High-pressure protein crystal structure analysis of Escherichia coli dihydrofolate reductase complexed with folate and NADP.
A high-pressure crystallographic study was conducted on Escherichia coli dihydrofolate reductase (ecDHFR) complexed with folate and NADP+ in crystal forms containing both the open and closed conformations of the M20 loop under high-pressure conditions of up to 800 MPa. At pressures between 270 and 500 MPa the crystal form containing the open conformation exhibited a phase transition from P21 to C2. Several structural changes in ecDHFR were observed at high pressure that were also accompanied by structural changes in the NADP+ cofactor and the hydration structure. In the crystal form with the closed conformation the M20 loop moved as the pressure changed, with accompanying conformational changes around the active site, including NADP+ and folate. These movements were consistent with the suggested hypothesis that movement of the M20 loop was necessary for ecDHFR to catalyze the reaction. In the crystal form with the open conformation the nicotinamide ring of the NADP+ cofactor undergoes a large flip as an intermediate step in the reaction, despite being in a crystalline state. Furthermore, observation of the water molecules between Arg57 and folate elucidated an early step in the substrate-binding pathway. These results demonstrate the possibility of using high-pressure protein crystallography as a method to capture high-energy substates or transient structures related to the protein reaction cycle.


Dickkopf3 (Dkk3) is required for maintaining the integrity of secretory vesicles in the mouse adrenal medulla.
REIC (reduced expression in immortalized cells) has been identified as a gene whose expression was reduced in immortalized cultured cells. The REIC gene is identical to Dickkopf-3 (Dkk3), which encodes a secreted glycoprotein belonging to the Dkk family. Previously, we showed that Dkk3 protein is present in the mouse adrenal medulla. However, its role in this tissue has not been elucidated. To explore it, we performed electron microscopic (EM) studies and RNA-sequencing (RNA-seq) analysis on Dkk3-null adrenal glands. EM studies showed that the number of dense core secretory vesicles were significantly reduced and empty vesicles were increased in the medulla endocrine cells. Quantitative PCR (qPCR) analysis showed relative expression levels of chromogranin A (Chga) and neuropeptide Y (Npy) were slightly but significantly reduced in the Dkk3-null adrenal glands. From the result of RNA-seq analysis as a parallel study, we selected three of the downregulated genes, uncoupled protein-1 (Ucp1), growth arrest and DNA-damage-inducible 45 gamma (Gadd45g), and Junb with regard to the estimated expression levels. In situ hybridization confirmed that these genes were regionally expressed in the adrenal gland. However, expression levels of these three genes were not consistent as revealed by qPCR. Thus, Dkk3 maintains the integrity of secreting vesicles in mouse adrenal medulla by regulating the expression of Chga and Npy.


Targeting senescence and inflammation in chronic destructive TNF-driven joint pathology.
We had shown that administration of the senolytic Dasatinib abolishes arthritis in the human TNF transgenic mouse model of chronic destructive arthritis when given in combination with a sub-therapeutic dose of the anti-TNF mAb Infliximab (1 mg/kg). Herein, we found that while the number of senescent chondrocytes (GL13+/Ki67-), assessed according to guideline algorithmic approaches, was not affected by either Dasatinib or sub-therapeutic Infliximab monotherapies, their combination reduced senescent chondrocytes by 50 %, which was comparable to levels observed with therapeutic Infliximab monotherapy (10 mg/kg). This combination therapy also reduced the expression of multiple factors of senescence-associated secretory phenotype in arthritic joints. Studies to elucidate the interplay of inflammation and senescence may help in optimizing treatment strategies also for age-related pathologies characterized by chronic low-grade joint inflammation.


The development and stability assessment of extemporaneous pediatric formulations of Accupril.
Quinapril, the active ingredient in Accupril tablets, is an ACE inhibitor used to treat hypertension. Quinapril is unstable in aqueous solution and therefore the development of a liquid formulation is a significant challenge. Previous studies show the rate of degradation of quinapril into its two major degradants to be pH dependent, indicating the parent compound to be most stable in the narrow pH range of 5.5-6.5. Accupril (20 mg) and readily available pharmaceutical components were combined to generate three formulations that are stable for at least 28 days, possess acceptable appearance, and are palatable to pediatric patients. To combat the presence of magnesium carbonate in the Accupril tablets, which increase the pH of the solution above 6.5, several pharmaceutically available buffers were incorporated. Nine prototypes were developed and their characteristics evaluated after 1 week under stressed conditions. The three that most closely matched the stability criteria were chosen for a definitive stability study. A stability-indicating method was developed and validated for these studies. All three formulations met the following specifications when stored at 5 degrees C for 6 weeks; Quinapril remained >or=90% intact and the two known degradants did not reach values >or=3.0% individually or >or=5.0% combined.


Sustained response to interferon-alpha plus ribavirin therapy for chronic hepatitis C is closely associated with increased dynamism of intrahepatic natural killer and natural killer T cells.
Previous studies have revealed that functional impairment of innate immune cells, including natural killer (NK) and natural killer T (NKT) cells, might be associated with the persistence of hepatitis C virus (HCV) infection. However, the involvement of innate immune cells, which predominate in the liver, in therapeutic HCV clearance is still unclear. To clarify the role of intrahepatic innate immune cells in the clinical outcome of patients with chronic hepatitis C (CHC) treated with interferon-alpha plus ribavirin (IFN/RBV), we prospectively investigated the status of NK and NKT cells in paired liver biopsy and peripheral blood (PB) samples obtained from 21 CHC patients before and immediately after IFN/RBV treatment by flow cytometry. Normal liver and PB samples were obtained from 10 healthy donors for living donor liver transplantation. Before treatment, intrahepatic NK and NKT cells constituted a significantly lower proportion in CHC patients than in healthy individuals (P < 0.05). After IFN/RBV treatment, the proportions and absolute numbers of CD3(-)CD161(+) NK and CD3(+)CD56(+) NKT cells in the liver, but not in PB, were significantly increased in sustained responders (SR) as compared with poor responders (P < 0.05). The proportion of CD3(+)CD161(+) NKT cells was also increased in the liver of SR after the treatment. Moreover, there was a striking increase of activated CD152(+) cells among CD3(+)CD56(+) NKT cells in the liver of SR (P = 0.041). These findings demonstrate that sustained response to IFN/RBV treatment for patients with CHC is closely associated with increased dynamism of NK and NKT cells in the liver.


Use of structure-activity relationships to estimate antiallergic activity of 4-hydroxy 3-nitro coumarins.
The antiallergic activity of a series of 4-hydroxy 3-nitro coumarins was studied using Hansch equations and CNDO/2 calculations. Following these calculations a new compound was synthetised which presents an interesting activity.


An explorative analysis of pharmacovigilance data of oxytocin and its analogue carbetocin, with a focus on haemodynamic adverse effects.
Oxytocin and its analogue carbetocin are uterotonics whose prophylactic use is recommended to prevent postpartum haemorrhage, which is one of the leading causes of maternal deaths worldwide. However, both drugs can cause specific adverse effects and haemodynamic challenges. The aim of this work was to exploratively examine reports of adverse drug events of both drugs and to establish a comparative haemodynamic profile. Using data extracted from the World Health Organization's pharmacovigilance database VigiBase, a descriptive analysis was performed of all reports for oxytocin and carbetocin as a suspected or interacting drug followed by a disproportionality analysis for haemodynamic events. Reporting odds ratios (ROR) of carbetocin for hypertension, hypotension, tachycardia, and bradycardia were calculated, with oxytocin-related reports serving as comparators. Oxytocin and carbetocin were mentioned as suspected or interacting drugs in 11,258 and 374 reports, respectively. Resulting RORs for carbetocin were 3.45 (95%CI: 1.72-6.92) for hypertension, 2.65 (1.64-4.28) for hypotension, 2.84 (1.79-4.49) for tachycardia, and 2.00 (0.87-4.60) for bradycardia, when compared to oxytocin. Of 231 patients for whom oxytocin-related tachycardia was reported, 2.6% died, and of 91 patients for whom bradycardia was reported, 2.2% died. No deaths were reported with carbetocin for any of the haemodynamic adverse events. Compared to oxytocin, carbetocin showed an elevated reporting for adverse hypertension, hypotension, and tachycardia in pharmacovigilance data. Clinicians should be aware of their patients' individual susceptibility and the possibility of haemodynamic deterioration until causal inferences are possible.


[Dark-field imaging and computed tomography : Novel X-ray-based contrast imaging modality with great promise for pulmonary imaging].
The spatial and contrast resolution of conventional planar or computed tomographic X‑ray techniques is not sufficient to investigate microstructures of tissues. Dark-field imaging with X‑rays is an emerging technology that recently provided the first clinical results and makes diagnostic use of interactions of the beams with tissue due to their wave character. Dark-field imaging can provide information about the microscopic structure or porosity of the tissue under investigation that is otherwise inaccessible. This makes it a valuable complement to conventional X‑ray imaging, which can only account for attenuation. Our results demonstrate that X‑ray dark-field imaging provides pictorial information about the underlying microstructure of the lung in humans. Given the close relationship between alveolar structure and the functional state of the lung, this is of great importance for diagnosis and therapy monitoring and may contribute to a better understanding of lung diseases in the future. In the early detection of chronic obstructive pulmonary disease, which is usually associated with structural impairment of the lung, this novel technique could help to facilitate its diagnosis. The application of dark-field imaging to computed tomography is still under development because it is technically difficult. Meanwhile, a prototype for experimental application has been developed and is currently being tested on a variety of materials. Use in humans is conceivable especially for tissues whose microstructure favors characteristic interactions due to the wave nature of the X‑rays.


Automated construction of detector models for efficiency interpolation in gamma-ray spectrometry.
A method was developed for automated construction of detector models in gamma-ray spectrometry, which can be used in Monte Carlo calculations of efficiency calibration curves. Full-energy peak efficiencies were first measured for different gamma-ray energies and for a given sample-detector arrangement and then calculated by the Monte Carlo method. For these calculations a detector model was employed along with a computer algorithm, which seeks agreement between the experimental efficiencies and the calculated ones by automatically determining the parameters of the model. The resulting agreement of the calculated data with the experimental one was within the relative uncertainty of the latter (3-4%) and the parameters of the detector models obtained were close to the values specified by the manufacturers. The detector models thus constructed can then be used for interpolation of calibration curves.


Clinical leadership: a role for students?
Since the publication of the 'To Err is Human' report, patient safety and quality improvement has been an increasingly important agenda in health care. This article explores the role that students can play in leading change in health-care systems.


