Folding kinetics of proteins and cold denaturation.
Folding kinetics of a lattice model of protein is studied. It uses the random energy model for the intrachain couplings and a temperature dependent free energy of solvation derived from a realistic hydration model of apolar solutes. The folding times are computed using Monte Carlo simulations in the region of the phase diagram where the chain occurs in the native structure. These folding times are roughly equals for the temperatures of cold and warm denaturations for a large range of solvent quality. Between these temperatures, the folding times reach maxima and thus, at low temperatures, the kinetics of the chain always speeds up as the temperature is decreased. The study of the conformational space as function of the temperature permits to elucidate this phenomenon. At low temperature, it shows that the activation barriers of the system decrease faster than the temperature as the temperature is decreased. At high temperature, the rate of the barriers over the temperature decreases as the temperature is increased because the height of the barrier is almost constant.


Tang-Luo-Ning, a Traditional Chinese Medicine, Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis of Schwann Cells under High Glucose Environment.
Tang-Luo-Ning (TLN) has a definite effect in the clinical treatment of diabetic peripheral neuropathy (DPN). Schwann cells (SCs) apoptosis induced by endoplasmic reticulum stress (ER stress) is one of the main pathogeneses of DPN. This study investigates whether TLN can inhibit SCs apoptosis by inhibiting ER stress-induced apoptosis. Our previous researches have demonstrated that TLN could increase the expression of ER stress marker protein GRP78 and inhibited the expression of apoptosis marker protein CHOP in ER stress. In this study, the results showed that TLN attenuated apoptosis by decreasing Ca2+ level in SCs and maintaining ER morphology. TLN could decrease downstream proteins of CHOP including GADD34 and Ero1α, while it increased P-eIF2α and decreased the upstream proteins of CHOP including P-IRE1α/IRE1α and XBP-1, thereby reducing ER stress-induced apoptosis.


Telocytes accompanying cardiomyocyte in primary culture: two- and three-dimensional culture environment.
Recently, the presence of telocytes was demonstrated in human and mammalian tissues and organs (digestive and extra-digestive organs, genitourinary organs, heart, placenta, lungs, pleura, striated muscle). Noteworthy, telocytes seem to play a significant role in the normal function and regeneration of myocardium. By cultures of telocytes in two- and three-dimensional environment we aimed to study the typical morphological features as well as functionality of telocytes, which will provide important support to understand their in vivo roles. Neonatal rat cardiomyocytes were isolated and cultured as seeding cells in vitro in two-dimensional environment. Furthermore, engineered myocardium tissue was constructed from isolated cells in three-dimensional collagen/Matrigel scaffolds. The identification of telocytes was performed by using histological and immunohistochemical methods. The results showed that typical telocytes are distributed among cardiomyocytes, connecting them by long telopodes. Telocytes have a typical fusiform cell body with two or three long moniliform telopodes, as main characteristics. The vital methylene blue staining showed the existence of telocytes in primary culture. Immunohistochemistry demonstrated that some c-kit or CD34 immuno-positive cells in engineered heart tissue had the morphology of telocytes, with a typical fusiform cell body and long moniliform telopodes. Also, a significant number of vimentin+ telocytes were present within engineered heart tissue. We suggest that the model of three-dimensional engineered heart tissue could be useful for the ongoing research on the functional relationships of telocytes with cardiomyocytes. Because the heart has the necessary potential of changing the muscle and non-muscle cells during the lifetime, telocytes might play an active role in the heart regeneration process. Moreover, telocytes might be a useful tool for cardiac tissue engineering.


