Directional and spatial motor intentional disorders in patients with right versus left hemisphere strokes.
Motor intentional disorders (MIDs) are characterized by dysfunction in the preparation, initiation, maintenance, and termination of goal-oriented actions. In this study, we investigated (1) whether patients with right hemisphere strokes (RHS) and left hemisphere strokes (LHS) differ in the frequency of delayed action initiation (hypokinesia) and motor impersistence; (2) whether there is a directional or hemispatial component of hypokinesia or motor impersistence; (3) whether there is an association between the presence of hemispatial neglect and tests for MID; and (4) the location of injury associated with MID. Thirty-two patients with acute unilateral stroke (21 with RHS and 11 with LHS) and 12 age-matched healthy controls participated in the study. To determine the presence and severity of directional and spatial hypokinesia and impersistence we used a new apparatus, the Directional Movement Tester (DMT). While being tested with the DMT, the participants held a static bar located either in the right or left hemispace using either their right or left hand and upon stimulus onset pushed the bar either leftward or rightward and maintained a given force for 10 sec. The frequency of hypokinesia and impersistence was higher in the RHS group than in the LHS group, but there were no hypokinetic directional or spatial asymmetries. The RHS group did demonstrate left contralesional directional impersistence, but there were no spatial asymmetries of impersistence. Signs of hemispatial neglect were not associated with these measures of MID. Participants with frontal or subcortical lesions were significantly more likely to demonstrate hypokinesia and impersistence than those with posterior lesions.


Response inhibition in children with different subtypes/presentations of attention deficit hyperactivity disorder: A near-infrared spectroscopy study.
Executive dysfunction in children with attention deficit hyperactivity disorder (ADHD) is thought to be closely related to the prefrontal cortex (PFC). However, there is controversy over the activation of the PFC in children with ADHD. Differences could be related to the subtype. Meanwhile, no study to date has used functional near-infrared spectroscopy (fNIRS) to explore the differences between subtypes. Thus, this study aimed to explore the activation of the PFC in children with different subtypes of ADHD during executive function task. Participants in this study include typically developing (TD) children (n = 28), ADHD-predominantly inattentive (ADHD-PI) (n = 39) and ADHD-combined (ADHD-C) (n = 24). To examine the executive function of ADHD, the Go/No-go task is chosen to assess the response inhibition function. The activation of PFC in all participants during the Go/No-go task was recorded by fNIRS. Meanwhile, behavioral data were also recorded. Both TD and ADHD children activated the right PFC [middle frontal gyrus (MFG) and inferior frontal gyrus (IFG)] during response inhibition. However, the range and degree of activation differed among these groups. Compared with TD children, those with ADHD-PI had a smaller extent of activation in the right PFC, and those with ADHD-C only had a tendency to enhance activation. In addition, children with ADHD-PI and ADHD-C had impaired activation of the temporal gyrus. Besides, compared with ADHD-C and TD, those with ADHD-PI also had impaired activation of the right precentral gyrus (PG), and the supplementary motor area (SMA). Compared with ADHD-PI, ADHD-C showed decreased activation of the right MFG. The activation of Ch34 (BA44, rPFC) in children with ADHD-PI and ADHD-C was negatively correlated with their clinical symptoms. The activation of the PFC in children with different subtypes of ADHD has both commonalities and differences. The degree of activation of the right PFC Ch34 in children with ADHD is negatively correlated with clinical symptoms. fNIRS could be served as a candidate hemodynamic biomarker for the diagnosis of ADHD.


Lewy bodies in the lateral hypothalamus: do they imply neuronal loss?
Lewy bodies have been found in the hypothalamic lateral tuberal nucleus (NTL) and the adjoining tuberomammillary nucleus (TM) in Parkinson's disease (PD). The NTL is severely atrophic in Huntington's disease; the TM seems unaffected. In this study, we examined the NTL and the TM of seven PD patients and one patient with presumed PD to assess whether the presence of Lewy bodies indicated neuronal loss. Most Lewy bodies were found in the TM, but they were also present in the NTL of seven of the eight patients. The number of NTL neurons in the PD patients was similar to a group of 14 nonneurological controls, seven Alzheimer's disease (AD) patients, and two AIDS patients with dementia. This challenges the hypothesis that Lewy bodies are a sign of significant cell death. The TM, whose cells could not be counted, did not seem depleted in neuronal numbers, although occasional neuronophagia was observed.


Shape decomposition algorithms for laser capture microdissection.
In the context of biomarker discovery and molecular characterization of diseases, laser capture microdissection is a highly effective approach to extract disease-specific regions from complex, heterogeneous tissue samples. For the extraction to be successful, these regions have to satisfy certain constraints in size and shape and thus have to be decomposed into feasible fragments. We model this problem of constrained shape decomposition as the computation of optimal feasible decompositions of simple polygons. We use a skeleton-based approach and present an algorithmic framework that allows the implementation of various feasibility criteria as well as optimization goals. Motivated by our application, we consider different constraints and examine the resulting fragmentations. We evaluate our algorithm on lung tissue samples in comparison to a heuristic decomposition approach. Our method achieved a success rate of over 95% in the microdissection and tissue yield was increased by 10-30%. We present a novel approach for constrained shape decomposition by demonstrating its advantages for the application in the microdissection of tissue samples. In comparison to the previous decomposition approach, the proposed method considerably increases the amount of successfully dissected tissue.


Predicting Nanoparticle Delivery to Tumors Using Machine Learning and Artificial Intelligence Approaches.
Low delivery efficiency of nanoparticles (NPs) to the tumor is a critical barrier in the field of cancer nanomedicine. Strategies on how to improve NP tumor delivery efficiency remain to be determined. This study analyzed the roles of NP physicochemical properties, tumor models, and cancer types in NP tumor delivery efficiency using multiple machine learning and artificial intelligence methods, using data from a recently published Nano-Tumor Database that contains 376 datasets generated from a physiologically based pharmacokinetic (PBPK) model. The deep neural network model adequately predicted the delivery efficiency of different NPs to different tumors and it outperformed all other machine learning methods; including random forest, support vector machine, linear regression, and bagged model methods. The adjusted determination coefficients (R2) in the full training dataset were 0.92, 0.77, 0.77 and 0.76 for the maximum delivery efficiency (DEmax), delivery efficiency at 24 h (DE24), at 168 h (DE168), and at the last sampling time (DETlast). The corresponding R2 values in the test dataset were 0.70, 0.46, 0.33 and 0.63, respectively. Also, this study showed that cancer type was an important determinant for the deep neural network model in predicting the tumor delivery efficiency across all endpoints (19-29%). Among all physicochemical properties, the Zeta potential and core material played a greater role than other properties, such as the type, shape, and targeting strategy. This study provides a quantitative model to improve the design of cancer nanomedicine with greater tumor delivery efficiency. These results help to improve our understanding of the causes of low NP tumor delivery efficiency. This study demonstrates the feasibility of integrating artificial intelligence with PBPK modeling approaches to study cancer nanomedicine.


[The use of lasers in the treatment of urolithiasis].
The treatment of calculi in the urinary tract has been subject to major changes over the last few years. Since extracorporeal shockwave lithotripsy (ESWL) is the first choice of treatment, there appears to be little need for endoscopic and surgical techniques. In case ESWL treatment is unsuccessful or inadequate, laser lithotripsy is a good alternative. In most cases, laser lithotripsy causes a good disintegration with use of very thin and flexible instrumentation. Hence, the risk of damage to the urinary tract is much less than with other endoscopic techniques such as ultrasonic and electrohydraulic lithotripsy. Our first results with 21 bladder and 18 ureter calculi in 25 patients were a successful disintegration of 84% of bladder calculi and a 70% success for ureter calculi. Only one complication of the ureteroscopic manipulation was observed. Disadvantages of laser lithotripsy are the high price of the equipment and the fact that not all calculi can be fragmented with one type of laser.


The association between non-alcoholic hepatic steatosis and mean platelet volume in an obese Korean population.
Non-alcoholic fatty liver disease (NAFLD) is now the most common liver disease. Since the prevalence of NAFLD in overweight/obese people is rather high, there is a general concern about the possibility that NAFLD may have an association with cardiovascular risk factors and atherosclerosis. Mean platelet volume (MPV) is becoming of increasing interest as a new independent cardiovascular risk factor. Accordingly, the aim of our study was to evaluate the relationship between NAFLD and MPV in obese patients. The study was performed at the health promotion center in Gangnam Severance Hospital between July 2007 and June 2008. A total of 6499 healthy subjects (age range, 20-65 years) were recruited in Seoul. We performed a cross-sectional study to evaluate the association with non-alcoholic hepatic steatosis (NAHS) and MPV in 628 obese subjects. The population was divided into three groups according to MPV values. (T1 : MPV ≤ 7.7 fL, T2 : 7.7 < ≤ 8.4, T3 : > 8.4) The odds ratios (ORs) for NAHS were calculated across all three groups. The prevalence of NAHS was significantly higher according to increased MPV values after adjustment for confounding variables. The adjusted OR for NAHS according to the three groups were 1.00, 2.01(1.14 ∼ 3.56), and 2.12(1.11 ∼ 4.06) in obese subjects. In summary, there was a significant association between NAHS and MPV in obese study population.


CRISPR/Cas9-mediated cervical cancer treatment targeting human papillomavirus E6.
High-risk human papillomavirus (HPV) is a common cause of cervical cancer. HPV E6 oncoprotein promotes the degradation of host tumor suppressor gene p53, leading to the development of tumors. Therapeutic strategies that specifically target E6, which is constitutively expressed in tumors and is not present in normal tissues, may be highly effective and safe. CRISPR-CRISPR associated protein 9 (Cas9) is one of the genome editing technologies that has recently garnered attention, and is used to knockout target gene expression. By combining cervical cancer cell lines engineered to constitutively express Cas9 and an adeno-associated virus (AAV) vector carrying a single guide (sg) RNA targeting E6 (AAV-sgE6), the present study sought to investigate the effects of this novel therapeutic approach on cervical cancer. The Cas9 gene was transfected into three high-risk HPV-positive cervical cancer cell lines (HeLa, HCS-2, and SKG-I) to establish cell lines that constitutively expressed Cas9. Using these cell lines, genetic mutations and their frequencies, as well as the levels of protein expression, apoptosis and cell proliferation were examined in vitro. In addition, the effects of AAV-sgE6 were examined in a mouse model of cervical cancer in vivo by a single administration of AAV-sgE6 directly into subcutaneous tumors. The results demonstrated that multiple mutations occurred frequently in the targeted E6 genomic sequence in cervical cancer cells transduced with AAV-sgE6. In addition, these AAV-sgE6-transduced cells had reduced expression of E6, increased expression of p53, increased apoptosis and their growth was suppressed in a concentration-dependent manner. Furthermore, subcutaneous tumor growth was significantly suppressed in vivo following intratumoral administration of AAV-sgE6, and adverse events due to AAV-sgE6 administration were not observed. Collectively, the present results indicated that targeting E6 expression in high-risk HPV by CRISPR-Cas9 is a highly specific and effective strategy that may be effective in treating patients with cervical cancer.