Simple and accurate visual detection of single nucleotide polymorphism based on colloidal gold nucleic acid strip biosensor and primer-specific PCR.
Single nucleotide polymorphism (SNP) was associated with many human diseases, therefore, SNP detection was important for early diagnosis and clinical prognosis. Herein, a simple and accurate method for visual detection SNP sites (A/A, G/G, A/G) in CYP1A1 gene related to cancers based on colloidal gold nucleic acid strip biosensor and primer-specific polymerase chain reaction (PCR) was established. This method could directly distinguish SNP sites on strip biosensor by introducing twice PCR amplifications. The second PCR (primer-specific PCR) was performed using specific product of the first PCR as template, thus this twice PCR could reduce non-specific amplification greatly and obtain target product. In addition, single-strand or double-strand DNA (ssDNA or dsDNA) was accurately produced by introducing mismatched base at the 3' end of forward primers in primer-specific PCR. The designed strip biosensor could only combine with the ssDNA, thus visual detection of SNP could be achieved within 10 min by color difference of a pair of strips. 61 human blood samples by this method were identical with those of pyrosequencing. This method had the advantages of rapid, visual and low-cost and was expected to be applied in medical diagnosis.


Pan-cancer analysis reveals the potential of hyaluronate synthase as therapeutic targets in human tumors.
Hyaluronic acid (HA) is a crucial component of the extracellular matrix, and its level of accumulation is related to the progression of various malignant tumors. In this study, a pan-cancer analysis of the three enzymes called hyaluronan synthases (HAS1, HAS2, and HAS3) that produce HA was performed. The study comprehensively describes the characteristics of HAS1, HAS2, and HAS3 in cancers using public databases and tools, to identify the potential biological pathways involved at the molecular, protein, cellular, and clinical sample levels. The analysis showed that dysregulation of the three genes often occurs in cancer, contributing to cancer progression, metastasis, and prognosis. Overexpression of HAS2 promotes secretion of HA in GBM and enhances cell proliferation and migration. The common and specific functions of HAS in certain diseases have important research implications for the treatment and prognosis of tumors.


Effects of gender on the sensitivity of rat cardiac muscle to extracellular Ca2+.
Experiments were designed to determine if the inotropic response to increasing buffer calcium concentration differs in male and female cardiac muscle. Left atrial and papillary muscles were isolated from hearts of 3-4-month old male and female rats, bathed in Krebs-Henseleit solution (30 degrees C), and stimulated at 1.5 Hz. Isometric developed tension was monitored continuously as extracellular Ca2+ was increased in a cumulative fashion. When compared to male atrial muscle, female atrial preparations were more sensitive to the resulting positive inotropic action; EC50 values were 2.89 +/- 0.22 and 1.86 +/- 0.21 mM in male and female atria, respectively. Two-way analysis of variance (ANOVA) also indicated that there was a significant gender-associated difference in the Ca2+ dose-response curves in atrial muscle. In contrast, papillary muscle did not show a significant gender-related difference in EC50 values (0.88 +/- 0.07 and 0.74 +/- 0.06 mM in males and females); however, the Ca2+ dose-response curves obtained from male and female preparations were found to be significantly different when compared by ANOVA.


Integrating geographical information and augmented reality techniques for mobile escape guidelines on nuclear accident sites.
During nuclear accidents, when radioactive materials spread into the environment, the people in the affected areas should evacuate immediately. However, few information systems are available regarding escape guidelines for nuclear accidents. Therefore, this study constructs escape guidelines on mobile phones. This application is called Mobile Escape Guidelines (MEG) and adopts two techniques. One technique is the geographical information that offers multiple representations; the other is the augmented reality that provides semi-realistic information services. When this study tested the mobile escape guidelines, the results showed that this application was capable of identifying the correct locations of users, showing the escape routes, filtering geographical layers, and rapidly generating the relief reports. Users could evacuate from nuclear accident sites easily, even without relief personnel, since using slim devices to access the mobile escape guidelines is convenient. Overall, this study is a useful reference for a nuclear accident emergency response.


Physical activity levels and coronary heart disease. Analysis of epidemiologic and supporting studies.
Coronary heart disease, the primary health problem in western life, is caused by the interaction of multiple factors. Absolute proof of the contributing role of physical inactivity is not possible owing to the complexity of the CHD problem and the infeasibility of a definitive clinical trial because of logistical and economic constraints. Despite limitations, existing epidemiologic studies strongly suggest, but fall short of proving, the concept that habitual physical exercise offers partial protection against primary or secondary events of CHD and associated mortality. However, experimental data support this hypothesis and provide evidence of possible mechanisms responsible for the protection. The available epidemiologic data also suggest that physical inactivity is probably not as potent an individual risk factor as elevated serum cholesterol levels, hypertension, and cigarette smoking, and that the protective effects of exercise may be overwhelmed by high levels of these major risk factors. On the other hand, there is some evidence that exercise may attenuate other risk factors both directly and through associated weight reduction. Epidemiologic studies also suggest a dose response relationship between physical activity and rates of CHD. About 2000 kcal per week of moderate intensity, dynamic, endurance-type of exercise (such as walking or jogging about 20 miles per week) or at least one hour of intermittent hard physical labor are required to obtain the optimal effect of exercise on coronary heart disease rates. Experimental studies suggest that this amount of exercise should provide sufficient stimulus to favorably alter blood HDL cholesterol levels and perhaps other CHD risk factors, especially if there is an accompanying reduction in weight. Possible mechanisms for the protective effects of exercise against CHD are illustrated in Figure 1. Insistence on final experimental proof prior to prudent medical practice or public health policy on physical inactivity or other coronary risk factors indicates a lack of understanding of the nature of scientific proof and evidence required for health actions.(ABSTRACT TRUNCATED AT 400 WORDS)


Analysis of the maturation process of dendritic cells deficient for TNF and lymphotoxin-alpha reveals an essential role for TNF.
Dendritic cells (DCs) generated from bone marrow (BM) precursor cells of C57BL/6 (B6.WT) mice and cultured in the presence of granulocyte macrophage-colony stimulating factor differentiate to mature BM-DCs spontaneously. These mature DCs are characterized by high levels of major histocompatibility complex (MHC) class II, CD40, and CD86 on their surface. To analyze the involvement of tumor necrosis factor (TNF) and the related cytokine lymphotoxin (LT)alpha in DC maturation, we studied the development of DCs from the BM of B6.TNF(-/-), B6.LTalpha(-/-), and B6.TNF/LTalpha(-/-) mice and compared it to B6.WT mice. Although the development of BM precursor cells to the level of immature DCs (CD11c(+), MHC class II(low), CD40(low), and CD86(low)) was equivalent in all genotypes, B6.TNF(-/-) and B6.TNF/LTalpha(-/-) cells showed an impaired capacity to differentiate to mature DCs. In contrast, mature BM-DCs generated from LTalpha-negative, immature DCs developed like B6.WT cells. Further studies revealed that once matured, the phenotype of all tested genotypes was comparable. They expressed high levels of CD40 and CD86, were exclusively positive for the chemokine receptor (CCR)7 but negative for CCR5 and CCR2, and were able to enter the paracortex of draining lymph nodes. The limited maturation of TNF-deficient BM-DCs could be restored by mixing TNF-negative with TNF-positive Ly5.1 BM cells, and maturation of B6.WT DCs could be blocked with an anti-TNF monoclonal antibody. The substitution of B6.TNF(-/-) BM cells with recombinant TNF revealed promotion or suppression of BM-DC maturation depending on the point of time of TNF addition.


Benefits of virtual externships with a pediatric dentistry program for potential residents.
To determine if a virtual externship (VE) is beneficial to potential applicants regarding their perceived knowledge of a pediatric dentistry residency program. Secondarily, this study identified general program characteristics that influence resident ranking decisions. All applicants who applied to a pediatric dentistry residency program in the Southeast were invited to participate in a VE. Those who participated in the externship (n = 65) were asked to voluntarily complete Pre- and Post-VE surveys. Participants were asked 22 questions about their level of knowledge of both tangible and intangible aspects of the program such as stipend, patient volume, faculty-resident interaction, and resident comradery. Participants were also asked to rank 9 general characteristics that influence ranking decisions such as geography, cost to attend, and reputation of the program and were asked to rate their satisfaction with the VE. Post-VE data were compared to pre-VE data to determine level of knowledge gained via Wilcoxin matched pairs signed rank test (significance set at p < 0.05). When comparing Pre- and Post-VE ratings of level of knowledge about each category, all 22 categories assessed showed statistically significant mean differences indicating perceived knowledge gain with the most knowledge gained for "resident satisfaction in the program." Of the nine program characteristics, clinical experience was the most important factor to participants. Participants (100%) were satisfied with the VE experience and indicated the VE gave them the opportunity to get to know the program. A virtual externship is a satisfactory option for increasing applicant knowledge of the tangible and intangible aspects of a residency program.


Contribution of HIF-1α to Heat Shock Response by Transcriptional Regulation of HSF1/HSP70 Signaling Pathway in Pacific Oyster, Crassostrea gigas.
Ocean temperature rising drastically threatens the adaptation and survival of marine organisms, causing serious ecological impacts and economic losses. It is crucial to understand the adaptive mechanisms of marine organisms in response to high temperature. In this study, a novel regulatory mechanism that is mediated by hypoxia-inducible factor-1α (HIF-1α) was revealed in Pacific oyster (Crassostrea gigas) in response to heat stress. We identified a total of six HIF-1α genes in the C. gigas genome, of which HIF-1α and HIF-1α-like5 were highly induced under heat stress. We found that the HIF-1α and HIF-1α-like5 genes played critical roles in the heat shock response (HSR) through upregulating the expression of heat shock protein (HSP). Knocking down of HIF-1α via RNA interference (RNAi) inhibited the expression of heat shock factor 1 (HSF1) and HSP70 genes in C. gigas under heat stress. Both HIF-1α and HIF-1α-like5 promoted the transcriptional activity of HSF1 by binding to hypoxia response elements (HREs) within the promoter region. Furthermore, the survival of C. gigas under heat stress was significantly decreased after knocking down of HIF-1α. This work for the first time revealed the involvement of HIF-1α/HSF1/HSP70 pathway in response to heat stress in the oyster and provided an insight into adaptive mechanism of bivalves in the face of ocean warming.


Meiotic chromosomes in an infertile male with an unbalanced Y/13 translocation.
An infertile male carrying an unbalanced Y/13 translocation is described. Meiotic studies suggest that the unbalanced translocation does not affect meiotic division.


