A Breathtaking Lift: Sex and Body Mass Index Differences in Cardiopulmonary Response in a Large Cohort of Unselected Subjects with Acute Exposure to High Altitude.
Vignati, Carlo, Massimo Mapelli, Benedetta Nusca, Alice Bonomi, Elisabetta Salvioni, Irene Mattavelli, Susanna Sciomer, Andrea Faini, Gianfranco Parati, and Piergiuseppe Agostoni. A breathtaking lift: sex and body mass index differences in cardiopulmonary response in a large cohort of unselected subjects with acute exposure to high altitude. High Alt Med Biol. 22:379-385, 2021. Background: Every year, thousands of people travel to high altitude and experience hypoxemia. At high altitude, the partial pressure of oxygen decreases. The aim of this observational study was to determine if there is a relationship between anthropometric features and basic cardiorespiratory variables, including oxygen saturation (SpO2), heart rate (HR), and blood pressure (BP), following acute exposure to high altitude. Materials and Methods: At the 3,466 m top of a cableway station, we installed an automated system for measuring peripheral SpO2, HR, BP, height, weight, and body mass index (BMI). Results: Between January and October 2020, out of 4,874 volunteers (age 39.9 ± 15.4 years, male 54.4%), 3,267 provided complete data (1,808 cases during winter and 1,459 during summer). SpO2 was 86.8% ± 6.8%. At multivariable analysis, SpO2 was significantly associated with age, sex, season, BMI, and HR but not with BP. We identified 391 (12%) subjects with SpO2 ≤80%: they were older, with a higher BMI and HR but without sex or BP differences. Finally, winter season was associated with greater frequency of SpO2 ≤80% (13.3% vs. 10.3%, p = 0.008). Conclusion: Our data show that high BMI, older age, and male sex were associated with greater degrees of hypoxemia following exposure to high altitude, particularly during the winter.


[Pulmonary complications after bone marrow transplantation].
Pulmonary toxicity occurs in approximately 10 to 50% of patients undergoing bone marrow transplantation (BMT). Bacterial pneumonia very commonly affects patients within the first 6 months post-BMT. Etiologic factors include neutropenia and the presence of graft-versus-host disease (GVHD). Pulmonary fungal infections, due to candida and aspergillus, may develop in 16% of patients receiving BMT, with a high mortality rate, being about 80%. A prolonged neutropenia as well as GVHD and associated immunosuppressive treatments are important factors in predisposing a patient to develop fungal pneumonitis. Interstitial pneumonitis occurs in 10-40% of patients; herpes viruses are the most commonly documented cause, with cytomegalovirus (CMV) being the most common pathogen. No causative organism is identified in up to 60% of the cases. It is likely that some of these cases may result from drug or radiation toxicity. Lung shielding and fractionation of the dose have decreased the incidence of interstitial pneumonitis to less than 5%. Patients with GVHD are predisposed to lung infections because of the immunosuppression that accompanies GVHD and its treatment. In addition, GVHD itself appears to have a direct effect on pulmonary epithelium. Cultural and serologic studies as well as radiographic investigations and other diagnostic procedures (ie bronchoalveolar lavage) are needed for appropriate management of pulmonary complications.


[Perinatal outcome in patients with meconial amniotic fluid in labor].
To evaluate the perinatal morbidity and mortality with the presence of meconial amniotic fluid. Retrospective study of case review, performed from 1st of June 1995 to May 1997. The patients included were at delivery, with a pregnancy of 32 weeks or older and had meconial amniotic fluid. The variables analyzed were: motherhood age, pre-existing associated illness, resolution of the pregnancy, PSS interpretation, fetal weight, Apgar and final destiny of the product. Of the 432 patients the motherhood aged varied from 13 to 43 years old, mean 27.4; with a number of pregnancies from 1 to 10, mean 2.25. The gestational age went from 32.2 to 42.4 weeks. The fetal weight varied form 1025 to 5080 g. The Apgar grade mean was 7 at the first minute and 8 at the fifth. The pregnancy was interrupted by cesarean in 52.5%. Although there was not a significant difference with the arterial gas, the density of the amniotic fluid did determine the final destiny of the product. There is a relation between the presence of amniotic fluid and the Apgar grade; both determining the final destiny of the product. When the amniotic fluid had thick meconium the products had a greater morbidity.


Chest discomfort in a patient with dengue - is it an acute myocardial infarction?
Cardiovascular symptoms presenting in a patient with dengue fever may post a diagnostic dilemma. We describe a case of dengue myocarditis mimicking an acute myocardial infarction in a 56-year-old woman.


Assessment of health-related quality of life of chronic kidney disease patients in aminu kano teaching hospital, Kano.
The prevalence of chronic kidney disease (CKD) is increasing globally. Recently, the concept of Health-Related Quality of Life (HRQOL) is receiving attention as a measure of treatment outcome in addition to traditional morbidity and mortality rates. To assess the HRQOL of CKD patients stages 1-5 using the Kidney Disease Quality of Life questionnaire (KDQOL). The study was a cross-sectional study of CKD patients at a teaching hospital in north-western Nigeria during the study period. The quality of life, sociodemographic, clinical, and laboratory variables were assessed using a pro forma and the KDQOL questionnaire during regular clinic visits/dialysis sessions. Age and sex-matched healthy volunteers without evidence of renal disease were recruited from the hospital environment into a comparison group. A total of 150 subjects with CKD and 150 individuals in the comparison group completed the study with 77 males and 73 females for both groups. The mean ± standard deviation (SD) ages of the CKD and comparison group was 52.83 ± 14.21 and 52.43 ± 14.50 years, respectively. Subjects in the comparison group had higher physical composite summary (PCS) and mental composite summary (MCS) scores than individuals with CKD (P value < 0.05). Subjects with CKD showed a progressive decline in the scores of all HRQOL domains with advancing CKD stages (P value < 0.05). The results suggest that subjects with CKD have worse HRQOL domain scores when compared to the normal population and these scores progressively worsened with advancing CKD stages.


Time-related increase of oxygen utilization in continuously activated human visual cortex.
Oxygen utilization increase is fractionally much less than that seen in glucose metabolism and blood flow soon after onset of neuronal activation, however its behavior during continued activation is less certain. We evaluated the effects of 25 min of visual stimulation on CBF, CMRO(2), and OEF using [(15)O] water and [(15)O] oxygen PET. Seven healthy volunteers underwent a PET session consisting of serial [(15)O] water and [(15)O] oxygen scans at the fixation-only baseline visual state and after 1, 13, and 25 min of the continuous visual stimulation using a black-white vertical grating. CBF, CMRO(2), and OEF values were calculated for the entire brain and for regions of interest in visual cortex centered over the area of activation. After 1 min of stimulation, CMRO(2) increased only 4.7% compared to baseline and CBF increased 40.7%. However, after 25 min of stimulation the increase in CMRO(2) compared to baseline was 15.0%, having tripled from that measured at 1 min (P < 0.05). CBF did not significantly change during this time. OEF was 48.3% at baseline. It decreased to 37.1% after 1 min of visual stimulation (P < 0.01) and then returned almost to baseline values after 25 min of activation OEF (45.7%). There were no significant variations in whole-brain values during the study. We suggest that in the activated brain, the increased energy demands initially are not fully met with oxidative metabolism and must predominantly be supported by increased glycolysis. With continued activation, oxygen utilization increases reducing the need for excess glycolysis.


Infrared signature and folding dynamics of a helical beta-peptide.
Synthetic foldamers consisting of beta-amino acids offer excellent model systems for examining the effect of backbone flexibility on the dynamics of protein folding. Herein, we study the folding-unfolding kinetics of a beta-peptide that folds into a 14-helical structure in water. We find that the T-jump induced relaxation kinetics of this peptide occur on the nanosecond time scale and are noticeably slower than those of alanine-based alpha-helical peptides, and additionally, the relaxation rates show a weaker dependence on temperature. These differences appear to indicate that the folding energy landscapes of these peptides are different. In addition, we find that the amide I' band of this beta-peptide exhibits a sharp feature at approximately 1612 cm(-1), which we believe is a distinct infrared reporter of 14-helix.


[A system to aid decision-making. Application to automatic interpretation of vectorcardiograms].
This paper presents a complete and autonomous system for the automated diagnosis (heuristic approach). The system was worked out by means of a small computer. A flexible, evolutive, quasi-universal system is achieved through original procedures. A specialised language enables the users to describe diagnoses and their criteria in symbolic form. A suitable compiler translates this symbolic writing into an interpretable object program. This, with the Interpreter program, constitutes the 'Automated Diagnosis Program'. Our data are vectorcardiograms recorded according to the Frank orthogonal system. After an interactive pre-processing process, 180 parameters--mostly spatial--are computed. The data, the computed parameters and additional information are stored in a data bank. Finally, the medical interpretation is automatically selected from 125 possibilities. The user could also utilise a data bank interrogation language.


Culturally sensitive care of the Muslim patient.
The number of Muslims in the United States is growing. This article outlines a few of the major beliefs in Islam. Religious and philosophical factors that affect health care are discussed, and practical suggestions are made for nursing actions that lead to culture care preservation, culture care accommodation, and culture care restructuring. Major topics covered include the need for cleanliness, preparation for prayer, modesty, family structure, fasting and diet, and care of the dying.


Comparison and characterization of pigments and dyes by Raman spectroscopy.
This review provides a general understanding of Raman spectroscopy for use in the identification of pigments and dyes. The methodologies associated with a number of different related applications are also summarized. The first part of this review clarifies our basic knowledge regarding natural minerals and pigments. The second part discusses the fundamentals of currently used Raman spectroscopy, including surface-enhanced Raman scattering, μ-Raman spectroscopy, Raman imaging and spatially offset Raman spectroscopy. The third part focuses on recent applications, including the identification and analysis of various pigments and dyes that are used in paintings and related artworks. These studies show that Raman spectroscopy has great potential for use as a method for the rapid, non-destructive identification of such substances.


