Effect of morphological heterogeneity of somatic embryos of Melia azedarach on conversion into plants.
Embryogenic cultures were initiated from immature Melia azedarach (Meliaceae) zigotic embryos. Explants were induced on Murashige and Skoog (1962) medium with 4.54 microM thidiazuron or 0.45 microM dichlorophenoxyacetic acid. After 6 weeks of culture on induction medium, somatic embryos were categorized in four morphological classes based on the presence of single or fused embryos and if they remained united or not to the original explant; that were evaluated histologically. The somatic embryos of every category were transferred, in groups or individually, on a 1/4 MS medium. Bipolar embryos, the more typically normal ones, had well defined shoot and root apical meristems and produced single plants; subcultured individually their conversion was 28%, and subcultured in groups the conversion declined to 6.8%. Fused embryos subcultured in groups had only a 2.1% conversion and produced plants with fused stems. None conversion rate in the others classes was associated to poorly developed shoot and root meristematic areas or with their absence. The converted plants were acclimatized and transferred, in a mist, to soil, with an independent of the class 95% survival rate.


Comparative in-vitro activity of fourteen antibiotics against clinical isolates of enterococci.
The in-vitro antibacterial activities of fourteen antimicrobial agents, including ampicillin, amikacin, Augmentin, ceftazidime, cefotaxime, ceftriaxone, ciprofloxacin, erythromycin, gentamicin, penicillin G, piperacillin, rifampicin, streptomycin and vancomycin, were compared against 195 enterococcal strains isolated from clinical specimens received at the King Abdulaziz University Hospital in Saudi Arabia. The antibacterial susceptibility was determined by the minimal inhibitory concentration (MIC) using an agar dilution method. Ampicillin, Augmentin and vancomycin exhibited the greatest activity, inhibiting 90% of the tested strains (MIC90) at 2 micrograms/ml, followed by penicillin G and piperacillin with MIC90 of 4 micrograms/ml. Erythromycin, third generation cephalosporins, aminoglycosides and rifampicin, on the other hand, had poor activity against enterococci with MIC90s well above the obtainable serum concentrations. The clinical implications of resistance to aminoglycosides and the alternative antimicrobial therapy in serious enterococcal infections are discussed in the text.


Layer-Dependent Short-Term Synaptic Plasticity Between Excitatory Neurons in the C2 Barrel Column of Mouse Primary Somatosensory Cortex.
Neurons process information through spatiotemporal integration of synaptic input. Synaptic transmission between any given pair of neurons is typically a dynamic process with presynaptic action potentials (APs) evoking depressing or facilitating postsynaptic potentials when presynaptic APs occur within hundreds of milliseconds of each other. In order to understand neocortical function, it is therefore important to investigate such short-term synaptic plasticity at synapses between different types of neocortical neurons. Here, we examine short-term synaptic dynamics between excitatory neurons in different layers of the mouse C2 barrel column through in vitro whole-cell recordings. We find layer-dependent short-term plasticity, with depression being dominant at many synaptic connections. Interestingly, however, presynaptic layer 2 neurons predominantly give rise to facilitating excitatory synaptic output at short interspike intervals of 10 and 30 ms. Previous studies have found prominent burst firing of excitatory neurons in supragranular layers of awake mice. The facilitation we observed in the synaptic output of layer 2 may, therefore, be functionally relevant, possibly serving to enhance the postsynaptic impact of burst firing.


Inexpensive stereoscopic CCRG camera for lens/cataract photography in vitro.
In 1978 the American Cooperative Cataract Research Group (CCRG) adopted a stereoscopic camera system for photographing human cataracts in vitro based upon a Zeiss OPMI 1 operating microscope (Carl Zeiss, Inc.; Oberkochen, West Germany). Photographs obtained with this system were used to classify human cataractous change according to the standardized CCRG protocol. Classification data correlated with laboratory data furthered the attempt to define the biochemical or biophysical basis for specific types of cataractous change. Presently, the high cost of this camera (exceeding $20,000) precludes its use by many laboratories wishing to do human lens research. This study describes an inexpensive (less than $2,200) alternative camera for this type of photography. Adjacent frames on the film strip constitute stereo pairs which can be viewed in a modified stereo viewer. In the original CCRG camera both members of a stereo pair were included in the same frame. The quality of the stereo images obtained with this new system nearly equals that with the original Zeiss system. It is hoped that this inexpensive system will allow more scientists to participate in CCRG-related research and increase the supply of intracapsularly extracted cataracts available to all collaborating CCRG scientists.


Modern Pathologic Diagnosis of Renal Oncocytoma.
Oncocytoma is a well-defined benign renal tumor, with classic gross and histologic features, including a tan or mahogany-colored mass with central scar, microscopic nested architecture, bland cytology, and round, regular nuclei with prominent central nucleoli. As a result of variations in this classic appearance, difficulty in standardizing diagnostic criteria, and entities that mimic oncocytoma, such as eosinophilic variant chromophobe renal cell carcinoma and succinate dehydrogenase-deficient renal cell carcinoma, pathologic diagnosis remains a challenge. This review addresses the current state of pathologic diagnosis of oncocytoma, with emphasis on modern diagnostic markers, areas of controversy, and emerging techniques for less invasive diagnosis, including renal mass biopsy and advanced imaging.


Staged complex abdominal wall hernia repair in morbidly obese patients.
The repair of complex abdominal wall hernias in morbidly obese patients is often associated with a higher risk of complications and hernia recurrences. Improvement in obesity and its associated metabolic complications are hypothesized to improve hernia repair outcomes. This study analyzes outcomes from morbidly obese patients who underwent bariatric surgery with staged complex abdominal wall reconstruction at Creighton University Medical Center (CUMC). This retrospective study included morbidly obese patients with complex abdominal wall hernia, who underwent bariatric surgery with staged abdominal wall reconstruction. Data points collected included patient demographics, obesity-related co-morbidities, pre-operative BMI, EBMIL at 12 months, hernia characteristics, postoperative complications, BMI at time of hernia repair, and hernia recurrence. Twelve patients with an average BMI of 48 and complex abdominal wall hernias (mean width 14.0 cm) met inclusion criteria. Seven patients (58%) had significant loss of domain. Bariatric procedures included six laparoscopic sleeve gastrectomies (LSG), three laparoscopic Roux-en-Y gastric bypasses (LRNYGB), and three revisional procedures (2 vertical band gastroplasties to LRNYGB and 1 LRNYGB revision). At 12-month follow-up, the mean excess BMI loss (EBMIL) was 64.6%. The average time to staged complex abdominal wall reconstruction was 22.3 months. Two non-elective hernia repairs were performed due to one incarceration and one strangulation. There were no recurrences after an average follow-up of 21.9 months. In this study, staged mesh repair of complex abdominal wall hernias after bariatric surgery in morbidly obese patients was associated with acceptable morbidity and no hernia recurrences at approximately 1.5 year follow-up.


Safety and efficacy of intravenous thrombolysis in patients with acute ischemic stroke taking direct oral anticoagulants prior to stroke: a meta-analysis.
To assess the safety and efficacy of intravenous thrombolysis (IVT) in patients with acute ischemic stroke (AIS) taking direct oral anticoagulants (DOACs) prior to stroke. Literature was searched in PubMed, Cochrane Library, and Embase until March 13, 2023. The primary outcome was symptomatic intracranial hemorrhage (sICH). Secondary outcomes included excellent outcome (modified Rankin Scale [mRS] 0-1), functional independence (mRS 0-2), and mortality. Odds ratios (OR) with 95% confidence intervals (CI) were estimated using a random-effects model. Five non-randomized studies included 239,879 patients with AIS treated with IVT, with 3400 (1.42%) taking DOACs prior to stroke. The rates of sICH did not differ statistically between patients taking DOACs and those not taking anticoagulants (unadjusted OR 0.98; 95% CI 0.67-1.44; P = 0.92; adjusted OR 0.81; 95% CI 0.64-1.03; P = 0.09). Patients taking DOACs had significantly higher adjusted rates of excellent outcome (adjusted OR 1.22; 95% CI 1.06-1.40; P < 0.01) and functional independence (adjusted OR 1.25; 95% CI 1.10-1.42; P < 0.01) at discharge than those not taking anticoagulants. No significant difference was observed in mortality and other efficacy outcomes between groups after adjustment. The meta-analysis indicated that taking DOACs prior to stroke does not significantly increase the risk of sICH in selected patients with AIS treated with IVT. Furthermore, the benefits of IVT in selected patients taking DOACs appear to be comparable to those not taking anticoagulants. Further research is warranted to confirm the findings.


Promoter modeling: the case study of mammalian histone promoters.
Histone proteins play important roles in chromosomal functions. They are significantly evolutionarily conserved across species, which suggests similarity in their transcription regulation. The abundance of experimental data on histone promoters provides an excellent background for the evaluation of computational methods. Our study addresses the issue of how well computational analysis can contribute to unveiling the biologically relevant content of promoter regions for a large number of mammalian histone genes taken across several species, and suggests the consensus promoter models of different histone groups. This is the first study to unveil the detailed promoter structures of all five mammalian histone groups and their subgroups. This is also the most comprehensive computational analysis of histone promoters performed to date. The most exciting fact is that the results correlate very well with the biologically known facts and experimental data. Our analysis convincingly demonstrates that computational approach can significantly contribute to elucidation of promoter content (identification of biologically relevant signals) complementing tedious wet-lab experiments. We believe that this type of analysis can be easily applied to other functional gene classes, thus providing a general framework for modelling promoter groups. These results also provide the basis to hunt for genes co-regulated with histone genes across mammalian genomes.


Swedish primary healthcare nurses' perceptions of using digital eHealth services in support of patient self-management.
Nurses have expressed doubts about the ongoing digitalisation of Swedish primary health care. Given the potential role of eHealth in primary health care, including supporting interactive self-management for people with chronic conditions, it is important to highlight nurses' experiences. This study is part of a larger project aimed at implementing person-centred interactive self-management support (iSMS) in primary health care. The aim of this study was to describe Swedish primary healthcare nurses' perceptions of using digital eHealth systems and services to support patient self-management. Focus group interviews were conducted with primary healthcare nurses (n = 20). The interview transcriptions were analysed using qualitative content analysis. Three themes emerged from the content analysis: caregiving in the midst of digital chaos; a lack of overview and control in daily work; and mixed feelings towards digitalisation. Each theme was subdivided into three subthemes. The results of this study provide insight into a number of concerns that stand in the way of success when it comes to the implementation and use of digital technology. If nurses are to adapt to the new policies and practices that accompany the current digitalised development in Swedish primary health care, the concept of a nurse's traditional work role needs to be amended in terms of the scope of work tasks and established views of traditional nursing. The study also highlights the need for more research to enable eHealth systems/services to be designed to fulfil multiple requirements. The digitised systems should be a tool for achieving good quality self-management support as well as giving the primary healthcare nurses adequate resources to support patients' self-management while still maintaining the values associated with person-centred care.