Effect of nano-structural properties of biomimetic hydroxyapatite on osteoimmunomodulation.
Immune cells are sensitive to the microstructural and textural properties of materials. Tuning the structural features of synthetic bone grafts could be a valuable strategy to regulate the specific response of the immune system, which in turn modulates the activity of bone cells. The aim of this study was to analyse the effect of the structural characteristics of biomimetic calcium deficient hydroxyapatite (CDHA) on the innate immune response of macrophages and the subsequent impact on osteogenesis and osteoclastogenesis. Murine RAW 264.7 cells were cultured, under standard and inflammatory conditions, on chemically identical CDHA substrates that varied in microstructure and porosity. The impact on osteogenesis was evaluated by incubating osteoblastic cells (SaOS-2) with RAW-CDHA conditioned extracts. The results showed that macrophages were sensitive to different textural and structural properties of CDHA. Under standard conditions, the impact of inflammatory cytokine production by RAW cells cultured on CDHA played a significant role in the degradation of substrates, suggesting the impact of resorptive behaviour of RAW cells on biomimetic surfaces. Osteoblast differentiation was stimulated by the conditioned media collected from RAW cells cultured on needle-like nanostructured CDHA. The results demonstrated that needle-like nanostructured CDHA was able to generate a favourable osteoimmune environment to regulate osteoblast differentiation and osteogenesis. Under inflammatory conditions, the incubation of RAW cells with less porous CDHA resulted in a decreased gene expression and release of pro-inflammatory cytokines.


[Cross-cultural adaptation of quality of life indices for oral health].
The aim of this study was to evaluate the cross-cultural adaptation of the main quality of life instruments related to oral health. Studies on cross-cultural adaptation of oral health-related quality of life measures were searched for in LILACS and MEDLINE. Twenty-nine articles were analyzed, identifying distinct methods for cross-cultural adaptation of oral health-related quality of life measures. Such differences could jeopardize the future use of these instruments, since the instruments may not adequately represent the health status of the respective target populations.


Substantiating the predictive role of ultrasound imaging in athletes with lower limb tendinopathy: a systematic review.
To explore the potential of ultrasound imaging to anticipate and monitor future symptoms of patellar or Achilles' tendinopathy. The systematic review comprised prospective studies that used ultrasound imaging of Achilles' OR patellar tendons in asymptomatic patients at baseline and measurements of pain and/or function at follow-up. The Critical Appraisal Skills Programme checklist used to assess study quality and it was done by two independent reviewers. Of the 19 studies reviewed, 9(47.3%) investigated patellar tendon alone, 6(31.5%) did both patellar and Achilles' tendon, and 4(21.2%) did Achilles tendon alone. The method of ultrasound administration was almost uniform for both the tendons. The studies showed that the use of ultrasound to predict lower limb tendinopathy was indefinite, but that a higher proportion of tendon disorganisation increased the risk of developing tendinopathy. In addition, promising results were obtained for the use of ultrasound in both Achilles' and patellar tendinopathy in monitoring the effect of load or treatment on tendon structure. The included studies had participants from different sports. Tendon irregularities at baseline on ultrasound were related to increased risk and future occurrence of both patellar and Achilles' tendinopathy. .


Synthesis and beta-lactamase inhibitory activity of new 6 beta-sulfonamidopenicillanic acids.
New 6 beta-aryl(alkyl)sulfonamidopenicillanic acids and their sulfoxides were synthesized by sulfonylation of 6 beta-aminopenicilanic acid or its beta-sulfoxide with an appropriate sulfonyl chloride. The corresponding 6 beta-sulfonamidopenicillanic acids sulfones were prepared by oxidation of the sulfoxides with potassium permanganate in aqueous medium. The obtained compounds reduced the minimum inhibitory concentrations of ampicillin against 8 reference and 7 clinically isolated strains.


Trends in health and health inequalities among major states of India: assessing progress through convergence models.
Convergence in health and health inequalities reflects not only a sense of equity, but also provides a critical assessment tool for monitoring the health progress of differently placed individuals. This study examines convergence hypothesis for health and health inequalities across major Indian states, using both standard and cutting-edge convergence metrics. The findings lend support to the convergence in average health status among the states and the socioeconomic group of India, examined through select health indicators. However, results also suggest a setback in convergence in decline of health inequalities in recent times, particularly in life expectancy at birth, child immunization and underweight. Evidence signals that from the late 1990s, convergence in decline of health inequalities are replaced by emerging divergence. This paper contributes to health policy and planning by identifying areas where, India needs to work to achieve efficiency with equity in health status across geographical divisions and social groups.


