Glycoprotein VI is Critical for the Detection and Progression of Abdominal Aortic Aneurysms.
A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (J) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist. Soluble glycoprotein VI, which is a platelet-derived blood biomarker, predicts a diagnosis of AAA, with high sensitivity and specificity in distinguishing patients with fast from slow-growing AAA.Blockade of glycoprotein VI in mice with established aneurysms reduces AAA progression and mortality, indicating therapeutic potential.


On Calderón's conjecture for the bilinear Hilbert transform.
We show that the bilinear Hilbert transform defined by maps Lp x Lq into Lr for 1 < p, q </= infinity, 1/p + 1/q = 1/r, and 2/3 < r < infinity.


Prenatal Dexamethasone Exposure Induced Ovarian Developmental Toxicity and Transgenerational Effect in Rat Offspring.
Prenatal dexamethasone exposure (PDE) induces multiorgan developmental toxicities in offspring. Here we verified the transgenerational inheritance effect of ovarian developmental toxicity by PDE and explored its intrauterine programming mechanism. Pregnant rats subcutaneously received 0.2 mg/kg/d dexamethasone from gestational day (GD) 9 to GD20. A subgroup was euthanized for fetuses on GD20, and the other group went on to spontaneous labor to produce F1 offspring. The adult F1 females were mated with normal males to produce the F2 and F3 generations. The PDE fetal rats exhibited ovarian mitochondrial structural abnormalities, decreased serum estradiol (E2) levels, and lower expression levels of ovarian steroidogenic factor 1 (SF1), steroidal synthetases, and insulinlike growth factor 1 (IGF1). On postnatal week (PW) 6 and PW12, the PDE F1 offspring showed altered reproductive behavior and ovarian morphology. The serum E2 level and ovarian expression of SF1, steroidal synthetases, and IGF1 were also decreased. The adult F3 offspring showed alterations in reproductive phenotype and ovarian IGF1, SF1, and steroidal synthetase expression similar to those of F1. PDE induces ovarian developmental toxicity and transgenerational inheritance effects. The mechanism by which this toxicity occurs may be related to PDE-induced low-functional programming of fetal ovarian IGF1/SF1 and steroidal synthetases.


Detection of transfusion-associated hepatitis caused by non-A, non-B, non-C flavivirus.
Sera of patients suffering from acute hepatitis, and different forms of chronic hepatitis were found to be reactive to reagents prepared from the yellow fever virus (YF) vaccine strain. Serum samples of 1974 patients were tested, and 133 of them were positive. Hepatitis C virus specific antibodies were absent from the majority of them. The frequency of antibodies to other flaviviruses (tick-borne encephalitis, West Nile) and hepatitis B virus markers was similar to that measured among the population in Hungary positive for any of the surrogate markers of hepatitis infections. Results of both immunofluorescence tests, and Western blots suggest that there is a non-A, non-B, non-C hepatitis virus circulating among the Hungarian population, which possesses antigenic cross-reactivity with the yellow fever virus, but the identity to any of the known flaviviruses could not be verified yet. No history of yellow fever vaccination could be revealed in any of the patients included into this study. The anamnestic data on previous transfusions or surgical operations can be verified only in the case of the half of YFV-positive patients, nevertheless, the sexual transmission seems to be very infrequent. Attempts are continued in order to detect the viral RNA using polymerase chain reaction, and clone cDNA sequences for sequence analysis.


A Reweighted Scheme to Improve the Representation of the Neural Autoregressive Distribution Estimator.
The neural autoregressive distribution estimator(NADE) is a competitive model for the task of density estimation in the field of machine learning. While NADE mainly focuses on the problem of estimating density, the ability for dealing with other tasks remains to be improved. In this paper, we introduce a simple and efficient reweighted scheme to modify the parameters of the learned NADE. We make use of the structure of NADE, and the weights are derived from the activations in the corresponding hidden layers. The experiments show that the features from unsupervised learning with our reweighted scheme would be more meaningful, and the performance of the initialization for neural networks has a significant improvement as well.


Accelerated-interrupted radiation therapy given concurrently with chemotherapy for locally advanced non-small cell lung cancer.
To evaluate the efficacy of multidrug chemotherapy combined with accelerated radiation therapy in the treatment of localized but unresectable non-small cell lung cancer. Between September 1990 and February 1993, 35 patients with Stage III (15 IIIA & 20 IIIB) non-small cell lung cancer were entered on a protocol using combined accelerated radiation therapy and chemotherapy. Radiation therapy consisted of 55.6 Gy in 30 fractions (1.8 Gy bid for 5 consecutive days given in 3 weeks [total of 15 days], every other week). Chemotherapy consisted of cisplatin (10 mg/m2), vinblastine (4 mg/m2), 6-thioguanine (40 mg bid), and 5-fluorouracil (400 mg/m2 as continuous infusion) given concomitantly with radiation therapy. Approximately 3 weeks following completion of radiation therapy, two cycles of consolidation chemotherapy were given, consisting of two doses of cisplatin (120 mg/m2) 4 weeks apart and six doses of vinblastine (4 mg/m2) given on two consecutive days every other week for 3 weeks. Six patients were still alive at last follow-up; for them the median follow-up time is 47 months (range, 39-55.8). The median survival time is 17.5 months. The 1-, 2-, 3- and 4.5-year survival rates are 69%, 37%, 20% and 17%, respectively. Overall response rate is 63%, with 51.5% partial response and 11.5% complete response rates. Esophagitis occurred as follows: Grade 4 = 0, Grade 3 = 1, Grade 2 = 6, and Grade 1 = 13. No patient developed Grade 3 or 4 acute respiratory toxicity. Significant hematologic toxicity occurred as follows: 37% Grade 3 and 31% Grade 4 leukopenia. Radiation pneumonitis occurred in two patients. The regimen tested in this protocol appears to be very well tolerated with minimal pulmonary or esophageal toxicity. This, coupled with the shortened course of radiation therapy and the ability to deliver the combined radiation and chemotherapy portion of the treatment on an outpatient basis most of the time, has made multi-modality treatment for this malignancy much easier and more convenient for patients. In addition, the favorable survival in this group of patients with locally advanced disease is very encouraging and warrants further study.


Differential amplification of murine bipotent megakaryocytic/erythroid progenitor and precursor cells during recovery from acute and chronic erythroid stress.
Two murine bipotent erythroid/megakaryocytic cells, the progenitor (MEP) and precursor (PEM) cells, recently have been identified on the basis of the phenotypes of linnegc-kitposSca-1neg CD16/CD32lowCD34low and TER119pos4A5pos or 2D5pos, respectively. However, the functional relationship between these two subpopulations and their placement in the hemopoietic hierarchy is incompletely understood. We compared the biological properties of these subpopulations in marrow and spleen of mice with and without acute or chronic erythroid stress. MEP cells, but not PEM cells, express c-kit, respond to stem cell factor in vitro, and form spleen colonies in vivo. PEM cells comprise up to 50%-70% of the cells in BFU-E-derived colonies but are not present among the progeny of purified MEP cells cultured under erythroid and megakaryocytic permissive conditions. PEM cells increase 10- to 20-fold under acute and chronic stress, whereas MEP cell increases (21%-84%) are observed only in acutely stressed animals. These data suggest that MEP and PEM cells represent distinct cell populations that may exist in an upstream-downstream differentiation relationship under conditions of stress. Whereas the dynamics of both populations are altered by stress induction, the differential response to acute and chronic stress suggests different regulatory mechanisms. A model describing the relationship between MEP, PEM, and common myeloid progenitor cells is presented.


Impact of training volume and intensity on RBC-NOS/NO pathway and endurance capacity.
Acute exercise increases red blood cell-nitric oxide synthase (RBC-NOS) activation and RBC deformability but the effect of regular training remains unclear. To detect the chronic effect of enduring moderate and high intensity training on the RBC-NOS/NO pathway and to detect a relation between RBC deformability and endurance capacity. 38 healthy male subjects were randomly assigned to one of three training groups: High Volume Training (HVT; 120-140 beats per minute (bpm)), High Intensity Training (HIT; 160-180 bpm) and Moderate Intensity Training (MIT; 140-160 bpm). Blood parameters, maximum oxygen capacity (VO2 max), RBC deformability, RBC nitrite level and RBC-NOS activation were measured after venous blood sampling at rest pre (T0) and after six weeks of training (T1). RBC-NOS activation, RBC nitrite concentration and RBC deformability were significantly increased at T1 in the HIT group. Parameters were unaltered in MIT and HVT. Maximum oxygen uptake was only significantly increased in the HIT group and regression analysis revealed positive regression between VO2 max and RBC deformability. High intensity training was the only training programme that sustainably affected RBC-NOS dependent NO production and performance capacity. HIT therefore represents a time efficient training program resulting in improved RBC function potentially improving physical condition.


Life history biology of early land plants: deciphering the gametophyte phase.
The ca. 400-million-year-old Rhynie chert biota represents a benchmark for studies of early terrestrial ecosystems. The exquisite preservation of the organisms documents an ancient biodiversity that also includes various levels of biological interaction. Absent from the picture until recently has been detailed information about the development of the gametophyte phase and the alternation of generations of the macroplants in this ecosystem. Here, we trace the development of the gametophyte phase of Aglaophyton, an early land plant with an unusual complement of structural and morphological characters. Mature gametophytes consist of a fleshy protocorm attached to the substrate by basal rhizoids; arising from the upper surface are one to several upright gametangiophores bearing multiple gametangia. Stomata are present on the upper surface of the protocorm and gametangiophore, and endomycorrhizal fungi extend throughout the gametophyte. Gametophytes are unisexual, producing either antheridiophores or archegoniophores. There is no evidence that gametophytes later become hermaphroditic. The sexual dimorphism of the Rhynie chert gametophytes is inconsistent with theoretical ideas about the haploid phase of early land plants. The gametophyte phase of early land plants can now be considered within an ecological and evolutionary framework that, in turn, can be used to develop hypotheses about some aspects of the population dynamics and growth of these early land plants.