Hemodynamic Differences in Intracranial Aneurysms before and after Rupture.
Rupture risk of intracranial aneurysms may depend on hemodynamic characteristics. This has been assessed by comparing hemodynamic data of ruptured and unruptured aneurysms. However, aneurysm geometry may change before, during, or just after rupture; this difference causes potential changes in hemodynamics. We assessed changes in hemodynamics in a series of intracranial aneurysms, by using 3D imaging before and after rupture. For 9 aneurysms in 9 patients, we used MRA, CTA, and 3D rotational angiography before and after rupture to generate geometric models of the aneurysm and perianeurysmal vasculature. Intra-aneurysmal hemodynamics were simulated by using computational fluid dynamics. Two neuroradiologists qualitatively assessed flow complexity, flow stability, inflow concentration, and flow impingement in consensus, by using flow-velocity streamlines and wall shear stress distributions. Hemodynamics changed in 6 of the 9 aneurysms. The median time between imaging before and after rupture was 678 days (range, 14-1461 days) in these 6 cases, compared with 151 days (range, 34-183 days) in the 3 cases with unaltered hemodynamics. Changes were observed for flow complexity (n = 3), flow stability (n = 3), inflow concentration (n = 2), and region of flow impingement (n = 3). These changes were in all instances associated with aneurysm displacement due to rupture-related hematomas, growth, or newly formed lobulations. Hemodynamic characteristics of intracranial aneurysms can be altered by geometric changes before, during, or just after rupture. Associations of hemodynamic characteristics with aneurysm rupture obtained from case-control studies comparing ruptured with unruptured aneurysms should therefore be interpreted with caution.


Paratrooper's ankle fracture: posterior malleolar fracture.
We assessed the frequency and types of ankle fractures that frequently occur during parachute landings of special operation unit personnel and analyzed the causes. Fifty-six members of the special force brigade of the military who had sustained ankle fractures during parachute landings between January 2005 and April 2010 were retrospectively analyzed. The injury sites and fracture sites were identified and the fracture types were categorized by the Lauge-Hansen and Weber classifications. Follow-up surveys were performed with respect to the American Orthopedic Foot and Ankle Society ankle-hindfoot score, patient satisfaction, and return to preinjury activity. The patients were all males with a mean age of 23.6 years. There were 28 right and 28 left ankle fractures. Twenty-two patients had simple fractures and 34 patients had comminuted fractures. The average number of injury and fractures sites per person was 2.07 (116 injuries including a syndesmosis injury and a deltoid injury) and 1.75 (98 fracture sites), respectively. Twenty-three cases (41.07%) were accompanied by posterior malleolar fractures. Fifty-five patients underwent surgery; of these, 30 had plate internal fixations. Weber type A, B, and C fractures were found in 4, 38, and 14 cases, respectively. Based on the Lauge-Hansen classification, supination-external rotation injuries were found in 20 cases, supination-adduction injuries in 22 cases, pronation-external rotation injuries in 11 cases, tibiofibular fractures in 2 cases, and simple medial malleolar fractures in 2 cases. The mean follow-up period was 23.8 months, and the average follow-up American Orthopedic Foot and Ankle Society ankle-hindfoot score was 85.42. Forty-five patients (80.36%) reported excellent or good satisfaction with the outcome. Posterior malleolar fractures occurred in 41.07% of ankle fractures sustained in parachute landings. Because most of the ankle fractures in parachute injuries were compound fractures, most cases had to undergo surgical repairs.


Statins and renovascular disease in the elderly: a population-based cohort study.
More than 90% of cases of renovascular disease (RVD) are caused by atherosclerosis; thus patients with this condition are at high risk for vascular events. We examined the association of statins with prognosis in patients with RVD. We performed a population-based cohort study in 4040 patients with RVD older than 65 years using province-wide health data in Ontario, Canada. The primary outcome was time to first cardiorenal event, specifically myocardial infarction, stroke, heart failure, acute renal failure, dialysis or death; the primary analysis used a time-dependent covariate for statin exposure. Despite having a greater burden of cardiovascular and renal comorbidity, the risk of the primary outcome was significantly lower in statin users than in non-users [unadjusted hazard ratio (HR) 0.51, 95% confidence interval (CI) 0.47-0.57; P < 0.0001]. This association was materially unchanged after adjusting for demographic characteristics, cardiovascular risk factors, other comorbidities, measures of health-care utilization, screening, and concomitant medications (adjusted HR 0.51, 95% CI 0.46-0.57). An analysis using the same endpoint in a propensity-matched cohort without time-dependent statin exposure revealed a lower risk of the primary outcome in statin-treated patients but with a substantially more conservative point estimate (HR 0.82, 95% CI 0.71-0.95). These data suggest that statins are associated with improved prognosis in elderly patients with RVD.


Occurrence of Vibrio and Salmonella species in mussels (Mytilus galloprovincialis) collected along the Moroccan Atlantic coast.
This study reports the occurrence of different Vibrio and Salmonella species in 52 samples of Mytilus galloprovincialis collected from four sites along the Atlantic coast between Agadir and Essaouira (Anza, Cap Ghir, Imssouane and Essaouira). The level of Escherichia coli (E. coli) was also determined to evaluate the degree of microbial pollution in the investigated areas. In this study three methods were used : AFNOR NF EN ISO 6579 V08-013 for Salmonella spp., the provisional method routinely used by several laboratories (Institut Pasteur, Paris,…) for Vibrio cholerae and Vibrio parahaemolyticus in the seafood, and the most probable number method (MPN) using Norm ISO/TS 16649-3 (2005) for E. coli. The most frequently isolated Vibrios were Vibrio alginolyticus (90.4% of samples), followed by V. cholerae non O1 non O139 (15.4%) and V. parahaemolyticus (7.7%). Salmonella spp. was found in 15% of the samples. The number of E. coli ranged between 0.2/100 g and 1.8 10(3) /100 g of mussel soft tissues. This study indicates the potential sanitary risk associated with the presence of pathogenic bacteria in cultivated mussels in the two populous regions of southern Morocco, where shellfish production and maritime tourism are important to the local economy.


Reward-weighted regression with sample reuse for direct policy search in reinforcement learning.
Direct policy search is a promising reinforcement learning framework, in particular for controlling continuous, high-dimensional systems. Policy search often requires a large number of samples for obtaining a stable policy update estimator, and this is prohibitive when the sampling cost is expensive. In this letter, we extend an expectation-maximization-based policy search method so that previously collected samples can be efficiently reused. The usefulness of the proposed method, reward-weighted regression with sample reuse (R3), is demonstrated through robot learning experiments. (This letter is an extended version of our earlier conference paper: Hachiya, Peters, & Sugiyama, 2009 .).


The distribution of cement penetration into bovine acetabular bone utilising various pressurisation techniques.
Most mechanical failures of acetabular fixation within ten years of primary cemented hip replacement are attributable to a failure to achieve good initial fixation of bone and cement. Several studies have suggested that to achieve good fixation between bone and cement between 3 mm and 5 mm of cement penetration into bone is desirable. Whilst several acetabular cement pressurisation systems exist, little is known about the effects of cement pressurisation on the pattern of penetration of cement into cancellous bone within the pelvis. The current paper assesses the penetration of bone cement into bovine acetabular bone by various pressurisation techniques. We found that pressurisation with the use of a swab in glove or the DePuy pressuriser led to improvement in cement penetration both in terms of maximum depth and also percentage cover of the cup by cement (p<0.05). There was no significant difference in mean maximal penetration between the use of the pressuriser and the swab in a glove technique (p=0.3). If only a plain cup was used as a pressuriser, the penetration achieved was significantly lower in comparison to use of a pressuriser (p<0.02). When compared to previously documented acrylic models, the pattern of intrusion noted in the bovine model was different: penetration was lower at the equatorial and base regions of the acetabulum.


A substrate-fusion protein is trapped inside the Type III Secretion System channel in Shigella flexneri.
The Type III Secretion System (T3SS) is a macromolecular complex used by Gram-negative bacteria to secrete effector proteins from the cytoplasm across the bacterial envelope in a single step. For many pathogens, the T3SS is an essential virulence factor that enables the bacteria to interact with and manipulate their respective host. A characteristic structural feature of the T3SS is the needle complex (NC). The NC resembles a syringe with a basal body spanning both bacterial membranes and a long needle-like structure that protrudes from the bacterium. Based on the paradigm of a syringe-like mechanism, it is generally assumed that effectors and translocators are unfolded and secreted from the bacterial cytoplasm through the basal body and needle channel. Despite extensive research on T3SS, this hypothesis lacks experimental evidence and the mechanism of secretion is not fully understood. In order to elucidate details of the T3SS secretion mechanism, we generated fusion proteins consisting of a T3SS substrate and a bulky protein containing a knotted motif. Because the knot cannot be unfolded, these fusions are accepted as T3SS substrates but remain inside the NC channel and obstruct the T3SS. To our knowledge, this is the first time substrate fusions have been visualized together with isolated NCs and we demonstrate that substrate proteins are secreted directly through the channel with their N-terminus first. The channel physically encloses the fusion protein and shields it from a protease and chemical modifications. Our results corroborate an elementary understanding of how the T3SS works and provide a powerful tool for in situ-structural investigations in the future. This approach might also be applicable to other protein secretion systems that require unfolding of their substrates prior to secretion.


Combined treatment: antifungal drugs with antibodies, cytokines or drugs.
To improve present results with antifungal drugs, modulation of the host immune response is being explored. Human phagocytes of various lineages work cooperatively in vitro with antifungal drugs to inhibit or kill fungal pathogens, and this activity is augmented by several recombinant cytokines. Monoclonal antibodies against the cryptococcal capsule have been shown to act as an adjunct in enhancing the outcome of cryptococcosis in animal models. This approach is now being pursued in systematic clinical trials. In experimental candidiasis, several manipulations of the immune system, via administration of cytokines, gene deletion or antibodies to cytokines, have been shown to significantly affect survival and fungal clearance in vivo. This approach has already been demonstrated to be of benefit with recombinant human granulocyte-colony stimulating factor adjunct therapy of human candidiasis. Combining antifungal drugs of different classes may enhance their therapeutic effect.