Quantification of urinary excretion of 1,N6-ethenoadenine, a potential biomarker of lipid peroxidation, in humans by stable isotope dilution liquid chromatography-electrospray ionization-tandem mass spectrometry: comparison with gas chromatography-mass spectrometry.
Etheno DNA adducts are promutagenic DNA lesions derived from exogenous as well as endogenous sources. The levels of etheno adducts in tissue DNA are elevated in cancer prone tissues, and the urinary excretion of etheno adducts is associated with oxidative stress. In this report, a new assay based on isotope dilution liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) is developed for the quantification of 1,N(6)-ethenoadenine (epsilonAde) in human urine samples without the need for derivatization. Sample purification before analysis by MS only requires a reversed phase solid phase extraction column. Two multiple reaction monitoring transitions with two product ion fragments generated from a common parent ion were used to quantify urinary epsilonAde. The detection limit of epsilonAde using LC-ESI-MS/MS is 2 pg injected standard epsilonAde on-column, and the assay allows accurate quantification of urinary epsilonAde at concentrations higher than 10 pg/mL. The presence of epsilonAde in human urine is confirmed by the collision-induced daughter ion spectrum. Using this assay, the levels of epsilonAde in the 24 h urine samples from 18 healthy individuals are determined, and the results are in very good agreement with those obtained using isotope dilution gas chromatography-negative ion chemical ionization-mass spectrometry. The high specificity and simple sample pretreatment of this LC-ESI-MS/MS method render it a valuable tool in measuring epsilonAde in the complex mixture of human urine as a promising noninvasive biomarker for DNA damage associated with oxidative stress and for cancer chemoprevention studies.


Absent right superior vena cava and persistent left superior vena cava. Clinical and surgical considerations.
From 4,100 patients who had cardiac catheterization for congenital heart disease and " normocardia ", 6 were found to have a persistent left superior vena cava ( PLSVC ) and an absence of right superior vena cava ( RSVC ). Because of the rarity of this finding (1.46%) the clinical and surgical implications are considered. Four of them were successfully operated upon.


Frequency of cardiac autonomic neuropathy in patients with type 2 diabetes mellitus reporting at a teaching hospital of Sindh.
To determine the frequency of Cardiac Autonomic Neuropathy (CAN) in patients with type 2 Diabetes mellitus. Descriptive study. Department of Medicine, Liaquat University Hospital, Jamshoro, Hyderabad from December 2004 to April 2005. Patients with type 2 Diabetes Mellitus (DM) of at least 10 years duration were selected. CAN was evaluated in terms of presence of resting tachycardia, loss of sinus arrhythmia and heart rate response to Valsalva maneuver by ECG. A R-R variation with respiration of > 15 beats per minute, 10-15 beats per minute and <10 beats per minute were taken as normal, borderline CAN and definitive CAN, respectively. QTc intervals were measured. The association between CAN, diabetic control and duration of diabetes were determined. The mean age was 53.62+/-8.30 years, with male to female ratio of 1:1. Mean values for known duration of diabetes and HbA1c were 14+/-3.5 years and 11.36+/-3.6 mg/dl respectively. Definitive and borderline CAN was noted in 30% and 40% patients respectively. Variability of heart rate with respiration was significantly related to duration but not to the control of diabetes (p < 0.05). QTc showed a significant correlation with the known duration of diabetes and heart rate variability with respiration (p < 0.05). Most of the patients had very bad glycemic status as evidenced by HbA1c. CAN is common in long-standing diabetics, specifically those treated with oral hypoglycemic agents than those with insulin. Intensive glycemic control is associated with a better cardiac autonomic nerve functions.


