VH gene replacement in hyperselected B cells of the quasimonoclonal mouse.
The primary repertoire of the quasimonoclonal mouse is monospecific. However, among peripheral B cells, there is a high frequency of variant cells with V(H) replacements, which are also hypermutated. We show in this work that these hyperselected cells expand in numbers as the animals increase in age, switch their isotypes, and with increasing age become the almost exclusive contributors to the pool of serum Ig. The fraction of such cells is higher in the peritoneum than in peripheral blood, supporting the view that the peritoneum is a site of production of nonspecific serum Ig. We have also isolated and partially sequenced the replacing V(H) gene segments from B220-positive, Id-negative cells, and mu-negative, lambda-positive (i.e., switched) cells, and matched them with their germline counterparts. V(H) families are represented proportional to the number of members in the germline, a finding that is consistent with the idea that environmental Ag pressure maintains the germline repertoire of V gene segment.


Differential Probing Behavior of Blissus insularis (Hemiptera: Blissidae) on Resistant and Susceptible St. Augustinegrasses.
Southern chinch bug, Blissus insularis Barber, is a severe pest of St. Augustinegrass throughout the southern United States. Host plant resistance is an environmentally friendly method to manage chinch bug infestations and is increasingly important, as the southern chinch bug develops resistance to insecticides. In this study, in an effort to understand resistance mechanisms in two varieties of St. Augustinegrass ('FX-10' and 'NUF-76'), we used the electrical penetration graph method to quantify stylet probing behaviors in two resistant and two susceptible St. Augustinegrass varieties. Overall, chinch bugs spent less time probing on resistant FX-10 and NUF-76 than on susceptible 'Floratam' and 'Palmetto', and individual probes were shorter in average duration but more numerous in resistant varieties than in susceptible varieties. During probing, chinch bugs spent more time in pathway-associated stylet activities (i.e., penetration through epidermal and mesophyll tissue) in the resistant varieties than in the susceptible varieties, likely indicating difficulty in finding and accessing an ingestion site. As a consequence, chinch bugs spent proportionately much less time engaged in xylem ingestion in both resistant varieties than in susceptible varieties but only in FX-10 were phloem-associated activities significantly reduced compared with those in susceptible varieties. We conclude that there is evidence for non-phloem-associated chinch-bug resistance factors in both NUF-76 and FX-10, and phloem-associated factors in FX-10.


Resilience for health-an emergent property of the "health systems as a whole".
Resilience has become a popular term, and its meaning varies widely depending on the context of its use. Its Latin origin, resilire, means "bouncing back"-should bouncing back be understood literally or rather metaphorically in the context of health, illness, dis-ease, and disease? This essay examines ecological, physiological, personal, and health system perspectives inherent in the concept of resilience. It emerges that regardless of the level of aggregation, resilience is a systems property-it is as much a property of each of the subsystems of network physiology, the person, and the health care delivery system as it is a property of the health system as a whole. Given the interdependencies between people, their internal and external environments, and the health service system, strengthening resilience, ie, the ability to positively adapt to challenges and changing circumstances, will require a broad-based public discourse: "How can we strengthen resilience and health for the benefit of people and society at large".


Multiple distant metastases of hepatocellular carcinoma to the oral cavity.
We describe the palliative therapy for multiple metachronous oral metastases of hepatocellular carcinoma in a 72-year-old patient with emphasis on maintaining oral functions by local debulking procedures in due consideration of the dissemination of the neoplasm to multiple organs. The first oral metastasis was the first evidence of multiple tumor spread after partial hepatectomy. Palliative chemotherapy with sorafenib was cancelled after three weeks due to tumor progression and hemiplegia following brain metastasis and stroke. Periodical screening of the patient for oral findings allowed the non-mutilating excision of further oral metastases at an early stage with no signs of local recurrence during the follow-up period. Oral metastases from hepatocellular carcinoma appear to occur more frequently than formerly supposed.


Families in supportive care--Part I: The transition of fading away: the nature of the transition.
The entire family unit is affected when one of its members is in need of supportive care; however, relatively few studies pertaining to palliative care have focused on the family as a unit. The purpose of this study was to examine the experience of families having a member with advanced cancer who was receiving palliative care either at home or in the hospital. Eight families (24 family members) participated in semistructured interviews which were audiotaped, transcribed, and subjected to qualitative methods of analysis. Results indicated that the families' experience can be conceptualized as a transition of fading away. The transition began with an ending, characterized by the processes of redefining and dealing with burden. A period of chaos, confusion, fear, and uncertainty characterized the neutral zone. The end point of the transition was a new beginning where families focused on living day-to-day and preparing for death.


Occupational health risk of working in garages: comparative study on blood pressure and hematological parameters between garage workers and Haramaya University community, Harar, eastern Ethiopia.
Occupational exposure to chemicals in garages causes a wide range of biological effects, depending upon the level and duration of exposure. In Ethiopia, there have been few studies conducted to assess the exposure of garage workers to chemicals. Preceding studies have not explored the effect of working in garage on blood pressure and hematological parameters. Therefore, this study aimed to assess differences in blood pressure and hematological parameters among garage workers compared to the Haramaya University community, Harar, eastern Ethiopia. A comparative cross-sectional study was conducted in Harar town, eastern Ethiopia. Thirty garage workers were selected and compared with 30 age- and sex-matched controls comprising of teachers and students. Demographic and occupational data were collected by using a structured questionnaire by a trained data collector. Blood pressure was measured using sphygmomanometry. Hematological parameters were measured with an automated hematology analyzer. Data were analyzed using Stata version 13. The majority of the garage workers did not implement effective preventive or control measures for workplace chemical exposure. Statistically significant increases were found in systolic (128.67±18.14 vs 106.33 ±9.27 mmHg, P<0.0001), diastolic blood pressure (90.33±11.29 vs 75.67 ±5.68 mmHg, P<0.0001), total white blood cells (7.9±1.51 vs 6.72±2.04×109 cells/L, P=0.0138), and platelets (323.20±48.82 vs 244.1±47.3×109 cells/L, P<0.0001) in garage workers compared to the control group. On the other hand, statistically significant decreases were found in red blood cells (5.13±0.38 vs 5.46±0.36×1012 cells/L, P=0.0006), hemoglobin (14.89±0.71 vs 15.45±0.87 g/dL, P=0.0062), hematocrit (43.98%±1.99% vs 46.4%3±2.32%, P<0.0001), and mean corpuscular volume (83.19±2.93 vs 85.11±3.87 fL, P=0.0353) among garage workers compared to the control group. There were significant differences in blood pressure and hematological parameters between garage workers and the control group. Therefore, appropriate and effective safety measures need to be taken by the workers to prevent possible chemical exposure during routine tasks.


Interfacial width in polymer bilayer films prepared by double-spin-coating and flotation methods.
A spin-coating method with the aid of selective solvents has been used to construct multilayer structures for organic devices under the assumption that the solvents do not invade a preformed structure. To confirm the assumption, we examined the interfacial width (lambda(i)) of model polymer bilayers, composed of polystyrene and perdeuterated poly(methyl methacrylate), prepared by spin-coating and flotation methods. Neutron reflectivity measurements revealed that the lambda(i) value was larger for the spin-coating method than for the flotation method. These results cast doubt on the validity of the assumption. This knowledge should be kept in mind when this method is applied to construct multilayer structures.


Stereotactic systems and procedures for depth electrode placement: technical aspects.
The authors describe the conversion of the Leksell spherical system to that of the orthogonal approach for depth electrode placement, by the addition of relatively simple devices to the main frame. These modifications have created the need for new instrumentation such as teleradiology with laser beam centering and the use of an all-purpose stereotactic chair. The main device used for the orthogonal approach is an instrument and electrode carrier moving on sliding side bars. This system can also take advantage of the newer imaging techniques, such as CT scanning, digital angiography and NMR, by the addition of computer markers which are interchangeable with the frame side bars.


[Survey of economic burden of hepatitis B-related diseases in 12 areas in China].
Objective: Less surveys on the economic burden of hepatitis B (HB)-related diseases have been conducted in China, so the socioeconomic harm caused by the diseases is not clear and the key parameters for economic evaluation of hepatitis B prevention and treatment are lacking. This study aimed to analyze the direct, indirect and intangible expenditures of hospitalized patients with HB-related diseases during hospitalization and during a year in different areas of China. Methods: The hospitals for infectious diseases and the large general hospitals in 12 areas in China were selected in the study. All the inpatients with HB-related diseases were surveyed by cluster sampling of consecutive cases. The direct expenditure included direct medical cost and direct non-medical cost. The indirect expenditure, including work loss of patients and caregivers, were calculated by using human capital method for urban and rural populations in 12 areas. The intangible expenditure were reflected by willing to pay and stochastic tournament. The influencing factors of direct and indirect costs were identified by stepwise linear multi-variation regression analysis. Results: A total of 27 hospitals in 12 areas were included in the survey. A total of 4 718 cases were surveyed, the overall response rate was 77.7%. The average hospital stay was 29.2 days (27-34) and the hospitalization expenditure was averagely 16 832.80 yuan (RMB) per case, in which the highest proportion (61.2%) was medicine fees [10 365.10 yuan (RMB)]. The average direct expenditure and indirect expenditure were consistent with the severity of illness, which were 18 336.10 yuan (RMB) and 4 759.60 yuan (RMB) respectively, with the ratio of 3.85 ∶ 1. The direct medical expenditure [17 434.70 yuan (RMB)] were substantially higher than the direct non-medical expenditure [901.40 yuan (RMB)]. It was found that the hospitalization expenses was highest in direct medical expenditure and the transportation expenses was highest in direct non-medical expenditures. Among the average indirect expenditure, the loss of income for the patients [3 832.50 yuan (RMB)] was higher than that for the caregivers [927.20 yuan (RMB)]. The total direct and indirect expenditure was highest for liver transplantation, followed by severe hepatitis, hepatocellular carcinoma and decompensated cirrhosis, acute hepatitis B, compensated cirrhosis and chronic hepatitis B. The influencing factors for both direct and indirect expenditure were high hospital level, severity of hepatitis B, living in urban area, antiviral therapy, long hospitalization and monthly income of family. For average 3.74 outpatient visits and 1.51 hospitalization, the average annual direct, indirect and intangible expenditure for HB-related diseases were 30 135.30, 6 253.80 and 44 729.90 yuan (RMB) [totally 81 119.00 yuan (RMB)], accounting for 37.3%, 7.7% and 55.0%, respectively. Of the annual direct medical expenditure [28 402.80 yuan (RMB)], which were much higher than non-medical expenditure [1 732.50 yuan (RMB)], hospitalization expenditure [26 074.20 yuan (RMB)] was higher than outpatient visit expenditure [4 061.10 yuan (RMB)]. The annual indirect expenditures for outpatient visit and hospitalization were 763.60 and 5 490.10 yuan (RMB), respectively. Of the annual intangible expenditure, the highest was that for primary hepatocellular carcinoma, followed by cirrhosis, chronic hepatitis B, severe hepatitis B, liver transplantation and acute hepatitis B. Conclusions: A heavy economic burden has been caused by HB-related diseases in China, and patients are more likely to rely on medical service rather than non-medical service. It is necessary to take effective treatment measures to prevent the adverse outcome of HB related diseases and achieve significant economic benefits. The influence of HB related diseases on mental health of the people can be reflected by an economics term, intangible expenditure.


