Anabolic properties of high mobility group box protein-1 in human periodontal ligament cells in vitro.
High mobility group box protein-1 (HMGB1) is mainly recognized as a chemoattractant for macrophages in the initial phase of host response to pathogenic stimuli. However, recent findings provide evidence for anabolic properties in terms of enhanced proliferation, migration, and support of wound healing capacity of mesenchymal cells suggesting a dual role of the cytokine in the regulation of immune response and subsequent regenerative processes. Here, we examined potential anabolic effects of HMGB1 on human periodontal ligament (PDL) cells in the regulation of periodontal remodelling, for example, during orthodontic tooth movement. Preconfluent human PDL cells (hPDL) were exposed to HMGB1 protein and the influence on proliferation, migration, osteogenic differentiation, and biomineralization was determined by MTS assay, real time PCR, immunofluorescence cytochemistry, ELISA, and von Kossa staining. HMGB1 protein increased hPDL cell proliferation, migration, osteoblastic marker gene expression, and protein production as well as mineralized nodule formation significantly. The present findings support the dual character of HMGB1 with anabolic therapeutic potential that might support the reestablishment of the structural and functional integrity of the periodontium following periodontal trauma such as orthodontic tooth movement.


8-quinolinamines and their pro prodrug conjugates as potent blood-schizontocidal antimalarial agents.
Synthesis and antimalarial activities of N8-(4-amino-1-methylbutyl)-5-alkoxy-4-ethyl-6-methoxy-8-quinolinamines (5) and their pro prodrug analogues (6-7) prepared by covalently linking 5 to the redox-sensitive (8) and esterase-sensitive (9) linkers through the amide linkage are reported. The most effective 8-quinolinamines [5c (R=C5H11) and 5f (R=C8H17)] have exhibited in vitro and in vivo biological efficacy superior to that of the standard drug chloroquine against both drug-sensitive and drug-resistant malaria strains. Analogues 6-7 were evaluated for in vivo blood-schizontocidal activity as potential pro prodrug models for the primary amino group containing 8-quinolinamines (5). The most effective pro prodrug analogue (6c) has displayed promising activities against drug-sensitive and drug-resistant strains of Plasmodia in vivo.


The current state of geriatric medicine: a national survey of fellowship-trained geriatricians, 1990 to 1998.
The rapid growth of the older population has focused national attention on the need for physicians trained in geriatric medicine. To gain insight into the evolving status of the field, with particular focus on career decision-making and academic career development of trainees, we conducted a survey of physicians recently completing geriatric fellowships. The 107 accredited extant geriatric fellowship programs in the United States and Puerto Rico were contacted to identify trainees from 1990 to 1998. A mailed survey addressed relevant career development and training issues. Four hundred ninety out of 787 (62%) physicians responded; 20% completed 1 year and 80% 2 or more years of training. Half made the decision to pursue a career in geriatrics during residency, 27% decided before/during medical school, and a mentor influenced 48%. Currently, 80% have a Certificate of Added Qualifications in geriatric medicine, 69% hold academic appointments, 78% teach, 39% participate in research, and 44% author publications. Most are doing predominantly clinical work in multiple settings. Further analysis of the 1996-to-1998 cohort revealed that those completing fellowships of 2 or more years are more likely to identify all geriatrics as their professional focus, conduct and author research, work with multidisciplinary teams, and participate in professional geriatric societies. This national survey documents career decision-making and the academic and clinical profiles of physicians completing geriatric fellowship training in the past decade. Longer fellowship training is associated with academic career development. Although there is a national need to train clinical geriatricians, the additional need to train and fund future geriatric academic leaders requires increased attention.


Apelin inhibited epithelial-mesenchymal transition of podocytes in diabetic mice through downregulating immunoproteasome subunits β5i.
The epithelial-mesenchymal transition (EMT) of podocytes had been reported to be involved in the glomerular fibrosis in diabetic kidney diseases, which was regulated by TGFβ and NFκB pathways. And apelin, an adipokine which is upregulated in diabetic kidney diseases, was reported to be negatively correlated to TGFβ in polycystic kidney disease and attenuate EMT in renal tubular cells. Therefore, it is hypothesized that apelin might inhibit the EMT of podocytes through downregulating the expression and activation of TGFβ/Smad pathway in diabetic kidney diseases. The results showed that apelin in glomeruli of diabetic mice were increased and exogenous apelin inhibited the EMT of podocytes in diabetic mice, which were accompanied with the decreased expression of proteasome subunits β5i. The results from β5iKO mice confirmed that the inhibiting effects of apelin on EMT of podocytes in diabetic mice were dependent on β5i. The results from culture podocytes showed that apelin decreased the degradation of pIκB and promoted the translocation of IκB into nucleus through decreasing the expression of β5i, which would inhibit the promoting effects of NFκB on expression of TGFβ and followed by decreased activation of Smad pathway and EMT in podocytes. In conclusion, apelin might act as an EMT suppressor for podocytes to decrease the process of glomerular fibrosis in diabetic mice.


The effect of transforming growth factor beta1 (TGF-beta1) on the regenerate bone in distraction osteogenesis.
Distraction osteogenesis is a well established clinical treatment for limb length discrepancy and skeletal deformities. Transforming growth factor beta 1 (TGF-beta1) is a multifunctional peptide which controls proliferation and expression of cells specific to bone like chondrocytes, osteoblasts, osteoclasts including mesenchymal precursor cells. To decrease the external fixation time with increasing the strength of regenerate (newly formed bone after distraction) we tested the effect of locally applied transforming growth factor beta 1 on distraction osteogenesis. A total of 28 mature female white New zealand rabbits weighing 3,5 kg-4,5 kg were studied. 10 animals were belonging to biomechanical testing group (5 for the study and 5 for the control subgroups), and the others were to histology group. In biomechanical group after tibial osteotomy TGF-beta1 was applied subperiosteally for 5 days just proximal to osteotomy site. Control group received only the solvent. Seven days after tibial osteotomy distraction was started at a rate of 0.25 mm/12 hours for 3 weeks with a unilateral fixator. Rabbits were sacrificed at the end of a consolidation period 8 week after tibial osteotomy. We assessed density of the elongation zone of rabbit tibial bones with the computed tomography. Then biomechanical parametres were assessed using the torsional testing using the material testing machine. In histology group rabbits were classified as control and study (rabbits that were given TGF-beta1). Rabbits were sacrificed at the end of first week, second week and fourth week also at the end of consolidation period 8 week after tibial osteotomy. Immunohistochemical and histologic parameters were examined. Biomechanical testing was applied as torsional testing. These values are used in determination of maximal loading, stiffness and energy absorbed during testing (brittleness). The histomorphometric examination looked for the differences between the study and control groups in terms of bone formation pattern, bone quality and quantity. The immunohistochemical studies investigated the mechanism of TGF-beta1, and its presence in different cell types. The results of this study suggest that locally applied TGF-beta1 improves the mineral density of distraction gap and load to failure(energy absorbed during testing). Though there is no significant histomorphometric difference between the study and control groups, there is an increased bone mineral density and an according maximum energy absorbance in the study group. This effect can be explained by the following mechanism: TGF-beta1 exerts its effect on two different receptor types (Type 1 and 2). Type 1 receptors are localized to bone matrix and type 2 receptors are localized to the intracellular space. The specific stains utilized in the current experiment are specific to type 2 receptors. They have been shown to be down-regulated by exogenous TGF-beta1 injections. Most probably, type 1 receptors are up-regulated by this exogenous administration, but unfortunately, there is currently no specific stain on tha market to display type 1 receptors and to prove this explanation.


Streamlined, two-column, simulated countercurrent chromatography for binary separation.
We report on a numerical and experimental study of two-column versions of streamlined, multicolumn, semi-continuous chromatography for binary separation. The systems combine a flexible node design, cyclic flow-rate modulation, and relayed operation of the inlet/outlet ports to extend the mass-transfer zone over the largest possible length, while keeping it inside the system at all times. One advantage of these streamlined designs is the simplicity of their physical realization: regardless of the number of columns, they only require two pumps to supply feed and desorbent into the system, while the flow rates of liquid withdrawn from the system are controlled by material balance using simple two-way valves. In one case, an extra pump is needed to recirculate the fluid in closed-loop. A rigorous model-based optimization approach is employed in the optimal design of the cycles to generate solutions that are physically realizable in the experimental set-ups. The optimized schemes for two-column operation supply fresh feed into the middle of the system where the composition of the circulating fluid is closest to that of the feedstock fluid, and recover the purified products, extract and raffinate, alternately at the downstream end of the unit, while desorbent is continuously supplied into the upstream end of the system. By internally recycling part of the non-pure cut fraction, the scheme with a step of closed-loop recycling significantly reduces its solvent consumption. The feasibility and effectiveness of the reported two-column processes have been verified experimentally on the linear separation of nucleosides by reversed phase subject to 99% purity constraints on both products. It is shown that our processes compare favorably against single-column batch chromatography, steady-state recycling, and four-column, open-loop SMB, for the same amount of adsorbent; they are also better than the four-column, closed-loop SMB at high feed throughputs.


Treatment of Pseudoangiomatous Stromal Hyperplasia of the Breast: Literature Review and Successful Management of a Teenage Girl by Breast Reduction With 10-Year Follow-up.
Pseudoangiomatous stromal hyperplasia is an uncommon benign condition of mesenchymal proliferation. Fewer than 1500 cases have been reported in previous literature. It is observed most commonly in postmenopausal and perimenopausal women and is extremely rare to present in children. Recommended treatment in severe cases is often mastectomy due to high incidence of recurrence. However, a careful review of the literature suggests that treatment of this benign disease should be tailored to the mode in which it presents. This case report describes a 16-year-old girl with a severe case of bilateral pseudoangiomatous stromal hyperplasia that was managed with reduction mammoplasty, along with a 10-year case follow-up. Based on a literature review of more than 2800 cases and the current case report, a conservative management strategy is suggested, depending on disease presentation.