"The ladder of the law has no top and no bottom": how therapeutic jurisprudence can give life to international human rights.
In the past two decades, therapeutic jurisprudence (TJ) has become one of the most important theoretical approaches to the law. But, there has, as of yet, been puzzlingly little written about the relationship between TJ and international human rights law. To be sure, there has been some preliminary and exploratory work on the relationship between TJ and international law in general, but virtually nothing on its relationship to international human rights law in a mental disability law context. This paper seeks to focus on this lack of consideration, to speculate as to why that might be, and to offer some suggestions as to how to infuse some new vitality and vigor into this important area of law and social policy. In this article, first, I offer a brief explanation of TJ. Next, I discuss, also briefly, the impact (and the potential future greater impact) of the recently-ratified United Nations Convention on the Rights of Persons with Disabilities (CRPD) on this area. Then, I consider the sparse commentary currently available on the intersection between TJ and international law in general, and will speculate as to why this is so sparse. Then, I offer some thoughts as to the TJ/international human rights law connection, looking specifically at three questions that require far more attention from this perspective (access to counsel, the use of state-sanctioned psychiatry as a tool of political oppression, and the potential redemptive power of the CRPD), and describe a research agenda that scholars might turn to in furtherance of the investigation of the relationships between therapeutic jurisprudence, international human rights law and mental disability law. I conclude by calling on scholars, activists, advocates and practitioners to begin to take this connection seriously in their future work.


Functional Proteomic Analysis of Repressive Histone Methyltransferase Complexes Reveals ZNF518B as a G9A Regulator.
Cell-type specific gene silencing by histone H3 lysine 27 and lysine 9 methyltransferase complexes PRC2 and G9A-GLP is crucial both during development and to maintain cell identity. Although studying their interaction partners has yielded valuable insight into their functions, how these factors are regulated on a network level remains incompletely understood. Here, we present a new approach that combines quantitative interaction proteomics with global chromatin profiling to functionally characterize repressive chromatin modifying protein complexes in embryonic stem cells. We define binding stoichiometries of 9 new and 12 known interaction partners of PRC2 and 10 known and 29 new interaction partners of G9A-GLP, respectively. We demonstrate that PRC2 and G9A-GLP interact physically and share several interaction partners, including the zinc finger proteins ZNF518A and ZNF518B. Using global chromatin profiling by targeted mass spectrometry, we discover that even sub-stoichiometric binding partners such as ZNF518B can positively regulate global H3K9me2 levels. Biochemical analysis reveals that ZNF518B directly interacts with EZH2 and G9A. Our systematic analysis suggests that ZNF518B may mediate the structural association between PRC2 and G9A-GLP histone methyltransferases and additionally regulates the activity of G9A-GLP.


Modulation of peroxidation in murine melanoma by dietary tyrosine-phenylalanine restriction, levodopa methylester chemotherapy, and sodium ascorbate supplementation.
Treatment with the drug combination of levodopa methylester and benserazide, supplemental ascorbate, and dietary deficiencies of tyrosine and phenylalanine more than doubled the median survival time of female (C57BL/6 X DBA/2)F1 mice bearing B16 melanoma tumors. The mechanism for this antitumor effect was not well defined. This study was designed to test the hypothesis that the antitumor activity of levodopa methylester and ascorbate against B16 melanoma is related to the generation of free radicals of oxygen, which peroxidize lipid constituents of cell membranes leading to cell death. As an indication of lipid peroxidation, the individual and combined effects of drug treatment and ascorbate supplementation on host and tumor malondialdehyde levels were examined in mice fed one of three test diets (commercial, purified, or deficient) containing decreasing amounts of tyrosine and phenylalanine. Malondialdehyde levels were increased in the livers of all untreated tumor-bearing mice, which suggests that the tumor alters host antioxidant defenses. Drug treatment and ascorbate supplementation alone and in combination increased hepatic malondialdehyde levels inversely to the amounts of tyrosine and phenylalanine in the diet, and the effects of drug and ascorbate on malondialdehyde levels were additive. Plasma levels remained unchanged by drug treatment, ascorbate supplementation, or tumors in mice fed the commercial or purified diets. Higher levels were observed only in tumor-bearing mice fed the deficient diet and given both drug treatment and ascorbate supplementation. Changes in tumor malondialdehyde levels generally correlated with the effects of the drug and ascorbate on survival time of mice bearing B16 melanoma. Tumors from mice fed the commercial diet accumulated little malondialdehyde, and therapy was relatively ineffective in this dietary group. In mice fed purified or deficient diets, drug treatment and ascorbate supplementation alone increased survival and tumor malondialdehyde levels, but the level of peroxidation in mice receiving the ascorbate supplementation was low compared to its greater antitumor effect on B16 melanoma. Although ascorbate enhanced the peroxidative activity of the drug on B16 melanoma tumors, the effects of the drug and ascorbate on malondialdehyde levels were not additive. Ascorbate enhanced survival of tumor-bearing mice that were fed the deficient diet and that were treated with drug, which indicated that ascorbate supplementation acted via other mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)


Mass extinction of lizards and snakes at the Cretaceous-Paleogene boundary.
The Cretaceous-Paleogene (K-Pg) boundary is marked by a major mass extinction, yet this event is thought to have had little effect on the diversity of lizards and snakes (Squamata). A revision of fossil squamates from the Maastrichtian and Paleocene of North America shows that lizards and snakes suffered a devastating mass extinction coinciding with the Chicxulub asteroid impact. Species-level extinction was 83%, and the K-Pg event resulted in the elimination of many lizard groups and a dramatic decrease in morphological disparity. Survival was associated with small body size and perhaps large geographic range. The recovery was prolonged; diversity did not approach Cretaceous levels until 10 My after the extinction, and resulted in a dramatic change in faunal composition. The squamate fossil record shows that the end-Cretaceous mass extinction was far more severe than previously believed, and underscores the role played by mass extinctions in driving diversification.


Effect of autologous stem cells on regenerated bone during distraction osteogenesis by Ilizarov technique in the radius of dogs. Histomorphometric analysis.
To investigate by histomorphometry the distraction osteogenesis by Ilizarov technique in dog radius with the use of autologous stem cells in regenerated bone. Ten dogs (20 radiuses) underwent the osteotomy of 20% of extension of their radiuses, and osteogenic distraction using the Ilizarov technique after this procedure at rate of 1mm per day divided into 0.5mm every 12 hours. The elongation was performed until the regeneration reached 20% of the total length of the radius. The stem cells were isolated, concentrated and injected in the regenerated bone, when it reached 10% of the length of the entire radius. The regenerated bone was evaluated using histomorphometric analysis when the elongation was 20% the size of radius. The bone formation was evidenced by histomorphometric indices were significantly greater in the study group. In the histology evaluation the type of healing was mixed in 80% (intra membrane and endocondral) in both groups; the osteoblastic activity from moderate to intense was greater in the study group; and the space occupied by the newly-formed bone tissue was more evident in the study group. The histomorphometric indices in this study expressing the microarchitecture, trabecular thickness, trabecular spacing, number of trabecula and quantity of bone that was significant in the group study. These data suggest that the use of undifferentiated stem cells autologous bone marrow in the regenerate bone induces osteogenesis and bone quality.


Interdomain signaling in a two-domain fragment of the human glucocorticoid receptor.
Studies of individual domains or subdomains of the proteins making up the nuclear receptor family have stressed their modular nature. Nevertheless, these receptors function as complete proteins. Studies of specific mutations suggest that in the holoreceptors, intramolecular domain-domain interactions are important for complete function, but there is little knowledge concerning these interactions. The important transcriptional transactivation function in the N-terminal part of the glucocorticoid receptor (GR) appears to have little inherent structure. To study its interactions with the DNA binding domain (DBD) of the GR, we have expressed the complete sequence from the N-terminal through the DBD of the human GR. Circular dichroism analyses of this highly purified, multidomain protein show that it has a considerable helical content. We hypothesized that binding of its DBD to the cognate glucocorticoid response element would confer additional structure upon the N-terminal domain. Circular dichroism and fluorescence emission studies suggest that additional helicity as well as tertiary structure occur in the two-domain protein upon DNA binding. In sum, our data suggest that interdomain interactions consequent to DNA binding imparts structure to the portion of the GR that contains a major transactivation domain.


Estimation of cognitive and affective disorders occurrence in patients with Lyme borreliosis.
Lyme borreliosis (LB) is a disease caused by the bacteria Borrelia burgdorferi. The most common symptoms are related to the skin, musculo-scelatal system, central and peripheral nervous system, rarely to the heart muscle and the eye, and may occur in the multistage course of the disease. LB may additionally be accompanied by psychopathological symptoms. The aim of the study is estimation of the cognitive and affective disorders occurence in patients with LB. The study was carried out in the group of 121 patients (61 females, 60 males) aged 18-65; mean age 46 years. All patients were diagnosed with late-stage of LB: 46 patients (38%) with Lyme arthritis and 75 patients (62%) with neuroborreliosis. Evaluation of the cognitive and affective functioning of patients was performed on the basis of a standardized interview and test methods: the Mini-Mental State Examination (MMSE), Clock Drawing Test (CDT) and the Beck Depression Inventory (BDI). Cognitive disorders occurred statistically significantly more often in patients with neuroborreliosis (14.7%) than in patients with Lyme arthritis (4.3%). A group of females with neuroborreliosis and a group of males with the same diagnosis demonstrated cognitive deficits significantly more often (23.3% and 8.9%, respectively), compared to groups of patients with Lyme arthritis (6.5% in females and no cognitive deficits in males). A significantly higher percentage of depressive disorders was also noted in the group of males and females with neuroborreliosis (50.7%), compared to the group of patients with Lyme arthritis (39.1%). The symptoms of depression were particularly frequent in the females with neuroborreliosis (60%). The severity of depression measured by BDI was mild or moderate in most cases. In the examined groups, more patients with neuroborreliosis (44%), both in females (36.7%) and males (48.9%), demonstrated anxiety disorders. The obtained results showed a higher frequency of affective disorders compared to cognitive deficits, both in patients with Lyme arthritis and neuroborreliosis. An increased frequency of depressive and neurotic disorders was observed in patients with LB, particularly in patients with neuroborreliosis. Neurotic disorders, mainly adaptive, were most common in males with LB, while depressive disorders were more frequent in females. An increased frequency of cognitive deficits was observed in patients with neuroborreliosis, particularly in females.