Improved cardiac metabolism and activation of the RISK pathway contributes to improved post-ischemic recovery in calorie restricted mice.
Recent evidence has suggested that activation of AMP-activated protein kinase (AMPK) induced by short-term caloric restriction (CR) protects against myocardial ischemia-reperfusion (I/R) injury. Because AMPK plays a central role in regulating energy metabolism, we investigated whether alterations in cardiac energy metabolism contribute to the cardioprotective effects induced by CR. Hearts from control or short-term CR mice were subjected to ex vivo I/R and metabolism, as well as post-ischemic functional recovery was measured. Even in the presence of elevated levels of fatty acids, CR significantly improved recovery of cardiac function following ischemia. While rates of fatty acid oxidation or glycolysis from exogenous glucose were similar between groups, improved functional recovery post-ischemia in CR hearts was associated with high rates of glucose oxidation during reperfusion compared to controls. Consistent with CR improving energy supply, hearts from CR mice had increased ATP levels, as well as lower AMPK activity at the end of reperfusion compared to controls. Furthermore, in agreement with the emerging concept that CR is a non-conventional form of pre-conditioning, we observed a significant increase in phosphorylation of Akt and Erk1/2 at the end of reperfusion. These data also suggest that activation of the reperfusion salvage kinase (RISK) pathway also contributes to the beneficial effects of CR in reducing post-ischemia contractile dysfunction. These findings also suggest that short-term CR improves post-ischemic recovery by promoting glucose oxidation, and activating the RISK pathway. As such, pre-operative CR may be a clinically relevant strategy for increasing ischemic tolerance of the heart.


Sitagliptin and cardiovascular outcomes in diabetic patients with chronic kidney disease and acute myocardial infarction: A nationwide cohort study.
The cardiovascular safety and efficacy of sitagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, in type 2 diabetic patients with chronic kidney disease (CKD) after acute myocardial infarction (AMI) are unclear. We analyzed data from the Taiwan National Health Insurance Research Database between March 1st, 2009 and December 31st, 2011. A total of 1025 AMI patients with diabetes with chronic kidney disease were selected as the study cohort. The study evaluated the cardiovascular safety and efficacy of sitagliptin by comparing 205 subjects (20%) who use sitagliptin to 820 matched subjects (80%) who do not. The primary outcomes included myocardial infarction, ischemic stroke or cardiovascular death. Primary composite outcomes occurred in 54 patients in the sitagliptin group (26.3%) and in 164 patients in the comparison group (20.0%) (HR, 1.32; 95% CI, 0.97-1.79; P=0.079) during the mean follow-up of 1.02years (SD=0.71years). The sitagliptin group had similar risks of ischemic stroke, all-cause mortality or hospitalization for heart failure (HF) compared to the non-sitagliptin group (P=0.938, 0.523 and 0.795 respectively). However, sitagliptin use was associated with increased risks of recurrent myocardial infarction (HR, 1.73; 95% CI, 1.15-2.58; P=0.008) and percutaneous coronary revascularization (HR, 1.43; 95% CI, 1.04-1.95; P=0.026). Among type 2 diabetic patients with CKD after AMI, the use of sitagliptin was not associated with an increased risk of cardiovascular death, ischemic stroke or hospitalization for HF but was associated with increased risks of recurrent MI and percutaneous coronary revascularization.


Type III collagen affects dermal and vascular collagen fibrillogenesis and tissue integrity in a mutant Col3a1 transgenic mouse model.
Type III collagen is a major fibrillar collagen consisting of three identical α1(III)-chains that is particularly present in tissues exhibiting elastic properties, such as the skin and the arterial wall. Heterozygous mutations in the COL3A1 gene result in vascular Ehlers-Danlos syndrome (vEDS), a severe, life-threatening disorder, characterized by thin, translucent skin and propensity to arterial, intestinal and uterine rupture. Most human vEDS cases result from a missense mutation substituting a crucial glycine residue in the triple helical domain of the α1(III)-chains. The mechanisms by which these mutant type III collagen molecules cause dermal and vascular fragility are not well understood. We generated a transgenic mouse line expressing mutant type III collagen, containing a typical helical glycine substitution (p.(Gly182Ser)). This Col3a1Tg-G182S mouse line displays a phenotype recapitulating characteristics of human vEDS patients with signs of dermal and vascular fragility. The Col3a1Tg-G182S mice develop severe transdermal skin wounds, resulting in early demise at 13-14weeks of age. We found that this phenotype was associated with a reduced total collagen content and an abnormal collagen III:I ratio, leading to the production of severely malformed collagen fibrils in the extracellular matrix of dermal and arterial tissues. These results indicate that expression of the glycine substitution in the α1(III)-chain disturbs formation of heterotypic type III:I collagen fibrils, and thereby demonstrate a key role for type III collagen in collagen fibrillogenesis in dermal and arterial tissues.


A cautionary note concerning the use of stabilized weights in marginal structural models.
Marginal structural models are commonly used to estimate the causal effect of a time-varying treatment in presence of time-dependent confounding. When fitting an MSM to data, the analyst must specify both the structural model for the outcome and the treatment models for the inverse-probability-of-treatment weights. The use of stabilized weights is recommended because they are generally less variable than the standard weights. In this paper, we are concerned with the use of the common stabilized weights when the structural model is specified to only consider partial treatment history, such as the current or most recent treatments. We present various examples of settings where these stabilized weights yield biased inferences while the standard weights do not. These issues are first investigated on the basis of simulated data and subsequently exemplified using data from the Honolulu Heart Program. Unlike common stabilized weights, we find that basic stabilized weights offer some protection against bias in structural models designed to estimate current or most recent treatment effects.


Homemade-device-induced negative pressure promotes wound healing more efficiently than VSD-induced positive pressure by regulating inflammation, proliferation and remodeling.
Vacuum sealing drainage (VSD) is an effective technique used to promote wound healing. However, recent studies have shown that it exerts positive pressure (PP) rather than negative pressure (NP) on skin. In this study, we created a homemade device that could maintain NP on the wound, and compared the therapeutic effects of VSD-induced PP to those of our homemade device which induced NP on wound healing. The NP induced by our device required less time for wound healing and decreased the wound area more efficiently than the PP induced by VSD. NP and PP both promoted the inflammatory response by upregulating neutrophil infiltration and interleukin (IL)‑1β expression, and downregulating IL‑10 expression. Higher levels of epidermal growth factor (EGF), transforming growth factor (TGF)‑β and platelet-derived growth factor (PDGF), and lower levels of basic fibroblast growth factor (bFGF) were observed in the wound tissue treated with NP compared to the wound tissue exposed to PP. Proliferation in the wound tissue exposed to NP on day 10 was significantly higher than that in wound tissue exposed to PP. NP generated more fibroblasts, keratinized stratified epithelium, and less epithelia with stemness than PP. The levels of ccollagen Ⅰ and Ⅲ were both decreased in both the NP and PP groups. NP induced a statistically significant increase in the expression of fibronectin (FN) on days 3 and 10 compared to PP. Furthermore, the level of matrix metalloproteinase (MMP)‑13 increased in the NP group, but decreased in the PP group on day 3. NP also induced a decrease in the levels of tissue inhibitor of metalloproteinase (TIMP)‑1 and TIMP‑2 during the early stages of wound healing, which was significantly different from the increasing effect of PP on TIMP‑1 and TIMP‑2 levels at the corresponding time points. On the whole, our data indicate that our homemade device which induced NP, was more efficient than VSD‑induced PP on wound healing by regulating inflammation, secretion, proliferation and the distribution of different cells in wound tissue.


Evaluation of Respondent-Driven Sampling Prevalence Estimators Using Real-World Reported Network Degree.
Respondent-driven sampling (RDS) is used to measure trait or disease prevalence in populations that are difficult to reach and often marginalized. The authors evaluated the performance of RDS estimators under varying conditions of trait prevalence, homophily, and relative activity. They used large simulated networks (N = 20,000) derived from real-world RDS degree reports and an empirical Facebook network (N = 22,470) to evaluate estimators of binary and categorical trait prevalence. Variability in prevalence estimates is higher when network degree is drawn from real-world samples than from the commonly assumed Poisson distribution, resulting in lower coverage rates. Newer estimators perform well when the sample is a substantive proportion of the population, but bias is present when the population size is unknown. The choice of preferred RDS estimator needs to be study specific, considering both statistical properties and knowledge of the population under study.


Oxygen-dependent hydroxylation by FIH regulates the TRPV3 ion channel.
Factor inhibiting HIF (FIH, also known as HIF1AN) is an oxygen-dependent asparaginyl hydroxylase that regulates the hypoxia-inducible factors (HIFs). Several proteins containing ankyrin repeat domains (ARDs) have been characterised as substrates of FIH, although there is little evidence for a functional consequence of hydroxylation on these substrates. This study demonstrates that the transient receptor potential vanilloid 3 (TRPV3) channel is hydroxylated by FIH on asparagine 242 within the cytoplasmic ARD. Hypoxia, FIH inhibitors and mutation of asparagine 242 all potentiated TRPV3-mediated current, without altering TRPV3 protein levels, indicating that oxygen-dependent hydroxylation inhibits TRPV3 activity. This novel mechanism of channel regulation by oxygen-dependent asparaginyl hydroxylation is likely to extend to other ion channels.


