Case report: A successful re-challenge report of GLS-010 (Zimberelimab), a novel fully humanized mAb to PD-1, in a case of recurrent endometrial cancer.
With the widespread use of immune checkpoint inhibitors (ICI), there is growing concern about reports of immune-related adverse events (irAE). In clinical practice, patients who experience severe toxicities by ICI-based therapies would require utmost caution in resuming ICI therapy because of the potential risk of serious irAEs caused by the reintroduction of immunotherapy. In this study, we report a case of recurrent endometrial cancer patient with PD-L1 positive as well as dMMR suffering from immunotherapy-associated myocarditis after first-line treatment with ICI combined with a multi-targeted anti-angiogenic agent. After symptomatic treatment, the patient was in complete remission from treatment toxicities. Subsequently, through MDT discussions, we selected a new PD-1 agent, zimberelimab, for rechallenge therapy, and the patient achieved a sustained disease remission without any treatment-related toxicities. To date, the manner and timing of the ICI re-challenge has been a subject of iterative deliberation. We believe that our experience could shed some light on ICI rechallenge therapy, and we look forward to more literatures to refine the ICI rechallenge scenarios.


Neonicotinoid-induced pathogen susceptibility is mitigated by Lactobacillus plantarum immune stimulation in a Drosophila melanogaster model.
Pesticides are used extensively in food production to maximize crop yields. However, neonicotinoid insecticides exert unintentional toxicity to honey bees (Apis mellifera) that may partially be associated with massive population declines referred to as colony collapse disorder. We hypothesized that imidacloprid (common neonicotinoid; IMI) exposure would make Drosophila melanogaster (an insect model for the honey bee) more susceptible to bacterial pathogens, heat stress, and intestinal dysbiosis. Our results suggested that the immune deficiency (Imd) pathway is necessary for D. melanogaster survival in response to IMI toxicity. IMI exposure induced alterations in the host-microbiota as noted by increased indigenous Acetobacter and Lactobacillus spp. Furthermore, sub-lethal exposure to IMI resulted in decreased D. melanogaster survival when simultaneously exposed to bacterial infection and heat stress (37 °C). This coincided with exacerbated increases in TotA and Dpt (Imd downstream pro-survival and antimicrobial genes, respectively) expression compared to controls. Supplementation of IMI-exposed D. melanogaster with Lactobacillus plantarum ATCC 14917 mitigated survival deficits following Serratia marcescens (bacterial pathogen) septic infection. These findings support the insidious toxicity of neonicotinoid pesticides and potential for probiotic lactobacilli to reduce IMI-induced susceptibility to infection.


Dissimilatory arsenate reduction by a facultative anaerobe, Bacillus sp. strain SF-1.
Bacillus sp. strain SF-1, isolated first as a selenate-reducing bacterium, was characterized as a novel arsenate-reducing bacterium. Strain SF-1 rapidly reduced 10 mM levels of arsenate to arsenite with concomitant cell growth and lactate oxidation under anoxic conditions, indicating that arsenate can act as the terminal electron acceptor for anaerobic respiration (dissimilatory arsenate reduction). Strain SF-1 can use various organic compounds including synthetic sewage mainly composed of peptone and meat extract as the electron donors for arsenate reduction. Although strain SF-1 can grow aerobically, which is very rare for dissimilatory arsenate-reducing bacteria, the presence of oxygen inhibited the arsenate reduction. On the other hand, the presence of nitrate or selenate, which can support the growth of strain SF-1 as electron acceptors, did not significantly inhibit the arsenate reduction. Arsenate-reducing activity, that is, arsenate reductase, was exhibited in strain SF-1 only when grown on arsenate, but the enzyme could not reduce other oxyanions including nitrate and selenate. It was presumed that arsenate reduction was carried out by an enzyme system separate from those of nitrate and selenate reduction, and the arsenate reductase was inducible and specific for arsenate. These results suggest that strain SF-1 may be utilized for extracting arsenic from contaminated soil for the purpose of bioremediation.


Magnetic Structure of SmCo5 from 5 K to the Curie Temperature.
The crystal and magnetic structure of SmCo5 is determined by neutron powder diffraction between 5 K and the Curie temperature. In order to overcome the enormous neutron absorption of samarium, a 154Sm isotopically enriched sample was used. The ordered magnetic moments of both crystallographically distinct cobalt atoms are not significantly different over the whole temperature range. They decrease from 2.2 μB at 5 K to about 0.6 μB at 1029 K. Samarium's ordered magnetic moment decreases from 1.0 μB at 5 K, runs through a minimum of 0.2 μB around 650 K, and becomes larger than cobalt's ordered magnetic moment above 950 K. No sign or orientation change of the samarium and cobalt ordered magnetic moments is found between the Curie temperature and 5 K. SmCo5 is thus a ferromagnet and does not switch to a ferrimagnetic state as discussed in the literature.


Metastatic retroperitoneal renal cell carcinoma. A case for more aggressive approach. Risk and results.
Our point of view in selected cases of bulky renal neoplastic disease was shown. A 43-year-old white man was referred for large disseminated retroperitoneal mass after right radical nephrectomy and hilar lymphadenectomy for locally advanced PT3 N3 M0 G3 renal cell carcinoma followed by interleukin-2 based immunotherapy. We attempted aggressive resection of visible disease with curative intent. Complete resection was technically very difficult with intraoperative bleeding representing the major risk. Accidental injuries of aortic wall and vena cava were repaired. A partial incision of the right external iliac vein was performed. Complete removal of the large adenopathy masses was obtained. At 9 month follow-up the patient was free of disease. In conclusion, aggressive surgical approach with complete resection of disseminated retroperitoneal renal cell carcinoma may prolong disease-free survival.


Non-traumatic keratitis due to Colletotrichum truncatum.
The fungal genus Colletotrichum is an uncommon cause of human infections. It has been implicated in cutaneous phaeohyphomycosis, artritis and keratitis secondary to traumatic implantation. We report two cases of keratitis due Colletotrichum truncatum in middle-aged, immunocompetent persons without history of trauma. The aetiological agents were identified based on DNA sequencing. Azoles and echinocandins showed high minimal inhibitory concentrations while amphotericin B was ≤ 0.25 mg l-1. Both patients failed topical antifungal treatment and needed penetrating keratoplasty with a favourable outcome. C. truncatum caused keratomycosis which did not respond to topical antifungal agents. To the best of our knowledge these are the first reported cases of keratitis due to this fungus in Cuba and Latin-America and highlights the expanding spectrum of fungal agents causing eye infections.


The influence of action effects in task-switching.
According to ideomotor theories, intended effects caused by a certain action are anticipated before action execution. In the present study, we examined the question of whether action effects play a role in cued task-switching. In our study, the participants practiced task-response-effect mappings in an acquisition phase, in which action effects occur after a response in a certain task context. In the ensuing transfer phase, the previously practiced mappings were changed in a random, unpredictable task-response-effect mapping. When changed into unpredictable action-effects, RT as well as switch-costs increased, but this occurred mainly in trials with short preparation time and not with long preparation time. Moreover, switch costs were generally smaller with predictable action-effects than with unpredictable action-effects. This suggests that anticipated task-specific action effects help to activate the relevant task-set before task execution when the task is not yet already prepared based on the cue.


Block the function of nonmuscle myosin II by blebbistatin induces zebrafish embryo cardia bifida.
Nonmuscle myosin II (NM II) is the name given to the multi-subunit protein product of three genes encoding different nonmuscle myosin heavy chains including NM II-A, NM II-B, and NM II-C. Blebbistatin is a small molecule that has been shown to be a relatively specific inhibitor of NM II. Blocking the function of NM II by blebbistatin induces zebrafish embryo cardia bifida at a dose-dependent manner. In situ hybridization analysis with ventricular marker ventricular myosin heavy chain (vmhc) and atrial marker atrial myosin heavy chain (amhc) showed each of the heart contained both distinct atria and ventricle. However, the cardia bifida embryos had highly variable distance between two separate ventricles. We also provided evidence that time window from 12 to 20 h post fertilization (hpf) is necessary and sufficient for cardia bifida formation caused by blebbistatin treatment. Expression of spinster homolog 2 (spns2) was decreased in blebbistatin-treated embryos, suggesting the cardia bifida phenotype caused by NM II inhibition was relevant to precardiac mesoderm migration defects. Through in situ hybridization analysis, we showed that foxa1 was expressed in endoderm of blebbistatin-treated embryos at 24-hpf stage, suggesting the endoderm formation is normal in cardia bifida embryos caused by blebbistatin treatment. In addition, we demonstrated that blebbistatin treatment resulted in morphology alteration of zebrafish cardiomyocytes in vivo and neonatal mouse cardiomyocytes in vitro.


Comparison of Outcomes of Frontline Immunosuppressive Therapy and Frontline Haploidentical Hematopoietic Stem Cell Transplantation for Children with Severe Aplastic Anemia Who Lack an HLA-Matched Sibling Donor.
We compared the outcomes of immunosuppressive therapy (IST) with those of T cell-replete haploidentical donor hematopoietic stem cell transplantation (haplo-HSCT) in children and adolescents with severe aplastic anemia (SAA). The medical records of 49 patients with SAA who received frontline IST (n = 29) or frontline haplo-HSCT (n = 20) between 2012 and 2016 were analyzed retrospectively. Fourteen patients responded after the first IST, and 1 patient responded after the second IST in the frontline IST group; 12 patients underwent salvage HSCT after IST failure. Sixteen of the 20 patients who underwent frontline haplo-HSCT survived without treatment failure. The 3-year overall survival of the frontline IST group was comparable to that of the frontline haplo-HSCT group (79.3 ± 7.5% versus 85.0 ± 8.0%; χ2 = 0.110; P = .740). The 3-year failure-free survival was lower in the frontline IST group compared with the frontline haplo-HSCT group (35.9 ± 10.9% versus 80.0 ± 8.9%; χ2 = 4.089; P = .043). Five patients of the IST group who underwent salvage HSCT achieved long survival without event. The event-free survival was lower in the salvage HSCT group compared with the haplo-HSCT group (41.7 ± 14.2% versus 80.0 ± 8.9%; χ2 = 3.992; P = .046), and the incidences of acute GVHD, grade II-IV acute GVHD, chronic GVHD, and severe infection were comparable between the 2 groups. Our results suggest that frontline haplo-HSCT may be a better treatment than IST for children and adolescents with SAA who lack an HLA age-matched familial donor.