Research utility of the National Violent Death Reporting System: a scoping review.
To better understand and prevent suicide and homicide, the National Center for Injury Prevention and Control of the US Centers for Disease Control and Prevention launched the National Violent Death Reporting System (NVDRS) in six states in 2002. As of 2018, the NVDRS has been expanded to include all 50 states, the District of Columbia and Puerto Rico. The purpose of this review was to assess the research utility of the NVDRS based on studies indexed in major bibliographical databases. We performed a scoping review of published studies that were based on data from the NVDRS, identified by searching six electronic databases: PubMed, EMBASE, Google Scholar, OVID, Scopus, and Web of Science. We examined the time trend of annual NVDRS-based research output, generated a word cloud using the keywords listed in the publications, and mapped the knowledge domains covered by NVDRS-based studies. Our review included a total of 150 studies published between 2005 and 2018. There was a marked increase in the annual number of NVDRS-based publications, with 120 (80.0%) of the 150 studies published between 2011 and 2018. Overall, 104 (69.3%) studies focused on suicide and 39 (26.0%) on homicide. Of the included studies, 100 (66.7%) were descriptive epidemiology, 31 (20.7%) were risk factor analyses, 9 (6.0%) were evaluations, 7 (4.7%) were trend analyses, and 4 (2.7%) were data quality assessments. Knowledge domain mapping identified two major clusters of studies, one on suicide and the other on homicide. The cluster on suicide was commonly linked to "circumstance," "alcohol" and "substance abuse" and the cluster on homicide was commonly linked to "firearm," "injury," and "gang." The two clusters were interlinked to overlapping networks of keywords, such as "firearm" and "mental health problem." Research utility of the NVDRS has increased considerably in recent years. Studies based on data from the NVDRS are clustered in two knowledge domains - suicide and homicide. The vast potential of the NVDRS for violence research and prevention remains to be fully exploited.


Effect of plasma welding parameters on the flexural strength of Ti-6Al-4V alloy.
The aim of this study was to assess the effect of different plasma arc welding parameters on the flexural strength of titanium alloy beams (Ti-6Al-4V). Forty Ti-6Al-4V and 10 NiCr alloy beam specimens (40 mm long and 3.18 mm diameter) were prepared and divided into 5 groups (n=10). The titanium alloy beams for the control group were not sectioned or subjected to welding. Groups PL10, PL12, and PL14 contained titanium beams sectioned and welded at current 3 A for 10, 12 or 14 ms, respectively. Group NCB consisted of NiCr alloy beams welded using conventional torch brazing. After, the beams were subjected to a three-point bending test and the values obtained were analyzed to assess the flexural strength (MPa). Statistical analysis was carried out by one-way ANOVA and Tukey's HSD test at 0.05 confidence level. Significant difference was verified among the evaluated groups (p<0.001), with higher flexural strength for the control group (p<0.05). No significant differences was observed among the plasma welded groups (p>0.05). The NCB group showed the lowest flexural strength, although it was statistically similar to the PL 14 group (p>0.05). The weld depth penetration was not significantly different among the plasma welded groups (p=0.05). Three representative specimens were randomly selected to be evaluated under scanning electron microcopy. The composition of the welded regions was analyzed by energy dispersive X-ray spectroscopy. This study provides an initial set of parameters supporting the use of plasma welding during fabrication of titanium alloy dental frameworks.


The real and subjective indoor environmental quality in schools.
Investigation of IEQ and subjective evaluation of IEQ by pupils is the main objective of this research work. For the monitoring two classrooms in primary school and two classrooms in art school were chosen. Very high CO2 levels were determined in both investigated schools. In three of four classrooms the statistically significant differences (p < 0.01) were reported between TVOC levels in autumn and spring. The recommended value for TVOC levels was exceeded in the range from 52 % to 53 % in autumn and from 52 % to 70 % in spring. Significant (p < 0.05) seasonal changes were found also for PM concentrations in each classroom. Significance difference in perception of IEQ factors between genders were observed for IAQ. This study showed a good consistency between data obtained from the measurement and data from the questionnaire study and thus, pointed to the good ability of pupils to evaluate the IEQ in their classrooms.


Synthesis and structural characterisation of a soluble, metastable indium(I) halide complex, [InBr(tmeda)].
The first example of an indium(i) halide complex, [InBr(tmeda)], has been prepared by the reversible dissolution of InBr in a tmeda-toluene mixture. The structural characterisation of the metastable compound shows it to be monomeric with weak InIn interactions in the solid state. In solution, it decomposes to either InBr or [In2Br4(tmeda)2].


Parent perspectives on augmentative and alternative communication in Sri Lanka.
Parental support is an important part of introducing an augmentative and alternative communication (AAC) system to a child. Professionals providing AAC services to children with complex communication needs should practice family-centered service provision. The aim of this study was to explore Sri Lankan parents' perspectives on AAC and their lived experiences. Semi-structured interviews were conducted with 10 parents of children with complex communication needs. Thematic analysis was used to analyze the findings, with the following themes identified: (a) External Systems, (b) Impact on the Family, (c) Impact on the Child, and (d) Communication (including AAC). Findings from this study provide important information for speech-language therapists providing services to families from low- and middle-income countries. In particular, parents reported several positive aspects of AAC. However, parents also reported challenges, including speech-language therapist's lack of knowledge of and training in AAC.


The role of Colchicine on actin polymerization dynamics: as a potent anti-angiogenic factor.
Over the years, cancer research has focused on different strategies to discover drugs and therapies to treat the metastatic stage of cancer. This stage depends upon the type, and the cause of cancer. One of the central facts about any cancer invasion is the formation of new blood vessels that provide nutrients to these uncontrollably dividing cells. This phenomenon is called angiogenesis and is responsible for tumor progression and metastasis. Tumor angiogenesis is a sequential process wherein various angiogenic factors produced by tumor cells bind to receptors of endothelial cells. This stimulates the cytoskeletal protein, especially actin to reorganize themselves and undergo the process of canalization. The driving force for such membrane transformation is spatially and temporally-regulated by polymerization of submembrane actin filaments. So far, Colchicine has been studied for its effectiveness in controlling microtubule reorganization during cell division, but its role is far from understood on actin polymerization. In our current study, we report the effect of Colchicine on actin polymerization dynamics using biophysical analysis like Right light scattering (RLS), Dynamic light scattering (DLS), Circular dichroism (CD) analysis, Scanning electron microscopy (SEM) study. Isothermal titration calorimetry (ITC) and kinetic measurements. Isothermal titration calorimetry (ITC) indicates multiple site binding for colchicine with actin aggregates. We have checked the in vivo effect of colchicine using end3 cells of Saccharomyces cerevisiae. We also report the anti-angiogenesis activity of colchicine via ex-ovo chicken chorioallantoic membrane (CAM) assay. We predict the target site of binding for the drug by docking studies. Based on our findings, we suggest the 'drug-repurposed' function for colchicine as a potential anti-angiogenic candidate.Communicated by Ramaswamy H. Sarma.


Efficacy of gemcitabine plus erlotinib in rash-positive patients with metastatic pancreatic cancer selected according to eligibility for FOLFIRINOX: A prospective phase II study of the 'Arbeitsgemeinschaft Internistische Onkologie'.
In metastatic pancreatic ductal adenocarcinoma (mPDAC) treatment, erlotinib is known to be more effective in patients developing skin rash. Treatment with the FOLFIRINOX regimen is only performed in fit patients following defined inclusion criteria. The present study investigates the efficacy of gemcitabine plus erlotinib (gem/erlotinib) in rash-positive patients fit for FOLFIRINOX. For this prospective phase II study, 150 patients were recruited in 20 centres. All patients received gem/erlotinib for 4 weeks (run-in phase); the subsequent treatment was determined by the development of skin rash: patients with rash grades 1-4 continued with gem/erlotinib, rash-negative patients were switched to FOLFIRINOX. Primary study end-point was to achieve a 1-year survival rate in rash-positive patients ≥40%. Ninety patients were deemed positive for skin rash by the end of the run-in phase, showing a 1-year survival rate of 40.0% (95% confidence interval [CI] 29.8-50.9). Median overall survival (OS) was 10.1 months, progression-free survival (PFS) was 3.8 months and overall response rate (ORR) was 23.3%. Patients switched to FOLFIRINOX (n = 27) had a 1-year survival rate of 48.1% (95% CI 28.7-68.1), a median OS of 10.9 months, a median PFS of 6.6 months and an ORR of 33.3%. Rash-negative patients had a lower quality of life at baseline but seemed to experience an improved control of pain during FOLFIRINOX. First-line treatment with gem/erlotinib was effective in fit, rash-positive mPDAC patients achieving a 1-year survival rate comparable to previous reports for FOLFIRINOX. The study was registered at clinicaltrials.gov (NCT0172948) and Eudra-CT (2011-005471-17).


Metalloenzyme-like catalyzed isomerizations of sugars by Lewis acid zeolites.
Isomerization of sugars is used in a variety of industrially relevant processes and in glycolysis. Here, we show that hydrophobic zeolite beta with framework tin or titanium Lewis acid centers isomerizes sugars, e.g., glucose, via reaction pathways that are analogous to those of metalloenzymes. Specifically, experimental and theoretical investigations reveal that glucose partitions into the zeolite in the pyranose form, ring opens to the acyclic form in the presence of the Lewis acid center, isomerizes into the acyclic form of fructose, and finally ring closes to yield the furanose product. The zeolite catalysts provide processing advantages over metalloenzymes such as an ability to work at higher temperatures and in acidic conditions that allow for the isomerization reaction to be coupled with other important conversions.


Suppression of large edge-localized modes in high-confinement DIII-D plasmas with a stochastic magnetic boundary.
A stochastic magnetic boundary, produced by an applied edge resonant magnetic perturbation, is used to suppress most large edge-localized modes (ELMs) in high confinement (H-mode) plasmas. The resulting H mode displays rapid, small oscillations with a bursty character modulated by a coherent 130 Hz envelope. The H mode transport barrier and core confinement are unaffected by the stochastic boundary, despite a threefold drop in the toroidal rotation. These results demonstrate that stochastic boundaries are compatible with H modes and may be attractive for ELM control in next-step fusion tokamaks.


The potential role of sterol regulatory element binding protein transcription factors in renal injury.
The disturbed lipid metabolism is a permanent finding in renal failure. It is supposed to be a main reason for the accelerated atherosclerosis and high cardiovascular and cerebrovascular mortality of patients with renal failure. Sterol regulatory element binding proteins (SREBPs) are the transcription factors involved in the regulation of lipid homeostasis. They are responsible for the transcription activation of genes associated with the synthesis of fatty acids, triglycerides, and cholesterol. SREBP-1 gene expression in adipose tissue and SREBP-2 in liver are significantly elevated in renal failure. This is accompanied with the up-regulation of genes encoding enzymes of both fatty acids and cholesterol synthesis and significant serum lipid enhancement. Moreover, it has been shown that a destructive accumulation of lipids in the kidney structures is associated with enhanced kidney SREBP gene expression and increased lipid production. This was found even in the absence of any abnormalities in serum lipids. One may suppose that SREBP transcription factors play an important role in disturbed lipid metabolism in renal failure.