A method for the analysis of low-mass molecules by MALDI-TOF mass spectrometry.
We report a novel method termed matrix suppressed laser desorption/ionization to improve the analysis of low-mass molecules by MALDI-TOF mass spectrometry. In this method, the surfactant of cetrimonium bromide (CTAB) is added to the conventional matrix of alpha-cyano-4-hydroxycinnamic acid solution to prepare the MALDI samples. During the MALDI process, the presence of CTAB could substantially or even completely suppress the matrix-related ion background. As a result, very clean mass spectra can be routinely obtained in the low-mass range. In addition, the presence of CTAB can significantly improve the mass resolution of low-mass molecules. It is seen that high-quality spectra were routinely obtained at a matrix/CTAB ratio of 1000:1. This method has been successfully used to analyze a variety of low-mass molecules.


The effective oncotic pressure of dextran.
Measurement of plasma volume before and after the acute infusion of commercial dextran revealed that all brands tested were hyperoncotic by a factor of approximately 2. By mixing 6% dextran with 0.9% saline in 1:1 proportion a 3% dextran solution was obtained which was nearly isoncotic in our dogs. The most likely explanation for the discrepancy is that the 6% solution contains a high proportion of molecules of lower molecular weight resulting in a greater oncotic pressure than predicted on the basis of the average molecular weight. In addition, this leads to a rapid loss of this solute from the blood. Clinicians and researchers should be aware of the possibility that the dextran preparation they are using is not truly isoncotic.


Erratum to: Axial imidazole binding strengths in porphyrinoid cobalt(III) complexes as studied by tandem mass spectrometry.
The Co(II) complexes of twelve meso-tetraaryl-porphyrins, -chlorins, and chlorin analogues containing non-pyrrolic heterocycles were synthesized and converted in situ to the corresponding Co(III) complexes coordinated to one or two imidazoles. Electrospray ionization tandem mass spectrometry (ESI-MS/MS) in conjunction with the energy-variable collision-induced dissociation (CID) technique was used to compare the relative gas-phase binding strength of the axially coordinated imidazoles to the octahedral and square planar Co(III) porphyrinoid complex ions. The observed binding energies of these ligands were rationalized in terms of the effects of porphyrinoid core structure and meso-substitution on the electron density on the central Co(III) centers. Some of these trends were supported by DFT-based computational studies. The study highlights to which extend porphyrins vary from chlorins and chlorin analogues in their coordination abilities and to which extraordinary degree meso-thienyl-substituents influence the electronic structure of porphyrins. The study also defines further the scope and limits CID experiments can be used to interrogate the electronic structures of metalloporphyrin complexes.


A prospective survey on chest malignancies following multiple fluroscopies during artificial pneumothorax therapy for pulmonary tuberculosis.
Patients with pulmonary tuberculosis treated in 4 sanatoria in Niigata prefecture during the period from 1941 to 1961 were followed up. Of 2,756 patients, 1,193 responded and sent us effective information. However, 1,224 did not come into contact because of changed and unknown adress, 326 did not respond, and 13 were omitted because of incomplete answers. Of 1,193 effective responders, 568 had been treated by artificial pneumothorax (the pneumothorax group), and 552 had been treated by the other measures than pneumothorax (the control group). There were 65 deaths in the pneumothorax, group, and 40 deaths in the control group. No deaths from chest malignancies were reported in the pneumothorax group, while 4 chest malignancies in the control. In this survey, no evidence of increased frequency of chest malignancies including leukemia following multiple fluoroscopies during artificial pneumothorax was detected.


Myeloid Cell Isolation from Mouse Skin and Draining Lymph Node Following Intradermal Immunization with Live Attenuated Plasmodium Sporozoites.
Malaria infection begins when the sporozoite stage of Plasmodium is inoculated into the skin of a mammalian host through a mosquito bite. The highly motile parasite not only reaches the liver to invade hepatocytes and transform into erythrocyte-infective form. It also migrates into the skin and to the proximal lymph node draining the injection site, where it can be recognized and degraded by resident and/or recruited myeloid cells. Intravital imaging reported the early recruitment of brightly fluorescent Lys-GFP positive leukocytes in the skin and the interactions between sporozoites and CD11c(+) cells in the draining lymph node. We present here an efficient procedure to recover, identify and enumerate the myeloid cell subsets that are recruited to the mouse skin and draining lymph node following intradermal injection of immunizing doses of sporozoites in a murine model. Phenotypic characterization using multi-parametric flow cytometry provides a reliable assay to assess early dynamic cellular changes during inflammatory response to Plasmodium infection.


Effects of Thoracic Epidural Anesthesia on Neuronal Cardiac Regulation and Cardiac Function.
Cardiac sympathetic blockade with high-thoracic epidural anesthesia is considered beneficial in patients undergoing major surgery because it offers protection in ischemic heart disease. Major outcome studies have failed to confirm such a benefit, however. In fact, there is growing concern about potential harm associated with the use of thoracic epidural anesthesia in high-risk patients, although underlying mechanisms have not been identified. Since the latest review on this subject, a number of clinical and experimental studies have provided new information on the complex interaction between thoracic epidural anesthesia-induced sympatholysis and cardiovascular control mechanisms. Perhaps these new insights may help identify conditions in which benefits of thoracic epidural anesthesia may not outweigh potential risks. For example, cardiac sympathectomy with high-thoracic epidural anesthesia decreases right ventricular function and attenuates its capacity to cope with increased right ventricular afterload. Although the clinical significance of this pathophysiologic interaction is unknown at present, it identifies a subgroup of patients with established or pending pulmonary hypertension for whom outcome studies are needed. Other new areas of interest include the impact of thoracic epidural anesthesia-induced sympatholysis on cardiovascular control in conditions associated with increased sympathetic tone, surgical stress, and hemodynamic disruption. It was considered appropriate to collect and analyze all recent scientific information on this subject to provide a comprehensive update on the cardiovascular effects of high-thoracic epidural anesthesia and cardiac sympathectomy in healthy and diseased patients.This review provides a comprehensive update on the cardiovascular effects of high-thoracic epidural anesthesia and cardiac sympathectomy in healthy and diseased patients.


Psychosocial Evaluation in Patients Undergoing Left Ventricular Assist Device Implantation Using the Transplant Evaluation Rating Scale.
It has been recommended that all candidates for left ventricular assist device (LVAD) implantation undergo preoperative psychologic evaluation for risk assessment. We used the transplant evaluation rating scale (TERS) that was established for pretransplant evaluation to investigate the psychosocial assessment of patients undergoing LVAD implantation. This study retrospectively analyzed data from 125 patients with advanced heart failure who were evaluated by the TERS before LVAD implantation. Postoperative follow-up included survival, total length of hospital stay, readmissions, and post-LVAD out-of-hospital days after discharge. The cohort was stratified according to the TERS scores into low-, moderate-, and high-risk groups. The outcomes were analyzed to evaluate whether the TERS score was associated with post-LVAD adverse events. The TERS, when stratified into 3 risk groups showed significant difference in 8 of the 10 psychosocial domains (p < 0.001). The mean number of outpatient days after discharge was significantly different between the low-, moderate-, and high-risk groups (p < 0.001). All other outcomes were not significantly different. This study showed that the TERS is successful in stratifying our patients with an LVAD into 3 risk groups, indicating the internal validity of this test. The number of out-of-hospital (outpatient) days after discharge was significantly shorter in the TERS high-risk group, which may affect the quality of life and cost of post-LVAD care.


Maternal obesity: A potential disruptor of female fertility and current interventions to reduce associated risks.
Currently, obesity has achieved epidemic levels in reproductive-aged women with a myriad of consequences. Obesity is susceptible to several reproductive complications that eventually affect fertility rates. These complications originate from the deteriorated quality of oocytes from mothers with obesity, which increases the probability of chromosomal aneuploidy, elevated reactive oxygen species production, compromised embryonic developmental competency, and eventually reduced fertility. Maternal obesity is linked to pregnancy complications such as implantation error, abortion, miscarriage, and early pregnancy loss. This review highlights the adverse effects of maternal obesity on female fertility, with a focus on the mechanistic link between maternal obesity and oocyte quality and discusses possible measures to reduce its associated risks.


[Study of the effect of Stressen on homocysteine blood levels in patients affected by vascular disease].
This study was carried out to confirm the results obtained in a previous trial, where Stressen had reduced homocysteinemia in patients with elevated concentrations of this amino acid and affected by vascular disease. 50 patients were enrolled and they received Stressen twice daily for 30 days. Basal levels of homocysteinemia were determined and, after the treatment, evaluation of this parameter was repeated. At enrollment homocysteinemia was 23.44 +/- 7.24 micromol/l; at the end of the treatment with Stressen it was reduced to 10.22 +/- 3.41 micromol/l, corresponding to a decrease of 56.4% (p<0.0001). No significant difference between sexes was noted. The results of this study confirm the efficacy of Stressen on homocysteine plasma levels and agree with literature about the relationship among vitamin B12, folate and homocysteine; the activity of the drug was therefore predictable considering its composition, constituted of cobamamide, calcium folinate and arginine glutamate.


Well-Being With Objects: Evaluating a Museum Object-Handling Intervention for Older Adults in Health Care Settings.
The extent to which a museum object-handling intervention enhanced older adult well-being across three health care settings was examined. The program aimed to determine whether therapeutic benefits could be measured objectively using clinical scales. Facilitator-led, 30 to 40 min sessions handling and discussing museum objects were conducted in acute and elderly care (11 one-to-ones), residential (4 one-to-ones and 1 group of five), and psychiatric (4 groups of five) settings. Pre-post measures of psychological well-being (Positive Affect and Negative Affect Schedule) and subjective wellness and happiness (Visual Analogue Scales) were compared. Positive affect and wellness increased significantly in acute and elderly and residential care though not psychiatric care whereas negative affect decreased and happiness increased in all settings. Examination of audio recordings revealed enhanced confidence, social interaction, and learning. The program allowed adults access to a museum activity who by virtue of age and ill health would not otherwise have engaged with museum objects.