First description of Grapevine leafroll-associated virus 5 in Argentina and partial genome sequence.
An accession of Vitis vinifera cv. Red Globe from Argentina, was found to be infected with Grapevine leafroll-associated virus-5 by ELISA. It was partially sequenced, and three ORFs, corresponding to HSP70h, HSP90h, and CP, were found. This isolate shares a high aminoacid identity with the previously reported sequence of the virus, and identities between 80% and 90% with previously reported GLRaV-9 and GLRaV-4 isolates. The analysis of the sequence supports the clustering together with GLRaV-4 and GLRV-9 inside the Ampelovirus genus.


The retarded electrophoretic migration of p56lck induced by vanadate in lymphoma cells correlates with modified kinase activity.
p56lck is a src related lymphocyte specific tyrosine protein kinase which undergoes specific changes during T-cell activation, particularly the appearance of slow migrating forms. To analyze these forms, LSTRA cells were treated with vanadate. This resulted in increased phosphorylation of p56lck with the appearance of slow migrating forms. Renaturation of the p56lck bands after gel migration showed that vanadate mostly increased the activity of the lower band of p56lck. The upper bands had a reduced specific activity. In addition, the upper bands from vanadate treated cells displayed additional phosphorylated sites.


Effect of stimulus repetition on negative sustained potentials elicited by auditory and visual stimuli in the human EEG.
Effect of repetition of auditory and visual stimuli on sensory-evoked sustained potentials was studied. The stimuli were tones and flashes of 1 sec duration presented in trains of six stimuli with an inter-stimulus-interval of 1 sec. The repetition rate of the trains was 1 train/min. The EEG was recorded from electrodes located at Cz, Pz and Oz. Both auditory and visual stimuli elicited negative sustained potentials which during the first stimuli of the trains were maximal in amplitude and shortest in latency at Cz. Repetition of the stimulus resulted in almost complete disappearance of the sustained potentials; for auditory stimulation a small negative shift was recorded only at Cz, whereas for visual stimulation a small sustained potential was seen only at Pz and Oz. The results indicate that the slow potentials evoked by short tones or lights are composed of at least two components. One of these components may reflect neural processing associated with orienting reflex. The other component seems to be related to specific neural processing of the stimulus.


A free total toe phalanx transplant to a finger: a case report.
A six-year-old boy sustained traumatic loss of the index finger middle phalanx of his right hand and one year after the accident the proximal phalanx of the fourth toe was transplanted to the index finger as a free graft. Four years after the operation x-ray films demonstrate acceptance of the graft and satisfactory function of the finger.


Saliva biomarkers in oral disease.
Saliva is a versatile biofluid that contains a wide variety of biomarkers reflecting both physiologic and pathophysiologic states. Saliva collection is noninvasive and highly applicable for tests requiring serial sampling. Furthermore, advances in test accuracy, sensitivity and precision for saliva has improved diagnostic performance as well as the identification of novel markers especially in oral disease processes. These include dental caries, periodontitis, oral squamous cell carcinoma (OSCC) and Sjögren's syndrome (SS). Numerous growth factors, enzymes, interleukins and cytokines have been identified and are the subject of much research investigation. This review highlights current procedures for successful determination of saliva biomarkers including preanalytical factors associated with sampling, storage and pretreatment as well as subsequent analysis. Moreover, it provides an overview of the diagnostic applications of these salivary biomarkers in common oral diseases.


Effects of electrokinetic and ultrasonication pre-treatment and two-step anaerobic digestion of biowastes on the nitrogen fertiliser value by injection or surface banding to cereal crops.
Biogas production from anaerobic digestion (AD) of biowastes is restricted by the recalcitrant nature of many substrates, and this may also reduce the fertiliser value of the produced digestate. The degradability of substrates can potentially be enhanced by physico-chemical pre-treatments before AD, and/or the degradation can be increased by a longer digestion time. In this study, we evaluated the effects of electrokinetic (high voltage) and ultrasonication pre-treatments of biowastes in a two-step AD process on nitrogen fertiliser replacement value (NFRV) of digestates obtained from two biogas plants with contrasting hydraulic retention time (HRT) in the primary AD step. The fertiliser value was tested by direct injection to spring barley and surface-banding to winter wheat, and the ammonium N was 15N-labelled to evaluate ammonia losses. The electrokinetic pre-treatment step significantly (p < 0.05) increased the NH4+-N/total N in the digestates before the second AD step but had an insignificant effect on the fertiliser value in winter wheat and spring barley. Ultrasonication pre-treatment had also no significant effect on the fertiliser value. The two-step AD significantly (p < 0.001) increased 15N recoveries and mineral fertiliser equivalence of labelled ammonium-N in winter wheat and reduced ammonia losses, with a significant effect (p < 0.001) observed in digestates sourced from a shorter HRT biogas reactor. The fertiliser equivalence of labelled ammonium-N in the digestates was 80-88% after injection, indicating relatively low N immobilisation with all the digestates. NFRV in the crops was mainly explained by the NH4+-N/total N ratio, C/N ratio and dry matter content of the digestates. The findings suggest that electrokinetic and ultrasonication pre-treatments combined with a second AD step have no considerable impact on the fertiliser value of digestates, whereas a second AD step significantly reduced ammonia losses after application by surface-banding in winter wheat.


Vitamin D levels reverberate in monocytes modulation in hemodialysis patients.
Patients with chronic kidney disease (CKD) have a severe vitamin D deficiency and increasing epidemiological data suggesting that this deficiency may play a role in overall morbidity and mortality associated with CKD. It is known that vitamin D regulates the immune system, however, in dialysis patients this deficiency and the modulation of proinflammatory cells is unclear. Among these, monocytes arouse interest considering they constitutively express vitamin D receptors. This study aimed the evaluation of monocytic profile in CKD patients according to vitamin D levels. Patients in hemodialysis (HD) were divided into two groups, regarding vitamin D levels: Group 1, vitamin D <26 ng/ml (n = 15) and Group 2, vitamin D ≥26 ng/ml (n = 18). Whole blood was collected aiming evaluation of (a) monocytic populations through CD14 and CD16 expression, (b) reactive oxygen species (ROS) generation, and (c) apoptosis. We observed that in Group 1, when compared to Group 2, there was a significant increase in intermediate monocytes (CD14++ CD16 + ; 34.7 ± 31.6 vs. 12.1 ± 6.3; p = 0.006, respectively) and decrease in classical ones (CD14 ++ CD16 - ; 45.3 ± 31.8 vs. 70.4 ± 25.1; p = 0.017, respectively). There was no difference between groups regarding nonclassical monocytes (CD14 + CD16 ++ ), as well as to apoptosis and to ROS generation. This study suggests that HD patients with lower vitamin D levels might have an intensified inflammatory outline as intermediate monocytes with an inflammatory pattern are increased in this population, when compared with patients with higher levels of vitamin D.


Development of four sandwich ELISAs for quantitation of capsular polysaccharides from Neisseria meningitidis serogroups A, C, W and Y in multivalent vaccines.
Neisseria meningitidis is a Gram negative bacterium that has been classified in 13 serogroups according to the biochemical composition of the capsular polysaccharide (CP). However, invasive infections are most frequently caused by six of these serogroups: A, B, C, W, X and Y (MenA, MenB, MenC, MenW, MenX, MenY). Individual CP quantitation in multivalent meningococcal CP-based vaccines is required for quality control testing of these products. In this regard, four sandwich enzyme-linked immunosorbent assays (ELISAs) were developed for the quantitation of CP. The quantitation and detection limits of the four ELISAs were below 1ng/mL. The assays showed good reproducibility and repeatability as calculated for each point of the standard curve (CV<15%). In addition, five multivalent meningococcal CP-based vaccines were evaluated and the proposed ELISAs showed that these vaccines were found into the accepted range (±30%) of CP content. These assays are suitable for screening multiple plain or conjugated meningococcal CP-based vaccines and could be useful for monitoring lot-to-lot consistency and stability analysis.


Photodegradation of CuBi2 O4 Films Evidenced by Fast Formation of Metallic Bi using Operando Surface-sensitive X-ray Scattering.
CuBi2 O4 has recently emerged as a promising photocathode for photo-electrochemical (PEC) water splitting. However, its fast degradation under operation currently poses a limit to its application. Here, we report a novel method to study operando the semiconductor-electrolyte interface during PEC operation by surface-sensitive high-energy X-ray scattering. We find that a fast decrease in the generated photocurrents correlates directly with the formation of a metallic Bi phase. We further show that the slower formation of metallic Cu, as well as the dissolution of the electrode in contact with the electrolyte, further affect the CuBi2 O4 activity and morphology. Our study provides a comprehensive picture of the degradation mechanisms affecting CuBi2 O4 electrodes under operation and poses the methodological basis to investigate the photocorrosion processes affecting a wide range of PEC materials.


Assessment of blood pressure skills and belief in clinical readings.
Accurate blood pressure (BP) measurement is essential for the diagnosis and management of hypertension. In clinical practice, BP is estimated using noninvasive methods with significant variability of application of guidelines in clinical practice, impacting the accuracy and certainty of BP measurements. We sought to assess how BP is measured in clinical practice. A survey was administered through professional societies that included predominantly cardiologists. Assessment of adherence to guideline recommendations for BP assessment was measured and compared to the level of confidence in clinic BP measurement. There were 571 surveys completed. The majority of respondents were cardiologists (61.1%), with 47 preventive cardiologists. BP was routinely checked in both arms by 53% at the initial visit, 48% check BP once each visit, and 64% wait 5 min before initial BP assessment. Automated BP assessment is used by 58% respondents. The majority (83%) trust their BP readings, and those who trust their BP readings are more likely to perform the initial BP assessment themselves, compared to those who do not trust the clinic BP readings (30.2% vs. 13.6%, P = 0.009). Accurate BP measurement is performed by 23% of cardiologists, and more likely performed accurately by a preventive cardiologist (38.3%) compared with other cardiologists (20.0%, P = 0.007). Accurate BP measurement is more likely for those who perform the initial BP themselves rather than any other staff (36.8% vs. 17.9%; P<0.001); and for those who repeat BP manually (80% vs. 54%; P<0.001), compared to those who do not measure BP accurately. Despite the inaccuracy of BP measurement, there is a high level of confidence in the BP readings. Accurate BP assessment continues to remain suboptimal in clinical practice. Reliability of BP assessment requires education, identifying barriers to implementation of recommendations and engagement of the entire team to improve BP assessment.