Lateral mass screw complications: analysis of 1662 screws.
Retrospective, consecutive patient series. To quantify the risks and the complications associated with screw fixation devices of the cervical spine. The usefulness of lateral mass internal fixation has been well documented in the clinical setting. However, there is a paucity of studies examining the complications associated with these devices in a degenerative clinical setting. From 1999 to 2007, 225 consecutive patients underwent posterior cervical fixation using a screw-plate and polyaxial screw-rod implant systems. There were 105 women and 120 men (age range: 45 to 84 y; mean, 68 y). In all patients, the surgical indication was cervical spondylosis with myelopathy. Mean follow-up interval was 18 months (range: 12 to 72 mo). Screw position was evaluated by computed tomography scanning postoperatively in all patients. Clinical and radiographic outcome was assessed at each visit after surgery. Intraoperative complications include fracture of lateral mass in 27 screws placement and nerve irritation in 3 bicortical screws. Early complications include hematoma formation in 2 cases and C5 root palsy in 5 cases after spinal canal decompression. Late complications include pseudarthrosis in 6 cases and screw pull-out in 3 cases. There were no cases of spinal cord or vertebral artery injury, infections, deaths, or adjacent segment disease. All patients had radiographic union, and no patient developed mechanical implant failure requiring removal of instrumentation. Reoperation was required in 14 (6.2%) cases because of nerve injury, hematoma formation, pseudarthrosis, and screw pull-out. Our clinical findings indicate that lateral mass fixation can be used safely with minimal complications and low rate of morbidity for cervical myelopathy treatment.


Cardiac Myosin Epitopes Recognized by Autoantibody in Acute and Convalescent Rheumatic Fever.
Acute rheumatic fever (ARF) is an autoimmune disorder associated with Streptococcus pyogenes infection. A prevailing hypothesis to account for this disease is that epitopes of self-antigens, such as cardiac myosin react to antibodies against S. pyogenes. The goal of our study was to confirm disease epitopes of cardiac myosin, identify immunodominant epitopes and to monitor the epitope response pattern in acute and convalescent rheumatic fever. Enzyme-linked immunosorbant assays were used to determine epitopes immunodominant in acute disease and to track the immune response longitudinally to document any changes in the epitope pattern in convalescent sera. Multiplex fluorescence immunoassay was used to correlate anti-streptolysin O (ASO) and anti-human cardiac myosin antibodies. Disease-specific epitopes in rheumatic fever were identified as S2-1, 4 and 8. Epitopes S2-1, 4, 8 and 9 were found to be immunodominant in acute sera and S2-1, 8, 9, 29 and 30 in the convalescent sera. Frequency analysis showed that 50% of the ARF subjects responded to S2-8. S2-8 responders tended to maintain their epitope pattern throughout the convalescent period, whereas the S2-8 nonresponders tended to spread their responses to other epitopes later in the immune response. There was a significant correlation between anti-cardiac myosin and ASO titers. In addition, S2-8 responders showed elevated ASO titers compared with S2-8 non responders. Our studies confirm the existence of S2-1, 4 and 8 as disease-specific epitopes. We provide evidence that cardiac myosin S2-8 responders remain epitope stable in convalescence, whereas S2-8 nonresponders shift to neoepitopes. Multiplex data indicated a correlation between elevated ASO and anti-human cardiac myosin antibody titers. Mapping of cardiac myosin epitopes recognized in rheumatic fever sera may identify immunophenotypes of rheumatic fever.


Interaction of iron nanoparticles with nervous system: an in vitro study.
Nanoparticles (NPs) are one of the interesting and widely studying issues mainly because of their particular physico-chemical features and broad applications in the field of biomedical sciences, such as diagnosis and drug delivery. In this study, the interaction of iron nanoparticles (Fe-NPs) with Tau protein and PC12 cell, as potential nervous system models, was investigated with a range of techniques including dynamic light scattering, intrinsic fluorescence spectroscopy, circular dichroism, [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium-bromid] assay, and acridine orange/ethidium bromide (AO/EB) dual staining method. An inverse correlation between Stern and Volmer constant (KSV) and temperature indicated a probable static quenching mechanism occurred between Tau protein and Fe-NPs. The number of binding site (n = 0.86) showed that there is almost one binding site of Fe-NP per protein. The negative values of ∆H (-53.21 kJ/mol) and T∆S (-42.44 kJ/mol) revealed that Fe-NPs interacts with Tau protein with dominate role of hydrogen bonds and van der Waals interactions and this interaction was spontaneous (∆G = -10.77 kJ/mol). Also, Fe-NPs stabilized the random coil structure of Tau protein. Moreover, Fe-NPs reduced PC12 cells viability by fragmentation of DNA in an apoptotic manner. In conclusion, induced conformational changes of Tau protein and cytotoxicity of PC12 cells by Fe-NP were revealed to be in a concentration and time-dependent manner.


Self-Healing Property of Ultra-Thin Wearing Courses by Induction Heating.
Ultra-thin wearing course (UTWC) has been developed in pavement preventive maintenance for many years. However, how to prolong the service life of UTWC still requires further research. This study introduced AC-5 and SMA-5 asphalt mixtures, which can be induction heated. Steel fiber and steel slag were used in the mixtures as additives. Marshall Stability and induction heating property of mixtures were characterized. In addition, self-healing property of UTWC materials had been emphatically conducted. Adding steel fiber in mixtures led to higher Marshall Stability and lower flow value, while steel slag generally showed a negative effect. Induction heating property showed a positive relationship with the additives. Induction heating time was positively correlated to the healing ratio of the mixtures. Induction heating on the mixtures could recover the strength of mixtures to a certain degree. Mixtures with more steel fiber showed a higher healing ratio. Basalt-steel slag based mixtures showed better healing ratios than the basalt based mixtures. The healing ratios of mixtures illustrated a decreasing tendency as the healing cycle increased.


Review of Endometriosis Diagnosis through Advances in Biomedical Engineering.
Endometriosis is characterized as the ectopic presence of endometrium in various locations within the abdominal cavity, such as the fallopian tube, the pouch of Douglas, the ovaries, outside the ovaries, and more. The inner lining of the uterus, endometrium, is a dynamic tissue that undergoes morphological and functional changes cyclically. The proliferation of endometrial cells during menstruation is influenced by increasing circulating estrogen levels. Adult progenitor stem cells are likely responsible for this remarkable regenerative capacity and hence, enhanced capacity to generate endometriosis. This chronic estrogen-dependent disease is characterized by the ectopic endometrial implant. The disorder occurs in 6%-10% of reproductive-aged women and in 35%-50% of women with pelvic pain and infertility. Currently, the preferred diagnostic methods are laparoscopic inspection by transvaginal ultrasound, MRI, and sensors. Diagnoses with transvaginal ultrasound have 92.7% sensitivity and 97% specificity in detecting endometriotic lesions. On average, MRI diagnoses of DIE have 74% sensitivity and 95% specificity. Lastly, chemical sensors have 91.7% sensitivity and 90.0% specificity in detecting endometriosis. The standard of care includes personalizing the treatment plan based on the individual's set of symptoms and their severity. Advances in biomedical engineering have aided professionals in personalizing the course of treatments as well as to increasing the quality of life of these patients through various therapies for managing pain. Because no one theory provides a full explanation for the manifestation of the disease, hormonal therapies, targeted therapeutics, and surgical options have emerged as elements of disease management. Clinicians are in the process of developing advanced pharmaceutical drugs with specific orphan target receptors of the ectopic tissue. Possible complications that accompany the condition include dyspareunia, hyperalgesia, infertility, and many others.


A new age for vaccine therapy in renal cell carcinoma.
Over the past several years, the dominant paradigm in drug development for metastatic renal cell carcinoma (mRCC) has been to more selectively and potently target moieties such as the vascular endothelial growth factor receptor. The effectiveness of this strategy appears to be nearing a plateau, however, underscoring the need for novel approaches. Vaccine-based therapies represent one such approach. Several distinct vaccines are currently being examined in mRCC, each using a distinct mechanism of action. For instance, the autologous dendritic cell vaccine AGS-003 uses patient-specific antigens derived from primary tumor tissue. In contrast, the poxvirus vaccine TG4010 produces an antigenic response to MUC1, a cell surface glycoprotein that reduces cell-cell interactions and thereby precludes contact inhibition. Other vaccines elicit a response to a broader spectrum of antigens-for instance, the vaccine IMA901 is based on 9 tumor-associated peptides identified from a novel biotechnology platform combining mass spectroscopy, microarray analysis of RNA expression, and immunogenicity assays. Herein, the current status of vaccine-based therapies for mRCC is described in detail. Furthermore, challenges to clinical implementation (eg, cost, optimal pairing with targeted agents, appropriate sequencing) are presented.


Disparity processing in primary visual cortex.
The first step in binocular stereopsis is to match features on the left retina with the correct features on the right retina, discarding 'false' matches. The physiological processing of these signals starts in the primary visual cortex, where the binocular energy model has been a powerful framework for understanding the underlying computation. For this reason, it is often used when thinking about how binocular matching might be performed beyond striate cortex. But this step depends critically on the accuracy of the model, and real V1 neurons show several properties that suggest they may be less sensitive to false matches than the energy model predicts. Several recent studies provide empirical support for an extended version of the energy model, in which the same principles are used, but the responses of single neurons are described as the sum of several subunits, each of which follows the principles of the energy model. These studies have significantly improved our understanding of the role played by striate cortex in the stereo correspondence problem.This article is part of the themed issue 'Vision in our three-dimensional world'.


