorder (ASD) have difficulty perceiving and expressing emotions. Since prosodic changes in speech (i.e. changes in intonation, stress, rhythm, etc.) are crucial for extracting information about the emotional state of a speaker, an inability to perceive and interpret these prosodic changes may be related to impairments in social communication. This study used non-verbal emotional voice-clips to examine the ability of autistic and typically-developing children (7-13 years old) to extract affect from changes in prosody. This research also explored whether difficulty extracting affective intent from changes in prosody may be related to social competence. Autistic (n = 26) and typically-developing (n = 26) children accurately matched emotional voice-clips to emotion words, suggesting autistic children can accurately extract the affective meaning conveyed by changes in prosody. Autistic children were less accurate at matching the voice-clips to emotional faces, suggesting that autistic children may struggle to make use of prosodic information in a social context. Across both autistic and typically-developing children, prosody-face matching accuracy was found to predict overall social competence, as well as social inferencing abilities, suggesting that the inability to utilize affective information derived from a speaker's voice may interfere with effective social communication.


Facial expressions of singers influence perceived pitch relations.
In four experiments, we examined whether facial expressions used while singing carry musical information that can be "read" by viewers. In Experiment 1, participants saw silent video recordings of sung melodic intervals and judged the size of the interval they imagined the performers to be singing. Participants discriminated interval sizes on the basis of facial expression and discriminated large from small intervals when only head movements were visible. Experiments 2 and 3 confirmed that facial expressions influenced judgments even when the auditory signal was available. When matched with the facial expressions used to perform a large interval, audio recordings of sung intervals were judged as being larger than when matched with the facial expressions used to perform a small interval. The effect was not diminished when a secondary task was introduced, suggesting that audio-visual integration is not dependent on attention. Experiment 4 confirmed that the secondary task reduced participants' ability to make judgments that require conscious attention. The results provide the first evidence that facial expressions influence perceived pitch relations.


My Croatian experience with general/ family practice.
Despite the differences in organizational level and training of the new generation of family physicians general practice between the United Kingdom and Croatia shows many similarities. This article highlights some of these similarities and differences. It is written after a visit to the Family Medicine Department at School of Public Health "Andrija Stampar" and observations in various clinics in multiple locations including rural area in Croatia. Each primary care team in Croatia consists of only a doctor and a practice and a public health nurses with no availability of administration staff As in the United Kingdom they have very heavy workload both clinical and nonclinical. In Croatia the lack of availability of commonly used community services in the United Kingdom brings extra challenges for Croatian colleagues. In Croatia presentation of patients with chronic disease and multiple co-morbidities and overall their management is not significantly different from the general practice of the United Kingdom.


Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals.
More than 30 years into the global HIV/AIDS epidemic, infection rates remain alarmingly high, with over 2.7 million people becoming infected every year. There is a need for HIV prevention strategies that are more effective. Oral antiretroviral pre-exposure prophylaxis (PrEP) in high-risk individuals may be a reliable tool in preventing the transmission of HIV. To evaluate the effects of oral antiretroviral chemoprophylaxis in preventing HIV infection in HIV-uninfected high-risk individuals. We revised the search strategy from the previous version of the review and conducted an updated search of MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE in April 2012. We also searched the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for ongoing trials. Randomised controlled trials that evaluated the effects of any antiretroviral agent or combination of antiretroviral agents in preventing HIV infection in high-risk individuals Data concerning outcomes, details of the interventions, and other study characteristics were extracted by two independent authors using a standardized data extraction form. Relative risk with a 95% confidence interval (CI) was used as the measure of effect. We identified 12 randomised controlled trials that meet the criteria for the review. Six were ongoing trials, four had been completed and two had been terminated early. Six studies with a total of 9849 participants provided data for this review. The trials evaluated the following: daily oral tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) versus placebo; TDF versus placebo and daily TDF-FTC versus intermittent TDF-FTC. One of the trials had three study arms: TDF, TDF-FTC and placebo arm. The studies were carried out amongst different risk groups, including HIV-uninfected men who have sex with men, serodiscordant couples and other high risk men and women.Overall results from the four trials that compared TDF-FTC versus placebo showed a reduction in the risk of acquiring HIV infection (RR 0.51; 95% CI 0.30 to 0.86; 8918 participants). Similarly, the overall results of the studies that compared TDF only versus placebo showed a significant reduction in the risk of acquiring HIV infection (RR 0.38; 95% CI 0.23 to 0.63, 4027 participants). There were no significant differences in the risk of adverse events across all the studies that reported on adverse events. Also, adherence and sexual behaviours were similar in both the intervention and control groups. Finding from this review suggests that pre-exposure prophylaxis with TDF alone or TDF-FTC reduces the risk of acquiring HIV in high-risk individuals including people in serodiscordant relationships, men who have sex with men and other high risk men and women.


Dealing with conflicting reviewers' comments.
Most nursing journals use two or three reviewers to help the editor decide on acceptance or rejection. Although this helps give the editor a wide range of perspectives for making the acceptance decision, it sometimes results in confusion if reviewers' comments conflict rather than compliment each other. This article describes strategies reviewers can use to prevent this problem and editors and authors can use to deal with the conflicts when they occur.


