Natural regulatory anticoagulants proteins among Sudanese patients with dengue virus infection.
Abnormalities in natural physiologic anticoagulants are observed in dengue infection. Laboratory values such as protein C (PC), protein S (PS), and antithrombin (AT) indicate this problem on the coagulation system in dengue. Recently, an interrelationship between dengue and the levels of natural anticoagulants has been observed. The study conducted to find out the effect of dengue on the natural anticoagulant proteins. A case-control study was conducted in Port Sudan Teaching Hospital from February 2013 to June 2014 for 334 cases of dengue caused by dengue virus, 217 (65%) males and 117 (35%) were females along with 101 cases of control 64 (63.4%) males and 37 (36.6%) were females. Laboratory-positive dengue cases were confirmed by immunoglobulin (Ig) M and IgG immune chromatography rapid test and the WHO criteria were used for classifying the dengue severity. Platelet count (PLT), plasma prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, D-dimer (DD), aspartate transaminase, alanine transaminase, PC, PS, and AT were performed. Of 334, 289 patients had dengue fever (DF) and 45 patients had dengue hemorrhagic fever (DHF). Thrombocytopenia was present in 279 (83.5%). PLT was found to be significantly low in the case of dengue (P < 0.000). There was a highly significant difference between the prolongations of PT and PTT in DF (P < 0.000). Prolongations of PT and PTT were significantly higher (90% and 76.2%, respectively) in DF than DHF patients (10% and 23.8%, respectively). PC and PS were significantly higher in DHF 100% and 80% than DF 89% and 57%, respectively. The findings of this study suggest that lower levels of these proteins in patients with dengue are attributed to disseminated intravascular coagulation.


Revisiting anomalous structures in liquid Ga.
In terms of an interatomic pair potential, which well characterizes the dynamic properties of liquid Ga, we investigate again the origin of the well known high-q shoulder in the static structure factor of the liquid. Similar to the results of Gong's simulation at high temperature, dimers with extremely short bond lengths are indeed found in our model just above the melting point, but our results indicate that it is unlikely for the high-q shoulder to be produced by these dimers. Instead, based on our model, the high-q shoulder is resulted from some medium-range order, which is related to the structures beyond the first shell of the radial distribution function, caused by Friedel oscillations within a nanoscale range.


Modulating Beta-Cardiac Myosin Function at the Molecular and Tissue Levels.
Inherited cardiomyopathies are a common form of heart disease that are caused by mutations in sarcomeric proteins with beta cardiac myosin (MYH7) being one of the most frequently affected genes. Since the discovery of the first cardiomyopathy associated mutation in beta-cardiac myosin, a major goal has been to correlate the in vitro myosin motor properties with the contractile performance of cardiac muscle. There has been substantial progress in developing assays to measure the force and velocity properties of purified cardiac muscle myosin but it is still challenging to correlate results from molecular and tissue-level experiments. Mutations that cause hypertrophic cardiomyopathy are more common than mutations that lead to dilated cardiomyopathy and are also often associated with increased isometric force and hyper-contractility. Therefore, the development of drugs designed to decrease isometric force by reducing the duty ratio (the proportion of time myosin spends bound to actin during its ATPase cycle) has been proposed for the treatment of hypertrophic cardiomyopathy. Para-Nitroblebbistatin is a small molecule drug proposed to decrease the duty ratio of class II myosins. We examined the impact of this drug on human beta cardiac myosin using purified myosin motor assays and studies of permeabilized muscle fiber mechanics. We find that with purified human beta-cardiac myosin para-Nitroblebbistatin slows actin-activated ATPase and in vitro motility without altering the ADP release rate constant. In permeabilized human myocardium, para-Nitroblebbistatin reduces isometric force, power, and calcium sensitivity while not changing shortening velocity or the rate of force development (ktr). Therefore, designing a drug that reduces the myosin duty ratio by inhibiting strong attachment to actin while not changing detachment can cause a reduction in force without changing shortening velocity or relaxation.


Simulation of self-assembly of polyzwitterions into vesicles.
Using the Langevin dynamics method and a coarse-grained model, we have studied the formation of vesicles by hydrophobic polymers consisting of periodically placed zwitterion side groups in dilute salt-free aqueous solutions. The zwitterions, being permanent charge dipoles, provide long-range electrostatic correlations which are interfered by the conformational entropy of the polymer. Our simulations are geared towards gaining conceptual understanding in these correlated dipolar systems, where theoretical calculations are at present formidable. A competition between hydrophobic interactions and dipole-dipole interactions leads to a series of self-assembled structures. As the spacing d between the successive zwitterion side groups decreases, single chains undergo globule → disk → worm-like structures. We have calculated the Flory-Huggins χ parameter for these systems in terms of d and monitored the radius of gyration, hydrodynamic radius, spatial correlations among hydrophobic and dipole monomers, and dipole-dipole orientational correlation functions. During the subsequent stages of self-assembly, these structures lead to larger globules and vesicles as d is decreased up to a threshold value, below which no large scale morphology forms. The vesicles form via a polynucleation mechanism whereby disk-like structures form first, followed by their subsequent merger.


Characterization of an Autophagy-Immune Related Genes Score Signature and Prognostic Model and its Correlation with Immune Response for Bladder Cancer.
The study aimed to identify an autophagy-related molecular subtype and characterize a novel defined autophagy-immune related genes score (AI-score) signature and prognosis model in bladder cancer (BLCA) patients using public databases. The transcriptome cohorts downloaded from TCGA and GEO database were carried out with genomic analysis and unsupervised methods to obtain autophagy-related molecular subtypes. The single-sample gene-set enrichment analysis (ssGSEA) was utilized to perform immune subtype clustering. We defined a novel autophagy subtype and evaluated the role in TME cell infiltration. Then, the principal-component analysis (PCA) was applied to construct an AI-score signature. Subsequently, two immunotherapeutic cohorts were used to evaluate the predictive value in immunotherapeutic benefits and immune response. Finally, univariate, Lasso and multivariate Cox regression algorithm were used to construct and evaluate an autophagy-immune-related genes prognosis model. Also, qRT-PCR and IHC was applied to validate the expression of the 6 genes in the model. Three distinct autophagy clusters and immune-related clusters were identified, and a novel autophagy-related molecular subtypes were defined. Furthermore, the roles in TME cell infiltration and clinical traits for the autophagy subtypes were characterized. Meanwhile, we constructed an AI-score signature and demonstrated it could predict genetic mutation, clinicopathological traits, prognosis, and TME stromal activity. We found that it could accurately predict the clinicopathological characteristics and immune response of individual BLCA patients and provide guidance for selecting immunotherapy. Ultimately, we constructed and verified an autophagy-immune-related prognostic model of BLCA patients and established a prognostic nomogram with a good prediction accuracy. We constructed AI-score signatures and prognosis risk model to characterize their role in clinical features and TME immune cell infiltration. It revealed that the AI-score signature and prognosis model could be a valid predictive tool, which could accurately predict the prognosis of BLCA patients and contribute to choosing effective personalized immunotherapy strategies.


Y145Stop is sufficient to induce de novo generation prions using protein misfolding cyclic amplification.
A point mutation in Prnp that converts tyrosine (Y) at position 145 into a stop codon leading to a truncated prion molecule as found in an inherited transmissible spongiform encephalopathy (TSE), Gertsmann-Sträussler-Scheincker syndrome, suggests that the N-terminus of the molecule (spanning amino acids 23-144) likely plays a critical role in prion misfolding as well as in protein-protein interactions. We hypothesized that Y145Stop molecule represents an unstable part of the prion protein that is prone to spontaneous misfolding. Utilizing protein misfolding cyclic amplification (PMCA) we show that the recombinant polypeptide corresponding to the Y145Stop of sheep and deer PRNP can be in vitro converted to PK-resistant PrP (Sc) in presence or absence of preexisting prions. In contrast, recombinant protein full-length PrP (C) did not show a propensity for spontaneous conformational conversion to protease resistant isoforms. Further, we show that seeded or spontaneously misfolded Y145Stop molecules can efficiently convert purified mammalian PrP (C) into protease resistant isoforms. These results establish that the N-terminus of PrP (C) molecule corresponding to residues 23-144 plays a role in seeding and misfolding of mammalian prions.


Giant hemosiderotic dermatofibroma: a case report and review of the literature.
Dermatofibroma is a common benign fibrohistiocytic lesion that usually appears as a slow-growing, firm dermal nodule with a predilection for the legs of middle-aged women. They are usually smaller than 2 cm in diameter. Many histological variants have been described. Generally, the clinical and histological diagnosis is straightforward, but differentiating it from other cutaneous tumors can be difficult in atypical cases and rare variants. Giant dermatofibroma is a rare clinical variant of dermatofibroma and less than 25 cases have been reported. It is characterized essentially by its unusually large size, which often mimics malignant tumors clinically. We first present the case of a giant hemosiderotic dermatofibroma in a 54-year-old patient, who presented with a large ulcerated mass of the left foot which was excised, and then review the literature briefly.


Winter illness and vitamin C: the effect of relatively low doses.
After their random -llocation to one of three treatment aroups, 622 volunteers received either vitamin C or placebo in a maintenance dose of 500 mg once weekly and a therapeutic dose of 1500 mg daily on the 1st day and 1000 mg on the next 4 days of any illness. Two forms of vitamin C were employed: a sustained-release capsule containing ascorbic acid and a regular tabet containing a mixture of sodium and calcium ascorbate. In the 448 subjects who completed an average of 15 weeks in the study of total of 635 episodes of illness were recroded. Respiratory symptoms were recorded on at least 1 day in 92 per cent of these episodes. There were no consistent or significant differences in the sickness experience of the subjects receiving the sustained-release vitamin capsules compared to those receiving the vitamin tablets, but subjects in both vitamin groups experienced less severe illness than subjects in the placebo group, with approximately 25 per cent fewer days spent indoors because of the illness (P smaller than 0.05). These results are compatible with the belief that supplementary vitamin C can reduce the burden of winter illness, but the intake need not be as high as has sometimes been claimed.