HIV-related knowledge, information, and their contribution to stigmatization attitudes among females aged 15-24 years: regional disparities in Indonesia.
Stigmatization attitudes among youths toward people living with HIV (PLWH) is still an issue and concern in Indonesia. The purpose of this study was to determine the regional disparities, levels of HIV-related knowledge, information, and contributions related to stigmatization attitudes among females aged 15-24 years in Indonesia. A cross-sectional study with The 2017 Indonesian Demographic Health Survey (IDHS) was used. A total of 12,691individual records of females aged 15-24 years were recruited through two-stage stratified cluster sampling. The endpoint was stigmatization attitude. Then, bivariate and multivariate binary logistics were performed. The findings showed that female youths who have no HIV-related knowledge (62.15%) and some source of information (52.39%). The highest prevalence of stigmatizing attitude was 59.82%, on Java Island. Multivariate analysis showed that females living in Sulawesi and Kalimantan; those living in a rural area; and those with more HIV-related knowledge were less likely to have a stigmatizing attitude. Conversely, females with the middle- to richest-wealth index and had some HIV-related information were more likely to have a stigmatizing attitude. An understanding of stigmatizing attitudes should be considered through demographic factors, knowledge, and source of HIV-related information. The Indonesian government should pay more attention to indicators of HIV-related knowledge and information. Moreover, we suggest that the government collaborates with youths to disseminate information and restructure and reanalyze policies about HIV.


Haloperidol and fluphenazine induce junB gene expression in rat striatum and nucleus accumbens.
Administration of neuroleptics such as haloperidol to rats is known to induce the expression of the immediate-early genes (IEGs) c-fos and zif/268 in striatal neurones. Another IEG, junB, is of interest because it may be involved in the suppression, rather than the enhancement, of downstream gene transcription. In this study, rat striatal tissue was assayed for IEG expression by in situ hybridisation, after the injection of haloperidol (1 mg/kg) or fluphenazine (3 mg/kg). In addition to c-fos mRNA and zif/268 mRNA, neurones in both the striatum and nucleus accumbens were found to contain high levels of junB mRNA, after treatment with either haloperidol or fluphenazine. The proportion of striatal neurones expressing junB mRNA strongly suggests that induction occurs in striatal projection neurones. A significant increase in the levels of the mRNA encoding another IEG, junD, was also detected after haloperidol treatment. The atypical neuroleptic clozapine (3 mg/kg) did not induce the expression of any of these IEGs in striatal tissue. The results show additional complexity in the pattern of IEG induction after neuroleptic administration and suggest that junB is involved in mediating some of the effects of neuroleptics on striatal gene expression.


Protein-Based Hydrogels and Their Biomedical Applications.
Hydrogels made from proteins are attractive materials for diverse medical applications, as they are biocompatible, biodegradable, and amenable to chemical and biological modifications. Recent advances in protein engineering, synthetic biology, and material science have enabled the fine-tuning of protein sequences, hydrogel structures, and hydrogel mechanical properties, allowing for a broad range of biomedical applications using protein hydrogels. This article reviews recent progresses on protein hydrogels with special focus on those made of microbially produced proteins. We discuss different hydrogel formation strategies and their associated hydrogel properties. We also review various biomedical applications, categorized by the origin of protein sequences. Lastly, current challenges and future opportunities in engineering protein-based hydrogels are discussed. We hope this review will inspire new ideas in material innovation, leading to advanced protein hydrogels with desirable properties for a wide range of biomedical applications.


[Velocity of nerve conduction in children and adolescents with type I diabetes mellitus: clinical, metabolic and immunologic correlations].
Clinical, metabolic, neurophysiologic and immunological data were obtained in a group of 50 patients with type I diabetes mellitus Results were compared with those obtained in 30 healthy subjects of comparable age. M.N.C. (median nerve conduction) velocities and sensitive latency were observed to be significant lower in the diabetic patients rather than in the controls. These abnormalities were correlated with the duration of diabetes rather than with the glucose control. The positivity for circulating immune complexes was found to be associated with a significant reduction of median sensory nerve conduction velocity. There results suggest that in addition to metabolic, genetic, vascular and hormonal abnormalities also immunologic factors may play a role in the pathogenesis of diabetic neuropathy.


Major urinary protein 5, a scent communication protein, is regulated by dietary restriction and subsequent re-feeding in mice.
Major urinary proteins (Mups) are important for rodent scent communication and sexual behaviour. Recent evidence suggests that Mup1 may be regulated by fasting and re-feeding (RF). However, other Mup isoforms are poorly investigated, and data on the impact of long-term dietary restriction (DR) and ad libitum RF on Mup expression are missing. We investigated the effects of long-term 25 per cent DR and subsequent RF on Mup expression in male C57BL6 mice. DR significantly decreased Mup gene expression, hepatic and urinary protein levels compared with ad libitum (AL) fed control mice, with the greatest downregulation found for Mup5 expression. The decline in Mup expression was inverted by six months of RF. Because of inhibitory glucocorticoid response elements in the genomic sequence of the Mup5 gene, the observed inverse correlation of nuclear glucocorticoid receptor levels with Mup expression in response to DR and subsequent RF is a possible regulatory mechanism. Additionally, gene-expression-inhibiting histone deacetylation (H3K9) occurred in the region of the Mup5 gene in response to DR. We assume that Mup may act as a molecular switch linking nutritional status to sexual behaviour of mice, and thereby regulating male fertility and reproduction in response to food supply.


[Assessment of physicians' competence. The continuous professional development].
Several stakeholders now request some sort of continuous assessment of physician performance. In the assessment of physicians it must be acknowledged that physicians often work in teams and systems, rendering it impossible to attribute quality of practice to a single person. The challenge is to design a concept that is a meaningful contribution to the development of quality of practice. There is a need to rethink the traditional discourse known from undergraduate and postgraduate specialist educations when applying concepts of assessment to the continuous professional development.


Transformed low-rank ANOVA models for high-dimensional variable selection.
High-dimensional data are often encountered in biomedical, environmental, and other studies. For example, in biomedical studies that involve high-throughput omic data, an important problem is to search for genetic variables that are predictive of a particular phenotype. A conventional solution is to characterize such relationships through regression models in which a phenotype is treated as the response variable and the variables are treated as covariates; this approach becomes particularly challenging when the number of variables exceeds the number of samples. We propose a general framework for expressing the transformed mean of high-dimensional variables in an exponential distribution family via ANOVA models in which a low-rank interaction space captures the association between the phenotype and the variables. This alternative method transforms the variable selection problem into a well-posed problem with the number of observations larger than the number of variables. In addition, we propose a model selection criterion for the new model framework with a diverging number of parameters, and establish the consistency of the selection criterion. We demonstrate the appealing performance of the proposed method in terms of prediction and detection accuracy through simulations and real data analyses.


Immunological insights into the resistance of Nile tilapia strains to an infection with tilapia lake virus.
The emergence of viral diseases affecting fish and causing very high mortality can lead to the disruption of aquaculture production. Recently, this occurred in Nile tilapia aquaculture where a disease caused by a systemic infection with a novel virus named tilapia lake virus (TiLV) caused havoc in cultured populations. With mortality surpassing 90% in young tilapia, the disease caused by TiLV has become a serious challenge for global tilapia aquaculture. In order to partly mitigate the losses, we explored the natural resistance to TiLV-induced disease in three genetic strains of tilapia which were kept at the University of Göttingen, Germany. We used two strains originating from Nilotic regions (Lake Mansala (MAN) and Lake Turkana (ELM)) and one from an unknown location (DRE). We were able to show that the virus is capable of overcoming the natural resistance of tilapia when injected, providing inaccurate mortality results that might complicate finding the resistant strains. Using the cohabitation infection model, we found an ELM strain that did not develop any clinical signs of the infection, which resulted in nearly 100% survival rate. The other two strains (DRE and MAN) showed severe clinical signs and much lower survival rates of 29.3% in the DRE strain and 6.7% in the MAN strain. The disease resistance of tilapia from the ELM strain was correlated with lower viral loads both at the mucosa and internal tissues. Our results suggest that the lower viral load could be caused by a higher magnitude of a mx1-based antiviral response in the initial phase of infection. The lower pro-inflammatory responses also found in the resistant strain might additionally contribute to its protection from developing pathological changes related to the disease. In conclusion, our results suggest the possibility of using TiLV-resistant strains as an ad hoc, cost-effective solution to the TiLV challenge. However, as the fish from the disease-resistant strain still retained significant virus loads in liver and brain and thus could become persistent virus carriers, they should be used within an integrative approach also combining biosecurity, diagnostics and vaccination measures.\.


Microbiology and prognostic prediction model of bloodstream infection in patients with hematological malignancies.
In recent years, with the continuous development of treatments for hematological malignancies (HMs), the remission and survival rates of patients with HMs have been significantly improved. However, because of severe immunosuppression and long-term recurrent neutropenia during treatment, the incidence and mortality of bloodstream infection (BSI) were all high in patients with HMs. Therefore, we analyzed pathogens' distribution and drug-resistance patterns and developed a nomogram for predicting 30-day mortality in patients with BSIs among HMs. In this retrospective study, 362 patients with positive blood cultures in HMs were included from June 2015 to June 2020 at West China Hospital of Sichuan University. They were randomly divided into the training cohort (n = 253) and the validation cohort (n = 109) by 7:3. A nomogram for predicting 30-day mortality after BSIs in patients with HMs was established based on the results of univariate and multivariate logistic regression. C-index, calibration plots, and decision curve analysis were used to evaluate the nomogram. Among 362 patients with BSIs in HMs, the most common HM was acute myeloid leukemia (48.1%), and the most common pathogen of BSI was gram-negative bacteria (70.4%). The final nomogram included the septic shock, relapsed/refractory HM, albumin <30g/l, platelets <30×109/l before BSI, and inappropriate empiric antibiotic treatment. In the training and validation cohorts, the C-indexes (0.870 and 0.825) and the calibration plots indicated that the nomogram had a good performance. The decision curves in both cohorts showed that the nomogram model for predicting 30-day mortality after BSI was more beneficial than all patients with BSIs or none with BSIs. In our study, gram-negative bacterial BSIs were predominant in patients with HMs. We developed and validated a nomogram with good predictive ability to help clinicians evaluate the prognosis of patients.