[Brain SPECT by intraarterial infusion of 99mTc-HMPAO for assessing the cerebral distribution of carotid artery infusions in patients with brain tumor].
In order to assess the cerebral distribution of intracarotid chemotherapy, 17 postoperative patients with brain tumor underwent brain SPECT obtained by intraarterial infusion of 18.5 MBq of 99mTc-HMPAO. Injection methods were continuous (5.0 ml/min) or pulsatile infusion with supraor infraophthalmic catheterization. The findings obtained by brain SPECT were frequently different from those of angiography and/or DSA. In supraophthalmic catheterization with continuous infusion, only 2 of 10 studies (20%) had homogeneous distribution and 5 of them (50%) had maldistribution of 99mTc-HMPAO which appears in association with laminar flow effect. The remaining 3 studies showed localized distribution (two: tumor localization, one: healthy brain localization). On the other hand, all of 5 studies with pulsatile infusion had homogeneous distribution of 99mTc-HMPAO. In infraophthalmic catheterization, all but one of 5 studies had homogeneous distribution with continuous infusion. These results suggest that pulsatile infusion may be effective in eliminating maldistribution of 99mTc-HMPAO in supraophthalmic catheterization. In conclusion, we are convinced that 99mTc-HMPAO is a useful intraarterial agent for assessing cerebral distribution of intracarotid chemotherapy.


Strain- and Substrate-Dependent Redox Mediator and Electricity Production by Pseudomonas aeruginosa.
Pseudomonas aeruginosa is an important, thriving member of microbial communities of microbial bioelectrochemical systems (BES) through the production of versatile phenazine redox mediators. Pure culture experiments with a model strain revealed synergistic interactions of P. aeruginosa with fermenting microorganisms whereby the synergism was mediated through the shared fermentation product 2,3-butanediol. Our work here shows that the behavior and efficiency of P. aeruginosa in mediated current production is strongly dependent on the strain of P. aeruginosa We compared levels of phenazine production by the previously investigated model strain P. aeruginosa PA14, the alternative model strain P. aeruginosa PAO1, and the BES isolate Pseudomonas sp. strain KRP1 with glucose and the fermentation products 2,3-butanediol and ethanol as carbon substrates. We found significant differences in substrate-dependent phenazine production and resulting anodic current generation for the three strains, with the BES isolate KRP1 being overall the best current producer and showing the highest electrochemical activity with glucose as a substrate (19 μA cm(-2) with ∼150 μg ml(-1) phenazine carboxylic acid as a redox mediator). Surprisingly, P. aeruginosa PAO1 showed very low phenazine production and electrochemical activity under all tested conditions. Microbial fuel cells and other microbial bioelectrochemical systems hold great promise for environmental technologies such as wastewater treatment and bioremediation. While there is much emphasis on the development of materials and devices to realize such systems, the investigation and a deeper understanding of the underlying microbiology and ecology are lagging behind. Physiological investigations focus on microorganisms exhibiting direct electron transfer in pure culture systems. Meanwhile, mediated electron transfer with natural redox compounds produced by, for example, Pseudomonas aeruginosa might enable an entire microbial community to access a solid electrode as an alternative electron acceptor. To better understand the ecological relationships between mediator producers and mediator utilizers, we here present a comparison of the phenazine-dependent electroactivities of three Pseudomonas strains. This work forms the foundation for more complex coculture investigations of mediated electron transfer in microbial fuel cells.


Impact of progesterone on the immune system in women: a systematic literature review.
The immune system is influenced by many factors, including female sex hormones. The extent of this influence, however, is not completely understood so far. This systematic literature review aims at giving an overview of the existing concepts on how endogenous progesterone influences the female immune system along the menstrual cycle. The inclusion criteria were healthy female subjects in their reproductive age with a regular menstrual cycle. The exclusion criteria were exogenous progesterone, animal models, nonhealthy study populations and pregnancy. This led to 18 papers covered in this review. The search was performed using the databases EMBASE, Ovid MEDLINE and Epub, and the last search was conducted on September 18, 2020. Our findings were analyzed in four categories: cellular immune defense, humoral immune defense, objective and subjective clinical parameters. We demonstrated that progesterone acts in an immunosuppressive way, favoring a Th-2-like cytokine profile. Further, we showed that progesterone inhibits mast cell degranulation and relaxes smooth muscle cells. Furthermore, we found supporting evidence for a so-called window of vulnerability after ovulation, where immune functions are lowered and mediated through progesterone. The clinical relevance of these findings is not completely understood yet. As the sample sizes of included studies were rather small and the content of them was broad, further investigations are needed to define to which extent the described changes actually clinically meaningful, whether they are capable of influencing the female health and how these findings can be used to increase well-being.


Desiccation tolerance in Acinetobacter baumannii is mediated by the two-component response regulator BfmR.
For the opportunistic pathogen Acinetobacter baumannii, desiccation tolerance is thought to contribute significantly to the persistence of these bacteria in the healthcare environment. We investigated the ability of A. baumannii to survive rapid drying, and found that some strains exhibited a profoundly desiccation-resistant phenotype, characterized by the ability of a large proportion of cells to survive on a dry surface for an extended period of time. However, this phenotype was only displayed during the stationary phase of growth. Most interestingly, we found that drying resistance could be lost after extended cultivation in liquid medium. Genome sequencing of isolates that became drying-sensitive identified mutations in bfmR, which encodes a two-component response regulator that is important for A. baumannii virulence. Additionally, BfmR was necessary for the expression of stress-related proteins during stationary phase, and one of these, KatE, was important for long-term drying survival. These results suggested that BfmR may control stress responses, and we demonstrated that the ΔbfmR mutant was more sensitive to hydrogen peroxide, nutrient starvation, and increased osmolarity. We also found that cross-protection against drying could be stimulated by either starvation, which required BfmR, or increased osmolarity. These results imply that BfmR plays a role in controlling stress responses in A. baumannii which help protect cells during desiccation, and they provide a regulatory link between this organism's ability to persist in the environment and pathogenicity.


Molecular dynamics investigation of ferrous-ferric electron transfer in a hydrolyzing aqueous solution: calculation of the pH dependence of the diabatic transfer barrier and the potential of mean force.
We present a molecular model for ferrous-ferric electron transfer in an aqueous solution that accounts for electronic polarizability and exhibits spontaneous cation hydrolysis. An extended Lagrangian technique is introduced for carrying out calculations of electron-transfer barriers in polarizable systems. The model predicts that the diabatic barrier to electron transfer increases with increasing pH, due to stabilization of the Fe3+ by fluctuations in the number of hydroxide ions in its first coordination sphere, in much the same way as the barrier would increase with increasing dielectric constant in the Marcus theory. We have also calculated the effect of pH on the potential of mean force between two hydrolyzing ions in aqueous solution. As expected, increasing pH reduces the potential of mean force between the ferrous and ferric ions in the model system. The magnitudes of the predicted increase in diabatic transfer barrier and the predicted decrease in the potential of mean force nearly cancel each other at the canonical transfer distance of 0.55 nm. Even though hydrolysis is allowed in our calculations, the distribution of reorganization energies has only one maximum and is Gaussian to an excellent approximation, giving a harmonic free energy surface in the reorganization energy F(DeltaE) with a single minimum. There is thus a surprising amount of overlap in electron-transfer reorganization energies for Fe(2+)-Fe(H2O)6(3+), Fe(2+)-Fe(OH)(H2O)5(2+), and Fe(2+)-Fe(OH)2(H2O)+ couples, indicating that fluctuations in hydrolysis state can be viewed on a continuum with other solvent contributions to the reorganization energy. There appears to be little justification for thinking of the transfer rate as arising from the contributions of different hydrolysis states. Electronic structure calculations indicate that Fe(H2O)6(2+)-Fe(OH)n(H2O)(6-n)(3-n)+ complexes interacting through H3O2- bridges do not have large electronic couplings.


Maternal cerebral venous thrombosis, uncommon but serious disorder, pathologic predictors and contribution of prothrombotic abnormalities.
Cerebral venous thrombosis (CVT) is a rare complication during pregnancy or the puerperium. Our aim was to identify thrombotic risk profiles that predispose to maternal CVT.The study comprised 151 individuals. All participants had a thrombotic workup that included the following: genetic markers: factor V Leiden G1691A and G20210A prothrombin mutations, methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms; protein assays: protein C, protein S and antithrombin; other tests: blood typing and screening for hyperhomocysteinemia. Maternal CVT has been associated with factor V Leiden, the prothrombin G20210A mutation, protein C deficiency and hyperhomocysteinemia. We also speculate that non-O blood groups and preeclampsia could be independent risk factors for CVT.


Integrated computer analysis and a self-built Chinese cohort study identified GSTM2 as one survival-relevant gene in human colon cancer potentially regulating immune microenvironment.
According to a recent report by GLOBOCAN, colorectal cancer is the third most common and second most deadly cancer in 2020. In our previous proteomic study, we found that the expression of GSTM2 in colon tissues was significantly lower than that in para-cancer tissues, and its lower expression was associated with reduced overall survival rate of patients, suggesting that this gene might play a role in the occurrence of colon cancer. As a member of the detoxifying enzyme family, GSTM2 is likely to play an important role in the initiation of tumors. Whereas, the functions of GSTM2 in colon cancer are barely known. In this study, using the RNA-Seq datasets of colon cancer patients from public database (ntumor = 457, nnormal = 41), we confirmed the reduced expression of GSTM2 and its prognostic value in colon cancer. Furthermore, we used our own Chinese cohort (ntumor = 100, nnormal = 72) verified the lower GSTM2 expression in colon cancer, and also its effects on patient prognosis. Subsequently, we uncovered two potential reasons for the lower expression of GSTM2 in colon cancer tissues, including the deep deletion of GSTM2 on genome, and the up-regulation of RAD21 or SP1. Moreover, we disclosed that GSTM2 might be involved in several immune-related pathways in colon cancer, such as chemokine signaling and leukocyte transendothelial migration. Finally, we revealed that the GSTM2 expression was closely related to the immune-related scores of colon cancer and the infiltration ratios of various immune cells, suggesting that GSTM2 might regulate the development of colon cancer by modulating immune microenvironment. In conclusion, we uncovered the prognostic value of GSTM2 based on the public data and our own data, revealed its potential regulatory role in tumor immune microenvironment, and disclosed the probable reasons for its lower expression in colon cancer. The findings of our study provide a potential prognostic biomarker and drug target for clinical diagnosis and treatment of colon cancer.