Chemical, spectroscopic characterization, DFT studies and antibacterial activities in vitro of a new gold(I) complex with rimantadine.
A novel gold(I) complex with rimantadine (RTD) was obtained and structurally characterized by a set of chemical and spectroscopic analysis. 1H, 13C and 15N nuclear magnetic resonance (NMR) and infrared (IR) spectroscopic measurements suggest coordination of the ligand to Au(I) through the N atom of the ethanamine group. Theoretical (DFT) calculations confirmed the IR assignments and permit proposing an optimized geometry for the complex. The gold(I)-rimantadine complex (Au-RTD) is soluble in methanol, ethanol, dimethylsulfoxide, acetone and acetonitrile. The preliminary kinetic studies based on UV-vis spectroscopic measurements indicate the stability of the compound in solution. Antibacterial activities of the complex were evaluated by an antibiogram assay. The Au-RTD complex showed an effective in vitro antibacterial activity against the Pseudomonas aeruginosa, Escherichia coli (Gram-negative), and Staphylococcus aureus (Gram-positive) bacterial strains.


New developments in skin-directed treatments of cutaneous T-cell lymphoma.
The therapeutic approach for mycosis fungoides, the most common type of primary cutaneous T-cell lymphoma, is based mainly on the stage of the disease, and skin-directed treatment is recommended by all international guidelines as the first-line of treatment for early-stage disease. Skin-directed treatments may be also given in combination with systemic therapies in early-stage mycosis fungoides patients recalcitrant to different types of skin-directed treatments, or in certain patients with high-risk features. Advanced-stage mycosis fungoides is treated mainly with systemic treatments, which may be combined with skin-directed treatments. Due to the rarity of mycosis fungoides, controlled clinical trials of the different skin-directed treatment modalities are almost non-existent, with a few exceptions, and therefore recommendations are largely based on cohort studies and expert opinion. This paper reviews the new developments in skin-directed treatments and provides an update on new studies of already well-known therapies, and an update on novel treatments.


CYP2S1: a short review.
A new member of the cytochrome P450 superfamily, CYP2S1, has recently been identified in human and mouse. In this paper, we review the data currently available for CYP2S1. The human CYP2S1 gene is located in chromosome 19q13.2 within a cluster including CYP2 family members CYP2A6, CYP2A13, CYP2B6, and CYP2F1. These genes also show the highest homology to the human CYP2S1. The gene has recently been found to harbor genetic polymorphism. CYP2S1 is inducible by dioxin, the induction being mediated by the Aryl Hydrocarbon Receptor (AHR) and Aryl Hydrocarbon Nuclear Translocator (ARNT) in a manner typical for CYP1 family members. In line with this, CYP2S1 has been shown to be inducible by coal tar, an abundant source of PAHs, and it was recently reported to metabolize naphthalene. This points to the involvement of CYP2S1 in the metabolism of toxic and carcinogenic compounds, similar to other dioxin-inducible CYPs. CYP2S1 is expressed in epithelial cells of a wide variety of extrahepatic tissues. The highest expression levels have been observed in the epithelial tissues frequently exposed to xenobiotics, e.g., the respiratory, gastrointestinal, and urinary tracts, and in the skin. The observed ubiquitous tissue distribution, as well as the expression of CYP2S1 throughout embryogenesis suggest that CYP2S1 is likely to metabolize important endogenous substrates; thus far, retinoic acid has been identified. In conclusion, CYP2S1 exhibits many features of interest for human health and thus warrants further investigation.


Accounting for speed-accuracy tradeoff in perceptual learning.
In the perceptual learning (PL) literature, researchers typically focus on improvements in accuracy, such as d'. In contrast, researchers who investigate the practice of cognitive skills focus on improvements in response times (RT). Here, we argue for the importance of accounting for both accuracy and RT in PL experiments, due to the phenomenon of speed-accuracy tradeoff (SAT): at a given level of discriminability, faster responses tend to produce more errors. A formal model of the decision process, such as the diffusion model, can explain the SAT. In this model, a parameter known as the drift rate represents the perceptual strength of the stimulus, where higher drift rates lead to more accurate and faster responses. We applied the diffusion model to analyze responses from a yes-no coherent motion detection task. The results indicate that observers do not use a fixed threshold for evidence accumulation, so changes in the observed accuracy may not provide the most appropriate estimate of learning. Instead, our results suggest that SAT can be accounted for by a modeling approach, and that drift rates offer a promising index of PL.


Adhesive incisional drapes during cesarean delivery for preventing wound infection: A systematic review and meta-analysis of randomized controlled trials.
To compare the incidence of wound infection after cesarean delivery in procedures conducted using adhesive incisional drapes verses no adhesive incisional drapes. Searches were performed in electronic databases (MEDLINE, ClinicalTrials.gov, the Cochrane Central Register of Controlled Trials, Scopus, OVID, EMBASE, and the PROSPERO International Prospective Register of Systematic Reviews). We included randomized controlled trials comparing adhesive incisional drapes to no adhesive incisional drapes during cesarean delivery. The primary outcome of this meta-analysis was wound infection. Meta-analysis was performed using the random effects model of DerSimonian and Laird, to produce relative risk (RR) with 95% confidence interval (CI). 52 publications were identified through initial search of databases and two randomized controlled trials were eligible and included in the meta-analysis. Our meta-analysis examined a total of 1943 subjects and showed a statistically significant increase in wound infections in patients in the adhesive incisional drape group when compared to the control group (RR: 1.29, 95% CI: 1.02-1.65). Adhesive incisional drapes may increase the incidence of wound infections after cesarean delivery. Further studies are necessary to explore this relationship in the setting of current postoperative infection prophylaxis, including broad-spectrum antibiotic coverage, skin preparation and vaginal cleansing.


Polarity sorting of axonal microtubules: a computational study.
We present a computational model to test a "polarity sorting" mechanism for microtubule (MT) organization in developing axons. We simulate the motor-based axonal transport of short MTs to test the hypothesis that immobilized cytoplasmic dynein motors transport short MTs with their plus ends leading, so "mal-oriented" MTs with minus-end-out are transported toward the cell body while "correctly" oriented MTs are transported in the anterograde direction away from the soma. We find that dynein-based transport of short MTs can explain the predominately plus-end-out polarity pattern of axonal MTs but that transient attachments of plus-end-directed motor proteins and nonmotile cross-linker proteins are needed to explain the frequent pauses and occasional reversals observed in live-cell imaging of MT transport. Static cross-linkers increase the likelihood of a stalled "tug-of-war" between retrograde and anterograde forces on the MT, providing an explanation for the frequent pauses of short MTs and the immobility of longer MTs. We predict that inhibition of the proposed static cross-linker will produce disordered transport of short MTs and increased mobility of longer MTs. We also predict that acute inhibition of cytoplasmic dynein will disrupt the polarity sorting of MTs by increasing the likelihood of "incorrect" sorting of MTs by plus-end-directed motors.


Pleth Variability Index-Based Goal-Directed Fluid Management in Patients Undergoing Elective Gynecologic Surgery.
Data concerning the usefulness of pleth variability index (PVI)-based goal-directed fluid management (GDFM) in gynecologic surgery is limited.This study purposed to compare the impact of PVI-based GDFM to conventional fluid management (CFM) on intraoperative hemodynamics and lactate levels in subjects undergoing gynecologic surgery. This randomized and controlled trial was conducted on 70 patients undergoing elective gynecologic surgery. Subjects were randomly assigned to CFM or GDFM. Hemodynamic data and results of the arterial blood gas analysis, and total amount of the fluid infused were recorded throughout the surgery at 1-h intervals. The amount of the total fluids was significantly higher in the CFM group compared to that of the GDFM group (p<0.001). Mean arterial pressure recorded at the 2nd h of the surgery was significantly lower in the CFM group compared to that of the GDFM group (p=0.047). While there were no significant differences between the baseline and the 2nd h lactate levels in the GDFM group, the lactate level significantly increased from baseline to the 2nd h in the CFM group (p=0.010). Implementation of PVI-based GDFM provides better intraoperative hemodynamic stability and lower lactate levels compared to the CFM in subjects undergoing gynecologic surgery.


Metformin treatment rescues CD8+ T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD.
Non-alcoholic steatohepatitis (NASH) represents the fastest growing underlying cause of hepatocellular carcinoma (HCC) and has been shown to impact immune effector cell function. The standard of care for the treatment of advanced HCC is immune checkpoint inhibitor (ICI) therapy, yet NASH may negatively affect the efficacy of ICI therapy in HCC. The immunologic mechanisms underlying the impact of NASH on ICI therapy remain unclear. Herein, using multiple murine NASH models, we analysed the influence of NASH on the CD8+ T-cell-dependent anti-PD-1 responses against liver cancer. We characterised CD8+ T cells' transcriptomic, functional, and motility changes in mice receiving a normal diet (ND) or a NASH diet. NASH blunted the effect of anti-PD-1 therapy against liver cancers in multiple murine models. NASH caused a proinflammatory phenotypic change of hepatic CD8+ T cells. Transcriptomic analysis revealed changes related to NASH-dependent impairment of hepatic CD8+ T-cell metabolism. In vivo imaging analysis showed reduced motility of intratumoural CD8+ T cells. Metformin treatment rescued the efficacy of anti-PD-1 therapy against liver tumours in NASH. We discovered that CD8+ T-cell metabolism is critically altered in the context of NASH-related liver cancer, impacting the effectiveness of ICI therapy - a finding which has therapeutic implications in patients with NASH-related liver cancer. Non-alcoholic steatohepatitis represents the fastest growing cause of hepatocellular carcinoma. It is also associated with reduced efficacy of immunotherapy, which is the standard of care for advanced hepatocellular carcinoma. Herein, we show that non-alcoholic steatohepatitis is associated with impaired motility, metabolic function, and response to anti-PD-1 treatment in hepatic CD8+ T cells, which can be rescued by metformin treatment.


Correction to: Mild endoplasmic reticulum stress ameliorates lipopolysaccharide-induced neuroinflammation and cognitive impairment via regulation of microglial polarization.
An amendment to this paper has been published and can be accessed via the original article.


Everyday life in the suburbs of Berlin: consequences for the social participation of aged men and women.
Against the background of demographic change, mobility issues are becoming crucial. Especially for the elderly, daily outdoor activities are essential for participation in social life. This article addresses the question of what extent older people, especially women, are threatened by limited social participation in Berlin's suburbia. The mobility of older women (70+) is characterized by the least number of trips, the shortest distances, and more than 50% walking trips. Besides, many older women are dissatisfied with their residential area. Given the lack of essential facilities, older women have to be considered as disadvantaged in terms of limited social participation.