Microbial Colonization of Pneumatic Tourniquets in the Orthopedic Operating Room.
Background The rate of surgical site infections following orthopedic procedures is approximately 2% globally. Potential sources of contamination in the operating room include pneumatic tourniquets, blood pressure cuffs, and stethoscopes, among others. Our study aims to investigate microbial colonization on reusable pneumatic tourniquets stored and used in the orthopedic department of our institution and evaluate the efficacy of the cleaning protocols employed. Methods Over a course of two weeks, 26 samples were obtained. A total of 14 pneumatic tourniquets were sampled preoperatively on Monday morning following the weekly cleaning protocol of soaking the tourniquets in sodium hypochlorite for 30 minutes while 12 tourniquets were cultured immediately following the postoperative cleaning protocol of wiping the tourniquet clean with a cloth soaked in sodium hypochlorite. Samples were cultured on MacConkey and sheep blood agar and incubated at 37-degrees centigrade for a total of 48 hours. Organisms were identified and colony count was documented. The analysis was performed using the Fisher Exact test on SPSS v23 (IBM Corp., Armonk, NY, US). Results All 14 samples obtained after being soaked in sodium hypochlorite for 30 minutes cultured negative. However, four out of 12 (33%) samples obtained after simply wiping the pneumatic tourniquet with a cloth soaked in sodium hypochlorite cultured coagulase-negative Staphylococci. The difference between the two was significant (p=0.002). Conclusion Postoperative tourniquets, wiped with a cloth soaked in sodium hypochlorite and ready to be used on the next patient, were found to be contaminated with coagulase-negative Staphylococcus. This species is notorious for causing surgical site infections following implant-related surgeries potentially through direct inoculation and cross-infections intraoperatively and in storage. Efforts to identify the relationship with postoperative surgical site infections need to be made to suggest more aggressive cleaning protocols.


[Non-invasive prenatal diagnosis of the most common aneuploidies with cell-free fetal DNA in maternal serum--preliminary results].
The aim of the study was to present initial results of non-invasive prenatal diagnosis of common aneuploidies of chromosomes 21, 18 and 13 based on cell-free fetal DNA in maternal serum in high-risk patients, and to compare the results with routine karyotyping. Before the invasive procedure, 10 ml of peripheral blood from 10 patients was collected to isolate cell-free fetal DNA and to perform a non-invasive fetal trisomy test (NIFTY provided by Beijing Genomics Institute, BGI, Shenzen, China). Three out of 10 samples showed an abnormal karyotype in traditional karyotyping. There were 9 conclusive NIFTY results. NIFTY detected 1 out of 2 trisomies 18. The quantity of cell-free fetal DNA in maternal plasma in the second probe with trisomy 18 was unsatisfactory fora conclusive NIFTY result. In 1 case traditional karyotyping revealed mosaicism impossible to detect with NIFTY


Disrupted sleep is associated with altered pain processing by sex and ethnicity in knee osteoarthritis.
Studies indicate that improving sleep decreases reported pain in patients with knee osteoarthritis, but it is unclear if this association extends to experimentally induced pain responses. A community-based sample of 88 African American and 52 non-Hispanic white adults (45-76 years) with knee osteoarthritis completed the Insomnia Severity Index and the arousal subscale of the Sleep Hygiene and Practices Scale. Participants underwent quantitative sensory testing, including measures of pain sensitivity and facilitation at the knee, and pain inhibition. Outcomes were analyzed with multiple Tobit hierarchical regression models, with adjustment for relevant covariates. Ethnicity and sex by sleep interactions were also entered into the models. After covariate adjustment, main associations were not observed. However, sex interacted with insomnia severity to predict greater temporal summation of heat and punctate pressure pain among women and lower heat temporal summation among men. Men and women who engaged in frequent arousal-associated sleep behaviors demonstrated higher and lower heat temporal summation, respectively. Non-Hispanic whites with greater insomnia severity displayed lower pressure pain thresholds and pain inhibition. Our findings are the first to demonstrate that disrupted sleep is associated with altered pain processing differentially by sex and ethnicity/race among people with knee osteoarthritis. This article presents the association between insomnia severity, maladaptive sleep behaviors, and experimentally induced pain responses among people with knee osteoarthritis. Disrupted sleep was associated with altered pain processing by sex and ethnicity/race. Offering sleep interventions may help ameliorate pain, but treatment may need to be tailored by sex and ethnicity/race.


Long term efficacy of DOTS regimens for tuberculosis: systematic review.
To identify published studies assessing tuberculosis recurrence after successful treatment with standard short course regimens for six months to determine the strength and sufficiency of evidence to support current guidelines. Systematic review. Medline, Embase, Cochrane clinical trials register, specialist tuberculosis journals, and reference lists. Only English language publications were eligible. Studies were included irrespective of methodology or quality. Abstracted information included inclusion and exclusion criteria for participants, duration of follow-up, and definitions of treatment success and disease recurrence. The primary outcome was the proportion of successfully treated patients recorded with recurrent tuberculosis during the follow-up period. 17 study arms from 16 studies met the inclusion criteria; 10 were controlled clinical trials and six were either studies done under programmatic conditions or observational studies from functioning tuberculosis programmes. Although several clinical trials supported the use of daily treatment regimens, studies reporting tuberculosis recurrence after intermittent regimens were limited. Few studies carried out under routine programmatic conditions reported disease recurrence. Overall there was wide variation in recurrence after successful treatment, ranging from 0% to 14%. Considerable heterogeneity across studies precluded the systematic assessment of factors contributing to tuberculosis recurrence. Despite DOTS (directly observed treatment, short course) being implemented for more than 10 years and millions of patients treated for tuberculosis, few studies have assessed the ability of standard DOTS regimens to result in lasting cure for patients treated under routine programmatic conditions.