Medulloblastoma: experimental models and reality.
Medulloblastoma is the most frequent malignant brain tumor in childhood, but it may also affect infants, adolescents, and young adults. Recent advances in the understanding of the disease have shed light on molecular and clinical heterogeneity, which is now reflected in the updated WHO classification of brain tumors. At the same time, it is well accepted that preclinical research and clinical trials have to be subgroup-specific. Hence, valid models have to be generated specifically for every medulloblastoma subgroup to properly mimic molecular fingerprints, clinical features, and responsiveness to targeted therapies. This review summarizes the availability of experimental medulloblastoma models with a particular focus on how well these models reflect the actual disease subgroup. We further describe technical advantages and disadvantages of the models and finally point out how some models have successfully been used to introduce new drugs and why some medulloblastoma subgroups are extraordinary difficult to model.


Exfoliative dermatitis.
Exfoliative dermatitis or erythroderma is a clinical syndrome characterized by widespread erythema, fine or large scales, and desquamation of a significant portion of the body surface. Appropriate management of the patient during the acute phase of erythroderma requires a firm understanding of the pathophysiology and consequences of this clinical syndrome.


Contrasting impact of androgens on male and female adiposity, fat distribution and insulin resistance in childhood and adolescence (EarlyBird 75).
To investigate associations between androgens (testosterone, dehydroepiandrosterone sulphate [DHEAS] and androstenedione), adiposity, fat distribution and insulin resistance (IR) during childhood and adolescence. Three hundred and seven children (170 [55.4%] boys; 137 [44.6%] girls) recruited at age 5 and studied annually until age 16: androgens (liquid chromatography tandem-mass spectrometry), anthropometry, body composition (dual-energy x-ray absorptiometry) and IR (homeostasis model assessment). Early adiposity was associated with earlier detection of androstenedione in both sexes, and DHEAS in boys. At puberty, higher androgen levels were associated with favourable metabolic changes in boys, but adverse metabolic effects in girls. In boys, higher free testosterone (FT) was associated with lower body fat and android/gynoid fat ratio (AGR) (both P < .001), but in girls higher total testosterone was associated with higher AGR. In girls only, higher androstenedione (P = .02) and FT (P = .01) was associated with higher IR during puberty. In pre-pubertal children, adiposity is associated with higher secretion of androgen precursors. After pubertal onset, higher testosterone is associated with lower adiposity and AGR in boys, but higher AGR and IR in girls. Therefore, androgens have modest sex-specific associations with children's total body fat, fat distribution and IR.


Adipose tissue-specific deletion of 12/15-lipoxygenase protects mice from the consequences of a high-fat diet.
Type 2 diabetes is associated with obesity, insulin resistance, and inflammation in adipose tissue. 12/15-Lipoxygenase (12/15-LO) generates proinflammatory lipid mediators, which induce inflammation in adipose tissue. Therefore we investigated the role of 12/15-LO activity in mouse white adipose tissue in promoting obesity-induced local and systemic inflammatory consequences. We generated a mouse model for fat-specific deletion of 12/15-LO, aP2-Cre; 12/15-LO(loxP/loxP), which we call ad-12/15-LO mice, and placed wild-type controls and ad-12/15-LO mice on a high-fat diet for 16 weeks and examined obesity-induced inflammation and insulin resistance. High-fat diet-fed ad-12/15-LO exhibited improved fasting glucose levels and glucose metabolism, and epididymal adipose tissue from these mice exhibited reduced inflammation and macrophage infiltration compared to wild-type mice. Furthermore, fat-specific deletion of 12/15-LO led to decreased peripheral pancreatic islet inflammation with enlarged pancreatic islets when mice were fed the high-fat diet compared to wild-type mice. These results suggest an interesting crosstalk between 12/15-LO expression in adipose tissue and inflammation in pancreatic islets. Therefore, deletion of 12/15-LO in adipose tissue can offer local and systemic protection from obesity-induced consequences, and blocking 12/15-LO activity in adipose tissue may be a novel therapeutic target in the treatment of type 2 diabetes.


Promoter 2 -1025 T/C polymorphism in the RUNX2 gene is associated with femoral neck bmd in Spanish postmenopausal women.
Stimulation of bone formation is a key therapeutic target in osteoporosis. Runx2 is a runt domain transcription factor essential to osteoblast differentiation, bone remodeling, and fracture healing. Runx2 knockout mice exhibit a complete lack of ossification, while overexpression of this gene in transgenic mice results in an osteoporotic phenotype. Thus, RUNX2 is a good candidate for the genetic determination of osteoporosis. In this association study, the effects of the -330 G/T polymorphism in promoter 1 and the -1025 T/C polymorphism (rs7771980) in promoter 2 of RUNX2 were tested in relation to lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD) in a cohort of 821 Spanish postmenopausal women. The minor allele frequencies for the two polymorphisms were 0.15 and 0.07, respectively. The two polymorphisms, located more than 90 kb apart, were not in linkage disequilibrium (D' = 0.27, r (2) = 0.028). In an ANCOVA test adjusting by weight, height, age, and years since menopause, the -330 G/T polymorphism was not associated with any of the phenotypes analyzed, while we found the -1025 T/C polymorphism to be associated with FN BMD (p = 0.001). In particular, individuals carrying the TC genotype had higher mean adjusted FN BMD values than those bearing the TT genotype. Our results highlight the importance of this RUNX2 promoter 2 polymorphism in FN BMD determination.


Reelin regulates postnatal neurogenesis and enhances spine hypertrophy and long-term potentiation.
Reelin, an extracellular protein essential for neural migration and lamination, is also expressed in the adult brain. To unravel the function of this protein in the adult forebrain, we generated transgenic mice that overexpress Reelin under the control of the CaMKIIalpha promoter. Overexpression of Reelin increased adult neurogenesis and impaired the migration and positioning of adult-generated neurons. In the hippocampus, the overexpression of Reelin resulted in an increase in synaptic contacts and hypertrophy of dendritic spines. Induction of long-term potentiation (LTP) in alert-behaving mice showed that Reelin overexpression evokes a dramatic increase in LTP responses. Hippocampal field EPSP during a classical conditioning paradigm was also increased in these mice. Our results indicate that Reelin levels in the adult brain regulate neurogenesis and migration, as well as the structural and functional properties of synapses. These observations suggest that Reelin controls developmental processes that remain active in the adult brain.


Net anionic poly(β-amino ester)s: synthesis, pH-dependent behavior, and complexation with cationic cargo.
As hydrolytically-labile, traditionally-cationic polymers, poly(β-amino ester)s (PBAEs) adeptly complex anionic compounds such as nucleic acids, and release their cargo as the polymer degrades. To engineer fully-degradable polyelectrolyte complexes and delivery vehicles for cationic therapeutics, we sought to invert PBAE net charge to generate net anionic PBAEs. Since PBAEs can carry up to a net charge of +1 per tertiary amine, we synthesized a series of alkyne-functionalized PBAEs that allowed installation of 2 anionic thiol-containing molecules per tertiary amine via a radical thiol-yne reaction. Finding dialysis in aqueous solution to lead to PBAE degradation, we developed a preparative size exclusion chromatography method to remove unreacted thiol from the net anionic PBAEs without triggering hydrolysis. The net anionic PBAEs display non-monotonic solution behavior as a function of pH, being more soluble at pH 4 and 10 than in intermediate pH ranges. Like cationic PBAEs, these net anionic PBAEs degrade in aqueous environments with hydrophobic content-dependent hydrolysis, as determined by 1H NMR spectroscopy. Further, these net anionic PBAEs form complexes with the cationic peptide (GR)10, which disintegrate over time as the polymer hydrolyzes. Together, these studies outline a synthesis and purification route to make previously inaccessible net anionic PBAEs with tunable solution and degradation behavior, allowing for user-determined complexation and release rates and providing opportunities for degradable polyelectrolyte complexes and cationic therapeutic delivery.


The use of rotifers for the maintenance of monoalgal mass cultures of Spirulina.
Zooplankton was successfully used for the biological control of unicellular algal contaminants in Spirulina mass cultures even under conditions adverse to the growth of Spirulina (maximal winter daily temperature of approximately 10 degrees C and very low bicarbonate concentration). Brachionus plicatilis (Rotifera) was the most successful species of zooplankton used. The interrelationships between Spirulina, green unicellular contaminant, and B. plicatilis were studied under various conditions. Two species of unicellular contaminant were used; Monoraphidium minutum was isolated from local cultures and Chlorella vulgaris, obtained from contaminated Spirulina cultures in Israel. The rotifer B. plicatilis successfully controlled the population size of both contaminants whether they were introduced in a single addition or as a daily dose. The biological control of the unicellular contaminants allows Spirulina to be cultured in a medium low in bicarbonate, thereby reducing the cost of the medium and increasing the quantity of CO(2) that may be freely absorbed from the atmosphere at the optimal pH for Spirulina cultivation.


Human granulocyte elastase is inhibited by the urinary trypsin inhibitor.
Two forms of urinary trypsin inhibitor, A and B, were purified from the urine of pregnant women. Form A was the only inhibitor present in fresh urine and inhibitor B arose from degradation of A upon storage of urine. The molecular masses of A and B were about 44 and 20 kDa, respectively, as judged from dodecyl-sulfate polyacrylamide gel electrophoresis, but about 60 kDa and 30 kDa, respectively, as judged from gel filtration analysis. The discrepancy can perhaps be explained by the carbohydrate content amounting to about 10% of each inhibitor. After reduction with mercaptoethanol, inhibitor A and inhibitor B had identical apparent molecular masses of about 20 kDa on dodecyl-sulfate gel electrophoresis. These results and the results of amino acid analysis suggest that one molecule of inhibitor A yields two molecules of inhibitor B. On agarose gel electrophoresis inhibitor A migrated as a rather broad band in the prealbumin region and inhibitor B as 3 well defined bands in the beta-region. Specific antisera were raised against inhibitor A and B. The two inhibitors showed the immunologic reaction of identity with each other and with the plasma inter-alpha-trypsin inhibitor, when using either antiserum. The inhibitors both gave quantitative inhibition of bovine trypsin, the results indicating a 4/1 trypsin/inhibitor molar ratio for A and a 2/1 ratio for B. The two substances also effectively inhibited granulocyte elastase. No inhibition of porcine pancreatic elastase was demonstrable.