Tooth discolouration and internal bleaching after the use of triple antibiotic paste.
To assess the discolouration of teeth with closed and open apices after placement of triple antibiotic paste (TAP, ciprofloxacin, metronidazole and minocycline) in the pulp chamber and whether discolouration could be reversed by internal bleaching procedures. Twenty extracted human mandibular premolars were divided into 2 groups (n = 10): teeth with closed apices (CA) and teeth with open apices (OA). After conventional access, the TAP was sealed in the pulp chamber for 3 weeks. The paste was removed by a rinse with sodium hypochlorite (NaOCl) and a mixture of sodium perborate and distilled water was sealed in the pulp chamber for 1, 2 and 3 weeks. The shade was measured by a spectrophotometer at six time periods: baseline (T0), after 3 weeks of placement of TAP (T1), after removal of TAP with a NaOCl rinse (T2) and after 1 (T3), 2 (T4) and 3 (T5) weeks of internal bleaching with sodium perborate paste. Data were collected based on the CIELAB-CIE1976 (L*a*b*) system and analysed using t-tests and anova. A significant decrease in the mean values of L* (lightness) was observed after treatment with TAP (T1, P < 0.05). Considerable increases in these values after bleaching with sodium perborate (T3 < T4 < T5) were found in both groups. The only significant difference in the intergroup analysis was between T1 and T2, in which ΔE values in the OA group were higher (P = 0.04). TAP discoloured the tooth structure, but discolouration could be reversed with sodium perborate paste. In general, teeth with closed and open apices had the same rates of discolouration and bleaching.


Nuclear loss and cytoplasmic expression of androgen receptor in penile carcinomas: role as a driver event and as a prognosis factor.
Androgen receptor (AR) is a member of the steroid and nuclear family receptor that acts as transcription factor. AR signaling plays pivotal role in the development and progression of prostate cancer. However, the role of AR in penile cancer (PeCa) is poorly explored. Our previous molecular studies unveiled frequent AR mRNA loss in PeCa, which was further predicted as a major driver alteration in this neoplasm. Herein, we assessed the AR protein expression in 59 usual PeCa tissues and 42 surrounding normal tissues (SNT) by immunohistochemistry using a tissue microarray. In a paired analysis, we found a total absence of nuclear AR expression in PeCa while 95.2% of SNT samples presented strong nuclear AR expression (P < 0.001). Interestingly, 17 of 42 PeCa presented weak or moderate cytoplasmic AR staining, contrasting with 5 of 42 SNT (P = 0.008). Increased levels of AR cytoplasmic expression were related with poor prognosis features including advanced clinical staging (P = 0.044), compromised surgical margins (P = 0.005), and pathological inguinal node status (P = 0.047). Furthermore, AR cytoplasmic expression was also related with shorter overall survival (P = 0.032). In conclusion, the frequent loss of nuclear AR protein levels suggests a potential function in PeCa development. Based on this result, the androgen deprivation therapy is not indicated for PeCa patients. In addition, the AR cytoplasmic expression found in a significant number of cases (40.5%) showed prognostic value and pathways activated by the non-genomic AR signaling may represent a promising therapeutic strategy.


Knowledge Development Trajectory of the Internet of Vehicles Domain Based on Main Path Analysis.
The Internet of vehicles (IoV) is an Internet-of-things-based network in the area of transportation. It comprises sensors, network communication, automation control, and data processing and enables connectivity between vehicles and other objects. This study performed main path analysis (MPA) to investigate the trajectory of research regarding the IoV. Studies were extracted from the Web of Science database, and citation networks among these studies were generated. MPA revealed that research in this field has mainly covered media access control, vehicle-to-vehicle channels, device-to-device communications, layers, non-orthogonal multiple access, and sixth-generation communications. Cluster analysis and data mining revealed that the main research topics related to the IoV included wireless channels, communication protocols, vehicular ad hoc networks, security and privacy, resource allocation and optimization, autonomous cruise control, deep learning, and edge computing. By using data mining and statistical analysis, we identified emerging research topics related to the IoV, namely blockchains, deep learning, edge computing, cloud computing, vehicular dynamics, and fifth- and sixth-generation mobile communications. These topics are likely to help drive innovation and the further development of IoV technologies and contribute to smart transportation, smart cities, and other applications. On the basis of the present results, this paper offers several predictions regarding the future of research regarding the IoV.


Seminoma in a koi carp Cyprinus carpio: histopathological and immunohistochemical findings.
A spontaneous seminoma in a 3 yr old male koi carp Cyprinus carpio L. is described. The animal, presenting a symmetric abdominal enlargement, showed a celomatic multinodular, white-yellowish and firm mass that infiltrated the liver and the intestine wall. Histologically, the neoplasm was non-encapsulated and poorly demarcated, showed invasive growth and was characterized by a lobular architecture, subdivided by abundant fibro-connective septa. Large necrotic and calcified areas together with small aggregates of residual spermatids were present. We diagnosed a classical seminoma with a diffuse pattern. Neoplastic cells cross-reacted with vimentin, placental alkaline phosphatase, and c-KIT. An immunohistochemical phenotypization of the tumor was performed to exclude other celomatic neoplasms and to compare this seminoma with those reported in mammals and humans.


Identifying Protein Complexes From Protein-Protein Interaction Networks Based on Fuzzy Clustering and GO Semantic Information.
Protein complexes are of great significance to provide valuable insights into the mechanisms of biological processes of proteins. A variety of computational algorithms have thus been proposed to identify protein complexes in a protein-protein interaction network. However, few of them can perform their tasks by taking into account both network topology and protein attribute information in a unified fuzzy-based clustering framework. Since proteins in the same complex are similar in terms of their attribute information and the consideration of fuzzy clustering can also make it possible for us to identify overlapping complexes, we target to propose such a novel fuzzy-based clustering framework, namely FCAN-PCI, for an improved identification accuracy. To do so, the semantic similarity between the attribute information of proteins is calculated and we then integrate it into a well-established fuzzy clustering model together with the network topology. After that, a momentum method is adopted to accelerate the clustering procedure. FCAN-PCI finally applies a heuristical search strategy to identify overlapping protein complexes. A series of extensive experiments have been conducted to evaluate the performance of FCAN-PCI by comparing it with state-of-the-art identification algorithms and the results demonstrate the promising performance of FCAN-PCI.


Ricin crosses polarized human intestinal cells and intestines of ricin-gavaged mice without evident damage and then disseminates to mouse kidneys.
Ricin is a potent toxin found in the beans of Ricinus communis and is often lethal for animals and humans when aerosolized or injected and causes significant morbidity and occasional death when ingested. Ricin has been proposed as a bioweapon because of its lethal properties, environmental stability, and accessibility. In oral intoxication, the process by which the toxin transits across intestinal mucosa is not completely understood. To address this question, we assessed the impact of ricin on the gastrointestinal tract and organs of mice after dissemination of toxin from the gut. We first showed that ricin adhered in a specific pattern to human small bowel intestinal sections, the site within the mouse gut in which a variable degree of damage has been reported by others. We then monitored the movement of ricin across polarized human HCT-8 intestinal monolayers grown in transwell inserts and in HCT-8 cell organoids. We observed that, in both systems, ricin trafficked through the cells without apparent damage until 24 hours post intoxication. We delivered a lethal dose of purified fluorescently-labeled ricin to mice by oral gavage and followed transit of the toxin from the gastrointestinal tracts to the internal organs by in vivo imaging of whole animals over time and ex vivo imaging of organs at various time points. In addition, we harvested organs from unlabeled ricin-gavaged mice and assessed them for the presence of ricin and for histological damage. Finally, we compared serum chemistry values from buffer-treated versus ricin-intoxicated animals. We conclude that ricin transverses human intestinal cells and mouse intestinal cells in situ prior to any indication of enterocyte damage and that ricin rapidly reaches the kidneys of intoxicated mice. We also propose that mice intoxicated orally with ricin likely die from distributive shock.


Rapid inactivation determines the rectification and [K+]o dependence of the rapid component of the delayed rectifier K+ current in cardiac cells.
Two characteristic features of the rapid component of the cardiac delayed rectifier current (IKr) are prominent inward rectification and an unexpected reduction in activating current with decreased [K+]o. Similar features are observed with heterologous expression of HERG, the gene thought to encode the channel carrying IKr, moreover, recent studies indicate that the mechanism underlying rectification of HERG current is the inactivation that channels rapidly undergo during depolarizing pulses. The present studies were designed to determine the mechanism of IKr rectification and [K+]o sensitivity in the mouse atrial myocyte cell line, AT-1 cells. Reducing [Mg2+]i to 0, which reverses inward rectification of some K+ channels, did not alter IKr current-voltage relationships, although it did decrease sensitivity to the IKr blockers dofetilide and quinidine 2- to 5-fold. To determine the presence and extent of fast inactivation of IKr in AT-1 cells, a brief hyperpolarizing pulse (20 ms to -120 mV) was applied during long depolarizations. Immediately after this pulse, a very large outward current that decayed rapidly to the previous activating current baseline was observed. This outward current component was blocked by the IKr-specific inhibitor dofetilide, indicating that it represented recovery from fast inactivation during the hyperpolarizing step, with fast reinactivation during the return to depolarized potential. With removal of inactivation using this approach, current-voltage relationships for IKr ([K+]o, 1 to 20 mmol/L) were linar and reversed close to the predicted Nernst potential for K+. In addition, decreased [K+]o decreased the time constants for open-->inactivated and inactivated-->open transitions. Thus, in these cardiac myocytes, as with heterologously expressed HERG, IKr undergoes fast inactivation that determines its characteristic inward rectification. These studies demonstrate that the mechanism underlying decreased activating current observed at low [K+]o is more extensive fast inactivation.


Mutations within A 35 amino acid region of P6 influence self-association, inclusion body formation, and Caulimovirus infectivity.
Cauliflower mosaic virus gene VI product (P6) is an essential protein that forms cytoplasmic, inclusion bodies (IBs). P6 contains four regions involved in self-association, termed D1-D4. D3 binds to D1, along with D4 and contains a spacer region (termed D3b) between two RNA-binding domains. Here we show D3b binds full-length P6 along with D1 and D4. Full-length P6s harboring single amino acid substitutions within D3b showed reduced binding to both D1 and D4. Full-length P6s containing D3b mutations and fused with green fluorescent protein formed inclusion-like bodies (IL-Bs) when expressed in Nicotiana benthamiana leaves. However, mutant P6s with reduced binding to D1 and D4, showed smaller IL-Bs, than wild type. Likewise, viruses containing these mutations showed a decrease in inoculated leaf viral DNA levels and reduced efficiency of systemic infection. These data suggest that mutations influencing P6 self-association alter IB formation and reduce virus infection.