An alcoholysis route to a Cu16 cluster, and the influence of the alcohol.
A systematic investigation of the alcoholysis of copper(II) pivalate (piv(-)) solutions has led to a series of Cu(2), Cu(6), and Cu(16) products, depending on the alcohol used as solvent. When Pr(n)OH or Bu(n)OH was employed, the products were the clusters [Cu(16)O(4)(OH)(4)(OR)(8)(piv)(12)(ROH)] (R = Pr(n), Bu(n)) that are almost isostructural. The Cu(16) clusters are antiferromagnetically-coupled with an S = 0 spin ground state.


[Lipogranuloma with marked eosinophile infiltration in male genitalia].
A characteristic lipogranuloma in the male genitalia is presented. Histopathological examination revealed a granuloma resembling sclerosing lipogranuloma with marked eosinophile infiltration. Only 11 cases with such a histopathological feature have been reported. Including this case all cases have similar localization, shape and clinical course. The genesis of these granulomas is discussed.


Suspected lead toxicosis in a bald eagle.
An immature bald eagle (Haliaeetus leucocephalus) was submitted to the University of Maryland, College Park, for clinical examination. The bird was thin, had green watery feces, and was unable to maintain itself in upright posture. Following radiography, the bird went into respiratory distress and died. Numerous lead shot were recovered from the gizzard, and chemical analysis of liver and kidney tissue revealed 22.9 and 11.3 ppm lead, respectively. The clinical signs, necropsy findings, and chemical analysis of the eagle were compatible with lead toxicosis.


NRF2 is essential for iron-overload stimulated osteoclast differentiation through regulation of redox and iron homeostasis.
Iron overload enhances osteoclastic bone resorption and induces osteoporosis. Excess iron is highly toxic. The modulation of redox and iron homeostasis is critical for osteoclast differentiation under iron-overload condition. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the cellular defense against oxidative stress and iron overload through the expression of genes involved in anti-oxidative processes and iron metabolism. Our studies demonstrated that NRF2 activation was suppressed during osteoclast differentiation. Under iron-overload condition, NRF2 and its mediated antioxidant and iron metabolism genes were activated by reactive oxygen species (ROS), which enhanced antioxidant capability. NRF2 mediated the upregulation of iron exporter ferroportin 1 (FPN1) and iron storage protein ferritin, contributing to decreased levels of intracellular iron. Nfe2l2 knockout induced oxidative stress and promoted osteoclast differentiation under normal condition, but induced ferroptosis under iron-overload condition. Nfe2l2 knockout alleviated iron overload induced bone loss by inhibiting osteoclast differentiation. Our results suggest that NRF2 activation is essential for osteoclast differentiation by enhancing antioxidant capability and reducing intracellular iron under iron-overload condition. Targeting NRF2 to induce ferroptosis could be a potential therapy for the treatment of iron-overload induced osteoporosis.


Morocco as a possible source for acquisition of Rhinocladiella mackenziei.
Rhinocladiella mackenziei cerebral phaeohyphomycosis is a rare severe disease that has been typically described in the Middle East. Here, we report 2 cases of R. mackenziei cerebral phaeohyphomycosis in patients from Morocco, diagnosed and treated in France, and raise a concern about the ever-going extension of the area at risk for this devastating invasive fungal infection.


Challenges for Joint Commission International accreditation: performance of orthopedic surgeons based on International Patient Safety Goals.
The Joint Commission International (JCI) is a US-based organization that accredits and certifies hospitals worldwide. Among the requirements for accreditation, the JCI emphasizes continuous quality improvement (CQI) with regard to international patient safety goals (IPSGs). Our university hospital treats about 26,000 hospitalized patients and 600,000 outpatients annually, and our goal is patient safety in compliance with IPSGs. The purpose of this study is to examine the activities of orthopedic surgeons in preparation for JCI accreditation, including clear identification of patients, preoperative timeout and marking to ensure correct surgery, timely approval of CT/MRI reports, care with pain management, prevention of infection, setting of quality indicators and daily monitoring, and teamwork. Examiners from the JCI visited our hospital to review medical records and documents, and to interview patients, nurses and doctors. There were 1270 evaluation items covering 16 fields, including reviews of IPSGs, patient evaluation and care, infection prevention and control, and governance and leadership. Most importantly, the efforts of all the medical staff in our hospital in obtaining the first JCI accreditation among national university hospitals in Japan have promoted the safety and quality of medical care from the perspective of the patient.


Flooding tolerance in interspecific introgression lines containing chromosome segments from teosinte (Zea nicaraguensis) in maize (Zea mays subsp. mays).
Nicaraguan teosinte (Zea nicaraguensis), a species found in frequently flooded areas, provides useful germplasm for breeding flooding-tolerant maize (Z. mays subsp. mays). The objective of this study was to select flooding-tolerant lines using a library of introgression lines (ILs), each containing a chromosome segment from Z. nicaraguensis in the maize inbred line Mi29. To produce the ILs, a single F1 plant derived from a cross between maize Mi29 and Z. nicaraguensis was backcrossed to Mi29 three times, self-pollinated four times and genotyped using simple sequence repeat markers. Flooding tolerance was evaluated at the seedling stage under reducing soil conditions. By backcrossing and selfing, a series of 45 ILs were developed covering nearly the entire maize genome. Five flooding-tolerant lines were identified from among the ILs by evaluating leaf injury. Among these, line IL#18, containing a Z. nicaraguensis chromosome segment on the long arm of chromosome 4, showed the greatest tolerance to flooding, suggesting the presence of a major quantitative trait locus (QTL) in that region. The presence of the QTL was verified by examining flooding tolerance in a population segregating for the candidate region of chromosome 4. There was no significant relationship between the capacity to form constitutive aerenchyma and flooding tolerance in the ILs, indicating the presence of other factors related to flooding tolerance under reducing soil conditions. A flooding-tolerant genotype, IL#18, was identified; this genotype should be useful for maize breeding. In addition, because the chromosome segments of Z. nicaraguensis in the ILs cover nearly the entire genome and Z. nicaraguensis possesses several unique traits related to flooding tolerance, the ILs should be valuable material for additional QTL detection and the development of flooding-tolerant maize lines.


A successful trial of enzyme replacement therapy in a case of argininemia.
A 5-year-old boy with severe mental retardation and spastic quadriplegia accompanied by tonic seizures and hyperammonemia was diagnosed as having argininemia due to an arginase deficiency in his erythrocytes. His motor and mental abilities began to deteriorate at the age of 3 years. Thereafter, he lost his ability to stand alone, to sit and even to crawl by himself. After he was diagnosed as argininemia , a protein restricted diet was given as therapy, which was accompanied with a supplement of essential amino acids. However, his clinical condition had not improved very much. The erythrocytes in a normal person was found to have the ability to decrease the patient's elevated plasma arginine level to normal when they are mixed in vitro. First we tried replacing his red cells by a blood transfusion. Then we replaced them with the aid of an IBM 2997 blood cell separator. Following this his clinical and biochemical condition improved, and as a result so did his sitting and crawling abilities. It appears that the replacement of red blood cells improves not only the clinical and biochemical conditions, but the general condition of the patient as well.


Evolution of Benjamin-Ono solitons in the presence of weak Zakharov-Kutznetsov lateral dispersion.
The effect of weak lateral dispersion of Zakharov-Kutznetsov-type on a Benjamin-Ono solitary wave is studied both asymptotically and numerically. The asymptotic solution is based on an approximate variational solution for the solitary wave, which is then modulated in time through the use of conservation equations. The effect of the dispersive radiation shed as the solitary wave evolves is also included in the modulation equations. It is found that the weak lateral dispersion produces a strongly anisotropic, stable solitary wave which decays algebraically in the direction of propagation, as for the Benjamin-Ono solitary wave, and exponentially in the transverse direction. Moreover, it is found that initial conditions with amplitude above a threshold evolve into solitary waves, while those with amplitude below the threshold evolve as lumps for a short time, then merge into radiation. The modulation equations are found to give a quantitatively accurate description of the evolution of an initial condition into an anisotropic solitary wave. The existence of stable solitary waves is in contrast to previous studies of Benjamin-Ono-type equations subject to the stronger Kadomstev-Petviashvili or Benjamin-Ono-type lateral dispersion, for which the solitary waves either decay or collapse. The present study then completes the catalog of possible behaviors under lateral dispersion.


The PICNIC Story.
This chapter describes how the Professionals and Citizens Network for Integrated Care (PICNIC) project was conducted in order to meet its objectives in preparing the regional healthcare providers to implement the next generation, comprehensive, user-friendly, secure healthcare network for patient centred care, and through it contribute to the de-fragmentation of the European market for health telematics. It describes the methodology followed in order to reach certain project results, starting from the selection of common documentation tools and methods, to the delivery of a new model for providing services, assessment plans, and a number of open source software components running on a number of diverse pilots throughout Europe in line with the overall PICNIC architecture.


Aerosol Mass Spectrometer for Simultaneous Detection of Polyaromatic Hydrocarbons and Inorganic Components from Individual Particles.
Online studies of single airborne particles represent a demanding challenge in aerosol chemistry. New technologies that help to unravel the role of ambient aerosols in earth climate and to assess local and specific health risks from air pollution are highly desired. Of particular relevance are polycyclic aromatic hydrocarbons (PAHs) from combustion processes that are associated with both acute and long-term health effects. Usually, online single particle analyses apply laser desorption/ionization (LDI) in a bipolar mass spectrometer, revealing elemental constituents and limited molecular information by detection of both positive and negative ions. Approaches for the detection of PAHs from single particles have been developed but the elemental information from LDI that allows particle classification and source apportionment is lost in that case. Here we present a novel laser desorption and ionization method delivering both the PAH-profile and the inorganic composition from the same, individual particle. Test measurements demonstrate the technique's capability to reveal the single-particle PAH-distribution in aerosols (mixing state) and its assignment to specific pollution sources in a new and direct way.