TonB-Dependent Transporters Expressed by Neisseria gonorrhoeae.
Neisseria gonorrhoeae causes the common sexually transmitted infection, gonorrhea. This microorganism is an obligate human pathogen, existing nowhere in nature except in association with humans. For growth and proliferation, N. gonorrhoeae requires iron and must acquire this nutrient from within its host. The gonococcus is well-adapted for growth in diverse niches within the human body because it expresses efficient transport systems enabling use of a diverse array of iron sources. Iron transport systems facilitating the use of transferrin, lactoferrin, and hemoglobin have two components: one TonB-dependent transporter and one lipoprotein. A single component TonB-dependent transporter also allows N. gonorrhoeae to avail itself of iron bound to heterologous siderophores produced by bacteria within the same ecological niche. Other TonB-dependent transporters are encoded by the gonococcus but have not been ascribed specific functions. The best characterized iron transport system expressed by N. gonorrhoeae enables the use of human transferrin as a sole iron source. This review summarizes the molecular mechanisms involved in gonococcal iron acquisition from human transferrin and also reviews what is currently known about the other TonB-dependent transport systems. No vaccine is available to prevent gonococcal infections and our options for treating this disease are compromised by the emergence of antibiotic resistance. Because iron transport systems are critical for the survival of the gonococcus in vivo, the surface-exposed components of these systems are attractive candidates for vaccine development or therapeutic intervention.


Direct modulation of secretory chloride channels by arachidonic and other cis unsaturated fatty acids.
The effect of fatty acids on Cl- channels and transepithelial Cl- secretion is investigated. Patch-clamp experiments show that arachidonic acid blocks Cl- channels in a dose-dependent manner. Kinetic analysis shows that the mean open time is decreased 10-fold with 25 microM arachidonic acid. There is a linear relationship between the reciprocal of mean open time and blocker concentration within the range of 1 to 25 microM. The reciprocal of mean blocked time does not change with arachidonic acid concentration. Other cis unsaturated fatty acids, including oleic, linoleic, and ricinoleic acids, demonstrate similar blocks. Trans unsaturated acids such as elaidic acid and saturated fatty acids, including stearic, palmitic, and myristic acids, do not inhibit the channel at 20 microM. Ricinoleic acid decreases short circuit current in T84 cells, a colonic carcinoma cell line that secretes Cl-. Our results suggest that the direct effect of arachidonic and other fatty acids on Cl- secretion is to block Cl- channel current.


Probing of the nuclear import and export signals and subcellular transport mechanism of varicella-zoster virus tegument protein open reading frame 10.
Varicella-zoster virus open reading frame 10 (ORF10), a tegument protein present in the virion, is a member of the alphaherpesvirus UL48 gene family that shares considerable amino acid sequence homology with the UL48 prototype, herpes simplex virus type 1 VP16. VP16 serves multiple functions, including transcriptional activation of viral immediate-early genes. Furthermore, VP16 has been shown to be involved in some aspects of virus assembly and/or maturation. However, little is known concerning the function of ORF10. Here, we found that transient expression of ORF10 fused to enhanced yellow fluorescent protein (EYFP) in COS-7 cells showed the predominantly nuclear localization in the absence of other viral proteins. By constructing a series of ORF10 variants fused to EYFP, a bona fide bipartite nuclear localization signal of ORF10 was, for the first time, determined and mapped to amino acids (aa) 302-347. Additionally, the nuclear export signal (NES) was identified and found to be in a leucine-rich region at aa 226-236. Finally, ORF10 was demonstrated to be targeted to the cytoplasm through the functional NES by chromosomal region maintenance 1-dependent pathway, and to the nucleus via Ran and importin β1-dependent pathway that does not require importin α5.


[Subdural empyema. The importance of rapid diagnosis].
We describe a fourteen year old girl with a subdural empyema. A survey of the literature is given with regard to the diagnosis, treatment and outcome. We emphasise the importance of fast diagnosis and proper treatment.


[Histological characteristics of the testis and epididymis of calves during postnatal development].
A histologic investigation was carried out of the testis and epididymis of a total of 42 calves of the Black-and-white grouped in 14 test groups. The animals were currently castrated after the age of 2 months and were raised in the open. Material for investigation was taken on the 1st and 15th day, and once in every following month up to the completion of 12 months of age. It was found that up to the 3rd month there was no lumen in the testicular tubules, but only differentiating Sertoli cells and gonocytes were seen. Spermatogonia and spermatocytes were first observed at the age of 4 months, and prespermatids and sporadic spermatids--in the 8th month. Single spermatozoa in the phase of final shaping appeared in the 10th month, and completed spermatogenesis--in the 11th month. The histogenesis of the wall of the tubules of the epididymis completed earlier as compared to the histogenesis process in the testis--by the age of 8 months. Later on there were morphologically in the epididymis some proliferation and folding of the tubules with widening of the lumen, whereupon the amount of the surrounding connective tissue relatively decreased.


Demonstration of elevated anti-Lewis antibodies in sera of cancer patients using a carcinoembryonic antigen-polyethylene glycol immunoassay.
The serum levels of carcinoembryonic antigen (CEA) and CEA-binding proteins of 68 controls and 170 cancer patients were determined. The CEA levels were determined by a double-antibody radioimmunoassay using radiolabeled CEA, and the CEA-binding proteins were determined by an immunoassay utilizing radiolabeled CEA and polyethylene glycol. The major CEA-binding proteins in serum were anti-blood group antibodies as demonstrated by differential binding of serum proteins from A, B, or O positive individuals to radiolabeled CEA's which were previously shown to carry specific blood group determinants. No statistically significant differences were observed for the binding of control versus cancer patient sera to CEA-A (carrying blood group A1), except, as expected, A negative (O or B positive) individuals gave high binding to CEA-A, while A positive individuals gave low binding to CEA-A. Statistically significant differences were observed for controls versus cancer patients for binding to CEA-Lewisab (CEA-Leab). CEA-Leab-binding activity was higher in females and smokers in the control group, but this distinction was not found in the cancer patients. The high levels of anti-Leab antibodies may be explained in females by exposure to fetal antigens during pregnancies and in smokers or cancer patients by exposure to precursors to blood group substances. The sera of 7% of the patients with colonic carcinoma, 18% of the patients with breast carcinoma, and 23% of the patients with bronchogenic carcinoma bound more CEA-Leab than did the serum of the highest male control. A correlation between CEA-Leab-binding activity and the levels of serum CEA was found for patients with colonic carcinoma but was not significant for the groups with other cancers or the control group. Serial determinations of CEA-Leab-binding activity for 21 patients with bronchogenic carcinoma changed congruently with the serum levels of CEA in 12 cases. The significance of these results in terms of expression of immature blood group antigens, the subsequent production of antibodies against them, and the prognostic value of this response is discussed.


A novel peroxisome proliferator--activated receptor alpha/gamma dual agonist ameliorates dyslipidemia and insulin resistance in prediabetic rhesus monkeys.
TAK-559, a newly developed non-thiazolidinedione, activates both peroxisome proliferator-activated receptors alpha and gamma. We investigated the effects of TAK-559 on dyslipidemia and insulin resistance in nonhuman primates. Five adult male obese prediabetic rhesus monkeys were studied on vehicle and after TAK-559 treatment (0.3, 1.0, 3.0 mg/kg per day) for a total of 12 weeks. No significant changes were observed in body weight and fasting plasma glucose, total plasma cholesterol, very low-density lipoprotein-triglyceride, and low-density lipoprotein cholesterol levels. TAK-559 treatment resulted in significant elevation of circulating high-density lipoprotein (HDL) cholesterol levels, consisting of an increase in large HDL particles and a decrease in small dense HDL particles. Nuclear magnetic resonance data exhibited a less atherogenic lipoprotein profile with treatment. Plasma triglyceride and apolipoprotein B-100 levels decreased, whereas apolipoprotein A-I increased during TAK-559 treatment. Hyperinsulinemia and insulin resistance (quantitative insulin sensitivity check index and homeostasis model assessment) were significantly corrected with the highest dose of 3.0 mg/kg per day in these prediabetic monkeys. In addition, no adverse effects on representative liver function parameters were observed during the study period. These results suggest that TAK-559 had beneficial effects on lipoprotein profiles and insulin sensitivity, without any side effect on body weight, which suggests that TAK-559 may provide a potentially safe approach for delaying the onset of type 2 diabetes mellitus and may reduce the risk of cardiovascular disease. The positive effects of TAK-559 in nonhuman primates have led to further clinical trials of TAK-559 in Europe and the United States.


The contribution of the synovium, synovial derived inflammatory cytokines and neuropeptides to the pathogenesis of osteoarthritis.
Osteoarthritis (OA) is one of the most common and disabling chronic joint disorders affecting horses, dogs and humans. Synovial inflammation or synovitis is a frequently observed phenomenon in osteoarthritic joints and contributes to the pathogenesis of OA through formation of various catabolic and pro-inflammatory mediators altering the balance of cartilage matrix degradation and repair. Catabolic mediators produced by the inflamed synovium include pro-inflammatory cytokines, nitric oxide, prostaglandin E(2) and several neuropeptides, which further contribute to the pathogenesis of OA by increasing cartilage degradation. Recent studies suggest that substance P, corticotropin-releasing factor, urocortin and vasoactive intestinal peptide may also be involved in OA development, but the precise role of these neuropeptides in the pathogenesis of OA is not known. Since increased production of matrix metalloproteinases by the synovium is stimulated by pro-inflammatory cytokines, future anti-inflammatory therapies should focus on the synovium as a means of controlling subsequent inflammatory damage.


DEAD-box RNA helicases and epigenetic control of abiotic stress-responsive gene expression.
Plant responses to abiotic stresses are controlled by a complex tier of epigenetic, transcriptional and post-transcriptional regulation. We have provided evidence that the DEAD-box RNA helicases, STRESS RESPONSE SUPPRESSOR (STRS) 1 and STRS2 are negative regulators of Arabidopsis thaliana stress-responsive transcription factors. Using GFP-STRS fusion proteins, we have demonstrated that the STRSs are localized to the nucleolus and chromocenters, and are rapidly removed to the nucleoplasm upon application of various abiotic stresses. The STRSs appear to act via RNA-directed DNA methylation to suppress Arabidopsis stress responses; this repressive epigenetic mechanism is abrogated by abiotic stress eventually leading to an open chromatin structure allowing expression of stress-responsive genes.


A new clinical olfactory test to quantify olfactory deficiencies.
We have recently developed a computer-assisted olfactory test to measure detection thresholds for five pure odorants. The reference group consisted of 30 subjects without olfactory complaints. Statistical analysis was carried out to identify a statistical criterion for determining olfactory deficiencies. This criterion was applied to 54 subjects suspected to have an olfactory deficiency, either on the basis of their subjective complaints or on clinical examinations (e.g. scanner radiography, endoscopic investigations, rhinomanometric measurements). Nine aetiological groups were screened: trauma, nasal polyposis, nasal obstruction, allergic rhinitis, post-influenza, post-anaesthesia, endocrine dysfunction, hereditary hyposmia, and subjective olfactory loss without a clear aetiology. In each group, this method allowed us to discriminate between deficient and non-deficient patients, and the olfactory deficit could be quantified. This rapid procedure was well-accepted by all subjects and gave reproducible quantitative results. It can provide useful information about the relationship between olfactory acuity and a given aetiologic category.