AM966, an Antagonist of Lysophosphatidic Acid Receptor 1, Increases Lung Microvascular Endothelial Permeability through Activation of Rho Signaling Pathway and Phosphorylation of VE-Cadherin.
Maintenance of pulmonary endothelial barrier integrity is important for reducing severity of lung injury. Lysophosphatidic acid (LPA) regulates cell motility, cytoskeletal rearrangement, and cell growth. Knockdown of LPA receptor 1 (LPA1) has been shown to mitigate lung injury and pulmonary fibrosis. AM966, an LPA1 antagonist exhibiting an antifibrotic property, has been considered to be a future antifibrotic medicine. Here, we report an unexpected effect of AM966, which increases lung endothelial barrier permeability. An electric cell-substrate sensing (ECIS) system was used to measure permeability in human lung microvascular endothelial cells (HLMVECs). AM966 decreased the transendothelial electrical resistance (TEER) value immediately in a dose-dependent manner. VE-cadherin and f-actin double immunostaining reveals that AM966 increases stress fibers and gap formation between endothelial cells. AM966 induced phosphorylation of myosin light chain (MLC) through activation of RhoA/Rho kinase pathway. Unlike LPA treatment, AM966 had no effect on phosphorylation of extracellular signal-regulated kinases (Erk). Further, in LPA1 silencing cells, we observed that AM966-increased lung endothelial permeability as well as phosphorylation of VE-cadherin and focal adhesion kinase (FAK) were attenuated. This study reveals that AM966 induces lung endothelial barrier dysfunction, which is regulated by LPA1-mediated activation of RhoA/MLC and phosphorylation of VE-cadherin.


Electron transport and electrochemistry of mesomorphic fullerenes with long-range ordered lamellae.
Fullerenes, C60, modified with long alkyl chains form long-range ordered lamellar mesophases permitting a high C60 content. The mesomorphic fullerenes feature reversible electrochemistry and a comparably high electron carrier mobility making them attractive components for fullerene-based soft materials.


GO/CNT-OH/Nafion Nanocomposite Humidity Sensor Based on the LC Wireless Method.
In recent years, LC resonant sensors have gained widespread attention for their extensive applications in industries such as pharmaceutical storage and food transportation. A wireless passive sensor with a good sensing performance is proposed based on a GO/CNT-OH/Nafion nanocomposite. The sensor was fabricated via inkjet printing technology, and the surface morphology of the GO/CNT-OH/Nafion nanocomposite was characterized by SEM measurement. It is found that the MWCNTs support the GO layer and the hydrophobic chains of Nafion interact with the hydrophobic layer of GO, resulting in a larger cavity and hydrophilic surface of the entire material. This structure well reflects the fact that the mixing of MWCNTs and Nafion provides the entire material with a stronger water absorption. The experimental study shows that the proposed humidity sensor has a frequency variation of 103 kHz/%RH at low humidity (30-60% RH) and a sensitivity of 931 kHz/%RH at high humidity (60-95% RH), while the sensitivity value from 30-95% RH is 547 kHz/% RH. The response time and recovery time are 110 s and 115 s, respectively. In addition, the tests showed that the GO/CNT-OH/Nafion nanocomposite applied to the humidity sensor had a maximum humidity hysteresis of about 3% RH at 30-95% RH, the resonant frequency remained basically unchanged after 50 h of testing, and the whole sensor possessed a good stability. After conducting several repeated experiments, it was found that the resonant frequency error of the whole sensor was low and did not affect the overall sensing test, which proved the reproducible preparation of the sensor. Finally, the humidity-sensing mechanism of the proposed sensor was analyzed in this paper, and it was found that GO enhanced the hygroscopic properties of GO/CNT-OH/Nafion nanocomposite when it was supported by MWCNT-OH and included uniformly dispersed Nafion. Therefore, our proposed humidity sensor is suitable for humidity detection above 30% RH in both sealed and open environments.


Onset of alveolar recirculation in the developing lungs and its consequence on nanoparticle deposition in the pulmonary acinus.
The structure of the gas exchange region of the human lung (the pulmonary acinus) undergoes profound change in the first few years of life. In this paper, we investigate numerically how the change in alveolar shape with time affects the rate of nanoparticle deposition deep in the lung during postnatal development. As human infant data is unavailable, we use a rat model of lung development. The process of postnatal lung development in the rat is remarkably similar to that of the human, and the structure of the rat acinus is indistinguishable from that of the human acinus. The current numerical predictions support our group's recent in vivo findings, which were also obtained by using growing rat lung models, that nanoparticle deposition in infants is strongly affected by the change in the structure of the pulmonary acinus. In humans, this major structural change occurs over the first 2 yr of life. Our current predictions would suggest that human infants at the age of ∼ 2 yr might be most at risk to the harmful effects of air pollution. Our results also suggest that dose estimates for inhalation therapies using nanoparticles, based on fully developed adult lungs with simple body weight scaling, are likely to overestimate deposition by up to 55% for newborns and underestimate deposition by up to 17% for 2-yr-old infants.


Acute health effects from exposure to indoor ultrafine particles-A randomized controlled crossover study among young mild asthmatics.
Particulate matter is linked to adverse health effects, however, little is known about health effects of particles emitted from typical indoor sources. We examined acute health effects of short-term exposure to emissions from cooking and candles among asthmatics. In a randomized controlled double-blinded crossover study, 36 young non-smoking asthmatics attended three exposure sessions lasting 5 h: (a) air mixed with emissions from cooking (fine particle mass concentration): (PM2.5 : 96.1 μg/m3 ), (b) air mixed with emissions from candles (PM2.5 : 89.8 μg/m3 ), and c) clean filtered air (PM2.5 : 5.8 μg/m3 ). Health effects (spirometry, fractional exhaled Nitric Oxide [FeNO], nasal volume and self-reported symptoms) were evaluated before exposure start, then 5 and 24 h after. During exposures volatile organic compounds (VOCs), particle size distributions, number concentrations and optical properties were measured. Generally, no statistically significant changes were observed in spirometry, FeNO, or nasal volume comparing cooking and candle exposures to clean air. In males, nasal volume and FeNO decreased after exposure to cooking and candles, respectively. Participants reported additional and more pronounced symptoms during exposure to cooking and candles compared to clean air. The results indicate that emissions from cooking and candles exert mild inflammation in asthmatic males and decrease comfort among asthmatic males and females.


Malfunction of Enzyme Systems Involved in the Regeneration of Glutathione in Perennials at Low Temperatures.
When frozen flower buds of apple trees started to thaw, an abrupt decrease of levels of reduced glutathione and glucose-6-phosphate occurred, even without freezing injuries. With freezing injuries, a steep decrease in the levels of the above substrates was observed, suggesting that the level of generating peroxide depends on freezing temperatures. Enzyme systems involved in the regeneration of reduced glutathione also do not seem to function properly in poplar twigs in a frozen milieu. At about - 10°C, a decrease in levels of reduced glutathione was detected and this decrease was followed by a decrease in levels of glucose 6-phosphate. When twigs that contained depressed levels of reduced glutathione and glucose-6-phosphate were transferred to 4°C, overcompensation for the decrease in reduced glutathione and glucose-6-phosphate occurred and the resultant surplus appeared to reflect the metabolic dysfunction in the supply and demand for reduced glutathione and glucose-6-phosphate that occurs under frozen conditions. These results suggest that the sequence of reactions which starts from the reaction catalyzed by hexokinase, through reactions catalyzed by glucose-6-phosphate dehydrogenase and glutathione reductase, does not function properly under frozen conditions in perennial plants.


Effects of angiotensin and prostaglandin A2 in perfused isolated kidneys of dogs.
Simultaneous recordings of pressure and flow were made from the renal artery in perfused isolate canine kidneys. The system was perturbated by the administration of angiotensin and prostaglandin A2. The data were recorded on frequency-modulated analog tape and converted to digital form, and a Fast Fourier Transform program was used to calculate input impedance. Changes in total renal volume and renal arterial pressure data were used to determine compliance values. in compliance were found, along with changes in both magnitude of impedance and phase angle, as a result of the perturbations introduced. Seemingly, renal vascular compliance has an important role in the autoregulatory mechanisms of the kidney.


Identifying work related injuries: comparison of methods for interrogating text fields.
Work-related injuries in Australia are estimated to cost around $57.5 billion annually, however there are currently insufficient surveillance data available to support an evidence-based public health response. Emergency departments (ED) in Australia are a potential source of information on work-related injuries though most ED's do not have an 'Activity Code' to identify work-related cases with information about the presenting problem recorded in a short free text field. This study compared methods for interrogating text fields for identifying work-related injuries presenting at emergency departments to inform approaches to surveillance of work-related injury. Three approaches were used to interrogate an injury description text field to classify cases as work-related: keyword search, index search, and content analytic text mining. Sensitivity and specificity were examined by comparing cases flagged by each approach to cases coded with an Activity code during triage. Methods to improve the sensitivity and/or specificity of each approach were explored by adjusting the classification techniques within each broad approach. The basic keyword search detected 58% of cases (Specificity 0.99), an index search detected 62% of cases (Specificity 0.87), and the content analytic text mining (using adjusted probabilities) approach detected 77% of cases (Specificity 0.95). The findings of this study provide strong support for continued development of text searching methods to obtain information from routine emergency department data, to improve the capacity for comprehensive injury surveillance.


Predictive markers in estimating the need for early intensive care in patients with adhesive small bowel obstruction in the emergency department.
Adhesive small-bowel obstruction (ASBO) is a common condition requiring emergency room admission, and predicting the need for intensive care unit (ICU) hospitalisation is crucial for optimal patient management. This study aimed to investigate the predictive value of various scores and indices in determining ICU requirements in patients with ASBO. Seventy patients diagnosed with ASBO and managed nonoperatively were included in the study. Data on patient demographics, laboratory values, imaging findings, previous hospitalisations and comorbidities were collected. The Sequential Organ Failure Assessment (SOFA) score, Charlson Comorbidity Index (CCI) score and C-reactive protein (CRP)/albumin ratio were calculated. Patients were categorised into ICU and non-ICU groups for analysis. The ICU group comprised patients with higher number of previous ASBO hospitalisations and longer hospitalisation days. Serum albumin levels were significantly lower and the maximum small-bowel horizontal diameter was significantly higher in the ICU group. The SOFA score and CCI score were significantly higher in the ICU group. The CRP/albumin ratio showed a trend towards significance. The number of days since the last stool discharge, SOFA score and CCI score demonstrated significant associations with ICU requirements in ASBO patients. These findings highlight the importance of assessing organ dysfunction, comorbidities and gastrointestinal function during patient triage. Our study provides valuable insights into predicting ICU need in ASBO patients, aiding in resource allocation and patient management.