Influence of Indole-3-Acetic Acid and Gibberellic Acid on Phenylpropanoid Accumulation in Common Buckwheat (Fagopyrum esculentum Moench) Sprouts.
We investigated the effects of natural plant hormones, indole-3-acetic (IAA) acid and gibberellic acid (GA), on the growth parameters and production of flavonoids and other phenolic compounds in common buckwheat sprouts. A total of 17 phenolic compounds were identified using liquid chromatography-mass spectrometry (LC-MS) analysis. Among these, seven compounds (4-hydroxybenzoic acid, catechin, chlorogenic acid, caffeic acid, epicatechin, rutin, and quercetin) were quantified by high-performance liquid chromatography (HPLC) after treating the common buckwheat sprouts with different concentrations of the hormones IAA and GA. At a concentration of 0.5 mg/L, both IAA and GA exhibited the highest levels of growth parameters (shoot length, root length, and fresh weight). The HPLC analysis showed that the treatment of sprouts with IAA at concentrations ranging from 0.1 to 1.0 mg/L produced higher or comparable levels of the total phenolic compounds than the control sprout and enhanced the production of rutin. Similarly, the supplementation with 0.1 and 0.5 mg/L GA increased the content of rutin in buckwheat sprouts. Our results suggested that the treatment with optimal concentrations of IAA and GA enhanced the growth parameters and accumulation of flavonoids and other phenolic compounds in buckwheat sprouts.


The distribution of cholinergic neurons and their co-localization with FMRFamide, in central and peripheral neurons of the spider Cupiennius salei.
The spider Cupiennius salei is a well-established model for investigating information processing in arthropod sensory systems. Immunohistochemistry has shown that several neurotransmitters exist in the C. salei nervous system, including GABA, glutamate, histamine, octopamine and FMRFamide, while electrophysiology has found functional roles for some of these transmitters. There is also evidence that acetylcholine (ACh) is present in some C. salei neurons but information about the distribution of cholinergic neurons in spider nervous systems is limited. Here, we identify C. salei genes that encode enzymes essential for cholinergic transmission: choline ACh transferase (ChAT) and vesicular ACh transporter (VAChT). We used in-situ hybridization with an mRNA probe for C. salei ChAT gene to locate somata of cholinergic neurons in the central nervous system and immunohistochemistry with antisera against ChAT and VAChT to locate these proteins in cholinergic neurons. All three markers labeled similar, mostly small neurons, plus a few mid-sized neurons, in most ganglia. In the subesophageal ganglia, labeled neurons are putative efferent, motor or interneurons but the largest motor and interneurons were unlabeled. Groups of anti-ChAT labeled small neurons also connect the optic neuropils in the spider protocerebrum. Differences in individual cell labeling intensities were common, suggesting a range of ACh expression levels. Double-labeling found a subpopulation of anti-VAChT-labeled central and mechanosensory neurons that were also immunoreactive to antiserum against FMRFamide-like peptides. Our findings suggest that ACh is an important neurotransmitter in the C. salei central and peripheral nervous systems.


Epidermolysis bullosa acquisita following bullous pemphigoid, successfully treated with the anti-CD20 monoclonal antibody rituximab.
Epidermolysis bullosa acquisita is a rare autoimmune subepidermal blistering disease, often resisting current treatments, especially systemic corticosteroids. We report a patient having a bullous pemphigoid who relapsed with clinical and immunological features of inflammatory epidermolysis bullosa acquisita. An anti-CD20 monoclonal antibody (rituximab) was proposed because of resistance to high-dose steroids and other immunosuppressive agents. The disease dramatically improved within a few weeks following rituximab infusion allowing the decrease in steroid therapy. Our case illustrates also the possible evolution from bullous pemphigoid to epidermolysis bullosa acquisita that should be suspected when clinical atypia occurs or in case of corticosteroid resistance.


ICG Flow 800 technology targeted STA-MCA microvascular bypass for exclusion of deep-seated fusiform MCA aneurysm: 2-dimensional operative video.
The authors present the case of an 18-year-old male with a deep-seated left fusiform dissecting M3 aneurysm for which endovascular treatment was not applicable. At the open surgery, they used the less commonly reported FLOW 800 fluorescent indocyanine green (ICG) videoangiography, before and after parental aneurysmal artery temporary clipping, to locate the distal outflow branch of the aneurysm and use it as the recipient artery for a superficial temporal artery-M4 bypass, excluding the aneurysm by clipping the parental artery. Repeated ICG FLOW 800 angiography confirmed bypass patency and adequate blood flow. The aneurysm's exclusion from circulation was confirmed by digital subtraction angiography postoperatively. The video can be found here: https://stream.cadmore.media/r10.3171/2021.10.FOCVID21183.


Inflammatory Biomarkers Affecting Survival Prognosis in Patients Receiving Veno-Venous ECMO for Severe COVID-19 Pneumonia.
Severe COVID-19 pneumonia in which mechanical ventilation is unable to achieve adequate gas exchange can be treated with veno-venous ECMO, eliminating the need for aggressive mechanical ventilation which might promote ventilator-induced lung injury and increase mortality. In this retrospective observational study, 18 critically ill COVID-19 patients who were treated using V-V ECMO during an 11-month period in a tertiary COVID-19 hospital were analyzed. Biomarkers of inflammation and clinical features were compared between survivors and non-survivors. Survival rates were compared between patients receiving ECMO and propensity matched mechanically ventilated controls. There were 7 survivors and 11 non-survivors. The survivors were significantly younger, with a higher proportion of females, higher serum procalcitonin at ICU admission, and before initiation of ECMO they had significantly lower Murray scores, PaCO2, WBC counts, serum ferritin levels, and higher glomerular filtration rates. No significant difference in mortality was found between patients treated with ECMO compared to patients treated using conventional lung protective ventilation. Hypercapnia, leukocytosis, reduced glomerular filtration rate, and increased serum ferritin levels prior to initiation of V-V ECMO in patients with severe COVID-19 pneumonia may be early warning signs of reduced chance of survival. Further multicentric studies are needed to confirm these findings.


Structural, spectroscopic, and magnetic study of bis(9,10-dihydro-9-oxo-10-acridineacetate)bis(imidazole)bis(methanol) nickel(II).
The mixed ligand complex [Ni(CMA)2(im)2(MeOH)2] (where CMA = 9,10-dihydro-9-oxo-10-acridineacetate ion, im = imidazole) was prepared, and its crystal and molecular structure were determined. The nickel ions are hexa-coordinated by four oxygen atoms of the carboxylate and hydroxyl groups and by two imidazole nitrogen atoms, to form a distorted octahedral arrangement. The structure consists of a one-dimensional network of the complex molecules connected by strong intermolecular hydrogen bonds. The weak intermolecular C-H...X hydrogen bonds and stacking interactions make up the 2-D structure. Very strong intramolecular hydrogen bonds significantly affect the geometry and vibrational characteristics of the carboxylate group. The UV-vis-NIR electronic spectrum was deconvoluted into Gaussian components. Electronic bands of the Ni(II) ion were assigned to suitable spin-allowed transitions in the D4h symmetry environment. The single ion zero-field splitting (ZFS) parameters for the S = 1 state of Ni(II), as well as the g components, have been determined by high-field and high-frequency EPR (HF-HFEPR) spectroscopy over the frequency range of 52-432 GHz and with the magnetic fields up to 14.5 T: D = 5.77(1) cm-1, E = 1.636(2) cm-1, gx = 2.29(1), gy = 2.18(1), and gz = 2.13(1). These values allowed us to simulate the powder magnetic susceptibility and field-dependent magnetization of the complex.


Recommendations of Common Data Elements to Advance the Science of Self-Management of Chronic Conditions.
Common data elements (CDEs) are increasingly being used by researchers to promote data sharing across studies. The purposes of this article are to (a) describe the theoretical, conceptual, and definition issues in the development of a set of CDEs for research addressing self-management of chronic conditions; (b) propose an initial set of CDEs and their measures to advance the science of self-management; and (c) recommend implications for future research and dissemination. Between July 2014 and December 2015 the directors of the National Institute of Nursing Research (NINR)-funded P20 and P30 centers of excellence and NINR staff met in a series of telephone calls and a face-to-face NINR-sponsored meeting to select a set of recommended CDEs to be used in self-management research. A list of potential CDEs was developed from examination of common constructs in current self-management frameworks, as well as identification of variables frequently used in studies conducted in the centers of excellence. The recommended CDEs include measures of three self-management processes: activation, self-regulation, and self-efficacy for managing chronic conditions, and one measure of a self-management outcome, global health. The self-management of chronic conditions, which encompasses a considerable number of processes, behaviors, and outcomes across a broad range of chronic conditions, presents several challenges in the identification of a parsimonious set of CDEs. This initial list of recommended CDEs for use in self-management research is provisional in that it is expected that over time it will be refined. Comment and recommended revisions are sought from the research and practice communities. The use of CDEs can facilitate generalizability of research findings across diverse population and interventions.


Scoring functions for transcription factor binding site prediction.
Transcription factor binding site (TFBS) prediction is a difficult problem, which requires a good scoring function to discriminate between real binding sites and background noise. Many scoring functions have been proposed in the literature, but it is difficult to assess their relative performance, because they are implemented in different software tools using different search methods and different TFBS representations. Here we compare how several scoring functions perform on both real and semi-simulated data sets in a common test environment. We have also developed two new scoring functions and included them in the comparison. The data sets are from the yeast (S. cerevisiae) genome. Our new scoring function LLBG (least likely under the background model) performs best in this study. It achieves the best average rank for the correct motifs. Scoring functions based on positional bias performed quite poorly in this study. LLBG may provide an interesting alternative to current scoring functions for TFBS prediction.


Barriers to Climate Disaster risk Management for Public Health: Lessons from a Pilot Survey of National Public Health Representatives.
This study sought to examine current national disaster risk management capacities, and identify governance barriers to strengthening national preparedness for responding to public health emergencies, associated with the anticipated climate-driven intensification of natural disaster cycles. A mixed-methods online survey, assessing broader governance constraints to climate change adaptation (CCA) for public health, was distributed to representatives of national public health associations, and societies of 82 member countries under the World Federation of Public Health Associations. Specific questions relevant to disaster risk management capacities and barriers were analyzed as part of a narrowed focus on the CCA subdomain of emergency preparedness. Existence of some technology, infrastructure, and/ or human resources, necessary to develop early warning and other surveillance systems for climate-related health risks was reported by 9 out of 11 responding countries. However, 7 reported persistent limitations and/ or regional discrepancies. Most significant identified barriers to strengthening emergency preparedness at the national level included governance coordination challenges, and, in the case of many developing countries, technical, medical, and human resource shortages. The development of new frameworks for intersectoral governance and large-scale resource mobilization will prove crucial to ongoing efforts to strengthen national climate-health resiliency and prepare for disaster-associated health threats.