The PRO-ACT database: design, initial analyses, and predictive features.
To pool data from completed amyotrophic lateral sclerosis (ALS) clinical trials and create an open-access resource that enables greater understanding of the phenotype and biology of ALS. Clinical trials data were pooled from 16 completed phase II/III ALS clinical trials and one observational study. Over 8 million de-identified longitudinally collected data points from over 8,600 individuals with ALS were standardized across trials and merged to create the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. This database includes demographics, family histories, and longitudinal clinical and laboratory data. Mixed effects models were used to describe the rate of disease progression measured by the Revised ALS Functional Rating Scale (ALSFRS-R) and vital capacity (VC). Cox regression models were used to describe survival data. Implementing Bonferroni correction, the critical p value for 15 different tests was p = 0.003. The ALSFRS-R rate of decline was 1.02 (±2.3) points per month and the VC rate of decline was 2.24% of predicted (±6.9) per month. Higher levels of uric acid at trial entry were predictive of a slower drop in ALSFRS-R (p = 0.01) and VC (p < 0.0001), and longer survival (p = 0.02). Higher levels of creatinine at baseline were predictive of a slower drop in ALSFRS-R (p = 0.01) and VC (p < 0.0001), and longer survival (p = 0.01). Finally, higher body mass index (BMI) at baseline was associated with longer survival (p < 0.0001). The PRO-ACT database is the largest publicly available repository of merged ALS clinical trials data. We report that baseline levels of creatinine and uric acid, as well as baseline BMI, are strong predictors of disease progression and survival.


Scanning electron microscopy of Trichuris trichiura (Nematoda).
Trichuris trichiura was examined in the scanning electron microscope and revealed a double row of sucker-like structures at the anterior part. It is postulated that they may support the attachment of the worm in host tissues. The sheath of the spicule is covered with spikes and the vulval opening is surrounded by an elevated rim-like structure with indentations.


A new method to quantify the effect of co-medication on the efficacy of abiraterone in metastatic castration-resistant prostate cancer patients.
Background and Objective: Patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA) have co-morbidities treated with different drugs. The aim was to quantify the potential effect of co-medications on AA treatment duration (TD) and overall survival (OS). Methods: A new parameter, called "individual drug score" (IDS) was calculated by summing the "drug score"-s (DS) of all co-medications for each patient. The DS was determined by quantifying the effect of a given co-drug on enzymes involved in steroidogenesis and metabolism of AA. The correlation between log (IDS) and TD was tested by non-linear curve fit. Kaplan-Meier method and multivariate Cox regression was used for analysis of TD and OS. Results: The IDS and TD of AA+prednisolone showed a dose-response correlation (n = 166). Patients with high IDS had significantly longer TD and OS (p <0.001). In multivariate analysis IDS proved to be an independent marker of TD and OS. The same analysis was performed in a separate group of 81 patients receiving AA+dexamethasone treatment. The previously observed relationships were observed again between IDS and TD or OS. After combining the AA+prednisolone and AA+dexamethasone groups, analysis of the IDS composition showed that patients in the high IDS group not only used more drugs (p <0.001), but their drugs also had a higher mean DS (p = 0.001). Conclusion: The more co-drugs with high DS, the longer the duration of AA treatment and OS, emphasizing the need for careful co-medication planning in patients with mCRPC treated with AA. It is recommended that, where possible, co-medication should be modified to minimize the number of drugs with negative DS and increase the number of drugs with high DS. Our new model can presumably be adapted to other drugs and other cancer types (or other diseases).


Dynamically configurable biomolecular nanoarrays.
Nanoarrays of distinct DNA and protein biomolecules were fabricated by electrochemically controlling their assembly/release from Au nanoelectrodes on a chip. The surface density, ratio, and activity of the biomolecules assembled on each nanoelectrode in the array can be configured quantitatively and temporally by adjusting the electrochemical potential applied on the nanoelectrode. The dynamically configurable biomolecular nanoarray can potentially activate combinatorial interactions with microbiosystems under the control of an electronic circuit for biological and medical applications.


Monitoring of strain-dependent responsiveness to TLR activation in the mouse anterior segment using SD-OCT.
To determine whether spectral-domain optical coherence tomography (SD-OCT) can be used to longitudinally monitor inflammation in the mouse anterior segment and to identify any strain-dependent differences in responsiveness to distinct toll-like receptor (TLR) ligands. Corneal inflammation was induced in BALB/c and C57BL/6 mice following central corneal abrasions and topical application of saline, TLR-4 ligand, lipopolysaccharide (LPS), or TLR-9 ligand, CpG-oligodeoxynucleotide (CpG-ODN; CpG). Anterior-segment images were captured using SD-OCT at baseline, 24 hours, and 1 week post treatment. Corneal thickness, stromal haze, and the number of keratic precipitates (KP) and anterior chamber (AC) cells were longitudinally compared to determine differences between mouse strains, time points, and TLR activation. In both mouse strains, treatment with CpG, but not saline or LPS, resulted in a similar number of KPs and AC cells. In C57BL/6 mice, central corneal thickness (CCT) increased in CpG- and LPS-treated eyes at 24 hours, which normalized by 1 week. In BALB/c mice, a significant increase in CCT occurred in eyes treated with CpG at 1 week. Stromal haze peaked in C57BL/6 eyes treated with LPS- or CPG-treatment at 24 hours; however, BALB/c eyes showed persistent and marked increases in corneal haze compared with baseline at 1 week post treatment. Spectral-domain OCT enables high-resolution, longitudinal, in vivo imaging of anterior segment inflammation in mice and revealed novel strain- and time-dependent differences in response to distinct TLR activation in the cornea.


Whole-Genome Sequencing of Kaposi's Sarcoma-Associated Herpesvirus from Zambian Kaposi's Sarcoma Biopsy Specimens Reveals Unique Viral Diversity.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent for Kaposi's sarcoma (KS). Both KSHV and KS are endemic in sub-Saharan Africa where approximately 84% of global KS cases occur. Nevertheless, whole-genome sequencing of KSHV has only been completed using isolates from Western countries-where KS is not endemic. The lack of whole-genome KSHV sequence data from the most clinically important geographical region, sub-Saharan Africa, represents an important gap since it remains unclear whether genomic diversity has a role on KSHV pathogenesis. We hypothesized that distinct KSHV genotypes might be present in sub-Saharan Africa compared to Western countries. Using a KSHV-targeted enrichment protocol followed by Illumina deep-sequencing, we generated and analyzed 16 unique Zambian, KS-derived, KSHV genomes. We enriched KSHV DNA over cellular DNA 1,851 to 18,235-fold. Enrichment provided coverage levels up to 24,740-fold; therefore, supporting highly confident polymorphism analysis. Multiple alignment of the 16 newly sequenced KSHV genomes showed low level variability across the entire central conserved region. This variability resulted in distinct phylogenetic clustering between Zambian KSHV genomic sequences and those derived from Western countries. Importantly, the phylogenetic segregation of Zambian from Western sequences occurred irrespective of inclusion of the highly variable genes K1 and K15. We also show that four genes within the more conserved region of the KSHV genome contained polymorphisms that partially, but not fully, contributed to the unique Zambian KSHV whole-genome phylogenetic structure. Taken together, our data suggest that the whole KSHV genome should be taken into consideration for accurate viral characterization. Our results represent the largest number of KSHV whole-genomic sequences published to date and the first time that multiple genomes have been sequenced from sub-Saharan Africa, a geographic area where KS is highly endemic. Based on our new sequence data, it is apparent that whole-genome KSHV diversity is greater than previously appreciated and differential phylogenetic clustering exists between viral genomes of Zambia and Western countries. Furthermore, individual genes may be insufficient for KSHV genetic characterization. Continued investigation of the KSHV genetic landscape is necessary in order to effectively understand the role of viral evolution and sequence diversity on KSHV gene functions and pathogenesis.


Immunization with dendritic cell-based DNA vaccine pRSC-NLDC145.gD-IL21 protects mice against herpes simplex virus keratitis.
The aim of this study is to investigate the effects of constructed dendritic cell (DC)-based DNA vaccine (pRSC-NLDC145.gD-IL21) carried by chitosan nanoparticle in preventing primary or recurrent herpes simplex virus keratitis (HSK) in mice. The expression of constructed plasmid 'pRSC-NLDC145.gD-IL21' was verified by western blot and immunofluorescence. Plasmids that were embedded in chitosan were inoculated to test its therapeutic effect against primary or recurrent HSK in mice. Humoral and cellular immune response, clinical scores of herpes keratitis and inflammatory infiltration were measured. The expressed glycoprotein D (gD) of pRSC-NLDC145.gD-IL21 DNA/chitosan nanoparticle vaccine could effectively target corneal DCs and significantly alleviate the symptoms of both primary and recurrent HSK mice via eliciting strong humoral and cellular immune response. Our data suggested that DC-based DNA vaccine could be a better choice for HSK treatment in the future.


Neural correlates of covert face processing: fMRI evidence from a prosopagnosic patient.
Brains can perceive or recognize a face even though we are subjectively unaware of the existence of that face. However, the exact neural correlates of such covert face processing remain unknown. Here, we compared the fMRI activities between a prosopagnosic patient and normal controls when they saw famous and unfamiliar faces. When compared with objects, the patient showed greater activation to famous faces in the fusiform face area (FFA) though he could not overtly recognize those faces. In contrast, the controls showed greater activation to both famous and unfamiliar faces in the FFA. Compared with unfamiliar faces, famous faces activated the controls', but not the patient's lateral prefrontal cortex (LPFC) known to be involved in familiar face recognition. In contrast, the patient showed greater activation in the bilateral medial frontal gyrus (MeFG). Functional connectivity analyses revealed that the patient's right middle fusiform gyrus (FG) showed enhanced connectivity to the MeFG, whereas the controls' middle FG showed enhanced connectivity to the LPFC. These findings suggest that the FFA may be involved in both covert and overt face recognition. The patient's impairment in overt face recognition may be due to the absence of the coupling between the right FG and the LPFC.