The biochemical properties of the two Arabidopsis thaliana isochorismate synthases.
The important plant hormone salicylic acid (SA; 2-hydroxybenzoic acid) regulates several key plant responses including, most notably, defence against pathogens. A key enzyme for SA biosynthesis is isochorismate synthase (ICS), which converts chorismate into isochorismate, and for which there are two genes in Arabidopsis thaliana One (AtICS1) has been shown to be required for increased SA biosynthesis in response to pathogens and its expression can be stimulated throughout the leaf by virus infection and exogenous SA. The other (AtICS2) appears to be expressed constitutively, predominantly in the plant vasculature. Here, we characterise the enzymatic activity of both isozymes expressed as hexahistidine fusion proteins in Escherichia coli. We show for the first time that recombinant AtICS2 is enzymatically active. Both isozymes are Mg2+-dependent with similar temperature optima (ca. 33°C) and similar Km values for chorismate of 34.3 ± 3.7 and 28.8 ± 6.9 µM for ICS1 and ICS2, respectively, but reaction rates were greater for ICS1 than for ICS2, with respective values for Vmax of 63.5 ± 2.4 and 28.3 ± 2.0 nM s-1 and for kcat of 38.1 ± 1.5 and 17.0 ± 1.2 min-1 However, neither enzyme displayed isochorismate pyruvate lyase (IPL) activity, which would enable these proteins to act as bifunctional SA synthases, i.e. to convert chorismate into SA. These results show that although Arabidopsis has two functional ICS enzymes, it must possess one or more IPL enzymes to complete biosynthesis of SA starting from chorismate.


Rumen protozoa in South African sheep with a summary of the worldwide distribution of sheep protozoa.
Protozoa species were identified in rumen contents of four domestic sheep (Ovis aries) from South Africa. All animals were fed a forage diet which consisted of 50% lucerne and 50% teff hay. Ten new host records were identified, bringing the total number of species and forms observed in sheep in South Africa to 30. The occurrence and geographic distribution of ciliate protozoa in both domestic and wild sheep from around the world are summarised. It was found that 15 genera and 131 species occur in domestic sheep globally.


[Necrotizing enterocolitis of the newborn infant].
The experience at the Hospital for Pediatric Surgery in Dortmund with 47 cases of necrotizing enterocolitis in 16 years are reviewed. 43 patients had been transferred from pediatric hospitals for immediate operation. 7 newborns had developed gastric perforation, 25 previously intestinal perforation. 4 patients had undergone laparotomy for other indication before. The chance to survive the necrotizing process is smaller in case of inflammation of the small bowel than of the large bowel. The current knowledge about necrotizing enterocolitis is summarized, including modern aspects about the indication to operate.


Exfoliated graphene nanosheets: pH-sensitive drug carrier and anti-cancer activity.
A straightforward and facile method for the exfoliation of graphene sheets using poly(vinylpyrrolidone) nanoparticles of an average size of 42nm was developed and their dual role as pH-sensitive drug carrier and anti-cancer agent was evaluated. The cytotoxic impact of the exfoliated nanosheets (GRP-PVP-NP) was examined on various cells (HCT-116, HeLa, SCC-9, NIH-3T3 and HEK-293cells) by a series of assays. Their cytotoxic nature was attributed to affecting the mitochondrial enzyme activity, proliferation capability, and the formation of tight junctions in cancer cells. The endocytosis was found to be internalization mechanism for the cellular uptake of nanosheets. The generation of reactive oxygen species and elicitation of caspase-3 activity which was undoubtedly associated with triggering of oxidative stress speculated to be the dominant cause of the cytotoxic pattern of nanosheets against cancer cells. Additionally, the results also showed the role of the nanosheets as a pH-sensitive drug carrier through drug loading by supramolecular interaction. The efficient release of doxorubicin was seen at low pH and in an environment with a low oxygen concentration, thus under conditions mimicking the typical tumor microenvironment. Therefore, these findings provide the first evidence for a dual function of exfoliated graphene sheets and also elucidate the cytotoxic mechanism responsible for the cancer cell death.


Histological and immunohistochemical aspects of papillary thyroid cancer.
Papillary thyroid carcinoma is one of the most common malignancies of the endocrine system. In recent years, its incidence has increased worldwide, including children, which concerns the entire community. Although the histopathological diagnosis seems rather easy, the existence of particular forms of thyroid cancer and the inclusion of the follicular aspect as a variant of papillary carcinoma lead to diagnostic confusion. Therefore, in the last 20 years were reviewed several immunohistochemical markers, which are useful in the positive and differential diagnosis, and which offer better data on disease prognosis. Our study included a total of 27 cases of papillary carcinomas, which we evaluated the immunohistochemical expression of Ki-67, p53, p63, E-cadherin, CD56, calretinin, and bcl-2 markers. The most intense expression was found in p53, E-cadherin, and bcl-2. Ki-67 and p63 expression were moderate and inconsistent, and CD56 and calretinin had a negative expression in all cases.


Evaluation of rapid post-mortem test kits for bovine spongiform encephalopathy (BSE) screening in Japan: Their analytical sensitivity to atypical BSE prions.
A classical type of bovine spongiform encephalopathy (C-BSE), recognized in 1987, had a large impact on public health due to its zoonotic link to variant Creutzfeldt-Jakob disease by the human consumption of dietary products contaminated with the C-BSE prion. Thus, a number of countries implemented BSE surveillance using rapid post-mortem test kits that were approved for detection of the C-BSE prion in the cattle brain. However, as atypical BSE (L- and H-BSE) cases emerged in subsequent years, the efficacy of the kits for the detection of atypical BSE prions became a matter of concern. In response to this, laboratories in the European Union and Canada evaluated the kits used in their countries. Here, we carried out an evaluation study of NippiBL®, a kit currently used for BSE screening in Japan. By applying the kit to cattle brains of field cases of C-BSE and L-BSE, and an experimental case of H-BSE, we showed its comparable sensitivities to C, L-, and H-BSE prions, and satisfactory performance required by the European Food Safety Authority. In addition to NippiBL®, two kits (TeSeE® and FRELISA®) formerly used in Japan were effective for detection of the L-BSE prion, although the two kits were unable to be tested for the H-BSE prion due to the discontinuation of domestic sales during this study. These results indicate that BSE screening in Japan is as effective as those in other countries, and it is unlikely that cases of atypical BSE have been overlooked.


Cognitive Change and Relaxation as Key Mechanisms of Treatment Outcome in Chronic Pain: Evidence From Routine Care.
Despite effective treatment approaches within the cognitive behavioral framework general treatment effects for chronic pain are rather small to very small. Translation from efficacy trials to naturalistic settings is questionable. There is an urgent need to improve the effectiveness of well-established treatments, such as cognitive-behavior therapy (CBT) and the investigation of mechanisms of change is a promising opportunity. We performed secondary data analysis from routine data of 1,440 chronic pain patients. Patients received CBT in a multidisciplinary setting in two inpatient clinics. Effect sizes and reliable change indices were computed for pain-related disability and depression. The associations between changes in the use of different pain coping skills (cognitive restructuring, activity despite pain, relaxation techniques and mental distraction) and changes in clinical outcomes were analyzed in structural equation models. Pre-post effect sizes range from g = 0.47 (disability) to g = 0.89 (depression). Changes in the use of cognitive restructuring, relaxation and to a lesser degree mental distraction were associated with changes in disability and depression. Effects from randomized trials can be translated to naturalistic settings. The results complement experimental research on mechanisms of change in the treatment of chronic pain and indicate an important role of cognitive change and relaxation as mechanisms of change. Our findings cautiously suggest that clinicians should optimize these processes in chronic pain patients to reduce their physical and emotional disability.


Insights into Adsorptive Drug Loading on Silica Aerogels from Supercritical CO2.
This work gives an insight into the process of adsorptive drug loading in silica aerogels from supercritical CO2 (scCO2). A prevalent method for such loading entails bringing the aerogels into contact with the drug-scCO2 solution followed by slow or isothermal depressurization. Our previous work established that drug precipitates during depressurization. Consequently, the adsorptive drug loading measured by the prevalent method includes precipitation. An alternative method is presented for accurate measurement of adsorption avoiding precipitation. To illustrate the disparity between the two methods, the concentration dependence of drug loadings in scCO2, obtained by both methods, is compared for fenofibrate, ibuprofen, and benzoic acid. A mechanism is proposed, and a mathematical model is developed for comparing the adsorptive drug loadings by both methods. The loading obtained by the present method is found to be much less than that by the prevalent method, though both correlate well with the formalism of the Langmuir adsorption equation with the same equilibrium constant at low concentrations. Equations are developed for the concentration dependence of drug loadings measured by both methods at all concentrations in scCO2.


Getting the measure of syphilis: qPCR to better understand early infection.
Until recently, PCR had been used to detect but not quantify Treponema pallidum. To understand infection kinetics of this uncultivable organism, a real-time PCR assay was developed to quantify 47 kDa membrane lipoprotein gene DNA (tpp47). Assay specificity was determined against DNA from humans, skin organisms and sexually transmitted pathogens. tpp47 DNA (Nichols strain) was used to construct a standard curve for T pallidum quantification. Blood and ulcer samples were obtained from 99 patients being investigated or screened for syphilis and tpp47 was quantified. The assay was specific, not cross-reactive with other organisms tested and sensitive, with a detection limit of a single copy of tpp47 DNA. For ulcer samples, the assay was 100% sensitive and 97.14% specific. Sensitivity fell to 34.1% for blood samples but specificity remained high (100%). tpp47 DNA was more commonly detected, and at a higher copy number, in blood of patients with secondary infection (sensitivity 57.89%) compared with primary infection. Quantity of tpp47 DNA was higher in primary infection ulcers, especially in HIV-1-positive patients, than in ulcers persisting into secondary disease. Quantifying T pallidum provides insight into syphilis infection kinetics: Ulcers of primary disease in HIV-1-positive patients are perhaps more infectious and the presence and load of T pallidum bacteraemia is variable, with a peak in the secondary stage. Quantitative PCR has the potential to map T pallidum infection and to highlight the impact of HIV on syphilis.


Cumulus expansion is impaired with advanced reproductive age due to loss of matrix integrity and reduced hyaluronan.
Reproductive aging is associated with ovulatory defects. Age-related ovarian fibrosis partially contributes to this phenotype as short-term treatment with anti-fibrotic compounds improves ovulation in reproductively old mice. However, age-dependent changes that are intrinsic to the follicle may also be relevant. In this study, we used a mouse model to demonstrate that reproductive aging is associated with impaired cumulus expansion which is accompanied by altered morphokinetic behavior of cumulus cells as assessed by time-lapse microscopy. The extracellular matrix integrity of expanded cumulus-oocyte complexes is compromised with advanced age as evidenced by increased penetration of fluorescent nanoparticles in a particle exclusion assay and larger open spaces on scanning electron microscopy. Reduced hyaluronan (HA) levels, decreased expression of genes encoding HA-associated proteins (e.g., Ptx3 and Tnfaip6), and increased expression of inflammatory genes and matrix metalloproteinases underlie this loss of matrix integrity. Importantly, HA levels are decreased with age in follicular fluid of women, indicative of conserved reproductive aging mechanisms. These findings provide novel mechanistic insights into how defects in cumulus expansion contribute to age-related infertility and may serve as a target to extend reproductive longevity.