[Protein C congenital deficiency. A case report].
Protein C is a plasmatic protein that is synthesized by the liver with the help of vitamin K. It regulates thrombin formation and consequently prevents thrombosis. We present a case of a newborn male with change in the color of the right foot index finger who after 4 h showed cyanosis that reached malleolus level. Upon admission we observed generalized pallor, tachycardia and a necrotic lesion in the rightfoot. We suspected a septic process and thus administered cefotaxime, vancomycin and heparin. Platelet levels were 70,000 mm3, thromboplastin 16/12 sec., partial thromboplastin 5829 sec. PCfunctionality 20% and protein S 100%. Even though the patient evolvedfavourably and showed partial recovery, an intratuberous amputation was needed. One year later a prosthesis was fitted. We need to carry out studies that support the use of PC monoclonal antibodies in order to offer better baseline treatment to patients with PC congenital deficiency and improve their quality of live.


Atrial natriuretic peptide in physiological doses does not inhibit the ACTH or cortisol response to corticotrophin-releasing hormone-41 in normal human subjects.
Whilst it has been postulated that atrial natriuretic peptide (ANP) may modulate pituitary hormone release, several investigations in non-human species have reported conflicting results when looking for an effect on the hypothalamo-pituitary-adrenal axis. However, in a recent study significant inhibition of corticotrophin-releasing hormone (CRH)-stimulated ACTH in cultured rat anterior pituitary cells occurred only with the complete peptide alpha-ANP(1-28). We have therefore investigated whether this form of ANP can inhibit CRH-stimulated ACTH and cortisol release in human subjects. Six healthy male volunteers received human alpha-ANP or placebo, and human CRH or placebo, on four separate occasions. ANP was infused at a rate of 0.01 micrograms/kg per min in order to achieve levels in the high physiological range. CRH was given as a bolus dose of 100 micrograms 30 min into the ANP infusion. Cortisol and ANP were measured by radioimmunoassay, the latter after extraction. ACTH was measured by immunoradiometric assay. The data were analysed by Student's paired t-test on basal, peak and incremental levels. Basal levels of ANP were within the normal range (2-5 pmol/l). With ANP infusion, mean +/- S.E.M. peak ANP levels were 29.6 +/- 3.1 pmol/l. There were no significant differences in mean basal cortisol and ACTH levels on each of the 4 study days. Mean peak cortisol and ACTH levels after CRH and ANP did not significantly differ from those achieved with CRH and placebo ANP. We thus conclude that at high physiological doses, circulating ANP does not inhibit CRH-stimulated ACTH or cortisol release.


Hyperinsulinemia precedes insulin resistance in mice lacking pancreatic beta-cell leptin signaling.
The adipocyte hormone leptin acts centrally and peripherally to regulate body weight and glucose homeostasis. The pancreatic beta-cell has been shown to be a key peripheral target of leptin, with leptin suppressing insulin synthesis and secretion from beta-cells both in vitro and in vivo. Mice with disrupted leptin signaling in beta-cells (lepr(flox/flox) RIPcre tg+ mice) display hyperinsulinemia, insulin resistance, glucose intolerance, obesity, and reduced fasting blood glucose. We hypothesized that hyperinsulinemia precedes the development of insulin resistance and increased adiposity in these mice with a defective adipoinsular axis. To determine the primary defect after impaired beta-cell leptin signaling, we treated lepr(flox/flox) RIPcre tg+ mice with the insulin sensitizer metformin or the insulin-lowering agent diazoxide with the rationale that pharmacological improvement of the primary defect would alleviate the secondary symptoms. We show that improving insulin sensitivity with metformin does not normalize hyperinsulinemia, whereas lowering insulin levels with diazoxide improves insulin sensitivity. Taken together, these results suggest that hyperinsulinemia precedes insulin resistance in beta-cell leptin receptor-deficient mice, with insulin resistance developing as a secondary consequence of excessive insulin secretion. Therefore, pancreatic beta-cell leptin receptor-deficient mice may represent a model of obesity-associated insulin resistance that is initiated by hyperinsulinemia.


Photoaffinity labeling combined with mass spectrometric approaches as a tool for structural proteomics.
Protein chemistry, such as crosslinking and photoaffinity labeling, in combination with modern mass spectrometric techniques, can provide information regarding protein-protein interactions beyond that normally obtained from protein identification and characterization studies. While protein crosslinking can make tertiary and quaternary protein structure information available, photoaffinity labeling can be used to obtain structural data about ligand-protein interaction sites, such as oligonucleotide-protein, drug-protein and protein-protein interaction. In this article, we describe mass spectrometry-based photoaffinity labeling methodologies currently used and discuss their current limitations. We also discuss their potential as a common approach to structural proteomics for providing 3D information regarding the binding region, which ultimately will be used for molecular modeling and structure-based drug design.


Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation.
Epithelial-mesenchymal transition (EMT), a critical process of cancer invasion and metastasis, is associated with stemness property of cancer cells. Though Oct4 and Nanog are homebox transcription factors essential to the self-renewal of stem cells and are expressed in several cancers, the role of Oct4/Nanog signaling in tumorigenesis is still elusive. Here microarray and quantitative real-time PCR analysis showed a parallel, elevated expression of Oct4 and Nanog in lung adenocarcinoma (LAC). Ectopic expressions of Oct4 and Nanog in LACs increased the percentage of CD133-expressing subpopulation and sphere formation, enhanced drug resistance, and promoted EMT. Ectopic expressions of Oct4 and Nanog activated Slug and enhanced the tumor-initiating capability of LAC. Furthermore, double knockdown of Oct4 and Nanog suppressed the expression of Slug, reversed the EMT process, blocked the tumorigenic and metastatic ability, and greatly improved the mean survival time of transplanted immunocompromised mice. The immunohistochemical analysis demonstrated that expressions of Oct4, Nanog, and Slug were present in high-grade LAC, and triple positivity of Oct4/Nanog/Slug indicated a worse prognostic value of LAC patients. Our results support the notion that the Oct4/Nanog signaling controls epithelial-mesenchymal transdifferentiation, regulates tumor-initiating ability, and promotes metastasis of LAC.


Tuberculous Lymphadenitis in a Patient Treated with Dupilumab: A Case Report.
Tuberculous lymphadenitis is among the most frequent presentations of extrapulmonary tuberculosis; the most common presentation is isolated chronic non-tender lymphadenopathy in young adults without systemic symptoms. Dupilumab is a fully human monoclonal antibody directed against interleukin-4 receptor-α that blocks the synergistic effects of interleukin-4 and interleukin-13 on allergic inflammation. Its well-known adverse events are allergic conjunctivitis, injection site reaction, and dupilumab facial redness. A 32-year-old female with severe atopic dermatitis was treated with dupilumab for 2 months at our clinic. She complained of multiple enlarged palpable lymph nodes on the right side of the neck and inguinal area for 2 months. Laboratory tests showed an increased total eosinophil count and immunoglobulin E level, as well as positive interferon-γ release assays. Radiological examination showed multiple low echoic and heterogeneous well-enhancing lymph nodes in level II, III, IV, and V of the neck. Histological examination revealed caseous necrosis and tuberculoid granuloma. The lymph node enlargements were completely relieved after antituberculosis treatment. The mechanism for the development of tuberculous lymphadenitis in a patient receiving dupilumab is not fully understood yet. In some previous studies, treatment with dupilumab suppressed the expression of genes related not only to T helper 2 and eosinophil response but also to proinflammatory responses. It could not inhibit the intracellular growth of Mycobacterium tuberculosis in macrophages, predisposing them to the development of tuberculous infection. To the best of our knowledge, this is the first report on the development of tuberculosis lymphadenitis in a patient treated with dupilumab.


[Local excision with transanal endoscopic microsurgery (TEM) after endoscopic R1/R2-polypectomy of pT1 "low-risk" carcinomas of the rectum].
The transanal endoscopic microsurgery (TEM) is an adequate method for the local full-thickness excision of large rectum polyps and pT1 "low-risk" rectal carcinomas. We studied prospectively the relevance of this surgical technique concerning complete tumour excision after R1/R2-polypectomy of malignant rectal polyps. 16 patients with pT1 "low-risk" rectal carcinoma and macroscopic (R2) or microscopic (R1) incomplete endoscopic polypectomy were locally resected by TEM. In 12 patients (75 %) no residual tumour was found. In the remaining four cases (25 %), one adenoma with high-grade atypia, two pT1 "low-risk" carcinomas and one tumour infiltration in the mesorectal fat were diagnosed. The patient with the mesorectal infiltration was immediately operated on with radical resection. No further tumour cells were found in this specimen. The median follow-up was 21 months. One patient with a pT1 "low-risk" carcinoma developed a local recurrence and a single hepatic metastasis in the left liver lobe after TEM. Both were completely resected. Currently, all patients are living without evidence of tumour recurrence. Transanal endoscopic microsurgery is a suitable method for the treatment of pT1 "low-risk" rectal carcinomas after incomplete endoscopic polypectomy. In cases of a "high-risk" tumour or deeper tumour infiltration (pT> 1) after TEM radical resection must be carried out.


Cardiac surgery, the brain, and inflammation.
Cognitive deterioration can reliably be measured after procedures requiring anesthesia and surgery. Cardiac surgery has had the spotlight because of the high reported incidence of postoperative cognitive dysfunction in early studies, but such effects occur after other surgical procedures as well. "Early" postoperative cognitive dysfunction should be considered as a different phenomenon, relating to acute pharmacological, physiological, and stress-related recovery. The focus should be on what is affecting patients at 3 months, 12 months, and 5 years later. Like with many other aspects of perioperative risk, a significant element is the patient's preoperative cognitive status. We now know that up to one-third of overtly "normal" elective cardiac surgical patients enter surgery with some degree of pre-existing cognitive impairment or, when applying psychogeriatric measures, mild cognitive impairment. The latter is a known prodrome or early stage of the amyloid associated Alzheimer's disease dementia. Inflammatory responses during cardiac surgery have been recognized for years, but our understanding of the complexity of systemic inflammatory response has grown significantly with the ability to assay neurohumoral markers such as interleukins. The blood-brain barrier is made vulnerable by both pre-existing disorders (mild cognitive impairment/amyloid; vascular disease) and by the inflammatory response to surgery and cardiopulmonary bypass. Inflammation affecting the brain at this time may set in motion accelerated neurological and hence cognitive decline that, despite an initial recovery and even functional improvement, may proceed to further long-term decline at an accelerated rate in susceptible individuals. Clinical data are emerging from longer-term studies to support this concern, but evidence for effective preventive or therapeutic strategies is limited.