Rare occurrence of eight-and-a-half syndrome as a clinically isolated syndrome.
Eight-and-a-half syndrome is a rare condition that is described as a combination of one-and-a-half syndrome and an ipsilateral facial nucleus lesion. We present a clinical case of occurrence of eight-and-a-half syndrome that was caused by a demyelinating lesion in the dorsal pontine tegmentum. A 44-year-old man presented to the hospital with a subacute onset of horizontal diplopia and left-sided facial weakness. MRI revealed a T2 hyperintense lesion in his dorsal pons, which was consistent with a demyelinating pathology. Treatment with intravenous steroids showed significant improvement in his symptoms. In our case, it occurred due to a suspected demyelinating lesion that was this patient's first and only demyelinating event, leaving him with a diagnosis of clinically isolated syndrome. His responsiveness to steroids represents the first case report of an adult patient presenting with an eight-and-a-half syndrome secondary to a suspected demyelinating pathology.


Metal-organic framework derived bimetal oxide CuCoO2 as efficient electrocatalyst for the oxygen evolution reaction.
Metal-organic framework (MOF) materials with tunable porous morphology, controlled crystalline structure, various compositions, and high specific surface area are widely used as precursors to synthesize electrocatalysts for water splitting, which is beneficial for improving their oxygen evolution reaction (OER) performance. Using ZIF-67 as a Co source and Cu-BTC as a Cu source, hexagonal MOF-derived CuCoO2 (MOF-CCO) nanocrystals with the size of ∼288 nm were prepared through a one-step solvothermal method. The influence of the content of the precursor solvents (absolute ethanol and deionized water), reaction temperature, mass ratio of reactants, NaOH addition, and reactant concentration of precursors on the structure and morphology of the products was investigated. The optimal CuCoO2 nanocrystals (MOF-CCO1) around 288 nm present the highest OER activity, such as a low overpotential of 364.7 mV at 10 mA cm-2, a small Tafel slope of 64.1 mV dec-1, and attractive durability in 1.0 M KOH solution. The XPS results showed that the higher catalytic efficiency of MOF-CCO1 nanocrystals could be due to the oxygen vacancies caused by lattice oxygen loss, the increase of OH- content on the surface, and the synergistic effect of Cu2+/Cu+ and Co2+/Co3+ redox pairs. Finally, a possible OER mechanism for MOF-CCO nanocrystals of water splitting was proposed. This study provides a new approach for the preparation of delafossite nanomaterials and for the improvement of their OER performances.


Specificity of the DNA product of RNA-dependent DNA polymerase in type C viruses. II. Quantitative analysis.
A number of mammalian Type C viruses were analyzed for relatedness by the technique of DNA.RNA hybridization. Viral DNAs were prepared in single-stranded form from complexes with 70S viral RNA formed during endogenous polymerase reactions. Extent of hybridization was assayed with the single-strand nuclease (S-1) from Aspergillus oryzae. Results obtained indicated a high degree of viral specificity, with significant cross-reactions being observed only with viruses obtained from within a species, as in the case of mouse and cat viruses, or in the special case of woolly monkey-gibbon comparisons. Comparisons of RD-114 virus, recently determined to be of feline origin, and conventional feline Type C viruses (FeLV), revealed minimal relatedness, especially when feline virus was grown on human cells, thus indicating the possibility of coexistence of greatly disparate Type C viruses within one species. A rat-specific virus, recovered from tumors induced by murine sarcoma virus, was found to contain genetic material common to both the original mouse virus and viruses indigenous to the rat, even though only rat-specific proteins have been detected during infection by this virus.


Pitfalls and promises of bile duct alternatives: There is plenty of room in the regenerative surgery.
Current abdominal surgery has several approaches for biliary reconstruction. However, the creation of functional and clinically applicable bile duct substitutes still represents an unmet need. In the paper by Miyazawa and colleagues, approaches to the creation of bile duct alternatives were summarized, and the reasons for the lack of development in this area were explained. The history of bile duct surgery since the nineteenth century was also traced, leading to the conclusion that the use of bioabsorbable materials holds promise for the creation of bile duct substitutes in the future. We suggest three ideas that may stimulate progress in the field of bile duct substitute creation. First, a systematic analysis of the causative factors leading to failure or success in the creation of bile duct substitutes may help to develop more effective approaches. Second, the regeneration of a bile duct is delicately balanced between epithelialization and subsequent submucosal maturation within limited time frames, which may be more apparent when using quantitative models to estimate outcomes. Third, the utilization of the organism's endogenous regeneration abilities may enhance the creation of bile duct substitutes. We are convinced that an interdisciplinary approach, including quantitative methods, machine learning, and deep retrospective analysis of the causes that led to success and failure in studies on the creation of bile duct substitutes, holds great value. Additionally, more attention should be directed towards the balance of epithelialization and submucosal maturation rates, as well as induced angiogenesis. These ideas deserve further investigation to pave the way for bile duct restoration with physiologically relevant outcomes.


Canadian expert consensus: optimal treatment of neovascular age-related macular degeneration.
New therapeutic approaches, particularly anti-vascular endothelial growth factor (anti-VEGF) therapies, prevent, and in some cases reverse, vision damage caused by age-related macular degeneration (AMD). Unequal access to care across Canada remains a problem for many retina specialists and their patients. To develop a consensus concerning the management of patients with exudative age-related macular degeneration (AMD). Consensus document. Ten Canadian retina specialists. The development of a consensus among Canadian experts concerning optimal treatment of AMD began with a review of the clinical evidence, daily practices, existing guidelines, and current national and international approvals and policies. The experts met on June 29, 2010, in Quebec City to discuss their findings and to propose strategies for consensus. The result of this expert panel is a consensus proposal for Canadian ophthalmologists and retina specialists who are treating patients with or at risk for developing neovascular AMD. The consensus provides guidelines to aid retina specialists in managing exudative AMD. Currently, ranibizumab is the only agent with sufficient Level I evidence and a Health Canada-approved indication for the treatment of wet AMD. Bevacizumab has been shown to be noninferior in preserving and improving visual acuity when compared to ranibizumab. Potential safety differences between the 2 drugs remain to be elucidated. The positioning of ranibizumab in this therapeutic area will be further defined as additional data for existing and emerging therapies become available. Until then, this agent remains the therapy of choice for individuals with neovascular AMD.


[Orthopaedic Management of Bone Metastasis].
Thanks to advancement in cancer therapy, an increasing number of cancer patients are expected to live longer with cancer in Japan. Activities of daily living(ADL)and quality of life(QOL)of cancer patients has become much more important than ever. Because a decline in mobility negatively affects ADL and QOL, the management of locomotive organs of cancer patients is crucial. In 2018, the Japanese Orthopaedic Association decided their annual activity theme as"locomotive syndrome in cancer patients", with the concept of preventing and improving locomotive syndrome for longer and healthier life of cancer patients. Bone metastasis, as a major cause of locomotive syndrome in cancer patients, needs to be evaluated and managed properly for better ADL and QOL of cancer patients. Pathological fractures, spinal instability, and spinal injury cause not only severe pain and massive functional impairment of patients but increased nursing care burden. To resolve these problems, surgery plays a major role. Possible surgical procedures include internal fixation, curettage, cementation, and arthroplasty for the long bones, whereas percutaneous vertebroplasty, decompression, posterior/anterior spinal fusion, and total en bloc spondylectomy for the spine. Less invasive surgical procedure tends to be chosen for a patient with poorer prognosis. The main purpose of bone metastasis surgery is to maintain ADL and QOL of cancer patients hopefully during the remaining survival time; therefore, estimated survival should be considered when determining the surgical strategy. In addition, case-by- case careful peri-operative management is required because cancer therapy can vary widely in patient age, cancer type, and tumor stage. To accommodate the variety of orthopaedic surgeries to the diversity of cancer therapy, the corporation between oncologists and orthopaedic surgeons is indispensable.


A Comparative Study of the Anticancer Activity and PARP-1 Inhibiting Effect of Benzofuran-Pyrazole Scaffold and Its Nano-Sized Particles in Human Breast Cancer Cells.
Breast cancer is considered the most common and deadly cancer among women worldwide. Nanomedicine has become extremely attractive in the field of cancer treatment. Due to the high surface to volume ratio and other unique properties, nanomaterials can be specifically targeted to certain cells and tissues to interact with the living systems. The strategic planning of this study is based on using the nanoprecipitation method to prepare nanoparticles BZP-NPs (3.8-5.7 nm) of the previously prepared benzofuran-pyrazole compound (IV) BZP which showed promising cytotoxic activity. The capacity of BZP and BZP-NPs to suppress the growth of human breast tumor MCF-7 and MDA-MB-231 cells was evaluated using MTT assay. The IC50 doses of BZP and BZP-NPs targeting normal breast cells MCF-12A exceeded those targeting the cancer cells by >1000-fold, demonstrating their reasonable safety profiles in normal cells. Furthermore, cell cycle analysis, apoptosis induction detection, assessment of p53, Bcl-2, caspase-3, and PARP-1 levels of BZP and its nano-sized-BZP-NPs particles were also evaluated. Although the obtained results were in the favor of compound IV in its normal-sized particles, BZP-NPs appeared as a hit compound which showed improved cytotoxicity against the tested human breast cancer cells associated with the induction of pre-G1 apoptosis as well as cell cycle arrest at G2/M phase. The increase in caspase-3 level, upregulation of p53, and downregulation of Bcl-2 protein expression levels confirmed apoptosis. Furthermore, ELISA results exhibited that BZP-NPs produced a more favorable impact as a PARP-1 enzyme inhibitor than the parent BZP.


Embodiment and ethics: constructing medicine's two bodies.
The first 'modern' presentation of medical ethics is generally acknowledged to be Percival's text of 1803. The main theme of this influential pamphlet was the way in which medical practitioners should relate to one another. Two centuries later, clinical practice has very different moral underpinnings: bioethics, which first emerged in the middle of the 20(th) century, is not concerned with how doctors should interact with each other but with the responsibilities of medical practitioners to their patients. The shift from an ethics based on the relationship between practitioners to one based on the relationship with their patients is viewed as a major advance brought about by a more enlightened society engaging with the consequences of new technologies. But rather than addressing the changing picture of medical ethics in its own terms (which over the last few decades has been from the perspective of bioethics) I examine the history of medical ethics in its close relationship to the form and nature of the medical profession. Further, in a parallel thread I describe contemporary developments in public health and explore the similarities and connections between the two.