Solution NMR of acetylcholine binding protein reveals agonist-mediated conformational change of the C-loop.
Previous X-ray crystallography, molecular dynamics simulation, fluorescence spectroscopy, and deuterium-hydrogen exchange of acetylcholine binding protein (AChBP) suggest that after binding of the agonist, the C-loop at the periphery of the binding site draws inward to cap the site and envelop the agonist. In this study, we use high-resolution solution NMR to monitor changes in the chemical environment of the C-loop without and with acetylcholine (ACh) bound. Substitution of [15N]cysteine for the native cysteines 123, 136, 187, and 188 provided intrinsic monitors of the chemical environments of the Cys- and C-loops, respectively. Two-dimensional transverse relaxation-optimized spectroscopy 15N-1H HSQC spectroscopy of apo-AChBP revealed seven well resolved cross-peaks for the group of cysteines. The spectrum of AChBP with Ser substituted for Cys 187 and 188 shows only two main cross-peaks, corresponding to Cys 123 and 136 from the Cys-loop, enabling resonance assignments. After binding of ACh, the five cross-peaks associated with cysteines from the C-loop condense into two predominant cross-peaks not observed in the spectrum from the apo protein, indicating a restricted range of conformations and change in chemical environment of the C-loop. The results show that isotopic cysteine can be incorporated into specified positions of AChBP expressed from a eukaryotic source, that the C-loop assumes multiple conformations without ACh, but that its conformation becomes restricted with ACh bound. The collective findings suggest a structural mechanism for agonist recognition in AChBP and related Cys-loop receptors.


The chimeric VirA-tar receptor protein is locked into a highly responsive state.
The wild-type VirA protein is known to be responsive not only to phenolic compounds but also to sugars via the ChvE protein (G. A. Cangelosi, R. G. Ankenbauer, and E. W. Nester, Proc. Natl. Acad. Sci. USA 87:6708-6712, 1990, and N. Shimoda, A. Toyoda-Yamamoto, J. Nagamine, S. Usami, M. Katayama, Y. Sakagami, and Y. Machida, Proc. Natl. Acad. Sci. USA 87:6684-6688, 1990). It is shown here that the mutant VirA(Ser-44, Arg-45) protein and the chimeric VirA-Tar protein are no longer responsive to sugars and the ChvE protein. However, whereas the chimeric VirA-Tar protein was found to be locked in a highly responsive state, the VirA(Ser-44, Arg-45) mutant protein appeared to be locked in a low responsive state. This difference turned out to be important for tumorigenicity of the host strains in virulence assays on Kalanchoë daigremontiana.


The sex with the reduced sex chromosome dies earlier: a comparison across the tree of life.
Many taxa show substantial differences in lifespan between the sexes. However, these differences are not always in the same direction. In mammals, females tend to live longer than males, while in birds, males tend to live longer than females. One possible explanation for these differences in lifespan is the unguarded X hypothesis, which suggests that the reduced or absent chromosome in the heterogametic sex (e.g. the Y chromosome in mammals and the W chromosome in birds) exposes recessive deleterious mutations on the other sex chromosome. While the unguarded X hypothesis is intuitively appealing, it had never been subject to a broad test. We compiled male and female longevity data for 229 species spanning 99 families, 38 orders and eight classes across the tree of life. Consistent with the unguarded X hypothesis, a meta-analysis showed that the homogametic sex, on average, lives 17.6% longer than the heterogametic sex. Surprisingly, we found substantial differences in lifespan dimorphism between female heterogametic species (in which the homogametic sex lives 7.1% longer) and male heterogametic species (in which the homogametic sex lives 20.9% longer). Our findings demonstrate the importance of considering chromosome morphology in addition to sexual selection and environment as potential drivers of sexual dimorphism, and advance our fundamental understanding of the mechanisms that shape an organism's lifespan.


Z-lengthening of the iliotibial band to treat recalcitrant cases of trochanteric bursitis.
Greater trochanteric bursitis is a relatively common presentation at hip clinics. It presents with pain around the greater trochanter. Diagnosis is usually made on clinical grounds when other hip and spinal pathologies are ruled out and there is tenderness present over the trochanteric region. Rheumatoid arthritis (1), athletic injury (2), total hip arthroplasty (3) and idiopathic disease (4) are some of the known causes of trochanteric bursitis. Treatment is mainly non-operative and expectant; however various operative interventions have been described in the literature. We present a series of 16 patients who had recalcitrant trochanteric bursitis following failed non-operative treatment and were treated with bursectomy and Z-lengthening of the iliotibial band. All 14 patients who answered the questionnaire were happy with the outcome of operation and 13/14 patients would undergo a similar procedure again. To the best of our knowledge, this is the only series in the literature describing this particular procedure for treatment of trochanteric bursitis.


Negative regulators of integrin activity.
Integrins are heterodimeric transmembrane adhesion receptors composed of α- and β-subunits. They are ubiquitously expressed and have key roles in a number of important biological processes, such as development, maintenance of tissue homeostasis and immunological responses. The activity of integrins, which indicates their affinity towards their ligands, is tightly regulated such that signals inside the cell cruicially regulate the switching between active and inactive states. An impaired ability to activate integrins is associated with many human diseases, including bleeding disorders and immune deficiencies, whereas inappropriate integrin activation has been linked to inflammatory disorders and cancer. In recent years, the molecular details of integrin 'inside-out' activation have been actively investigated. Binding of cytoplasmic proteins, such as talins and kindlins, to the cytoplasmic tail of β-integrins is widely accepted as being the crucial step in integrin activation. By contrast, much less is known with regard to the counteracting mechanism involved in switching integrins into an inactive conformation. In this Commentary, we aim to discuss the known mechanisms of integrin inactivation and the molecules involved.


Dyspnoea after antiplatelet agents: the AZD6140 controversy.
Recent randomised studies suggest that experimental oral reversible platelet P2Y12 receptor inhibitor, AZD6140, causes dyspnoea. This also raises similar concerns about the parent compound, and another adenosine triphosphate (ATP) analogue (AR-69931MX or cangrelor), which is currently in Phase 3 trial in patients undergoing coronary interventions. We analysed package inserts, and available clinical trials safety data for antiplatelet agents with regard to the incidence of dyspnoea. We found that dyspnoea is a very rare complication of the presently approved platelet inhibitors, mostly caused by underlying disease, rather than antiplatelet therapy per se. The main reasons for respiratory distress after oral (AZD6140), and intravenous (cangrelor) agents may be the development of mild asymptomatic thrombotic thrombocytopenic purpura, fluid retention and dyspnoea because of the reversible nature of these drugs. Also, these agents are ATP analogues, which rapidly metabolise to adenosine, a well-known bronchoprovocator causing dyspnoea as well. In summary, dyspnoea is seldom considered, there are no treatment algorithms when it does occur, plausible mechanisms exist and despite these plausible mechanisms, the true cause of dyspnoea in these exposed individuals is unknown. Additional pulmonary function testing, immunological investigations and platelet receptor studies are urgently needed to determine the cause of dyspnoea after AZD6140, and to point out how such serious adverse reactions can be prevented, or at least minimised, raising potential concerns about this drug.


Task-based attentional and default mode connectivity associated with science and math anxiety profiles among university physics students.
Attentional control theory (ACT) posits that elevated anxiety increases the probability of re-allocating cognitive resources needed to complete a task to processing anxiety-related stimuli. This process impairs processing efficiency and can lead to reduced performance effectiveness. Science, technology, engineering, and math (STEM) students frequently experience anxiety about their coursework, which can interfere with learning and performance and negatively impact student retention and graduation rates. The objective of this study was to extend the ACT framework to investigate the neurobiological associations between science and math anxiety and cognitive performance among 123 physics undergraduate students. Latent profile analysis (LPA) identified four profiles of science and math anxiety among STEM students, including two profiles that represented the majority of the sample (Low Science and Math Anxiety; 59.3% and High Math Anxiety; 21.9%) and two additional profiles that were not well represented (High Science and Math Anxiety; 6.5% and High Science Anxiety; 4.1%). Students underwent a functional magnetic resonance imaging (fMRI) session in which they performed two tasks involving physics cognition: the Force Concept Inventory (FCI) task and the Physics Knowledge (PK) task. No significant differences were observed in FCI or PK task performance between High Math Anxiety and Low Science and Math Anxiety students. During the three phases of the FCI task, we found no significant brain connectivity differences during scenario and question presentation, yet we observed significant differences during answer selection within and between the dorsal attention network (DAN), ventral attention network (VAN), and default mode network (DMN). Further, we found significant group differences during the PK task were limited to the DAN, including DAN-VAN and within-DAN connectivity. These results highlight the different cognitive processes required for physics conceptual reasoning compared to physics knowledge retrieval, provide new insight into the underlying brain dynamics associated with anxiety and physics cognition, and confirm the relevance of ACT theory for science and math anxiety.


Responsiveness of arthropod herbivores and their natural enemies to modified weed management in corn.
Alteration of weed flora as consequence of the deployment of genetically modified herbicide-tolerant crops may affect higher trophic levels in agrosystems. A 4-yr study is being conducted in Spain to investigate interrelations between weeds and associated arthropods in corn fields. In a first step, the work aimed to detect the most responsive arthropods to weed management changes. To identify the most responsive arthropods, arthropod composition and abundance in herbicide-tolerant corn plots treated twice with glyphosate and untreated plots were compared for 2 yr. Plots were sampled seven times during the season by visual inspection and pitfall and yellow sticky traps to estimate abundance and activity of the main arthropod herbivores, predators, and parasitoids. As intended, the abundance and composition of weed flora was strongly altered by the differential herbicide treatments. Several groups of arthropods responded to the weed changes but in variable directions. Whereas leafhoppers and aphids were more abundant on herbicide-treated plots, the contrary was found for phytophagous thrips. Among predators, Orius sp., spiders, and trombidids were more abundant on treated plots, whereas nabids and carabids were more abundant in untreated plots; the same case was found for carabids and spiders caught in pitfall traps. Among parasitoids, ichneumonids were more abundant in untreated plots and mymarids in treated plots. These results cannot be interpreted in terms of nontarget effects of postemergence treatments with broad-spectrum herbicides; for this, a comparison with conventional weed management practices should be done and this is the current step in the study.