Toxicity of boron nitride nanoparticles influencing bio-physicochemical responses in freshwater green algae.
Boron nanoparticles have emerged as promising nanomaterials with a wide array of applications in the biomedical, industrial, and environmental fields. However, the potential impact of these nanoparticles on aquatic organisms is not yet known. In the present study, the comparative impact of boron nitride nanoparticles and its bulk form is investigated on two freshwater algae. For this purpose, the effect on the physiological index, cellular morphology, and biochemistry profiles are examined. In Chlorella vulgaris, nano form of boron nitride is found to reduce the growth more (40%) than its bulk form (with ~ 25% growth reduction) at 50 mgl-1 treatment level. While in case of Coelastrella terrestris, 40% reduction under nano form and 33.33% reduction under bulk form is observed at 100 mgl-1 of boron nitride. Chlorophyll and carotenoid levels were also reduced under nanoparticles compared to the bulk. Proline, lactate dehydrogenase, and malondialdehyde assay were found significantly high under nanoparticle exposure. Additionally, increased catalase and superoxide dismutase enzyme activity under nanoparticle exposure revealed that the antioxidant system was activated in both the algae to eliminate the adverse influence of reactive oxygen species. The shading effect and aggregation of nanoparticles over the surface of algal cells are also important factors in attributing toxicity which are confirmed through the compound, TEM, and SEM micrographs. The study suggests that the nano form is more toxic than the bulk form and toxicity is concentration-dependent.


EPR mapping of interactions between spin-labeled variants of human carbonic anhydrase II and GroEL: evidence for increased flexibility of the hydrophobic core by the interaction.
Human carbonic anhydrase II (HCA II) interacts weakly with GroEL at room temperature. To further investigate this interaction we used electron paramagnetic resonance (EPR) spectroscopy to study HCA II cysteine mutants spin-labeled at selected positions. From our results it is evident that protein-protein interactions can be specifically mapped by site-directed spin-labeling and EPR measurements. HCA II needs to be unfolded to about the same extent as a GuHCl-induced molten-globule intermediate of the enzyme to interact with GroEL. The interaction with GroEL includes interactions with outer parts of the HCA II molecule, such as peripheral beta-strands and the N-terminal domain, which have previously been shown to be rather unstable. As a result of the interaction, the rigid and compact hydrophobic core exhibits higher flexibility than in the molten globule, which is likely to facilitate rearrangements of misfolded structure during the folding process. The degree of binding to GroEL and accompanying inactivation of the enzyme depend on the stability of the HCA II variant, and nonspecific hydrophobic interactions appear to be most important in stabilizing the GroEL-substrate complex.


Crucial questions in cell biology and in neurobiology.
Forty-two proper questions about the research methods, the structure, physiology, biochemistry, pathology and theory of cell biology and 27 more about neurobiology are listed. These have not hitherto been addressed in the literature, other than in my previous publications. The answers to some of them show anomalies in current views, or draw attention to control experiments, which have never been done. Progress will be limited until these important questions are addressed.


[Visual acuity, quality of life, and patient satisfaction after PDT treatment in AMD patients].
The efficacy of PDT to prevent the progression of AMD has been established. This study now assesses the patients' quality of life and self-reported satisfaction after PDT. All patients who underwent PDT during 2000 and 2001 at the University Eye Hospital of Mainz were interviewed using an AMD-specific modification of a standardized 82-item questionnaire on quality of life and satisfaction in ophthalmological patients. Different aspects of those parameters were derived as scores, which were then related to clinical outcome parameters. During the period of PDT treatment, the median decrease in visual acuity was three stages in the patients examined. Patients who reported a subjective increase in visual function during this period showed for example a median "private flexibility" score of 1.86, and patients with the subjective impression of a decrease in visual function a median score of 2.71. The established clinical efficacy of PDT treatment to prevent AMD progression coincides with an encouraging patient satisfaction after the treatment.


Use of Hologic LOCalizer radiofrequency identification (RFID) tags to localise impalpable breast lesions and axillary nodes: experience of the first 150 cases in a UK breast unit.
To report the outcome of 150 patients using the Hologic LOCalizer RFID (radiofrequency identification) tag system, including the first reported use of RFID tags in the axilla. Data were collected prospectively from the first tag insertion (12 June 2019) until 150 consecutive patients had undergone surgery (excision date 9 January 2020). A total of 177 tags were targeted to 177 malignant lesions in 150 women. Tags were inserted an average of 7.8 days before surgery (range 0-71 days). One hundred and twenty-six tags were targeted to a single lesion in one breast only; the remainder of tags were targeted to multiple lesions in one or both breasts, as well as to axillary lymph nodes. In addition, two cases involved the use of two tags to bracket microcalcification. All except three tags were satisfactorily deployed at their initial intended target. The majority of target lesions were masses (n=142, mean size 13.8 mm), with a range of other targets including post-vacuum-assisted biopsy cavities, marker clips post-neoadjuvant chemotherapy, architectural distortions, and clipped metastatic lymph nodes. All tags were successfully retrieved at surgical excision. Re-excision rate was 8.7%. There were no tag-specific surgical complications. The RFID tag system demonstrates many advantages over guidewires, and is effective at targeting axillary lymph nodes and multiple sites within the same breast.


Incidence of Cardiac Implantable Electronic Device Complications in Patients With Left Ventricular Assist Devices.
The objective of this study was to describe the risk of cardiac implantable electronic devices (CIEDs) complications in patients with left ventricular assist devices (LVADs). Patients with LVADs are predisposed to ventricular arrhythmias and frequently have CIEDs before receiving their LVAD. However, the role of CIED procedures such as generator changes (GC) are unclear in this population, given the potential complications of bleeding and infection. This was a retrospective, multicenter study from January 1, 2012, to September 30, 2018. All patients with LVADs were screened and those who had a CIED GC, implantation, or revision were included in the study and followed until December 31, 2018. A total of 179 patients across 6 centers had a CIED procedure after LVAD implantation. The mean age was 59.5 ± 13.4, with the cohort comprising mostly men (78%), destination LVAD therapy (53.8%), and GC (66%). The 30-day primary composite endpoint of hematoma or device infection occurred in 34 (19%) patients. The secondary endpoints of rehospitalization within 30 days and appropriate device therapy during follow-up occurred in 40 (22%) and 42 (24%) patients respectively. Of the 126 patients without previous device therapy, 14.3% received appropriate therapy during follow-up. In this large, multicenter cohort, we report the incidence of complications for CIED procedures in the LVAD population; specifically, LVAD patients are at increased risk of pocket hematomas, without downstream risk of infection, and do experience a high rate of appropriate device therapies.


In vitro controlled release of sodium ferulate from Compritol 888 ATO-based matrix tablets.
A controlled release matrix formulation for freely water-soluble drug of sodium ferulate (SF) was designed and developed to achieve a 24h release profile. Using Compritol 888 ATO as an inert matrix-forming agent to control the release of SF, formulation granules containing the physical mixtures or solid dispersions were investigated. The matrix tablets for these formulations were prepared by direct compression and their in vitro release tests were carried out. The solid dispersion based tablets were found to be more effective than those compressed from physical mixtures in retarding the release of SF. Drug release from the matrix tablets containing physical mixtures nearly completed within 12h, while that from the solid dispersion formulations lasted for over 24h. Images of the tablet surface and cross-section were characterized by scanning electron microscopy to show the formed pores and channels in the matrices. These might provide the release pathway for the inner embedded drugs. Drug released fast from the matrix tablets with the release-enhancer of lactose. The addition of surfactants was also found to increase the release rate of SF effectively. Moreover, the co-mixing of polyethylene glycol 6000 (PEG 6000) in the waxy matrices played a meaningful role in controlling the drug release for 24h. The drug release from the novel formulation might be attributed to the diffusion-controlled mechanism.


Pediatric Severe Chronic Upper Airway Disease (P-SCUAD).
The term SCUAD (severe chronic upper airway disease) has been previously introduced to describe cases with upper airway disorders and symptoms not adequately controlled despite correct diagnosis and management. It has been so far applied mainly in adults and no specific focus has been given on the pediatric population. When the term SCUAD is considered for children specifically, a series of issues may arise. These issues involve accurate definition, epidemiology, clinical characteristics, pathophysiology, and socioeconomic implications. These issues seem to clearly differentiate adult from pediatric SCUAD. We attempt to shed light on these issues in an effort to provide directions for future guideline development and research. In this context, P-SCUAD (pediatric severe chronic upper airway disease) is hereby introduced.


[Acetylcholine induced reciprocal changes in the Na, K-ATPase and acetylcholinesterase activity of nerve and membrane preparations of Na, K-ATF-azy].
ATPase and cholinesterase activities in the homogenate of the frog nerve and membrane Na,K-ATPase preparation of the bovine brain were investigated. Preliminary treatment of the nerve and the preparation by acetylcholine solution (10(-6)--10(-7) M) enhanced their Na,K-ATPase activity and reduced their cholinesterase activity. Possible mechanisms of this phenomenon are discussed.


Enantiomeric resolution of bupivacaine by high-performance liquid chromatography and chiroptical detection.
This work reports a new analytical procedure for the separation and determination of the enantiomers of bupivacaine and the determination of the enantiomeric purity. The isomers were separated using a Chirex 3020 (250 mm x 4.6 mm) with a mobile phase of n-hexane:dichloroethane:ethanol (82:9:9, v/v/v) at a flow-rate of 1 ml min(-1) and UV, polarimetric and circular dichroism (CD) detection. Obtained retention times were 5.93 and 7.53 min (R and S) with a resolution of Rs=2.36. Precisions (RSD) were 1.83 and 2.02% (CD detection) and 3.07 and 1.26% (UV detection) for R- and S-enantiomers, respectively (at 10 microg level). Detection limits were 0.5 and 0.5 microg (R and S) with CD detection, and 0.9 and 0.3 microg with UV detection. Polarimetric detection was inadequate to perform a quantitative method at similar concentration ranges as UV and CD because of poor sensitivity. A procedure for determination of enantiomeric purity using a conventional chromatographic column (RP18, Luna) coupled to a CD detector and anisotropy factor (CD/UV) as analytical signal was also developed. Obtained results show that RSDs of 6.7-1.6% were obtained in the range of 0-100% enantiomeric purity.