A Review of Child and Adolescent Diagnostic Interviews for Clinical Practitioners.
The publication of the DSM-5 poses a challenge for many interview instruments due to the changes for many of the diagnoses. Six of the more widely used and studied interview instruments (structured and semistructured) were reviewed with a focus on usefulness for the practicing clinician and researcher. Use of these types of assessment procedures can facilitate the accuracy of diagnoses given by potentially reducing clinician bias. Each interview instrument varied in its strengths and characteristics related to amount of flexibility associated with administration of items; breadth of coverage of diagnoses based on DSM-IV; time required for administration; presence of screening items or modular format; and psychometric support for its reliability and validity, as well as amount of training required for use, and costs associated with acquiring and learning the format. Recommendations were made regarding the utilization of different instruments for specific diagnostic questions along with future recommendations for enhancing the format and utility of these instruments, especially in relation to the publication of the DSM-5.


New data on the stem and leaf anatomy of two conifers from the Lower Cretaceous of the Araripe Basin, northeastern Brazil, and their taxonomic and paleoecological implications.
Pseudofrenelopsis and Brachyphyllum are two conifers that were part of the Lower Cretaceous (Aptian) taphoflora of the Crato Formation, Araripe Basin, northeastern Brazil. The former genus includes, so far, P. capillata and indeterminate species, whilst the latter is mainly represented by B. obesum, the most common plant megafossil recovered from that stratigraphic unit. Here, the stem and leaf anatomy of Pseudofrenelopsis sp. and B. obesum specimens is revisited, including the first report of some epidermal and vascular traits for both taxa from the Crato Formation. Along with its paleoecological significance, the new data suggest the presence of more than one Pseudofrenelopsis species in the Aptian taphoflora of the Araripe Basin and further support the taxonomic placement of B. obesum within Araucariaceae.


Bronchoscopic delivery of lipiodol as a fiducial marker in lung tumors before radiotherapy.
Definitive radiotherapy treatment of thoracic tumors may be hampered by poor tumor visualization on radiological imaging and the effects of tumor motion. Fiducial markers act to enhance tumor visualization and tracking. Traditional solid fiducial markers, however, may result in complications, particularly in proximal lung lesions. These complications may be mitigated through the use of a liquid fiducial marker. This article presents four cases which demonstrate the feasibility of bronchoscopic delivery of lipiodol as a fiducial marker, to aid in guided radiotherapy for certain lung tumors.


Elevated intraocular levels of insulin-like growth factor I in a diabetic patient with acromegaly.
Growth factors have become increasingly associated with various events of vitreoretinal disease. In the presence of proliferative retinopathy, elevated levels of insulin growth factor I (IGF-I) have been demonstrated in the vitreous. IGF-I expression itself is regulated by growth hormone, a hormone that is involved in the pathogenesis of acromegaly. In the present paper we report on the detection of very high IGF-levels in the subretinal fluid of a patient with acromegaly who was operated for retinal detachment. With a very sensitive RIA assay we found a four-fold elevation of the serum levels of IGF-I (604 ng/ml) and a high level of IGF-1 in the subretinal fluid (13 ng/ml). It is concluded that acromegaly may lead to an overexpression of IGF-I not only seen as increased concentrations in serum and vitreous, but in the subretinal space as well. This study emphasizes the need for further investigation of growth factor presence in pathological cavities, such as the subretinal space during retinal detachments.


The simultaneous measurement of energy and linear polarization of the scattered radiation in resonant inelastic soft x-ray scattering.
Resonant Inelastic X-ray Scattering (RIXS) in the soft x-ray range is an element-specific energy-loss spectroscopy used to probe the electronic and magnetic excitations in strongly correlated solids. In the recent years, RIXS has been progressing very quickly in terms of energy resolution and understanding of the experimental results, but the interpretation of spectra could further improve, sometimes decisively, from a full knowledge of the polarization of incident and scattered photons. Here we present the first implementation, in a high resolution soft-RIXS spectrometer used to analyze the scattered radiation, of a device allowing the measurement of the degree of linear polarization. The system, based on a graded W/B4C multilayer mirror installed in proximity of the CCD detector, has been installed on the AXES spectrometer at the ESRF (European Synchrotron Radiation Facility); it has been fully characterized and it has been used for a demonstration experiment at the Cu L3 edge on a high-Tc superconducting cuprate. The loss in efficiency suffered by the spectrometer equipped with this test facility was a factor 17.5. We propose also a more advanced version, suitable for a routine use on the next generation of RIXS spectrometers and with an overall efficiency up to 10%.


The adverse effects of kava.
In Fiji, kava is also known as yaqona or grog. A convenient sample of 300 kava drinkers in Nadi, Lautoka, Ba and Sigatoka were studied to see whether local people in Fiji experienced side effects of kava use. Because males usually consume kava in Fiji, we approached specific groups of people and asked them to participate in the survey. To evaluate the side effects of kava consumption, we interviewed housewives of male kava drinkers regarding specific effects of kava. We interviewed these housewives during kava drinking sessions since they were usually not taking part in the kava drinking. We also interviewed employers of these kava drinkers and the market vendors in Nadi Town since they were closely involved with kava drinkers. Wives of kava users felt deprived of basic family needs due to the amount of money spent on kava. In Urban schools, 64% males and 46.2% had tried kava. The present study aims to assess the prevalence of side effects of kava usage among a community sample of kava drinkers in Fiji and to compare the result with some of the side effects provided by other studies. The questionnaire also asked how much kava was consumed and the reasons. Since kava use is very much part of our everyday culture and existence, convincing people to change their behavior and kava consumption is a major tasks. I hope that this study would emphasize the need at a national level to educate people on the harmful effects of kava and the need for the health ministry to view very heavy kava intake as contributing to morbidity in Fiji.


Synthesis and anti-tumor activity evaluation of 1H-pyrrolo[2,3-b]pyridine-2-carboxamide derivatives with phenyl sulfonamide groups as potent RSK2 inhibitors.
Ribosome S6 Protein Kinase 2 (RSK2) is involved in many signal pathways such as cell growth, proliferation, survival and migration in tumors. Also, RSK2 can phosphorylate YB-1, which induces the expression of tumor initiating cells, leading to poor prognosis of triple negative breast cancer. Herein, phenyl sulfonamide was introduced to a series of 1H-pyrrolo[2,3-b]pyridine-2-carboxamide derivatives to obtain novel RSK2 inhibitors which were evaluated RSK2 inhibitory activity and proliferation inhibitory activity against MDA-MB-468. The newly introduced sulfonamide group was observed to form a hydrogen bond with target residue LEU-74 which played crucial role in activity. The results showed that most of compounds exhibited RSK2 enzyme inhibitory with IC50 up to 1.7 nM. Compound B1 exhibited the strongest MDA-MB-468 cell anti-proliferation activity (IC50 = 0.13 μM). The in vivo tumor growth inhibitory activities were evaluated with compounds B1-B3 in MDA-MB-468 xenograft model which gave up to 54.6% of TGI.


Evaluating amber force fields using computed NMR chemical shifts.
NMR chemical shifts can be computed from molecular dynamics (MD) simulations using a template matching approach and a library of conformers containing chemical shifts generated from ab initio quantum calculations. This approach has potential utility for evaluating the force fields that underlie these simulations. Imperfections in force fields generate flawed atomic coordinates. Chemical shifts obtained from flawed coordinates have errors that can be traced back to these imperfections. We use this approach to evaluate a series of AMBER force fields that have been refined over the course of two decades (ff94, ff96, ff99SB, ff14SB, ff14ipq, and ff15ipq). For each force field a series of MD simulations are carried out for eight model proteins. The calculated chemical shifts for the 1 H, 15 N, and 13 Ca atoms are compared with experimental values. Initial evaluations are based on root mean squared (RMS) errors at the protein level. These results are further refined based on secondary structure and the types of atoms involved in nonbonded interactions. The best chemical shift for identifying force field differences is the shift associated with peptide protons. Examination of the model proteins on a residue by residue basis reveals that force field performance is highly dependent on residue position. Examination of the time course of nonbonded interactions at these sites provides explanations for chemical shift differences at the atomic coordinate level. Results show that the newer ff14ipq and ff15ipq force fields developed with the implicitly polarized charge method perform better than the older force fields.


Effect of primary particle morphology on the structure of gels formed in intense turbulent shear.
We study the effect of primary particle morphology on intense shear-induced gelation without adding electrolytes. The primary particles are composed of a rubbery core grafted with a polystyrene shell. Depending on the shell-to-core mass ratio, the core can be partially covered by the shell, leading to strawberry-like morphology. It is found that at a fixed core mass the fractal dimension of the clusters constructing the gel decreases (i.e., more open cluster structure) as the shell mass increases, until reaching a plateau. The SEM pictures of the gels reveal that the structure variations are due to the occurrence of partial coalescence among particles, which decreases as the shell mass increases. In the region where the fractal dimension reaches a plateau, the coalescence is negligible. The conversion of the primary particles to gels is incomplete and increases as the extent of coalescence decreases. This is related to the fact that the smaller the extent of coalescence, the larger the cluster size. Thus, because of its cubic dependence on the cluster size, the aggregation rate increases as the extent of coalescence decreases, leading to increased conversion. It is therefore evident that the key parameter controlling the gel structure and the particle conversion is the core surface coverage by the shell. To further verify this conclusion, we have carried out the shear-induced gelation of another set of particles with varying core mass. It is found that the only parameter that can well correlate the values of the fractal dimension and particle conversion from the two sets of particles is the core surface coverage.


Use of a diffusion model for assessing the performance of poly(vinyl alcohol) bioartificial pancreases.
Islets of Langerhans surrounded by a semipermeable membrane to prevent an immune response by the host immunosystem is a potential way of treating type I diabetes mellitus. In this study, poly(vinyl alcohol) (PVA) tubular membranes with added polyethylene glycol to create pores in the skin layer were prepared to improve their diffusion property. In a static incubation study, islets cultured in the PVA tubular membranes still demonstrated their function of secreting insulin after 30 days. When the tubular PVA bioartificial pancreas was perifused in a small chamber with RPMI-1640 medium containing glucose at concentrations of 5.6-16.6 mmol/L, insulin release began to increase without delay. Therefore, such a membrane is an alternative potential material for a bioartificial pancreas. In addition, a mathematical mass transfer model of insulin release was developed and compared with the perifusion data. It was shown that satisfactory kinetics could be achieved with a PVA membrane. However, the model showed that the insulin output of islets cultured in the PVA tubular membrane must be increased to improve the performance significantly. These findings suggest that a bioartificial pancreas using a PVA membrane is a promising material, but the technique for seeding islets in the chamber requires further modification.