Research Progress in Antineoplastic, Antibacterial, and Anti-inflammatory Activities of Seven-membered Heterocyclic Derivatives.
Seven-membered heterocyclic compounds are important drug scaffolds because of their unique chemical structures. They widely exist in natural products and show a variety of biological activities. They have been used commonly in central nervous system drugs in the past 30 years. In the past decade, many studies have been conducted on their activities, including antitumor, antibacterial, etc. Herein, we summarize the research advances in different kinds of seven-membered heterocyclic compounds containing nitrogen, oxygen, and sulfur heteroatoms with antitumor, antisepsis, and anti-inflammation activities in the past ten years, which are expected to be beneficial to the development and design of novel drugs for the corresponding indications.


Stakeholder perspectives on the implementation and impact of Indigenous health interventions: A systematic review of qualitative studies.
Evaluations of health interventions for Indigenous peoples rarely report outcomes that reflect participant and community perspectives of their experiences. Inclusion of such data may provide a fuller picture of the impact of health programmes and improve the usefulness of evaluation assessments. To describe stakeholder perspectives and experiences of the implementation and impact of Indigenous health programmes. We conducted a systematic review of qualitative studies evaluating complex health interventions designed for Indigenous communities in high-income countries. We searched 6 electronic databases (through to January 2020): MEDLINE, PreMEDLINE, Embase, PsycINFO, EconLit and CINAHL and hand-searched reference lists of relevant articles. From 28 studies involving 677 stakeholders (mostly clinical staff and participants), six main themes were identified: enabling engagement, regaining control of health, improving social health and belonging, preserving community and culture, cultivating hope for a better life, and threats to long-term programme viability. The prominence of social, emotional and spiritual well-being as important aspects of the health journey for participants in this review highlights the need to reframe evaluations of health programmes implemented in Indigenous communities away from assessments that focus on commonly used biomedical measures. Evaluators, in consultation with the community, should consistently assess the capacity of health professionals to meet community needs and expectations throughout the life of the programme. Evaluations that include qualitative data on participant and community-level outcomes can improve decision-makers' understanding of the impact that health programmes have on communities. This paper is a review of evaluation studies and did not involve patients or the public.


The role of NK cells in fighting the virus infection and sepsis.
Natural killer cells, one of the important types of innate immune cells, play a pivotal role in the antiviral process in vivo. It has been shown that increasing NK cell activity may promote the alleviation of viral infections, even severe infection-induced sepsis. Given the current state of the novel coronavirus (SARS-CoV-2) global pandemic, clarifying the anti-viral function of NK cells would be helpful for revealing the mechanism of host immune responses and decipher the progression of COVID-19 and providing important clues for combating this pandemic. In this review, we summarize the roles of NK cells in viral infection and sepsis as well as the potential possibilities of NK cell-based immunotherapy for treating COVID-19.


Fetal hyperglycemia and a high-fat diet contribute to aberrant glucose tolerance and hematopoiesis in adult rats.
Children exposed to gestational diabetes mellitus (GDM) during pregnancy are at increased risk of obesity, diabetes, and hypertension. Our goal was to identify metabolic and hematopoietic alterations after intrauterine exposure to maternal hyperglycemia that may contribute to the pathogenesis of chronic morbidities. Streptozotocin treatment induced maternal hyperglycemia during the last third of gestation in rat dams. Offspring of control mothers (OCM) and diabetic mothers (ODM) were evaluated for weight, glucose tolerance, insulin tolerance, and hematopoiesis defects. The effects of aging were examined in normal and high-fat diet (HFD)-fed young (8-wk-old) and aged (11-mo-old) OCM and ODM rats. Young adult ODM males on a normal diet, but not females, displayed improved glucose tolerance due to increased insulin levels. Aged ODM males and females gained more weight than OCM on a HFD and had worse glucose tolerance. Aged ODM males fed a HFD were also neutrophilic. Increases in bone marrow cellularity and myeloid progenitors preceded neutrophilia in ODM males fed a HFD. When combined with other risk factors like HFD and aging, changes in glucose metabolism and hematopoiesis may contribute to the increased risk of obesity, type 2 diabetes, and hypertension observed in children of GDM mothers.


Differential genome evolution and speciation of Coix lacryma-jobi L. and Coix aquatica Roxb. hybrid guangxi revealed by repetitive sequence analysis and fine karyotyping.
Coix, Sorghum and Zea are closely related plant genera in the subtribe Maydeae. Coix comprises 9-11 species with different ploidy levels (2n = 10, 20, 30, and 40). The exclusively cultivated C. lacryma-jobi L. (2n = 20) is widely used in East and Southeast Asia for food and medicinal applications. Three fertile cytotypes (2n = 10, 20, and 40) have been reported for C. aquatica Roxb. One sterile cytotype (2n = 30) closely related to C. aquatica has been recently found in Guangxi of China. This putative hybrid has been named C. aquatica HG (Hybrid Guangxi). The genome composition and the evolutionary history of C. lacryma-jobi and C. aquatica HG are largely unclear. About 76% of the genome of C. lacryma-jobi and 73% of the genome of C. aquatica HG are repetitive DNA sequences as shown by low coverage genome sequencing followed by similarity-based cluster analysis. In addition, long terminal repeat (LTR) retrotransposable elements are dominant repetitive sequences in these two genomes, and the proportions of many repetitive sequences in whole genome varied greatly between the two species, indicating evolutionary divergence of them. We also found that a novel 102 bp variant of centromeric satellite repeat CentX and two other satellites only appeared in C. aquatica HG. The results from FISH analysis with repeat probe cocktails and the data from chromosomes pairing in meiosis metaphase showed that C. lacryma-jobi is likely a diploidized paleotetraploid species and C. aquatica HG is possibly a recently formed hybrid. Furthermore, C. lacryma-jobi and C. aquatica HG shared more co-existing repeat families and higher sequence similarity with Sorghum than with Zea. The composition and abundance of repetitive sequences are divergent between the genomes of C. lacryma-jobi and C. aquatica HG. The results from fine karyotyping analysis and chromosome pairing suggested diploidization of C. lacryma-jobi during evolution and C. aquatica HG is a recently formed hybrid. The genome-wide comparison of repetitive sequences indicated that the repeats in Coix were more similar to those in Sorghum than to those in Zea, which is consistent with the phylogenetic relationship reported by previous work.


Ab initio study of (13)C(alpha) chemical shift anisotropy tensors in peptides.
This study reports magnitudes and the orientation of the (13)C(alpha) chemical shift anisotropy (CSA) tensors of peptides obtained using quantum chemical calculations. The dependency of the CSA tensor parameters on the energy optimization of hydrogen atom positions and hydrogen bonding effects and the use of zwitterionic peptides in the calculations are examined. Our results indicate that the energy optimization of the hydrogen atom positions in crystal structures is necessary to obtain accurate CSA tensors. The inclusion of intermolecular effects such as hydrogen bonding in the calculations provided better agreement between the calculated and experimental values; however, the use of zwitterionic peptides in calculations, with or without the inclusion of hydrogen bonding, did not improve the results. In addition, our calculated values are in good agreement with tensor values obtained from solid-state NMR experiments on glycine-containing tripeptides. In the case of peptides containing an aromatic residue, calculations on an isolated peptide yielded more accurate isotropic shift values than the calculations on extended structures of the peptide. The calculations also suggested that the presence of an aromatic ring in the extended crystal peptide structure influences the magnitude of the delta(22) which the present level of ab initio calculations are unable to reproduce.


Factors associated with quality of life after attempted suicide: a cross-sectional study.
To describe factors associated with the subjective quality of life of individuals who had attempted suicide. Although quality of life has been a focus of concern in mental health care, data are lacking on what life is like and what factors are related to an individual's quality of life after a suicide attempt. A cross-sectional, descriptive design was used. Participants comprised a convenience sample of 103 individuals who had attempted suicide within the previous three months and received follow-up care from one suicide-prevention centre in northern Taiwan. Participants were assessed for depression and quality of life using the Beck Depression Inventory, Taiwan version and the World Health Organisation Quality of Life Instrument-BREF, Taiwan version, respectively. Almost half the participants (n = 49) had severe depression and one-third of them (n = 30) reattempted suicide while receiving follow-up care. Depression and quality-of-life scores were statistically significantly inversely correlated. participants' quality-of-life scores were most associated with their depressive level, reattempting suicide during suicidal follow-up care, high educational level and older age. The present study indicates that factors associated with quality of life decreased more in individuals with moderate/severe depression than in those with mild depression. In addition, individuals who reattempted suicide during follow-up care were more likely to suffer from poor life quality. Mental health professionals should include frequent evaluation of depressive status and quality of life in follow-up care for patients who have recently attempted suicide. Particularly, mental health professionals must treat suicidal individuals with a high tendency to reattempt suicide by establishing trust with them and allowing them to narrate their painful experiences during follow-up care.


[Involvement of caspase on apoptosis in ischemia-induced neuronal cell death: usefulness of caspase inhibitors for stroke therapy].
This overviews recent understanding of the mechanisms of apoptosis on ischemia-induced neuronal cell death. Apoptosis is a prominent feature of the developing nervous system. Several lines of evidence suggest that apoptosis is also an important mechanism of cell death in adult brain in acute or chronic diseases such as stroke and Alzheimer's disease. In animal models of stroke, markers of apoptosis such as cytoplasmic and nuclear condensation and DNA fragmentation appear in neurons. A variety of physiological and pathological stimuli can activate signal-transduction pathways that result in the sequential proteolytic activation of caspase family members. The activation of caspases can be inhibited by several molecules, including peptide aldehydes (caspase-1 and or caspase-3 inhibitors) and crmA that target the active-site cysteine of caspase family members, Bcl-2, IAP (inhibitor of apoptosis protein) and NAIP (neuronal apoptosis inhibitory protein). Once activated, caspase-1 protease can activate the caspase family members and hydrolyze a discrete set of cellular targets. Poly (ADP-ribose)polymerase (PARP), which appears to facilitate apoptosis, was recognized as a substrate of activated caspase-3. These results suggest that caspase family, bcl-2 family, IAP family and substrates such PARP contribute to mechanisms of cell death in ischemic brain injury. Inhibition of the caspase family, particularly by non-peptide inhibitors that cross the blood-brain barrier and easily penetrate neurons and glia, could provide novel treatments for stroke and other forms of brain and spinal cord injury in humans.