Effect of potassium depletion of cells on their sensitivity to diphtheria toxin and pseudomonas toxin.
When Vero cells were depleted of potassium, the cells were protected against diphtheria toxin. Potassium depletion of Vero cells strongly reduced the binding of the toxin to cell surface receptors. Likewise, potassium depleted L-cells were protected against pseudomonas toxin. Diphtheria toxin binding was completely restored upon addition of potassium to the cells. This restoration was not prevented by inhibition of protein synthesis by cycloheximide. When cells were depleted of potassium in the presence of metabolic inhibitors, and then treated with diphtheria toxin, protein synthesis was reduced to the same extent as in cells with normal intracellular level of potassium. The results indicate that potassium depletion of Vero cells reduces the ability of the cells to bind diphtheria toxin by an ATP requiring process, and that binding, endocytosis and transfer of diphtheria fragment A across the membrane may occur at low intracellular levels of potassium.


Chiral plasmons without magnetic field.
Plasmons, the collective oscillations of interacting electrons, possess emergent properties that dramatically alter the optical response of metals. We predict the existence of a new class of plasmons-chiral Berry plasmons (CBPs)-for a wide range of 2D metallic systems including gapped Dirac materials. As we show, in these materials the interplay between Berry curvature and electron-electron interactions yields chiral plasmonic modes at zero magnetic field. The CBP modes are confined to system boundaries, even in the absence of topological edge states, with chirality manifested in split energy dispersions for oppositely directed plasmon waves. We unveil a rich CBP phenomenology and propose setups for realizing them, including in anomalous Hall metals and optically pumped 2D Dirac materials. Realization of CBPs will offer a powerful paradigm for magnetic field-free, subwavelength optical nonreciprocity, in the mid-IR to terahertz range, with tunable splittings as large as tens of THz, as well as sensitive all-optical diagnostics of topological bands.


Cellular distribution and subcellular localization of mCLCA1/2 in murine gastrointestinal epithelia.
mCLCA1/2 are members of the CLCA protein family that are widely expressed in secretory epithelia, but their putative physiological role still awaits elucidation. mCLCA1/2 have 95% amino acid identity, but currently no specific antibody is available. We have generated a rabbit polyclonal antibody (pAb849) against aa 424-443 of mCLCA1/2. In HEK293 cells transfected with mCLCA1; pAb849 detected two specific protein bands at approximately 125 kDa and 90 kDa, representing full-length precursor and N-terminal cleavage product, respectively. pAb849 also immunoprecipitated mCLCA1 and labeled the protein by immunostaining. But pAb849 crossreacted with mCLCA3/4/6 despite < or =80% amino acid identity of the antigenic epitope. We therefore investigated the cellular localization of mCLCA1/2 in epithelial tissues, which do not express mCLCA3/4/6 (salivary glands, pancreas, kidney) or express mCLCA3/6 with known localization (mucus cells of stomach and small intestine; villi of small intestine). mCLCA1/2 mRNA and protein expression were found in both parotid and submandibular gland, and immunohistochemistry revealed labeling in parotid acinar cells, in the luminal membrane of parotid duct cells, and in the duct cells of submandibular gland. In exocrine pancreas, mCLCA1/2 expression was restricted to acinar zymogen granule membranes, as assessed by immunoblotting, immunohistochemistry, and preembedding immunoperoxidase and immunogold electron microscopy. Moreover, mCLCA1/2 immunolabeling was present in luminal membranes of gastric parietal cells and small intestinal crypt enterocytes, whereas in the kidney, mCLCA1/2 protein was localized to proximal and distal tubules. The apical membrane localization and overall distribution pattern of mCLCA1/2 favor a transmembrane protein implicated in transepithelial ion transport and protein secretion.


A prenatally sonographically diagnosed conotruncal anomaly with mosaic type trisomy 21 and 22q11.2 microdeletion/DiGeorge syndrome.
A prenatally sonographically diagnosed conotruncal anomaly with mosaic type trisomy 21 and 22q11.2 microdeletion/DiGeorge syndrome: We report a prenatally sonographically diagnosed conotruncal and urogenital anomaly. Postnatally, the patient presented with seizures, hypocalcemia, hypoparathyroidism and thymic aplasia and diagnosed as DiGeorge syndrome. Echocardiography showed malalignment VSD, supravalvular pulmonary stenosis and overriding aorta. Chromosome and FISH studies showed the association of mosaic type trisomy 21 and 22q11.2 microdeletion. The present patient is the second case of mosaic type of Down syndrome associated with 22q11.2 microdeletion. In addition the patient also had clinical and laboratory features of DiGeorge syndrome.


The relative contributions of colour and luminance signals towards the visuomotor localisation of targets in human peripheral vision.
We sought to determine the extent to which colour (and luminance) signals contribute towards the visuomotor localization of targets. To do so we exploited the movement-related illusory displacement a small stationary window undergoes when it has a continuously moving carrier grating behind it. We used drifting (1.0-4.2 Hz) red/green-modulated isoluminant gratings or yellow/black luminance-modulated gratings as carriers, each curtailed in space by a stationary, two-dimensional window. After each trial, the perceived location of the window was recorded with reference to an on-screen ruler (perceptual task) or the on-screen touch of a ballistic pointing movement made without visual feedback (visuomotor task). Our results showed that the perceptual displacement measures were similar for each stimulus type and weakly dependent on stimulus drift rate. However, while the visuomotor displacement measures were similar for each stimulus type at low drift rates (<4 Hz), they were significantly larger for luminance than colour stimuli at high drift rates (>4 Hz). We show that the latter cannot be attributed to differences in perceived speed between stimulus types. We assume, therefore, that our visuomotor localization judgements were more susceptible to the (carrier) motion of luminance patterns than colour patterns. We suggest that, far from being detrimental, this susceptibility may indicate the operation of mechanisms designed to counter the temporal asynchrony between perceptual experiences and the physical changes in the environment that give rise to them. We propose that perceptual localisation is equally supported by both colour and luminance signals but that visuomotor localisation is predominantly supported by luminance signals. We discuss the neural pathways that may be involved with visuomotor localization.


Clinical factors affecting the translucency of monolithic Y-TZP ceramics.
The use of monolithic yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) ceramics in aesthetically critical regions is questionable because of the insufficient translucency and opacity of the restorations. Intrinsic (manufacturing process) and extrinsic factors (laboratory procedures and clinical factors) can affect the translucency of monolithic zirconia. In this narrative review, the clinical factors (thickness, cementation type, colour of the monolithic zirconia, surface finishing methods and wear, dental background, cement colour, low temperature degradation) affecting the translucency of monolithic Y-TZP ceramics were reported.


Giant nevus sebaceus: definition, surgical techniques, and rationale for treatment.
A reduction in the reported incidence of malignant degeneration within nevus sebaceus has led many physicians to recommend serial clinical evaluation and biopsy of suspicious areas rather than prophylactic surgical excision. Unfortunately, no well-defined inclusion criteria, including lesion size and location, have been described for the management of nevus sebaceus. To assess whether the incidence or timing of malignant degeneration contraindicates surgical excision, the authors performed a PubMed literature search for any studies, excluding case reports, related to malignant change within nevus sebaceus since 1990. They then defined giant nevus sebaceus to consist of lesions greater than 20 cm or greater than 1 percent of the total body surface area and retrospectively examined their experience and outcomes treating giant nevus sebaceus. Data were pooled from six large retrospective institutional studies (2520 patients). The cumulative incidence of benign and malignant tumors was 6.1 and 0.5 percent, respectively. Of the authors' 195 patients with giant congenital nevi, only six (3.0 percent) met the definition of giant nevus sebaceus. All patients required tissue expansion for reconstruction, and two patients required concomitant skin grafting. Two complications required operative intervention. Early malignant degeneration within nevus sebaceus is rare. Management, however, must account for complex monitoring, particularly for lesions within the scalp, associated alopecia, involvement of multiple facial aesthetic subunits, and postpubertal transformation affecting both appearance and monitoring of the lesions. The latter considerations, rather than the reported incidence of malignant transformation, should form the bases for surgical intervention in giant nevus sebaceus. Therapeutic, V.


Assessment of lung involvement in sarcoidosis - the use of an open-source software to quantify data from computed tomography.
Computed tomography (CT) plays a pivotal role in the initial evaluation of patients suspected of sarcoidosis. Although it has significant limitations associated with radiation exposure, CT scanning is also occasionally used to follow-up patients with sarcoidosis. Hitherto, no widely accepted method of quantitative assessment of pulmonary involvement in sarcoidosis has been established. The aims of the study were as follows: (1) to assess the utility of the open-source, free of charge DICOM Viewer software in quantitative analysis of pulmonary involvement in sarcoidosis; (2) to compare the parameters of quantitative CT analysis with the results of pulmonary function tests (PFTs). We included contrast-enhanced thorax CT examinations of 80 patients with sarcoidosis. Post-processing analysis of CT data was carried out using OsiriX Lite software (Pixmeo, Switzerland). Following densitometric parameters were measured: CT-derived lung volume (CT-LV), mean lung attenuation (MLA), kurtosis, skewness and standard deviation of lung radiodensity (SDLR). Kurtosis was significantly lower in patients with lung fibrosis comparing to those with mediastinal and/or hilar lymphadenopathy (MHL) and pulmonary involvement (median 1.49 vs 1.93). Furthermore, SDLR was significantly higher in patients with lung fibrosis comparing to those with isolated MHL and MHL with pulmonary involvement (median 163.6 vs 137.4). Also, significant correlations between densitometric parameters and the results of PFTs were demonstrated, including correlation between CT-LV and TLC (R=0.7). Our study showed that post-processing of the CT data with the use of Osirix Lite DICOM Viewer might be a valuable method of quantitative analysis of pulmonary involvement in sarcoidosis. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 315-325).