Molecular binding of different classes of organophosphates to methyl parathion hydrolase from Ochrobactrum species.
Methyl parathion hydrolase (MPH) is an enzyme of the metallo-β-lactamase superfamily, which hydrolyses a wide range of organophosphates (OPs). Recently, MPH has attracted attention as a promising enzymatic bioremediator. The crystal structure of MPH enzyme shows a dimeric form, with each subunit containing a binuclear metal ion center. MPH also demonstrates metal ion-dependent selectivity patterns. The origins of these patterns remain unclear but are linked to open questions about the more general role of metal ions in functional evolution and divergence within enzyme superfamilies. We aimed to investigate and compare the binding of different OP pesticides to MPH with cobalt(II) metal ions. In this study, MPH was modeled from Ochrobactrum sp. with different OP pesticides bound, including methyl paraoxon and dichlorvos and profenofos. The docked structures for each substrate optimized by DFT calculation were selected and subjected to atomistic molecular dynamics simulations for 500 ns. It was found that alpha metal ions did not coordinate with all the pesticides. Rather, the pesticides coordinated with less buried beta metal ions. It was also observed that the coordination of beta metal ions was perturbed to accommodate the pesticides. The binding free energy calculations and structure-based pharmacophore model revealed that all the three substrates could bind well at the active site. However, profenofos exhibit a stronger binding affinity to MPH in comparison to the other two substrates. Therefore, our findings provide molecular insight on the binding of different OP pesticides which could help us design the enzyme for OP pesticides degradation.


A Clinical Tool to Predict Low Serum Selenium in Patients with Worsening Heart Failure.
Selenium is an essential micronutrient, and a low selenium concentration (<100 µg/L) is associated with a poorer quality of life and exercise capacity, and an impaired prognosis in patients with worsening heart failure. Measuring selenium concentrations routinely is laborious and costly, and although its clinical utility is yet to be proven, an easy implemented model to predict selenium status is desirable. A stepwise multivariable logistic regression analysis was performed using routinely measured clinical factors. Low selenium was independently predicted by: older age, lower serum albumin, higher N-terminal pro-B-type natriuretic peptide levels, worse kidney function, and the presence of orthopnea and iron deficiency. A 10-points risk-model was developed, and a score of ≥6 points identified >80% of patients with low selenium (sensitivity of 44%, specificity of 80%). Given that selenium and iron overlap in their physiological roles, we evaluated the shared determinants and prognostic associates. Both deficiencies shared similar clinical characteristics, including the model risk factors and, in addition, a low protein intake and high levels of C-reactive protein. Low selenium was associated with a similar or worse prognosis compared to iron deficiency. In conclusion, although it is difficult to exclude low selenium based on clinical characteristics alone, we provide a prediction tool which identifies heart failure patients at higher risk of having a low selenium status.


Angong Niuhuang Wan reduces hemorrhagic transformation and mortality in ischemic stroke rats with delayed thrombolysis: involvement of peroxynitrite-mediated MMP-9 activation.
Hemorrhagic transformation (HT) is a common complication of delayed tissue plasminogen activator (t-PA) treatment for ischemic stroke. Peroxynitrite plays an important role in the breakdown of blood-brain barrier (BBB) and the development of HT. We tested the hypothesis that Angong Niuhuang Wan (AGNHW), a traditional Chinese medicinal formula, could be used in conjunction with t-PA to protect the BBB, minimize HT, and improve neurological function by suppressing peroxynitrite-mediated matrix metalloproteinase-9 (MMP-9) activation. We first performed quality control study and chemical identification of AGNHW by using UPLC. In animal experiments, male Sprague-Dawley rats were subjected to 5 h of middle cerebral artery occlusion (MCAO) followed by 19 h of reperfusion plus t-PA infusion (10 mg/kg) at 5 h of cerebral ischemia. AGNHW (257 mg/kg) was given orally at 2 h after MCAO. Hemorrhagic transformation was measured using hemorrhagic scores and hemoglobin levels in ischemic brains. Evans blue leakage was utilized to assess the severity of the blood-brain barrier (BBB) damage. The modified neurologic severity score (mNSS) test was used to assess neurological functions. Peroxynitrite and superoxide was detected by using fluorescent probes. MMP-9 activity and expression were examined by gelatin zymography and immunostaining. The antioxidant effects were also studied by using brain microvascular endothelial b.End3 cells exposed to 5 h of oxygen and glucose deprivation (OGD) plus 5 h of reoxygenation with t-PA treatment (20 µg/ml). AGNHW significantly reduced the BBB damage, brain edema, reduced hemorrhagic transformation, enhanced neurological function, and reduced mortality rate in the ischemic stroke rats with t-PA treatment. AGNHW reduced peroxynitrite and superoxide in vivo and in vitro and six active chemical compounds were identified from AGNHW with peroxynitrite scavenging activity. Furthermore, AGNHW inhibited MMP-9 activity, and preserved tight junction protein claudin-5 and collagen IV in the ischemic brains. AGNHW could be a potential adjuvant therapy with t-PA to protect the BBB integrity, reduce HT, and improve therapeutic outcome in ischemic stroke treatment via inhibiting peroxynitrite-mediated MMP-9 activation.