Size distribution analysis of influenza virus particles using size exclusion chromatography.
Size exclusion chromatography is a standard method in quality control of biopharmaceutical proteins. In contrast, vaccine analysis is often based on activity assays. The hemagglutination assay is a widely accepted influenza quantification method, providing no insight in the size distribution of virus particles. Capabilities of size exclusion chromatography to complement the hemagglutination assay are investigated. The presented method is comparatively robust regarding different buffer systems, ionic strength and additive concentrations. Addition of 200mM arginine or sodium chloride is necessary to obtain complete virus particle recovery. 0.5 and 1.0M arginine increase the hydrodynamic radius of the whole virus particles by 5nm. Sodium citrate induces virus particle aggregation. Results are confirmed by dynamic light scattering. Retention of a H1N1v strain correlates with DNA contents between 5ng/mL and 670ng/mL. Quantitative elution of the virus preparations is verified on basis of hemagglutination activity. Elution of hemagglutination inducing compounds starts at a flow channel diameter of 7000nm. The universal applicability is demonstrated with three different influenza virus samples, including an industrially produced, pandemic vaccine strain. Size distribution of the pandemic H1N1v 5258, H1N1 PR/8/34, and H3N2 Aichi/2/68 preparations spreads across inter- and intra-particle volume and extends to the secondary interaction dominated range. Thus, virus particle debris seems to induce hemagglutination. Fragments generated by 0.5% Triton™ X-100 treatment increase overall hemagglutination activity.


Does Listening to Music during Tonsillectomy Affect Sevoflurane Consumption?
The aim of this study was to investigate the effect of listening to music on the consumption of an anesthetic agent as well as postoperative recovery and pain in children undergoing elective tonsillectomy. Fifty patients were randomized into those to whom music was played during surgery (group M) and a control group to whom music was not played (group C). The depth of anesthesia was provided by entropy levels of 50 ± 5 in both groups. Demographic characteristics and hemodynamic parameters were recorded perioperatively. The duration of surgery, sevoflurane consumption, eye opening time, and extubation time were also recorded. p < 0.05 was considered statistically significant. Surgical pleth index values measured intraoperatively were statistically lower in group M than in group C. In the postanesthesia care unit children in the music group felt less pain than those in the control group according to the Wong-Baker Faces Pain Rating Scale (p = 0.035). The heart rates of the patients in the music group were statistically lower at 30 min intraoperatively and at the end of the procedure compared to the values of the control group (p = 0.015). The consumption of sevoflurane was lower in group M than in group C but the difference was not statistically significant. The need for additional fentanyl was significantly lower in group M than in group C. In this study, the children exposed to music intraoperatively needed less analgesia during surgery, and reported less pain postoperatively, but there was no difference in sevoflurane requirements.


Reg proteins direct accumulation of functionally distinct macrophage subsets after myocardial infarction.
Myocardial infarction (MI) causes a massive increase of macrophages in the heart, which serve various non-redundant functions for cardiac repair. The identities of signals controlling recruitment of functionally distinct cardiac macrophages to sites of injury are only partially known. Previous work identified Regenerating islet-derived protein 3 beta (Reg3β) as a novel factor directing macrophages to sites of myocardial injury. Herein, we aim to characterize functionally distinct macrophage subsets and understand the impact of different members of the Reg protein family including Reg3β, Reg3γ, and Reg4 on their accumulation in the infarcted heart. We have determined dynamic changes of three phenotypically distinct tissue macrophage subpopulations in the mouse heart after MI by flow cytometry. RNA sequencing and bioinformatics analysis identified inflammatory gene expression patterns in MHC-IIhi/Ly6Clo and MHC-IIlo/Ly6Clo cardiac tissue macrophages while Ly6Chi cardiac tissue macrophages are characterized by gene activities associated with healing and revascularization of damaged tissue. Loss- and gain-of-function experiments revealed specific roles of Reg proteins for recruitment of cardiac tissue macrophage subpopulations to the site of myocardial injury. We found that expression of Reg3β, Reg3γ, and Reg4 is strongly increased after MI in mouse and human hearts with Reg3β providing the lead, followed by Reg3γ and Reg4. Inactivation of the Reg3β gene prevented the increase of all types of cardiac tissue macrophages shortly after MI whereas local delivery of Reg3β, Reg3γ, and Reg4 selectively stimulated recruitment of MHC-IIhi/Ly6Clo and MHC-IIlo/Ly6Clo but repressed accumulation of Ly6Chi cardiac tissue macrophages. We conclude that distinct cardiac macrophage subpopulations are characterized by substantially different gene expression patterns reflecting their pathophysiological role after MI. We argue that sequential, local production of Reg proteins orchestrates accumulation of macrophage subsets, which seem to act in a parallel or partially overlapping rather than in a successive manner.


Long-term male aggregations of Euglossa melanotricha Moure (Hymenoptera: Apidae) on fern fronds Serpocaulon triseriale (Pteridophyta: Polypodiaceae).
A communal dormitory of male orchid bees, Euglossa melanotricha Moure, was monitored over a one-year period, when they passed the night in the fronds of a Serpocaulon triseriale (Polypodiaceae) fern. The bees used the same fronds continuously, moving to neighboring fronds as senescence set in. As many as 49 males were observed together on any one night, clinging to the midribs on the abaxial surface of up to five fern blades with their mandibles. A number of males returned to the same site to pass the night continuously over a number of months, and were observed making physical contact with one another without provoking agonistic behavior. Males of E. melanotricha appeared to prefer sleeping at sites close to nests and potential sources of odoriferous essences, such as orchids (Orchidaceae).


[Ahmed valve in high-risk glaucoma surgery].
We used the Ahmed valve for the treatment of 142 eyes with high-risk glaucoma. The glaucoma was neovascular in 74 cases, aphakic or pseudophakic in 19 eyes and occurred after previous faliure of filtering surgery in 49 eyes. Preoperative mean IOP was 31.6+/-10.4 mmHg under topical and/or systemic treatment. The success rate (IOP<22 mmHg with only topical treatment) was 56.3% with a mean follow-up of 32.4 months. Complications were fewer and milder compared with those reported for other types of drainage implants and for other types of antiglaucoma procedures.


Biological implication for loss of function at major histocompatibility complex loci.
Despite relatively frequent gene or segment duplications, the number of functional loci in the major histocompatibility complex (MHC) is relatively small. The dual function of MHC molecules (triggering the immune system and limiting T-cell receptor repertoires) is likely to balance the number of functional loci. The effect of this dual function on the number of functional MHC loci has been argued mainly in the theoretical and computer simulation studies, but the evidence from empirical data has not been fully examined. Here, we attempt to evaluate this effect based on the analysis of nucleotide sequence data. We hypothesized that due to the dual function, even becoming a pseudogene (pseudogenization) of MHC is advantageous for the organisms. To evaluate this hypothesis, we compared the distribution of the waiting time (T (W)) till pseudogenization for HLA (human MHC) with that of the human olfactory receptor (OR) and bitter taste receptor (T2R) genes. The result shows that T (W) in HLA has a tendency to be relatively shorter as the emergence time (T) of the gene becomes older, while in OR T (W) becomes proportionally longer as T becomes older and in T2R it is almost null irrespective of T. Furthermore, T (W) in HLA is strongly influenced by the extent of functional differentiation in the peptide-binding region. Taken together, these results show that MHC molecules have optimal numbers of functional loci, and these numbers are regulated by the advantageous pseudogenization of duplicated copies.


The rebirth of the cool: a narrative review of the clinical outcomes of cold stored low titer group O whole blood recipients compared to conventional component recipients in trauma.
There has been renewed interest in the use of low titer group O whole blood (LTOWB) for the resuscitation of civilian casualties. LTOWB offers several advantages over conventional components such as providing balanced resuscitation in one bag that contains less additive/preservative solution than an equivalent volume of conventional components, is easier and faster to transfuse than multiple components, avoids blood product ratio confusion, contains cold stored platelets, and reduces donor exposures. The resurgence in its use in the resuscitation of civilian trauma patients has led to the publication of an increasing number of studies on its use, primarily amongst adult recipients but also in pediatric patients. These studies have indicated that hemolysis does not occur amongst adult and pediatric non-group O recipients of a modest quantity of LTOWB. The published studies to date on mortality have shown conflicting results with some demonstrating a reduction following LTOWB transfusion while most others have not shown a reduction; there have not been any studies to date that have found significantly increased overall mortality amongst LTOWB recipients. Similarly, when other clinical outcomes, such as venous thromboembolism, sepsis, hospital or intensive care unit lengths of stay are evaluated, LTOWB recipients have not demonstrated worse outcomes compared to conventional component recipients. While definitive proof of the trends in these morbidity and mortality outcomes awaits confirmation in randomized controlled trials, the evidence to date indicates the safety of transfusing LTOWB to injured civilians.


Erythema migrans--influence of posture. Case report.
Despite widespread awareness of the most classical clinical presentation with central clearing of erythema migrans, a pathognomonic sign of infection with Borrelia burgdorferi, diagnosis of other forms of erythema migrans remains more difficult. We describe a case of a patient with secondary lesions of erythema migrans that within three months formed a complicated pattern and affected at last nearly the entire lower limb of the patient. In addition, the erythema appeared to be posture-dependent in the way that the lesion was with central clearing in the supine and with homogeneous appearance in the upright position. The borrelial infection was confirmed by PCR sequencing that detected DNA of B. afzelii in the skin biopsy specimen. The lesions disappeared during antibiotic therapy. This case shows how posture can be important in the examination of patients with a suspected erythema migrans.


[Imaging of non-functional retroperitoneal paragangliomas. Apropos of a case].
The non functional extraperitoneal paragangliomas are rare tumors (less than 50 cases reported). We report a case with ultrasound and CT scan imaging. The tumor is usually large with important necrotic areas leading to a cystic aspect. The malignant tumors more frequent than the benign tumors present with a regional extension and delayed metastasis.