β-structure of the coat protein subunits in spherical particles generated by tobacco mosaic virus thermal denaturation.
Conversion of the rod-like tobacco mosaic virus (TMV) virions into "ball-like particles" by thermal denaturation at 90-98 °C had been described by R.G. Hart in 1956. We have reported recently that spherical particles (SPs) generated by thermal denaturation of TMV at 94-98 °C were highly stable, RNA-free, and water-insoluble. The SPs were uniform in shape but varied widely in size (53-800 nm), which depended on the virus concentration. Here, we describe some structural characteristics of SPs using circular dichroism, fluorescence spectroscopy, and Raman spectroscopy. It was found that the structure of SPs protein differs strongly from that of the native TMV and is characterized by coat protein subunits transition from mainly (about 50%) α-helical structure to a structure with low content of α-helices and a significant fraction of β-sheets. The SPs demonstrate strong reaction with thioflavin T suggesting the formation of amyloid-like structures.


Impairment of the rod outer segment membrane guanylate cyclase dimerization in a cone-rod dystrophy results in defective calcium signaling.
Rod outer segment membrane guanylate cyclase1 (ROS-GC1) is the original member of the membrane guanylate cyclase subfamily whose distinctive feature is that it transduces diverse intracellularly generated Ca(2+) signals in the sensory neurons. In the vertebrate retinal neurons, ROS-GC1 is pivotal for the operations of phototransduction and, most likely, of the synaptic activity. The phototransduction- and the synapse-linked domains are separate, and they are located in the intracellular region of ROS-GC1. These domains sense Ca(2+) signals via Ca(2+)-binding proteins. These proteins are ROS-GC activating proteins, GCAPs. GCAPs control ROS-GC1 activity through two opposing regulatory modes. In one mode, at nanomolar concentrations of Ca(2+), the GCAPs activate the cyclase and as the Ca(2+) concentrations rise, the cyclase is progressively inhibited. This mode operates in phototransduction via two GCAPs: 1 and 2. The second mode occurs at micromolar concentrations of Ca(2+) via S100beta. Here, the rise of Ca(2+) concentrations progressively stimulates the enzyme. This mode is linked with the retinal synaptic activity. In both modes, the final step in Ca(2+) signal transduction involves ROS-GC dimerization, which causes the cyclase activation. The identity of the dimerization domain is not known. A heterozygous, triple mutation -E786D, R787C, T788M- in ROS-GC1 has been connected with autosomal cone-rod dystrophy in a British family. The present study shows the biochemical consequences of this mutation on the phototransduction- and the synapse-linked components of the cyclase. (1) It severely damages the intrinsic cyclase activity. (2) It significantly raises the GCAP1- and GCAP2-dependent maximal velocity of the cyclase, but this compensation, however, is not sufficient to override the basal cyclase activity. (3) It converts the cyclase into a form that only marginally responds to S100beta. The mutant produces insufficient amounts of the cyclic GMP needed to drive the machinery of phototransduction and of the retinal synapse at an optimum level. The underlying cause of the breakdown of both types of machinery is that, in contrast to the native ROS-GC1, the mutant cyclase is unable to change from its monomeric to the dimeric form, the form required for the functional integrity of the enzyme. The study defines the CORD in molecular terms, at a most basic level identifies a region that is critical in its dimer formation, and, thus, discloses a single unifying mechanistic theme underlying the complex pathology of the disease.


Summary of the Faraday Discussion on New memory paradigms: memristive phenomena and neuromorphic applications.
The Faraday Discussion on New memory paradigms: memristive phenomena and neuromorphic systems was held from October 15-17 on the campus of the Rheinisch-Westfälische Technische Hochschule Aachen University, or RWTH Aachen University, under the auspices of the Royal Society of Chemistry. The Discussion brought together over 100 experts and students from over 20 different countries to present, question, and debate the latest breakthroughs in a field that is exhibiting dramatic growth. There were a large number of excellent oral presentations and posters covering the topics of the Discussion, and the conversations among the participants were lively and informative. The first day and a half encompassed the experimental characterization and analysis of memristors for which the primary resistive switching mechanisms involved electrochemical metallization, chemical valence transformation, or thermodynamic phase change, which illustrated the diversity of the physical properties that can be harnessed for building memristive systems. The final half-day of the Discussion was devoted to synaptic and neuromorphic functions of memristors, which have been growing explosively in the past few years and demonstrate that resistive switching is important for much more than a non-volatile memory, but can also be utilized for learning and computation. The high quality of the presentations and discussions in this section demonstrated that this new research area has been solidly launched and we can expect significant advancements and real applications within a few years as new discoveries from biology are incorporated into neuromorphic hardware. I will not attempt to recapitulate the content of all of the sessions here, since the papers collected for this Faraday Discussions volume speak more eloquently for themselves than I can affect. What I hope to accomplish is to point out a few general concepts that arose when considering multiple papers together, especially during the discussions, and point out a particularly novel concept that deserves special attention.


Cell cycle control of chorion gene amplification.
Over-replication of two clusters of chorion genes in Drosophila ovarian follicle cells is essential for rapid eggshell biosynthesis. The relationship of this amplification to the follicle cell cycles has remained unclear. To investigate the regulation of amplification, we developed a technique to detect amplifying chorion genes in individual follicle cells using BrdU incorporation and FISH. Amplification occurs in two developmental phases. One of the gene clusters begins to amplify periodically during S phases of follicle cell endocycles. Subsequently, after endocycles have ceased, both clusters amplify continuously during the remainder of oogenesis. In contrast to the early phase, late amplification commences synchronously among follicle cells. The pattern of Cyclin E expression mirrors these two phases. We present evidence that Cyclin E is required positively for amplification. We suggest that Cyclin E also acts negatively to inhibit refiring of most origins within a cycle, and that specific factors at chorion origins allow them to escape this negative rereplication control. Our findings suggest that chorion amplification is a model for understanding metazoan replicons and the controls that restrict replication to once per cell cycle.


Differential regulation of 11 beta-hydroxylase and aldosterone synthase in human adrenocortical H295R cells.
In humans the last steps in the synthesis of aldosterone and cortisol rely on the activity of two cytochrome P450 genes termed CYP11B2 (aldosterone synthase; P450aldo) and CYP11B1 (11 beta hydroxylase; P450cl1). The mechanisms which lead to differential expression of these two genes within the adrenal cortex are not well-defined. The human adrenocortical cell line. H295R, was utilized in this study to examine the intracellular second messenger pathways regulating expression of P450aldo and P450c11. using specific ribonuclease protection assays. Treatment of H295R cells with angiotensin II or potassium (K+) caused a time-dependent induction in the level of P450aldo transcripts. While K+ treatment was more specific for the induction of P450aldo mRNA, treatment with angiotensin II increased levels of both P450aldo and P450c11 transcripts. To define the second messenger systems which influence transcript levels for these enzymes, the effects of agonists of the protein kinase A, protein kinase C, and calcium pathways were tested on the expression of P450aldo and P450c11. Activation of the protein kinase A pathway by the agonists, dibutyryl cAMP or forskolin, preferentially increased the P450c11 transcript to a greater degree than P450aldo. Interestingly, activation of the protein kinase C pathway by tetradecanoylphorbol acetate (TPA) did not alter transcripts for either P450aldo or P450c11. The calcium channel agonist BAYK 8644 mimicked the effects of K+ by increasing the transcript for P450aldo. However, the calcium channel blocker nifedipine attenuated the stimulatory effects of angiotensin II and K+ on the levels of P450aldo. However, the calcium channel blocker nifedipine attenuated the stimulatory effects of angiotensin II and K+ on the levels of P450aldo transcripts without affecting the stimulatory effect of dbcAMP. This study demonstrates that the protein kinase A pathway preferentially induces P450c11 mRNA over that of P450aldo. In addition, pharmacologic agents that affect calcium levels provide evidence for an additional regulatory mechanism in modulating the expression of P450aldo. This is of importance since the major physiologic regulators of aldosterone secretion, angiotensin II and K+ are able to increase intracellular calcium but have little effect on intracellular cAMP levels.


Prevalence of abdominal ultrasonographic abnormalities in patients with sickle cell disease.
The aim of this study was to evaluate the type and prevalence of abdominal ultrasonographic abnormalities in patients with sickle cell disease. A total of 102 patients with sickle cell disease at the Center of Hemoglobinopathy of the Antakya State Hospital were screened for intra-abdominal abnormalities by abdominal ultrasonography (US). Eightyfour patients were homozygous for sickle-cell disease (S/S), and 18 patients were compound heterozygotes for sickle cell-Beta thalassemia (S/Beta(thal)). At the time of examination, 15.7% (16/102) of patients had undergone splenectomy, and 18.6% (19/102) of patients had undergone cholecystectomy. The most frequent US findings (expressed as percentages of all patients) were hepatomegaly (71.6%), renal enlargement (30.4%), autosplenectomy (33.3%), cholelithiasis (30.4%) and splenomegaly (17.4%). A bright liver was identified in 6 patients (5.9%), an echogenic pancreas in 4 patients (3.9%), and pancreatic punctate echogenic foci were identified in 5 patients (4.9%). Medullary or diffusely increased renal echogenicity was observed in 16 patients (15.7%). Sonographic findings typical of renal papillary necrosis were observed in one patient with S/S. Periportal lymphadenopathy was detected in 10 (11.9%) of 84 patients of the S/S group, and 2 (11.1%) of 18 patients of S/Beta(thal) group. Abdominal ultrasonographic imaging of patients with sickle cell disease revealed a high prevalence of abdominal abnormalities, especially in solid organs.


Fast and ballistic contractions involve greater neuromuscular power production in older adults during resistance exercise.
Neuromuscular power is critical for healthy ageing. Conventional older adult resistance training (RT) guidelines typically recommend lifting slowly (2-s; CONV), whereas fast/explosive contractions performed either non-ballistically (FAST-NB) or ballistically (FAST-B, attempting to throw the load) may involve greater acute power production, and could ultimately provide a greater chronic power adaptation stimulus. To compare the neuromechanics (power, force, velocity, and muscle activation) of different types of concentric isoinertial RT contractions in older adults. Twelve active older adult males completed three sessions, each randomly assigned to one type of concentric contraction (CONV or FAST-NB or FAST-B). Each session involved lifting a range of loads (20-80%1RM) using an instrumented isoinertial leg press dynamometer that measured power, force, and velocity. Muscle activation was assessed with surface electromyography (sEMG). Peak and mean power were markedly different, according to the concentric contraction explosive intent FAST-B > FAST-NB > CONV, with FAST-B producing substantially more power (+ 49 to 1172%, P ≤ 0.023), force (+ 10 to 136%, P < 0.05) and velocity (+ 55 to 483%, P ≤ 0.025) than CONV and FAST-NB contractions. Knee and hip extensor sEMG were typically higher during FAST-B than CON (all P < 0.02) and FAST-NB (≤ 50%1RM, P ≤ 0.001). FAST-B contractions produced markedly greater power, force, velocity and muscle activation across a range of loads than both CONV or FAST-NB and could provide a more potent RT stimulus for the chronic development of older adult power.