Neuroprotective Activity of Sibjeondaebo-tang on Aβ Peptide-Induced Damages.
Background. Sibjeondaebo-tang (SJDBT) has been used to treat diverse disorders including neuropsychiatric disabilities in traditional Korean medicine. Objective. The present study aims to investigate the potential effects of SJDBT on neuroprotection against Aβ peptide-induced damage using in vitro culture and in vivo rat brain systems. Materials and Methods. PC12 cell viability was analyzed by MTT assay, and neurite arborizations and caspase 3 protein signals in cultured PC12 cells and in vivo cortical neurons were analyzed by immunofluorescence staining. Phospho-Erk1/2 protein was analyzed by immunofluorescence staining and western blot analysis. Results. In PC12 cells, atrophied cell body and reduced neurite extension by Aβ treatment were recovered by SJDBT treatment. Caspase 3 protein signals were increased in Aβ-treated PC12 cells, but SJDBT treatment decreased apoptotic cell death. Caspase 3 activation in cortical neurons, which was induced similarly by Aβ treatment, was reduced by SJDBT treatment. Furthermore, phospho-Erk1/2 protein levels, which had been decreased by Aβ treatment, were elevated in the cortical neurons by SJDBT treatment. Conclusion. These data show that SJDBT may play a role in protecting from damages induced by Aβ in neuronal tissue and further suggest that SJDBT can be explored as the potential therapeutic target for AD treatments in human.


Detection of Very Low-Level Somatic Mosaic COL4A5 Splicing Variant in Asymptomatic Female Using Droplet Digital PCR.
Alport syndrome is a hereditary glomerulopathy featured by haematuria, proteinuria, and progressive renal failure. X-linked Alport syndrome (XLAS) due to COL4A5 disease-causing variants is the most common form. In the case of XLAS resulting from 10-18% presumed de novo COL4A5 disease-causing variants, there are only a few studies for mosaicism in the probands or parents. Very low-level (<1.0%) somatic mosaicism for COL4A5 disease-causing variants has not been published. Chinese XLAS families with suspected parental mosaicism were enrolled in the present study to evaluate the forms of mosaicism, to offer more appropriate genetic counseling. PCR and direct sequencing were used to detect COL4A5 disease-causing variants harbored by the affected probands in parental multi-tissue DNAs (peripheral blood, urine sediments, saliva, hair), and droplet digital PCR (ddPCR) was used to quantify the mutant COL4A5 allelic fractions in parental different samples such as peripheral blood, saliva, and urine sediments. A Chinese asymptomatic female with suspected somatic and germline mosaicism was enrolled in the present study. She gave birth to two boys with XLAS caused by a hemizygous disease-causing variant c. 2245-1G>A in COL4A5 (NM_033380) intron 28, whereas this disease-causing variant was not detected in genomic DNA extracted from peripheral blood leukocytes in the woman using Sanger sequencing. She had multiple normal urine test results, and continuous linear immunofluorescence staining of α2 (IV) and α5 (IV) chains of skin tissue. Sanger sequencing demonstrated that COL4A5 disease-causing variant c. 2245-1G>A was not detected in her genomic DNAs isolated from urine sediments, saliva, and hair roots. Using ddPCR, the wild-type and mutant-type (c.2245-1G>A) COL4A5 was identified in the female's genomic DNAs isolated from peripheral blood, saliva, and urine sediments. The mutant allelic fractions in these tissues were 0.26% (peripheral blood), 0.73% (saliva), and 1.39% (urine), respectively. Germline and very low-level somatic mosaicism for a COL4A5 splicing variant was detected in an asymptomatic female, which highlights that parental mosaicism should be excluded when a COL4A5 presumed de novo disease-causing variant is detected.


Experience with newer central nervous system autoantibodies.
In the last decade, a large number of neuronal cell-surface antibodies have been described which are responsible for a range of neuroimmunological central nervous system disorders. Unlike the paraneoplastic antibodies which target intracellular antigens, these antibodies appear to be pathogenic and hence identification and prompt treatment can make a substantial impact on clinical outcomes of these patients. We review the common antibodies against the ionotropic glutamate receptors (NMDAR, AMPAR), metabotropic glutamate receptors (mGluR1 and mGluR5), voltage-gated potassium channel-complex proteins (LGI1, CASPR2), and other antibodies targeted against glycine receptor, glutamic acid decarboxylase, gamma-amino butyric acid B, dopamine-2-receptor and dipeptidyl-peptidase-like protein 6.


Electro-peroxone pretreatment for enhanced simulated hospital wastewater treatment and antibiotic resistance genes reduction.
Hospital wastewater is one of the possible sources responsible for antibiotic resistant bacteria spread into the environment. This study proposed a promising strategy, electro-peroxone (E-peroxone) pretreatment followed by a sequencing batch reactor (SBR) for simulated hospital wastewater treatment, aiming to enhance the wastewater treatment performance and to reduce antibiotic resistance genes production simultaneously. The highest chemical oxygen demand (COD) and total organic carbon (TOC) removal efficiency of 94.3% and 92.8% were obtained using the E-peroxone-SBR process. The microbial community analysis through high-throughput sequencing showed that E-peroxone pretreatment could guarantee microbial richness and diversity in SBR, as well as reduce the microbial inhibitions caused by antibiotic and raise the amount of nitrification and denitrification genera. Specially, quantitative real-time PCRs revealed that E-peroxone pretreatment could largely reduce the numbers and contents of antibiotic resistance genes (ARGs) production in the following biological treatment unit. It was indicated that E-peroxone-SBR process may provide an effective way for hospital wastewater treatment and possible ARGs reduction.


[Papillary fibroelastoma of the right atrium; report of a case].
Papillary fibroelastoma is a rare benign tumor commonly arising from a heart valve. We describe an unusual papillary fibroelastoma that arose from the right side of the interatrial septum. An intracardiac tumor was discovered by routine echocardiography in an asymptomatic 68-year-old woman. The echocardiographic examination revealed a 20 mm mobile tumor in the right atrium. Tricuspid obstruction was not observed, nor was regurgitation. The tumor was resected through a right atriotomy. It had multiple papillary fronds and arose from the interatrial septum. Pathologic examination confirmed papillary fibroelastoma. The postoperative course was uneventful, and the patient was discharged on postoperative day 13.


A novel transcriptome subtraction method for the detection of differentially expressed genes in highly complex eukaryotes.
We have designed a novel transcriptome subtraction method for the genome-scale analysis of differential gene expression in highly complex eukaryotes, in which suppression subtractive hybridization (SSH) is performed first to enrich the target and, after exchange of adapters, negative subtraction chain (NSC) is then used to eliminate the remaining background. NSC evolved from differential subtraction chain (DSC). We designed novel adapters which make the subtraction system more robust. SSH and NSC were then combined to successfully detect differentially expressed genes in Solanum. The combined technique improves qualitatively upon SSH, the only commercially available transcriptome subtraction system, by detecting target genes in the middle abundance class, to which most differentially expressed genes in highly complex eukaryotes are expected to belong. The main advantage of the combined technique with SSH/NSC is its ability to isolate differentially expressed genes quickly and cost-efficiently from non-standard models, for those microarrays are unavailable.


Monitoring peripheral perfusion and microcirculation.
Microcirculatory alterations play a major role in the pathogenesis of shock. Monitoring tissue perfusion might be a relevant goal for shock resuscitation. The goal of this review was to revise the evidence supporting the monitoring of peripheral perfusion and microcirculation as goals of resuscitation. For this purpose, we mainly focused on skin perfusion and sublingual microcirculation. Although there are controversies about the reproducibility of capillary refill time in monitoring peripheral perfusion, it is a sound physiological variable and suitable for the ICU settings. In addition, observational studies showed its strong ability to predict outcome. Moreover, a preliminary study suggested that it might be a valuable goal for resuscitation. These results should be confirmed by the ongoing ANDROMEDA-SHOCK randomized controlled trial. On the other hand, the monitoring of sublingual microcirculation might also provide relevant physiological and prognostic information. On the contrary, methodological drawbacks mainly related to video assessment hamper its clinical implementation at the present time. Measurements of peripheral perfusion might be useful as goal of resuscitation. The results of the ANDROMEDA-SHOCK will clarify the role of skin perfusion as a guide for the treatment of shock. In contrast, the assessment of sublingual microcirculation mainly remains as a research tool.


Dietary amino acids promote pancreatic protease synthesis at the translation stage in rats.
In some tissues, amino acids (AA) stimulate translation initiation via interactions between eukaryote initiation factor (eIF) 4E-binding protein 1 (4E-BP1), eIF4E and eIF4G. Dietary AA have been shown to induce pancreatic proteases independently of cholecystokinin in rats, the mechanism of which has not yet been clarified. In the present study, we examined the mechanism in rats for protease induction by dietary AA and determined the involvement of translation initiation. Male Wistar/ST rats were fed a 20 or 60% casein or AA mixture diet for 7 d and were intravenously injected with [35S] methionine (Met) 30 min before killing on d 7 (expt. 1). In expt. 2, rats were fed a 20 or 60% AA diet for 7 d and after food deprivation and refeeding with the respective diet on d 7 were killed at 0, 1 or 3 h. We measured mRNA and [35S] Met incorporation into chymotrypsinogen, phosphorylation status of 4E-BP1 and the association of eIF4E with 4E-BP1 or eIF4G. In expt. 1, chymotrypsin activity and synthesis were higher in both of the 60% diet groups than in the 20% diet groups, but the mRNA level and 4E-BP1 status did not differ. In expt. 2, chymotrypsin activity increased in the 60% AA diet group in a time-dependent manner. The translation initiation activity via the mTOR pathway indicated an increase similar to chymotrypsin activity. There were no differences in chymotrypsin mRNA level at any point. These results indicate that dietary AA induce chymotrypsin synthesis by promoting translation, and transient activation of translation initiation via mTOR may be associated with this induction.