Polycyclic Aromatic Hydrocarbons in Sediments/Soils of the Rapidly Urbanized Lower Reaches of the River Chaohu, China.
Polycyclic aromatic hydrocarbons (PAHs) are highly teratogenic, persistent carcinogens, and ubiquitous environmental pollutants. To determine the impact of rapid urbanization on sediment/soil PAHs, we collected 30 cm soil cores in ditch wetlands, riverine wetlands, and agricultural lands along the lower reaches of the Shiwuli River feeding Chaohu Lake, China. Ecological risk effects were evaluated by two models based upon Benzo[a]pyrene toxic equivalency (TEQ-BaP) and total toxic units (TUs). The presence of PAHs, such as BbF, BkF, InP, and BgP, that are known pollutants of concern, suggests certain ecological risks. The concentration of PAHs in the surface layer followed in the order of: ditch wetlands (617.2 ng/g average), riverine wetlands (282.1 ng/g average), agricultural lands (103.7 ng/g average). PAHs in ditch sediments were vertically distributed evenly, and PAHs in agricultural soils were concentrated in the surface soil. In riverine wetland sediments, the 2-, 3-, and 4-ring PAHs had a uniform distribution, whereas the 5- and 6-ring PAHs were concentrated in the surface soil. Redundancy analysis (RDA) explored the correlation between the environmental properties and the occurrence of PAHs. Total organic carbon (p = 0.010), percent clay (p = 0.020), and distance (p = 0.020) were the primary factors in ditch wetlands. Depth (p = 0.010) and distance (p = 0.006) were the main factors in agricultural lands. There were no significant correlations in riverine wetlands. The correlation between the distance from the built-up urban areas and pollutant concentration showed that the closer the distance, the greater the concentration of PAHs.


Uncovering new structural insights for antimalarial activity from cost-effective aculeatin-like derivatives.
A series of new aculeatin-like analogues were synthesized in two steps by combining two sets of building blocks. Many compounds showed inhibitory activities in vitro against Plasmodium falciparum and have helped to gain more insight into structure-activity relationships around the spirocyclohexadienone pharmacophoric scaffold. Plasmodium falciparum thioredoxin reductase (PfTrxR) has been investigated as a putative cellular target. Moreover, a new aculeatin-like scaffold without Michael acceptor properties, efficient at 0.86 μM against P. falciparum 3D7, was identified and raises the prospect of developing a new antimalarial agent.


Validation of an ICD-10 case-finding algorithm for endometrial cancer in US insurance claims.
To evaluate the positive predictive value (PPV) of an endometrial cancer case finding algorithm using International Classification of Disease 10th revision Clinical Modification (ICD-10-CM) diagnosis codes from US insurance claims for implementation in a planned post-marketing safety study. Two algorithm variants were evaluated. Provisional incident endometrial cancer cases were identified from 2016 through 2020 among women aged ≥50 years. One algorithm variant used diagnosis codes for malignant neoplasms of uterine sites (C54.x), excluding C54.2 (malignant neoplasm of myometrium); the other used only C54.1 (malignant neoplasm of endometrium). A random sample of medical records of recent incident provisional cases (2018-2020) was requested for adjudication. Confirmed cases showed biopsy evidence of endometrial cancer, documentation of cancer staging, or hysterectomy following diagnosis. We estimated the PPV of the variants with 95% confidence intervals (CI) excluding cases that had insufficient information. Of 294 provisional cases adjudicated, 85% were from outpatient settings (n = 249). Mean age at diagnosis was 69.3 years. Among the 294 adjudicated cases (identified with the broader algorithm variant), the same 223 were confirmed endometrial cancer cases by both algorithm variants. The PPV (95% CI) for the broader algorithm variant was 84.2% (79.2% and 88.3%), and for the variant using only C54.1 was 85.8% (80.9% and 89.8%). We developed and validated an algorithm using ICD-10-CM diagnosis codes to identify endometrial cancer cases in health insurance claims with a sufficiently high PPV to use in a planned post-marketing safety study.


Postural sway during single and repeated cold exposures.
Tissue cooling changes sensory and neuromuscular functions that are also involved in postural control. The purpose of the study was to determine how acute and repeated exposures to cold affect whole body postural control. Postural sway was measured from 10 subjects during standing with eyes open (EO) and closed (EC) using an inclinometer-based method. Sway was assessed at at 10 degrees C on 10 consecutive days and at 25 degrees C on days 1, 5, and 10. Sway path length, area, velocity, side-to-side and forward-backward movement were assessed. At the same time, rectal and skin temperatures, muscle tonus/ shivering, thermal sensations, and comfort were recorded. Acute exposure to 10 degrees C caused thermal discomfort, significantly lowered (26.1-26.5 degrees C) mean skin temperatures, slightly lowered rectal temperature (36.7 degrees C) and increased (140-260%) muscle tone, increased sway path length (67-87%, p < 0.05), velocity (63-71%, p < 0.05), total sway area (42-67%, p < 0.05), and forward-backward movement (35-57%, p < 0.05) compared with 25 degrees C. Side-to-side movements were not altered in the cold. Postural sway increased with EC, and further when exposed to cold, but the effect of cold was smaller compared with EO. Repeated exposures over the 10-d period decreased sway 10-40% both at 25 degrees C and at 10 degrees C (p < 0.05-0.01), suggesting motor learning. The difference in sway between 25 degrees C and 10 micro C remained the same throughout the 10-d period, suggesting that the observed cold habituation responses do not affect sway. The results demonstrate that postural control is impaired in cold, which may affect physical performance in cold environmental conditions.


Natural orifice surgery applied for colorectal diseases.
Clinical natural orifice surgery has been applied to abdominal surgery in recent years, mostly using transvaginal and transgastric access. Rectal and transcolonic natural orifice transluminal endoscopic surgery (NOTES) were tested in animal and cadaver models by a few research groups. Despite the potential advantages of transcolonic NOTES for colorectal diseases, it has not yet been clinically applied. The first successful series of human applications of transcolonic NOTES in the literature from the NOTES Research Group in Brazil provide new possibilities in the field in new transrectal procedures for rectal cancer and benign disease. Successful first human reports on Transcolonic NOTES potentially brings new frontiers and applications for minimally invasive surgery. The treatment of colorectal diseases through flexible Perirectal NOTES Access is a promising new approach alongside existing laparoscopic and open surgery to improve patient care.


High rates of uninsured among HCV-positive individuals.
There are no published data on the health insurance status of Hepatitis C virus (HCV)-positive individuals. To address this issue, we analyzed data from the Third National Health and Nutrition Examination Survey (NHANES III). Individuals 18 years of age and older who participated in NHANES III were included in the study. We determined the rates of health insurance coverage according to HCV status. We also determined healthcare status and health service utilization according to health insurance status among HCV-positive persons. HCV-positive individuals were more likely to be uninsured compared with those who were HCV-negative (29.6% vs. 12.2%, P = 0.0002). Among those with health insurance, HCV-positive individuals were more likely to have government insurance compared with those who were HCV-negative (42.9% vs. 27.6%, P < 0.005). Among HCV-positive individuals, being uninsured was associated with younger age, being unmarried, living in the South, Mexican-American race/ethnicity, and not graduating from high school. Additionally, the uninsured were less likely than their insured counterparts to identify a healthcare facility for sick or routine care, and less likely to have regular contact with a healthcare professional. A high proportion of HCV-positive individuals are uninsured, and many HCV-positive individuals with health insurance have publicly funded insurance. This finding may have implications for access to health care and for liver-related disease outcomes in HCV-positive persons.


Tool and object affordances: An ecological eye-tracking study.
In the present eye-tracking study, we analysed the visuo-spatial attentional patterns of participants looking at 3D images depicting single tools and object-tool pairs. The object-tool pairs could be thematically consistent, thematically inconsistent or spatially inconsistent. During the first 500 ms of visual exploration, tools were fixated longer on their functional area in all experimental conditions. However, extending the time-window of analysis to 1750 ms, the visual scene was encoded in a faster and more suited-for-action way in the thematically consistent condition (e.g., hammer-nail). Most important, the visual exploration of the thematically consistent pairs focused on the manipulation area of the tool (e.g., the handle of the hammer) more than on its functional area (e.g., the head of the hammer). Finally, when single tools were shown and the entire time-window of analysis was considered (1750 ms), fixation focused on the tool's manipulation area. These results are discussed within the reasoning-based framework of tool use. They highlight the relative role of the visuo-perceptual context in affordance perception and suggest a novel interpretation of the cognitive mechanisms underlying the processing of tools and object-tool pairs in terms of action reappraisal (i.e., a re-functionalization process when the action possibility is mined by the visuo-perceptual context).


Anesthetic Preconditioning of Traumatic Brain Injury Is Ineffective in a Drosophila Model of Obesity.
We tested the hypothesis that obesity influences the pharmacodynamics of volatile general anesthetics (VGAs) by comparing effects of anesthetic exposure on mortality from traumatic brain injury (TBI) in lean and obese Drosophila melanogaster We induced TBI with a high-impact trauma device. Starvation-selection over multiple generations resulted in an obese phenotype (SS flies). Fed flies served as lean controls (FC flies). Adult (1-8-day-old) SS and FC flies were exposed to equianesthetic doses of isoflurane or sevoflurane either before or after TBI. The principal outcome was percent mortality 24 hours after injury, expressed as the Mortality Index at 24 hours (MI24). TBI resulted in a lower MI24 in FC than in SS flies [21 (2.35) and 57.8 (2.14), respectively n = 12, P = 0.0001]. Pre-exposure to isoflurane or sevoflurane preconditioned FC flies to TBI, reducing the risk of death to 0.53 (0.25 to 1.13) and 0.82 (0.43 to 1.58), respectively, but had no preconditioning effect in SS flies. Postexposure to isoflurane or sevoflurane increased the risk of death in SS flies, but only postexposure to isoflurane increased the risk in FC flies [1.39 (0.81 to 2.38)]. Thus, obesity affects the pharmacodynamics of VGAs, thwarting the preconditioning effect of isoflurane and sevoflurane in TBI. SIGNIFICANCE STATEMENT: Inadvertent preconditioning in models of traumatic brain injury (TBI) is a recognized confounder. The findings in a fruit fly (Drosophila melanogaster) model of closed-head TBI indicate that anesthetic pharmacodynamics are profoundly affected by obesity. Specifically, obesity thwarts the brain-protective effect of anesthetic preconditioning. This finding is important for experimental studies of TBI and supports the versatility of the fruit fly as a model for the exploration of anesthetic pharmacodynamics in a wide parameter space.