Exploring Orthographic Representation in Chinese Handwriting: A Mega-Study Based on a Pedagogical Corpus of CFL Learners.
Writing and reading are closely related and are thus likely to have a common orthographic representation. A fundamental question in the literature on the production of written Chinese characters concerns the structure of orthographic representations. We report on a Chinese character handwriting pedagogical corpus involving a class of 22 persons, 232 composite character types, 1,913 tokens, and 13,057 stroke records, together with the inter-stroke interval (ISI), which reflects the parallel processing of multilevel orthographic representation during the writing execution, and 50 orthographic variables from the whole character, logographeme, and stroke. The results of regression analyses show that orthographic representation has a hierarchy and that different representational levels are active simultaneously. In the multilevel structure of orthographic representation, the representation of the logographeme is absolutely dominant. Writing and reading have both commonalities and individual differences in their orthographic representations. The online processing of the logographeme unit probably occurs at the ISI before the initial stroke of the current logographeme, which may also cascade to the first subsequent logographeme. In addition, we propose a new effective character structure unit for describing orthographic complexity.


Insulin and C-peptide in human brain neurons (insulin/C-peptide/brain peptides/immunohistochemistry/radioimmunoassay).
The regional distribution and cellular localization of insulin and C-peptide immunoreactivities were studied in human cadaver brains using the indirect immunofluorescence method, the peroxidase-antiperoxidase technique, and radioimmunoassay. Products of the immune reactions to both polypeptides were observed in most nerve cells in all areas of the brain examined. Immunostaining was mainly restricted to the cell soma and proximal dendrites. Radioimmunoassay revealed that human brain contains insulin and C-peptide in concentrations much higher than the blood, the highest being in the hypothalamus. These findings support the hypothesis that the "brain insulin" is--at least in part--produced in the CNS.


Serum Glial Fibrillary Acidic Protein: A Neuromyelitis Optica Spectrum Disorder Biomarker.
Blood tests to monitor disease activity, attack severity, or treatment impact in neuromyelitis optica spectrum disorder (NMOSD) have not been developed. This study investigated the relationship between serum glial fibrillary acidic protein (sGFAP) concentration and NMOSD activity and assessed the impact of inebilizumab treatment. N-MOmentum was a prospective, multicenter, double-blind, placebo-controlled, randomized clinical trial in adults with NMOSD. sGFAP levels were measured by single-molecule arrays (SIMOA) in 1,260 serial and attack-related samples from 215 N-MOmentum participants (92% aquaporin 4-immunoglobulin G-seropositive) and in control samples (from healthy donors and patients with relapsing-remitting multiple sclerosis). At baseline, 62 participants (29%) exhibited high sGFAP concentrations (≥170 pg/ml; ≥2 standard deviations above healthy donor mean concentration) and were more likely to experience an adjudicated attack than participants with lower baseline concentrations (hazard ratio [95% confidence interval], 3.09 [1.6-6.1], p = 0.001). Median (interquartile range [IQR]) concentrations increased within 1 week of an attack (baseline: 168.4, IQR = 128.9-449.7 pg/ml; attack: 2,160.1, IQR = 302.7-9,455.0 pg/ml, p = 0.0015) and correlated with attack severity (median fold change from baseline [FC], minor attacks: 1.06, IQR = 0.9-7.4; major attacks: 34.32, IQR = 8.7-107.5, p = 0.023). This attack-related increase in sGFAP occurred primarily in placebo-treated participants (FC: 20.2, IQR = 4.4-98.3, p = 0.001) and was not observed in inebilizumab-treated participants (FC: 1.1, IQR = 0.8-24.6, p > 0.05). Five participants (28%) with elevated baseline sGFAP reported neurological symptoms leading to nonadjudicated attack assessments. Serum GFAP may serve as a biomarker of NMOSD activity, attack risk, and treatment effects. ANN NEUROL 2021;89:895-910.


Influence of Reduced Graphene Oxide on Effective Absorption Bandwidth Shift of Hybrid Absorbers.
The magnetic nanoparticle composite NiFe2O4 has traditionally been studied for high-frequency microwave absorption with marginal performance towards low-frequency radar bands (particularly L and S bands). Here, NiFe2O4 nanoparticles and nanohybrids using large-diameter graphene oxide (GO) sheets are prepared via solvothermal synthesis for low-frequency wide bandwidth shielding (L and S radar bands). The synthesized materials were characterized using XRD, SEM, FTIR and microwave magneto dielectric spectroscopy. The dimension of these solvothermally synthesized pristine particles and hybrids lies within 30-58 nm. Microwave magneto-dielectric spectroscopy was performed in the low-frequency region in the 1 MHz-3 GHz spectrum. The as-synthesized pristine nanoparticles and hybrids were found to be highly absorbing for microwaves throughout the L and S radar bands (< -10 dB from 1 MHz to 3 GHz). This excellent microwave absorbing property induced by graphene sheet coupling shows application of these materials with absorption bandwidth which is tailored such that these could be used for low frequency. Previously, these were used for high frequency absorptions (typically > 4 GHz) with limited selective bandwidth.


Group therapy with parolees in a community mental health center.
Seeing parolees, who were reluctantly seeking mental health services, in individual therapy was unsatisfactory. Although there were identifiable mental health reasons for their referral, they did not recognize a need for individual therapy. In addition, as the therapist, I felt frustrated, and I lacked empathy. Recognizing a problem, I utilized the nursing process: assessment, planning, implementation, and evaluation, to solve the problem and provide better nursing therapy. A modified self-help group provided support to the parolees to resolve their disequilibrium, to enhance their self-esteem, to teach them to structure their own time and to satisfy the requirements of their paroles. This therapist, as well as the group members and cotherapist, gained personally from the group experience. I developed an awareness of the parolees disequilibrium and I broadened my capacity for empathy.


[Pathophysiology of heat illness].
Human core temperature is strictly controlled by mechanism of radiation, conduction, convection, and evaporation from skin surface. Serial hot and humid climate induces dehydration which interferes heat pump-out from the body. Heart dysfunction is the third factor to rise body temperature. Hyperthermia and hypo-perfusion caused by dehydration and heart failure deteriorate specific organ functions, i.e. central nervous system, liver and renal functions and coagulation system. Disseminated intravascular coagulopathy is one of the standard indicators of severity and mortality of heat stroke.


Protein secondary structure from circular dichroism spectroscopy. Combining variable selection principle and cluster analysis with neural network, ridge regression and self-consistent methods.
Different approaches to improve the analysis of protein secondary structure from circular dichroism spectra are compared. Grouping proteins based on the similarity of their circular dichroism spectra, using cluster analysis methods, was utilized as a new way of implementing variable selection. The performance of three basic methods (neural networks, ridge regression and singular value decomposition) was evaluated in combination with three approaches to improve the predictions; namely, variable selection, cluster analysis and the self-consistent method. Cluster analysis performed on the basis set proteins resulted in three clusters, subanalyses of which provide a new way of performing variable selection. The neural network with two hidden layers performed better than that with one hidden layer and was combined with variable selection. Inclusion of the variable selection principle improved the performance of all three basic methods. While the neural network method performed slightly better than the other two methods at the basic level, the inclusion of variable selection led to similar performance indices for all three methods.


Transforming growth factor-beta induces expression of vascular endothelial growth factor in human retinal pigment epithelial cells: involvement of mitogen-activated protein kinases.
Vascular endothelial growth factor (VEGF) is a major agent in choroidal and retinal neovascularization, events associated with age-related macular degeneration (AMD) and diabetic retinopathy. Retinal pigment epithelium (RPE), strategically located between retina and choroid, plays a critical role in retinal disorders. We have examined the effects of various growth factors on the expression and secretion of VEGF by human retinal pigment epithelial cell cultures (HRPE). RT-PCR analyses revealed the presence of three isoforms of mRNA corresponding to VEGF 121, 165, and 189 that were up regulated by TGF-beta1. TGF-beta1, beta2, and beta3 were the potent inducers of VEGF secretion by HRPE cells whereas bFGF, PDGF, TGF-alpha, and GM-CSF had no effects. TGF-beta receptor type II antibody significantly reversed induction of VEGF secretion by TGF-beta. In contrast activin, inhibin and BMP, members of TGF-beta super family, had no effects on VEGF expression in HRPE. VEGF mRNA levels and protein secretion induced by TGF-beta were significantly inhibited by SB203580 and U0126, inhibitors of MAP kinases, but not by staurosporine and PDTC, protein kinase C and NF-kappaB pathway inhibitors, respectively. TGF-beta also induced VEGF expression by fibroblasts derived from human choroid of eye. TGF-beta induction of VEGF secretion by RPE and choroid cells may play a significant role in choroidal neovascularization (CNV) in AMD. Since the secretion of VEGF by HRPE is regulated by MAP kinase pathways, MAP kinase inhibitors may have potential use as therapeutic agents for CNV in AMD.


Impacts of albumin synergized with hydroxyethyl starch on early microvascular albumin leakage after major abdominal surgery in rabbits.
To investigate the impacts of albumin synergized with hydroxyethyl starch (HES) on early microvascular albumin leakage after major abdominal surgery in rabbits. Forty male Japanese rabbits were randomly divided into four groups: the control group, the saline group, the albumin group, and the Syn group (hydroxyethyl starch+albumin). The latter three groups were performed gastrectomy plus resection of pancreatic body and tail and splenectomy. The serum albumin concentration was detected before and 48h after surgery, and the conditions of mesenteric microvascular leakage in these 4 groups were observed under microscope 48 h after surgery to calculate the leakage rate. Compared with the saline group, the albumin group and the Syn group exhibited significantly increased serum albumin concentrations 48h after surgery (P<0.05). The albumin leakage rate was the most obvious in the albumin group, followed by the saline group, while that in the Syn group was the minimal, and there existed significant differences among these groups (P<0.05) . Simple administration of albumin in the early stage after major abdominal surgery could increase the albumin leakage, while the synergization of albumin and hydroxyethyl starch could reduce the albumin leakage.