[Economic consequences of complications in abdominal and thoracic surgery in the German DRG payment system].
The Surgical Department of the University Hospital Grosshadern has been making a systematic record of complications since 2005. With respect to the ongoing problem of under-financing from DRG reimbursements, an analysis of the relationship between surgical cases with severe complications and insufficient reimbursement warranted a detailed analysis. Out of 16 762 in-house patients during 2005-2007 we assigned 6707 cases into four divisions - hepato-pancreato-biliary, colorectal, minimal invasive and general abdominal surgery as well as 1469 cases of thoracic surgery, for costs and reimbursement. In all groups patients with mandatory treament of complications were compared to the remaining cases without complications. Within these, further subgroups were analysed: patients with a need for artificial ventilation (partition A of the G-DRG system), cases with excessive loss (underfunding above 10 000 Euro) and their intersections. With the exception of minimal invasive surgery, each division featured 10-15 % of serious complications. Losses for these cases ranged from 159 % (thoracic surgery) to 102 % (other abdominal surgery) of the overall loss in each division. Cases with excessive losses, representing 1.5 % of all patients, caused 80 % to 100 % of this deficit. Complicated cases alloted to DRGs for artificial ventilation still represented 50 % of the under-fund-ing. Cases with mandatory complication treatment can be discerned as separate economic entities. They are considerably overlapping cases with excessive underfunding, so further analysis might lead to an improved reimbursement policy. In addition, the connection between quality management and economic efficiency is highlighted.


Anterior crowns & porcelain laminate veneers: a conservative approach.
The final results of this case were pleasing to the patient and the dentist (Fig.5). The diastemas had been closed (Fig. 6), and the bioesthetic symmetry and harmony had been restored (Fig. 7). The patient reported an increase in self confidence with his peers and professors, especially during assignments both at work and at the university. (Fig. 8) I want to especially thank Felipe Don Sanders, C.D.T. for his skill in producing the excellent laboratory work for this case.


Co-circulation of four types of infectious bronchitis virus (793/B, 624/I, B1648 and Massachusetts).
Eighteen isolates of infectious bronchitis virus (IBV) from Italy and Poland in 1997 to 1998 were comprehensively analysed by serum haemagglutination inhibition and virus neutralization tests, and by type-specific polymerase chain reactions and spike protein S1 gene sequencing. Four types of IBV (793/B, 624/I, B1648 and Massachusetts) were detected in Italy, while the presence of 793/B was confirmed in Poland. This showed that not only were four types of IBV co-existing within a single year, but also that several types of IBV have persisted in Europe for many years (at least 13 to 14 years for types B1648 and 793/B). Sequencing of the S1 gene of the 624/I isolate confirmed this as a unique type of IBV.


Is Concussion a Risk Factor for Epilepsy?
Epidemiologic studies have suggested that concussion, or mild traumatic brain injury (mTBI), is associated with a twofold or greater increase in relative risk for the development of post-traumatic epilepsy. To assess the clinical validity of these findings, we analyzed the incidence of epilepsy in a large cohort of post-concussion patients in whom concussion was strictly defined according to international guidelines. A retrospective cohort study of 330 consecutive post-concussion patients followed by a single concussion specialist. Exclusion criteria: abnormal brain CT/MRI, Glasgow Coma Scale48 hours. Independent variable: concussion. Outcome measure: epilepsy incidence (dependent variable). The mean number of concussions/patient was 3.3 (±2.5), mean age at first clinic visit 28 years (±14.7), and mean follow-up after first concussion 7.6 years (±10.8). Eight patients were identified whose medical records included mention of seizures or convulsions or epilepsy. Upon review by an epileptologist none met criteria for a definite diagnosis of epilepsy: four had episodic symptoms incompatible with epileptic seizures (e.g., multifocal paraesthesiae, multimodality hallucinations, classic migraine) and normal EEG/MRI investigations; four had syncopal (n=2) or concussive (n=2) convulsions. Compared with annual incidence (0.5/1000 individuals) in the general population, there was no difference in this post-concussion cohort (p=0.49). In this large cohort of post-concussion patients we found no increased incidence of epilepsy. For at least the first 5-10 years post-injury, concussion/mTBI should not be considered a significant risk factor for epilepsy. In patients with epilepsy and a past history of concussion, the epilepsy should not be presumed to be post-traumatic.


Latitudinal trends in the structure, similarity and beta diversity of plant communities invaded by Alternanthera philoxeroides in heterogeneous habitats.
Variations in latitudinal gradients could lead to changes in the performance and ecological effects of invasive plants and thus may affect the species composition, distribution and interspecific substitution of native plant communities. However, variations in structure, similarity and beta (β) diversity within invaded communities across latitudinal gradients in heterogeneous habitats remain unclear. In this study, we conducted a two-year field survey along 21°N to 37°N in China, to examine the differential effects of the amphibious invasive plant Alternanthera philoxeroides on native plant communities in terrestrial and aquatic habitats. We compared the differences in the invasion importance value (IV), species distribution, community similarity (Jaccard index and Sorenson index) and β diversity (Bray-Curtis index and βsim index) between terrestrial and aquatic communities invaded by A. philoxeroides, as well as analyzed their latitudinal trends. We found that the IV of A. philoxeroides and β diversity in aquatic habitats were all significantly higher than that of terrestrial, while the terrestrial habitat had a higher community similarity values. The aquatic A. philoxeroides IV increased with increasing latitude, while the terrestrial IV had no significant latitudinal trend. With increasing latitude, the component proportion of cold- and drought-tolerant species in the terrestrial communities increased, and the dominant accompanying species in the aquatic communities gradually changed from hygrophytes and floating plants to emerged and submerged plants. In addition, the aquatic communities had lower community similarity values and higher β diversity in higher latitudinal regions, while terrestrial communities had the opposite parameters in these regions. Our study indicates that the bioresistance capacities of the native communities to invasive A. philoxeroides in heterogeneous habitats are different; A. philoxeroides invasion leads to higher community homogenization in terrestrial habitats than in aquatic habitats, and terrestrial communities experience more severe homogenization in higher latitudinal regions. These findings are crucial for predicting the dynamics of invasive plant communities under rapid global change.


Bacillus spore inactivation differences after combined mild temperature and high pressure processing using two pressurizing fluids.
Spores of six species (28 strains) of dairy Bacillus isolates were added to sterile reconstituted skim milk and pressure processed (600 MPa for 60 s at 75 degrees C) using either a water-based pressurizing fluid or silicon oil. Processing temperatures peaked at 88 and 90 degrees C, respectively, for both fluids. For all strains, the log inactivation was consistently higher in the silicon oil than in the water-based fluid. This has potential implications for food safety assessment of combined pressure-temperature processes. High pressure processing causes mild heating during pressurization of both the target sample (i.e., spores) and the pressurizing fluid used for pressure delivery. Primarily, the adiabatic heat of compression of the fluids as well as other heat-transfer properties of the fluids and equipment determines the magnitude of this heating. Pressure cycles run with silicon oil were 7 to 15 degrees C higher in temperature during pressurization than pressure cycles run with the water-based pressurizing fluid, due to the greater adiabatic heat of compression of silicon oil. At and around the target pressure, however, the temperatures of both pressurizing fluids were similar, and they both dropped at the same rate during the holding time at the target pressure. We propose that the increased spore inactivation in the silicon oil system can be attributed to additional heating of the spore preparation when pressurized in oil. This could be explained by the temperature difference between the silicon oil and the aqueous spore preparation established during the pressurization phase of the pressure cycle. These spore-inactivation differences have practical implications because it is common practice to develop inactivation kinetic data on small, jacketed laboratory systems pressurized in oil, with extensive heat loss. However, commercial deployment is invariably on large industrial systems pressurized in water, with limited heat loss. Such effects should be considered in food safety assessments of combined pressure-temperature processes.


Cationic N-Heterocyclic Carbene Copper-Catalyzed [1,3]-Alkoxy Rearrangement of N-Alkoxyanilines.
The [1,3]-alkoxy rearrangement reactions of N-alkoxyanilines were efficiently catalyzed by cationic N-heterocyclic carbene (NHC)-Cu catalysts in affording 2-alkoxyaniline derivatives in good to excellent yields with high functional group compatibility. For N-alkoxyanilines having an electron-withdrawing substituent at the meta-position, the alkoxy group selectively migrated to the more hindered ortho-position. In contrast, the alkoxy group migrated to the less hindered ortho-position for N-alkoxyanilines having an electron-donating substituent. Mechanistic studies suggest that the rearrangement reactions proceed via an intramolecular route.


Differentiation among prostate cancer patients with Gleason score of 7 using histopathology whole-slide image and genomic data.
Prostate cancer is the most common non-skin related cancer affecting 1 in 7 men in the United States. Treatment of patients with prostate cancer still remains a difficult decision-making process that requires physicians to balance clinical benefits, life expectancy, comorbidities, and treatment-related side effects. Gleason score (a sum of the primary and secondary Gleason patterns) solely based on morphological prostate glandular architecture has shown as one of the best predictors of prostate cancer outcome. Significant progress has been made on molecular subtyping prostate cancer delineated through the increasing use of gene sequencing. Prostate cancer patients with Gleason score of 7 show heterogeneity in recurrence and survival outcomes. Therefore, we propose to assess the correlation between histopathology images and genomic data with disease recurrence in prostate tumors with a Gleason 7 score to identify prognostic markers. In the study, we identify image biomarkers within tissue WSIs by modeling the spatial relationship from automatically created patches as a sequence within WSI by adopting a recurrence network model, namely long short-term memory (LSTM). Our preliminary results demonstrate that integrating image biomarkers from CNN with LSTM and genomic pathway scores, is more strongly correlated with patients recurrence of disease compared to standard clinical markers and engineered image texture features. The study further demonstrates that prostate cancer patients with Gleason score of 4+3 have a higher risk of disease progression and recurrence compared to prostate cancer patients with Gleason score of 3+4.