Could a Non-Cellular Molecular Interactome in the Blood Circulation Influence Pathogens' Infectivity?
We advance the notion that much like artificial nanoparticles, relatively more complex biological entities with nanometric dimensions such as pathogens (viruses, bacteria, and other microorganisms) may also acquire a biomolecular corona upon entering the blood circulation of an organism. We view this biomolecular corona as a component of a much broader non-cellular blood interactome that can be highly specific to the organism, akin to components of the innate immune response to an invading pathogen. We review published supporting data and generalize these notions from artificial nanoparticles to viruses and bacteria. Characterization of the non-cellular blood interactome of an organism may help explain apparent differences in the susceptibility to pathogens among individuals. The non-cellular blood interactome is a candidate therapeutic target to treat infectious and non-infectious conditions.


Mammogenic hormones differentially modulate keratinocyte growth factor (KGF)-induced proliferation and KGF receptor expression in cultured mouse mammary gland epithelium.
Stromally derived keratinocyte growth factor (KGF) can play an important role in mammary gland development as a mesenchymal/stromal mediator of epithelial growth and morphogenesis. However, the possible coordinate regulation of mammary gland development by mammogenic hormones and KGF is unexplored. In these studies, the direct effect of mammogenic hormones on KGF-mediated mammary epithelial mitogenesis and expression of the KGF receptor was examined using primary mouse mammary epithelium growing in serum-free, collagen gel cell culture. Addition of KGF produced an average 7-fold increase in cell number after 10 days of culture. This effect of KGF was further increased in the presence of PRL (9-fold) or progesterone (P; 15-fold), with the combination of P and PRL (22-fold) producing the strongest synergistic stimulation. Estrogen did not show any additional stimulation of growth either alone or in combination with PRL and/or P. Ribonuclease protection analysis showed that epithelial cells grown in medium supplemented with P, but not PRL or estrogen, exhibited a 10-fold higher steady state level of KGF receptor (KGFR) messenger RNA (mRNA). KGFR expression was not induced by short term P exposure, suggesting an effect on mRNA stability rather than transcriptional activation. Time-course studies showed that an early decrease in the level of KGFR mRNA in basal cultures was significantly reduced by P addition. Measurement of RNA turnover after actinomycin D treatment showed that P increased the t(1/2) of KGFR mRNA compared with basal medium. Thus, P and PRL may differentially potentiate the direct mitogenic effect of KGF: P partly by elevation of the level of KGFR mRNA, and PRL principally by intracellular pathways not affecting KGFR expression.


[Results of cytogenetic screening of people employed in liquidation of accident consequences at the Chernobyl nuclear plant in 5 years].
The liquidators of Chernobyl power station accident consequences were subjected to cytogenetic examination in 5 years after the accident. The analysis included a routine method of peripheral blood lymphocyte culture. The exposed and reference groups turned out to differ in the occurrence of distorted cells and chromosomal aberrations in peripheral blood lymphocytes. The highest cytopathogenic effect was seen in those, who had been working at the station in May-June 1986. The authors suggest to form the groups at high risk on the base of cytogenetic data and subject the groups to thorough examination for various diseases including malignancies.