Modelling Future Coronary Heart Disease Mortality to 2030 in the British Isles.
Despite rapid declines over the last two decades, coronary heart disease (CHD) mortality rates in the British Isles are still amongst the highest in Europe. This study uses a modelling approach to compare the potential impact of future risk factor scenarios relating to smoking and physical activity levels, dietary salt and saturated fat intakes on future CHD mortality in three countries: Northern Ireland (NI), Republic of Ireland (RoI) and Scotland. CHD mortality models previously developed and validated in each country were extended to predict potential reductions in CHD mortality from 2010 (baseline year) to 2030. Risk factor trends data from recent surveys at baseline were used to model alternative future risk factor scenarios: Absolute decreases in (i) smoking prevalence and (ii) physical inactivity rates of up to 15% by 2030; relative decreases in (iii) dietary salt intake of up to 30% by 2030 and (iv) dietary saturated fat of up to 6% by 2030. Probabilistic sensitivity analyses were then conducted. Projected populations in 2030 were 1.3, 3.4 and 3.9 million in NI, RoI and Scotland respectively (adults aged 25-84). In 2030: assuming recent declining mortality trends continue: 15% absolute reductions in smoking could decrease CHD deaths by 5.8-7.2%. 15% absolute reductions in physical inactivity levels could decrease CHD deaths by 3.1-3.6%. Relative reductions in salt intake of 30% could decrease CHD deaths by 5.2-5.6% and a 6% reduction in saturated fat intake might decrease CHD deaths by some 7.8-9.0%. These projections remained stable under a wide range of sensitivity analyses. Feasible reductions in four cardiovascular risk factors (already achieved elsewhere) could substantially reduce future coronary deaths. More aggressive polices are therefore needed in the British Isles to control tobacco, promote healthy food and increase physical activity.


Congruence of total and perfused capillary network in rat brains.
In awake normocapnic rats, the density of the total and of the perfused capillary network was determined in 10 brain areas. The density of perfused capillaries was measured by using fluorescein isothiocyanate (FITC) globulin or Evans blue as intravenous marker and by fluorescent microscopy. The density of morphologically existing capillaries was determined according to either the histochemical alkaline phosphatase method or a newly developed immunohistochemical fluorescent method that allows marking of the capillary wall constituent fibronectin with a primary antibody directed against fibronectin. This antibody is made visible by a second FITC-coupled antibody (indirect immunofluorescence). Comparison of perfused and existing capillary counts revealed high congruence when fluorescent results were compared. In contrast, the alkaline phosphatase technique yielded capillary counts that were consistently 30% lower than the fibronectin and the FITC globulin counts. The identity of the perfused and the morphologically existing capillary network could be confirmed by a newly developed double-staining technique. First, the perfused capillaries were quantified by intravascular Evans blue. Then, the existing capillaries were relocated in the same measuring field by the fibronectin technique. Such double staining resulted in identical capillary counts in 97% of all cases. The following conclusions have been reached: 1) Fluorescent methods show a perfusion of virtually all capillaries in the brain of the awake normocapnic rat. 2) The alkaline phosphatase technique appears to underestimate the capillary density in the rat brain.


Loss of detoxification in inflammatory bowel disease: dysregulation of pregnane X receptor target genes.
Phase 1, phase 2, and cellular efflux transporters are critical components in intestinal barrier function against xenobiotics and bacteria. We therefore performed global gene expression profiling in patients with ulcerative colitis (UC) and Crohn's disease as well as control specimens, with a special emphasis on genes involved in detoxification and epithelial membrane integrity. Mucosal biopsy specimens from nonaffected regions of the colon and the terminal ileum were subjected to DNA microarray analysis and pathway-related data mining. Real-time reverse-transcription polymerase chain reaction was used for verification of selected regulated candidate genes in larger inflammatory bowel disease sample numbers and intestinal cell lines. Several dysregulated genes were identified in both disease groups and tissues. A set of genes coordinately down-regulated in the colon of patients with UC was composed of cellular detoxification and defense genes, which are target genes for the transcription factor pregnane X receptor (PXR). Messenger RNA expression of ABCB1 (MDR1) and PXR was significantly reduced in the colon of patients with UC but was unaffected in patients with Crohn's disease. In contrast to some of its target genes, the expression of PXR was not sensitive to tumor necrosis factor alpha stimulation of intestinal cell lines. A disease- and tissue-specific decrease in the expression of detoxification enzymes and ABC transporters was observed, which may be explained by a loss of PXR expression. Thus, dysregulation of xenobiotic metabolism and PXR activity in the gut is likely to contribute to the pathophysiology of UC.


Master equation simulations of a model of a thermochemical system.
Master equation approach is used to study the influence of fluctuations on the dynamics of a model thermochemical system. For appropriate values of parameters, the deterministic description of the system gives the subcritical or supercritical Hopf bifurcations. For small systems (containing 100 000 particles) close to the supercritical Hopf bifurcation, the stochastic trajectories obtained from numerical simulations do not allow to distinguish between damped oscillations around a stable focus and sustained oscillations around a small stable limit cycle. This uncertainty disappears if the number of particles in the system is increased (up to 1 000 000). Close to subcritical Hopf bifurcation the stochastic trajectory of the system jumps from the basin of attraction of a stable focus to the basin of attraction of a stable limit cycle. In this case the time dependencies of temperature and concentration of reactant in the system are apparently similar to intermittent chaotic oscillations. The mean first passage time for the transitions from the stable focus to the stable limit cycle show the characteristic exponential dependence on the number of particles. This passage time depends very strongly on the bifurcation parameter (reaction heat), which determines the distance between the stable focus and an unstable limit cycle.


Polymorphisms of the TPMT gene in the Czech healthy population and patients with inflammatory bowel disease.
Genetic variation in thiopurine S-methyltransferase (TPMT) is a major factors for wide variation in the metabolism and safety of thiopurine drugs. We investigated the frequency of functional gene polymorphisms in 396 patients with inflammatory bowel disease and 300 healthy subjects. Frequencies of functionally deficient alleles TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3B in the patient group were 0.1%, 4.3%, 0.1%, and 0.4%, respectively, and were similar to those of healthy subjects in the Czech population. Our results provide necessary information for pharmacoeconomic studies in the Czech Republic.


Interleukin 6 gene expression in normal and neoplastic B cells.
In the present report we demonstrate that the IL-6 gene is expressed in anti-Ig-activated and neoplastic B cells. After activation with anti-Ig, splenic B cells rapidly expressed IL-6 mRNA with peak expression occurring at 4 h and declining rapidly thereafter. In an attempt to exclude that the IL-6 mRNA expression was in non-B cells, T cells and monocytes were extensively depleted. In this highly purified B cell population, IL-6 mRNA was retained, whereas the expression of the T cell- and monocyte-restricted CD2 and CD14 genes was nearly undetectable. These results are consistent with the conclusion that activated B cells express IL-6 mRNA. Because we found IL-6 mRNA expression in normal activated B lymphocytes, we examined the expression of IL-6 mRNA in B cell neoplasms. 11 of 25 non-Hodgkins B cell lymphomas and 4 of 4 myelomas and plasma cell leukemias expressed IL-6 mRNA, whereas only 1 of 19 B cell leukemias was positive. To exclude that IL-6 mRNA expression in neoplastic B cells was the result of contaminating non-B cells, T cells and monocytes were extensively depleted from the tumor specimens. In the three IL-6-positive tumor samples depleted of T cells and monocytes, IL-6 mRNA expression was retained in all cases. These observations provide support for the idea that the IL-6 gene is expressed in normal activated and neoplastic B cells.


Anti-inflammatory immune skewing is atheroprotective: Apoe−/−FcγRIIb−/− mice develop fibrous carotid plaques.
Stroke, caused by carotid plaque rupture, is a major cause of death in the United States. Whereas vulnerable human plaques have higher Fc receptor (FcγR) expression than their stable counterparts, how FcγR expression impacts plaque histology is unknown. We investigated the role of FcγRIIb in carotid plaque development and stability in apolipoprotein (Apo)e−/− and Apoe−/−FcγRIIb−/− double knockout (DKO) animals. Plaques were induced by implantation of a shear stress‐modifying cast around the carotid artery. Plaque length and stenosis were followed longitudinally using ultrasound biomicroscopy. Immune status was determined by flow cytometry, cytokine release, immunoglobulin G concentration and analysis of macrophage polarization both in plaques and in vitro. Surprisingly, DKO animals had lower plaque burden in both carotid artery and descending aorta. Plaques from Apoe−/− mice were foam‐cell rich and resembled vulnerable human specimens, whereas those from DKO mice were fibrous and histologically stable. Plaques from DKO animals expressed higher arginase 1 (Arg‐1) and lower inducible nitric oxide synthase (iNOS), indicating the presence of M2 macrophages. Analysis of blood and cervical lymph nodes revealed higher interleukin (IL)‐10, immune complexes, and regulatory T cells (Tregs) and lower IL‐12, IL‐1β, and tumor necrosis factor alpha (TNF‐α) in DKO mice. Similarly, in vitro stimulation produced higher IL‐10 and Arg‐1 and lower iNOS, IL‐1β, and TNF‐α in DKO versus Apoe−/− macrophages. These results define a systemic anti‐inflammatory phenotype. We hypothesized that removal of FcγRIIb would exacerbate atherosclerosis and generate unstable plaques. However, we found that deletion of FcγRIIb on a congenic C57BL/6 background induces an anti‐inflammatory Treg/M2 polarization that is atheroprotective.


The Impact of a Neonatal Sleep Care Training Program on Nurses' Knowledge and Performance in Neonatal Intensive Care Units.
Sleep is essential for organizing and maturation of the brain in premature infants; it also plays a role in maintaining the natural balance between different nervous centers. Given the role of nurses in neonatal sleep care, this study aimed at assessing the impact of a training program on the nurses' knowledge and performance in a Neonatal Intensive Care Unit (NICU). In this quasi-experimental study which structured into three stages, 35 nurses working in an NICU in Isfahan, Iran, were included. The neonatal sleep training program was in the form of a lecture with questions and answers and then placing posters and booklets in the NICU. The data were collected by a questionnaire for nurses' knowledge and performance assessment which its validity and reliability were determined through content validity and internal consistency, respectively. The nurses' knowledge was assessed via 40 multiple-choice questions before, immediately after, and 1 month after the training program, and their performance was evaluated before and 1 month after intervention using 15 multiple-choice questions. The data were analyzed by descriptive and inferential statistics using the SPSS software version 16. The results showed that the mean score of nurses' knowledge after training has significantly increased as compared to before training (33.33 (4.4) vs. 19.33 (4.1)) (P < 0.001); however, the score of performance was slightly improved although it did not reveal any significant differences (P = 0.07, 42.6 (7.6) vs. 45.1 (7.8)). The results indicated that this method of training program could lead to an increase in nurses' knowledge, but it did not significantly improve their performance. It may be due to a low number of training sessions; therefore, it is recommended to implement long-term training programs in this field.