Whole grain intake and survival among Scandinavian colorectal cancer patients.
To our knowledge, no studies of associations between intake of whole grain (WHG) and survival of colorectal cancer have been published, despite evidence that dietary fiber, and to some extent WHG, are associated with lower risk of colorectal cancer. Scandinavia is an area where the WHG consumption traditionally is high. We performed a case-only (N = 1119) study in the Scandinavian HELGA cohort of pre-diagnosis WHG intake (total WHG, WHG wheat, WHG rye, and WHG oats) and survival of colorectal cancer. Cox regression analyses were used to study the associations, both in categorical and continuous models, stratified by location (proximal, distal, rectum) and country. No evidence of an association was found, neither for total WHG intake (hazard ratio = 1.32, 95% confidence interval: 0.88-1.97 lowest vs. highest tertile, adjusted for age at diagnosis, metastasis status, smoking, folate, margarine, and energy), nor for specific grains. Prediagnosis consumption of WHG does not seem to improve survival of colorectal cancer in subjects diagnosed within this prospective population-based Scandinavian cohort.


Antiapoptotic and antioxidant effects of rosmarinic acid in astrocytes.
The protective effects of rosmarinic acid (RA), a polyphenolic compound, on apoptosis induced by hydrogen peroxide in astrocytes were studied. Pretreating cells with RA significantly increased cell viability and decreased apoptosis rate induced by H2O2. The antiapoptotic effect of RA was further confirmed by increase of mitochondrial membrane potential and inhibition of caspase-3 activity. RA also attenuated cellular oxidative stress by decreasing the amount of reactive oxygen species and malondialdehyde. Results clearly show that RA was able to attenuate H2O2-induced cell injury by its antiapoptotic and antioxidant activity.


Biophysical, mutational, and functional investigation of the chromophore-binding pocket of light-oxygen-voltage photoreceptors.
As light-regulated actuators, sensory photoreceptors underpin optogenetics and numerous applications in synthetic biology. Protein engineering has been applied to fine-tune the properties of photoreceptors and to generate novel actuators. For the blue-light-sensitive light-oxygen-voltage (LOV) photoreceptors, mutations near the flavin chromophore modulate response kinetics and the effective light responsiveness. To probe for potential, inadvertent effects on receptor activity, we introduced these mutations into the engineered LOV photoreceptor YF1 and determined their impact on light regulation. While several mutations severely impaired the dynamic range of the receptor (e.g., I39V, R63K, and N94A), residue substitutions in a second group were benign with little effect on regulation (e.g., V28T, N37C, and L82I). Electron paramagnetic resonance and absorption spectroscopy identified correlated effects for certain of the latter mutations on chromophore environment and response kinetics in YF1 and the LOV2 domain from Avena sativa phototropin 1. Carefully chosen mutations provide a powerful means to adjust the light-response function of photoreceptors as demanded for diverse applications.


[Management of errors in medicine].
If negligent actions are ruled out, medical errors must be prevented or attenuated enhancing security in all the health care system. Prudent and confidential information and assessment are crucial to obtain good results, discarding to look for whom to blame and assuming collectively the supervision of suspected conditions. Massive introduction of technology, intervention of multiple agents in the care of patients and the number of alternatives offered to manage health problems, contribute to increase medical errors. Not of lesser importance are the increasing expectations of patients on health benefits, that must be synchronized to the continuous improvement in medical care.


Comparison of mortality risk by choice of CAPD versus hemodialysis among elderly patients.
To evaluate patient survival among geriatric patients by dialytic treatment of choice we assigned all patients aged 65 years and older treated in Michigan to either CAPD at home or center hemodialysis (HD) according to the treatment used on day 120 of ESRD therapy. Michigan Kidney Registry files on all 308 CAPD and 1244 HD patients who started ESRD therapy during 1980-1987 were used for this study. The Cox proportional hazards model revealed a significantly increased relative death rate (RR) for patients with diabetes (RR = 1.91, p less than 0.001) and hypertension (RR 1.4, p less than 0.01) as cause of ESRD when adjusting for age, sex, race, treatment and year of incidence. White patients had a 51% higher relative death rate overall when compared to black patients (p less than 0.001) and specifically among hypertensive (RR = 1.65, p less than 0.001) and diabetic patients (RR = 1.59, p less than 0.001). Those differences were still significant when taking higher rates of withdrawal from dialysis among white patients into account. The relative death rates for CAPD patients was essentially the same as for HD patients overall, however, diabetic CAPD patients appeared to have a higher than diabetic HD patients (RR = 1.58, p = 0.1). This statistically not significant difference may be related to selection of patients with cardiovascular risk into CAPD. There was no trend in mortality over time. By modality on day 120, CAPD has similar outcomes as HD in geriatric non diabetic patients.


Imaging patients with chronic kidney disease: CIN or NSF?
Patients with chronic kidney disease (CKD) frequently require contrast-enhanced imaging studies in order to manage their condition. Radiologists are often confronted with selecting the best imaging modality for each patient based on the patient's degree of renal impairment. In the past, when patients required a contrast-enhanced imaging study, the tendency was to select magnetic resonance (MR) imaging with a gadolinium (Gd)-based contrast agent over computed tomography (CT) with iodinated contrast media (CM) due to the known nephrotoxic nature of iodinated CM, which is associated in some patients with the development of contrast-induced nephropathy (CIN). However, recently, the administration of Gd-based contrast agents has been associated with a severe, potentially fatal, adverse reaction, termed nephrogenic systemic fibrosis (NSF), in patients with moderate-to-severe renal insufficiency. Therefore, this same patient population is now at risk for developing either CIN or NSF. In order to optimise patient outcomes, imaging of patients with CKD requires an understanding of the risk factors for both CIN and NSF.


An assessment of diagnostic procedures preparatory to retroperitoneoscopic removal of adenoma in cases of primary hyperaldosteronism.
The goal of this study was to improve assessment of diagnostic measures for lateral localization of aldosterone-producing adrenal adenomas preparatory to retroperitoneoscopic removal, in view of the fact that this technique allows for only unilateral access. A retrospective study was carried out of the medical records of 64 patients (38 women, 26 men, average age 46.8+/-11.2) who underwent surgery at University Hospital, Münster, between 1969 and 1998. Seventeen of the 64 patients presented with hyperplasia and 47 had adrenal adenoma. In cases of hyperplasia, computerized tomography imaged a false-positive unilateral tumor 10 times, a false-negative 3 times, and a unilateral hyperplasia 1 time (ultrasonography: tumor 2 times, false-negative 3 times; 131I-Iodomethylnorcholesterol scintigraphy: tumor 5 times, false-negative 1 time, correct 1 time). In cases of adenoma, computerized tomography yielded accurate results 40 times, imaged a false-negative 2 times, and indicated the incorrect side 1 time (Ultrasonography: false-negative 12 times, correct side 9 times, incorrect side 1 time; 131I-Iodomethylnorcholesterol scintigraphy: correct side 19 times, false-positive (both sides) 5 times, negative 3 times, incorrect side 2 times). Venous sampling, which was carried out seven times, yielded accurate results six times, and failed technically one time. Venous sampling appears to be the method of choice for preoperative lateral localization. Thus, retroperitoneoscopic treatment of Conn's syndrome should not be carried out unless venous sampling is carried out first.


A three-dimensional model for the substrate binding domain of the multidrug ATP binding cassette transporter LmrA.
Multidrug resistance presents a major obstacle to the treatment of infectious diseases and cancer. LmrA, a bacterial ATP-dependent multidrug transporter, mediates efflux of hydrophobic cationic substrates, including antibiotics. The substrate-binding domain of LmrA was identified by using photo-affinity ligands, proteolytic degradation of LmrA, and identification of ligand-modified peptide fragments with matrix-assisted laser desorption ionization/time of flight mass spectrometry. In the nonenergized state, labeling occurred in the alpha-helical transmembrane segments (TM) 3, 5 and 6 of the membrane-spanning domain. Upon nucleotide binding, the accessibility of TM5 for substrates increased, whereas that of TM6 decreased. Inverse changes were observed upon ATP-hydrolysis. An atomic-detail model of dimeric LmrA was generated based on the template structure of the homologous transporter MsbA from Vibrio cholerae, allowing a three-dimensional visualization of the substrate-binding domain. Labeling of TM3 of one monomer occurred in a predicted area of contact with TM5 or TM6 of the opposite monomer, indicating substrate-binding at the monomer/monomer interface. Inverse changes in the reactivity of TM segments 5 and 6 suggest that substrate binding and release involves a repositioning of these helices during the catalytic cycle.


Epithelial-to-Mesenchymal Transition: A Mediator of Sorafenib Resistance in Advanced Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide and its incidence is steadily rising. Currently, sorafenib remains the only approved standard treatment for patients with advanced HCC, as it has proven to increase survival in these patients. However, clinical and preclinical observations indicate that sorafenib treatment may have limited efficacy due to tumor progression from the rapid development of acquired resistance. Elucidation of the underlying mechanisms of evasive resistance to sorafenib is a major challenge in HCC research. In recent years, the role of epithelial-to-mesenchymal transition (EMT) in the advancement of HCC and development of drug resistance has gained increasing attention. EMT is a developmental multistep molecular and cellular reprogramming process that is hijacked by cancer cells to enable aggressiveness. In this review, we provide an overview of the currently available preclinical studies on the EMT mechanisms underlying resistance to sorafenib treatment. Recent studies report enrichment of cancer stem cells (CSCs) after sorafenib treatment. Interestingly, EMT process has been implicated in the generation of CSCs associated with therapy resistance. We discuss how combination of sorafenib with EMT inhibitors could enhance the clinical response to sorafenib, resulting in longer duration of responses, than observed with sorafenib monotherapy. In particular, we discuss how these new insights may facilitate rational development of combination therapies in the future to impact survival of patients with advanced HCC.