Using explainable machine learning to identify patients at risk of reattendance at discharge from emergency departments.
Short-term reattendances to emergency departments are a key quality of care indicator. Identifying patients at increased risk of early reattendance could help reduce the number of missed critical illnesses and could reduce avoidable utilization of emergency departments by enabling targeted post-discharge intervention. In this manuscript, we present a retrospective, single-centre study where we created and evaluated an extreme gradient boosting decision tree model trained to identify patients at risk of reattendance within 72 h of discharge from an emergency department (University Hospitals Southampton Foundation Trust, UK). Our model was trained using 35,447 attendances by 28,945 patients and evaluated on a hold-out test set featuring 8847 attendances by 7237 patients. The set of attendances from a given patient appeared exclusively in either the training or the test set. Our model was trained using both visit level variables (e.g., vital signs, arrival mode, and chief complaint) and a set of variables available in a patients electronic patient record, such as age and any recorded medical conditions. On the hold-out test set, our highest performing model obtained an AUROC of 0.747 (95% CI 0.722-0.773) and an average precision of 0.233 (95% CI 0.194-0.277). These results demonstrate that machine-learning models can be used to classify patients, with moderate performance, into low and high-risk groups for reattendance. We explained our models predictions using SHAP values, a concept developed from coalitional game theory, capable of explaining predictions at an attendance level. We demonstrated how clustering techniques (the UMAP algorithm) can be used to investigate the different sub-groups of explanations present in our patient cohort.


Real-space imaging of an orbital Kondo resonance on the Cr(001) surface.
The Kondo effect is usually connected with the interaction between a localized spin moment and itinerant electrons. This interaction leads to the formation of a narrow resonance at the Fermi level, which is called the Abrikosov-Suhl or Kondo resonance. Scanning tunnelling microscopy is an ideal technique for real-space investigations of complicated electronic structures and many-body phenomena, such as the formation of the Kondo resonance or d-wave pairing in high-T(c) superconductors. Theory has predicted that similar, Kondo-like many-electron resonances are possible for scattering centres with orbital instead of spin degrees of freedom--the quadruple momenta in uranium-based compounds or two-level systems in metallic glasses are examples of such 'pseudo-Kondo' scattering centres. Here we present evidence for the orbital Kondo resonance on a transition-metal surface. Investigations of an atomically clean Cr(001) surface at low temperature using scanning tunnelling microscopy reveal a very narrow resonance at 26 meV above the Fermi level, and enable us to visualize the orbital character of the corresponding state. The experimental data, together with many-body calculations, demonstrate that the observed resonance is an orbital Kondo resonance formed by two degenerate d(xz), d(yz) surface states.


Assessment of adipose tissue distribution by computed axial tomography in obese women: association with body density and anthropometric measurements.
1. Abdominal obesity is associated with numerous metabolic complications. Deep abdominal adipose tissue is critical in the association between the level of abdominal obesity and cardiovascular risk factors. 2. Adipose tissue localization was assessed by computed axial tomography (CAT), and its association with body density and anthropometric measurements was investigated in a sample of fifty-one obese women (percentage body fat 45.9 (SD 5.6)) aged 35.7 (SD 5.5) years. The CAT scans were performed at three levels: lower chest, abdomen and mid-thigh. 3. The total adipose tissue volume computed from these three scans was highly correlated with body fat mass (r 0.94, P less than 0.001). The proportion of deep abdominal fat as measured by the ratio of deep: total adipose tissue areas at the abdominal level was not significantly correlated with body fat mass, but it was moderately associated with the ratio of waist: hip circumferences (WHR) (r 0.49, P less than 0.001). The absolute amount of deep abdominal fat was, however, significantly correlated with body fat mass (r 0.72, P less than 0.001). 4. The subscapular (r 0.38) and the abdominal (r 0.38) skinfolds were the only two skinfolds that were significantly associated with the proportion of deep abdominal fat (P less than 0.01). These skinfolds were also those which showed the highest correlation with the absolute amount of deep abdominal fat (r 0.65, P less than 0.001, for both skinfolds). 5. A three-site CAT-scan procedure can be used for the estimation of body fat mass in premenopausal obese women. 6. In these obese women, there was no significant association between total adiposity and the proportion of deep adipose tissue at the abdominal level. 7. In premenopausal obese women, the absolute amount of deep abdominal fat can be predicted from anthropometric measurements with more accuracy than the relative amount of deep abdominal fat.


Acetylcholinesterase in immature thalamic neurons: relation to afferentation, development, regulation and cellular distribution.
The transient appearance of intense acetylcholinesterase reactivity in some immature, noncholinergic neurons has not been adequately explained. In this study two questions were investigated that relate to several possible roles for acetylcholinesterase. First, what factors influence the onset and maintenance of reactivity? Second, what are the temporal and spatial features of the cellular expression in relation to stages of neuronal development? Using light- and electron-microscopic histochemical methods, the non-cholinergic ventrobasal complex in thalamus of the immature rat was examined. Ultrastructural observations on fetal ventrobasal complex demonstrated that the onset of acetylcholinesterase reactivity precedes ingrowth of most extrinsic afferents. These inputs are, therefore, unlikely to provide the signal for onset. In transplants and explants, acetylcholinesterase persisted in ventrobasal complex neurons independent of their principal afferents. However, afferentation can affect reactivity. The patterned variation in intensity, characteristic of infant ventrobasal complex, was dramatically altered by unilateral interruption of its afferentation. The changes in intensity patterning could reflect changes in acetylcholinesterase metabolism, since postnatal treatment with an irreversible inhibitor (diisofluorophosphate) in vivo demonstrated resynthesis of acetylcholinesterase. The period of peak intensity of acetylcholinesterase reactivity normally began abruptly at 18 days of gestation +/- 12 h and continued until 4-6 days postnatally. This period follows neurogenesis and migration, but precedes active synaptogenesis. It coincides with outgrowth and initial contacting of cell processes in the ventrobasal complex. The timing complements the ultrastructural finding that acetylcholinesterase-dependent reaction product most commonly is localized to small patches of surface membrane, where distal processes contact each other, non-synaptically. Together these data suggest three points. First, that the expression of acetylcholinesterase in the immature ventrobasal complex neuron is probably under active metabolic control, responsive to both intrinsic and environmental factors. Second, that acetylcholinesterase expression is unlikely to result from a transient cholinergic input. Third, that the temporal and spatial characteristics of histochemical reactivity enable exclusion of several previously suggested explanations for the occurrence of acetylcholinesterase in the ventrobasal complex.(ABSTRACT TRUNCATED AT 400 WORDS)


Cardiac magnetic resonance in a patient with MRI-conditional pacemaker.
An implanted pacemaker is generally considered a contraindication for magnetic resonance imaging (MRI). The increasing number of indications for MRI and the rising prevalence of implanted cardiac pacemakers have prompted the recent development of MRI-conditional pacemaker systems. We present the case of a 68-year-old woman with left ventricular hypertrophy, hypertension, aortic valve stenosis and a family history of cardiac amyloidosis, who developed complete heart block. In view of the foreseeable need for cardiac MRI, an MRI-conditional dual chamber pacemaker was implanted. The MRI scan confirmed moderate left ventricular hypertrophy and aortic valve stenosis, and showed no delayed enhancement suggestive of amyloid heart disease. This case illustrates the feasibility of cardiac MRI in this setting and the usefulness of the recently introduced MRI-conditional pacemaker systems.


Effect of the entomopathogenic fungus Beauveria bassiana (Balsamo) on eggs and eclosing larvae of the tick Argas (Persicargas) persicus (Oken).
The present study was carried out to investigate the pathogenicity of the fungus Beauveria bassiana when diluted in triton X100 at concentrations of 106, 107, 108, 109, and 1010 conidia/ml and sprayed on the eggs of the tick Argas persicus. For each concentration, three replicates were made (each included about 10-16 eggs). Scanning electron microscopy was used to examine the surface morphology of the eggs and their eclosing larvae after treatment with a selected concentration of 107 conidia/ml B. bassiana. Biological studies revealed that all treated eggs demonstrated a delay in the hatching period (a highly significant increase) and a marked decrease in the hatching percentage, which increased as fungal concentrations increased, reaching 30 days (p < 0.001) and 2.9%, respectively, using 108 conidia/ml. Total inhibition of both parameters was observed at higher concentrations (109 and 1010 conidia/ml). Scanning electron microscopy of the eggs after using a concentration of 107 conidia/ml, revealed signs of fungal adhesion 2 days after treatment, whereas germination occurred after 7 days. Excessive conidiogenesis and sporulation on the egg surface were observed after 15 days of treatment. All eclosing larvae appeared paralyzed 1-4 days after hatching with many conidia covering their whole bodies. The findings suggest that the fungus affected tick larvae are either directly infected in the eggs or indirectly during eclosion.


A new arrhythmia clustering technique based on Ant Colony Optimization.
In this paper, a new method for clustering analysis of QRS complexes is proposed. We present an efficient Arrhythmia Clustering and Detection algorithm based on medical experiment and Ant Colony Optimization technique for QRS complex. The algorithm has been developed based on not only the general signal detection knowledge, but also on the ECG signal's specific features. Furthermore, our study brings the power of Ant Colony Optimization technique to the ECG clustering area. ACO-based clustering technique has also been improved using nearest neighborhood interpolation. At the beginning of our algorithm, we implement signal filtering, baseline wandering and parameter extraction procedures. Next is the learning phase which consists of clustering the QRS complexes based on the Ant Colony Optimization technique. A Neural Network algorithm is developed in parallel to verify and measure the success of our novel algorithm. The last stage is the testing phase to control the efficiency and correctness of the algorithm. The method is tested with MIT-BIH database to classify six different arrhythmia types of vital importance. These are normal sinus rhythm, premature ventricular contraction (PVC), atrial premature contraction (APC), right bundle branch block, ventricular fusion and fusion. Our simulation results indicate that this new approach has correctness and speed improvements.