Neurospora chromosomes are organized by blocks of importin alpha-dependent heterochromatin that are largely independent of H3K9me3.
Eukaryotic genomes are organized into chromatin domains with three-dimensional arrangements that presumably result from interactions between the chromatin constituents-proteins, DNA, and RNA-within the physical constraints of the nucleus. We used chromosome conformation capture (3C) followed by high-throughput sequencing (Hi-C) with wild-type and mutant strains of Neurospora crassa to gain insight into the role of heterochromatin in the organization and function of the genome. We tested the role of three proteins thought to be important for establishment of heterochromatin, namely, the histone H3 lysine 9 methyltransferase DIM-5, Heterochromatin Protein 1 (HP1), which specifically binds to the product of DIM-5 (trimethylated H3 lysine 9 [H3K9me3]), and DIM-3 (importin alpha), which is involved in DIM-5 localization. The average genome configuration of the wild-type strain revealed strong intra- and inter-chromosomal associations between both constitutive and facultative heterochromatic domains, with the strongest interactions among the centromeres, subtelomeres, and interspersed heterochromatin. Surprisingly, loss of either H3K9me3 or HP1 had only mild effects on heterochromatin compaction, whereas dim-3 caused more drastic changes, specifically decreasing interactions between constitutive heterochromatic domains. Thus, associations between heterochromatic regions are a major component of the chromosome conformation in Neurospora, but two widely studied key heterochromatin proteins are not necessary, implying that undefined protein factors play key roles in maintaining overall chromosome organization.


Diabetes and Hepatitis C: A Two-Way Association.
Diabetes and hepatitis C infection are both prevalent diseases worldwide, and are associated with increased morbidity and mortality. Most studies, but not all, have shown that patients with chronic hepatitis C are more prone to develop type 2 diabetes (T2D) compared to healthy controls, as well as when compared to patients with other liver diseases, including hepatitis B. Furthermore, epidemiological studies have revealed that patients with T2D may also be at higher risk for worse outcomes of their hepatitis C infection, including reduced rate of sustained virological response, progression to fibrosis and cirrhosis, and higher risk for development of hepatocellular carcinoma. Moreover, hepatitis C infection and mainly its treatment, interferon α, can trigger the development of type 1 diabetes. In this review, we discuss the existing data on this two-way association between diabetes and hepatitis C infection with emphasis on possible mechanisms. It remains to be determined whether the new curative therapies for chronic hepatitis C will improve outcomes in diabetic hepatitis C patients, and conversely whether treatment with Metformin will reduce complications from hepatitis C virus infection. We propose an algorithm for diabetes screening and follow-up in hepatitis C patients.


[Production and application of monoclonal antibodies].
The following article describes both theoretical basis and detailed method for producing monoclonal antibodies in the systems of mouse and man. It further outlines methods to characterize monoclonal antibodies and produce them on a larger scale. Finally, reference is made to their application in research and medicine, and further developments are indicated.


Analysis of the validity of the vignette approach to correct for heterogeneity in reporting health system responsiveness.
Despite the growing popularity of the vignette methodology to deal with self-reported, categorical data, the formal evaluation of the validity of this methodology is still a topic of research. Some critical assumptions need to hold in order for this method to be valid. In this paper we analyse the assumption of "vignette equivalence" using data on health system responsiveness contained within the World Health Survey. We perform several tests to check the assumption of vignette equivalence. First, we use a test based on the global ordering of the vignettes. A minimal condition for the assumption of vignette equivalence to hold is that individual responses are consistent with the global ordering of vignettes. Secondly, using the hierarchical ordered probit model (HOPIT) model on the pool of countries, we undertake sensitivity analyses, stratifying countries according to the Inglehart-Welzel scale and the Human Development Index. The results of this analysis are robust, suggesting that the vignette equivalence assumption is not contradicted. Thirdly, we model the reporting behaviour of the respondents through a two-step regression procedure to evaluate whether the vignettes construct is perceived by respondents in different ways. Overall, across the analyses the results do not contradict the assumption of vignette equivalence and accordingly lend support to the use of the vignette methodology when analysing self-reported data and health system responsiveness.


Internal and External Factors Underlying Variations in Adolescents' Daily Optimal Experiences.
This study investigated how the internal psychological states (i.e., challenge-skill perception, positive and negative affect, and effortless attention) and contextual features (i.e., activity and company) of momentary experiences relate to optimal experience in adolescents' lives. Data were collected from 245 Portuguese adolescents (14-19 years old, 63% female) by using the experience sampling method. Multilevel modeling revealed that challenge-skill and positive affect were positively associated with optimal experience, while negative affect was negatively associated with optimal experience. Effortless attention mediated the associations between internal states and optimal experience, while activity and company only moderated some of these associations. These findings will inform practitioners about the factors that should be addressed in interventions with adolescents to promote optimal experiences in their lives.


Silicon doped boron clusters: how to make stable ribbons?
A doping of small boron clusters with silicon atoms leads to the formation of stable boron nanoribbon structures. We present an analysis on the geometric and electronic structure, using MOs and electron localization function (ELF) maps, of boron ribbons represented by the dianions B10Si22- and B12Si22-. The effect of Si dopants and the origin of the underlying electron count [π2(n+1)σ2n] are analyzed. Interaction between both systems of delocalized π and σ electrons creating alternant B-B bonds along the perimeter of a ribbon induces its high thermodynamic stability. The enhanced stability is related to the self-locked phenomenon.


The Missing Manuscript of Dr. Jose Delgado's Radio Controlled Bulls.
Neuroscience systems level courses teach: 1) the role of neuroanatomical structures of the brain for perception, movement, and cognition; 2) methods to manipulate and study the brain including lesions, electrophysiological recordings, microstimulation, optogenetics, and pharmacology; 3) proper interpretation of behavioral data to deduce brain circuit operation; and 4) the similarities, differences, and ethics of animal models and their relation to human physiology. These four topics come together quite dramatically in Dr. Jose Delgado's 1960s famous experiments on the neural correlates of aggression in which he stopped bulls in mid-charge by electrically stimulating basal ganglia and thalamic structures. Technical documentation on these experiments is famously difficult to find. Here I translate and discuss a Spanish language article written by Dr. Delgado in 1981 for an encyclopedia on bull fighting published in Madrid. Here Dr. Delgado appears to give the most complete explanation of his experiments on microstimulation of bovine brains. Dr. Delgado's motivations, methods, and his interpretation of the bull experiments are summarized, as well as some accompanying information from his 1970 English language book: "Physical Control of the Mind." This review of Dr. Delgado's written work on the bull experiments can provide a resource to educators and students who desire to learn more about and interpret the attention-calling experiments that Dr. Delgado did on a ranch in Andalucía over 50 years ago.


[Metastatic ovarian melanoma in a 26-year-old patient].
In a 16 year old patient a superficially spreading malignant melanoma had been excised from the left temple. Ten years later, she represented with lower abdominal pain. On examination cystic adnexal masses were found and median laparotomy was performed. Intraoperatively bilateral polycystic, dark-coloured ovarian tumors were found, each measuring about 10 x 10 x 10 cm. Hysterectomy with bilateral salpingo-oophorectomy and resection of the great omentum was performed. Uterus and ovaries weighed 3.480 g. At microscopic examination large metastases of a pigmented melanoblastoma were found in both ovaries. Two months after surgery she succumbed to multiple cerebral metastases. For primary ovarian melanoma radical surgery with lymphonodectomy is mandatory. The operation is to be followed by immuno- and chemotherapy. In case of metastatic melanoma of the ovaries individual decisions concerning the extent of the surgical procedure are to be made. In any case, however, bilateral salpingo-oophorectomy should be performed, preferably combined with hysterectomy.


[The chrysotherapy of patients with Reiter's disease].
Chrisanol therapy was provided to 172 men suffering from Reiter's disease, having histocompatibility antigen B35 and its combination with B27 as well as B17 and B11 indicating that the articular syndrome may run a persistent and grave course. Chrisanol therapy brought about a decrease of the activity of complement, lysozyme, bactericidal activity of blood serum, a reduction of the content of serum IgG, and autoimmune reactions parameters. Chrisanol therapy was tolerated well. The ten-year follow-up revealed relapses in 8.3% of the patients.


Recombinant Treponema pallidum protein Tp0965 activates endothelial cells and increases the permeability of endothelial cell monolayer.
The recombinant Treponema pallidum protein Tp0965 (rTp0965), one of the many proteins derived from the genome of T. pallidum subsp. pallidum, shows strong immunogenicity and immunoreactivity. In this study, we investigated the effects of rTp0965 on the endothelial barrier. Treatment of human umbilical vein endothelial cells (HUVECs) with rTp0965 resulted in increased levels of ICAM-1, E-selectin, and MCP-1 mRNA and protein expression. These increases contributed to the adhesion and chemataxis of monocytes (THP-1 cells) to HUVECs preincubated with rTp0965. In addition, rTp0965 induced reorganization of F-actin and decreased expression of claudin-1 in HUVECs. Interestingly, inhibition of the RhoA/ROCK signal pathway protected against rTp0965-induced higher endothelial permeability as well as transendothelial migration of monocytes. These data indicate that Tp0965 protein may play an important role in the immunopathogenesis of syphilis.


Ultrastructural evaluation of activated forms of microglia in human brain in selected neurological diseases (SSPE, Wilson's disease and Alzheimer's disease).
Activated forms of microglia were ultrastructurally evaluated in three neurological diseases of different aetiology (subacute sclerosing panencephalitis--SSPE, Wilson's disease and Alzheimer's disease). The occurrence of activated rod, ramified and amoeboid microglia was found in the investigated diseases. The widest ultrastructural variability of microglia was in SSPE, including the presence of mitotic chromosomes or centrioles in its cytoplasm, which indicates microglia proliferation. In the nuclei of activated microglia, some nuclear bodies with different structures were frequently seen, whereas lamellar structures (similar to developing Birbeck's bodies--pathognomonic to Langerhans-type dendritic cells) were observed in the cytoplasm. The activated forms of microglia with apoptotic features were found only in SSPE cases. Some apoptotic nuclei were filled with nucleocapsids of measles virus. In Alzheimer's disease, activated microglia was most frequently bound to senile plaques. Ramified microglia was in contact with amyloid fibrils, which penetrated its cytoplasm and reached the nuclear membrane and channels of rough endoplasmic reticulum, or was situated among dystrophic neurites. Rod microglia was found predominantly at the edge of senile plaques. In Wilson's disease, the ultrastructure of activated microglia showed mostly indirect forms between rod, ramified and amoeboid microglia. The microglia ultrastructure suggests that its morphological form may express functional involvement in the pathogenesis of a given disease entity.