A defined clathrin-mediated trafficking pathway regulates sFLT1/VEGFR1 secretion from endothelial cells.
FLT1/VEGFR1 negatively regulates VEGF-A signaling and is required for proper vessel morphogenesis during vascular development and vessel homeostasis. Although a soluble isoform, sFLT1, is often mis-regulated in disease and aging, how sFLT1 is trafficked and secreted from endothelial cells is not well understood. Here we define requirements for constitutive sFLT1 trafficking and secretion in endothelial cells from the Golgi to the plasma membrane, and we show that sFLT1 secretion requires clathrin at or near the Golgi. Perturbations that affect sFLT1 trafficking blunted endothelial cell secretion and promoted intracellular mis-localization in cells and zebrafish embryos. siRNA-mediated depletion of specific trafficking components revealed requirements for RAB27A, VAMP3, and STX3 for post-Golgi vesicle trafficking and sFLT1 secretion, while STX6, ARF1, and AP1 were required at the Golgi. Live-imaging of temporally controlled sFLT1 release from the endoplasmic reticulum showed clathrin-dependent sFLT1 trafficking at the Golgi into secretory vesicles that then trafficked to the plasma membrane. Depletion of STX6 altered vessel sprouting in 3D, suggesting that endothelial cell sFLT1 secretion influences proper vessel sprouting. Thus, specific trafficking components provide a secretory path from the Golgi to the plasma membrane for sFLT1 in endothelial cells that utilizes a specialized clathrin-dependent intermediate, suggesting novel therapeutic targets.


Noninvasive in vivo analysis of human small intestinal paracellular absorption: regulation by Na+-glucose cotransport.
Activation of intestinal Na+-glucose cotransport increases paracellular movement of inert tracers in cultured monolayers, isolated rodent intestinal mucosae, and in rodents in vivo. However, not all studies have demonstrated comparable effects on human intestinal paracellular absorption. We sought to assess the effects of Na+-glucose cotransport on paracellular absorption in human beings using a simple noninvasive assay. Study subjects drank six 200-ml doses of test solution, composed of 0.8% w/v creatinine (sufficient to overwhelm endogenous creatinine) in 277 mM glucose or mannitol and urine was collected. Intestinal creatinine absorption is paracellular. Once absorbed, creatinine is cleared into the urine. Therefore, urinary creatinine recovery reflects intestinal paracellular creatinine absorption. Total urinary creatinine recovery was 55% +/- 4% of creatinine ingested with glucose and 38% +/- 9% of creatinine ingested with mannitol (p < 0.001). Thus, intestinal paracellular absorption of creatinine is increased by the presence of luminal glucose. Our results are consistent with in vivo human regulation of mucosal permeability by Na+-glucose cotransport.


Absence of concentration congruity in six compounded polidocanol samples obtained for leg sclerotherapy.
In the arena of venous sclerotherapy, sodium tetradecyl sulfate (STS), hypertonic saline, and polidocanol (POL) are the most widely used agents in the world for treating endothelial vein wall destruction. Pharmaceutical-grade STS and hypertonic saline are available from manufacturers. Until 2010, POL was only available in the United States through compounding pharmacies. To identify whether a risk exists when using freely available compounded POL samples for venous sclerotherapy. Six samples of 1% POL solutions obtained from four compounding pharmacies were evaluated using gas chromatography mass spectrometry (GC/MS) assays for POL concentration and identification of material impurities. Disparities in POL concentrations between six samples ranged from 1.0% to 3.1%. The GC/MS analysis showed impurities in all six compounded POL samples. In this study, compounded POL solutions did not deliver the claimed concentration five out of six times. This inconsistency poses risks to the patient and the treating physician during venous sclerotherapy with pharmacy-compounded POL. Merz Aesthetics provided funding for this study.


[Release by agitation of constituents from cell walls of Pseudomonas aeruginosa. III. Communication: Electron microscopy (author's transl)].
A thermovariable inhibition of agglutination (EA) was demonstrated in two randomly chosen strains of Pseudomonas aeruginosa (table 1, article I). The temperature range from the loss of agglutinability to its recovery was as described in previous articles (II). The agglutination patterns were similar to those of the O-group-type strains 1 and 4, indicating that the IA is a widespread property among Pseudomonas aeruginosa strains. Shaking at moderate intensities for 20-60 hours restored the thermosensitive agglutinability (Table 2, article I), and the times necessary for restoration were somewhate dependent on the specific culture media and the strains used (table3, article I). After restoration of agglutinability the bacteria had maintained their capability to form stable suspensions in physiological saline solution (table 2, article I). Another treatment at elevated temperature did not result in an IA (table 5c, article I). During the shaking the pelleted bacteria did no longer exhibit their normal slimy stickiness, similar to what has been observed after treatment with hyaluronidase (17). When the shaking was continued after restoration of agglutinability a special serological phenomenon ("Rauh-Phänomen," cf. table 5b in article I) was noted. Suspension of the bacteria in physiological saline for 7 days did not result in the recovery from the thermovariable IA (table 4, article 1). The secondary forms of the agglutinates were similar to those of Enterobacteriaceae, the typical primary form of the agglutination into slimy networks and spheres was not observed upon the restoration of agglutinability. The hypothesis that loosely bound surface components are responsible for the thermovariable IA was examined by chemical analyses of the fractionated supernatants obtained during the shaking treatments. The first supernatant fractions obtained after relatively brief shaking periods exhibited a high viscosity, in contrast to the low viscosity of supernatants harvested later. Total acetone-precipitable material from the supernatants contained lipids, proteins and carbohydrates, however, at different ratios (tables 1, 2, 3, article II). The amounts of lipids recovered from the supernatants were similar in all fractions during the shaking treatment, whereas protein-carbohydrate complex material was maximal in the first fractions and significantly decreased in fractions harvested later (table 1 and 2, article II). The data indicated, that the restored agglutinability at elevated temperatures and the maintained suspensibility in physiological saline was due to the removal of a limited amount of material from the most superficial layer of the bacterial wall; however in the continuous presence of the cell membrane and perhaps also of the internal cell wall layers (see also 8). This concept was examined by electron microscopy. The morphology of the native bacteria is illustrated in figures 1-3 (article III)...