Smoking recognition by family physicians.
Family physicians have an essential, unique, and vital role to play in preventive health care. However, the actual practice of and emphasis upon preventive medicine varies widely. Cigarette smoking is the leading preventable cause of illness and high medical costs in the United States today. This study examined the recognition of smoking patients by family physicians. The results show that physicians fail to recognize large numbers of their patients who smoke and that physician behavior is disease oriented rather than preventive. A modest educational program was very successful in improving physician awareness and recognition of smoking patients. This study suggests that family physicians can and need to become better prevention specialists and they must document the smoking habits of all their patients before attempting to counsel or intervene with smoking cessation programs.


The Mutation Portraits of Oncogenes and Tumor Supressor Genes in Predicting the Overall Survival in Pancreatic Cancer: A Bayesian Network Meta-Analysis.
In pancreatic cancer, the carcinogenesis can not be separated from genetics mutations. The portraits of genes alterations majorily including oncogenes (KRAS, HER2, PD-L1) and tumor supressor genes (P53, CDKN2A, SMAD4). Besides being notorious a screening marker, the genetic mutations were related to the prognosis of pancreatic cancer. The aim of this study is to determine the genetic mutations portrait in predicting the overall survival in pancreatic cancer. The network meta analysis (NMA) was registered in PROSPERO (CRD42023397976) and conducted in accordance with the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) in addition of NMA extension guidance. Comprehensive searches were done including all studies which reported the overall survival of pancreatic cancer subjects with KRAS, HER2, PD-L1, P53, CDKN2A, SMAD4. Data were collected and analysis will be done based on Bayesian method, Markov Chain Monte Carlo algorithm, using BUGSnet package in R studio. Transivity was controlled by methods and consistency of the NMA will be fitted by deviance information criterion. Data analysis in NMA were presented in Sucra plot, league table, and forest plot. Twenty-four studies were included in this NMA with 4613 total subjects. The NMA was conducted in random-effects, consistent, and convergence model. Relative to control, the genetic mutation of SMAD4 (HR 1.84; 95%CI 1.39-2.46), HER2 (HR 1.76; 95%CI 1.14-2.71), and KRAS (HR 1.7; 95%CI 1.19-2.48) were significant to have worse survival. The mutations of PD-L1, P53, and CDKN2A also showed poor survival, but not statistically significant compared to control. In pancreatic cancer, the mutation of SMAD4 predicted the worst overall survival, compared to control, also mutation of HER2, KRAS, PD-L1, P53, and CDKN2A.


Cationic lipophosphoramidates with two different lipid chains: synthesis and evaluation as gene carriers.
Cationic lipids constitute a family of synthetic vectors commonly used for nucleic acids delivery. We herein report the results of a systematic study that aimed to compare the transfection efficacies of cationic lipophosphoramidates possessing either two identical lipid chains (termed symmetric cationic lipids) or two different lipid chains (non-symmetric cationic lipids). In addition, we also compared the transfection results of such a 'molecular approach' (the two different lipid chains being included in the same molecule) with those of a 'supramolecular approach' in which two types of symmetrical cationic lipids were mixed in one liposomal formulation. Thus, the present work allowed us first to optimize the methods used to synthesize non-symmetric cationic lipophosphoramidates. In addition, we could also identify two non-symmetric cationic lipids exhibiting high transfection efficiencies with a series of mammalian cell lines, both vectors being characterized by a single phytanyl chain and either an oleyl or a lauryl lipid chain.


Selective gene expression in magnocellular neurons in rat supraoptic nucleus.
Oxytocin- and vasopressin-producing magnocellular neurons (MCNs) of the hypothalamo-neurohypophysial system are the only neuronal phenotypes present in the rat supraoptic nucleus (SON). Laser microdissection of the SON, extraction and T7-based amplification of its RNAs, and analysis of the resulting cDNAs by hybridization on a 35, 319 element DNA microarray have provided a detailed composite view of the gene expression profile of the MCNs. The genes expressed in the SON were compared with those expressed in a reference tissue consisting of total hypothalamus, and this "expression ratio" indicated which genes were preferentially expressed in the SON. Of the 26,000 unique genes on the array, 1385 were found to be expressed in the SON at levels more than two times greater than in the hypothalamus as a whole. Of these, 123 were expressed > or =3.4-fold higher in the SON versus hypothalamus. Most of these preferentially expressed genes were not previously known to be expressed in the MCNs. Quantitative and double-label in situ hybridization histochemistry was used selectively to confirm a number of these microarray observations and to evaluate the osmotic regulation and cell-specific expression of these genes, respectively.


Neonatal hemophilia B with intracranial hemorrhage. Case report.
It is uncommon for infants with hemophilia to have excessive bleeding during the neonatal period. Even if bleeding occurs, it rarely becomes life-threatening, such as in intracranial hemorrhage (ICH). We here report a case of a 4-day-old boy who had intracranial hemorrhage as the first complication of hemophilia B. Computerized axial tomography (CT scan) and ultrasonography were very useful for early diagnosis. Only a few cases of neonatal hemophilia with intracranial hemorrhage have been reported, but the occurrence of this complication is probably more frequent. We reviewed seven cases (including our case) with intracranial hemorrhage as the first manifestation of neonatal hemophilia. Although these infants showed good prognosis as to survival, permanent residual neurological deficits remained in all of them. It is emphasized that intracranial hemorrhage due to hemophilia may occur in neonates even without a family history. Urgent neuroimaging and coagulation studies are necessary for an early and adequate diagnosis.


Cutaneous T-Cell Acute Lymphoblastic Leukemia and the Expression Pattern of Terminal Deoxynucleotidyl Transferase Immunostaining in Mycosis Fungoides and Spongiotic Dermatitis.
T-cell acute lymphoblastic leukemia (T-ALL) is an uncommon, aggressive malignancy that rarely presents in the skin and is generally not considered as part of the differential diagnosis by dermatologists and dermatopathologists. We describe an unusual case of T-ALL presenting with folliculocentric, erythematous papules on the face, histologically resembling mycosis fungoides (MF). Immunostaining for terminal deoxynucleotidyl transferase (TdT) was positive in tumor cells, supporting the diagnosis of cutaneous involvement by T-ALL. TdT is a nuclear enzyme expressed by immature lymphoid malignancies, but the expression pattern of this marker is not well characterized in the skin. We aimed to assess TdT staining in skin biopsies with similar-appearing lymphocytic infiltrates. We evaluated the immunostaining profile of TdT in a cohort of 23 patients, including 13 cases of MF and 10 cases of spongiotic dermatitis. The lymphocytes in the MF and spongiotic dermatitis cases lacked nuclear staining for TdT. Nonspecific, granular, cytoplasmic staining was observed in a small number of background cells. TdT may assist dermatopathologists in discriminating malignant infiltrates of T-ALL from other conditions.


Exploring the relationship between polygenic risk for cannabis use, peer cannabis use and the longitudinal course of cannabis involvement.
Few studies have explored how polygenic propensity to cannabis use unfolds across development, and no studies have yet examined this question in the context of environmental contributions such as peer cannabis use. Outlining the factors that contribute to progression from cannabis initiation to problem use over time may ultimately provide insights into mechanisms for targeted interventions. We sought to examine the relationships between polygenic liability for cannabis use, cannabis use trajectories from ages 12-30 years and perceived peer cannabis use at ages 12-17 years. Mixed-effect logistic and linear regressions were used to examine associations between polygenic risk scores, cannabis use trajectory membership and perceived peer cannabis use. United States. From the Collaborative Study on the Genetics of Alcoholism (COGA) study, a cohort of 1167 individuals aged 12-26 years at their baseline (i.e. first) interview. Key measurements included life-time cannabis use (yes/no), frequency of past 12-month cannabis use, maximum life-time frequency of cannabis use, cannabis use disorder (using DSM-5 criteria) and perceived peer cannabis use. Polygenic risk scores (PRS) were created using summary statistics from a large (n = 162 082) genome-wide association study (GWAS) of cannabis use. Three trajectories reflecting no/low (n = 844), moderate (n = 137) and high (n = 186) use were identified. PRS were significantly associated with trajectory membership [P = 0.002-0.006, maximum conditional R2 = 1.4%, odds ratios (ORs) = 1.40-1.49]. Individuals who reported that most/all of their best friends used cannabis had significantly higher PRS than those who reported that none of their friends were users [OR = 1.35, 95% confidence interval (CI) = 1.04, 1.75, P = 0.023]. Perceived peer use itself explained up to 11.3% of the variance in trajectory class membership (OR = 1.50-4.65). When peer cannabis use and the cannabis use PRS were entered into the model simultaneously, both the PRS and peer use continued to be significantly associated with class membership (P < 0.01). Genetic propensity to cannabis use derived from heterogeneous samples appears to correlate with longitudinal increases in cannabis use frequency in young adults.


Global spatial normalization of human brain using convex hulls.
Global spatial normalization transforms a brain image so that its principal global spatial features (position, orientation and dimensions) match those of a standard or atlas brain, supporting consistent analysis and referencing of brain locations. The convex hull (CH), derived from the brain's surface, was selected as the basis for automating and standardizing global spatial normalization. The accuracy and precision of CH global spatial normalization of PET and MR brain images were evaluated in normal human subjects. Software was developed to extract CHs of brain surfaces from tomographic brain images. Pelizzari's hat-to-head least-square-error surface-fitting method was modified to fit individual CHs (hats) to a template CH (head) and calculate a nine-parameter coordinate transformation to perform spatial normalization. A template CH was refined using MR images from 12 subjects to optimize global spatial feature conformance to the 1988 Talairach Atlas brain. The template was tested in 12 additional subjects. Three major performance characteristics were evaluated: (a) quality of spatial normalization with anatomical MR images, (b) optimal threshold for PET and (c) quality of spatial normalization for functional PET images. As a surface model of the human brain, the CH was shown to be highly consistent across subjects and imaging modalities. In MR images (n = 24), mean errors for anterior and posterior commissures generally were <1 mm, with SDs < 1.5 mm. Mean brain-dimension errors generally were <1.3 mm, and bounding limits were within 1-2 mm of the Talairach Atlas values. The optimal threshold for defining brain boundaries in both 18F-fluorodeoxyglucose (n = 8) and 15O-water (n = 12) PET images was 40% of the brain maximum value. The accuracy of global spatial normalization of PET images was shown to be similar to that of MR images. The global features of CH-spatially normalized brain images (position, orientation and size) were consistently transformed to match the Talairach Atlas in both MR and PET images. The CH method supports intermodality and intersubject global spatial normalization of tomographic brain images.