The effects of nucleoside/nucleotide analogues on host immune cells: the baseline for future immune therapy for HBV?
HBV is a non-cytopathic virus and the progression of liver fibrosis is attributed to the host immune response. Complete suppression of viral replication using nucleotide or nucleoside analogues (NUCs) can prevent most complications related to chronic HBV infection. Unfortunately, antiviral treatment has to be administered lifelong to the majority of patients as HBV persists in the hepatocytes. However, although NUCs are very frequently administered in clinical practice, their effects on vital parts of the host immune response to HBV are not well established. In this review we summarize the currently available data gathered from longitudinal studies that investigated treatment-associated alterations of HBV-specific CD4+ and CD8+ T-cells, regulatory T-cells and natural killer (NK) cells. These observations are important, as they can guide the design of studies that investigate the efficacy of new immune therapeutic agents. Novel experimental compounds will likely be added to ongoing NUC treatment, which leads to a functional cure in only a small minority of patients.


Precision livestock farming: real-time estimation of daily protein deposition in growing-finishing pigs.
Precision feeding using real-time models to estimate daily tailored diets can potentially increase nutrient utilization efficiency. However, to improve the estimation of amino acid requirements for growing-finishing pigs, it is necessary to accurately estimate the real-time body protein (BP) mass. The aim of this study was to predict individual BP over time in order to obtain individual daily protein content of the gain (i.e., protein deposition/daily gain, PD/DG) to be integrated into a real-time model used for precision feeding. Two databases were used in this study: one for the development of the equations for the model and the other for model evaluation. For the equations, data from 79 barrows (25 to 144 kg BW) were used to estimate the parameters for a Gompertz function and a mixed linear-quadratic regression. Individual BP predictions obtained by dual X-ray absorptiometry were regressed as a function of BW. Individual pig BP estimates were obtained by linear-quadratic regression using the MIXED procedure of SAS, considering pig measurements repeated in time. Individual Gompertz curves were obtained using the NLMIXED procedure of SAS. Both procedures generate an average or a general model, which was assessed for accuracy with the database used to generate the equations. Coefficients of concordance and determination were both 0.99, and the RMSE was 0.21 kg for the linear-quadratic regression. The Gompertz curve coefficients of concordance and determination were both 0.99, and the RMSE was 0.36 kg. In sequence, the linear-quadratic regression and Gompertz curve were evaluated in an independent data set (488 observations; 21 to 126 kg BW). The linear-quadratic regression to predict BP mass was accurate (mean absolute percentage error (MAPE) = 2.5%; bias = 0.03); the Gompertz model performed worse (MAPE = 3.9%; bias = 0.04) than the linear-quadratic regression. When using the derivative of these equations to predict PD/DG, the linear-quadratic regression was more accurate (MAPE = 4.8%, bias = 0.17%) compared to the Gompertz (MAPE = 10.6%, bias = -0.99%) mainly due to the linear decrease in PD/DG in the observed data. Further analysis using individual pig data showed that the goodness of fit of PD/DG curve depends on the individual shape of the growth curve, with either the Gompertz or the linear-quadratic regression being more accurate for specific individuals. Therefore, both approaches are provided to allow end users to select the model that best fits their needs. The proposed update of the empirical component of the original model, using either linear-quadratic regression or the Gompertz function, is able to predict BP in real-time with good accuracy.


Social Media and Social Functioning in Psychosis: A Systematic Review.
Individuals with psychosis are heavy consumers of social media. It is unknown to what degree measures of social functioning include measures of online social activity. To examine the inclusion of social media activity in measures of social functioning in psychosis and ultrahigh risk (UHR) for psychosis. Two independent authors conducted a search using the following electronic databases: Epistemonikos, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, MEDLINE, Embase, and PsycINFO. The included articles were required to meet all of the following criteria: (1) an empirical study published in the English language in a peer-reviewed journal; (2) the study included a measure of objective or subjective offline (ie, non-Web-mediated contact) and/or online social functioning (ie, Web-mediated contact); (3) the social functioning measure had to be used in samples meeting criteria (ie, Diagnostic and Statistical Manual of Mental Disorders or International Classification of Diseases) for a psychotic disorder or UHR for psychosis; and (4) the study was published between January 2004 and February 2019. Facebook was launched as the first large-scale social media platform in 2004 and, therefore, it is highly improbable that studies conducted prior to 2004 would have included measures of social media activity. The electronic search resulted in 11,844 distinct articles. Full-text evaluation was conducted on 719 articles, of which 597 articles met inclusion criteria. A total of 58 social functioning measures were identified. With some exceptions, reports on reliability and validity were scarce, and only one measure integrated social media social activity. The ecological validity of social functioning measures is challenged by the lack of assessment of social media activity, as it fails to reflect an important aspect of the current social reality of persons with psychosis. Measures should be revised to include social media activity and thus avoid the clinical consequences of inadequate assessment of social functioning. International Prospective Register of Systematic Reviews (PROSPERO) CRD42017058514; http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017058514.


Irradiated oocysts in combination with inulin adjuvant-induced potent immune responses against Eimeria tenella infection in broiler chickens.
Coccidiosis is the leading parasitic disease in poultry. One of the most critical Eimeria species, Eimeria tenella, lives inside the cecal epithelial cells and induces bloody coccidiosis. The present study evaluated the effect of radiation-attenuated E. tenella oocytes mixed with inulin adjuvant on broiler chicken. Initially, the effect of irradiation on oocyst attenuation was confirmed. Then, one-day-old broilers (n = 90) were divided into nine groups on seven days of age as follow: Group 1 (400 attenuated oocysts + 1.00 mg of adjuvant), group 2 (400 attenuated oocysts + 0.50 mg adjuvant), group 3 (200 attenuated oocysts + 1.00 mg of adjuvant), group 4 (200 attenuated oocysts + 0.50 mg adjuvant), group 5 (1.00 mg adjuvant), group 6 (400 attenuated oocysts), group 7 (commercial vaccine), group 8 (negative control) and group 9 (blank). On day 21, we performed a challenge with E. tenella oocytes and investigated oocyst output and average weekly weight throughout the study. At the end of the study, we evaluated macroscopic lesion, histology, cytokine level and leukogram status. The results showed a statistically significant difference among groups. Furthermore, the optimal dose was 400 irradiated oocysts and 1.00 mg of inulin. Moreover, an X-ray could reduce the virulence of E. tenella oocytes. Inulin alone or combined with attenuated oocysts showed an acceptable effect on evaluated parameters.


Variable Colonization after Reciprocal Fecal Microbiota Transfer between Mice with Low and High Richness Microbiota.
Several associations have been made between characteristics of the resident gut microbiota and human health and disease susceptibility. Animal models provide the means to test these correlations prospectively and evaluate causality. Experimental fecal microbiota transfer (FMT), or the intentional transplantation of gut microbes into recipient mice depleted of their autochthonous microbes with antibiotics, is a commonly used method of testing these relationships. The true completeness of microbial transfer through such procedures is poorly documented in the literature, particularly in the context of reciprocal transfer of microbes between recipient and donor mice harboring microbial populations of differing richness and diversity. Moreover, it is unclear whether the use of frozen fecal contents or cecal contents would confer any difference in the outcomes of transfer. Herein, groups of mice colonized with distinct gut microbiota of differing richness and composition were used in a reciprocal FMT study, with different groups receiving transfer of material prepared from fresh cecal contents, fresh feces, or frozen feces. Targeted 16S rRNA gene amplicon sequencing was used at intervals throughout the study to characterize the microbiota. Notably, despite comparable depletion of the microbiota in recipient mice prior to transfer, donor-specific taxa reliably colonized recipients only when relatively rich donor material was transferred to mice originally colonized with a simpler microbiota. It is unclear whether these differences were due to differences in the endogenous recipient microbiota or host factors induced in early life by microbial factors. These findings are of practical import for researchers using FMT to prospectively assess the influence of the gut microbiota in mouse models, and to those studying host-microbial interactions and their influence on gut barrier function.


Granular cell tumors.
A lesion of unknown etiology and histogenesis, the granular cell tumor usually arises in the skin or soft tissue. It has been reported, however, in other sites and can be multifocal. The authors have seen 31 such tumors in 26 patients in their institutions since 1970. Most (21) patients were females, and 12 patients were black. The average age was 41.8 years, excluding two newborns with a congenital granular cell myoblastoma of the gingiva. The most common site of occurrence was the skin; seven tumors originated from the trunk and five from the extremities. Four lesions were found in the breast, three on the vulva, two in the axilla, two in the gum, two in the buccal cavity, two in the esophagus, and one each in the stomach, gluteus muscle, eyelid, and bronchus. Two patients had multiple synchronous lesions. These were bilateral hand lesions in one patient, and lesions of the breast and axilla in the other. A third patient had three separate lesions which arose over the course of 5 years, involving the bronchus, the gluteus muscle, and the buccal mucosa. An additional esophageal lesion was an incidental finding 3 years after excision of a granular cell tumor of the breast. All of the tumors were removed with local, simple excision, except for the 2-cm lesion in the stomach for which a wedge resection of the fundus was necessary and the bronchial lesion for which a wedge resection of the left upper lobe of the lung was performed.(ABSTRACT TRUNCATED AT 250 WORDS)


Mitochondrial miRNA Determines Chemoresistance by Reprogramming Metabolism and Regulating Mitochondrial Transcription.
miRNAs that translocate from the nucleus to mitochondria are referred to as mitochondrial microRNAs (mitomiR). mitomiRs have been shown to modulate the translational activity of the mitochondrial genome, yet their role in mitochondrial DNA (mtDNA) transcription remains to be determined. Here we report that the mitomiR-2392 regulates chemoresistance in tongue squamous cell carcinoma (TSCC) cells by reprogramming metabolism via downregulation of oxidative phosphorylation and upregulation of glycolysis. These effects were mediated through partial inhibition of mtDNA transcription by mitomiR-2392 rather than through translational regulation. This repression required specific miRNA-mtDNA base pairing and Argonaute 2. mitomiR-2392 recognized target sequences in the H-strand and partially inhibited polycistronic mtDNA transcription in a cell-specific manner. A retrospective analysis of TSCC patient tumors revealed a significant association of miR-2392 and regulated mitochondrial gene expression with chemosensitivity and overall survival. The clinical relevance of targeted mitochondrial genes was consistently validated by The Cancer Genome Atlas RNA sequencing in multiple types of cancer. Our study revealed for the first time the role of mitomiR in mtDNA transcription and its contribution to the molecular basis of tumor cell metabolism and chemoresistance.Significance: These findings uncover a novel mechanism by which mitomiRNA regulates mitochondrial transcription and provide rationale for use of mitomiRNA and mtDNA-encoded genes to predict chemosensitivity and patient clinical prognosis.