The Fam50a positively regulates ameloblast differentiation via interacting with Runx2.
Differentiated ameloblasts secret enamel matrix proteins such as amelogenin, ameloblastin, and enamelin. Expression levels of these proteins are regulated by various factors. To find a new regulatory factor for ameloblast differentiation, we performed 2D-PAGE analysis using mouse ameloblast lineage cell line (mALCs) cultured with mineralizing medium. Of identified proteins, family with sequence similarity 50 member A (Fam50a) was significantly increased during differentiation of mALCs. Fam50a protein was also highly expressed in secretory ameloblasts of mouse tooth germs. In mALCs cultures, forced expression of Fam50a up-regulated the expression of enamel matrix protein genes such as amelogenin, ameloblastin, and enamelin. In addition, up-regulation of Fam50a also increased ALP activity and mineralized nodule formation in a dose-dependent manner. In contrast, knockdown of Fam50a decreased expression levels of enamel matrix protein genes, ALP activity, and mineralized nodule formation. By fluorescence microscopy, endogenous Fam50a protein was found to be localized to the nucleus of ameloblasts. In addition, Fam50a synergistically increased Ambn transactivation by Runx2. Moreover, Fam50a increased binding affinity of Runx2 to Ambn promoter by physically interacting with Runx2. Taken together, these results suggest Fam50a might be a new positive regulator of ameloblast differentiation.


Non-equilibrium molecular dynamics study of human aquaporin-2 in the static external electric fields.
In this paper, non-equilibrium MD simulations (NEMD) of human aquaporin-2 (AQP2) in the presence of an external static electric field have been performed along + z and - z directions of the pore axis. The impacts of the electric field direction on the gating mechanism corresponding to the selectivity filter (SF) region of AQP2 have been studied. Besides, the effects of applied external electric field on the PMF profile of water molecules translocation, water permeability, and molecules dipole orientation are investigated. Our results showed that when the external electric field is implemented along the + z direction of the channels, the selectivity filter region is kept in the wide conformation for the majority of the time. Therefore, a remarkable increase in the overall water permeability can be seen compared to the case without any external electric field. This is in contrast to the effects of - z-directed electric field on the conformations of the selectivity filter, which induces mostly narrow conformations in this constriction region. A substantial higher energy barrier emerged in the middle of the AQP2's pores under the effect of -z-directed electric field in comparison with the zero and + z-directed electric field strengths, which is mainly ascribed to the deviation from bipolar dipole orientation within the AQP2's pores.Communicated by Ramaswamy H. Sarma.


ATM mediates cytotoxicity of a mutant telomerase RNA in human cancer cells.
Telomeres are elongated by the enzyme telomerase, which contains a template-bearing RNA (TER or TERC) and a protein reverse transcriptase. Overexpression of a particular mutant human TER with a mutated template sequence (MT-hTer-47A) in telomerase-positive cancer cells causes incorporation of mutant telomeric sequences, telomere uncapping, and initiation of a DNA damage response, ultimately resulting in cell growth inhibition and apoptosis. The DNA damage pathways underlying these cellular effects are not well understood. Here, we show that the ataxia-telangiectasia mutated (ATM) protein is activated and forms telomeric foci in response to MT-hTer-47A expression. Depletion of ATM from two cancer cell lines, including the p53-mutant UM-UC-3 bladder cancer line, rendered the cells largely unresponsive to MT-hTer-47A. Relative to ATM-competent controls, ATM-depleted cells showed increased proliferation and clonogenic survival and reduced cell death following MT-hTer-47A treatment. In contrast, ATM depletion sensitized the cancer cells to treatment with camptothecin, a topoisomerase inhibitor that induces DNA double-strand breaks. We show that the effects of ATM depletion on the MT-hTer-47A response were not due to decreased expression of MT-hTer-47A or reduced activity of telomerase at the telomere. Instead, ATM depletion allowed robust cancer cell growth despite the continued presence of dysfunctional telomeres containing mutant sequence. Notably, the number of end-to-end telomere fusions induced by MT-hTer-47A treatment was markedly reduced in ATM-depleted cells. Our results identify ATM as a key mediator of the MT-hTer-47A dysfunctional telomere response, even in cells lacking wild-type p53, and provide evidence that telomere fusions contribute to MT-hTer-47A cytotoxicity.


Effects of Vertical Transmission of Respiratory Viruses to the Offspring.
Overt and subclinical maternal infections in pregnancy can have multiple and significant pathological consequences for the developing fetus, leading to acute perinatal complications and/or chronic disease throughout postnatal life. In this context, the current concept of pregnancy as a state of systemic immunosuppression seems oversimplified and outdated. Undoubtedly, in pregnancy the maternal immune system undergoes complex changes to establish and maintain tolerance to the fetus while still protecting from pathogens. In addition to downregulated maternal immunity, hormonal changes, and mechanical adaptation (e.g., restricted lung expansion) make the pregnant woman more susceptible to respiratory pathogens, such as influenza virus, respiratory syncytial virus (RSV), and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Depending on the infectious agent and timing of the infection during gestation, fetal pathology can range from mild to severe, and even fatal. Influenza is associated with a higher risk of morbidity and mortality in pregnant women than in the general population, and, especially during the third trimester of pregnancy, mothers are at increased risk of hospitalization for acute cardiopulmonary illness, while their babies show higher risk of complications such as prematurity, respiratory and neurological illness, congenital anomalies, and admission to neonatal intensive care. RSV exposure in utero is associated with selective immune deficit, remodeling of cholinergic innervation in the developing respiratory tract, and abnormal airway smooth muscle contractility, which may predispose to postnatal airway inflammation and hyperreactivity, as well as development of chronic airway dysfunction in childhood. Although there is still limited evidence supporting the occurrence of vertical transmission of SARS-CoV-2, the high prevalence of prematurity among pregnant women infected by SARS-CoV-2 suggests this virus may alter immune responses at the maternal-fetal interface, affecting both the mother and her fetus. This review aims at summarizing the current evidence about the short- and long-term consequences of intrauterine exposure to influenza, RSV, and SARS-CoV-2 in terms of neonatal and pediatric outcomes.


Spatial Patterns of Soil Microbial Communities in a Norway Spruce (Picea abies) Plantation.
The phospholipid fatty acid (PLFA) profiles of soil microbial communities were determined in relation to the patterns of tree cover in a mature Norway spruce plantation. Replicate samples of the surface organic layers were taken close to the trunk, at 1 m and at 2 m (under the edge of the canopy) beneath five trees. Samples were analyzed for standard PLFAs to assess the initial composition of the microbial communities. Replicate samples were then incubated under constant or fluctuating moisture conditions for 30 d to test the hypothesis that the patterns of microbial community structure (or its physiological state) might be determined by biophysical conditions under the tree canopies. The PLFA profiles near the trunks and at 2 m were similar, but samples taken 1 m from the bases of the trees contained lower concentrations of polyunsaturated (fungal) and monounsaturated PLFAs, and higher concentrations of saturated PLFAs. These differences in PLFA profiles were maintained during laboratory incubation under a regime of drying and wetting cycles, but there was some evidence of convergence in community structure under constant moisture conditions resulting from significant increases and decreases in specific bacterial PLFA concentrations. There were no effects of either moisture treatment on fungal PLFA concentrations. It is concluded that variation in the soil biophysical environment beneath the tree canopies resulted in the differentiation of spatially defined bacterial communities that were tolerant of moisture stress. The anomaly that differences in community structure were largest at an intermediate position of 1 m between the trunk and below the canopy edge was not explained but may relate to tree root distribution.


Charge ordering, commensurability, and metallicity in the phase diagram of the layered NaxCoO2.
The phase diagram of nonhydrated NaxCoO2 has been determined by changing the Na content x using a series of chemical reactions. As x increases from 0.3, the ground state goes from a paramagnetic metal to a charge-ordered insulator (at x=1/2), then to a "Curie-Weiss metal" (around 0.70), and finally to a weak-moment magnetically ordered state (x>0.75). The unusual properties of the state at 1/2 (including particle-hole symmetry at low T and enhanced thermal conductivity) are described. The strong coupling between the Na ions and the holes is emphasized.


Baseline Susceptibility of Helicoverpa armigera (Lepidoptera: Noctuidae) to Indoxacarb, Emamectin Benzoate, and Chlorantraniliprole in Australia.
Baseline susceptibility of Helicoverpa armigera (Hübner) to emamectin benzoate, chlorantraniliprole, and indoxacarb was determined in feeding assays on insecticide-incorporated artificial diet in the laboratory. The intraspecific variation of H. armigera was established from field populations collected between September 2012 and March 2013, primarily from commercial farms across eastern Australia. Emamectin benzoate had the highest toxicity with a median lethal concentration (LC50) of 0.01 µg/ml diet (n=20 strains). The LC50 for chlorantraniliprole was 0.03 µg/ml diet (n=21 strains), while indoxacarb had the lowest relative toxicity with an average LC50 of 0.3 µg/ml diet (n=22 strains). Variation in susceptibility amongst field strains was 2.3-fold for emamectin benzoate and 2.9-fold for chlorantraniliprole and indoxacarb. Discriminating concentrations of 0.2, 1, and 12 µg of insecticide per milliliter of diet for emamectin benzoate, chlorantraniliprole, and indoxacarb, respectively, were calculated from toxicological data from field H. armigera strains as a first step in resistance management of these classes of insecticide in Australia. The low intraspecific tolerance, high slope values, and goodness-of-fit to a probit binomial model obtained in this study suggest that a feeding assay using diet incorporated insecticide is an effective laboratory method for measuring the dose-responses of these classes of insecticides in H. armigera.