Heteroatom-Induced Accelerated Kinetics on Nickel Selenide for Highly Efficient Hydrazine-Assisted Water Splitting and Zn-Hydrazine Battery.
Hydrazine-assisted water electrolysis is a promising energy conversion technology for highly efficient hydrogen production. Rational design of bifunctional electrocatalysts, which can simultaneously accelerate hydrogen evolution reaction (HER)/hydrazine oxidation reaction (HzOR) kinetics, is the key step. Herein, we demonstrate the development of ultrathin P/Fe co-doped NiSe2 nanosheets supported on modified Ni foam (P/Fe-NiSe2) synthesized through a facile electrodeposition process and subsequent heat treatment. Based on electrochemical measurements, characterizations, and density functional theory calculations, a favorable "2 + 2" reaction mechanism with a two-step HER process and a two-step HzOR step was fully proved and the specific effect of P doping on HzOR kinetics was investigated. P/Fe-NiSe2 thus yields an impressive electrocatalytic performance, delivering a high current density of 100 mA cm-2 with potentials of - 168 and 200 mV for HER and HzOR, respectively. Additionally, P/Fe-NiSe2 can work efficiently for hydrazine-assisted water electrolysis and Zn-Hydrazine (Zn-Hz) battery, making it promising for practical application.


Research advances in the relationship between nonalcoholic fatty liver disease and atherosclerosis.
Nonalcoholic fatty liver disease (NAFLD) is a metabolic stress-induced liver disease that is closely related not only to genetic susceptibility but also to insulin resistance and highly linked with metabolic syndrome. In recent years, the prevalence of NAFLD has increased rapidly, paralleling the epidemic of type 2 diabetes mellitus and obesity leading to cardiovascular disease. It has been demonstrated that NAFLD is highly associated with atherosclerosis. With recently gained knowledge, it appears that NAFLD may induce insulin resistance, dyslipidemia, oxidative stress, inflammation, and fluctuation of adipokines associated with atherosclerosis. In this review, we aimed to summarize recent discoveries related to both NAFLD and atherosclerosis, and to identify possible mechanisms linking them.


Use of light-emitting diode fluorescence microscopy to detect acid-fast bacilli in sputum as proficient alternative tool in the diagnosis of pulmonary tuberculosis in countries with limited resource settings.
Despite recent advances in the development of more sensitive technologies for the diagnosis of tuberculosis (TB), in resource-limited settings, the diagnosis continues to rely on sputum smear microscopy. This is because smear microscopy is simple, cost-efficient and the most accessible tool for the diagnosis of TB. Our study evaluated the performance of light-emitting diode fluorescence microscopy (LED-FM) using auramine/rhodamine (auramine) and the fluorescein di-acetate (FDA) vital stain in the diagnostic of pulmonary TB in Bamako, Mali. Sputum smear microscopy was conducted using the FDA and auramine/rhodamine staining procedures on fresh samples using LED-FM to evaluate the Mycobacterium TB (MTB) metabolic activity and to predict contagiousness. Mycobacterial culture assay was utilized as a gold standard method. Out of 1401 TB suspected patients, 1354 (96.65%) were retrieved from database, which were MTB complex culture positive, and 47 (3.40%) were culture negative (no mycobacterial growth observed). Out of the 1354 included patients, 1343 (95.86%), were acid-fast bacillus (AFB) positive after direct FDA staining, 1352 (96.50%) AFB positive after direct Auramine, and 1354 (96.65%) AFB positive with indirect auramine after digestion and centrifugation. Overall, the FDA staining method has a sensitivity of 98.82%, while the sensitivity of Auramine with direct observation was 99.48%, and 99.56% with the indirect examination. This study showed that, using fresh sputum both auramine/rhodamine and FDA are highly sensitive methods in diagnosing pulmonary TB and could be easily used in countries with limited resource settings.


Echocardiographic evaluation of the right ventricular dimension and systolic function in dogs with pulmonary hypertension.
Right ventricular (RV) enlargement and dysfunction are associated with prognosis in humans with pulmonary hypertension (PH). To assess RV size and systolic function in dogs with PH and to determine if they are associated with disease severity and right-sided congestive heart failure (R-CHF). 89 dogs with PH and 74 healthy dogs. Prospective observational study. PH was classified according to the tricuspid regurgitation pressure gradient. RV end-diastolic area (RVEDA) index was calculated as RVEDA divided by body surface area. RV systolic function was assessed with the tricuspid annular plane systolic excursion (TAPSE) and the RV fractional area change (FAC) normalized for body weight (TAPSEn and FACn, respectively). RVEDA index was higher in dogs with moderate PH (10.8 cm2 /m2 ; range, 6.2-14.4 cm2 /m2 ) and severe PH (12.4 cm2 /m2 ; range, 7.7-21.4 cm2 /m2 ) than in those with mild PH (8.4 cm2 /m2 ; range, 4.8-11.6 cm2 /m2 ) and control dogs (8.5 cm2 /m2 ; range, 2.8-11.6 cm2 /m2 ; P < .001). RVEDA index was significantly higher in dogs with R-CHF (13.7 cm2 /m2 ; range, 11.0-21.4 cm2 /m2 ) than in dogs without R-CHF (9.4 cm2 /m2 ; range, 4.8-17.1 cm2 /m2 ; P < .001). The severity of tricuspid regurgitation (TR) was the only independent predictor of the RVEDA index (P < .001). TAPSEn and FACn were not significantly different among varying degrees of PH severity and between dogs with and without R-CHF. The RVEDA index can be used to evaluate RV size in dogs. It can provide additional information in dogs with PH and predict R-CHF. Severity of TR is the main determinant of RV enlargement in dogs with PH.


Polycyclic Aromatic Hydrocarbons in Mussels from a South American Estuary.
Bivalves, especially mussels, have been pointed as putative species to monitor polycyclic aromatic hydrocarbons (PAHs) in marine environment. After several environmental PAHs baseline reports, the present study was conducted to assess for the first time the levels of PAHs in native mussels (Brachidontes rodriguezii) collected from a critical industrialized estuary of Argentina. Under this objective, after an 18-month sampling period, 34 pools of mussels were assessed for 17 PAHs, including the 16 compounds prioritized by United States Environmental Protection Agency. By means of gas chromatography-mass spectrometry analysis, results showed total PAHs concentrations in mussel's tissue ranged from under laboratory detection limits to 482.4 ng/g dry weight. Mussel body burdens were dominated by lower molecular weight PAHs, such as phenanthrene, naphthalene, and pyrene, whereas the overall PAHs profile suggested the predominance of petrogenic sources. Finally, the potential ecotoxicological impact was evaluated by applying Environmental Assessment Criteria and benzo[a]pyrene toxic equivalent factors.


Morphological correlates of male mating success in Triprion petasatus and Hyla marmorata (Anura: Hylidae).
Multivariate analyses of 18 morphological variables recorded for amplectant males and females and non-amplectant males of Hyla marmorata and Triprion petasatus reveal that in both of these explosive breeding species, mating is significantly non-random. Females of H. marmorata from the relatively aseasonal environment of the Upper Amazon Basin average larger than males, and amplectant males average larger than non-amplectant males. Females of Triprion petasatus from the seasonal environment of the Yucatan Peninsula average larger than males, the sizes of males are significantly correlated with the sizes of the females with which they are paired in amplexus, and amplectant males have shorter internarial distances than non-amplectant males. For both species, non-random mating is interpretable in terms of sexual selection, but the relative importance of male-male competition and female choice cannot be assessed.


Ecthyma gangrenosum: a rare manifestation of Stenotrophomonas maltophilia infection in acute myelogenous leukemia patient.
Ecthyma gangrenosum is a cutaneous infection typically associated with Pseudomonas aeruginosa. However, it is rarely caused by Stenotrophomonas maltophilia which might be overlooked leading to devastating consequences. We describe this case to avoid delays in the diagnosis and treatment of this aggressive infection, especially in immunocompromised patients.


No effect of Trp64Arg beta3-adrenoceptor polymorphism on the plasma leptin concentration in Pima Indians.
In rodents, administration of leptin promotes beta3-adrenergic stimulation of thermogenesis in brown adipose tissue. Conversely, administration of a beta3-adrenoceptor (beta3-AR) agonist decreases leptin mRNA expression and secretion, suggesting that leptin and sympathetic nervous system activity mediated through the beta3-AR comprise a negative-feedback loop. It has recently been proposed that a defect in the beta3-AR in humans may contribute to a resistance to the sympathetically mediated effects of leptin on thermogenesis and lipolysis, thus leading to obesity and type 2 diabetes mellitus. We thus hypothesized that the Trp64Arg variant in the human beta3-AR would be associated with elevated plasma leptin concentrations. We studied 101 healthy nondiabetic Pima Indians: 11 Arg64 homozygotes, 35 Trp64 homozygotes, and 55 heterozygotes. The fasting plasma leptin concentration as an absolute value or after adjustment for percent body fat and sex was not associated with the beta3-AR genotype. Thus, the data do not support an influence of the Trp64Arg variant on the plasma leptin concentration.


Common misconceptions.
Certain misconceptions about the law are common among physicians. The purpose of the legal system is to resolve disputes rather than dispense "justice." The rules of law are neither stable nor clear. Truth cannot be recovered for purposes of litigation; therefore, the evidence alone must determine the merit of a case. Many factors other than merit may also contribute substantially to the outcome of litigation.


The haptic perception of spatial orientations.
This review examines the isotropy of the perception of spatial orientations in the haptic system. It shows the existence of an oblique effect (i.e., a better perception of vertical and horizontal orientations than oblique orientations) in a spatial plane intrinsic to the haptic system, determined by the gravitational cues and the cognitive resources and defined in a subjective frame of reference. Similar results are observed from infancy to adulthood. In 3D space, the haptic processing of orientations is also anisotropic and seems to use both egocentric and allocentric cues. Taken together, these results revealed that the haptic oblique effect occurs when the sensory motor traces associated with exploratory movement are represented more abstractly at a cognitive level.


Uranium remobilization and migration evaluation through aerial spectrometric gamma technique in Syrian Desert (Area-1), Syria.
Uranium remobilization and migration in the Syrian Desert (Area-1) has been evaluated through analyzing the data of aerial spectrometric gamma technique and examining different radioactive geophysical approaches. The ten geological units identified on the already established scored map have been well characterized through analyzing their contents of eU, eTh, and K%, and studying the mutual relationships between those elements and their ratios. This is done in order to define the regional variation trends of the uranium migration in Area-1, and to evaluate the degree of uranium remobilization. The uranium potential in the studied Area-1 has been explained by applying and analyzing two prospecting indicators of the uranium favorability index UI and alteration-F. It was demonstrated that uranium remobilization took place in all the described lithological units, but to different degrees. The uranium migration and its haloes redistributions have been explained by establishing different plausible geological model interpretations. Several localities such as wadi Ratka are found to be favorable possible traps for uranium accumulation, which necessitate more further detailed uranium exploration.