Liquid-liquid extraction and facilitated transport of f-elements using an N-pivot tripodal ligand.
Diglycolamide (DGA)-functionalized tripodal ligands offer the required nine-coordinated complex for effective binding to a trivalent lanthanide/actinide ion. A N-pivot tripodal ligand (TREN-DGA) containing three DGA pendant arms was evaluated for the extraction and supported liquid membrane transport studies using PTFE flat sheets. Solvent extraction studies indicated preferential extraction of 1:1 (M:L) species, while the metal ion extraction increased with increasing HNO3 concentration conforming to a solvated species extraction. Flat sheet-supported liquid membrane studies, carried out using 4.0 × 10-3 M TREN-DGA in 95% n-dodecane + 5% iso-decanol indicated faster mass transport for Eu3+ ion as compared to Am3+ ion. The determined transport parameters indicated slow diffusion of the M-TREN-DGA (M = Am or Eu) complex being the rate-determining step. The transport of lanthanides and actinides followed the trend: Eu3+ > Am3+∼ Pu4+ >> UO22+ and Am can be selectively separated from a mixture of U and Pu by oxidizing the latter to its +6 oxidation state. The liquid membrane stability was not encouraging and was deteriorating the transport efficiency with time, which was attributed to carrier loss into the aqueous phases.


Early Diagnosis and Management of Nitrogen Deficiency in Plants Utilizing Raman Spectroscopy.
Nutrient deficiency alters growth and development of crop plants and compromises yield. Real-time non-invasive monitoring of the nutritional status of crops would allow timely applications of fertilizers to optimize for growth and yield at different times of the plant's life cycle. Here, we used Raman spectroscopy to characterize Arabidopsis and two varieties of leafy vegetable crops under nitrogen sufficient and deficient conditions. We showed that the 1046 cm-1 Raman peak serves as a specific signature of nitrogen status in planta, which can be used for early diagnosis of nitrogen deficiency in plants before onset of any visible symptoms. Our research can be applied toward crop management for sustainable and precision agriculture.


[Parathyreoidectomy in Rats Using Microsurgery and Medical Adhesive Sulfacrylate].
One of the main difficulties in assessing the effectiveness of etiologic treatment of hypoparathyroidism is absence of its standardized model. The aim of the study was to develop a method of hypoparathyroidism modeling. Controlled nonrandomized study was performed on female Wistar rats aged 10 month. Group 1 (n =14) was performed with destruction of parathyroid glands with electrocoagulation; group 2 (n =12)--parathyroidectomy by the developed method. In 3 and 14 days after the surgery the levels of ionized calcium, parathyroid hormone, number of white blood cells, blood leukocyte formula, indicators of immunological tests, histological examination of organs in the area of operations were performed. Statistical analysis was performed using the nonparametric Mann-Whitney-Wilcoxon test. Selection of animals by sex and age criteria, angular skin incision, use of the operating microscope, microsurgical techniques, extirpation of parathyroid glands via resection of thyroid gland with the closure of the wound defect glue appeared to be the distinctive features of the developed method. In 14 days the group 2 showed decrease in ionized calcium (p = 0.016), PTH (p = 0.094), leucocytes (p = 0.004), PI (p = 0.003), spontaneous NBT test (p = 0.004), induced NBT test (p = 0.003) compared with group 1. Histological examination in the group 2 revealed no changes in thyroid gland, thin connective tissue capsule, cavity with a small amount of glue, however, there were determined foci of necrosis with perifocal inflammation in the group 1. Combination of several techniques allowed to simulate metabolic disorders with persistent hypocalcemia as well as lack of mortality in early postoperative period.


Chromatographic and electrophoretic migration parameters in capillary electrochromatography.
Chromatographic retention factor, k', as defined in high-performance liquid chromatography (HPLC) in terms of the migration times of the separand and the inert tracer, has limited applicability to capillary electrochromatography (CEC) when both chromatographic and electrophoretic processes determine the magnitude of the overall migration rates of the separands. This situation is unlike that in HPLC, where k' serves as a useful peak locator for the various sample components, as well as, provides thermodynamic insights into the interactions between the components and the stationary phase. Most publications have borrowed the definition of k' from HPLC and applied it on CEC. However, due to the dual separation mechanisms that are in action in CEC, the system is significantly complicated in comparison to that of HPLC. This paper discusses the impossibility of defining with a k' which would have all the attributes that it has in regular chromatography. The interplay of the two separation mechanisms in determining the overall migration process in CEC is discussed and the various definitions of the electrochromatographic retention factor are presented.


Genuair®/Pressair® Inhaler in COPD: The Patient Perspective.
This article reviews the latest data pertaining to the Genuair®/Pressair® device, a breath-actuated, multi-dose dry-powder inhaler with a two-step inhalation process, which is marketed for the delivery of aclidinium alone or in combination with formoterol for long-term maintenance bronchodilation treatment in chronic obstructive pulmonary disease. It contains multiple feedback mechanisms to guide effective use, and safety features to avoid double-dosing or attempted use when empty. In addition to describing the design of Genuair®, the article will provide an update on inhaler operability and performance, focusing on recent patient preference and satisfaction studies. The evidence suggests that patients find Genuair® easy to use, with patients requiring less training and making fewer inhalation errors than with other inhalers, and that patient satisfaction with the device is high.


Psychometric properties of the Cognitive Failures Questionnaire.
The Cognitive Failures Questionnaire (CFQ) is used in ergonomics research to measure behavioural problems associated with attentiveness and memory in everyday life. CFQ scores have been related to constructs such as accident proneness and outcomes such as human error and psychological strain. The two-year test-retest reliability of the CFQ is reported together with the findings of factor analyses of CFQ data from 535 respondents. Evidence for the predictive and criterion validity and internal reliability of the CFQ is provided. Psychological strain was measured concurrently with CFQ on both testing occasions, two years apart. The test-retest reliability of the summated CFQ score was found to be 0.71, while for the General Health Questionnaire (GHQ-12) strain measure it was 0.32.The relative variance stability was five times greater for the CFQ than the GHQ, indicating that scores on these questionnaires are not covariates. The use of the CFQ as a measure of cognitive control capacity is also discussed. Ergonomists have long been interested in human error and the role of high work demands due to poor equipment design and excessive workload. The CFQ measures attentiveness in daily life and is shown to have excellent psychometric properties that make it suitable for use in both laboratory and field studies as a trait measure of attentiveness in daily life.


Inhaled corticosteroid related adrenal suppression detected by poor growth and reversed with ciclesonide.
This case series intends to highlight the association between decreased linear growth velocity and adrenal suppression in patients receiving inhaled corticosteroids for asthma. A potential treatment option is also discussed. Adrenal suppression secondary to inhaled corticosteroids has previously been reported and is often underrecognized. A decrease in linear height velocity has also been associated with inhaled corticosteroids. However, a decrease in height velocity has not been shown to predict adrenal suppression. This case series of 15 patients receiving inhaled corticosteroids for control of asthma were noted to have a decrease in linear growth velocity ultimately associated with adrenal suppression. A change in inhaled corticosteroid to ciclesonide led to recovery of adrenal function without impacting asthma control. Chart review from a pediatric pulmonology clinic was performed. Growth parameters and laboratory studies were recorded and analyzed. A mean decrease in height standard deviation score in the year prior to diagnosis of adrenal suppression was -0.59, -0.11, and -0.18, in pre-puberty, peri-puberty, and post-puberty patients, respectively. After ciclesonide therapy was initiated, a mean change in height standard deviation score of +0.40, +0.13, and -0.13, was noted for pre-puberty, peri-puberty, and post-puberty patients, respectively. A change in growth velocity of +5.3 cm/yr, +2.1 cm/yr, and -1.9 cm/yr, was noted for pre-puberty, peri-puberty, and post-puberty patients, respectively, after starting ciclesonide. Height velocity should be monitored closely during routine asthma visits to identify potential adrenal suppression associated with inhaled corticosteroids use. Ciclesonide is a good option for asthma treatment that allows for adrenal recovery.


[Epidemiology of classical Hodgkin lymphoma].
EPIDEMIOLOGY OF CLASSICAL HODGKIN LYMPHOMA. Classical Hodgkin lymphoma is a rare neoplasia but represents one of the most common cancers in adults younger than 40 years old. Epidemiology of Hodgkin lymphoma remains fascinating with specific incidence patterns depending of age, socio-economic status, histological subtypes and Epstein-Barr virus (EBV) tumor status. These findings are in favor of several diseases with different pathogenesis. A better understanding of biological specificities of some Hodgkin lymphoma subgroups such as those presenting by older patients might be helpful to improve treatment strategies and outcome. Currently, no causal agent has been identified. Some risk factors are described, especially genetic ones, but no specific screening or prevention procedure are currently indicated.


Running injuries and associated factors in participants of ING Taipei Marathon.
To investigate the distribution of lower extremity running injuries and their associated factors. Descriptive and exploratory study. 1004 participants of the 2005 ING Taipei International Marathon. We used a self-developed questionnaire to collect data of previous running injuries and applied multivariate logistic regression modeling to examine relationships between these injuries and associated factors. Of the 893 valid questionnaires, 396 (44.4%) reported having previous lower extremity pain related to running. Knee joint pain was the most common problem (32.5%). Hip pain was associated with the racing group, training duration, and medial arch support. Use of knee orthotics (P = 0.002) and ankle braces (P = 0.007) was related to a higher rate of knee and ankle pain. Participants of the full marathon group who practiced on a synthetic track had a higher incidence of ankle pain. A training duration of >60 min was linked to an increased rate of foot pain (P = 0.003). Our data indicated that running injuries were associated with training duration and use of orthotics. Clinicians can use this information in treating or preventing running associated injuries and pain.


Advising cancer patients on natural health products--a structured approach.
Many patients with cancer (45-60%) use natural health products (NHPs). Pharmacists often find it difficult to advise these patients effectively. To explore pharmacists' perceptions of the information needed to advise cancer patients on NHPs and develop a structured counseling approach. A qualitative study was conducted using a focus group of pharmacists from an integrated cancer care organization in Canada. The outcome measures were the definitions of and reasons for the information needed to advise patients on NHPs and a counseling approach using laymen terms. Eight focus group sessions took place, from which 6 categories of information emerged: role of the advisor, evaluation of evidence, assessment of efficacy, assessment of toxicity, monitoring parameters, and provision of a closure. A patient counseling approach was developed based on this information. The findings provided a description of and rationale for categories of information needed to advise cancer patients on NHPs. A structured, step-by-step approach to counseling these patients was developed.