Reducing the incidence of domestic violence: An observational study of an equine-assisted intervention.
This paper is presenting results from an observational study which has measured the impact of an equine-assisted education (EAE) intervention on the future occurrence of domestic violence within the family over 1 year following completion of the intervention as part of the troubled families program. The data analyzed were collected by the local authority troubled family's team from the different agencies involved including crime, health, and social care data. The data were analyzed and compared across four groups, those families on the troubled families program who had a key worker with a member or members who had attended and completed the equine-assisted intervention (n = 268); those families who were on the troubled families program but no support had been offered (n = 10,569), those families who were on the program and were being supported by a key worker only (n = 2119), and those families on the program who were being supported by a key worker and had received further support, not from the equine-assisted intervention (N = 1119). Significant reductions in domestic violence and child in need status were found for those families who had a member or members attend and complete the equine-assisted intervention under study. Those families referred to the equine-assisted intervention also had significantly more complex needs than those in the other groups. Referrals to this intervention are normally for those families for whom talk-based interventions such as parenting, or education-based interventions are not working.


[Diagnosis and therapy of basilar artery occlusion].
In view of the poor prognosis for untreated patients with basilar artery occlusion, rapid delivery of effective treatment has the highest priority. Early recanalization by intra-arterial thrombolysis can improve the outcome in some patients. Apart from this method, specialized centers are increasingly using mechanical devices and glycoprotein IIb/IIIa inhibitors to achieve recanalization. This review focuses on current developments in the diagnosis and treatment of acute basilar artery occlusion.


Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.
Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.


Electrostatic attraction between neutral microdroplets by ion fluctuations.
The interaction between two aqueous droplets containing ions is investigated. The ion-fluctuation correlation gives rise to attraction between two neutral microdroplets, similar to the van der Waals interaction between neutral atoms. Electrostatic attraction consists of contributions from various induced multipole-multipole interactions, including dipole-dipole < P(2)(z) >(2) r(-6), dipole-quadrupole < P(2)(z) > < Q (2)(zz ) > r(-8), dipole-octupole < P(2)(z) > < O (2)(zzz ) > r(-10), and quadrupole-quadrupole interactions < Q (2)(zz ) >(2) r(-10). The mean-square multipole moments are determined analytically by linear response theory. The fluctuation-driven attraction is so strong at short distance that it may dominate over the Coulomb repulsion between like-charged droplets. These theoretical results are confirmed by Monte Carlo simulations.


Membrane fluidity and oxygen diffusion in cholesterol-enriched erythrocyte membrane.
This work studied the effect of cholesteryl hemisuccinate incorporation on membrane fluidity and on the kinetics of oxygen diffusion at different depths in the erythrocyte membrane. Cholesterol concentration in the membrane was expressed as the cholesterol-protein ratio (C/Pt). The membrane fluidity, as assessed by a fluorescence polarization method with diphenyl-hexatriene and 1-(4-trimethylamino)-6-phenylhexa-1,3,5-triene, decreased as the C/Pt ratio increased. Time-resolved fluorescence spectroscopy of pyrene dodecanoic acid (PDA) under an increasing C/Pt ratio in the erythrocyte membrane revealed enhanced oxygen diffusion in the middle of the membrane bilayer (in which PDA was incorporated), which was not the case with pyrene butyric acid (PBA) incorporated in the internal part of the membrane surface. It has generally been accepted that increased membrane fluidity reduces the physical barrier to oxygen permeation. Such conflicting observations on oxygen permeation in the rigidified erythrocyte membrane could be due to variations in oxygen solubility (preferential partitioning) in different polarity microdomains (cholesterol and phospholipid partitions).


[Determination of Sevoflurane, Isoflurane and Enflurane in the air of workplace by gas chromatography].
Objective: To establish a solvent desorption gas chromatographic method for determination of Sevoflurane, Isoflurane and Enflurane in the air of the Workplace. Methods: Sevoflurane, Isoflurane and Enflurane were collected with activated carbon tube and desorbed with dichloromethane, separated with DB-1 capillary columns, and then detected with flame ionization detector. Results: The linearity ranges were 1.9-304.8 μg/ml for Sevoflurane, 2.1-300.4 μg/ml for Isoflurane and 1.7-305.2 μg/ml for Enflurane, The correlation coefficient was both >0.999. Their limits of detection were 0.6 μg/ml, 0.6 μg/ml and 0.5 μg/ml, and Their limits of quatification were 1.9 μg/ml, 2.1 μg/ml and 1.7 μg/ml, and their minimum detectable concentrations were 0.1、0.2 and 0.1 mg/m(3) per 4.5 L of air. Their relative standard deviations (RSD) were 2.5%-3.0%, 2.3%-3.1% and 2.2%-3.0%. The average desorption efficiencies were 101.1%-103.3%, 100.7%-102.7% and 101.0%-102.9%. The sampling efficiency was both 100%. The breakthrough volume of 100 mg actived carbon was 3.7 mg, 3.4 mg and 3.4 mg. Sevoflurane, Isoflurane and Enflurane in activated carbon tube could be kept at least 10 days at room temperature without significant losses. Conclusion: The method shows lower detection limit, high accuracy and precision. It is feasible for determination of Sevoflurane, Isoflurane and Enflurane in the air of workplace.


Functional and Structural Characterization of a (+)-Limonene Synthase from Citrus sinensis.
Terpenes make up the largest and most diverse class of natural compounds and have important commercial and medical applications. Limonene is a cyclic monoterpene (C10) present in nature as two enantiomers, (+) and (-), which are produced by different enzymes. The mechanism of production of the (-)-enantiomer has been studied in great detail, but to understand how enantiomeric selectivity is achieved in this class of enzymes, it is important to develop a thorough biochemical description of enzymes that generate (+)-limonene, as well. Here we report the first cloning and biochemical characterization of a (+)-limonene synthase from navel orange (Citrus sinensis). The enzyme obeys classical Michaelis-Menten kinetics and produces exclusively the (+)-enantiomer. We have determined the crystal structure of the apoprotein in an "open" conformation at 2.3 Å resolution. Comparison with the structure of (-)-limonene synthase (Mentha spicata), which is representative of a fully closed conformation (Protein Data Bank entry 2ONG ), reveals that the short H-α1 helix moves nearly 5 Å inward upon substrate binding, and a conserved Tyr flips to point its hydroxyl group into the active site.


Dipole and multipole models of dielectrophoresis for a non-negligible particle size: Simulations and experiments.
Mathematical models of dielectrophoresis play an important role in the design of experiments, analysis of results, and even operation of some devices. In this paper, we test the accuracy of existing models in both simulations and laboratory experiments. We test the accuracy of the most common model that involves a point-dipole approximation of the induced field, when the small-particle assumption is broken. In simulations, comparisons against a model based on the Maxwell stress tensor show that even the point-dipole approximation provides good results for a large particle close to the electrodes. In addition, we study a refinement of the model offered by multipole approximations (quadrupole, and octupole). We also show that the voltages on the electrodes influence the error of the model because they affect the positions of the field nulls and the nulls of the higher-order derivatives. Experiments with a parallel electrode array and a polystyrene microbead reveal that the models predict the force with an error that cannot be eliminated even with the most accurate model. Nonetheless, it is acceptable for some purposes such as a model-based control system design.


Comparative analysis of fecal microbial communities in cattle and Bactrian camels.
Bactrian camels may have a unique gastrointestinal (GI) microbiome because of their distinctive digestive systems, unique eating habits and extreme living conditions. However, understanding of the microbial communities in the Bactrian camel GI tract is still limited. In this study, microbial communities were investigated by comparative analyses of 16S rRNA hypervariable region V4 sequences of fecal bacteria sampled from 94 animals in four population groups: Inner Mongolian cattle (IMG-Cattle), Inner Mongolian domestic Bactrian camels (IMG-DBC), Mongolian domestic Bactrian camels (MG-DBC), and Mongolian wild Bactrian camels (MG-WBC). A total of 2,097,985 high-quality reads were obtained and yielded 471,767,607 bases of sequence. Firmicutes was the predominant phylum in the population groups IMG-Cattle, IMG-DBC and MG-WBC, followed (except in the Inner Mongolian cattle) by Verrucomicrobia. Bacteroidetes were abundant in the IMG-DBC and MG-WBC populations. Hierarchical clustered heatmap analysis revealed that the microbial community composition within the three Bactrian camel groups was relatively similar, and somewhat distinct from that in the cattle. A similar result was determined by principal component analysis, in which the camels grouped together. We also found several species-specific differences in microbial communities at the genus level: for example, Desulfovibrio was abundant in the IMG-DBC and MG-WBC groups; Pseudomonas was abundant in the IMG-Cattle group; and Fibrobacter, Coprobacillus, and Paludibacter were scarce in the MG-WBC group. Such differences may be related to different eating habits and living conditions of the cattle and the various camel populations.