Exosomes derived from umbilical cord mesenchymal stem cells protect cartilage and regulate the polarization of macrophages in osteoarthritis.
Osteoarthritis (OA) is one of the most common joint diseases and a major global public health concern. Mesenchymal stem cells (MSCs) have been widely used for the treatment of OA owing to their paracrine secretion of trophic factors, a phenomenon in which exosomes may play a major role. Here, we investigate the potential of exosomes from human umbilical cord-derived MSCs (hUC-MSCs-Exos) in alleviating OA. The hUC-MSCs-Exos were harvested from hUC-MSC-conditioned medium using ultracentrifugation. Rats with surgically-induced OA were intra-articularly injected with hUC-MSCs-Exos. The effect of hUC-MSCs-Exos in repairing osteoarticular cartilage was assessed using hematoxylin and eosin (HE) staining, safranin-O and fast green staining and immunohistochemistry. The in vitro experiments were further carried out to verify the therapeutic effect. The effects of hUC-MSCs-Exos on the proliferation and migration of human chondrocytes were evaluated using the cell counting kit-8, EdU-555 cell proliferation kit, and transwell assays. Annexin V-FITC/PI staining were used to evaluate the effect of exosomes on chondrocyte apoptosis. An in vitro model of human articular chondrocytes treated with interleukin 1 beta (IL-1β) was used to evaluate the effects of exosomes, analyses involved using quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, and western blotting. The role of hUC-MSCs-Exos in macrophage polarization was examined in the monocyte cell line, Tohoku Hospital Pediatrics-1 (THP-1) by qRT-PCR and immunofluorescence. The results showed that hUC-MSCs-Exos prevented severe damage to the knee articular cartilage in the rat OA model. We confirmed the high efficacy of hUC-MSCs-Exos in promoting chondrocyte proliferation and migration and inhibiting chondrocyte apoptosis. Additionally, hUC-MSCs-Exos could reverse IL-1β-induced injury of chondrocytes and regulate the polarization of macrophages in vitro. There is potential for hUC-MSCs-Exos to be used as a treatment strategy for OA.


Transcriptomic characterization of classical monocytes highlights the involvement of immuno-inflammation in bone erosion in Rheumatoid Arthritis.
Evidence-based data suggest that under inflammatory conditions, classical monocytes are the main source of osteoclasts and might be involved in bone erosion pathophysiology. Here, we analyze the transcriptomic profile of classical monocytes in erosive and non-erosive rheumatoid arthritis patients in order to better understand their contribution to bone erosion. Thirty-nine premenopausal RA patients were consecutively enrolled and divided into two groups based on the presence of bone erosions on hand joints. Classical monocytes were isolated from peripheral blood through negative selection, and RNA-seq was performed using a poly-A enrichment kit and Illumina® platform. Classical monocytes transcriptome from healthy age-matched women were also included to identify differentially expressed genes (DEGs). Therefore, gene sets analysis was performed to identify the enriched biological pathways. RNA-seq analysis resulted in the identification of 1,140 DEGs of which 89 were up-regulated and 1,051 down-regulated in RA patients with bone erosion compared to those without bone erosions. Among up-regulated genes, there was a highlighted expression of IL18RAP and KLF14 related to the production of pro-inflammatory cytokines, innate and adaptive immune response. Genes related to collagen metabolism (LARP6) and bone formation process (PAPPA) were down-regulated in RA patients with erosions. Enriched pathways in patients with erosions were associated with greater activation of immune activation, and inflammation. Interestingly, pathways associated with osteoblast differentiation and regulation of Wnt signaling were less activated in RA patients with erosions. These findings suggest that alterations in expression of monocyte genes related to the inflammatory process and impairment of bone formation might have an important role in the pathophysiology of bone erosions in RA patients.


Veterinary Curriculum Leaders: Motivators, Barriers, and Attributes.
Curriculum leaders (individuals with responsibility for an institution's veterinary curriculum) play a vital role in driving local curriculum priorities, development, and accreditation. This study aimed to describe the career paths of curriculum leaders, and identify what motivates them, the barriers they face, and the knowledge, skills, and attributes they perceive as essential for the role. Self-determination theory was used to identify tensions experienced within the role. An international online survey targeted at those identifying as curriculum leaders was completed by 45 participants. 91% of participants held a doctoral level qualification and/or clinical Boards; 82% had additional training in leadership; 38% had additional formal training in education. Motivators included a desire to make a difference, personal satisfaction with teaching and working with students, and social influences. Participants experienced barriers relating to self-development and achievement of their curriculum goals; participants described essential knowledge (of the profession, educational theory, and wider higher education context) and skills (leading teams, change management, and communication). Attributes considered important related both to self (open-minded, patient, resilient, able to see the big picture as well as detail) and relationships with others (approachable, listener, respectful and respected, supportive, credible). Tensions arose in participants' need for autonomy (experiencing barriers to achieving their goals), in their social relatedness (achieving curriculum goals while working with colleagues with conflicting priorities), and in perceptions of necessary competence (a need, but lack of opportunity, for advanced training in educational theory). The findings may help institutions more effectively support and train current and future curriculum leaders.


LIFE-HISTORY EVOLUTION IN GUPPIES: 2. REPEATABILITY OF HELD OBSERVATIONS AND THE EFFECTS OF SEASON ON LIFE HISTORIES.
Natural populations of guppies that co-occur with the pike cichlid Crenicichla alta and associated predators mature at smaller body sizes, produce more and smaller offspring per litter reproduce more frequently, and have higher reproductive allotments (weight of developing embryos/total body weight) than guppies that co-occur with just the killifish Rivulus harti (Reznick and Endler, 1982). I here consider three forms of repeatability in these life-history patterns: i) among replicate samples collected on the same day from the same locality, ii) between Crenicichla and Rivulus communities among a new series of localities, and iii) among a smaller series of Crenicichla and Rivulus localities sampled in two wet and two dry seasons. In the analysis of replicate collections from two localities, seven of eight statistical comparisons revealed no significant difference. The usual methodology for estimating these variables therefore accurately represents guppy life-history patterns at a given locality. Differences among guppies from Rivulus and Crenicichla localities, covering a wider geographical area than considered by Reznick and Endler (1982), were virtually identical to the previous comparison. Wet-season samples were associated with significant decreases in reproductive allotment and fecundity and significant increases in the size of mature males and the minimum size of reproducing females. Differences between guppies from Rivulus and Crenicichla localities persisted across all samples and were consistent with all other observations, although they tended to be smaller during the wet season. Discriminant analyses on female reproductive traits showed that fecundity and offspring size made strong, independent contributions to discriminating between guppies from the two types of localities. The contribution from reproductive allotment was considerably smaller. There was more overlap between predator treatments during the wet season. Only 8.5% of the individuals were misclassified during the dry season, but 19.5% were misclassified during the wet season.


Up-regulation of matrix metalloproteinase-9 in T lymphocytes of mammary tumor bearers: role of vascular endothelial growth factor.
Matrix metalloproteinase-9 (MMP-9), a matrix-degrading enzyme, is crucial in tumor invasion and metastasis and is implicated in leukocyte extravasation. In this report, we demonstrate that during growth of the D1-7,12-dimethylbenzanthracene-3 mammary tumor in BALB/c mice, there is progressive up-regulation of MMP-9 in splenic T cells at both the transcriptional and translational levels. Our previous work has identified several factors produced by this tumor, including PGE(2), GM-CSF, and phosphatidyl serine; however, none of these agents induces increased production of MMP-9 by normal splenic T cells. Although not produced by the tumor, TNF-alpha and IL-6 are up-regulated in both macrophages and B cells in tumor-bearing mice. Exposure of normal T cells to these two cytokines, however, also fails to up-regulate MMP-9 production. Vascular endothelial growth factor (VEGF) is produced by many tumors, and we determined that the mammary tumor used in our studies expresses high levels of this angiogenic growth factor. Importantly, splenic T cells from tumor bearers constitutively produce increased amounts of VEGF, and treatment of normal T cells with VEGF results in up-regulated MMP-9 production. Of crucial importance is the finding that tumor-infiltrating T cells also produce high levels of VEGF and MMP-9. Our studies indicate that VEGF can act directly on T lymphocytes and that elevated VEGF levels may contribute to the aberrant MMP-9 secretion by mammary tumor bearers' T cells.


EGF +61 gene polymorphism and susceptibility to and prognostic markers in cutaneous malignant melanoma.
CMM is the most serious cutaneous malignancy and is increasing in frequency among most Caucasian populations, where the most important risk factor is exposure to UV light. Relatively little is known of the genetic factors that mediate susceptibility to and prognosis in sporadic CMM, although a number of genes have been implicated. A striking association between EGF polymorphism and Breslow thickness of invasive CMM has been reported. We have sought confirmation of this finding in an independent study of 159 patients and 310 controls using TaqMan fluorescence-based genotyping for EGF +61. In our study group, there were no significant differences in EGF genotype frequencies between patients and controls nor was EGF genotype associated with tumour growth phase, stage or mitotic count. However, correlation between EGF genotype and Breslow thickness showed a modestly significant increase in frequency of the EGF (G/G) genotype among tumours >3.5 mm thick (30.0% vs. 9.8%, p = 0.03). In summary, in our group, the EGF +61 polymorphism was not a risk factor for CMM susceptibility, but this polymorphism may play a role in disease progression.