The maintenance of transferrin polymorphism in pigeons (saccharomyces cerevisiae-eggwhite).
Transferrin, a nonheme iron-binding protein, is polymorphic in most vertebrate species that have been examined. In pigeons, it is controlled by an autosomal gene, with two known codominant alleles, Tf(A) and Tf(B). The two alleles are found in nearly equal frequencies and the three genotypes are at Hardy-Weinberg equilibrium in all populations studied. This report shows that ovotransferrins from heterozygous females inhibit microbial growth, by use of yeast as an assay organism, better than ovotransferrins from either of the homozygous types, or those from a mixture of homozygous types. Heterozygous females hatch a larger percentage of their eggs than homozygous females. This difference is probably accounted for by the transferrin effect. The failure of the mixture of the homozygous types to act like the heterozygous type calls into question the currently accepted structure of transferrin as a monomeric protein. The greater fecundity of heterozygous females can account for the maintenance of transferrin polymorphism in pigeons.


Retinal potentials in patients with primary open-angle glaucoma: physiological evidence for temporal frequency tuning deficits.
The pattern-reversal retinal potential is a bio-electrical signal which can be recorded from the cornea of the human eye when a phase-alternating (contrast-reversing) pattern is viewed. The PRRP is correlated with activity of the retinal ganglion cells and visual diseases which affect the proximal retinal layers (such as optic atrophy and optic neuritis) and cause significant alterations in the waveform of the human PRRP. This study examined the PRRP in 32 patients with primary open-angle glaucoma (POAG) and 32 age-matched visual normals (AMVNs). Counterphasing (2, 4, 8 and 16 reversals/sec) checkerboard patterns (15', 30', 60', and 120' checks) were used as visual stimuli. PRRP amplitude was significantly reduced in patients with POAG. When temporal frequency was held constant, the magnitude of the observed PRRP amplitude reductions was identical for all check sizes. However, the magnitude of the observed amplitude reductions increased as temporal frequency increased. Therefore, in patients with POAG, the shape of the PRRP spatial tuning function was normal (although uniformly reduced for all check sizes), while the temporal tuning function was attenuated for high frequencies. Statistically significant increases in PRRP latency were also observed in the POAG patients, but these increases were quite small (mean = 3.6 ms).


COMPARATIVE ANALYSIS OF EFFECTIVENESS OF OBESITY TREATMENT IN PRIMARY CARE USING PATIENT-ORIENTED APPROACH WITH MOTIVATIONAL COUNSELING FOR LIFESTYLE CORRECTION AND ITS COMBINATION WITH ARMODAFINIL THERAPY IN PATIENTS WITH CONCOMITANT SHIFT WORK SLEEP DISORDER.
Aim: Conduct a comparative analysis of effectiveness of obesity treatment in primary care using patient-oriented approach with motivational counseling for lifestyle correction and its combination with armodafinil therapy in patients with concomitant shift work sleep disorder. Materials and Methods: 75 patients with obesity were studied, 38 patients had shift work disorder. Patients were divided into 2 groups: I (37 patients with obesity treated with motivational counseling) and II (38 patients with obesity and shift work disorder treated additionally with armodafinil 150 mg daily). The examination was at baseline, after 1st, 3th and 6th months. Statistical analysis was provided. Results: After 1 month of treatment, there were improvement of eating behavior, level of anxiety and depression, prognosis of diabetes development. At 3rd month, more pronounced changes were observed in 2nd group: 10% body weight loss, changes in eating behavior, sleep quality, anxiety level (p<0.05). After 6 months, examined indicators in both groups normalized, but dynamics in 2nd group was more significant; armodafinil-treated group had significantly better results in body weight loss, BMI, WC, HC, ConI, AVI, BPs, HOMA index, serotonin, leptin, levels of anxiety and depression, eating behavior, daytime dysfunction, level of sleepiness, quality of life and risk of developing diabetes. Conclusions: The use of armofafinil in addition to patientoriented motivational counseling in lifestyle correction ("5 As" and "5R") in patients with obesity connected with shift work disorder and excessive daytime sleepiness allows to reduce body weight by more than 16,52%, in contrast to isolated use of the same technique of motivational counseling in obese patients without sleep disorder (only 5,51%).


Circular RNAs: A novel type of biomarker and genetic tools in cancer.
Circular RNAs (circRNAs) are a novel type of universal and diverse endogenous noncoding RNAs (ncRNAs) and they form a covalently closed continuous loop without 5' or 3' tails unlike linear RNAs. Most circRNAs are presented with characteristics of abundance, stability, conservatism, and often exhibiting tissue/developmental-stage-specific expression. CircRNAs are generated either from exons or introns by back splicing or lariat introns. CircRNAs play important roles as miRNA sponges, gene transcription and expression regulators, RNA-binding protein (RBP) sponges and protein/peptide translators. Emerging evidence revealed the function of circRNAs in cancer and may potentially serve as a required novel biomarker and therapeutic target for cancer treatment. In this review, we discuss about the origins, characteristics and functions of circRNA and how they work as miRNA sponges, gene transcription and expression regulators, RBP sponges in cancer as well as current research methods of circRNAs, providing evidence for the significance of circRNAs in cancer diagnosis and clinical treatment.


Occult metoprolol overdose.
A patient with an apparent dilantin and phenobarbital overdose displayed hypotension and oliguria resistant to usual cardiotonic drugs and volume loading. In addition, she required an unusually high dose of epinephrine for resuscitation. Metoprolol, a beta-blocker not included on the drug screen, was subsequently implicated. An overdose of this drug should be suspected in patients whose hypotension is resistant to usually effective doses of inotropic and chronotropic agents.


A reproducible semi-automatic method to quantify the muscle-lipid distribution in clinical 3D CT images of the thigh.
Many studies use threshold-based techniques to assess in vivo the muscle, bone and adipose tissue distribution of the legs using computed tomography (CT) imaging. More advanced techniques divide the legs into subcutaneous adipose tissue (SAT), anatomical muscle (muscle tissue and adipocytes within the muscle border) and intra- and perimuscular adipose tissue. In addition, a so-called muscle density directly derived from the CT-values is often measured. We introduce a new integrated approach to quantify the muscle-lipid system (MLS) using quantitative CT in patients with sarcopenia or osteoporosis. The analysis targets the thigh as many CT studies of the hip do not include entire legs The framework consists of an anatomic coordinate system, allowing delineation of reproducible volumes of interest, a robust semi-automatic 3D segmentation of the fascia and a comprehensive method to quantify of the muscle and lipid distribution within the fascia. CT density-dependent features are calibrated using subject-specific internal CT values of the SAT and external CT values of an in scan calibration phantom. Robustness of the framework with respect to operator interaction, image noise and calibration was evaluated. Specifically, the impact of inter- and intra-operator reanalysis precision and addition of Gaussian noise to simulate lower radiation exposure on muscle and AT volumes, muscle density and 3D texture features quantifying MLS within the fascia, were analyzed. Existing data of 25 subjects (age: 75.6 ± 8.7) with porous and low-contrast muscle structures were included in the analysis. Intra- and inter-operator reanalysis precision errors were below 1% and mostly comparable to 1% of cohort variation of the corresponding features. Doubling the noise changed most 3D texture features by up to 15% of the cohort variation but did not affect density and volume measurements. The application of the novel technique is easy with acceptable processing time. It can thus be employed for a comprehensive quantification of the muscle-lipid system enabling radiomics approaches to musculoskeletal disorders.


Determinants of ligand binding specificity in the glial cell line-derived neurotrophic factor family receptor alpha S.
The glial cell line-derived neurotrophic factor (GDNF) family comprise a subclass of cystine-knot superfamily ligands that interact with a multisubunit receptor complex formed by the c-Ret tyrosine kinase and a cystine-rich glycosyl phosphatidylinositol-anchored binding subunit called GDNF family receptor alpha (GFRalpha). All four GDNF family ligands utilize c-Ret as a common signaling receptor, whereas specificity is conferred by differential binding to four distinct GFRalpha homologues. To understand how the different GFRalphas discriminate ligands, we have constructed a large set of chimeric and truncated receptors and analyzed their ligand binding and signaling capabilities. The major determinant of ligand binding was found in the most conserved region of the molecule, a central domain predicted to contain four conserved alpha helices and two beta strands. Distinct hydrophobic and positively charged residues in this central region were required for binding of GFRalpha1 to GDNF. Interaction of GFRalpha1 and GFRalpha2 with GDNF and neurturin required distinct subsegments within this central domain, which allowed the construction of chimeric receptors that responded equally well to both ligands. C-terminal segments adjacent to the central domain are necessary and have modulatory function in ligand binding. In contrast, the N-terminal domain was dispensable without compromising ligand binding specificity. Ligand-independent interaction with c-Ret also resides in the central domain of GFRalpha1, albeit within a distinct and smaller region than that required for ligand binding. Our results indicate that the central region of this class of receptors constitutes a novel binding domain for cystine-knot superfamily ligands.


Design, Implementation and Validation of a GNSS Measurement Exclusion and Weighting Function with a Dual Polarized Antenna.
Global Navigation Satellite Systems (GNSSs) have become a ubiquitous tool for our modern society to carry out vital tasks such as transportation, civil engineering or precision agriculture. This breath has reached the realm of safety-critical applications such as time management of critical infrastructures or autonomous vehicles, in which GNSS is an essential tool nowadays. Unfortunately, current GNSS performance is not enough to fulfill the requirements of these professional and critical applications. For this reason, the FANTASTIC project was launched to boost the adoption of these applications. The project was funded by the European GNSS agency (GSA) in order to enhance the robustness and accuracy of GNSS in harsh environments. This paper presents the part related to the development of a weighting and exclusion function with a dual circularly polarized antenna. The idea is to reduce the effects of multipath by weighting and/or excluding those measurements affected by multipath. The observables and other metrics obtained from a dual polarized antenna will be exploited to define an exclusion threshold and to provide the weights. Real-world experiments will show the improvement in the positioning solution, using all available constellations, obtained with the developed technique.