Patient reported outcome measures in septorhinoplasty surgery.
Surgical procedures incorporating a cosmetic element such as septorhinoplasty and otoplasty are currently under threat in the National Health Service (NHS) as they are deemed to be procedures of 'limited clinical benefit' by many primary care providers. Patient reported outcome measures (PROMs), which assess the quality of care delivered from the patients' perspective, are becoming increasingly important in documenting the effectiveness of such procedures. The Rhinoplasty Outcomes Evaluation (ROE) questionnaire, a validated PROM tool, was used to assess patient satisfaction in 141 patients undergoing septorhinoplasty surgery over a 90-month period at the University Hospital Southampton NHS Foundation Trust. Overall, 100 patients with a mean follow-up period of 36 months completed the study. The mean ROE score was 73.3%. In addition, 75% of patients questioned were happy with the final result of their operation and 83% would undergo the procedure again if required. These benefits occurred irrespective of age, sex and primary versus revision surgery, and were maintained for up to 71 months following surgery. This study has shown that patients are generally satisfied with their functional and cosmetic outcomes following septorhinoplasty surgery. These results help support the case for septorhinoplasty surgery to continue being funded as an NHS procedure.


Response pattern based on the amplitude of ear canal recorded cochlear microphonic waveforms across acoustic frequencies in normal hearing subjects.
Low-frequency otoacoustic emissions (OAEs) are often concealed by acoustic background noise such as those from a patient's breathing and from the environment during recording in clinics. When using electrocochleaography (ECochG or ECoG), such as cochlear microphonics (CMs), acoustic background noise do not contaminate the recordings. Our objective is to study the response pattern of CM waveforms (CMWs) to explore an alternative approach in assessing cochlear functions. In response to a 14-msec tone burst across several acoustic frequencies, CMWs were recorded at the ear canal from ten normal hearing subjects. A relatively long tone burst has a relatively narrow frequency band. The CMW amplitudes among different frequencies were compared. The CMW amplitudes among different frequencies were compared. Two features were observed in the response pattern of CMWs: the amplitude of CMWs decreased with an increase of stimulus frequency of the tone bursts; and such a decrease occurred at a faster rate at lower frequencies than at higher frequencies. Five factors as potential mechanisms for these features are proposed. Clinical applications such as hearing screening are discussed. Therefore, the response pattern of CMWs suggests that they may be used as an alternative to OAEs in the assessment of cochlear functions in the clinic, especially at low frequencies.


Primary and predicted secondary structures of the caseins in relation to their biological functions.
In free solution, the caseins behave as non-compact and largely flexible molecules with a high proportion of residues accessible to solvent. Historically, they have been described as random coil-type proteins with only a nutritional function. Nevertheless, secondary structure prediction algorithms indicate that many parts of the (unphosphorylated, unglycosylated) polypeptide chains can form regular structures. In particular, a recurrent motif of the Ca2+-sensitive caseins in man, rat, mouse, guinea pig and ruminant species is an alpha-helix--loop--alpha-helix conformation in which the loop region typically contains a cluster of sites of phosphorylation. The biological function of the caseins is considered and it is suggested that the potential or actual conformations of the group of Ca2+-sensitive caseins are suited to the function of modulating the precipitation of calcium phosphate from solution. Either they can act as sites for nucleation or they can bind rapidly to calcium phosphate nuclei as they form spontaneously from supersaturated solution.


Diabetes Risk Score in a Young Student Population in Jordan: A Cross-Sectional Study.
Background. The Middle East is the home to the most obese population in the world, and type 2 diabetes mellitus is endemic in the region. However, little is known about risk factors for diabetes in the younger age groups. Methods. The Finnish Diabetes Risk Score (FINDRISC) is a simple, validated tool to identify persons at risk of diabetes. We investigated students at Hashemite University in Jordan with FINDRISC and measured fasting plasma glucose in those who were categorized in the high-risk group. Results. Overall, 1821 students (881 [48.4%] female) were included in the study. Risk factors for diabetes were common: 422 (23.2%) were overweight or obese and 497 (27.3%) had central obesity. Using the FINDRISC score, 94 (5.2%) students were at moderate risk and 32 (1.8%) at high risk of diabetes. The mean FINDRISC score was significantly higher in men than women (5.9 versus 5.4; p = 0.002). Twenty-eight students in the high-risk group had a subsequent plasma glucose measurement, and 8 (29%) of them fulfilled the diagnostic criteria for diabetes. Conclusions. Risk factors for diabetes were common in a young student population in Jordan, suggesting that preventive measures should be initiated early in adulthood to turn the diabetes epidemic in the region.


Astroglial Glutamate Signaling and Uptake in the Hippocampus.
Astrocytes have long been regarded as essentially unexcitable cells that do not contribute to active signaling and information processing in the brain. Contrary to this classical view, it is now firmly established that astrocytes can specifically respond to glutamate released from neurons. Astrocyte glutamate signaling is initiated upon binding of glutamate to ionotropic and/or metabotropic receptors, which can result in calcium signaling, a major form of glial excitability. Release of so-called gliotransmitters like glutamate, ATP and D-serine from astrocytes in response to activation of glutamate receptors has been demonstrated to modulate various aspects of neuronal function in the hippocampus. In addition to receptors, glutamate binds to high-affinity, sodium-dependent transporters, which results in rapid buffering of synaptically-released glutamate, followed by its removal from the synaptic cleft through uptake into astrocytes. The degree to which astrocytes modulate and control extracellular glutamate levels through glutamate transporters depends on their expression levels and on the ionic driving forces that decrease with ongoing activity. Another major determinant of astrocytic control of glutamate levels could be the precise morphological arrangement of fine perisynaptic processes close to synapses, defining the diffusional distance for glutamate, and the spatial proximity of transporters in relation to the synaptic cleft. In this review, we will present an overview of the mechanisms and physiological role of glutamate-induced ion signaling in astrocytes in the hippocampus as mediated by receptors and transporters. Moreover, we will discuss the relevance of astroglial glutamate uptake for extracellular glutamate homeostasis, focusing on how activity-induced dynamic changes of perisynaptic processes could shape synaptic transmission at glutamatergic synapses.


Outcome of four years experience in laparoscopic ventral hernia repair.
To find out the short term outcomes of laparoscopic ventral hernia repair (LVHR) during the last four years. It was a descriptive and prospective case series of 53 consecutive patients out of 107 at Department of General Surgery, Jinnah Post Graduate Medical Center, Unit II, Karachi, from January 2009 to December 2012. These patients were admitted through out patient department with complain of lump, pain and discomfort. Most of the patients were obese. All patients were clinically examined and baseline investigations done. Fifty three (49.5%) patients underwent laparoscopic repair with mesh placement and remaining 54 by open surgical repair. Among 53 patients, mean age was 46 years range (30 - 55). While females were 33(62.2%) and males 20(37.7%). We observed variety of hernias, in which midline and epigastric hernia were predominant. The commonest symptom was lump and dragging sensation. The duration of symptoms ranged between 6 months to one year. About 53 patients (49.5%) had laparoscopic repair with mesh placement. Average hospital stay was two days. Out of 53 patients, 4 (7.5%) had cellulitis at trocar site, seroma in 2(3.7%), 2(3.7%) patient complained of persistent pain postoperatively, port site minor infection was in 2(3.7%) patients, while conversion to open approach was done in 2 (3.7%), postoperative ileus was observed in one (1.8%) patients. This study provides the evidence that, laparoscopic repair with mesh placement in ventral hernia is safe and effective approach compared to open surgical procedure. It has a low complication rate, less hospital stay and low recurrence.


A palladium catalyzed asymmetric desymmetrization approach to enantioenriched 1,3-disubstituted isoindolines.
Herein, we report the first palladium/MPAA catalyzed enantioselective C-H activation/[4 + 1] annulation of diarylmethyltriflamide and olefins to construct chiral cis-1,3-disubstituted isoindoline derivatives. The use of a readily accessible mono-N-protected amino acid as a chiral ligand improves the efficiency and enantioselectivity of the catalytic transformation. The developed method provides access to both enantiomers of a product using either d or l-phenylalanine derivative as a chiral ligand facilitating the synthesis of both optically active 1,3-disubstituted isoindoline derivatives.


The use of combined single photon emission computed tomography and X-ray computed tomography to assess the fate of inhaled aerosol.
Gamma camera imaging is widely used to assess pulmonary aerosol deposition. Conventional planar imaging provides limited information on its regional distribution. In this study, single photon emission computed tomography (SPECT) was used to describe deposition in three dimensions (3D) and combined with X-ray computed tomography (CT) to relate this to lung anatomy. Its performance was compared to planar imaging. Ten SPECT/CT studies were performed on five healthy subjects following carefully controlled inhalation of radioaerosol from a nebulizer, using a variety of inhalation regimes. The 3D spatial distribution was assessed using a central-to-peripheral ratio (C/P) normalized to lung volume and for the right lung was compared to planar C/P analysis. The deposition by airway generation was calculated for each lung and the conducting airways deposition fraction compared to 24-h clearance. The 3D normalized C/P ratio correlated more closely with 24-h clearance than the 2D ratio for the right lung [coefficient of variation (COV), 9% compared to 15% p < 0.05]. Analysis of regional distribution was possible for both lungs in 3D but not in 2D due to overlap of the stomach on the left lung. The mean conducting airways deposition fraction from SPECT for both lungs was not significantly different from 24-h clearance (COV 18%). Both spatial and generational measures of central deposition were significantly higher for the left than for the right lung. Combined SPECT/CT enabled improved analysis of aerosol deposition from gamma camera imaging compared to planar imaging. 3D radionuclide imaging combined with anatomical information from CT and computer analysis is a useful approach for applications requiring regional information on deposition.


Neurovascular mechanisms of Alzheimer's neurodegeneration.
In contrast to traditional neuroncentric views of Alzheimer's disease (AD), recent findings indicate that neurovascular dysfunction contributes to cognitive decline and neurodegeneration in AD. Here, I propose the neurovascular hypothesis of AD, suggesting that faulty clearance of amyloid beta peptide (A beta) across the blood-brain barrier (BBB), aberrant angiogenesis and senescence of the cerebrovascular system could initiate neurovascular uncoupling, vessel regression, brain hypoperfusion and neurovascular inflammation. Ultimately, this would lead to BBB compromise, to chemical imbalance in the neuronal environment and to synaptic and neuronal dysfunction, injury and loss. Based on the neurovascular hypothesis, I suggest an array of new potential therapeutic approaches that could be developed for AD, to enhance A beta clearance and neurovascular repair, and to protect the neurovascular unit from divergent inducers of injury and apoptosis.