Deoxycholic Acid and Lithocholic Acid Alleviate Liver Injury and Inflammation in Mice with Klebsiella pneumoniae-Induced Liver Abscess and Bacteremia.
Klebsiella pneumoniae-induced liver abscess and baiacterem is a serious infectious disease with high mortality. Secondary bile acids (SBAs) are produced by intestinal flora through the metabolism of primary bile acids and play a role in promoting or inhibiting inflammation in some diseases. However, the immunomodulatory role of SBAs in bacterial infections of the liver remains unclear. This study aimed to investigate the anti-inflammatory and liver-protective effects of SBAs in K. pneumoniae-infected mice. The absolute concentrations of deoxycholic acid (DCA) and lithocholic acid (LCA) in feces and serum were analyzed, and intestinal flora alterations between K. pneumoniae-infected and healthy control mice were examined. The effect of SBAs was investigated by analyzing the survival, tissue bacterial load, histopathology, and inflammatory factor levels in SBA-treated mice. The expression of crucial proteins implicated in the NF-κB pathway, as well as the G-protein-coupled bile acid receptor TGR5, was detected. The content of SBAs in feces and serum of the K. pneumoniae-infected group was significantly reduced, and significant changes in the composition of the intestinal flora were detected. The intestinal flora are directly related to the synthesis of SBAs. Ruminococcaceae levels in K. pneumoniae-infected mice were significantly lower than in healthy control mice. Oral administration of SBAs improved the survival and liver pathology of K. pneumoniae-infected mice, and reduced the bacterial load and the level of inflammatory factors. SBAs down-regulated the expression of key proteins in the NF-κB inflammatory signaling pathway, including the phosphorylation of IκBα and NF-κB p50 and the nuclear translocation of NF-κB p65. The protective effect of SBAs may be dependent on high TGR5 expression. SBAs downregulate the NF-κB inflammatory signaling pathway through TGR5, protecting the liver and inhibiting inflammation in K. pneumoniae-induced liver abscess and bacteremia.


Contemporary review of severe aortic stenosis.
Severe aortic stenosis (AS) is the most common form of valvular heart disease in the developed world, with a rising prevalence due to an ageing Australian population. Transcatheter aortic valve implantation (TAVI) offers a less invasive option for the treatment of severe AS, with evidence supporting TAVI compared with medical therapy in inoperable patients and superior with surgical aortic valve replacement (SAVR) in high-risk patients. Equal outcomes have been observed in all-comer intermediate-risk populations. The Heart Team utilises a shared decision-making approach between physicians and surgeons in risk-stratifying patients and reduces the intrinsic bias that may occur if decisions are made in isolation. Geriatric assessment is useful for identifying preoperative frailty, a major risk factor for death post-aortic valve intervention. In severe AS, a decision can be made collaboratively to pursue TAVI, SAVR, a Ross Procedure or conservative management. The learning curve associated with TAVI has improved markedly, with overall complication rates decreasing around the world. Contemporary changes in practice, such as conscious sedation without general anaesthesia, expedited recovery and early discharge, will likely improve cost-effectiveness. In 2018, TAVI is a well-established procedure in Australia that has revolutionised the management of severe AS. In the future, with an expanding elderly population, the number of patients to benefit from transcatheter therapies for severe AS is hypothesised to increase 4-10-fold. Heart Team assessment is crucial in patients with severe AS to direct appropriate management.


Effect of HEMADO on Level of CK-MB and LDH Enzymes after Ischemia/Reperfusion Injury in Isolated Rat Heart.
Ischemia/Reperfusion (IR) injury mainly causes the increase of enzymes involved in myocytes injury including CK-MB (creatine kinase-MB) isoenzyme and LDH (lactate dehydrogenase). Leakage of CK-MB isoenzyme and LDH from myocardial tissues to blood is indicator of acute myocardial infarction. The aim of this study was to assess the effect of HEMADO on IR injury and its relationship with mitochondrial ATP-sensitive K+ channels (mitoKATP) in rat heart. Twenty eight male Wistar rats (250-300g) were divided into four groups (seven members in each group): control (without ischemia), I/R (with ischemia+without HEMADO), ischemia received HEMADO (HEMADO), ischemia received HEMADO and 5-HD (5-hydroxydecanoate, specific mitoKATP channel blocker) (HEMADO+5-HD). The animals were anesthetized and the hearts were quickly removed and mounted on Langendorff apparatus and perfused by Krebs-Henseleit solution under constant pressure and temperature of 37ºC. After 20 minutes of stabilization, ischemic groups were exposed to 40 minutes of global ischemia and consecutive 90 minutes of reperfusion. IR injury increased the level of LDH and CK-MB in the collected coronary flow during 5 minutes since start of reperfusion. HEMADO reduced the enzymes' levels and using 5-HD abolished the effect of HEMADO. Our findings indicated that HEMADO could protect the heart against ischemia-reperfusion injury by decreasing the CK-MB and LDH levels. The cardioprotective effect of HEMADO may be mediated in part by mitoKATP.


TPR-Mediated self-association of plant SGT1.
The tetratricopeptide repeat (TPR) domain mediates inter-protein associations in a number of systems. The domain is also thought to mediate oligomerization of some proteins, but this has remained controversial, with conflicting data appearing in the literature. By way of investigating such TPR-mediated self-associations we used a variety of biophysical techniques to characterize purified recombinant Sgt1, a TPR-containing protein found in all eukaryotes that is involved in a broad range of biological processes, including kinetochore assembly in humans and yeast and disease resistance in plants. We show that recombinant Sgt1 from Arabidopsis, barley, and yeast self-associates in vitro while recombinant human Sgt1 does not. Further experiments on barley Sgt1 demonstrate unambiguously a TPR-mediated dimerization, which is concentration- and ionic-strength-dependent and results in a global increase in helical structure and stability of the protein. Dimerization is also redox sensitive, being completely abolished by the formation of an intramolecular disulfide bond where the contributing cysteines are conserved in plant Sgt1s. The dimer interface was mapped through cross-linking and mass spectrometry to the C-terminal region of the TPR domain. Our study, which provides the first biophysical characterization of plant Sgt1, highlights how TPR domains can mediate self-association in solution and that sequence variation in the regions involved in oligomerization affects the propensity of TPR-containing proteins to dimerize.


Embryotoxic and pharmacologic potency ranking of six azoles in the rat whole embryo culture by morphological and transcriptomic analysis.
Differential gene expression analysis in the rat whole embryo culture (WEC) assay provides mechanistic insight into the embryotoxicity of test compounds. In our study, we hypothesized that comparative analysis of the transcriptomes of rat embryos exposed to six azoles (flusilazole, triadimefon, ketoconazole, miconazole, difenoconazole and prothioconazole) could lead to a better mechanism-based understanding of their embryotoxicity and pharmacological action. For evaluating embryotoxicity, we applied the total morphological scoring system (TMS) in embryos exposed for 48h. The compounds tested showed embryotoxicity in a dose-response fashion. Functional analysis of differential gene expression after 4h exposure at the ID10 (effective dose for 10% decreased TMS), revealed the sterol biosynthesis pathway and embryonic development genes, dominated by genes in the retinoic acid (RA) pathway, albeit in a differential way. Flusilazole, ketoconazole and triadimefon were the most potent compounds affecting the RA pathway, while in terms of regulation of sterol function, difenoconazole and ketoconazole showed the most pronounced effects. Dose-dependent analysis of the effects of flusilazole revealed that the RA pathway related genes were already differentially expressed at low dose levels while the sterol pathway showed strong regulation at higher embryotoxic doses, suggesting that this pathway is less predictive for the observed embryotoxicity. A similar analysis at the 24-hour time point indicated an additional time-dependent difference in the aforementioned pathways regulated by flusilazole. In summary, the rat WEC assay in combination with transcriptomics could add a mechanistic insight into the embryotoxic potency ranking and pharmacological mode of action of the tested compounds.


Screening and medical evaluation of adults: contraindications for invasive dental procedures.
Implant and preprosthetic surgeries aim to restore normal anatomical contours, function, comfort, esthetics, and oral health. Systemic screening of a patient prior to implant and/or biomaterial insertion is critical to patient well being and success of the surgical procedure(s). It is no longer appropriate to limit the general contraindications to the malfunction of major organs and systems and not consider the devastating long-term effects of an unhealthy lifestyle (smoking, inadequate diet, etc.). Modern standards of care should not systematically exclude patients with relative or marginal health conditions without exploring the possibilities of improving and stabilizing those conditions. Based on the classification of the American Society of Anesthesiology, a number of absolute and relative contraindications are presented. Treatments are proposed for optimizing some marginal health conditions and stabilizing unbalanced physiological function prior to surgery. A knowledge of the fundamentals of internal medicine is an important prerequisite for predictable implant and preprosthetic surgery. This paper reflects the opinion of a physician and dentist who has been actively involved in implant and preprosthetic surgery for the past quarter of a century in both private and university hospital practice.


Teaching Airway Management Using Virtual Reality: A Scoping Review.
Airway management, a defined procedural and cognitive skillset embracing routine tracheal intubation and emergency airway rescue, is most often acquired through an apprenticeship model of opportunistic learning during anesthesia or acute care residency training. This training engages a host of modalities to teach and embed skill sets but is generally time- and location-constrained. Virtual reality (VR)-based simulation training offers the potential for reproducible and asynchronous skill acquisition and maintenance, an advantage that may be important with restricted trainee work hours and low frequency but high-risk events. In the absence of a formal curriculum from training bodies-or expert guidance from medical professional societies-local initiatives have filled the VR training void in an unstructured fashion. We undertook a scoping review to explore current VR-based airway management training programs to assess their approach, outcomes, and technologies to discover programming gaps. English-language publications addressing any aspect of VR simulation training for airway management were identified across PubMed, Embase, and Scopus. Relevant articles were used to craft a scoping review conforming to the Scale for quality Assessment of Narrative Review Articles (SANRA) best-practice guidance. Fifteen studies described VR simulation programs to teach airway management skills, including flexible fibreoptic bronchoscopic intubation (n = 10), direct laryngoscopy (n = 2), and emergency cricothyroidotomy (n = 1). All studies were single institution initiatives and all reported different protocols and end points using bespoke applications of commercial technology or homegrown technologic solutions. VR-based simulation for airway management currently occurs outside of a formal curriculum structure, only for specific skill sets, and without a training pathway for educators. Medical educators with simulation training and medical professional societies with content expertise have the opportunity to develop consensus guidelines that inform training curricula as well as specialty technology use.


A gigantic nothosaur (Reptilia: Sauropterygia) from the Middle Triassic of SW China and its implication for the Triassic biotic recovery.
The presence of gigantic apex predators in the eastern Panthalassic and western Tethyan oceans suggests that complex ecosystems in the sea had become re-established in these regions at least by the early Middle Triassic, after the Permian-Triassic mass extinction (PTME). However, it is not clear whether oceanic ecosystem recovery from the PTME was globally synchronous because of the apparent lack of such predators in the eastern Tethyan/western Panthalassic region prior to the Late Triassic. Here we report a gigantic nothosaur from the lower Middle Triassic of Luoping in southwest China (eastern Tethyan ocean), which possesses the largest known lower jaw among Triassic sauropterygians. Phylogenetic analysis suggests parallel evolution of gigantism in Triassic sauropterygians. Discovery of this gigantic apex predator, together with associated diverse marine reptiles and the complex food web, indicates global recovery of shallow marine ecosystems from PTME by the early Middle Triassic.