Baroreflex sensitivity as a new marker for risk stratification.
As the arterial baroreflex importantly contributes to modulation of the autonomic influences on the heart and thereby arrhythmogenesis, baroreflex sensitivity has been used as a measure of the interaction between sympathetic and parasympathetic activities at the cardiac level. The most widely applied technique both in the experimental and clinical setting is the measurement of the heart rate slowing in response to a blood pressure rise induced by small intravenous boluses of phenylephrine. Baroreflex sensitivity is expressed as ms/mmHg and prevailing vagal reflexes are reflected by the wider R-R interval lengthening. The experimental evidence that the occurrence of ventricular fibrillation was inversely related to baroreflex sensitivity, opened the way to clinical studies. The ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) trial has definitely demonstrated not only that a depressed baroreflex sensitivity (< 3 ms/mmHg) is a strong risk factor for cardiac death, but also that the information gained by the analysis of autonomic markers adds to the information obtained by better recognized measures of cardiovascular outcome such as left ventricular function and ventricular arrhythmias. The value of a depressed baroreflex sensitivity as a risk stratifier is meaningful in patients below age 65 in combination of a simultaneously depressed left ventricular ejection fraction. In these patients, the analysis of autonomic activity might be of value in the identification of patients who may need an implantable automatic defibrillator for primary prevention of sudden cardiac death.


Development of an Automatic Chronological Record Creation System Using Voice AI to Facilitate Information Aggregation and Sharing in the Event of a Disaster.
In the event of a disaster, the chain of command and communication of each relevant agency is important. In this study, a chronological record creation system using voice AI (V-CRS) was developed, and an experiment was conducted to determine whether the obtained information could be quickly and easily summarized in chronological order. After a lecture by Japanese Disaster Medical Assistant (DMAT) Team members and 8 medical clerks on how to use the developed tool, a comparison experiment was conducted between manual input and V-CRS utilization of the time to compile disaster information. Results proved that V-CRS can collect information gathered at headquarters more quickly than handwriting. It was also suggested that even medical clerks who have never been trained to record information during disasters could record information at the same speed as trained DMAT personnel. V-CRS can transcribe audio information even in situations where technical terms and physical units must be recorded, such as radiation disasters. It has been proven that anyone can quickly organize information using this method, to some extent.


The shifting perception on antioxidants: the case of vitamin E and β-carotene.
Antioxidants are vital for aerobic life, and for decades the expectations of antioxidants as health promoting agents were very high. However, relatively recent meta-analyses of clinical studies show that supplementation of antioxidants does not result in the presumed health benefit, but is associated with increased mortality. The dilemma that still needs to be solved is: what are antioxidants in the end, healthy or toxic? We have evaluated this dilemma by examining the presumed health effects of two individual antioxidants with opposite images i.e. the "poisonous" β-carotene and the "wholesome" vitamin E and focused on one aspect, namely their role in inducing BPDE-DNA adducts. It appears that both antioxidants promote DNA adduct formation indirectly by inhibition of the protective enzyme glutathione-S-transferase π (GST π). Despite their opposite image, both antioxidants display a similar type of toxicity. It is concluded that, in the appreciation of antioxidants, first their benefits should be identified and substantiated by elucidating their molecular mechanism. Subsequently, the risks should be identified including the molecular mechanism. The optimal benefit-risk ratio has to be determined for each antioxidant and each individual separately, also considering the dose.


Application of flow cytometry and automated image analysis to the study of prostate cancer.
Flow cytometry and image analysis are complementary quantitative cytologic techniques that have demonstrated utility in the assessment and analysis of prostate cancer and other urologic and nonurologic tumors. This review is intended to assess the current state of the art and to project future directions and applications of these modalities in the pathologic assessment of prostate cancer. Special attention is directed toward the topics of prostate cancer detection and diagnosis, determination of patient prognosis, and the monitoring of patient response to therapy. We recommend that 1) flow cytometry and image analysis be used to determine pathologic parameters that will help in predicting poor patient prognosis and 2) quantitative cytologic determinations of DNA content be included in clinical trials so that their ultimate role in monitoring patient response to therapy can be determined. This knowledge will allow the development of protocols designed to test the value of earlier institution of multimodal therapy in high-risk populations.


AC-driven multicolor electroluminescence from a hybrid WSe2 monolayer/AlGaInP quantum well light-emitting device.
Light-emitting diodes (LEDs) are used widely, but when operated at a low-voltage direct current (DC), they consume unnecessary power because a converter must be used to convert it to an alternating current (AC). DC flow across devices also causes charge accumulation at a high current density, leading to lowered LED reliability. In contrast, gallium-nitride-based LEDs can be operated without an AC-DC converter being required, potentially leading to greater energy efficiency and reliability. In this study, we developed a multicolor AC-driven light-emitting device by integrating a WSe2 monolayer and AlGaInP-GaInP multiple quantum well (MQW) structures. The CVD-grown WSe2 monolayer was placed on the top of an AlGaInP-based light-emitting diode (LED) wafer to create a two-dimensional/three-dimensional heterostructure. The interfaces of these hybrid devices are characterized and verified through transmission electron microscopy and energy-dispersive X-ray spectroscopy techniques. More than 20% energy conversion from the AlGaInP MQWs to the WSe2 monolayer was observed to boost the WSe2 monolayer emissions. The voltage dependence of the electroluminescence intensity was characterized. Electroluminescence intensity-voltage characteristic curves indicated that thermionic emission was the mechanism underlying carrier injection across the potential barrier at the Ag-WSe2 monolayer interface at low voltage, whereas Fowler-Nordheim emission was the mechanism at voltages higher than approximately 8.0 V. These multi-color hybrid light-emitting devices both expand the wavelength range of 2-D TMDC-based light emitters and support their implementation in applications such as chip-scale optoelectronic integrated systems, broad-band LEDs, and quantum display systems.


Survey of methadone-drug interactions among patients of methadone maintenance treatment program in Taiwan.
Although methadone has been used for the maintenance treatment of opioid dependence for decades, it was not introduced in China or Taiwan until 2000s. Methadone-drug interactions (MDIs) have been shown to cause many adverse effects. However, such effects have not been scrutinized in the ethnic Chinese community. The study was performed in two major hospitals in southern Taiwan. A total of 178 non-HIV patients aged ≥ 20 years who had participated in the Methadone Maintenance Treatment Program (MMTP) ≥ 1 month were recruited. An MDI is defined as concurrent use of drug(s) with methadone that may result in an increase or decrease of effectiveness and/or adverse effect of methadone. To determine the prevalence and clinical characteristics of MDIs, credible data sources, including the National Health Insurance (NHI) database, face-to-face interviews, medical records, and methadone computer databases, were linked for analysis. Socio-demographic and clinical factors associated with MDIs and co-medications were also examined. 128 (72%) MMTP patients took at least one medication. Clinically significant MDIs included withdrawal symptoms, which were found among MMTP patients co-administered with buprenorphine or tramadol; severe QTc prolongation effect, which might be associated with use of haloperidol or droperidol; and additive CNS and respiratory depression, which could result from use of methadone in combination with chlorpromazine or thioridazine. Past amphetamine use, co-infection with hepatitis C, and a longer retention in the MMTP were associated with increased odds of co-medication. Among patients with co-medication use, significant correlates of MDIs included the male gender and length of co-medication in the MMTP. The results demonstrate clinical evidence of significant MDIs among MMTP patients. Clinicians should check the past medical history of MMTP clients carefully before prescribing medicines. Because combinations of methadone with other psychotropic or opioid medications can affect treatment outcomes or precipitate withdrawal symptoms, clinicians should be cautious when prescribing these medications to MMTP patients and monitor the therapeutic effects and adverse drug reactions. Although it is difficult to interconnect medical data from different sources for the sake of privacy protection, the incumbent agency should develop pharmacovigilant measures to prevent the MDIs from occurring. Physicians are also advised to check more carefully on the medication history of their MMTP patients.


Managing Synchronous Liver Metastases in Colorectal Cancer.
The most common site of blood-borne metastases from colorectal cancers (CRC) is the liver. Resection of (liver) metastases is a part of standard treatment of metastatic colorectal cancer. Hepatic resection is the first-line treatment of liver metastases, with 5-year survival rates between 25 and 58%. The enhanced efficacy of systemic chemotherapeutic regimens has increased tumor response rates and improved the progression-free and overall survival of patients with these malignancies. In approximately 20% of patients with initially unresectable liver metastases, the metastases may become resectable after administration of neoadjuvant chemotherapy. Unresectable liver metastases can be managed with systemic therapy and/or a variety of liver-directed techniques such as radiofrequency ablation, hepatic artery infusion, or yttrium-90 radioembolization. Our examination of the literature led us to propose a new patient-oriented algorithm to guide clinicians' decisions on the best choice of upfront therapy for CRC and synchronous liver metastases. The need for multidisciplinary consensus has become especially important for metastatic CRC.


Measurement of the B(+) production cross section in pp collisions at sqrt[s]=7 TeV.
Measurements of the total and differential cross sections dσ/dp(T)(B) and dσ/dy(B) for B(+) mesons produced in pp collisions at sqrt[s]=7 TeV are presented. The data correspond to an integrated luminosity of 5.8 pb(-1) collected by the CMS experiment operating at the LHC. The exclusive decay B(+)→J/ψK(+), with J/ψ→μ(+)μ(-), is used to detect B(+) mesons and to measure the production cross section as a function of p(T)(B) and y(B). The total cross section for p(T)(B)>5 GeV and |y(B)|<2.4 is measured to be 28.1±2.4±2.0±3.1 μb, where the first uncertainty is statistical, the second is systematic, and the last is from the luminosity measurement.


Emerging nanostructured materials for musculoskeletal tissue engineering.
The musculoskeletal tissues are highly ordered nanostructured materials, and they have self-healing capability. However, when the tissue damage is beyond the capability, therapeutic approaches to repair or regenerate the tissues are needed. Nanomaterials have attracted much research attention to create novel tissue engineering scaffolds, because of their small size, large surface area, enhanced mechanical properties, tunable molecular and chemical structures, and various surface functionalities. With the development of nanotechnology, nanostructured materials with properties that more closely fulfill the requirement in the course of recovery of native tissues were designed, synthesized, characterized and utilized systematically. Here, we introduce the microenvironment of the extracellular matrix in musculoskeletal tissues. We further summarize the nanostructured materials currently used in musculoskeletal tissue engineering including natural polymers, synthetic polymers and inorganic materials. Specifically, the fabrication and applications of different nanomaterials in bone, cartilage, and muscle tissue engineering are discussed in detail. The most recent research achievements in each category are presented and discussed. Overall, nanostructured materials can be synthesized with controlled composition, size, geometry, and morphology. In order to enhance biocompatibility, immune compatibility and cell adhesion, the surface of these materials can be modified for different applications in musculoskeletal tissue scaffolds. Although more tasks and challenges need to be addressed and resolved in order to translate them into commercialized products, nanostructured materials represent very promising candidates in the development of musculoskeletal tissue engineering in the future.