[Characteristics of dysfunction of islet beta-cell in newly diagnosed type 2 diabetic patients].
To investigate the characteristics of the dysfunction of islet beta-cell in newly diagnosed type 2 diabetic patients. Intravenous glucose tolerance test (IVGTT) was carried out on 352 newly diagnosed type 2 diabetic patients and 48 subjects with normal glucose tolerance (NGT) and then blood samples were collected 1, 2, 4, 6, and 10 minutes later to measure the plasma glucose and insulin to calculate the acute insulin response (AIR) and the area under the curve of insulin (AUC of insulin), homeostasis model assessment beta-cell (Homabeta), and Homa IR (insulin resistance). The median AIR of the type 2 diabetic patients was -33.7 pmol/L, significantly lower than that of the NGT subjects (6962.0 pmol/L, P < 0.001). The median AUC of the type 2 diabetic patients was 834.2 pmol/L, significantly lower than that of the NGT subjects (7934.7 pmol/L, P < 0.001). When the fasting plasma glucose (FPG) of the type 2 diabetic patients was above 7.0 mmol/L, the AIR value was remarkably reduced with a median level of 317.3 pmol/L, and then subsequently disappeared when the FPG was above 9.0 mmol/L. After adjustment of the insulin resistance assessed by HOMA IR, the Homabeta of the type 2 diabetic patients was reduced to be 30% that of the NGT subjects (3.7 +/- 0.9 vs 5.9 +/- 0.9, P < 0.001). Both the fasting proinsulin concentration and the ratio of fasting proinsulin to fasting insulin of the type 2 diabetic patients were significantly higher those of the NGT subjects (22.6 pmol/L +/- 14.7 pmol/L vs 11.5 pmol/L +/- 7.1 pmol/L, P < 0.001; and 30.1% +/- 20.5% vs. 12.1% +/- 9.6%, P < 0.001). The dysfunction of islet beta-cell in newly diagnosed type 2 diabetic patients is mainly represented by the disappearance of AIR and the evident decline of AUC and HOMA B, and the decrease of quality of insulin secretion.


Frequency and pattern of medical emergency team activation among medical cardiology patient care units.
Medical emergency teams are developing across the United States. The organization and implementation for a rapid response team to failing medical-surgical patients has been shown to reduce in-house cardiac arrest rates. Further investigation into the frequency and pattern for rapid response team calls has been shown to have a diurnal pattern and clustered around times associated with routine care activities. The medical emergency calls in the descriptive analysis reveal that calls to the medical cardiology units constitute--% of the total calls. The calls are found to be called with--frequency during the hours of 7 AM and 7 PM. The frequency of calls is shown to be clustered around the times of. The small descriptive analysis here suggests that further investigation in the patterns and monitoring of patient for early recognition to call for help is still needed.


Divergent Synthesis of Heteroatom-Centered 4,8,12-Triazatriangulenes.
The increasing attention devoted to triangulenes and their heteroatom derivatives inspired us to explore a divergent synthesis of heteroatom-centered 4,8,12-triazatriangulenes, which involved the preparation of a nitrogen-containing macrocyclic precursor and subsequent central heteroatom introduction by electrophilic C-Li and C-H substitution. The boron-centered triangulene has a planar structure unlike the bowl-shaped phosphorus- and silicon-centered triangulenes. The described synthetic procedure can be used to fabricate a broad range of attractive functional materials, for example, for organic light-emitting diodes, based on heteroatom-centered triangulenes.


[Kawasaki syndrome].
Kawasaki syndrome is not usual in our country. We report this case to stress the clinical importance of this syndrome in which dermatological signs predominate.


Anxiety, arousal and visual attention: a mechanistic account of performance variability.
Despite extensive research devoted to determining the nature of the relationship between stress and performance, there has been little systematic examination of the mechanisms underlying this relationship. Recently, researchers have begun to empirically address the attentional mechanisms underlying theoretical accounts of how stress, anxiety and arousal influence performance. Given the critical role of visual attention to sport expertise, this paper focuses primarily on literature dealing with how visual cues are differentially identified and processed when performers are anxious. Emerging evidence indicates that gaze behaviour tendencies are reliably altered when performers are anxious, leading to inefficient and often ineffective search strategies. Alterations of these visual search indices are addressed in the context of both self-paced and externally paced sports events. Recommendations concerning the utility of perceptual training programmes and how these training programmes might be used as anxiety regulation interventions are discussed. The theoretical implications and directions for future research are also addressed.