Outcome of lung transplantation for patients requiring concomitant cardiac surgery.
The clinical results of lung transplantation and concomitant cardiac surgery are unclear. The effect of cardiopulmonary bypass on the pulmonary allograft is controversial, and the effect of cardiac arrest and cardiac surgery in this setting is unknown. Our aim was to review the operative results and long-term survival in this group of patients. A retrospective review of all lung transplantations between 1988 and 2003 was performed. Patients who had concomitant cardiac surgery during lung transplantation were compared with those who underwent lung transplantation alone. The variables analyzed included allograft ischemic times, use of cardiopulmonary bypass, early graft dysfunction, postoperative morbidity, survival, length of mechanical ventilation, length of stay in the intensive care unit, and overall hospital stay. During this period, 35 of 700 lung transplant recipients (15 single and 20 bilateral transplantations) underwent concomitant cardiac surgery. The cardiac procedures were for patent foramen ovale (n = 18), atrial septal defect (n = 9), ventricular septal defect (n = 2), coronary bypass (n = 4), and "other" (n = 2). Allograft ischemic time, use of extracorporeal membrane oxygenation, length of hospital stay, operative mortality, and survival were not significantly different between the 2 groups. Ventilator time and intensive care unit stay were longer in the cardiac surgery group. Cardiac surgery at the time of lung transplantation can be performed with acceptable morbidity and mortality. The immediate and long-term survival in these patients is similar to that of other lung transplant recipients. Lung transplantation should continue to be offered to patients with normal ventricular function who require concomitant limited cardiac surgery.


Safe Synthesis of 4,7-Dibromo[1,2,5]thiadiazolo[3,4-d]pyridazine and Its SNAr Reactions.
A safe and efficient synthesis of 4,7-dibromo[1,2,5]thiadiazolo[3,4-d]pyridazine from the commercial diaminomaleonitrile is reported. Conditions for selective aromatic nucleophilic substitution of one or two bromine atoms by oxygen and nitrogen nucleophiles are found, whereas thiols formed the bis-derivatives only. Buchwald-Hartwig or Ullmann techniques are successful for incorporation of a weak nitrogen base, such as carbazole, into the [1,2,5]thiadiazolo[3,4-d]pyridazine core. The formation of rather stable S…η²-(N=N) bound chains in 4,7-bis(alkylthio)-[1,2,5]thiadiazolo[3,4-d]pyridines makes these compounds promising for the design of liquid crystals.


Characterization of FtsY, its interaction with Ffh, and proteomic identification of their potential substrates in Mycobacterium tuberculosis.
The universally conserved signal recognition particle (SRP) pathway that mediates co-translational targeting of membrane and secretory proteins is essential for eukaryotic and prokaryotic cells. The Mycobacterium tuberculosis SRP pathway consists of 2 proteins, Ffh and FtsY, and a 4.5S RNA molecule. Although the Escherichia coli SRP pathway is well studied, understanding of the M. tuberculosis SRP pathway components is very limited. In this study, we have overexpressed and characterized the M. tuberculosis SRP receptor (SR) FtsY as a GTP binding protein. Further, we established the direct protein-protein interaction between Ffh and FtsY. The Ffh-FtsY complex formation resulted in mutual stimulation of their GTP hydrolysis activity. We also attempted to biochemically characterize the SRP components by constructing the antisense gene knockdown strains of ffh and ftsY in M. tuberculosis. Loss of ffh and ftsY resulted in a decreased in vitro growth rate of the antisense ffh strain as compared with the antisense ftsY strain. Finally, 2-D gel electrophoresis of antisense depleted ffh and ftsY strains identified differential expression of 14 proteins.


Survey mode and nonresponse bias: A meta-analysis based on the data from the international social survey programme waves 1996-2018 and the European social survey rounds 1 to 9.
The constant increase in survey nonresponse and fieldwork costs are the reality of survey research. Together with other unpredictable events occurring in the world today, this increase poses a challenge: the necessity to accelerate a switch from face-to-face data collection to different modes, that have usually been considered to result in lower response rates. However, recent research has established that the simple response rate is a feeble measure of study quality. Therefore, this article aims to analyze the effect of survey characteristics, especially the survey mode, on the nonresponse bias. The bias measure used is the internal criteria first proposed by Sodeur and first applied by Kohler. The analysis is based on the survey documentation and results from the International Social Survey Programme waves 1996-2018 and the European Social Survey rounds 1 to 9. Random-effects three-level meta-regression models, based on data from countries from each inhabited continent, were created in order to estimate the impact of the survey mode or modes, sampling design, fieldwork experience, year of data collection, and response rate on the nonresponse bias indicator. Several ways of nesting observations within clusters were also proposed. The results suggest that using mail and some types of mixed-mode surveys were connected to lower nonresponse bias than using face-to-face mode surveys.


The panacea statistical toolbox of a biomedical peer reviewer.
The main role of a peer reviewer is to make judgments on the research articles by asking a number of questions to evaluate the quality of the research article. Statistics is a major part of any biomedical research article, and most reviewers gain their experiences in manuscript reviewing by undertaking it but not through an educational process. Therefore, reviewers of the biomedical journals normally do not have enough knowledge and skills to evaluate the validity of statistical methods used in biomedical research articles submitted for consideration. Hence, inappropriate statistical analysis in medical journals can lead to misleading conclusions and incorrect results. In this paper, the most common basic statistical guidelines are described that might be a road map to the biomedical reviewers. It is not meant for statisticians or medical editors who have special interest and expertise in statistical analysis.


Characteristics of diabetic macular edema on optical coherence tomography may change over time or after treatment.
To investigate optical coherence tomography (OCT) characteristics in diabetic macular edema (DME) over time and after treatment. OCT morphological features in DME eyes treated with ranibizumab with at least 1 year of follow-up were retrospectively analyzed. Thirty-five eyes were included. From baseline to Month 12, mean visual gain was 7.2±13.6 letters and mean central retinal thickness reduction was 61.9±121.8 μm. Fovea-involving ellipsoid zone (EZ) disruption was significantly associated with final vision of <70 letters. Subretinal fluid at baseline was present only in eyes naïve to previous intravitreal pharmacotherapy and was related to better visual gain and fewer injections. Treatment-naïve eyes had shorter DME duration and less EZ damage. DME characteristics on OCT may change over time or after treatment. Subretinal fluid may be associated with earlier change and less EZ damage in DME.


Anxiety Levels among Five-Year-Old Children Undergoing ART Restoration- A Cross-Sectional Study.
Atraumatic Restorative Treatment (ART) involves manually excavating the carious part of the tooth and restoring the prepared cavity with chemically adhesive restorative material [Glass Ionomer Cement (GIC)] and it may induce and/or impact the dental anxiety in children. It is well established that ART procedure is less anxiety producing when compared with other restorative procedures using dental drill. The aim of this study was to evaluate the anxiety levels among five-year-old children undergoing ART restoration in I.T.S. Dental College, Greater Noida, India. A sample of 50, five-year-old children visiting the Outpatient Department (OPD) of ITS Dental College, Greater Noida was selected for ART treatment using Fuji IX GIC. Modified Venham Anxiety Scale based on their behaviour and heart rate of the children were measured and recorded before, during and after the ART procedure. Heart rate was measured using Radial Pulse examination method. Chi-square test was used and tests were conducted using IBM SPSS software (ver.20.0; IBM, Chicago, IL, USA). Before the ART treatment, heart rates and Modified Venham Anxiety Scores of majority of children were higher than that after the treatment. A p-value was statistically significant (0.028 and 0.048 respectively) for association of gender with heart rate and Modified Venham's score before the ART treatment. No statistically significant relation was found between the variables during and after the ART treatment. The level of anxiety for ART treatment in children was higher before the treatment than that during and after the treatment. There is a correlation between the gender of children and their level of anxiety for ART treatment.


Photoactivated 3-azioctanol irreversibly desensitizes muscle nicotinic ACh receptors via interactions at alphaE262.
3-Azioctanol is a photoactivatable analogue of octanol that noncompetitively inhibits nicotinic acetylcholine receptors (nAChRs). Photolabeling studies using [3H]-3-azioctanol in Torpedo nAChR identified alphaE262 as a site of desensitization-dependent incorporation. However, it is unknown whether photolabeling of alphaE262 causes functional effects in nAChRs and what other roles this residue plays in gating, desensitization, and channel block. We used ultrafast patch-perfusion electrophysiology and ultraviolet (UV) irradiation to investigate the state-dependence of both reversible nAChR inhibition by 3-azioctanol and the irreversible effects of photoactivated 3-azioctanol. Channels with mutations at alphaE262 were studied to determine ACh EC50s, desensitization rates, and sensitivities to reversible and photoirreversible 3-azioctanol inhibition. Exposure to 3-azioctanol in the presence of 365 nm UV light produced irreversible inhibition of wild-type nAChRs. Desensitization with ACh dramatically increased the degree of irreversible inhibition by photoactivated 3-azioctanol. Mutations at alphaE262 that reduce diazirine photomodification decreased the irreversible inhibition induced by photoactivated 3-azioctanol. Hydrophobic mutations at alphaE262 significantly slowed rapid ACh-induced desensitization and dramatically slowed fast resensitization. In contrast, alphaE262 mutations minimally affected 3-azioctanol channel block, and a half blocking concentration of 3-azioctanol did not alter the rate of ACh-induced fast desensitization. Our results indicate that position alphaE262 on muscle nAChRs contributes to an allosteric modulator site that is strongly coupled to desensitization. Occupation of this pocket by hydrophobic molecules stabilizes a desensitized state by slowing resensitization.


Benchmarking post-GWAS analysis tools in major depression: Challenges and implications.
Our knowledge of complex disorders has increased in the last years thanks to the identification of genetic variants (GVs) significantly associated with disease phenotypes by genome-wide association studies (GWAS). However, we do not understand yet how these GVs functionally impact disease pathogenesis or their underlying biological mechanisms. Among the multiple post-GWAS methods available, fine-mapping and colocalization approaches are commonly used to identify causal GVs, meaning those with a biological effect on the trait, and their functional effects. Despite the variety of post-GWAS tools available, there is no guideline for method eligibility or validity, even though these methods work under different assumptions when accounting for linkage disequilibrium and integrating molecular annotation data. Moreover, there is no benchmarking of the available tools. In this context, we have applied two different fine-mapping and colocalization methods to the same GWAS on major depression (MD) and expression quantitative trait loci (eQTL) datasets. Our goal is to perform a systematic comparison of the results obtained by the different tools. To that end, we have evaluated their results at different levels: fine-mapped and colocalizing GVs, their target genes and tissue specificity according to gene expression information, as well as the biological processes in which they are involved. Our findings highlight the importance of fine-mapping as a key step for subsequent analysis. Notably, the colocalizing variants, altered genes and targeted tissues differed between methods, even regarding their biological implications. This contribution illustrates an important issue in post-GWAS analysis with relevant consequences on the use of GWAS results for elucidation of disease pathobiology, drug target prioritization and biomarker discovery.