Simultaneous quantification of enalapril and enalaprilat in human plasma by high-performance liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study.
A rapid, selective and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed to simultaneously determine enalapril and enalaprilat in human plasma. With benazepril as internal standard, sample pretreatment involved in a one-step protein precipitation (PPT) with methanol of 0.2 ml plasma. Analysis was performed on an Ultimate XB-C(18) column (50 mm x 2.1 mm, i.d., 3 microm) with mobile phase consisting of methanol-water-formic acid (62:38:0.2, v/v/v). The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction-monitoring (MRM) mode via electrospray ionization (ESI) source. Each plasma sample was chromatographed within 2.5 min. The linear calibration curves for enalapril and enalaprilat were both obtained in the concentration range of 0.638-255 ng/ml (r(2) > or = 0.99) with the lower limit of quantification (LLOQ) of 0.638 ng/ml. The intra-day precision (R.S.D.) was below 7.2% and inter-day R.S.D. was less than 14%, while accuracy (relative error R.E.) was within +/-8.7 and +/-5.5%, determined from QC samples for enalapril and enalaprilat which corresponded to requirement of the guidance of FDA. The HPLC-MS/MS method herein described was fully validated and successfully applied to the pharmacokinetic study of enalapril maleate capsules in 20 healthy male volunteers after oral administration.


SARS-CoV-2 prevalence in domestic and wildlife animals: A genomic and docking based structural comprehensive review.
The SARS-CoV-2 virus has been identified as the infectious agent that led to the COVID-19 pandemic, which the world has seen very recently. Researchers have linked the SARS-CoV-2 outbreak to bats for the zoonotic spread of the virus to humans. Coronaviruses have a crown-like shape and positive-sense RNA nucleic acid. It attaches its spike glycoprotein to the host angiotensin-converting enzyme 2 (ACE2) receptor. Coronavirus genome comprises 14 ORFs and 27 proteins, spike glycoprotein being one of the most critical proteins for viral pathogenesis. Many mammals and reptiles, including bats, pangolins, ferrets, snakes, and turtles, serve as the principal reservoirs for this virus. But many experimental investigations have shown that certain domestic animals, including pigs, chickens, dogs, cats, and others, may also be able to harbor this virus, whether they exhibit any symptoms. These animals act as reservoirs for SARS-CoV, facilitating its zoonotic cross-species transmission to other species, including humans. In this review, we performed a phylogenetic analysis with multiple sequence alignment and pairwise evolutionary distance analysis, which revealed the similarity of ACE2 receptors in humans, chimpanzees, domestic rabbits, house mice, and golden hamsters. Pairwise RMSD analysis of the spike protein from some commonly reported SARS-CoV revealed that bat and pangolin coronavirus shared the highest structural similarity with human coronavirus. In a further experiment, molecular docking confirmed a higher affinity of pig, bat, and pangolin coronavirus spike proteins' affinity to the human ACE2 receptor. Such comprehensive structural and genomic analysis can help us to forecast the next likely animal source of these coronaviruses that may infect humans. To combat these zoonotic illnesses, we need a one health strategy that considers the well-being of people and animals and the local ecosystem.


Chiral recognition and conglomerate crystallization induced by self-organization of cobalt(III) complexes of a tripodal ligand containing three imidazole groups.
The effect of a counteranion on chiral recognition inducing conglomerate crystallization of a cobalt(III) complex is reported. An achiral tripodal ligand involving three imidazole groups, tris{[2-{(imidazol-4-yl)methylidene}amino]ethyl}amine (H3L), was prepared by condensation of tris(2-aminoethyl)amine and 4-formylimidazole in a 1:3 mole ratio. The reaction of H3L and trans-[CoIIICl2(py)4]+ afforded the chiral (Delta or Lambda) [CoIII(H3L)]3+ complex. The formally hemideprotonated complexes [CoIII(H(1.5)L)]X(1.5).nH2O (where X = Cl, Br, I, BF4, ClO4, or PF6) were synthesized by controlled deprotonation of the uncoordinated imidazole NH groups of [Co(H3L)]3+. In crystals of the hemideprotonated complex, two components, [Co(H3L)]3+ and [Co(L)], with the same absolute configuration are linked by imidazole-imidazolate hydrogen bonds to form an extended homochiral 2D sheet structure, which is composed of a hexanuclear unit with a trigonal void. There are two ways of stacking the sheets: One is via homochiral stacking, and the other is via heterochiral stacking. When the size of the counterion is small (i.e., X = Cl, Br, I, or BF4), adjacent homochiral sheets with the same chirality are stacked to form a homochiral crystal (conglomerate). With large anions (i.e., ClO4- and PF6-), a homochiral sheet consisting of Delta enantiomers and a sheet consisting of Lambda enantiomers are stacked alternately to give a heterochiral crystal (a racemic crystal). Optically active Lambda-[Co(H(1.5)L)](ClO4)(1.5).H2O was synthesized from Lambda-[Co(H3L)]3+, and the crystal structure was compared to that of the racemic complex. There are two conflicting factors governing the crystal structure: the skeletal density; the size of the channels. The 2D sheets are more closely packed in the homochiral crystal than in the heterochiral crystal. However, the channels, where the counterions are accommodated, are smaller in the homochiral crystal, and the steric congestion between the anions increases with increasing anion size. The heterochiral crystal has a flexible, zigzag channel structure, and the size of the channels can increase to accommodate larger anions. Thus, complexes with large anions (i.e., ClO4- and PF6-) preferentially form heterochiral crystals rather than homochiral crystals.


Use of analgesic and sedative drugs in VLBW infants in German NICUs from 2003-2010.
Very low birth weight (VLBW) infants frequently receive analgesia and/or sedation for painful procedures and mechanical ventilation to avoid negative stress. Yet, concerns remain regarding potential adverse long-term effects of these drugs on VLBW infants' neurocognitive outcome. Recent studies have shown that less invasive surfactant application (LISA) and early nasal CPAP treatment reduce the need for mechanical ventilation and painful procedures. Therefore, these measures might also reduce the application of analgesic and/or sedative drugs in VLBW infants. To evaluate this hypothesis and to identify potential changes in analgesic treatment concepts in recent years, we retrospectively analyzed data on analgesia and sedation, respiratory support, and the method of surfactant application in VLBW infants enrolled in the German Neonatal Network (GNN) trial between 2003 and 2009 (period 1) and compared it with data from infants participating in GNN in 2010 (period 2). In both periods, about one third of all infants were treated with analgesic and/or sedative drugs using a wide variety of substances. The administration of novel drugs such as propofol, sufentanil, or intravenous paracetamol was higher in 2010 (6.7 vs. 12.2 %). Infants who were treated with CPAP only received significantly less analgesic/sedative medication than infants who were mechanically ventilated (12 vs. 65 %, p=<0.001). Similarly, infants treated with LISA received less analgesic or sedative drugs as compared to infants who received surfactant via endotracheal intubation (36 vs. 63 %, p=0.001). Although both avoidances of mechanical ventilation and less invasive surfactant application are associated with reduced analgesic or sedative treatment, the percentage of VLBW infants who received analgesia and/or sedation remained unchanged in Germany in recent years.


Evaluating the validity of clinical codes to identify cataract and glaucoma in the UK Clinical Practice Research Datalink.
The aim of this study is to determine (i) the positive predictive value (PPV) of an algorithm using clinical codes to identify incident glaucoma and cataract events in the Clinical Practice Research Datalink (CPRD) and (ii) the ability to capture the correct timing of these clinical events. A total of 21,339 and 5349 potential cataract and glaucoma cases, respectively, were identified in CPRD between 1 January 1990 and 31 December 2010. Questionnaires were sent to the general practitioners (GP) of 1169 (5.5%) cataract and 1163 (21.7%) glaucoma cases for validation. GPs were asked to verify the diagnosis and the timing of the diagnosis and to provide other supporting information. A total of 986 (84.3%) valid cataract questionnaires and 863 (74.2%) glaucoma questionnaires were completed. 92.1% and 92.4% of these used information beyond EMR to verify the diagnosis. Cataract and glaucoma diagnoses were confirmed in the large majority of the cases. The PPV (95% CI) of the cataract and glaucoma Read code algorithm were 92.0% (90.3-93.7%) and 84.1% (81.7-86.6%), respectively. However, timing of diagnosis was incorrect for a substantial proportion of the cases (20.3% and 32.8% of the cataract and glaucoma cases, respectively) among whom 30.4% and 49.2% had discrepancies in diagnosis timing greater than 1 year. High PPV suggests that the algorithms based on the clinical Read codes are sufficient to identify the cataract and glaucoma cases in CPRD. However, these codes alone may not be able to accurately identify the timing of the diagnosis of these eye disorders. Ltd.


Enantioselective Synthesis of Highly Substituted Chromans via the Oxa-Michael-Michael Cascade Reaction with a Bifunctional Organocatalyst.
A highly enantioselective synthesis of chiral chroman derivatives via an oxa-Michael-Michael cascade reaction has been developed using a bifunctional thiourea organocatalyst. The products were obtained with excellent enantioselectivities (up to >99%), good yields (up to 95%), and diastereoselectivities (up to 5:1).


CTCF induces histone variant incorporation, erases the H3K27me3 histone mark and opens chromatin.
Insulators functionally separate active chromatin domains from inactive ones. The insulator factor, CTCF, has been found to bind to boundaries and to mediate insulator function. CTCF binding sites are depleted for the histone modification H3K27me3 and are enriched for the histone variant H3.3. In order to determine whether demethylation of H3K27me3 and H3.3 incorporation are a requirement for CTCF binding at domain boundaries or whether CTCF causes these changes, we made use of the LacI DNA binding domain to control CTCF binding by the Lac inducer IPTG. Here we show that, in contrast to the related factor CTCFL, the N-terminus plus zinc finger domain of CTCF is sufficient to open compact chromatin rapidly. This is preceded by incorporation of the histone variant H3.3, which thereby removes the H3K27me3 mark. This demonstrates the causal role for CTCF in generating the chromatin features found at insulators. Thereby, spreading of a histone modification from one domain through the insulator into the neighbouring domain is inhibited.