The Bacillus zanthoxyli HS1 Strain Renders Vegetable Plants Resistant and Tolerant against Pathogen Infection and High Salinity Stress.
Various management systems are being broadly employed to minimize crop yield loss resulting from abiotic and biotic stresses. Here we introduce a Bacillus zanthoxyli HS1 strain as a potent candidate for managing manifold stresses on vegetable plants. Considering 16S rDNA sequence and biochemical characteristics, the strain is closely related to B. zanthoxyli. The B. zanthoxyli HS1's soil-drench confers disease resistance on tomato and paprika plants against infection with Ralstonia solanacearum and Phytophthora capsici, respectively. Root and shoot growths are also increased in B. zanthoxyli HS1-treated cabbage, cucumber, and tomato plants, compared with those in mock-treated plants, after application of high salinity solution. Moreover, the pretreatment of B. zanthoxyli HS1 on cabbage plants inhibits the degradation of chloroplast pigments caused by high salinity stresses, whereas the inhibitory effect is not observed in cucumber plants. These findings suggest that B. zanthoxyli HS1 stain inhibits disease development and confers tolerance to salinity stress on vegetable plants.


Sexual harassment in the veterinary academic environment.
To survey faculty and house officers of clinical departments of colleges of veterinary medicine (CVM) to identify characteristics of sexual harassment (SH) in the veterinary academic environment, to report the opinions of survey respondents on how SH is being handled, and to determine how the process can be improved at veterinary academic institutions. On the basis of lists obtained from 25 CVM, a survey was mailed to 1,294 academic veterinarians. Four hundred seventy-eight completed surveys were returned. The prevalence of SH in the population of respondents was 31%. Nonphysical forms of SH were reported 6 times as often as physical forms of harassment, with the most common type reported being offensive sexual comments and unwanted attention. Fear of reprisal was the most prevalent reason cited by respondents for not confronting the harasser. Survey respondents rated the following as very important to improve the system of dealing with SH at their academic institution: guarantee of protection from retaliation, assurance of confidentiality, clear explanation of what will happen to you, and a clearer definition of SH. A clear definition of SH is the first step in preventing SH. Other cited steps include professional development programs to educate the academic population as to what constitutes SH, inform the entire academic population what the institution's SH policy is, and enforce this policy with sensitivity, fairness, confidentiality, and quick resolve to protect the victim.


Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration.
In this Phase I trial, patients' peripheral blood dendritic cells were pulsed with peptides eluted from the surface of autologous glioma cells. Three biweekly intradermal vaccinations of peptide-pulsed dendritic cells were administered to seven patients with glioblastoma multiforme and two patients with anaplastic astrocytoma. Dendritic cell vaccination elicited systemic cytotoxicity in four of seven tested patients. Robust intratumoral cytotoxic and memory T-cell infiltration was detected in two of four patients who underwent reoperation after vaccination. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous peptide-pulsed dendritic cell vaccine for patients with malignant glioma.


An integrated understanding of the complex drivers of emergency presentations and admissions in cancer patients: Qualitative modelling of secondary-care health professionals' experiences and views.
The number of cancer-related emergency presentations and admissions has been steadily increasing in the UK. Drivers of this phenomenon are complex, multifactorial and interlinked. The main objective of this study was to understand the complexity of emergency hospital use in cancer patients. We conducted semi-structured interviews with 42 senior clinicians (20 doctors, 22 nurses) with diverse expertise and experience in caring for acutely ill cancer patients in the secondary care setting. Data analysis included thematic analysis and purposive text analysis to develop Causal Loop Diagrams. Our Causal Loop Diagrams represent an integrated understanding of the complex factors (13) influencing emergency hospital use in cancer patients. Eight factors formed five reinforcing feedback loops and therefore were high-leverage influences: Ability of patients and carers to self-care and cope; Effective and timely management of ambulatory care sensitive conditions by primary and community care; Sufficient and effective social care for patients and carers; Avoidable emergency hospital use; Bed capacity; Patients accessing timely appropriate specialist inpatient or ambulatory care; Prompt and effective management and prevention of acute episode; Timely and safe discharge with appropriate support. The loops show that reduction of avoidable hospital use helps relieve hospital bed pressure; improved bed capacity then has a decisive, positive influence on patient pathway and thus outcome and experience in the hospital; in turn, better in-hospital care and discharge help patients and carers self-care and cope better back home with better support from community-based health and social care services, which then reduces their future emergency hospital use. To optimise acute and emergency cancer care, it is also essential that patients, carers and other clinicians caring for cancer patients have prompt access to senior cancer specialists for advice, assessment, clinical decision and other support. The findings provide a useful framework and focus for service planners aiming to optimise care.


Activation of p38 MAPK in the rostral ventromedial medulla by visceral noxious inputs transmitted via the dorsal columns may contribute to pelvic organ cross-sensitization in rats with endometriosis.
Whether visceral organ cross-sensitization is involved in endometriosis-associated pain remains elusive. Previous studies have shown that visceral noxious stimuli may trigger a cascade of signal transductions in the rostral ventromedial medulla (RVM) via the spinal dorsal column (DC) pathway and the RVM plays a critical role in the descending control of visceral nociception. In the current study, we hypothesized that the p38 mitogen-activated protein kinase (MAPK) activation in the RVM by noxious visceral inputs from ectopic growths via the DC was involved in the development of pelvic organ cross-sensitization in established endometriosis. A rat model of experimental endometriosis was established. To examine ectopic growths-to-colon cross-sensitization, graded colorectal distention (CRD) was performed and abdominal withdrawal reflex (AWR) scores were recorded in female rats at 8weeks after the uterine or fat (control) auto-transplantation. Western blot study was carried out to examine the phosphorylated form and the total level of p38 MAPK protein in the RVM. Our results showed that lesions of bilateral DCs immediately following uterine or fat auto-transplantation in female rats significantly attenuated the later development of ectopic growths-to-colon cross-sensitization and the increased p38 MAPK activation in the RVM, as compared to sham DC lesions. Furthermore, intra-RVM microinjection of a p38 MAPK inhibitor (SB 203580), but not vehicle, in female rats with established endometriosis significantly attenuated ectopic growths-to-colon cross-sensitization and the increased activation of p38 MAPK in the RVM. These findings suggest that the noxious inputs from ectopic growths may activate p38 MAPK in the RVM via the DC, which may contribute to the development of ectopic growths-to-colon cross-sensitization in established endometriosis.


Plastid 16S rRNA gene diversity among eukaryotic picophytoplankton sorted by flow cytometry from the South Pacific Ocean.
The genetic diversity of photosynthetic picoeukaryotes was investigated in the South East Pacific Ocean. Genetic libraries of the plastid 16S rRNA gene were constructed on picoeukaryote populations sorted by flow cytometry, using two different primer sets, OXY107F/OXY1313R commonly used to amplify oxygenic organisms, and PLA491F/OXY1313R, biased towards plastids of marine algae. Surprisingly, the two sets revealed quite different photosynthetic picoeukaryote diversity patterns, which were moreover different from what we previously reported using the 18S rRNA nuclear gene as a marker. The first 16S primer set revealed many sequences related to Pelagophyceae and Dictyochophyceae, the second 16S primer set was heavily biased toward Prymnesiophyceae, while 18S sequences were dominated by Prasinophyceae, Chrysophyceae and Haptophyta. Primer mismatches with major algal lineages is probably one reason behind this discrepancy. However, other reasons, such as DNA accessibility or gene copy numbers, may be also critical. Based on plastid 16S rRNA gene sequences, the structure of photosynthetic picoeukaryotes varied along the BIOSOPE transect vertically and horizontally. In oligotrophic regions, Pelagophyceae, Chrysophyceae, and Prymnesiophyceae dominated. Pelagophyceae were prevalent at the DCM depth and Chrysophyceae at the surface. In mesotrophic regions Pelagophyceae were still important but Chlorophyta contribution increased. Phylogenetic analysis revealed a new clade of Prasinophyceae (clade 16S-IX), which seems to be restricted to hyper-oligotrophic stations. Our data suggest that a single gene marker, even as widely used as 18S rRNA, provides a biased view of eukaryotic communities and that the use of several markers is necessary to obtain a complete image.


Nonstationary harmonic modeling for ECG removal in surface EMG signals.
We present a compact approach for mitigating the presence of electrocardiograms (ECG) in surface electromyographic (EMG) signals by means of time-variant harmonic modeling of the cardiac artifact. Heart rate and QRS complex variability, which often account for amplitude and frequency time variations of the ECG, are simultaneously captured by a set of third-order constant-coefficient polynomials modulating a stationary harmonic basis in the analysis window. Such a characterization allows us to significantly suppress ECG from the mixture by preserving most of the EMG signal content at low frequencies (less than 20 Hz). Moreover, the resulting model is linear in parameters and the least-squares solution to the corresponding linear system of equations efficiently provides model parameter estimates. The comparative results suggest that the proposed method outperforms two reference methods in terms of the EMG preservation at low frequencies.


Missing Linkers: An Alternative Pathway to UiO-66 Electronic Structure Engineering.
UiO-66 is a promising metal-organic framework for photocatalytic applications. However, the ligand-to-metal charge transfer of an excited electron is inefficient in the pristine material. Herein, we assess the influence of missing linker defects on the electronic structure of UiO-66 and discuss their ability to improve ligand-to-metal charge transfer. Using a new defect classification system, which is transparent and easily extendable, we identify the most promising photocatalysts by considering both relative stability and electronic structure. We find that the properties of UiO-66 defect structures largely depend on the coordination of the constituent nodes and that the nodes with the strongest local distortions alter the electronic structure most. Defects hence provide an alternative pathway to tune UiO-66 for photocatalytic purposes, besides linker modification and node metal substitution. In addition, the decomposition of MOF properties into node- and linker-based behavior is more generally valid, so we propose orthogonal electronic structure tuning as a paradigm in MOF design.


The effect of selected food phytochemicals on breast cancer metastasis based on in vivo capture of circulating tumor cells.
The number of circulating tumor cells (CTCs) in a mouse tumor model fed with different dietary factors was first evaluated by in vivo CTC capture at different time points of cancer progression. The results showed that the number of CTCs reflected the degree of cancer progression. A new assessment method of dietary factor effects on cancer metastasis was established.