Use of the indirect fluorescent antibody test in the detection of bovine respiratory syncytial virus antibodies in bovine serum.
The indirect fluorescent antibody test was adapted for identifying bovine respiratory syncytial virus and its specific antibody, using goat turbinate (GTU) cells. The virus caused maximal cytopathic effects in GTU cells 4 to 8 days postinfection, but fluorescence was not readily detected during this period. Fluorescence was maximal in infected GTU cells at 24 to 36 hours postinfection, but could be detected 48 hours postinfection. Bovine serums (331) which had been submitted to the Oklahoma Animal Disease Diagnostic Laboratory were tested for antibodies to this virus, and 73.6% were found to be positive.


[Perfusion MR imaging of the heart with TrueFISP].
Development and test of a saturation-recovery TrueFISP (SR-Trufi) pulse sequence for myocardial perfusion MR imaging (MRI) using improved gradient hardware. Measurements were performed on a 1.5 T scanner with prototype gradients (50 mT/m, minimum rise time 300 microseconds). T1-weighted first-pass MRI of Gd-DTPA (0.025 mumol/kg) kinetics in the myocardium was performed using an SR-Trufi pulse sequence (TR/TE/alpha = 2.6 ms/1.4 ms/55 degrees) with a saturation preparation of TD = 30 ms before the TrueFISP readout. Measurements were performed in volunteers (n = 4) and in a pig model of chronic ischemia (n = 1). In phantoms, the signal intensity was linear with contrast concentration up to 0.9 mmol/kg Gd-DTPA. MR images obtained with SR-Trufi had a good image quality and high spatial resolution of 2.1 mm x 2.1 mm. Differences of the contrast agent's kinetics between a subendocardial perfusion deficit and neighboring myocardium were well visible on both MR images and signal-time curves derived from the region-of-interest analysis. SR-Trufi appears to be an interesting new technique for the assessment of myocardial microcirculation using dedicated cardiovascular MR systems.


Language evaluation: science of art?
This study was designed to determine the degree of agreement between standardized tests of language development and clinical judgment. The Test of Auditory Comprehension of Language (TACL), the Carrow Elicited Language Inventory (CELI), and the Sequenced Inventory of Communication Development (SICD) were used. Three-year-old white preschool children were tested individually by experienced speech-language pathologists in day-care centers. Each examiner also made a clinical judgment of normal or impaired language behavior, based on observations during the testing. The results indicated that the CELI agreed the most with the clinical judgment of the examiners, followed by the SICD and TACL. The clinical significance of these results is discussed.


C5aR is frequently expressed in metastatic renal cell carcinoma and plays a crucial role in cell invasion via the ERK and PI3 kinase pathways.
The anaphylatoxin C5a is a chemoattractant for leukocyte migration via the C5a receptor (C5aR). We recently reported that C5aR was aberrantly expressed in a wide variety of human related cancers, while it also promotes cancer cell invasion by C5a stimulation. However, the biological significance of C5aR expression in renal cell carcinoma (RCC) has not yet been clarified. In the present study, we aimed to elucidate the biological role of C5aR in RCC progression. Clinical RCC specimens were analyzed for C5aR expression and its relationship with baseline demographic data and clinicopathological parameters was analyzed. Moreover, renal carcinoma Renca cells stably expressing C5aR were generated and used to assess the effects of C5a-C5aR axis activation on various cellular phenomena in culture. Immunohistochemistry revealed that 96.7% of the metastatic RCCs (mRCCs) showed C5aR expression, whereas only 50.5% of the non-metastatic RCCs expressed C5aR (P<0.001). Although C5a stimulation did not significantly alter anoikis of C5aR‑expressing Renca cells, C5a elicited cell morphological change and scattering of those cells accompanied with dynamic actin rearrangement, which was not observed in the Renca cells harboring the empty vector only. Moreover, C5a triggered ERK and PI3K‑dependent invasion of the C5aR-expressing renal carcinoma cells. These results are consistent with the idea that the C5a-C5aR axis plays a crucial role in renal carcinoma cell invasion, which may be one of the key steps for RCC metastasis. The present study provides proof‑of‑concept that the C5a-C5aR axis may be a useful therapeutic target for preventing RCC progression.


A dual role of the putative RNA dimerization initiation site of human immunodeficiency virus type 1 in genomic RNA packaging and proviral DNA synthesis.
In retroviruses, the genomic RNA is in the form of a 60S-70S complex composed of two identical genome-length RNA molecules tightly associated through numerous interactions. A major interaction, called the dimer linkage structure, has been found near the RNA 5' end and is probably involved in the control of translation, packaging, and recombination during proviral DNA synthesis. Recently, a small sequence corresponding to a stem-loop structure located in the 5' leader of human immunodeficiency virus type 1 (HIV-1) RNA was found to be required for the initiation of HIV-1 RNA dimerization in vitro and named the dimerization initiation site (E. Skripkin, J.-C. Paillart, R. Marquet, B. Ehresmann, and C. Ehresmann, Proc. Natl. Acad. Sci. USA 91: 4945-4949, 1994). To investigate the possible role of this 5' stem-loop in HIV-1 virion formation and infectivity, four mutant viruses were generated and analyzed in vivo. Results show that deletion of the stem-loop structure reduces infectivity by a factor of 10(3) whereas loop substitutions cause a decrease of 10- to 100-fold. The level of genomic RNA packaging was found to be decreased fivefold in mutants virions containing the stem-loop deletion and only twofold in the loop-substituted virions. Surprisingly, the second DNA strand transfer during reverse transcription was found to be severely impaired upon stem-loop deletion. Taken together, these results indicate that the stem-loop structure called the dimerization initiation site is a cis element acting on both genomic RNA packaging and synthesis of proviral DNA.


Unconventional oil and gas development and health outcomes: A scoping review of the epidemiological research.
Hydraulic fracturing together with directional and horizontal well drilling (unconventional oil and gas (UOG) development) has increased substantially over the last decade. UOG development is a complex process presenting many potential environmental health hazards, raising serious public concern. To conduct a scoping review to assess what is known about the human health outcomes associated with exposure to UOG development. We performed a literature search in MEDLINE and SCOPUS for epidemiological studies of exposure to UOG development and verified human health outcomes published through August 15, 2019. For each eligible study we extracted data on the study design, study population, health outcomes, exposure assessment approach, statistical methodology, and potential confounders. We reviewed the articles based on categories of health outcomes. We identified 806 published articles, most of which were published during the last three years. After screening, 40 peer-reviewed articles were selected for full text evaluation and of these, 29 articles met our inclusion criteria. Studies evaluated pregnancy outcomes, cancer incidence, hospitalizations, asthma exacerbations, sexually transmitted diseases, and injuries or mortality from traffic accidents. Our review found that 25 of the 29 studies reported at least one statistically significant association between the UOG exposure metric and an adverse health outcome. The most commonly studied endpoint was adverse birth outcomes, particularly preterm deliveries and low birth weight. Few studies evaluated the mediating pathways that may underpin these associations, highlighting a clear need for research on the potential exposure pathways and mechanisms underlying observed relationships. This review highlights the heterogeneity among studies with respect to study design, outcome of interest, and exposure assessment methodology. Though replication in other populations is important, current research points to a growing body of evidence of health problems in communities living near UOG sites.


Operant discrimination of relative frequency ratios in black-capped chickadee song.
The two-note fee bee song of the black-capped chickadee (Poecile atricapillus) is sung at many different absolute frequencies, but the relative frequencies, or "pitch ratios", between the start and end of the fee note (glissando) and the fee and the bee notes (inter-note interval) are preserved with each pitch-shift. Ability to perceive these ratios and their relative salience varies with sex of the bird and setting: while both sexes appear to perceive changes in the inter-note interval, males appear to attend to the glissando in the field, and females appear to attend to both ratios. In this study, we compared directly whether male and female chickadees could discriminate between normal fee bee songs and songs that had one or both of the pitch ratios altered, and whether birds attended to one type of alteration over another. Both sexes learned to discriminate normal from altered songs; songs lacking an inter-note interval were more easily discriminated than songs with only the glissando removed. Females performed slightly better than males, including in the most difficult task with the stimuli lacking the glissando. Our study illustrates the value of using perceptual tasks to directly compare performance between the sexes and to demonstrate the difference between perception of and attention to acoustic features of vocal communication.


The Molecular Pathways of Lung Damage by E-Cigarettes in Male Wistar Rats.
This study aimed to analyse the stages of lung tissue damage caused by exposure to electronic cigarette (e-cigarette) smoke. The negative health effects of e-cigarettes remain debatable. Several studies have shown the adverse effects, but others opine that e-cigarettes are safer to use than their tobacco counterparts. There is, however, a possibility that the long-term health effects, such as respiratory and even kidney function impairment, are presently not obvious. The amounts of increased free radicals and pro-inflammatory cytokines from e-cigarettes result in various physiological disorders, which trigger cell damage and even cell death in the body. An experimental study was conducted between March and September 2019 in Airlangga University using a control and an experimental group of male Wistar rats to assess the levels of malondialdehyde, interleukin (IL)-8, IL-10, matrix metalloprotein-8 and type-2 collagen. The results were obtained using immunohistochemical staining methods on alveolar macrophages through Hematoxylin-Eosin staining. The results showed that exposure to e-cigarette smoke caused an increase in free radicals, triggered an inflammatory process and degraded the type-2 collagen present in the lung tissue. Exposure to e-cigarette smoke can cause cell damage in lung tissues.