Effect of pregnancy and human immunodeficiency virus infection on intracellular interleukin-2 production patterns.
Human immunodeficiency virus type 1 (HIV-1) infection decreases the production of interleukin-2 (IL-2) from CD4+ and CD8+ T cells. Recombinant IL-2 (rIl-2) has been given to HIV-infected individuals to generate significant increases in CD4+ T-cell counts. There are limited data regarding the effects of pregnancy and HIV infection on IL-2 production in humans. To investigate the effects of human pregnancy, HIV infection, and HIV therapy on IL-2 production, we evaluated 61 women. Intracellular IL-2 production by CD4+ T cells from nonpregnant HIV-infected women was significantly lower than in that in uninfected women (45% +/- 8% versus 52% +/- 8%, P = 0.04). In contrast, there was no difference in levels of intracellular IL-2 production between HIV-infected and uninfected pregnant women. These observations suggest that pregnancy may down-regulate IL-2 production regardless of HIV infection status. Future studies should evaluate IL-2 production patterns in larger cohorts of women so that the physiological significance of IL-2 down-regulation in pregnancy can be further evaluated. This information is essential to assess the possible use of IL-2 supplementation therapy as a means of enhancing immune responses among HIV-infected pregnant women.


Nutrition in Pediatric Extracorporeal Membrane Oxygenation: A Narrative Review.
Extracorporeal membrane oxygenation (ECMO) support is increasingly utilized in quaternary pediatric intensive care units. Metabolic derangements and altered nutritional requirements are common in critically ill children supported on ECMO. However, there remains no consensus on the optimal approach to the prescription of nutrition in these patients. This narrative review aims to summarize the current medical literature on various aspects of nutrition support in pediatric patients on ECMO. These include: (1) nutritional adequacy, (2) pros and cons of feeding on ECMO, (3) enteral vs. parenteral nutrition, and (4) proposed recommendations and future directions for research in this area.


alpha-Melanocyte stimulating hormone (MSH) decreases cyclosporine a induced apoptosis in cultured human proximal tubular cells.
The pathogenesis of chronic cyclosporine A (CsA) nephrotoxicity has not been elucidated, but apoptosis is thought to play an important role in CsA induced tubular atrophy. Recently Fas-Fas ligand system mediated apoptosis has been frequently reported in many epithelial cells as well as in T lymphocytes. We investigated the ability of CsA to induce apoptosis in cultured human proximal tubular epithelial cells and also the effect of alpha-MSH on them. Fas, Fas ligand, and an intracellular adaptor protein, Fas-associating protein with death domain (FADD) expression, and poly-ADP ribose polymerase (PARP) cleavage were also studied. CsA induced apoptosis in cultured tubular epithelial cells demonstrated by increased number of TUNEL positive cells and it was accompanied by a significant increase in Fas mRNA and Fas ligand protein expressions. FADD and the cleavage product of PARP also increased, indicating the activation of caspase. In alpha-MSH co-treated cells, apoptosis markedly decreased with downregulation of Fas, Fas ligand and FADD expressions and also the cleavage product of PARP. In conclusion, these data suggest that tubular cell apoptosis mediated by Fas system may play a role in tubular atrophy in chronic CsA nephrotoxicity and pretreatment of alpha-MSH may have a some inhibitory effect on CsA induced tubular cell apoptosis.


Environmental Factors Modify the Severity of Acute DSS Colitis in Caspase-11-Deficient Mice.
Human and mouse studies implicate the inflammasome in the pathogenesis of inflammatory bowel diseases, though the effects in mice are variable. The noncanonical inflammasome activator caspase-11 (Casp11) reportedly attenuates acute dextran sodium sulfate (DSS) colitis in mice. However, the effects of Casp11 on chronic experimental colitis and factors that influence the impact of Casp11 on acute DSS colitis are unknown. We studied the role of Casp11 in Il10-/- mice and acute and chronic DSS colitis mouse models. We quantified colonic Casp11 mRNA using quantative polymerase chain reaction and colitis using weight loss, blinded histological scoring, IL-12/23p40 secretion by colonic explants, and fecal lipocalin-2. We determined fecal microbial composition using 16S amplicon sequencing. We detected increased colonic Casp11 mRNA in Il10-/- mice with chronic colitis, but not in mice with DSS colitis. The presence of Casp11 did not alter the severity of chronic colitis in DSS-treated or Il10-/- mice. Contrary to prior reports, we initially observed that Casp11 exacerbates acute DSS colitis. Subsequent experiments in the same animal facility revealed no effect of Casp11 on acute DSS colitis. There were pronounced stochastic changes in the fecal microbiome over this time. The majority of bacterial taxa that changed over time in wild-type vs Casp11-/- mice belong to the Clostridiales. Casp11 does not impact chronic experimental colitis, and its effects on acute DSS colitis vary with environmental factors including the microbiota, particularly Clostridiales. Stochastic drifts in intestinal microbiota composition, even in mice in the same housing facility, should be considered when interpreting studies of acute DSS colitis models.


Construction and Validation of an Immune-Related Risk Score Model for Survival Prediction in Glioblastoma.
As one of the most important brain tumors, glioblastoma (GBM) has a poor prognosis, especially in adults. Immune-related genes (IRGs) and immune cell infiltration are responsible for the pathogenesis of GBM. This study aimed to identify new tumor markers to predict the prognosis of patients with GBM. The Cancer Genome Atlas (TCGA) database and ImmPort database were used for model construction. The Wilcoxon rank-sum test was applied to identify the differentially expressed IRGs (DEIRGs) between the GBM and normal samples. Univariate Cox regression analysis and Kaplan-Meier analysis was performed to investigate the relationship between each DEIRG and overall survival. Next, multivariate Cox regression analysis was exploited to further explore the prognostic potential of DEIRGs. A risk-score model was constructed based on the above results. The area under the curve (AUC) values were calculated to assess the effect of the model prediction. Furthermore, the Chinese Glioma Genome Atlas (CGGA) dataset was used for model validation. STRING database and functional enrichment analysis were used for exploring the gene interactions and the underlying functions and pathways. The CIBERSORT algorithm was used for correlation analysis of the marker genes and the tumor-infiltrating immune cells. There were 198 DEIRGs in GBM, including 153 upregulated genes and 45 downregulated genes. Seven marker genes (LYNX1, PRELID1P4, MMP9, TCF12, RGS14, RUNX1, and CCR2) were filtered out by sequential screening for DEIRGs. The regression coefficients (0.0410, 1.335, 0.005, -0.021, 0.123, 0.142, and -0.329) and expression data of the marker genes were used to construct the model. The AUC values for 1, 2, and 3 years were 0.744, 0.737, and 0.749 in the TCGA-GBM cohort and 0.612, 0.602, and 0.594 in the CGGA-GBM cohort, respectively, which indicated a high predictive power. The results of enrichment analysis revealed that these genes were enriched in the activation of T cell and cytokine receptor interaction pathways. The interaction network map demonstrated a close relationship between the marker genes MMP9 and CCR2. Infiltration analysis of the immune cells showed that dendritic cells (DCs) could identify GBM, while LYNX1, RUNX1, and CCR2 were significantly positively correlated with DCs expression. This study analyzed the expression of IRGs in GBM and identified seven marker genes for the construction of an immune-related risk score model. These marker genes were found to be associated with DCs and were enriched in similar immune response pathways. These findings are likely to provide new insights for the immunotherapy of patients with GBM.


[Pituitary adenoma with initial symptom of cerebrospinal fluid rhinorrhea: a case report].
Pituitary adenoma with cerebrospinal fluid rhinorrhea is rare clinically. In this paper, through the analysis of a pituitary adenoma patient with initial symptom of cerebrospinal fluid rhinorrhea, we look forward to provide evidence for clinical diagnosis, so that we can avoid misdiagnosis.


Implementation of integrated geriatric care at a German hospital: a case study to understand when and why beneficial outcomes can be achieved.
Many health systems have implemented integrated care as an alternative approach to health care delivery that is more appropriate for patients with complex, long-term needs. The objective of this article was to analyse the implementation of integrated care at a German geriatric hospital and explore whether the use of a "context-mechanisms-outcomes"-based model provides insights into when and why beneficial outcomes can be achieved. We conducted 15 semi-structured interviews with health professionals employed at the hospital. The data were qualitatively analysed using a "context-mechanisms-outcomes"-based model. Specifically, mechanisms were defined as the different components of the integrated care intervention and categorised according to Wagner's Chronic Care Model (CCM). Context was understood as the setting in which the mechanisms are brought into practice and described by the barriers and facilitators encountered in the implementation process. These were categorised according to the six levels of Grol and Wensing's Implementation Model (IM): innovation, individual professional, patient, social context, organisational context and economic and political context. Outcomes were defined as the effects triggered by mechanisms and context, and categorised according to the six dimensions of quality of care as defined by the World Health Organization, namely effectiveness, efficiency, accessibility, patient-centeredness, equity and safety. The integrated care intervention consisted of three main components: a specific reimbursement system ("early complex geriatric rehabilitation"), multidisciplinary cooperation, and comprehensive geriatric assessments. The inflexibility of the reimbursement system regarding the obligatory number of treatment sessions contributed to over-, under- and misuse of services. Multidisciplinary cooperation was impeded by a high workload, which contributed to waste in workflows. The comprehensive geriatric assessments were complemented with information provided by family members, which contributed to decreased likelihood of adverse events. We recommend an increased focus on trying to understand how intervention components interact with context factors and, combined, lead to positive and/or negative outcomes.


Induction of apoptosis by curcumin: mediation by glutathione S-transferase P1-1 inhibition.
Expression of glutathione S-transferase P1-1 (GSTP1-1) is correlated to carcinogenesis and resistance of cancer cells against chemotherapeutic agents. Curcumin, a natural compound extracted from Curcuma longa, has shown strong antioxidant and anticancer properties and also the ability to regulate a wide variety of genes that require activating protein 1 and nuclear factor kappaB (NF-kappaB) activation. In the present study, we examined the inhibitory effect of curcumin on the expression of GSTP1-1 mRNA as well as protein, and we correlated this inhibition with the apoptotic effect of curcumin on K562 leukemia cells. Curcumin efficiently inhibited the tumour necrosis factor alpha- and phorbol ester-induced binding of AP-1 and NF-kappaB transcription factors to sites located on the GSTP1-1 gene promoter. TNFalpha-induced GSTP1-1 promoter activity was also inhibited by curcumin as shown by reporter gene assay. In parallel, curcumin induced pro-caspases 8 and 9 as well as poly ADP ribose polymerase cleavage and thus leading to apoptosis in K562 cells. Our results overall add a novel role for curcumin as this chemoprotective compound could contribute to induce apoptosis by its ability to inhibit the GSTP1-1 expression at the level of transcription.