Identity management and sense of belonging to gay community among young rural Thai same-sex attracted men: implications for HIV prevention and treatment.
Young Thai men who have sex with men continue to have high HIV prevalence and incidence in spite of much investment in community-based prevention approaches. To make HIV services more appropriate for same-sex attracted young men in Thailand, it needs to be considered how target groups view themselves and manage their identities. This paper derives from a qualitative study of 25 same-sex attracted rural young Thai men. It identifies five tactics men employed to manage the discrepancy between their preferences and parental/societal expectations regarding gender and sexuality, and discusses how the young men viewed themselves in the wider context of Thai society, including whether they felt part of a separate gay community. Participants usually did not adopt a gay social identity and were reluctant to join in gay community activities beyond dating. Hence, they would likely experience barriers in accessing gay community-based HIV services. HIV services targeting young same-sex attracted Thai men need to be diversified if they are to be more inclusive, appropriate and effective.


It's Never Too Late for a Diagnosis.
Zellweger spectrum disorder (ZSD) (OMIM#214100) is a phenotypic continuum ranging from severe to mild presentations. ZSD is now used in all individuals with a defect in one of the 13 ZSD-PEX genes, regardless of phenotype. Diagnosis can be suggested by abnormal levels of very long-chain fatty acids, phytanic acid, pristanic acid, plasmalogens, pipecolic acid, or bile acids. However, false negatives are frequent, mostly in older patients. Definite diagnosis is established in a proband with suggestive clinical findings by identification of biallelic pathogenic variants in one of the 13 ZSD-PEX genes. A 39-year-old female patient had a global development delay since her first year of life. Never developed oral language but had sphincter control and was able to walk and laugh. At 8 years old, she had her first seizure and lost sphincter control when she was 20 years old. At 28 years old, she had an episode of status epilepticus, with severe prostration and became bedridden. She is currently mute, without capacity for communication or motor control. She has no consanguineous parents, has a 35 year old brother with global developmental delay and their mother had a history of an abortion, without other relevant family history. Brain MRI of the patient revealed severe leukodystrophy mainly periventricular, bilateral and symmetric, and less prominent in the cerebellar white matter, with severe cerebral and corpus callosum atrophy. Molecular study with a leukodystrophy gene panela identified a homozygotic pathogenic variant on PEX 1 gene (NM_000466.3) - c.2528G>A (p.(Gly843Asp)), confirming the diagnosis of ZSD. Homozygosity for PEX1 p.Gly843Asp seems to be associated with an intermediate/milder ZSD phenotype,with survival until adulthood. Some patients develop progressive degeneration of CNS myelin, a leukodystrophy pattern, like this patient, which may lead to regression. This girl with ZSD had a rapid and severe loss of previous skills after a seizure. Even though there is no specific treatment for this disease, a correct diagnosiswas very important for the parents and for family genetic counselling.


Sigma 1 receptor activation modifies intracellular calcium exchange in the G93AhSOD1 ALS model.
Aberrations in intracellular calcium (Ca2+) have been well established within amyotrophic lateral sclerosis (ALS), a severe motor neuron disease. Intracellular Ca2+ concentration is controlled in part through the endoplasmic reticulum (ER) mitochondria Ca2+ cycle (ERMCC). The ER supplies Ca2+ to the mitochondria at close contacts between the two organelles, i.e. the mitochondria-associated ER membranes (MAMs). The Sigma 1 receptor (Sig1R) is enriched at MAMs, where it acts as an inter-organelle signaling modulator. However, its impact on intracellular Ca2+ at the cellular level remains to be thoroughly investigated. Here, we used cultured embryonic mice spinal neurons to investigate the influence of Sig1R activation on intracellular Ca2+ homeostasis in the presence of G93AhSOD1 (G93A), an established ALS-causing mutation. Sig1R expression was increased in G93A motor neurons relative to non-transgenic (nontg) controls. Furthermore, we demonstrated significantly reduced bradykinin-sensitive intracellular Ca2+ stores in G93A spinal neurons, which were normalized by the Sig1R agonist SA4503. Moreover, SA4503 accelerated cytosolic Ca2+ clearance following a) AMPAR activation by kainate and b) IP3R-mediated ER Ca2+ release following bradykinin stimulation in both genotypes. PRE-084 (another Sig1R agonist) did not exert any significant effects on cytosolic Ca2+. Both Sig1R expression and functionality were altered by the G93A mutation, indicating the centrality of Sig1R in ALS pathology. Here, we showed that intracellular Ca2+ shuttling can be manipulated by Sig1R activation, thus demonstrating the value of using the pharmacological manipulation of Sig1R to understand Ca2+ homeostasis.