Immobilization after pinning of supracondylar distal humerus fractures in children: use of the A-frame cast.
Circumferential casts can contribute to elevated compartment pressures in the setting of acute swelling. We have developed a novel casting method (A-frame cast) that allows cast placement while leaving the antecubital fossa free of casting material. The purpose of this study was to evaluate the safety, efficacy, and complications associated with acute placement of this definitive cast after closed reduction percutaneous pinning (CRPP) of acute supracondylar distal humerus fractures. A retrospective medical record reviewed 436 patients treated with CRPP of supracondylar fractures by 3 surgeons who routinely used an A-frame cast over a 12-year period. All complications or the need for cast modification were noted. Patients with open reduction, ipsilateral fractures, or patients lost to follow-up were excluded. There were 387 patients who met inclusion criteria, including 204 type 2 fractures and 183 type 3 fractures. Forty-three patients had preoperative nerve palsy and 1 had preoperative vascular injury. Of these 387 patients, 369 (95.3%) had an uneventful postoperative course. Nineteen patients (4.9%) required either cast splitting (15) or strict elevation (4) secondary to pain and swelling. Seven of these 19 patients had preoperative nerve palsy and 1 had preoperative vascular injury. The average time from procedure to cast splitting was 17.6 hours. No patients lost their reduction or required a second surgical procedure related to a complication from casting. An "A-frame" cast provides sturdy immobilization without increased risk of compartment syndrome after CRPP of supracondylar fractures in the pediatric population. Consideration should be given to splitting the cast prophylactically in patients with preoperative neurological or vascular deficits. IV-Case Series.


Differential diagnosis of urothelial carcinoma in situ from non-neoplastic urothelia: Analysis of CK20, CD44, P53 and Ki67.
Flat urothelial lesions comprise a spectrum of morphologic changes ranging from reactive atypia to carcinoma in situ (CIS). Urothelial dysplasia and CIS are associated with the recurrence and progression of urothelial carcinoma. Distinguishing CIS and dysplasia from reactive atypia based on histolopathogical features alone is often difficult. Using different immunohistochemical markers such as Cytokeratin 20 (CK20), CD44, p53, and Ki-67 is recommended for differential diagnosis. The aim of this study was to evaluate the immunohistochemical pattern of these antibodies to differentiate different flat urothelial lesions. In this cross- sectional study, three groups of bladder biopsy specimens were evaluated: 20 samples with reactive urothelial lesions, 20 histologically diagnosed as CIS, and 20 morphologically normal samples. Immunohistochemical staining of CK20, p53, CD44 and Ki-67 markers was performed on paraffin-embedded blocks. The groups were compared using chi square test, and the diagnostic value of the markers were evaluated with sensitivity, specificity, positive and negative predictive values. CK20 was full thickness positive in 15 (75%) CIS samples and negative in all samples of the normal and reactive groups (p<0.001); CD44 was positive in 2 (10%) cases of the CIS group and in 17 (85%) of the reactive group; this marker was negative in all the normal samples (p<0.001). P53 was positive in 12 (60%) samples of the CIS group and negative in all samples of the normal and reactive groups (p<0.001). Ki67 was positive in 13 (65%) samples of the CIS group and 1 (5%) sample of the reactive group. This marker was negative in all samples of the normal group (p<0.001). The results of this study revealed that CK20, CD44, P53 and Ki67 are useful in distinguishing CIS from reactive and normal samples. However, they should be used in a panel including at least three markers. Correlation with the morphologic features is necessary.


Strain-based fatigue analysis of wheelchairs on a double roller fatigue machine.
Results are presented from an experimental program that recorded the outputs of strain gages mounted on two wheelchair frames (one manual, one power) as the wheelchairs were run on a double roller fatigue machine. Rectangular strain gage rosettes were attached to the frames near the cross tube center pin and on the side frame behind a front caster. Thirty data sets were recorded from each rosette on each wheelchair frame. The fatigue test machine and test protocol were in substantial conformance with the recently published ANSI/RESNA Standard for wheelchair fatigue testing. Two analyses have been performed on the recorded strain data. The von Mises stress histories were computed from the strain data and show that peak stresses are frequently twice the mean value. Also, estimates of the number of fatigue machine cycles to failure have been made using a strain-based fatigue analysis. These data will provide wheelchair designers with useful data to incorporate into their design process.


Identification of amino acids essential for calmodulin binding and activation of smooth muscle myosin light chain kinase.
Smooth muscle myosin light chain kinase (smMLCK) is a Ca(2+)-calmodulin (CaM)-dependent enzyme that phosphorylates the 20-kDa light chains of myosin. In a previous study (Bagchi, I.C., Kemp, B.E., and Means, A.R. (1989) J. Biol. Chem. 264, 15843-15849), we expressed in bacteria a 40-kDa fragment of smMLCK that displayed Ca(2+)-CaM-regulated catalytic activity. Initial mutagenesis experiments indicated that Gly811 and Arg812 were important for CaM-dependent activation of this 40-kDa enzyme. We have now carried out site-directed mutagenesis within the CaM-binding domain (Ser787 to Leu813) of this enzyme to identify amino acids that are critical for CaM binding and activation. Our studies reveal that the individual mutation of several hydrophobic amino acid residues such as Leu813, Ile810, and Trp800 and the glycine residue Gly804 also resulted in a severe decrease in or complete loss of CaM binding and activation of smMLCK. The hydrophobic residue (Trp800) and the basic residue (Arg812), both of which are mandatory for CaM binding to smMLCK, occur in analogous positions within the CaM-binding domain of a number of CaM-regulated enzymes. We conclude from these results that CaM binding by smMLCK is determined by an interplay of specific hydrophobic and electrostatic interactions which appear to be conserved among various target enzymes of CaM.


[Air sac midwifery technique for shortening course of labor].
Air sac midwifery technique is developed in this hospital to cut down the duration of labor (birth process). A special small sac is placed inside the ripe cervix and vagina of women of term pregnancy, and aerated slowly till a positive pressure of 16-25 kPa is reached. The cervix can be dilated to 6 to 8 cm, and the vagina 10 to 12 cm in 1 to 2 minutes. The labor course may be cut down by 8 to 10 hours, thus relieving the parturient from pain, lessening perineal laceration and perinatal mortality which is important for eugenics sake.


Using Etomidate in a Two-month-old Infant with Cushing Syndrome due to Adrenocortical Carcinoma
Cushing syndrome (CS) is a rare disease caused by hypercortisolemia. Although surgical treatment is the first-line treatment in CS, the appropriate medication for the patient's condition should be selected when medical treatment is needed. Etomidate is an adrenal-blocking drug used to treat CS and the most suitable for severe hypercortisolemia and adrenocortical carcinoma (ACC), due to cardiovascular stability and an anti-tumorigenic effect. However, its use and safe recommended dosage in infants with CS is unreported. Here we describe the case of a 2-month-old girl treated with etomidate for CS caused by ACC. Even though radical mass excision was performed, severe hypercortisolemia persisted, resulting from metastatic lesions in the liver, and medical treatment was considered. The etomidate doses, no bolus dose and infusion rate of 0.03 mg/kg/hour, may be an appropriate dose for severe hypercortisolemia in infants. This case will help determine future treatment strategies for similar cases in infants.


Sequences of taxol and cisplatin: a phase I and pharmacologic study.
Untreated and minimally pretreated solid tumor patients received alternating sequences of taxol and cisplatin. Sequential dose escalation of each agent using taxol doses of 110 or 135 mg/m2 and cisplatin doses of 50 or 75 mg/m2 resulted in four dosage permutations that induced grades 3 and 4 neutropenia in 72% to 84% and 50% to 53% of courses, respectively. Neutropenia was brief, and hospitalization for neutropenia and fever was required in 13% to 24% of courses. However, further escalation of taxol to 170 or 200 mg/m2 induced grade 4 neutropenia in 79% to 82% of courses. At the highest taxol-cisplatin dose level (200 mg/m2 to 75 mg/m2), the mean neutrophil count nadir was 98/microL, and hospitalization for neutropenia and fever was required in 64% of courses. The sequence of cisplatin before taxol, which has less antitumor activity in vitro, induced more profound neutropenia than the alternate sequence. Pharmacologic studies indicated that this difference was probably due to 25% lower taxol clearance rates when cisplatin preceded taxol. Although neurotoxicity was initially thought to be a potentially serious effect of the combination, mild to modest neurotoxicity occurred in only 27% of patients. Adverse effects also included myalgias, alopecia, vomiting, diarrhea, bradycardia, and asymptomatic ventricular tachycardia. Objective responses were noted in melanoma, as well as non-small-cell lung, ovarian, breast, head and neck, colon, and pancreatic carcinomas. Based on these results, the sequence of taxol before cisplatin at doses of 135 and 75 mg/m2, respectively, is recommended for phase II/III trials, with escalation of taxol to 170 mg/m2 if treatment is well tolerated.


Late midtrimester pregnancy termination in the presence of placenta previa.
To examine the operative outcome in women undergoing late midtrimester pregnancy termination by dilatation and evacuation in the presence of complete placenta previa. The records of 306 consecutive women undergoing pregnancy termination at 19-24 weeks' gestation from January 1997 to December 2000 were reviewed and divided into those with and without complete placenta previa based on an ultrasound examination before the procedure. These two groups were then compared for differences in patient characteristics, previous gynecologic history and operative outcome, reflected by operative time, need for blood transfusion, discharge time, postoperative bleeding and postoperative fever. Complete placenta previa occurred in 2.6% of patients (8 of 306). Significantly more women with placenta previa were married (P = .04). There was also a significant difference between the two groups considering the indication for pregnancy termination, as all patients with placenta previa underwent late midtrimester termination due to structural and chromosomal fetal malformations, whereas 33.8% of patients without placenta previa demonstrated fetal malformations (P = .005). Furthermore, significantly more women with placenta previa had had previous pelvic surgery (P = .01). However, there was no significant difference between the two groups with regard to age, percentage of smokers, number of previous abortions, parity or number of previous cesarean sections. There was no significant difference in the number of inserted Laminaria, operative time, need for blood transfusion, postoperative morbidity and duration of hospital stay. Late midtrimester pregnancy termination by dilatation and evacuation in the presence of placenta previa appears to be safe and apparently does not increase maternal morbidity as compared with the outcome in patients without placenta previa undergoing the same procedure.