Population genetic structure of the prairie dog flea and plague vector, Oropsylla hirsuta.
Oropsylla hirsuta is the primary flea of the black-tailed prairie dog and is a vector of the plague bacterium, Yersinia pestis. We examined the population genetic structure of O. hirsuta fleas collected from 11 prairie dog colonies, 7 of which had experienced a plague-associated die-off in 1994. In a sample of 332 O. hirsuta collected from 226 host individuals, we detected 24 unique haplotype sequences in a 480 nucleotide segment of the cytochrome oxidase II gene. We found significant overall population structure but we did not detect a signal of isolation by distance, suggesting that O. hirsuta may be able to disperse relatively quickly at the scale of this study. All 7 colonies that were recently decimated by plague showed signs of recent population expansion, whereas 3 of the 4 plague-negative colonies showed haplotype patterns consistent with stable populations. These results suggest that O. hirsuta populations are affected by plague-induced prairie dog die-offs and that flea dispersal among prairie dog colonies may not be dependent exclusively on dispersal of prairie dogs. Re-colonization following plague events from plague-free refugia may allow for rapid flea population expansion following plague epizootics.


Inhibition of neutral sphingomyelinase protects mice against systemic tuberculosis.
Tuberculosis is one of the most serious infectious diseases worldwide. The initial pulmonal localization of the pathogens often develops into systemic infection with high lethality. We investigated the role of the mammalian neutral sphingomyelinase (Nsm)/ceramide system in systemic infection of mice and murine macrophages with Mycobacterium bovis Bacillus Calmette-Guerin (BCG). Our results demonstrate that BCG infection of RAW cells, a macrophage cell line, results in rapid activation of Nsm but not of acid sphingomyelinase (Asm). Activation of Nsm is associated with a massive release of superoxide. Genetic knock-down of Nsm in RAW cells prevented superoxide production upon BCG infection. Superoxide suppressed autophagy in BCG-infected macrophages in vitro and in vivo: Knock-down of Nsm or inhibition of superoxide restored autophagy in macrophages and increased killing of intracellular bacteria upon BCG infection. Most importantly, autophagy was also massively increased in Nsm-heterozygous mice, protecting these mice from systemic BCG infections, granuloma development, and chronic infections of liver and spleen. These findings indicate that the Nsm/ceramide system plays a role in protecting mice against systemic tuberculosis by preventing superoxide-mediated inhibition of autophagy.


Calcium action potentials in hair cells pattern auditory neuron activity before hearing onset.
We found rat central auditory neurons to fire action potentials in a precise sequence of mini-bursts before the age of hearing onset. This stereotyped pattern was initiated by hair cells in the cochlea, which trigger brief bursts of action potentials in auditory neurons each time they fire a Ca2+ spike. By generating theta-like activity, hair cells may limit the influence of synaptic depression in developing auditory circuits and promote consolidation of synapses.


Clinical management of endometriosis.
Endometriosis is a relatively common chronic gynecologic disorder that usually presents with chronic pelvic pain or infertility. The societal effect of this disorder is enormous both in monetary costs and in quality of life. The diagnosis of the disease can only be definitively made with surgical intervention. Fertility may be enhanced with surgical intervention, but medical suppressive therapy has no role apart from in vitro fertilization. Assisted reproductive technology is associated with excellent outcomes. Management of endometriomas is particularly complex because surgical intervention may reduce ovarian reserve. Both medical and surgical treatment of endometriosis-associated chronic pelvic pain are effective in the short-term. Recurrence is common with both modalities. Recurrence after surgical intervention can be decreased with the use of postoperative suppressive medical therapy such as hormonal contraceptives. This article presents the different types of peritoneal disease found in endometriosis patients. The technique used to safely and completely remove the disease is discussed. The specific areas of involvement include the pelvic side wall, the cul-de-sac, and bladder peritoneum.


Hormonal contraceptive use, bone density and biochemical markers of bone metabolism in British Army recruits.
Hormonal contraceptive use might impair bone health and increase the risk of stress fracture by decreasing endogenous oestrogen production, a central regulator of bone metabolism. This cross-sectional study investigated bone density and biochemical markers of bone metabolism in women taking hormonal contraceptives on entry to basic military training. Forty-five female British Army recruits had biochemical markers of bone metabolism, areal bone mineral density (aBMD) and tibial speed of sound (tSOS) measured at the start of basic military training. Participants were compared by their method of hormonal contraception: no hormonal contraception (NONE), combined contraceptive pill (CP) or depot-medroxyprogesterone acetate (DMPA) (20±2.8 years, 1.64±0.63 m, 61.7±6.2 kg). aBMD was not different between groups (p≥0.204), but tSOS was higher in NONE (3%, p=0.014) when compared with DMPA users. Beta C-terminal telopeptide was higher in NONE (45%, p=0.037) and DMPA users (90%, p=0.003) compared with CP users. Procollagen type 1 N-terminal propeptide was higher in DMPA users compared with NONE (43%, p=0.045) and CP users (127%, p=0.001), and higher in NONE compared with CP users (59%, p=0.014). Bone alkaline phosphatase was higher in DMPA users compared with CP users (56%, p=0.044). DMPA use was associated with increased bone turnover and decreased cortical bone integrity of the tibia. Lower cortical bone integrity in DMPA users was possibly mediated by increased intracortical remodelling, but trabecular bone was not affected by contraceptive use.