A morphometric study of age-related changes in the elastic systems of the common carotid artery and internal carotid artery in humans.
The present study aims to quantify the distribution of the elastic fiber system in the walls of the common carotid artery and the internal carotid artery in humans. In order to identify specific fibers, segments of carotid arteries were stained using the Verhoeff (for elastic fibers), Weigert (for elastic and elauninic fibers) and Weigert-oxone (for elauninic and oxytalanic fibers) methods. A histomorphometric study was undertaken in order to estimate the linear density (LV) of the fibrous components present in the elastic system and determine the total length of these components in each segment. Microscopic fields were sampled using a test system in which the colors and bands defined in the current study were superimposed on the histological preparations. Data were analyzed through linear regression using first-order rate equations and computer software. The internal carotid artery can be loosely defined as muscular in nature. In order to classify common carotid arteries, it is necessary to consider subject age. From 0 to 30 years of age, the LV of mature elastic fibers does not change significantly in either (left or right) common carotid artery, although a significant reduction in the LV of this type of fiber occurs in the right internal carotid artery. The most marked reduction in oxytalanic and elauninic fibers occurs between 0 and 10 years of age, becoming less intense between the ages of 10 and 30.


Histologic transformation in lung cancer: when one door shuts, another opens.
Histologic transformation (HT) is a major cause of drug resistance to therapy in patients with lung cancer. HTs to small-cell lung cancer (SCLC) have been reported frequently in patients with epidermal growth factor receptor (EGFR)-mutated lung cancer. Although HTs have an impact on the clinical outcomes in patients owing to a high refractoriness to treatments, there is limited data on the prevalence, causes, mechanisms, treatment efficacy, and future treatment strategies. In this review, we assess the literature regarding HTs comprehensively, including those describing EGFR-tyrosine kinase inhibitors, other molecular targeted drugs, and immune checkpoint inhibitors. Furthermore, we discuss the mechanisms of HTs and the lineage plasticity to SCLC and squamous cell carcinoma in lung cancer. In addition, we summarize the treatment efficacy and future perspectives of HTs in patients with lung cancer, and propose better management strategies for this group of patients.


Preliminary investigation of the role of previous exposure to potentially traumatizing events in generalized anxiety disorder.
Theories of generalized anxiety disorder (GAD) highlight the relevance of stressful life events to this disorder's etiology. However, little empirical work has addressed the stressful events that may act as historical contributors to the development or maintenance of GAD. The present study provides an initial exploration of the association between exposure to potentially traumatizing events and GAD. In both analogue and clinical samples, GAD individuals were found to be more likely than nonanxious controls to report exposure to a potentially traumatizing event. These findings are discussed within the context of current theories of worry and GAD.


Prediction Model for unfavorable Outcome in Spontaneous Intracerebral Hemorrhage Based on Machine Learning.
The spontaneous intracerebral hemorrhage (ICH) remains a significant cause of mortality and morbidity throughout the world. The purpose of this retrospective study is to develop multiple models for predicting ICH outcomes using machine learning (ML). Between January 2014 and October 2021, we included ICH patients identified by CT or MRI and treated with surgery. At the 6-month check-up, outcomes were assessed using the modified Rankin Scale (mRS). In this study, four machine learning models, including Support Vector Machine (SVM), Decision Tree C5.0, Artificial Neural Network (ANN), Logistic Regression (LR) were used to build ICH prediction models. In order to evaluate the reliability and the ML models, we calculated the area under the receiver operating characteristic curve (AUC), specificity, sensitivity, accuracy, positive likelihood ratio (PLR), negative likelihood ratio (NLR), Diagnostic Odds Ratio (DOR). We identified 71 patients who had favorable outcomes and 156 who had unfavorable outcomes. The results showed that the SVM model achieved the best comprehensive prediction efficiency. For the SVM model, the AUC, accuracy, specificity, sensitivity, PLR, NLR and DOR were 0.91, 0.92, 0.92, 0.93, 11.63, 0.076 and 153.03 respectively. For the SVM model, we found the importance value of time to operating room (TOR) was higher significantly than other variables. The analysis of clinical reliability showed that the SVM model achieved the best comprehensive prediction efficiency and the importance value of TOR was higher significantly than other variables.


Exit routes for secretory proteins from the dog pancreas.
The relative importance of the pancreatic venous and lymphatic routes for the transport of enzymes away from the pancreas was investigated. The activities of lipase and amylase were compared in arterial plasma, pancreaticoduodenal lymph and venous plasma, pancreatic interstitial fluid and juice in 31 anaesthetized dogs. Enzyme activities were determined before, during and after stimulation of the acinar parenchyma by 4 U/kg b.w. secretin + CCK-PZ for 60 min. During stimulation either is the juice secreted into the duodenum or we ligated the main pancreatic duct. Enzyme output was calculated as the volume x enzyme activity. Initial activities of both enzymes were higher in lymph than in plasma samples. Pancreatic stimulation raised the level of both enzymes in plasma. Stimulation raised lymph lipase activity higher than in plasma, even without duct ligation. Duct ligation increased enzyme activities to considerably higher values in oedema fluid than in lymph. When enzyme output in the stimulated juice for 60 min was considered 100%, output in plasma volume (5% of b.w.) was about 15% both for lipase and for amylase during stimulated secretion, 25--30% for both enzymes when duct had been ligated. Lymphatic enzyme output was found negligible. during pancreatic stimulation biologically important amounts of secretory proteins enter the blood circulation. The lymphatic transport is negligible, since pancreatic lymph flow is several hundred times less than blood flow.


Morphological study of the oesophagus and stomach of the Gopher snake Pituophis catenifer.
The gastrointestinal tract of the snake has various distinctions from mammals, birds and other reptiles. Five gopher snakes (Pituophis catenifer) were studied in relation to the gross anatomical measurements of visceral organs relative to body length as well as the histology of the oesophagus and the stomach. The oesophagus closely resembles the empty stomach upon gross examination. A small palpable thickening was observed at the junction of the oesophagus with the stomach. In both the oesophagus and the stomach, there were cellular and structural differences observed in the tunica mucosa which can be linked to the feeding habits and natural biology of the snake when compared to those of mammals. Both oesophagus and stomach were lined by simple columnar to pseudostratified columnar epithelium. There were no glands in the wall of the oesophagus. Scattered ciliated triangular cells (brush cells) were present among the columnar epithelial cells in the distal portion of the oesophagus. The stomach can be divided into three portions (proximal, middle and distal). The stomach has a small non-glandular portion with low folds. After this small non-glandular portion, glands started to appear and gradually increase in quantity. The largest quantity of glands appeared in the middle portion of the stomach with more branching folds resulting in a decrease in the lumen diameter. The tunica muscularis increased in thickness at the oesophageal and the pyloric-duodenal junctions. Positive statistical correlations were established in thickness of the tunica muscularis between proximal and distal portions of the oesophagus and the stomach.


Nerve conduction studies in patients with dermatomyositis or polymyositis.
Involvement of peripheral nerves in dermatomyositis (DM) and polymyositis (PM) is less well known. In the present study we retrospectively analyzed the clinical and electrophysiological records of hospital inpatients with a diagnosis of DM or PM to investigate the association of DM/PM and peripheral neuropathy. The data of inpatients diagnosed with DM or PM were collected in Peking Union Medical College Hospital, and 186 patients (118 patients with DM and 68 with PM) were retrospectively analyzed. Nerve conduction studies (NCSs) of the median nerve, ulnar nerve, posterior tibial nerve, and common peroneal nerve were examined simultaneously. There were 71 (38.2%) patients with abnormal NCS findings, 37 (19.9%) with pure motor involvement (decreased compound muscle action potential, CMAP), and 34 (18.3%) with peripheral neuropathy. Of the 34 peripheral neuropathy patients, 14 (7.5%) had polyneuropathy, 1 (0.5%) had multiple mononeuropathy, 16 (8.6%) had carpal tunnel syndrome (CTS), 1 (0.5%) had trigeminal sensory neuropathy, 1 (0.5%) had ulnar sensory neuropathy, and 1 (0.5%) had brachial plexus involvement. The prevalence of malignant disease (3/34, 8.8%), other connective tissue diseases (CTDs) (7/34, 20.6%) and diabetes (6/34, 17.6%) was significantly greater in DM/PM patients with peripheral neuropathy (chi(2) = 15.855, P = 0.000) compared with DM/PM patients without involvement of peripheral nerves (5/115, 4.3% and 7/115, 6.1%, respectively). Peripheral neuropathy in DM/PM often suggests a complication with cancer, other CTDs, diabetes or CTS. From a practical point of view, NCS for DM/PM may help find the underlying disorders.


Assessment of gene-by-sex interaction effect on bone mineral density.
Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.


Direct Difluorination-Hydroxylation, Trifluorination, and C(sp2)-H Fluorination of Enamides.
A direct double functionalization involving both difluorination and hydroxylation of enamides is reported. With the appropriate combination of an electrophilic fluorinating reagent and H2O, the most convenient and ecofriendly hydroxylating agent, the preparation of 3-(difluoroalkyl)-3-hydroxyisoindolin-1-ones was achieved under basic or Brønsted acidic conditions. Suitable conditions for trifluorination as well as C(sp2)-H fluorination were also identified. Subsequent asymmetric functionalization of the obtained gem-difluorinated products has also been demonstrated.


TNFalpha regulation of Fas ligand expression on the vascular endothelium modulates leukocyte extravasation.
It is generally believed that the vascular endothelium serves as an inflammatory barrier by providing a nonadherent surface to leukocytes. Here, we report that Fas ligand (FasL) is expressed on vascular endothelial cells (ECs) and that it may function to actively inhibit leukocyte extravasation. TNFalpha downregulates FasL expression with an accompanying decrease in EC cytotoxicity toward co-cultured Fas-bearing cells. Local administration of TNFalpha to arteries downregulates endothelial FasL expression and induces mononuclear cell infiltration. Constitutive FasL expression markedly attenuates TNFalpha-induced cell infiltration and adherent mononuclear cells undergo apoptosis under these conditions. These findings suggest that endothelial FasL expression can negatively regulate leukocyte extravasation.


The dTTPase mechanism of T7 DNA helicase resembles the binding change mechanism of the F1-ATPase.
Bacteriophage T7 DNA helicase is a ring-shaped hexamer that catalyzes duplex DNA unwinding using dTTP hydrolysis as an energy source. Of the six potential nucleotide binding sites on the hexamer, we have found that three are noncatalytic sites and three are catalytic sites. The noncatalytic sites bind nucleotides with a high affinity, but dTTPs bound to these sites do not dissociate or hydrolyze through many dTTPase turnovers at the catalytic sites. The catalytic sites show strong cooperativity which leads to sequential binding and hydrolysis of dTTP. The elucidated dTTPase mechanism of the catalytic sites of T7 helicase is remarkably similar to the binding change mechanism of the ATP synthase. Based on the similarity, a general mechanism for hexameric helicases is proposed. In this mechanism, an F1-ATPase-like rotational movement around the single-stranded DNA, which is bound through the central hole of the hexamer, is proposed to lead to unidirectional translocation along single-stranded DNA and duplex DNA unwinding.