Epidemiological study of relapsing fever borreliae detected in Haemaphysalis ticks and wild animals in the western part of Japan.
The genus Borrelia comprises arthropod-borne bacteria, which are infectious agents in vertebrates. They are mainly transmitted by ixodid or argasid ticks. In Hokkaido, Japan, Borrelia spp. were found in deer and Haemaphysalis ticks between 2011 and 2013; however, the study was limited to a particular area. Therefore, in the present study, we conducted large-scale surveillance of ticks and wild animals in the western part of the main island of Japan. We collected 6,407 host-seeking ticks from two regions and 1,598 larvae obtained from 32 engorged female ticks and examined them to elucidate transovarial transmission. In addition, we examined whole blood samples from 190 wild boars and 276 sika deer, as well as sera from 120 wild raccoons. We detected Borrelia spp. in Haemaphysalis flava, Haemaphysalis megaspinosa, Haemaphysalis kitaokai, Haemaphysalis longicornis, and Haemaphysalis formosensis. In addition, we isolated a strain from H. megaspinosa using Barbour-Stoenner-Kelly medium. The minimum infection rate of ticks was less than 5%. Transovarial transmission was observed in H. kitaokai. Phylogenetic analysis of the isolated strain and DNA fragments amplified from ticks identified at least four bacterial genotypes, which corresponded to the tick species detected. Bacteria were detected in 8.4%, 15%, and 0.8% of wild boars, sika deer, and raccoons, respectively. In this study, we found seasonal differences in the prevalence of bacterial genotypes in sika deer during the winter and summer. The tick activity season corresponds to the season with a high prevalence of animals. The present study suggests that a particular bacterial genotype detected in this study are defined by a particular tick species in which they are present.


Effects of chronic toluene inhalation on avoidance conditioned behavior in rats.
Thirty-two Wistar albino rats were distributed at random in a factorial design 2 x 2, with two age groups (20 and 90 days old), and two treatments (chronically exposed to toluene vapors 30,000-40,000 ppm in air/15 minutes per day for 30 days, and controls with only air). Twenty-four hours after the last exposure, the rats were tested for conditioned behavior in a "T" maze of avoidance electric shock. Latency of initial response to escape (LIRE) and latency of escape (LE) were measured in seconds. Adult rats both exposed to chronic toluene inhalation and non-exposed showed higher values of LIRE and LE with respect young rats. Animals exposed to chronic toluene inhalation also presented higher values of latency in both LIRE and LE when compared to non-exposed to toluene (controls) of the same age. The differences were evaluated by Friedman's test. The findings are suggestive of brain dysfunction associated with chronic toluene inhalation, and may represent a delay to respond to a displeasure stimulus probably due to defect of internal mechanisms of facilitation-inhibition of neural impulses, mediated by neurotransmitters.


Microbiome and ecotypic adaption of Holcus lanatus (L.) to extremes of its soil pH range, investigated through transcriptome sequencing.
Plants can adapt to edaphic stress, such as nutrient deficiency, toxicity and biotic challenges, by controlled transcriptomic responses, including microbiome interactions. Traditionally studied in model plant species with controlled microbiota inoculation treatments, molecular plant-microbiome interactions can be functionally investigated via RNA-Seq. Complex, natural plant-microbiome studies are limited, typically focusing on microbial rRNA and omitting functional microbiome investigations, presenting a fundamental knowledge gap. Here, root and shoot meta-transcriptome analyses, in tandem with shoot elemental content and root staining, were employed to investigate transcriptome responses in the wild grass Holcus lanatus and its associated natural multi-species eukaryotic microbiome. A full factorial reciprocal soil transplant experiment was employed, using plant ecotypes from two widely contrasting natural habitats, acid bog and limestone quarry soil, to investigate naturally occurring, and ecologically meaningful, edaphically driven molecular plant-microbiome interactions. Arbuscular mycorrhizal (AM) and non-AM fungal colonization was detected in roots in both soils. Staining showed greater levels of non-AM fungi, and transcriptomics indicated a predominance of Ascomycota-annotated genes. Roots in acid bog soil were dominated by Phialocephala-annotated transcripts, a putative growth-promoting endophyte, potentially involved in N nutrition and ion homeostasis. Limestone roots in acid bog soil had greater expression of other Ascomycete genera and Oomycetes and lower expression of Phialocephala-annotated transcripts compared to acid ecotype roots, which corresponded with reduced induction of pathogen defense processes, particularly lignin biosynthesis in limestone ecotypes. Ascomycota dominated in shoots and limestone soil roots, but Phialocephala-annotated transcripts were insignificant, and no single Ascomycete genus dominated. Fusarium-annotated transcripts were the most common genus in shoots, with Colletotrichum and Rhizophagus (AM fungi) most numerous in limestone soil roots. The latter coincided with upregulation of plant genes involved in AM symbiosis initiation and AM-based P acquisition in an environment where P availability is low. Meta-transcriptome analyses provided novel insights into H. lanatus transcriptome responses, associated eukaryotic microbiota functions and taxonomic community composition. Significant edaphic and plant ecotype effects were identified, demonstrating that meta-transcriptome-based functional analysis is a powerful tool for the study of natural plant-microbiome interactions.


[The immunologic processes of the etiopathogenesis of Sjögren's syndrome].
In this study 32 Sjögren's syndrome cases--16 primary and 16 secondary--have been followed-up for 3 years in Hacettepe University Medicine Faculty Ophthalmology Department. The serum levels of rheumatoid factor and complement have been determined and autoantibodies have been looked for by the indirect immunofluorescence technique. The immunological processes that play a role in the pathogenesis of Sjögren's syndrome have been discussed with regard to the results of the study.


The E protein HEB is preferentially expressed in developing muscle.
Myogenesis is regulated by the MyoD class of myogenic regulatory factors (MRFs). These basic helix-loop-helix transcription factors dimerize with E proteins to bind conserved E-box sequences in the promoter regions of muscle-specific genes. Perhaps due to their expression in a wide array of tissues, the specific interactions of E proteins with different MRFs have been largely ignored. Likewise, the expression of E proteins in muscle tissue remains mostly uncharacterized. We investigated the expression of the E proteins HEB, E12, and E47 in rat L6 myoblasts, which express only embryonic and fast (2X) myosin heavy chains (MyHCs) in vitro, C2C12 myosatellite cells, and a number of muscle tissues, to determine whether myosin heavy chain diversity is mirrored by diversity in E protein or MRF expression. Although L6 and C2C12 myotubes demonstrate strong expression of embryonic and 2X (fast) MyHCs, immunofluorescence demonstrated the additional expression of type 1 (slow), 2A, and 2B MyHCs in the C2C12 cell line. Immunofluorescence and western blot analyses show that HEB was expressed in differentiating L6 myoblasts, C2C12 cells, and neonatal rat primary myotubes. In contrast, E12 and E47 expression was not detected in either cell line or in any adult muscle tissue examined. These data strongly implicate HEB in the development of skeletal muscle. However, because HEB is expressed in L6 myoblasts, C2C12 myosatellite cells, and neonatal hindlimb muscles, it is unlikely to be involved in a fiber type-specific manner, and may have a more general role in differentiation of myotubes.


Repetitive exposures to nicotine induce a hyper-responsiveness via the cAMP/PKA/CREB signal pathway in Drosophila.
Nicotine, in addition to acute effects, has long-lasting effects on mammalian behaviors, such as those leading to addiction. Here we present genetic and pharmacological evidence in Drosophila suggesting that repetitive exposures to nicotine induce a hyper-responsiveness through synthesis of new protein(s) via CREB-mediated gene transcription. Single exposure to volatilized nicotine dose-dependently inhibited the startle-induced climbing response. Compared with this effect of nicotine in wild-type flies, it was stronger in dunce, which has defective phosphodiesterase, and in wild-type flies treated with a phosphodiesterase inhibitor, whereas it was weaker in DC0, which has defective protein kinase A (PKA), and in wild-type flies treated with a PKA blocker. Thus, the effect of nicotine is enhanced by a mechanism involving the cAMP/PKA cascade. However, in wild-type flies, an increase in head cAMP was not detected within 2 min after single exposure to nicotine, during which the nicotine effect on the behavior was maximal. In wild-type flies, after repetitive exposures to nicotine, the nicotine effect was significantly enhanced and the head cAMP was elevated. The responsiveness to nicotine at second exposure increased with a 4 h interval but not with a 2 h interval, suggesting that the observed hyper-responsiveness was not due to accumulation of residual nicotine. Both enhancement of the nicotine effect and elevation of cAMP during repetitive exposures to nicotine were blocked by a protein synthesis inhibitor. Induction of a dominant negative CREB transgene also blocked the enhancement, suggesting that CREB-mediated gene transcription is required for the hyper-responsiveness.


Tilapia follicle-stimulating hormone (FSH): immunochemistry, stimulation by gonadotropin-releasing hormone, and effect of biologically active recombinant FSH on steroid secretion.
In fish, FSH is generally important for early gonadal development and vitellogenesis. As in mammals, FSH is a heterodimer composed of an alpha subunit that is noncovalently associated with the hormone-specific beta subunit. The objective of the present study was to express glycosylated, properly folded, and biologically active tilapia FSH (tFSH) using the Pichia pastoris expression system. Using this material, we aimed to develop a specific ELISA and to enable the study of FSH response to GnRH. The methylotrophic yeast P. pastoris was used to coexpress recombinant genes formed by fusion of mating factor alpha leader and tilapia fshb and cga coding sequences. Western blot analysis of tilapia pituitary FSH, resolved by SDS-PAGE, yielded a band of 15 kDa, while recombinant tFSH beta (rtFSH beta) and rtFSH beta alpha had molecular masses of 17-18 kDa and 26-30 kDa, respectively. Recombinant tFSH beta alpha was found to bear only N-linked carbohydrates. Recombinant tFSH beta alpha significantly enhanced 11-ketotestosterone (11-KT) and estradiol secretion from tilapia testes and ovaries, respectively, in a dose-dependent manner (similar to tilapia pituitary extract, affinity-purified pituitary FSH, and porcine FSH). Using antibodies raised against rtFSH beta, FSH-containing cells were localized adjacent to hypothalamic nerve fibers ramifying in the proximal pars distalis (PPD), while LH cells were localized in a more peripheral region of the PPD. Moreover, FSH is under the control of hypothalamic decapeptide GnRH, an effect that was abolished through the use of specific bioneutralizing antisera, anti-rtFSH beta. It also reduced basal secretion of 11-KT.