Influence of continuous or intermittent blood flow restriction on muscle activation during low-intensity multiple sets of resistance exercise.
Low-intensity resistance exercise with blood flow restriction (BFR) has been shown to induce a prominent increase in muscle activation in response to muscle fatigue. However, the magnitude of muscle fatigue between continuous (Con-BFR) and intermittent BFR (Int-BFR, BFR only during exercise) is currently unknown. We examined the effect of Con-BFR or Int-BFR on muscle activation during exercise. Unilateral arm curl exercise (20% of one-repetition maximum, four sets, 30 sec rest period between sets) was performed without (CON) or with Con-BFR or Int-BFR. During BFR conditions, the cuff was inflated to 160 mmHg on the proximal region of testing arm. Surface electromyography (EMG) was recorded from the biceps brachii muscle, and integrated EMG (iEMG) was analyzed. During the exercise, iEMG increased progressively in Con-BFR and Int-BFR and both conditions were greater (p < 0.05) than CON at the 3rd and 4th set. However, there were no differences (p > 0.05) in iEMG between Con-BFR and Int-BFR during exercise (∼2.45 and ∼2.40 times, respectively). Thus, the magnitude of increase in muscle activation may be similar between Con-BFR and Int-BFR when BFR exercise was performed at a high level of cuff pressure intensity.


Effect of Proton Pump Inhibitors on Colorectal Cancer.
Proton pump inhibitors (PPIs) are administered commonly to aged people; however, their effect on colorectal cancer (CRC) has still not been fully elucidated. Here, we examined the effect of PPIs and consequent alkalization on CRC cells. PPI administration alkalized the fecal pH and increased serum gastrin concentration. PPI and pH8 treatment (alkalization) of CMT93 mouse colon cancer cells inhibited cell growth and invasion, increased oxidative stress and apoptosis, and decreased mitochondrial volume and protein levels of cyclin D1 and phosphorylated extracellular signal-regulated kinase (pERK) 1/2. In contrast, gastrin treatment enhanced growth and invasion, decreased oxidative stress and apoptosis, and increased mitochondrial volume and cyclin D1 and pERK1/2 levels. Concurrent treatment with a PPI, pH8, and gastrin increased aldehyde dehydrogenase activity and also enhanced liver metastasis in the BALB/c strain of mice. PPI administration was associated with Clostridium perfringens enterotoxin (CPE) in CRC lesions. CPE treatment activated yes-associated protein (YAP) signals to enhance proliferation and stemness. The orthotopic colon cancer model of CMT93 cells with long-term PPI administration showed enhanced tumor growth and liver metastasis due to gastrin and YAP activation, as indicated by gastrin receptor knockdown and treatment with a YAP inhibitor. These findings suggest that PPI promotes CRC growth and metastasis by increasing gastrin concentration and YAP activation, resulting in gut flora alteration and fecal alkalization. These findings suggest that PPI use in colorectal cancer patients might create a risk of cancer promotion.


Polyinosinic-polycytidylic acid, an interferon inducer, ameliorates bleomycin-induced lung fibrosis in mice.
The inhibitory effect of polyinosinic-polycytidylic acid (Poly IC), an inducer of interferons, on bleomycin-induced lung collagen accumulation was investigated in mice. Poly IC (10 mg/kg, intraperitoneally) or saline was given for 2 days and immediately prior to intratracheal instillation of bleomycin (0.125 units/mouse) or an equivalent volume of saline and thereafter daily for 13 days. Lung hydroxyproline levels in saline-saline (control), Poly IC-saline (Poly IC), bleomycin-saline and bleomycin-Poly IC groups averaged 279, 287, 459, and 358 micrograms/lung, respectively. The bleomycin + Poly IC mice had significantly less lung hydroxyproline than bleomycin mice, but significantly more hydroxyproline than control or Poly IC mice. Similarly, bleomycin + Poly IC mice had significantly less protein in bronchoalveolar lavage fluid (BALF) supernatant than bleomycin mice, but significantly more protein than control or Poly IC mice. Total cell counts for cells recovered from BALF showed significant increases of 174 and 167% in bleomycin and bleomycin + Poly IC as compared to controls, while the Poly IC group showed a significant decrease of 47% which was primarily due to a decrease in alveolar macrophages. The bleomycin group had significantly more neutrophils, monocytes, macrophages, and lymphocytes than control mice, while bleomycin + Poly IC mice lacked the significant increase in lymphocytes. Bleomycin + Poly IC mice had significantly more monocytes than the bleomycin group. All bleomycin-treated mice had lung lesions, but no lesions were observed in control or Poly IC mice. Bleomycin + Poly IC mice had significantly more (58%) lesions than bleomycin. In contrast, the volume of interstitial lesion in bleomycin + Poly IC mice showed significantly less extracellular fibers (decreased by 62%) and no difference in fibroblasts as compared to bleomycin mice. Fibrotic lesions in bleomycin mice were multifocal and varied from large areas of organized connective tissue to thickened septa lined by cuboidal epithelial cells. Interstitial lesions in bleomycin + Poly IC had a significantly greater volume of mononuclear phagocytes and lymphocytes, but less organized connective tissue than the bleomycin group. Poly IC treatment ameliorated bleomycin-induced lung collagen accumulation.