Human Speedy: a novel cell cycle regulator that enhances proliferation through activation of Cdk2.
The decision for a cell to self-replicate requires passage from G1 to S phase of the cell cycle and initiation of another round of DNA replication. This commitment is a critical one that is tightly regulated by many parallel pathways. Significantly, these pathways converge to result in activation of the cyclin-dependent kinase, cdk2. It is, therefore, important to understand all the mechanisms regulating cdk2 to determine the molecular basis of cell progression. Here we report the identification and characterization of a novel cell cycle gene, designated Speedy (Spy1). Spy1 is 40% homologous to the Xenopus cell cycle gene, X-Spy1. Similar to its Xenopus counterpart, human Speedy is able to induce oocyte maturation, suggesting similar biological characteristics. Spy1 mRNA is expressed in several human tissues and immortalized cell lines and is only expressed during the G1/S phase of the cell cycle. Overexpression of Spy1 protein demonstrates that Spy1 is nuclear and results in enhanced cell proliferation. In addition, flow cytometry profiles of these cells demonstrate a reduction in G1 population. Changes in cell cycle regulation can be attributed to the ability of Spy1 to bind to and prematurely activate cdk2 independent of cyclin binding. We demonstrate that Spy1-enhanced cell proliferation is dependent on cdk2 activation. Furthermore, abrogation of Spy1 expression, through the use of siRNA, demonstrates that Spy1 is an essential component of cell proliferation pathways. Hence, human Speedy is a novel cell cycle protein capable of promoting cell proliferation through the premature activation of cdk2 at the G1/S phase transition.


In vitro evaluation of shear bond strength of veneering ceramics to zirconia.
The bond strength between veneering ceramic and zirconia framework is the weakest link in the layered structure. To investigate the shear bond strength (SBS) of veneering ceramics to zirconia, four types of zirconia ceramics (Zirkonzahn, Cercon, Lava, DC-Zirkon) were selected. For each zirconia system, 30 disk specimens were layered with IPS e.max Ceram, Vita VM9, and a manufacturer-recommended veneering ceramic. SBS test was conducted, and fracture surface analysis was also performed to determine the failure modes. One-way ANOVA, two-way ANOVA, and Tukey's HSD tests were used to analyze the data. On shear bond strength between zirconia and their recommended veneering ceramics, statistically significant differences were observed among the different zirconia systems (p<0.001). DC-Zirkon exhibited the highest SBS value (40.49+/-8.43 MPa), followed by Lava (27.11+/-2.72 MPa), Zirkonzahn (24.46+/-3.72 MPa), and Cercon (20.19+/-5.12 MPa). On shear bond strength to IPS e.max Ceram and Vita VM9, significantly lower (p<0.001) were observed for these veneering ceramics than their recommended veneering ceramics for DC-Zirkon and Lava. For Zirkonzahn and Cercon, similar SBS values were observed for all kinds of veneering ceramics (p>0.05). In conclusion, the bonding of manufacturer-recommended veneering ceramic to the zirconia framework differed according to zirconia type.


Perceiving affordances in rugby union.
To succeed in competitive environments, players need to continuously adjust their decisions and actions to the behaviour of relevant others. Players' interactions demand ongoing decisions that are constrained by what is previously defined (e.g., coaches' prescriptions that establish 'what' to do) and by information that is available in the context and specifies not only 'what' the player should do, but also 'how', 'when' and 'where'. We describe what affordances emerge to the ball carrier as a consequence of changes in kinematic variables, such as interpersonal distances or distances to the nearest sideline. Changes in these variables determine whether and when different actions are possible. The ball carrier tended to perform a pass when the tackler was farthest from the sideline and the velocity of approach to the tackler did not seem to effect the ball carrier's decision. In the few episodes where the ball carrier moved forward instead of passing the ball, he was mainly influenced by contextual information, such as the variability of the players' distance to the nearest sideline. In sum, actors must be aware of the affordances of others that are specified by particular variables that become available just before decision-making.


Perineal rectosigmoidectomy in the elderly.
Between April 1989 and October 1991, 20 consecutive patients underwent perineal rectosigmoidectomy and coloanal anastomosis for full-thickness rectal prolapse. These 16 females and 4 males, with a mean age of 82 (range, 68-101) years, were evaluated by detailed functional assessment and physiologic testing. A grading scale from 0 to 24 was based upon the frequency and type of incontinence, 0 representing full continence. The mean preoperative continence score was 14.5, while the mean postoperative continence score was 8.4. The mean length of resected rectosigmoid was 23 cm. There was one postoperative death and one significant complication, a postoperative pelvic hematoma that required reoperation. There were no full-thickness recurrences at a mean follow-up of 26 months. Six of the 10 patients who underwent preoperative pudendal nerve terminal motor latency (PNTML) testing had evidence of severe neuropathy (latencies greater than 2.5 milliseconds). Prolonged PNTML, however, was not shown to be an accurate predictor of postoperative incontinence because four of the six patients with neuropathy regained excellent to good control. In conclusion, perineal rectosigmoidectomy is a safe operation for the treatment of full-thickness rectal prolapse in the elderly patient. Improved postoperative continence was noted in 90 percent of patients, with improvement seen even in those patients with severe pudendal neuropathy.


Synthesis, structural characterisation and stereochemical investigation of chiral sulfur-functionalised N-heterocyclic carbene complexes of palladium and platinum.
Palladium and platinum complexes containing a sulfur-functionalised N-heterocyclic carbene (S-NHC) chelate ligand have been synthesised. The absolute conformations of these novel organometallic S-NHC chelates were determined by X-ray structural analyses and solution-phase 2D (1)H-(1)H ROESY NMR spectroscopy. The structural studies revealed that the phenyl substituents on the stereogenic carbon atoms invariably take up the axial positions on the Pd-C-S coordination plane to afford a skewed five-membered ring structure. All of the chiral complexes are structurally rigid and stereochemically locked in a chiral ring conformation that is either (Rs ,S,R)-λ or (Ss ,R,R)-δ in both the solid state and solution.


Chronic cyanide exposure: a clinical, radioisotope, and laboratory study.
The effect of chronic cyanide exposure in the electroplating sections of three factories employing 36 workers was studied and compared with a control group. The concentration of cyanides to which the workers were exposed was measured. The regression line showing the relationship between thiocyanates in urine and the concentration of cyanides in the air was plotted. Increased percentages of haemoglobin and lymphocyte count were present in all exposed workers, in addition to punctate basophilia in 28 workers. Cyanmethaemoglobin was found to be characteristic. Apart from other complaints, two men with psychosis similar to one case reported in therapeutic thiocyanate intoxication were found. Twenty of the workers had thyroid enlargements to a variable degree and consistency, in two of whom it resembled lymphadenoid goitre. Thyroid 131I uptakes at 4 and 24 hours were significantly higher than in the controls, while 131PBI was unchanged. The reason for this iodine deficiency-like action is discussed.


Comparing Trainee and Staff Perceptions of Patient Safety Culture.
The Accreditation Council for Graduate Medical Education implemented the Clinical Learning Environment Review (CLER) program to evaluate and improve the learning environment in teaching hospitals. Hospitals receive a report after a CLER visit with observations about patient safety, among other domains, the accuracy of which is unknown. Thus, the authors set out to identify complementary measures of trainees' patient safety experience. In 2014, they administered the Hospital Survey on Patient Safety Culture to residents and fellows and general staff at 10 hospitals in an integrated health system. The survey measured perceptions of patient safety in 12 domains and incorporated two outcome measures (number of medical errors reported and overall patient safety). Domain scores were calculated and compared between trainees and staff. Of 1,426 trainees, 926 responded (65% response rate). Of 18,815 staff, 12,015 responded (64% response rate). Trainees and staff scored five domains similarly-communication openness, facility management support for patient safety, organizational learning/continuous improvement, teamwork across units, and handoffs/transitions of care. Trainees scored four domains higher than staff-nonpunitive response to error, staffing, supervisor/manager expectations and actions promoting patient safety, and teamwork within units. Trainees scored three domains lower than staff-feedback and communication about error, frequency of event reporting, and overall perceptions of patient safety. Generally, trainees had comparable to more favorable perceptions of patient safety culture compared with staff. They did identify opportunities for improvement though. Hospitals can use perceptions of patient safety culture to complement CLER visit reports to improve patient safety.


Regulatory and policy barriers to effective clinical data exchange: lessons learned from MedsInfo-ED.
MedsInfo-ED is a proof-of-concept clinical data exchange project that uses prescription claims data to deliver patient medication history to emergency department clinicians at the point of care. This patient safety initiative, while limited in scope and scale, has been crucial in identifying numerous policy and regulatory barriers to successful clinical data exchange. The lessons learned and strategies to overcome the barriers are the focus of this paper. Through commitment and effective collaboration, MA-SHARE was able to address some of these barriers that are embedded in existing government regulations and corporate business practice.


Pterygium surgery: fibrin glue versus Vicryl sutures for conjunctival closure.
To compare the short-term results of conjunctival closure in pterygium surgery using fibrin adhesive versus Vicryl sutures with respect to operative time, postoperative ocular signs and symptoms, and overall patient satisfaction. A comparative prospective randomized clinical trial was performed in 65 patients (65 eyes) with primary nasal pterygium. Surgery in all patients consisted of the bare sclera technique combined with intraoperative mitomycin C. Patients were randomized to undergo conjunctival closure with a fibrin tissue adhesive (Quixil; n = 39) or 8-0 Vicryl absorbable interrupted sutures (n = 26). Clinical assessment was performed on days 1, 3, 10, and 21 after surgery. Patients completed a questionnaire at each follow-up visit, grading pain, discomfort, and satisfaction with the procedure. The groups were compared for operative time, ocular signs and symptoms, and overall satisfaction. Average operative time was 16 minutes (range, 14-16 minutes) in the fibrin glue group and 20 minutes (range, 20-29 minutes) in the Vicryl suture group (P < 0.05). Significantly less pain, photophobia, foreign body sensation, irritation, epiphora, itching, local hyperemia, conjunctival chemosis, and dry eye were noted in the subjects treated with glue than in controls (P < 0.05). There were no complications during the 3-week follow-up period in the glue-treated patients. One of the patients in the suture group had a medically treatable corneal delle. The use of fibrin glue in pterygium surgery significantly reduces operative time and patient symptoms, pain, and discomfort. A longer follow-up is needed to evaluate the influence of fibrin glue on rate of recurrence and long-term complications.