Separation of oxalate, formate and glycolate in human body fluid samples by capillary electrophoresis with contactless conductometric detection.
A new method for rapid determination of toxic metabolites after methanol and ethylene glycol intoxication - oxalate, formate and glycolate in various body fluid samples (blood serum, saliva, urine, exhaled breath condensate) by capillary electrophoresis with contactless conductometric detection was developed. A selective separation of the three target analytes from other constituents present in the analyzed biological matrices was achieved in less than 6min in a fused silica capillary of 25μm I.D. using an electrolyte comprising 50mM l-histidine and 50mM 2-(N-morpholino)ethanesulfonic acid at pH 6.1. The only sample preparation was dilution with deionized water. The limits of detection were 0.4, 0.6 and 1.3μM and limits of quantitation 1.3, 1.9 and 4.2μM for oxalate, formate and glycolate, respectively. The method provides a simple and rapid diagnostic test in suspected intoxication and is able to distinguish the ingested liquid, based on its metabolite trace. The method presents a fast screening tool that can be applicable in clinical practice.


Outcomes by line of therapy and programmed death ligand 1 expression in patients with advanced melanoma treated with pembrolizumab or ipilimumab in KEYNOTE-006: A randomised clinical trial.
Predictive biomarkers of patients likely to benefit from anti-programmed death 1 inhibitor therapy have clinical relevance. We examined whether line of therapy or tumour programmed death ligand 1 (PD-L1) expression affects the efficacy and safety of pembrolizumab, compared with ipilimumab, in advanced melanoma. Of 834 patients enrolled in the randomised, open-label phase III KEYNOTE-006 study, 833 were included in this analysis. Patients were randomly assigned 1:1:1 to receive pembrolizumab 10 mg/kg every 2 or 3 weeks (for 24 months) or ipilimumab 3 mg/kg every 3 weeks (for four doses) until disease progression/intolerable toxicity. This analysis evaluated progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Data cut-off: 03 November 2016. Of the patients, 60.3% were male, 65.9% were treatment naive and 80.6% had PD-L1-positive tumours (median follow-up was 33.9 months). Twenty-four-month survival rates were higher with pembrolizumab than with ipilimumab in treatment-naive (PFS 31.0% versus 14.6%; OS 58.0% versus 44.7%) and previously treated patients (PFS 25.7% versus 11.3%; OS 49.2% versus 37.9%). Twenty-four-month survival rates were higher with pembrolizumab than with ipilimumab in patients with PD-L1-positive tumours (PFS 33.2% versus 13.1%; OS 58.4% versus 45.0%) and similar in PD-L1-negative tumours (PFS 14.9% versus NR [no data at 24 months for a PFS estimate]; OS 43.6% versus 31.8%). Safety of pembrolizumab by subgroup was consistent with previous reports. Findings support pembrolizumab monotherapy as standard of care in patients with advanced melanoma, regardless of first- or second-line therapy or PD-L1 status. CLINICALTRIALS. NCT01866319.


Antimicrobial resistance: impact on clinical and economic outcomes and the need for new antimicrobials.
Antimicrobial resistance is a well-recognized global threat; thus, the development of strong infection control policies coupled with antimicrobial stewardship strategies and new therapies is required to reverse this process. In its 2013 report on antimicrobial resistance, the Centers for Disease Control and Prevention focused on this problem while presenting estimated annual rates of infections with antimicrobial-resistant organisms and their related mortality rates. Whereas some resistant pathogens were considered less threatening, others such as carbapenem-resistant Enterobacteriaceae were associated with higher mortality rates owing to limited treatment options. An overview of the most common antimicrobial-resistant pathogens, focusing on risk factors for acquisition, clinical and economic outcomes, as well as current treatment options. Strategies to optimize antimicrobial therapy with currently available agents, in addition to newly developed antimicrobials are also discussed. The emergence of pathogens with a variety of resistance mechanisms has intensified the challenges associated with infection control and treatment strategies. Therefore, prudent use of currently available antimicrobial agents, as well as implementing measures to limit spread of resistance is paramount. Although several new antimicrobials have been recently approved or are in the pipeline showing promise in the battle against resistance, the appropriate use of these agents is required as the true benefits of these treatments are to be recognized in the clinical care setting.


[Research on the"Association of Han medicine of State of Manchuria"].
The"Association of Han medicine of State of Manchuria"was a puppet TCM academic society founded by the Puppet Manchukuo government, with well-organization system and widespread scope. During its period, though some efforts were made to promoting the TCM academic progress, improving the quality of TCM doctors, developing TCM clinic, education, academic research and administration, its essence was still a tool for the puppet government to controlling, transforming and utilizing TCM.


Percutaneous antecubital transvenous cholangiography. A modified technique using a flexible needle.
A percutaneous antecubital transvenous cholangiography technique using a flexible 20 gauge needle is described. The porcedure was successful in 6 patients with obstructive jaundice but failed in 2 patients without bile duct dilatation. The authors feel that this technique is easier and safer than present transvenous methods. Modifications for the femoral approach and use of the technique in pediatric patients are described.


A pair of DICER1-positive monozygotic twins: One with pleuropulmonary blastoma, another with acute transient hepatitis.
Pleuropulmonary blastoma (PPB) is the most common primary malignant neoplasm of the lung in children that is associated with a germline mutation in DICER1. In this report, we share an interesting case of a pair of monozygotic twins: one of them developed PPB when she was 4-year old, while the other developed acute transient hepatitis when she was 5-year old. Next-Gen sequencing for DICER1 mutations of their family revealed that both twins and their mother had c.C3675A mutation. The mother also had a history of multinodular goiter. Identification of DICER1 mutation carriers and close surveillance of individuals at risk for DICER1 syndrome may allow early detection and hence better outcome.


Calcitonin gene expression induced by lipopolysaccharide in the rat pituitary.
Procalcitonin (PCT), the precursor protein of calcitonin (CT), has been considered recently as a significant indicator of bacterial infection and sepsis. However, the major source of PCT in sepsis remains unclear. The hypothalamic-pituitary-adrenal axis is activated during sepsis. Moreover, immunoreactive CT (iCT) can be detected in the pituitary. Therefore, we examined the effects of lipopolysaccharide (LPS) administration on CT mRNA expression in the pituitary. After administration of LPS, CT mRNA expression in the pituitary was increased significantly. The increase of CT mRNA was associated with significant elevations of the iCT levels in the serum. These results imply that the pituitary is one of the sources of the serum PCT during sepsis.


The surface exposed amino acid residues of monomeric proteins determine the partitioning in aqueous two-phase systems.
It is of great interest and importance how different amino acid residues contribute to and affect the properties of a protein surface. Partitioning in aqueous two-phase systems has the potential to be used as a rapid and simple method for studying the surface properties of proteins. The influence on partitioning of the surface exposed amino acid residues of eight structurally determined monomeric proteins has been studied. The proteins were characterized in terms of surface exposed residues with a computer program, Graphical Representation and Analysis of Surface Properties (GRASP), and partitioned in two EO30PO70-dextran aqueous two-phase systems, only differing in polymer concentrations (system I: 6.8% EO30PO70, 7.1% dextran; system II: 9% EO30PO70, 9% dextran). We show for the first time that the partitioning behaviour of different monomeric proteins can be described by the differences in surface exposed amino acid residues. The contribution to the partition coefficient of the residues was found to be best characterized by peptide partitioning in the aqueous two-phase system. Compared to hydrophobicity scales available in the literature, each amino acid contribution is characterized by the slope given by the graph of log K against peptide chain length, for peptides of different length containing only one kind of residue. It was also shown that each amino acid contribution is relative to the total protein surface and the other residues on the surface. Surface hydrophobicity calculations realized for systems I and II gave respectively correlation coefficients of 0.961 and 0.949 for the linear relation between log K and calculated hydrophobicity values. To study the effect on the partition coefficient of different amino acids, they were grouped into classes according to common characteristics: the presence of an aromatic group, a long aliphatic chain or the presence of charge. Using these groups it was possible to confirm that aromatic residues have the strongest effect on the partition coefficient, giving preference to the upper EO30PO70 phase of the system; on the other hand the presence of charged amino acids on the protein surface enhances the partition of the protein to the lower dextran phase. It is also important to note that the sensitivity of the EO30PO70-dextran system for the surface exposed residues was increased by increasing the polymer concentrations. The partition coefficient of a monomeric protein can thus be predicted from its surface exposed amino acid residues and the system can also be used to characterize protein surfaces of monomeric proteins in general.


[Altered expression of Lewis antigens associated with malignant transformation in endometrial tissues].
Fetal, normal adult, and malignant tissues of the uterine endometrium were examined by immunoperoxidase staining for Lewis antigens. Pronounced expression of Lewis-a, Lewis-b, and Lewis-Y antigens in malignant tissues was observed, compared with that in normal adult tissues. Moreover, the amplified expression of Lewis-b antigen was considerably higher than that of Lewis-a and Lewis-Y antigens. On the other hand, Lewis-X antigen was less expressed in malignant tissues than in normal adult tissues. These results suggest that fucose-transferase activity might be increased in malignant tissues and that the type I carbohydrate chain may play a role in the malignant transformation. In addition, Lewis-b and Lewis-Y antigens can be considered to be oncofetal antigens since they were frequently expressed in fetal and malignant tissues, but not in normal adult tissues. However, the functional significance of these changes in the expression of Lewis antigens remains to be investigated.


The higher disinfectant resistance of nosocomial isolates of Klebsiella oxytoca: how reliable are indicator organisms in disinfectant testing?
The Children's Clinic in Giessen, Germany recently reported several severe infections with Klebsiella oxytoca resulting in deaths of two neonates. The putative source of the infections was a contaminated infusion solution. The resistance to disinfectant of the K. oxytoca isolates was investigated in three independent laboratories and was indeed found to be significantly increased. Comparative tests with standard strains of K. oxytoca and other recommended bacterial surrogates showed the disinfection procedures used were fully effective. The higher resistance of the nosocomial isolates may have developed due to improper handling and storage of the cleaning utensils. This report describes the events and draws conclusions concerning the use of disinfectants, the treatment of cleaning utensils, the reliability of procedures for testing disinfectants, and suggests additional measures.


Enabling active and healthy ageing decision support systems with the smart collection of TV usage patterns.
Smart monitoring of seniors behavioural patterns and more specifically activities of daily living have attracted immense research interest in recent years. Development of smart decision support systems to support the promotion of health smart homes has also emerged taking advantage of the plethora of smart, inexpensive and unobtrusive monitoring sensors, devices and software tools. To this end, a smart monitoring system has been used in order to extract meaningful information about television (TV) usage patterns and subsequently associate them with clinical findings of experts. The smart TV operating state remote monitoring system was installed in four elderly women homes and gathered data for more than 11 months. Results suggest that TV daily usage (time the TV is turned on) can predict mental health change. Conclusively, the authors suggest that collection of smart device usage patterns could strengthen the inference capabilities of existing health DSSs applied in uncontrolled settings such as real senior homes.