Cadmium in food: Source, distribution and removal.
Since its discovery, cadmium (Cd) has played an important role in industry and brought certain conveniences to mankind, used for electroplating and making rechargeable batteries, etc. Cd is also a harmful pollutant, which will enter the food chain and cause damage to human tissues and organs. Food is the main source of Cd in the human body, so various technologies for removing Cd from food have been studied. These technologies are based on the binding mechanism between Cd and proteins. In this work, the enrichment of Cd and the harm of Cd are described. And the binding mechanism between Cd and protein is summarized. Finally, the removal technologies of Cd are prospected. This review analyzes the methods of removing cadmium from food from the perspective of the combination of cadmium and protein, which provides insights for ensuring food safety and reducing the harm of heavy metals to the human body.


Can online learning adequately prepare medical students to undertake a first female pelvic examination?
To determine whether a novel web-based learning module could adequately prepare first-year undergraduate medical students to skilfully perform their first female pelvic examination. First-year Queen's University medical students without prior training or experience in female pelvic examination were recruited for this study. After viewing key segments of the learning module, students were evaluated while performing a pelvic examination on a female volunteer using a standardized assessment checklist (total score = 30 points). Descriptive and comparative statistics were generated. Forty-five students participated with a mean age of 24 years (range 20 to 40). The mean score (±SD) on the assessment checklist was 23.9 ± 3.6 points, (range 17 to 30). All study participants received a passing grade of ≥ 50% (15/30 points), and 53.3% (24/45) received an honours grade of ≥ 80% (24/30 points). Of the participants, 88.9% (40/45) agreed that they were well prepared for their first female pelvic examination after viewing the training video. Mean scores were similar for male students (23.9, n = 22) and female students (23.8, n = 23) (P = 0.90, t test). Mean scores were not higher in those who watched key segments of the learning module more than once. This learning module viewed immediately prior to a simulated clinic session afforded first-year medical students the necessary knowledge and skills to perform a first female pelvic examination. This was accomplished with as little as one viewing, and could lead to savings in organizational costs and instruction time for medical school curricula.


Routine cervical screening with primary HPV testing and cytology triage protocol in a randomised setting.
The role of high-risk human papillomavirus (hrHPV) testing in primary cervical screening has not been established. We generated a randomised evaluation design ultimately to clarify whether primary hrHPV testing implemented into routine screening can bring increase in the programme effectiveness. The aim of the present report on first-year results was to assess the cross-sectional relative validity parameters for routine hrHPV screening, in comparison with conventional screening. An equal number of women invited to routine screening was randomly allocated to primary hrHPV screening (n=7060) and to cytological screening (n=7089). In the hrHPV screening arm, after a single positive hrHPV test result, the need of colposcopy referral was determined by a cytological triage test. Compared with the conventional arm, more colposcopy referrals were made in the hrHPV screening arm (relative risk 1.51, confidence interval 95% 1.03-2.22). Specificity of the primary screening with sole hrHPV test (91.5-92.1%) was much lower than that with the cytology triage (98.7-99.3%), which was not quite as specific as screening with conventional cytology (99.2-99.6%). Compared with conventional cytology, primary screening with hrHPV test results in increased cross-sectional relative sensitivity at the level of all positive lesions at the cost of substantial loss in specificity. With cytology triage, the specificity improves to the level of conventional cytology.


Piecing together stakeholder puzzles-puzzling about (opioid substitute treatment---OST) stakeholders and their pieces: a rambling point-of-view.
This point-of-view presentation explores "stakeholders" and "opioid substitute treatment," their dimensions, selected enabling necessary conditions to operate, or not, implications, and consequences from a range of selected perspectives.


Scientific progress specific to biology: an epistemological overview.
Progresses in leading edge life sciences are undeniable, but there is more to it: from an epistemological perspective, they rest on a paradox vitalizing the very project of biology. Making our understanding of organic functioning all the more objective, life sciences yet exploit a paradigm which structurally rules out any opportunity to explain why biological phenomena are explainable the way we claim they are. As such a blind spot is constitutive of the disciplinary boundaries that condition and permit objective modelling, evolutions in scientists' mode of thought (i.e. paradigm shifts) may require at crucial points some interaction with epistemologists or historians of sciences. The model case of ontophylogenesis thus shows not only how such cooperation can be useful (both in normal science and in transitional contexts), but mostly why it plays a role in helping biology to get out of its intrinsic paradox. The most innovative feature of ontophylogenesis would thus be the following: to give account for the mode of intelligibility it chose by explaining it - in a truly Darwinian manner -in the core of the theory. Though this epistemic move definitely confirms biology to be an autonomous science as long as it faces its constitutive paradox, the methodological detour such realization implied would go through occasional interplay with "exclusively reflexive approaches" - that is to say, humanities.


Research design considerations for linkage studies of affective disorders using recombinant DNA markers.
A genetic linkage study is one approach to resolving the etiology of a major psychiatric disorder either by testing involvement of a specific candidate gene or by demonstrating the existence of some unidentified gene in a specific place on the genome. Because of the complexities of psychiatric disorders, a successful linkage study must be built upon accurate and reliable diagnosis, families with multiple affected members, highly informative genetic markers, and powerful multipoint linkage methods. Over the last decade, great advances have been made in all these areas. Linkage studies are not only appropriate for affective and other major psychiatric disorders but are already beginning to yield promising results.


Rice husk-intensified cathode driving bioelectrochemical reactor for remediating nitrate-contaminated groundwater.
To achieve economical and eco-friendly denitrification, rice husk-intensified cathode driving bioelectrochemical reactor (RCBER) was constructed with rice husk as solid-phase carbon source and microbial carrier. Results demonstrated that the application of current improved the utilization of rice husk and enhanced the denitrification, and the quenching of anodic hydroxyl radicals by rice husk also improved the microbial resistance to current. The highest nitrate removal rate as 0.34 mg-N/(L∙d), higher economic benefits, i.e., current efficiency as 31.6% and energy consumption as 2.43 kWh/g NO3--N, and the highest environmental benefit, i.e., hydrogenotrophic denitrification contribution as 37.9%, were obtained at 200 mA/m2. The best performance at 200 mA/m2 was related to its better microenvironment, such as lower accumulation of anodic by-products and higher bioavailability of rice husks, as well as higher microbial metabolic activity, such as stable extracellular polymeric substance, the maximum electron transport system activity as 11.63 ± 0.14 μg O2·g-1·min-1·mg protein-1 and the highest activity of nitrate reductase (3.15-fold that of control check). The application of current realized the coexistence of heterotrophic and hydrogenotrophic denitrifiers, and multiple functional bacteria such as anaerobic denitrifiers Flavobacterium, aerobic denitrifiers Comamonas, hydrogenotrophic denitrifiers Thermomonas and electron transfer-related Enterobacter coexisted at 200 mA/m2, thereby improving RCBER's adaptability to the complex microenvironment. This study provides the theoretical basis for realizing a win-win situation of environmental pollution remediation and agricultural waste disposal.


Laparoscopic intragastric stapled resection of gastric submucosal tumors located near the esophagogastric junction.
Laparoscopic resection cannot be applied easily to tumors located near the esophagogastric junction or the pyloric ring. We evaluated our laparoscopic intragastric surgical technique for gastric submucosal tumors located near the esophagogastric junction and the results of a clinical study. We performed our technique in six patients: one man and five woman with a mean age of 61 years. Using the laparoscopic procedure, after inflation of the stomach, we inserted two or three balloon-type ports into the stomach through the abdominal wall. A stapled resection of gastric submucosal tumors using a laparoscopic linear stapler was performed successfully in all the patients. Without exception, stapled resections were successfully performed. The mean operation time was 168 min, and the blood loss was minimal There were no intra- or postoperative complications. The mean postoperative hospital stay was 9.8 days. The mean maximal diameter size of the resected specimens was 2.4 cm. Histopathologic diagnoses were gastrointestinal stromal tumors in five cases and enterogenous cyst in one. There were no recurrences during a mean follow-up period of 27 +/- 11.6 months. Although we need to evaluate the long-term outcomes, our procedure is considered technically feasible, safe, and useful for the resection of gastric submucosal tumors located near the esophagogastric junction.


Glucose tolerance, plasma insulin and alpha-lipoproteins in young male myocardial infarction survivors compared with controls matched on serum cholesterol concentration.
In order to identify metabolic risk factors other than hypercholesterolaemia, all cases of acute myocardial infarction, diagnosed in males aged under 40 years, were studied over a period of 6 years in Göteborg, Sweden. Twenty out of twenty-four patients who were alive at the time of the study were compared with forty controls matched for serum cholesterol concentration. A previous report has noted lower apolipoprotein A (apoA) and a higher alpha-lipoprotein triglyceride concentration in these young myocardial infarction patients compared with the matched controls. Basal blood glucose, oral glucose tolerance and plasma insulin levels did not differ between the patients and controls, i.e. decreased glucose tolerance and elevated plasma insulin levels were not found to be additional risk factors for myocardial infarction in young males if serum cholesterol concentration was taken into consideration. This finding could be explained by the fact that patients and controls were all high cholesterol individuals and a difference between the patients and the general population is still possible. Low apoA was a risk factor independent of serum cholesterol as well as glucose intolerance and elevated plasma insulin levels.


Development of an effective sample preparation method for the proteome analysis of body fluids using 2-D gel electrophoresis.
A sample preparation is still the most critical step in two-dimensional electrophoresis (2-DE) and should be optimized for each type of sample. In this study, a protein extraction method from body fluids was developed using a combined centrifugal filter device and a sample treating buffer. When plasma, amniotic fluid, urine, and tear were tested with this method, the recovery of protein reached almost 90% and high-quality separation of 2-DE gel was obtained.


Inclusion of quinestrol and 2,6-di-O-methyl-β-cyclodextrin: Preparation, characterization, and inclusion mode.
An inclusion complex between chemosterilant quinestrol and 2,6-di-O-methyl-β-cyclodextrin (DM-β-CD) was prepared using the solution-ultrasonic method. A 1:1 stoichiometry was confirmed by elemental analysis. Analytical techniques such as UV-vis spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy were used to characterize the complex. Proton NMR and nuclear Overhauser effect spectroscopy results indicate that the hydroxyl end and alkynyl end of quinestrol was included in the DM-β-CD cavity, which agrees with the most predominant configuration optimized by molecular modeling. The water solubility of quinestrol was significantly increased through complexation with DM-β-CD. The DM-β-CD complexes can be used in the design of a novel formulation of quinestrol for rat control products in agriculture.