[The epidemiologic situation of tuberculosis in West Siberia in 1991-1995].
Analyzing the major tuberculosis epidemiological indices in West Siberia in 1991-1995 has indicated that the epidemic situation in the region tends to catastrophically deteriorate. Its general morbidity doubled, amounting to 83.5 per 100,000 inhabitants. Among children, there was a rise in morbidity rates from 18.5 per 100,000 in 1993 ot 21.3 in 1995. This index was 33.1% for children aged 0 to 4 years. Morbidity in adolescents increased by 30.2%. Deaths from tuberculosis and its sequelae showed a 1.7-fold increase, accounting for 16.0 per 100,000 inhabitants. During the first year, the deceased increased in number from 9.1% in 1991 to 17.3% in 1996.


High Treatment Retention Rate in HIV-Infected Patients Receiving Antiretroviral Therapy at Two Large HIV Clinics in Hanoi, Vietnam.
Loss to follow-up (LTFU) is viewed as a major challenge in improving retention in HIV treatment. In Vietnam, the reasons for disengagement from clinics and the effect of injection drug use (IDU) on LTFU with unknown outcome (true LTFU) are not well known. Patients receiving antiretroviral therapy (ART) from two HIV clinics in Hanoi were included in this observational study between 2007 and 2012, and followed up every 6 months until the end of 2013. The reasons for disengagement from the clinic, and ART status during imprisonment were investigated in patients with a history of IDU to identify true LTFU. The retention rate at 6-54 months and true LTFU rate were calculated. Cox proportional hazards regression models were performed to identify factors associated with true LTFU. There were 1,431 patients, with a follow-up time of 4,371 person-years (median 2.49 years). At the end of the follow-up period, 71 (5.0%) patients died, 79 (5.5%) transferred to other clinics, 16 (1.1%) disengaged from the clinics, and the calculated true LTFU was 45 (3.1%), with 12-month ART retention rate of 95.3% for the entire study population. Imprisonment was the most frequent reason for disengagement from the clinics. True LTFU correlated significantly with low CD4 count and high plasma viral load, but not history of IDU. Imprisonment is a major cause of disengagement from HIV care among patients with a history of IDU.


Idiopathic Pulmonary Embolism in a case of Severe Family ANKRD26 Thrombocytopenia.
Venous thrombosis affecting thrombocytopenic patients is challenging. We report the case of a woman affected by deep vein thrombosis and pulmonary embolism in a thrombocytopenic context leading to the discovery of a heterozygous mutation in the gene encoding ankyrin repeat domain 26 (ANKRD26) associated with a heterozygous factor V (FV) Leiden mutation. This woman was diagnosed with lower-limb deep vein thrombosis complicated by pulmonary embolism. Severe thrombocytopenia was observed. The genetic study evidenced a heterozygous FV Leiden mutation. Molecular study sequencing was performed after learning that her family had a history of thrombocytopenia. Previously described heterozygous mutation c-127C>A in the 5'untranslated region (5'UTR) of the ANKRD26 gene was detected in the patient, her aunt, and her grandmother. ANKRD26-related thrombocytopenia and thrombosis are rare. This is, to our knowledge, the first case reported in the medical literature. This mutation should be screened in patients with a family history of thrombocytopenia.


Diverse biological activities displayed by phenothiazines, benzo[a]phenothiazines and benz[c]acridins (review).
This review summarizes our experiments which are investigating the relationship between the structure and activity of mainly phenothiazines, benzo[a]phenothiazines and benz[c]acridines. Phenothiazines had potent antiplasmid and antibacterial activities, but induced weak antimicrobial activity in vivo. Their antiplasmid activity seemed to be enhanced by Cl- or CF3- substitution at the 2C position of phenothiazines and modified by the side-chain length and hydrophobicity. Benzo[a]phenothiazines did not show any significant antiplasmid or antibacterial activity, but stimulated the differentiation of human myelogenous leukemic cell lines and natural killing activity of human peripheral blood mononuclear cells in vitro, and induced antimicrobial activity in vivo. Circuit current energy (CRE), circuit current (CC), bond current (BC), diatropic and paratropic properties of benzo[a]phenothiazines might be correlated with their biological activity. Benz[a]acridine showed both in vitro and in vivo antimicrobial activities, and carcinogenic activity for skin tumor. The carcinogenic benz[c]acridines showed out-of-phase in the L-region and their energy was accumulated in the K-region of the molecular orbitals. The results suggest the involvement of different molecular orbitals for the expression of various biological activities by phenothiazines, benzo[a]phenothiazines and benz[c]acridines.


Deacylative oxidation strategy for the preparation of alpha-functionalized carbonyls.
[reaction: see text] alpha-Alkoxylation and amination of carbonyl derivatives is made possible through a unique deacylative coupling reaction that proceeds via in situ Rh-carbene formation and subsequent heteroatom-H (X-H) insertion. Reactions perform optimally with five- and six-membered ring lactone and lactam derivatives using both alcohol and carbamate substrates as coupling partners. Substituted ethylbenzoyl acetate starting materials have also proven to be effective for this oxidative process, affording alpha-functionalized esters under particularly mild and operationally facile conditions.


Changes in the visceral functions of Plasmodium berghei-infected and -uninfected rats following administration of artemether.
1. The effects of artemether (12.5, 25.0 and 50.0 mg/kg per day, i.m.), administered to different groups of Plasmodium berghei-infected and -uninfected adult Wistar rats for 1 week, were investigated. 2. The parameters evaluated were the feeding, drinking and urinating patterns of the rats and these were compared with those of rats that received normal saline. 3. Artemether caused a significant dose-dependent reduction in food consumption of both P. berghei-infected and -uninfected rats (P < 0.05). Food intake in infected rats was reduced by approximately 7 g/24 h. This reduction in food intake was further reduced during drug treatment with artemether. Artermether also reduced food intake in uninfected rats. The food consumption of rats that received 12.5 and 25.0 mg/kg artemether was restored after stopping treatment, in contrast with rats that received 50.0 mg/kg, in which the significant reduction in food consumption persisted 1 week after drug administration. 4. During treatment with artemether, the water intake of infected rats was significantly lower than that of uninfected rats in the 12.5 mg/kg artemether-treated group, but was significantly higher in infected rats than in uninfected rats dosed with 25.0 and 50.0 mg/kg artemether. 5. For all doses of artemether tested, a significant increase in urine output was observed in infected rats during treatment and 1 week after treatment, whereas in uninfected rats a significant increase in urine output was observed only following 25.0 and 50.0 mg/kg artemether 1 week after drug administration. 6. The present study confirms the anorexic activity of a high dose of artemether in both P. berghei-infected and -uninfected rats. It also indicates that high doses of the drug could cause impaired renal function in rats and that the significant increase in urine output could also be due to other effects of artemether, namely those on thirst, anti-diuretic hormone output and the osmotic pressure of the blood.


Vibrational spectroscopy and theory of the protonated benzene dimer and trimer.
Protonated benzene cluster ions, H(C(6)H(6))(2)(+) and H(C(6)H(6))(3)(+), are produced in a pulsed electrical discharge source coupled to a supersonic expansion. Mass-selected complexes are investigated with infrared photodissociation spectroscopy in the 1000-3200 cm(-1) region using the method of argon tagging. The IR spectra of H(C(6)H(6))(2)(+)-Ar and H(C(6)H(6))(3)(+)-Ar contain broad bands in the high frequency region resulting from CH-π hydrogen bonds. Sharp peaks are observed in the fingerprint region arising from the ring modes of both the C(6)H(7)(+) and C(6)H(6) moieties. M06-2X calculations have been performed to investigate the structures and vibrational spectra of energetically low-lying configurations of these complexes. H(C(6)H(6))(2)(+) is predicted to have three nearly isoenergetic conformers: the parallel displaced (PD), T-shaped (TS), and canted (C) structures [Jaeger, H. M.; Schaefer, H. F.; Hohenstein, E. G.; Sherrill, C. D. Comput. Theor. Chem. 2011, 973, 47-52]. A comparison of the experimental dimer spectrum with those predicted for the three isomers suggests an average structure between the TS and PD conformers, which is consistent with the low energy barrier predicted to separate these two structures. No evidence is found for the C dimer even though it lies only 1.2 kcal/mol above the PD dimer. Although the trimer is also computed to have many low lying isomers, the IR spectrum limits the possible species present.


A web-tool for visualizing quantitative protein-protein interaction data.
Quantitative interaction proteomics data can be a challenge to efficiently analyze and subsequently present to an audience in a simple and easy to understand format that still conveys sufficient levels of information. Here we present freely accessible and open-source web tools for displaying multiple parameters from quantitative protein-protein interaction data sets in a visually intuitive format. Given a set of "bait" proteins with detected "prey" interactions, dot plots can be generated to display absolute spectral counts for the preys, relative spectral counts between baits and confidence levels for the interactions (e.g. as determined by SAINTexpress). Additional tools are available for displaying fold change results between numerous baits with their associated confidence level (e.g. resulting from intensity measurements) and pairwise bait analyses displaying spectral counts, confidence score and fold change differences in a scatter plot format. These tools make it easy for the user to identify important interaction changes, interpret their data, and present this information to others in an intuitive way.


The nucleotide sequence and codon recognition of proline tRNA from Torulopsis utilis.
Proline tRNA from Torulopsis (Candida) utilis was purified by chromatography on columns of DEAE-Sephadex A-50 at pH 7.6 and 4.0, DEAE-Sephadex A-50 at pH 6.0, and RPC-5 at pH 4.0. This tRNA was sequenced by combining conventional chromatographic methods with rapid read-out chemical and enzymatic gel sequencing methods. The tRNA consists of 75 nucleotides and had the following sequence: pG-G-C-Cm-G-C-G-U-m1G-G-U-C-psi-A-G-D-G-G-D-A-U-G-A-U-A-C-U-C-G-C-U-U-N-G-G-m1G -psi-G-psi-G-A-G-U-G-m7G-D-m5C-m5C-A-G-G-G-T-psi-C-A-m1A-U-U-C-C-C-U-G-C-U-C-G- G-C-C-C-C-C-A. An unknown nucleotide in the first position of the anticodon was shown to be an uridine derivative by UV-spectrum, mobility on thin-layer chromatogram, and preliminary measurement of NMR spectrum. The specificity of this tRNA for codon recognition was studied by the ribosomal binding technique. Three out of four proline codons were recognized: CCA and CCU preferentially, and CCC weakly. Unexpectedly, CCG failed to bind this tRNA to ribosomes.