[Genetic diagnosis of growth disorders].
The capability of examining genetic material with DNA probes and restriction endonucleases has opened up a new approach to clinical problems. Genetic disorders involving growth hormone can now be studied because the growth hormone gene (hGH-N) can be examined directly. Several distinct Mendelian disorders are associated with hGH deficiency. Some are caused by deletion of the hGH-N structural gene. In other instances, linkage analysis confirm that genetic disorders with hGH deficiency may be due to undetectable alterations in the hGH gene, or establish that the genetic abnormality does not involve the GH gene as such but rather affects some other gene essential for the production or release of factors involved in the regulation of growth hormone action.


Looking at Fog Computing for E-Health through the Lens of Deployment Challenges and Applications.
Fog computing is a distributed infrastructure where specific resources are managed at the network border using cloud computing principles and technologies. In contrast to traditional cloud computing, fog computing supports latency-sensitive applications with less energy consumption and a reduced amount of data traffic. A fog device is placed at the network border, allowing data collection and processing to be physically close to their end-users. This characteristic is essential for applications that can benefit from improved latency and response time. In particular, in the e-Health field, many solutions rely on real-time data to monitor environments, patients, and/or medical staff, aiming at improving processes and safety. Therefore, fog computing can play an important role in such environments, providing a low latency infrastructure. The main goal of the current research is to present fog computing strategies focused on electronic-Health (e-Health) applications. To the best of our knowledge, this article is the first to propose a review in the scope of applications and challenges of e-Health fog computing. We introduce some of the available e-Health solutions in the literature that focus on latency, security, privacy, energy efficiency, and resource management techniques. Additionally, we discuss communication protocols and technologies, detailing both in an architectural overview from the edge devices up to the cloud. Differently from traditional cloud computing, the fog concept demonstrates better performance in terms of time-sensitive requirements and network data traffic. Finally, based on the evaluation of the current technologies for e-Health, open research issues and challenges are identified, and further research directions are proposed.


Essential structure of the κ opioid receptor agonist nalfurafine for binding to the κ receptor.
The selective κ opioid receptor agonist nalfurafine was launched in 2009 as an antipruritic drug for patients undergoing hemodialysis. It is the first clinically used compound with high selectivity for the κ opioid receptor. Nalfurafine had a different pharmacological feature from other κ opioid agonists. Nalfurafine induced neither addictive nor aversive effects, whereas other κ agonists such as U- 50,488H or salvinorin A produced psychotomimetic effects like dysphoria. Therefore, identification of the essential structural moieties of nalfurafine for binding to the κ opioid receptor was important for elucidation of the pharmacological discrepancies observed with these κ opioid agonists. Based on the investigations of various nalfurafine derivatives, the essential structural moieties of nalfurafine were unveiled. Both the nitrogen substituted by a cyclopropylmethyl group and the 6-amide side chain were indispensable. The phenol ring was important for obtaining strong binding affinities for the opioid receptors, but not indispensable for exerting selectivity for the κ receptor. This structure-activity information is expected to lead to the development of novel κ opioid receptor selective agonists.


[Relationship between patient profile and feverishness developed during interferon-ribavirin combination therapy of chronic hepatitis C patients].
To investigate the relation between tendency of feverishness and patient profile in pegylated interferon (peginterferon) and ribavirin combination therapy, we performed a retrospective survey of the medical charts of patients with chronic hepatitis C that have been on interferon therapy for the past two years. The sample was 36 patients (18 males, 18 females, aged 30 to 67 years, average of 57.5 years) who were hospitalized for the introduction of peginterferon-alpha 2b and ribavirin combination therapy and did not use NSAIDs before the administration of interferon. We examined body temperature and laboratory values (AST, ALT, WBC, Hb, PLT, BUN, Cr, HCV RNA level, and HCV genotype) for one week from the initiation of peginterferon administration to one week after the administration. Tendency of feverishness was classified into two groups according to the time to reach maximum body temperature. The early fever-developing group reached maximum body temperature within 12 hours of the administration, and the slow fever-developing group reached maximum body temperature after 12 hours post administration. The early fever-developing group had a significantly higher maximum body temperature (early group, 38.5 degrees C+/-0.55; slow group, 37.8 degrees C+/-0.55), more persistent fever (early group, 71.0 h+/-31.3; slow group, 36.5 h+/-41.8), and a higher percentage of females (early group, 80.0%; slow group, 28.6%). Moreover, females and elderly patients developed significantly higher fever (temperature difference 0.78 degrees C) early (8.5 h) after peginterferon administration. These results indicate the need for careful observation of females and elderly patients in the early stage of an initial treatment of chronic hepatitis C with peginterferon.


Humane design for hospital landscapes: a case study in landscape architecture of a healing garden for nurses.
The overall goal of this study was to design a beautiful garden to provide a spatial experience of renewal for hospital nursing staff and for their ecologically- and culturally-specific healing. The first objective of this study was to identify the physical, social, and spiritual attributes of an existing courtyard to determine which features encouraged or discouraged use. A site-specific design concept and user-specific survey instrument were developed to gather data directly from the nursing staff on campus. There has been growing evidence that landscapes for renewal have measurable characteristics. Physical, social, and spiritual characteristics of the landscape interrelate to determine the appropriateness of a landscape for a particular health outcome. Increasingly, evidence demonstrates that contact with the living world around us is an important part of healing and recovery. This design project created a natural opportunity to research the effect of landscape improvements on renewal. The method combined standard landscape architecture ecological site design process with a qualitative empirical study of staff characteristics and landscape preferences. The transparency of the landscape design process provided the basis for a post-occupancy evaluation in the future. Sixty-one nurses participated in the qualitative phase of the design process. Preferences for contact with nature and privacy were significant among the staff. The spatial structure of the concepts was revised to include private table-and-chair places for one or two people and features that would encourage a contemplative pedestrian walk along existing shortcuts. To encourage the benefits of the typical staff's very short exposure to the garden, archetypal landscape features-thresholds, contemplative paths, garden benches, a symbolic creek, and sacred springs-were arranged to shift the spiritual dimension of the place from that of an exposed, dry gulley ravine to a green, fertile oasis. The courtyard was designed based on survey results. The final design was reviewed and found to satisfy the preferences of the nursing staff. Currently, the design is being detailed for construction, and a post-occupancy evaluation is being developed to ascertain the quality of the outcome for the nurses.


Urine collection from disposable nappies.
Urine was collected for microscopy and culture by standard use of sterile adhesive bags and by extraction from wet disposable nappies from 45 patients aged 1 to 23 months. Urine can readily be obtained by compression of wet nappy fibres within a 20 ml syringe if highly absorbent brands that contain gel beads are avoided. Red and white cell numbers were reduced on light microscopy of specimens obtained from nappies, but bacterial counts were unchanged. On culture, 6 children were shown to have urinary tract infections by both methods; of the children who did not have a urine infection, the contamination rate was lower from nappy collections (10/39 vs 17/39 from urine bags). Biochemical analysis of urine collected from 11 older children showed very close correlation for sodium, potassium, urea, and creatinine concentrations and osmolality between freshly voided urine and samples obtained after they were soaked into disposable nappies for 3 h and reclaimed, although there was greater variation for measurements of calcium and phosphate. Extraction of urine from disposable nappies put on within 4 h and which are not soiled by faeces is an inexpensive, rapid, and simple method to collect urine from young children for culture, microscopy for bacteria, and biochemical analysis.


Allergy immunotherapy tablet: Grazax® for the treatment of grass pollen allergy.
Immunotherapy is the only treatment for allergy that alters the natural course of this disease. Sublingual immunotherapy has been developed to make immunotherapy more suitable for allergic patients. In the largest clinical program ever conducted with grass allergen-specific immunotherapy, over 2000 adults and more than 500 children have been exposed to Grazax(®) (ALK-Abello A/S, Hoersholm, Denmark). Grazax is an oral lyophilisate tablet (allergy immunotherapy tablet [AIT]) for sublingual administration, containing 75,000 standardized quality tablet units of allergen extract of grass pollen (Phleum pratense). Grazax is indicated for treatment of grass pollen-induced rhinitis and conjunctivitis in adult and pediatric patients. Results from the GT-08 trial (first, second and third treatment years) showed a reduction of 31, 36 and 29%, respectively, in symptom scores and a reduction of 38, 45 and 40% of medication scores, respectively, compared with placebo. Subjects treated with Grazax also had an increased number of well days and a relevant improvement in quality of life. More subjects experienced excellent and complete rhinoconjunctivitis control in comparison with patients treated with symptomatic medications only. Grazax treatment is also associated with a sustained and relevant increase of specific IgG4. This increase is also observed after stopping AIT treatment. The most common adverse events related to Grazax treatment are local reactions, such as oral itch, edema of the mouth, ear pruritus, throat irritation and sneezing. Clinical efficacy of Grazax is observed also after 1 and 2 years of follow-up after stopping the AIT treatment. Grazax is efficacious and safe for treatment of grass-pollen rhinoconjunctivitis in both adults and children. Grazax is the first AIT showing a disease-modifying effect on grass pollen-induced allergic rhinoconjuctivitis.


RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia.
The roles of RNA 5-methylcytosine (RNA:m5C) and RNA:m5C methyltransferases (RCMTs) in lineage-associated chromatin organization and drug response/resistance are unclear. Here we demonstrate that the RCMTs, namely NSUN3 and DNMT2, directly bind hnRNPK, a conserved RNA-binding protein. hnRNPK interacts with the lineage-determining transcription factors (TFs), GATA1 and SPI1/PU.1, and with CDK9/P-TEFb to recruit RNA-polymerase-II at nascent RNA, leading to formation of 5-Azacitidine (5-AZA)-sensitive chromatin structure. In contrast, NSUN1 binds BRD4 and RNA-polymerase-II to form an active chromatin structure that is insensitive to 5-AZA, but hypersensitive to the BRD4 inhibitor JQ1 and to the downregulation of NSUN1 by siRNAs. Both 5-AZA-resistant leukaemia cell lines and clinically 5-AZA-resistant myelodysplastic syndrome and acute myeloid leukaemia specimens have a significant increase in RNA:m5C and NSUN1-/BRD4-associated active chromatin. This study reveals novel RNA:m5C/RCMT-mediated chromatin structures that modulate 5-AZA response/resistance in leukaemia cells, and hence provides a new insight into treatment of leukaemia.