[Carbohydrate transport systems in Escherichia coli and regulation of catabolism].
The mechanism of carbohydrate uptake in E. coli with involvement of the phosphoenol pyruvate-dependent phosphotransferase system (PTS) is dealt with. The genetic structure of the glucose transport system and fructose operon is given in detail. How the products of these systems can affect the total bacterial cellular catabolism dependent of complex of cyclic 3'5'-monophosphate + protein regulator of the above nucleotide is shown. Some section is devoted to the bacterial transport of beta-glycosides with the participation of Po-independent terminator and to the role of PTS as a highly sensitive sensory system associated with carbohydrate catabolism.


p16(INK4a) and histology-specific methylation of CpG islands by exposure to tobacco smoke in non-small cell lung cancer.
The p16(INK4a) protein inhibits cyclin-dependent kinase 4, a key regulator of progression through the G(1) phase of the cell cycle. Methylation of CpG islands in the promoter region is an important avenue for inactivation of p16. The mechanism of methylation of the p16 promoter region, however, has not been elucidated. Recent reports investigating p16 methylation in non-small cell lung cancer (NSCLC) suggest that carcinogens in tobacco smoke induce the DNA methylation process. We investigated the association between methylation of the p16 promoter region and exposure to tobacco smoke in 185 primary NSCLCS: We also studied the relationship of p16 methylation with mutation of the K-ras and p53 genes, as well as with methylation at the DAP-kinase and p14(ARF) loci. Finally, we evaluated the prognostic significance of p16 methylation in NSCLC. The prevalence of p16 methylation was greater in squamous cell carcinoma (41%) compared with adenocarcinoma (22%; P = 0.03; Fisher's exact test). Methylation of p16 was significantly associated with pack-years smoked (P = 0.007; Wilcoxon rank sum test), duration of smoking (P = 0.0009; Wilcoxon rank sum test), and negatively with the time since quitting smoking (P = 0.03; Wilcoxon rank sum test). No methylation of the nearby p14(ARF) locus was detected, and methylation of the DAP-kinase locus was not associated with either p16 methylation or with exposure to tobacco smoke. In patients with stage 1 adenocarcinoma, p16 methylation was an independent risk factor predicting significantly shorter postsurgery survival (P = 0.03), controlling for the significant effects of other factors, including K-ras mutation. These findings suggest that methylation of CpG islands in tobacco-associated cancers occurs in a gene- and tissue-specific manner and is induced directly or indirectly by exposure to tobacco smoke in NSCLC.


Do plant-microbe interactions support the Stress Gradient Hypothesis?
The Stress Gradient Hypothesis (SGH), which predicts increasing ratios of facilitative:competitive interactions with increasing stress, has long been a guiding framework for conceptualizing plant-plant interactions. Recently, there has been a growing recognition of the roles of microbes in mitigating or exacerbating environmental stress for their plant hosts. As such, we might predict, based on the SGH, that beneficial microbial effects on plant performance should be positively associated with stress. Specifically, we hypothesized that support for the SGH would depend on the host plant's habitat specialization such that species that specialize in high stress habitats and thus likely coevolved with the resident microbes would exhibit stronger support for the SGH than non-specialist plant species. We further hypothesized that support for the SGH would vary with germination frequency, since boosting germination of low-frequency germinators is one effective means by which microbes can benefit plant species performance. Here, we explore whether plant-microbial interactions support the SGH using 12 plant species native to the Florida rosemary scrub. We conducted factorial experiments that manipulated the presence of microbes in nine soils collected along an elevational stress gradient, and recorded germination frequency and biomass. Microbes increased the germination frequency of four species, all of which had relatively low germination rates. Furthermore, we found support for the SGH in nearly one-half of the species examined, with soil microbes facilitating germination with increasing stress for 5 of the 12 species tested, and none of the species exhibiting the opposite trend. Support for the SGH was not predicted by either the plant hosts' habitat specialization or germination frequency. In contrast to germination, biomass results showed little support for the SGH, with four of 12 species refuting and one species supporting SGH predictions. Taken together, our study documents that interactions between the soil microbial community and plant species along a stress gradient can support the SGH, but emphasizes that these effects are life-history-stage dependent. This work also identifies a common mechanism (germination facilitation) by which microbes can benefit plant species in stressful habitats.


[Cerebral Small Vessel Disease: Advances in Understanding its Pathophysiology].
Sporadic cerebral small vessel disease determines age- and vascular-risk-factor-related processes of the small brain vasculature. The underlying pathology develops in a stage-dependent manner - probably over decades - often already starting in midlife. Endothelial and pericyte activation precedes blood-brain barrier leaks, extracellular matrix remodeling and neuroinflammation, which ultimately result in bleeds, synaptic and neural dysfunction. Hemodynamic compromise of the small vessel walls promotes perivascular drainage failure and accumulation of neurotoxic waste products in the brain. Clinical diagnosis is mainly based on magnetic resonance imaging according to the Standards for Reporting Vascular Changes on Neuroimaging 2. Cerebral amyloid angiopathy is particularly stratified according to the Boston v2.0 criteria. Small vessel disease of the brain could be clinically silent, or manifested through a heterogeneous spectrum of diseases, where cognitive decline and stroke-related symptoms are the most common ones. Prevention and therapy are centered around vascular risk factor control, physically and cognitively enriched life style and, presumably, maintenance of a good sleep quality, which promotes sufficient perivascular drainage. Prevention of ischemic stroke through anticoagulation that carries at the same time an increased risk for large brain hemorrhages - particularly in the presence of disseminated cortical superficial siderosis - remains one of the main challenges. The cerebral small vessel disease field is rapidly evolving, focusing on the establishment of early disease stage imaging and biofluid biomarkers of neurovascular unit remodeling and the compromise of perivascular drainage. New prevention and therapy strategies will correspondingly center around the dedicated targeting of, e. g., cellular small vessel wall and perivascular tissue structures. Growing knowledge about brain microvasculature bridging neuroimmunological, neurovascular and neurodegenerative fields might lead to a rethink about apparently separate disease entities and the development of overarching concepts for a common line of prevention and treatment for several diseases.


Nanoreporter Identifies Lysosomal Storage Disease Lipid Accumulation Intracranially.
Dysregulated lipid metabolism contributes to neurodegenerative pathologies and neurological decline in lysosomal storage disorders as well as more common neurodegenerative diseases. Niemann-Pick type A (NPA) is a fatal neurodegenerative lysosomal storage disease characterized by abnormal sphingomyelin accumulation in the endolysosomal lumen. The ability to monitor abnormalities in lipid homeostasis intracranially could improve basic investigations and the development of effective treatment strategies. We investigated the carbon nanotube-based detection of intracranial lipid content. We found that the near-infrared emission of a carbon nanotube-based lipid sensor responds to lipid accumulation in neuronal and in vivo models of NPA. The nanosensor detected lipid accumulation intracranially in an acid sphingomyelinase knockout mouse via noninvasive near-infrared spectroscopy. This work indicates a tool to improve drug development processes in NPA, other lysosomal storage diseases, and neurodegenerative diseases.


A microphysiological model of the bronchial airways reveals the interplay of mechanical and biochemical signals in bronchospasm.
In asthma, the contraction of the airway smooth muscle and the subsequent decrease in airflow involve a poorly understood set of mechanical and biochemical events. Organ-level and molecular-scale models of the airway are frequently based on purely mechanical or biochemical considerations and do not account for physiological mechanochemical couplings. Here, we present a microphysiological model of the airway that allows for the quantitative analysis of the interactions between mechanical and biochemical signals triggered by compressive stress on epithelial cells. We show that a mechanical stimulus mimicking a bronchospastic challenge triggers the marked contraction and delayed relaxation of airway smooth muscle, and that this is mediated by the discordant expression of cyclooxygenase genes in epithelial cells and regulated by the mechanosensor and transcriptional co-activator Yes-associated protein. A mathematical model of the intercellular feedback interactions recapitulates aspects of obstructive disease of the airways, which include pathognomonic features of severe difficult-to-treat asthma. The microphysiological model could be used to investigate the mechanisms of asthma pathogenesis and to develop therapeutic strategies that disrupt the positive feedback loop that leads to persistent airway constriction.


[Tonsillar cancer and Epstein-Barr virus].
Epstein-Barr Virus is an important aetiological factor in the development of nasopharyngeal carcinoma (NPC). Serology suggested that besides NPC some other tumours located within the lymphoepithelial ring of the throat (Waldeyer's ring) might be associated with EBV. Nucleic-acid hybridizations were carried out to detect the presence of EBV-DNA in tumour biopsies derived from tonsillar carcinomas. We were able to demonstrate the presence of EBV-DNA in the tumour cells of two poorly differentiated carcinomas. We think that only a small fraction of tonsillar carcinomas is positive for EBV. The aetiologic relationship of EBV with tumours of Waldeyer's ring is discussed.


Effect of time and dose of recombinant follicle stimulating hormone agonist on the superovulatory response of sheep.
The objective of this study was to determine the superovulatory potential of a single-chain analog of human FSH (Fcα) when administered to ewes either 3 days before, or coincident with, simulated luteolysis (pessary removal [PR]). A total of 40 animals were randomly assigned to receive Fcα at doses of 0.62, 1.25, or 2.5 IU/kg of body weight (bwt) 3 days before PR or 0.31, 0.62, 1.25, or 2.5 IU/kg of bwt at PR. Control ewes received protein without FSH activity. Blood samples were collected during the periovulatory period and ovarian tissue was collected 11 days after PR. Ovulation rate did not differ from the control group in ewes receiving the smallest doses of Fcα (0.31 and 0.62 IU/kg). However, a significant superovulatory response was noted in sheep receiving Fcα at doses of 1.25 and 2.5 IU/kg and this response was comparable in animals receiving the largest dose levels of Fcα at, or 3 days before, PR. The interval between PR and the LH surge was significantly extended and the LH surges were less synchronous in animals receiving Fcα at PR when compared with animals receiving the potent FSH agonist 3 days before PR. Taken together, these data indicate that the human single-chain gonadotropin with FSH activity promotes superovulation in ewe lambs in the breeding season. A single injection of the recombinant gonadotropin 3 days before luteolysis synchronizes the LH surge. The use of the single-chain analog of FSH in assisted reproduction for domestic animals is likely to be of practical significance as an alternative to conventional gonadotropins in superovulation protocols in livestock species.