Topomer CoMFA and virtual screening studies of azaindole class renin inhibitors.
Direct renin inhibitors (DRIs) have increasingly shown a significant advantage in the treatment of hypertension and protection of target organs. In this paper, a series of azaindole class renin inhibitors were subjected to 3D-QSAR study using Topomer CoMFA. Five kinds of splitting mode for different fragment cutting and 6 different training and test sets grouping were attempted to build consensus models. The results indicated that 6 consensus models had similar predictability (q(2) and r(2) pred) and stability (r(2)). The best model showed good stability and predictability (q(2) of 0.616, r(2) of 0.908). The r(2) pred value of the external test set was 0.70, which means that the model had an excellent external predictive ability, and the robustness of the developed model was assessed by the Y-randomization test. This study also adopted the methodology of fragment-based drug design (FBDD) to virtual screen new renin inhibitors by using Topomer Search technology. The R1-group of the compound No. 13 with the highest activity was chosen as the basic scaffold, and its remaining R2-group acted as a query to screen 142,025 molecules of ZINC database for similar fragments. The obtained 30 fragments with the highest R2-group contribution values were added to the basic scaffold respectively. Finally 30 new azaindole compounds with potent high activities were obtained. Further the binding modes were studied by using Surflex- Dock. The docking results showed good binding interactions of the designed compounds with the renin protein, thus the rationality of this design was further verified from the perspective of the renin receptor.


[Agglutination of intravenous lipid emulsions by acute phase proteins of inflammation].
Agglutination of intravenous fat emulsions (IVFE) by sera of acutely ill children was studied in vitro in 23 patients. C-Reactive protein (CRP) has been showed to agglutinate with IVFE; after discarding CRP, serum of acutely ill patients still agglutinate with IVFE. The agglutination score in generalized sepsis is significantly highest than in localized sepsis. We studied agglutination during three periods: first days of treatment by antibiotics (period 1), between the fourth day and the end of treatment (period 2), and after the end of treatment (period 3). In period 2, when orosomucoid concentrations; nevertheless, the observation of an agglutination in periods 1 and 3 where the mean orosomucoid level is within normal range, strongly suggests that one or more others acute phase proteins are also involved in occurrence of agglutination.


DNA aptamers developed against a soman derivative cross-react with the methylphosphonic acid core but not with flanking hydrophobic groups.
Twelve rounds of systematic evolution of ligands by exponential enrichment (SELEX) were conducted against a magnetic bead conjugate of the para-aminophenylpinacolylmethylphosphonate (PAPMP) derivative of the organophosphorus (OP) nerve agent soman (GD). The goal was to develop DNA aptamers that could scavenge GD in vivo, thereby reducing or eliminating the toxic effects of this dangerous compound. Aptamers were sequenced and screened in peroxidase-based colorimetric plate assays after rounds 8 and 12 of SELEX. The aptamer candidate sequences exhibiting the highest affinity for the GD derivative from round 8 also reappeared in several clones from round 12. Each of the highest affinity PAPMP-binding aptamers also bound methylphosphonic acid (MPA). In addition, the aptamer with the highest overall affinity for PAPMP carried a sequence motif (TTTAGT) thought to bind MPA based on previously published data (J. Fluoresc 18: 867-876, 2008). This sequence motif was found in several other relatively high affinity PAPMP aptamer candidates as well. In studies with the nerve agent GD, pre-incubation of a large molar excess of aptamer candidates failed to protect human butyrylcholinesterase (BuChE) from inhibition. With the aid of three-dimensional molecular modeling of the GD derivative it appears that a hydrophilic cleft sandwiched between the pinacolyl group and the p-aminophenyl ring might channel nucleotide interactions to the phosphonate portion of the immobilized GD derivative. However, bona fide GD free in solution may be repulsed by the negative phosphate backbone of aptamers and rotate its phosphonate and fluorine moieties away from the aptamer to avoid being bound. Future attempts to develop aptamers to GD might benefit from immobilizing the pinacolyl group of bona fide GD to enhance exposure of the phosphonate and fluorine to the random DNA library.


[Tolerance of beta blockader treatment in dilated cardiomyopathy].
We studied 78 consecutive patients with dilatative cardiomyopathy who were in our hospital because of heart failure. We wanted to evaluate which parameters could be useful in identifying patients who could be treated with betablockers. All patients were hemodynamically well balanced. They were treated with effective dosage of digoxin and diuretics. We evaluated the following hemodynamic parameters: heart rate, mean arterial pressure, mean pulmonary arterial pressure (MPAP), right atrial pressure, pulmonary wedge pressure, cardiac output, cardiac index, systemic vascular resistance, pulmonary vascular resistance, and also the neurohumoral parameters: VO2, max exercise duration, plasmatic norepinephrine levels (NE) and plasmatic renin activity (PRA). Then all patients were treated with atenolol 25 mg/die followed by 50 mg/die. In the overall population, 37 patients well tolerated the therapy with betablocker (Group A); 41 patients did not tolerate the therapy (Group B). Between the 2 groups we only found a significant difference in MPAP 31 +/- 20 vs 51 +/- 31 mmHg (p = 0.02), NE 781 +/- 467 vs 1551 +/- 1249 pg/ml (p = 0.01), PRA 1.8 +/- 2.9 vs 5.6 +/- 4.5 ng/ml/h (p = 0.02). On the basis of our results we hypothesize that patients with high neurohumoral activation do not tolerate betablocker treatment.


Isolation and characterization of a Psathyrostachys huashanica Keng 6Ns chromosome addition in common wheat.
The development of alien addition lines is important for transferring useful genes from exotic species into common wheat. A hybrid of common wheat cv. 7182 (2n = 6x = 42, AABBDD) and Psathyrostachys huashanica Keng (2n = 2x = 14, NsNs) via embryo culture produced the novel intergeneric disomic addition line 59-11. The seed morphology of 59-11 resembled the parent 7182 and it exhibited extreme agronomic characteristics, i.e., twin stable spikelets, fertile florets, and multi-kernel clusters. Furthermore, 59-11 produced plump kernels with a high seed-setting percentage during the advanced maturation stage. The line was screened based on genomic in situ hybridization, EST-SSR, EST-STS, and gliadin to identify P. huashanica chromatin in the wheat background. The chromosome number and configuration of 59-11 was 2n = 44 = 22 II and we confirmed the 6Ns disomic chromosome additions based on A-PAGE analysis and molecular markers. The results suggested that the production of twin spikelets and multiple kernels per spike in the wheat-P. huashanica addition line was related to homologous group 6 in the wheat chromosome. This is the first report of the introduction of improved spike traits into common wheat from the alien species P. huashanica and it opens up the possibility of increasing the wheat yield based on this enlarged gene pool.


Practical means for the study of electron correlation in atoms.
Electron correlation is basic to the understanding of a diverse range of physical and chemical phenomena, yet, there have been no direct measurements of the correlated motion of electrons. Measurement of the correlated momenta of atomic electrons is possible via electron-impact double ionization provided that the ionizing collisions are both impulsive and binary, and the three-body scattering mechanism is known. The results reported here satisfy these conditions, and a practical means for the study of atomic electron correlation through measurement of two-electron momentum densities is presented.


Thelazia callipaeda (Spirurida, Thelaziidae) of carnivores and humans: morphological study by light and scanning electron microscopy.
Thelazia nematodes cause ocular infection in several mammals and are transmitted by dipteran flies. Thelazia callipaeda Railliet and Henry 1910 (Spirurida, Thelaziidae) is common in the Far East, where it causes eyeworm infection in carnivores and humans. In the past few years, it has also been reported in dogs, cats and foxes in Northern and Southern Italy. Although a great deal of work has been carried out in China and other Eastern countries, knowledge of the morphology of T. callipaeda is scanty. Eighty-three nematodes collected from the eyes of naturally infected dogs from the Basilicata region (southern Italy) were examined by light and scanning electron microscopy, and the most important features of the nematodes were described. The morphological characteristics useful for the identification of T. callipaeda are discussed.


[Subxiophoyd echocardiography: pulmonary artery or aorta (author's transl)].
Six patients with chronic obstructive pulmonary diseases, have been examinated by subxiophoyd echocardiography associated with ultrasonic contrast of right heart. It is detected that the vessel placed behind anterior cavity is aorta. This is confirmed by study of calcific aortic stenosis too, where the calcifications allows sure localisation of the vessel. Main pulmonary artery, or its branches, is instead visible behind aorta.


The effects of postoperative pain and its management on postoperative cognitive dysfunction.
To determine risks for postoperative cognitive dysfunction (POCD), the authors conducted a prospective cohort study of 225 patients > or = 65 years of age undergoing noncardiac surgery. Cognitive testing using the Word List, Verbal Fluency, and Digit Symbol tests was conducted for each patient preoperatively and 1 and 2 days postoperatively in patients without postoperative delirium. POCD was defined as meeting statistical criteria for decline from the patient's preoperative performance levels on at least two of the three cognitive tests. Multivariate logistic regression analysis determined the association between pain and postoperative analgesia with POCD after controlling for demographics, comorbidities, preoperative level of cognitive and daily functioning, preoperative medications, duration and type of anesthesia, and adverse events. Patients were on average 72 years old and 13% of patients experienced POCD on day 1, 7% on day 2, and 15% had POCD on either day 1 or day 2 after the surgery. Multivariate regression analyses revealed that only postoperative analgesia was associated with the development of POCD. Compared with those receiving postoperative analgesia through a patient-controlled analgesia device that administered opioids intravenously, those who received postoperative analgesia orally were at significantly lower risk for the development of POCD (odds ratio: 0.22; 95% confidence interval: 0.06-0.80; Wald chi-square = 5.36, df = 1, p = 0.02). Older patients undergoing noncardiac surgery who are not delirious can experience significant declines in cognitive functioning postoperatively. Those at least risk of experiencing POCD were those who received postoperative analgesia orally.


Magnetic resonance imaging of the shoulder in the primary care setting.
MRI is an excellent noninvasive method of diagnosing difficult shoulder problems. Although usually not needed for classic primary impingement syndrome or clinically obvious rotator cuff tears, MRI may be helpful in diagnosing secondary causes of impingement or in some cases involving partial rotator cuff tears. Some surgeons may use MRI preoperatively to define the extent of the rotator cuff tear, as this may alter their surgical approaches.