Association of ocular dominance and myopia development: a 2-year longitudinal study.
To investigate the effect of ocular dominance on myopia development. One hundred seventy-eight myopic children (age range, 7-13 years) were recruited for a 2-year longitudinal study. The development of myopia was evaluated by the change of objective refractive error, determined with cycloplegic autorefraction, and axial length, determined with A-scan ultrasonography. Ocular dominance was determined with the hole-in-the-card test. The change in refractive error and axial length between dominant and nondominant eyes were compared by using the paired t-test. Twenty-nine subjects were lost to follow-up, and 19 reported poor compliance of wearing spectacles. The mean age of the retained 130 subjects was 10.9 +/- 1.6 years on entry. Sixty-nine (53.1%) subjects were boys. The mean refractive error of the two eyes was -1.73 +/- 0.69 D in spherical equivalent refractive error (SE) and the average anisometropia was 0.22 +/- 0.19 D. The percentages of right dominance, left dominance, and alternating ocular dominance were 64.6%, 34.6%, and 0.8%, respectively. After a 2-year follow-up, the mean change in SE was -1.34 +/- 0.59 and -1.33 +/- 0.64 D in the dominant and nondominant eye, respectively (P = 0.72). The mean increase in axial length was 0.67 +/- 0.42 and 0.64 +/- 0.37 mm, respectively (P = 0.48). The findings demonstrated no statistically significant effect of ocular dominance on the development of myopia over a 2-year period. There was no sufficient evidence to support the idea that bias is introduced into myopia intervention clinical trials when myopia progression is evaluated without consideration of potential effects of ocular dominance on refractive development.


Fat embolism: the reaming controversy.
Intramedullary nailing is the preferred treatment method for stabilizing femoral diaphyseal fractures. Despite its superior biomechanical advantages over other implants, its use, particularly in selected groups of patients, has been questioned because of the possible harmful systemic effects of intramedullary reaming. The increase in intramedullary canal pressure during intramedullary nailing can result in intravasation of bone marrow and fat into the venous blood system. The subsequent consequences can be fat embolism syndrome (FES), adult respiratory distress syndrome (ARDS), and multiple organ failure. The lung seems to be the primary target for fat embolization and for the mediated effects primed by inflammatory reactions. In laboratory studies, both reamed and unreamed intramedullary nailing has been shown to alter selected pulmonary variables. Although transient, this effect appears to be more prominent with reamed than unreamed techniques. Additional studies are required to determine whether a subgroup of trauma patients is adversely affected by intramedullary reaming, thus necessitating other fixation techniques.


Susceptibility of dipel-resistant and -susceptible Ostrinia nubilalis (Lepidoptera: Crambidae) to individual Bacillus thuringiensis protoxins.
Dipel-resistant and -susceptible strains of Ostrinia nubilalis (Hübner) were evaluated for larval mortality and growth inhibition when fed diets containing individual Bacillus thuringiensis protoxins. Resistance ratios for four of the protoxins in Dipel (Cry1Aa, Cry1Ab, Cry1Ac, and Cry2Aa) were 170-, 205-, 524-, and > 640-fold, respectively, considerably higher than the 47-fold resistance to Dipel. The Dipel-resistant strain was 36-fold resistant to Cry1Ba, a protoxin not present in Dipel. Another non-Dipel protoxin, Cry1Ca, did not cause significant mortality for either resistant or susceptible larvae with doses as high as 1.0 mg/ml. In an evaluation of larval growth inhibition, resistance to Cry1Aa, Cry1Ab, Cry1Ac, and Cry1Ba was significant at concentrations of 0.054 and 0.162 microg/ml. However, growth inhibition with Cry2Aa was not significant at either dose. These data provide information on the spectrum of resistance and cross-resistance to individual Cry protoxins in this strain.


Subcortical biophysical abnormalities in patients with mood disorders.
Cortical-subcortical circuits have been implicated in the pathophysiology of mood disorders. Structural and biochemical abnormalities have been identified in patients diagnosed with mood disorders using magnetic resonance imaging-related approaches. In this study, we used magnetization transfer (MT), an innovative magnetic resonance approach, to study biophysical changes in both gray and white matter regions in cortical-subcortical circuits implicated in emotional regulation and behavior. Our study samples comprised 28 patients clinically diagnosed with major depressive disorder (MDD) and 31 non-depressed subjects of comparable age and gender. MT ratio (MTR), representing the biophysical integrity of macromolecular proteins within key components of cortical-subcortical circuits-the caudate, thalamic, striatal, orbitofrontal, anterior cingulate and dorsolateral regions-was the primary outcome measure. In our study, the MTR in the head of the right caudate nucleus was significantly lower in the MDD group when compared with the comparison group. MTR values showed an inverse relationship with age in both groups, with more widespread relationships observed in the MDD group. These data indicate that focal biophysical abnormalities in the caudate nucleus may be central to the pathophysiology of depression and critical to the cortical-subcortical abnormalities that underlie mood disorders. Depression may also accentuate age-related changes in the biophysical properties of cortical and subcortical regions. These observations have broad implications for the neuronal circuitry underlying mood disorders across the lifespan.


Ventral pallidal encoding of reward-seeking behavior depends on the underlying associative structure.
Despite its being historically conceptualized as a motor expression site, emerging evidence suggests the ventral pallidum (VP) plays a more active role in integrating information to generate motivation. Here, we investigated whether rat VP cue responses would encode and contribute similarly to the vigor of reward-seeking behaviors trained under Pavlovian versus instrumental contingencies, when these behavioral responses consist of superficially similar locomotor response patterns but may reflect distinct underlying decision-making processes. We find that cue-elicited activity in many VP neurons predicts the latency of instrumental reward seeking, but not of Pavlovian response latency. Further, disruption of VP signaling increases the latency of instrumental but not Pavlovian reward seeking. This suggests that VP encoding of and contributions to response vigor are specific to the ability of incentive cues to invigorate reward-seeking behaviors upon which reward delivery is contingent.


Properties of the protein subunit of central-pair and outer-doublet microtubules of sea urchin flagella.
The subunit protein has been isolated from the central-pair and outer-doublet microtubules of sea urchin sperm tails. Both proteins have a sedimentation constant of 6S and a molecular weight of 120,000. Both are converted to a 60,000 molecular weight species by denaturation in 6 M guanidine hydrochloride and reduction with mercaptoethanol. The reduced-alkylated proteins have the same R(f) on disc electrophoresis, and the same amino acid composition, which is very similar to that of muscle actin. The central-pair protein has one binding site for colchicine per 120,000 g. Both proteins appear to have a guanine nucleotide binding site, but the ability to bind GTP in solution has been demonstrated only for the central-pair protein. Although 1 mole of guanine nucleotide is bound per 60,000 g to outer-doublet tubules, the protein obtained by dissolving the doublets at pH 10.5 has lost the guanine nucleotide-binding site and also shows little or no colchicine-binding activity. Comparison of the properties of the isolated protein with electron microscopic evidence on structure of microtubules suggests that the chemical subunit (M = 120,000) consists of two of the 40 A morphological subunits.


A 1-year, double-blind, placebo-controlled trial of ziprasidone 40, 80 and 160 mg/day in chronic schizophrenia: the Ziprasidone Extended Use in Schizophrenia (ZEUS) study.
We evaluated relapse in patients with stable, chronic schizophrenia over a 1-year period; inpatients were randomized to ziprasidone 40 mg/day (n = 72), 80 mg/day (n = 68), 160 mg/day (n = 67) or placebo (n = 71). The probability of relapse (Kaplan-Meier) at 1 year was significantly lower in the ziprasidone 40, 80, and 160 mg/day groups (43%, 35% and 36%, respectively) compared to placebo (77%; P = 0.002, P < 0.001 and P < 0.001, respectively). In those patients who remained on treatment for at least 6 months, only 9% subsequently relapsed on ziprasidone compared to 42% on placebo (P = 0.001). All three doses of ziprasidone were significantly superior to placebo on Positive and Negative Syndrome Scale (PANSS) efficacy variables (all P < 0.05). Ziprasidone was associated with a significantly greater mean improvement in the PANSS negative symptom subscale compared to placebo (P < 0.05). Discontinuation due to adverse events was similar with ziprasidone and placebo. Ziprasidone treatment was indistinguishable from placebo in assessments of movement disorders and was not associated with weight gain or cardiovascular abnormalities. These results demonstrate that ziprasidone was effective in reducing the frequency of relapse and was associated with long-term improvement in negative symptoms. Ziprasidone was well tolerated in this population of patients with chronic, stable schizophrenia.


Monoclonal antibodies 323/A3 and Ca1 identify a paracrine function of breast carcinoma on adjacent benign histological components.
The 323/A23 monoclonal antibody (MAb) is expressed with increasing breast atypia, whilst Ca1 has been suggested as a marker of cancer risk in benign breast disease. To establish whether they would be useful as markers of malignancy the staining characteristics in benign tissue components associated with malignant biopsies have been compared with the staining patterns of benign biopsies from patients with no known malignancy. Staining with 323/A3 and Ca1 MAb was carried out on formalin-fixed paraffin-embedded tissue sections using ABC Vectastain Reagents (Vector Laboratories) and diaminobenzidine as the chromogen. All biopsies contained ductolobular tissues. Apocrine metaplasia was present in 35 of 79 malignant biopsies, in 42 of 77 selected and 20 of 50 prospective unselected benign biopsies. The 323/A3 MAb stained strongly the cytoplasm of apocrine metaplasia in breast carcinoma biopsies in 18 of 35 cases, in the selected benign group this was two out of 42 (P less than 0.001) and in the prospective benign group one of 19 (P less than 0.01). No differences in staining were noted for ductolobular tissue. The Ca1 MAb showed strong apical staining in ductolobular tissue in 66 of 79 invasive carcinoma biopsies, in 20 of 50 prospective benign biopsies and 53 of 77 selected biopsies. The prospective and selected benign group staining was significantly different from that of the invasive carcinomas (P less than 0.005 and less than 0.05 respectively). These data suggest that 323/A3 staining of apocrine metaplasia and Ca1 staining of ductolobular tissue is affected by a paracrine function of breast cancer.