Memristor Neural Network Circuit Based on Operant Conditioning With Immediacy and Satiety.
Most of the operant conditioning only consider the basic theory, but the influencing factors such as immediacy and satiety are ignored. In this paper, a memristor neural network circuit based on operant conditioning with immediacy and satiety is proposed. The designed circuit is mainly composed of voltage control modules, synapse modules and promotion-suppression modules. The various processes of operant conditioning theory are realized. The relationship between positive reward and negative punishment is implemented through promotion-suppression modules and synapse modules. The influence of immediacy on operant conditioning is achieved through voltage control module. The effect of satiety on operant conditioning is discussed using memristive non-volatility. The study of operant conditioning may provide a reference for smarter brain-like nerves.


Application of Bacillus megaterium MCR-8 improved phytoextraction and stress alleviation of nickel in Vinca rosea.
The current research was performed to evaluate the effect of Bacillus megaterium MCR-8 on mitigation of nickel (Ni) stress in Vinca rosea grown on Ni-contaminated soil (50, 100, and 200 mg Ni kg-1 soil). The treated plants exhibited reduced growth, biomass, gas exchange capacity, and chlorophyll (Chl) content under Ni stress. The inoculated plants growing in Ni-contaminated media exhibited relatively higher growth, total soluble protein, and proline contents. Similarly, bacterial inoculation improved the activity of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and ascorbate peroxidase (APX) under Ni stress. The Ni stress alleviation in inoculated plants was attributed to the reduced level of malondialdehyde (MDA) and hydrogen peroxide (H2O2), enhanced synthesis of protein, proline, phenols, and flavonides in conjunction with improved activity of antioxidant enzymes. The growth-promoting characteristics of microbe such as 1-aminocyclopropane-1-carboxylate deaminase (ACCD) and phosphate solubilization activity, siderophore, and auxin production capability also improved the growth and stress mitigation in inoculated plants. Furthermore, the inoculated plants exhibited higher value for bioconcentration factor (BCF), translocation factor (TF), and resulted in higher loss of Ni content from soil. The current results exhibited the beneficial role of B. megaterium MCR-8 regarding stress alleviation and Ni phytoextraction by V. rosea.


Clinical and histopathological features of cutaneous manifestations of adult-onset Still disease.
Adult-onset Still disease (AOSD) is a rare autoinflammatory syndrome characterized by recurring fevers, arthralgia, and consistent laboratory abnormalities that include leukocytosis and hyperferritinemia. Skin findings accompany the disease in nearly 90% of the cases. Early reports described evanescent, pruritic, salmon-pink or urticarial lesions, referred to as the typical eruption of AOSD. Histopathologic findings consist of superficial perivascular dermatitis with varying number of interstitial neutrophils. Later reports described a more persistent rash that tended to be photodistributed, hyperpigmented, often in a linear configuration, sometimes in a rippled pattern, referred to as the atypical eruption of AOSD. The presence of individual necrotic keratinocytes in the upper spinous layer has been the consistent histopathologic finding. The persistent rash may not represent an atypical presentation of AOSD as recent reports indicate a high prevalence of the rash. Emerging data also suggest that patients with persistent eruption have a worse prognosis. The recognition of the clinical and histopathological findings of skin eruptions of AOSD may facilitate an earlier diagnosis, potentially improving disease outcome. Herein, clinical and histopathological features of cutaneous manifestation of AOSD in 2 Asian women are highlighted accompanied by a relevant review of the disease.


Simple Technique for Study of Cortical Arousal Response.
A new method is described for eliciting a stable spindle burst response after the production of unilateral lesions in the reticular formation of the cat. This permits quantifying the effects of stimulation of the reticular activating system, either electrically or by injection of epinephrine, on the cortical arousal response.


Effect of early immunization on antibody response to reimmunization with measles vaccine as demonstrated by enzyme-linked immunosorbent assay (ELISA).
A measles epidemic in San Antonio, Texas provided a population of children who were immunized at less than or equal to 10 months of age and reimmunized at greater than or equal to 15 months of age. Of these children, 302 were evaluated for measles antibody by the sensitive enzyme-linked immunosorbent assay (ELISA), and their responses were compared with those of 300 children who had been immunized at the customary time (greater than or equal to 15 months) with a single immunization. There were only five seronegative findings in each group. The children immunized at the customary time did have significantly higher (P less than .001) antibody titers than the children immunized at less than or equal to 10 months and reimmunized at greater than or equal to 15 months. These results indicate that early immunization followed by reimmunization may be indicated when young infants are at significant risk of measles exposure. This approach should not create an increased number of serologically nonresponsive children when reimmunized at greater than or equal to 15 months.


Robust Optimization of Biological Protocols.
When conducting high-throughput biological experiments, it is often necessary to develop a protocol that is both inexpensive and robust. Standard approaches are either not cost-effective or arrive at an optimized protocol that is sensitive to experimental variations. We show here a novel approach that directly minimizes the cost of the protocol while ensuring the protocol is robust to experimental variation. Our approach uses a risk-averse conditional value-at-risk criterion in a robust parameter design framework. We demonstrate this approach on a polymerase chain reaction protocol and show that our improved protocol is less expensive than the standard protocol and more robust than a protocol optimized without consideration of experimental variation.


C. elegans PAT-4/ILK functions as an adaptor protein within integrin adhesion complexes.
Mammalian integrin-linked kinase (ILK) was identified in a yeast two-hybrid screen for proteins binding the integrin beta(1) subunit cytoplasmic domain. ILK has been implicated in integrin-mediated signaling and is also an adaptor within integrin-associated cytoskeletal complexes. We identified the C. elegans pat-4 gene in previous genetic screens for mutants unable to assemble integrin-mediated muscle cell attachments. Here, we report that pat-4 encodes the sole C. elegans homolog of ILK. In pat-4 null mutants, embryonic muscle cells form integrin foci, but the subsequent recruitment of vinculin and UNC-89 as well as actin and myosin filaments to these in vivo focal adhesion analogs is blocked. Conversely, PAT-4/ILK requires the ECM component UNC-52/perlecan, the transmembrane protein integrin, and the novel cytoplasmic attachment protein UNC-112 to be properly recruited to nascent attachments. Transgenically expressed "kinase-dead" ILK fully rescues pat-4 loss-of-function mutants. We also identify UNC-112 as a new binding partner for ILK. Our data strengthens the emerging view that ILK functions primarily as an adaptor protein within integrin adhesion complexes and identifies UNC-112 as a new ILK binding partner.


[A new model for medical care to multi-admitted patients].
Patients with chronic conditions are often readmitted to hospital. A study was designed to improve health care to these patients. Patients attended at the Internal Medicine Department of a hospital area who were admitted to hospital at least three times in a year were included in the study. Within a prospective study, patients were attended by means of specific consultation with care upon request and telephone care, with the possibility of programmed admission. Patients were followed for 32 months, with a 45% decrease in the admission rate, 50% in visits to the Emergency Department, and 26% in hospital stay days. The proposed care model decrease the attending needs for these patients.


RNA-dependent RNA polymerase activity of Classical swine fever virus NS5B protein expressed in natural host cells.
The NS5B gene, cloned from Classical swine fever virus (CSFV) genome, was expressed in porcine kidney cells PK-15, natural host of CSFV. In purifying cytoplasmic extracts from these cells by means of different concentrations of salt, glycerol and detergent four fractions, namely crude supernatant (SC) and different purified supernatants (S1, S2 and S3) were obtained. Using Western blot analysis the NS5B protein was found in all these fractions, showing that it was soluble in both higher and lower concentrations of salt, glycerol and detergent. The NS5B protein present in the four different fractions exhibited RNA-dependent RNA polymerase (RdRp) activity, but it was unable to complete the whole process of RNA synthesis. Site-directed mutation analysis showed that Thy216 and Cyt228 were essential for RNA synthesis while Cyt219 was not, suggesting that CSFV RdRp was template-specific. We conclude that initiation of RNA synthesis by CSFV RdRp includes also template priming.


Randomized double-blind placebo-controlled trial of perhexiline in heart failure with preserved ejection fraction syndrome.
Recently heart failure with preserved ejection fraction (HFpEF) has emerged as a huge epidemic. Increasing evidence shows the role of energy deficiency in the pathophysiology of HFpEF. In the current study, we hypothesize that the use of metabolic modulator perhexiline would correct myocardial energy deficiency and improve exercise capacity and diastolic abnormalities in patients with this syndrome.


Real-time polymerase chain reaction and laser capture microdissection for the diagnosis of BK virus infection in renal allografts.
We used real-time polymerase chain reaction (PCR) technology to detect BK virus (BKV) in H and E-stained kidney biopsy sections, using laser capture microdissection. Renal allograft biopsy specimens from 4 patients with the histopathologic diagnosis of BKV-associated nephropathy (BKVAN; group 1) and 3 patients suspected to have BKVAN but without diagnostic histologic features (group 2) were retrieved. Diagnostic inclusion-bearing cells were microdissected by laser capture microscopy from group 1. Renal tubular epithelial cells were microdissected randomly in group 2. DNA was extracted and real-time amplification performed using primers targeting the large "T" and small "t" regions of the BKV and JC virus genomes. Tubular epithelial cells from a case without evidence of BKV infection were used as negative controls in a similar reaction. BKV presence was demonstrated only in epithelial cells containing typical viral inclusions. Group 2 and negative control samples were confirmed as negative for BKVAN. Real-time PCR technology can be used to detect BKV in H and E-stained, paraffin-embedded tissue sections. This technique detected BKV in tubular epithelial cells of renal allografts. To our knowledge, this is the first report of detecting BKV in laser capture microdissected renal biopsy specimens using real-time PCR.