Outcomes of Surgical Interventions in Primary Congenital Glaucoma Patients.
The aim was to report long-term surgical success of primary congenital glaucoma (PCG) patients in Thailand. PCG patients who underwent one of the following primary operations: trabeculotomy, goniotomy, trabeculectomy, combined trabeculotrabeculectomy (CTT) and diode transscleral cyclophotocoagulation (TSCPC) between January 1992 and January 2018 were reviewed. Surgical success was defined as intraocular pressure (IOP) between 5 and 21 mm Hg with or without antiglaucoma medications. Failure was defined as IOP ≤5 or ≥21 mm Hg for 2 consecutive visits, or when an additional glaucoma surgery was required to control IOP. Survival curves were analyzed using multilevel mixed-effect Weibull model. A total of 81 eyes from 55 PCG patients were included. Surgical procedures involved 20 goniotomies, 15 trabeculotomies, 16 trabeculectomies, 15 CTT, and 15 TSCPC. Median follow-up time was 24 months (interquartile range: 9 to 60 mo). Overall success rates were 68.8% at 1 year, 63.8% at 3 years, and 53.7% at 5 years. All types of surgery except TSCPC had comparable cumulative 1 year success rates ranging from 78.5% to 83.3%. Cumulative success rates of trabeculotomy (80.05%) and CTT (79.4%) were maintained at 3 and 5 years and were the highest among all procedures at 5 years. TSCPC had a significantly lower success rate compared with other types of surgery (hazard ratio: 7.4 to 13.1, all P=0.01). All patients receiving primary TSCPC showed no success at 48 months. Primary trabeculotomy and primary CTT demonstrated the highest long-term success rates in PCG patients.


Localization of the KRAS2 oncogene in the domestic rabbit (Oryctolagus cuniculus).
The KRAS2 gene was localized in the rabbit by chromosomal in situ hybridization, using a 3H-labeled human cDNA probe. There were 201 silver grains on 144 metaphase spreads; 12.9% of the grains resided on chromosome 16, and 54% of these grains were located close to the centromere at 16p11----q11. Statistical analysis indicated that labeling at this region represents a significant deviation from a random distribution and thus provided evidence for the assignment of KRAS2 to 16p11----q11. In addition to the predominant labeling site on 16, there was a positive signal at the telomere of 9q, possibly representing a sequence of another member of the ras family. Our assignment of KRAS2 to rabbit chromosome 16 strengthens the argument that a fragment on this chromosome is homologous to one on human chromosome 12, which bears the KRAS2 locus.


Influence of Ebola on tuberculosis case finding and treatment outcomes in Liberia.
Setting: National Leprosy and Tuberculosis (TB) Control Programme, Liberia. Objectives: To assess TB case finding, including human immunodeficiency virus (HIV) associated interventions and treatment outcomes, before (January 2013-March 2014), during (April 2014-June 2015) and after (July-December 2015) the Ebola virus disease outbreak. Design: A cross-sectional study and retrospective cohort analysis of outcomes. Results: The mean quarterly numbers of individuals with presumptive TB and the proportion diagnosed as smear-positive were: pre-Ebola (n = 7032, 12%), Ebola (n = 6147, 10%) and post-Ebola (n = 6795, 8%). For all forms of TB, stratified by category and age group, there was a non-significant decrease in the number of cases from the pre-Ebola to the Ebola and post-Ebola periods. There were significant decreases in numbers of cases with smear-positive pulmonary TB (PTB) from the pre-Ebola period (n = 855), to the Ebola (n = 640, P < 0.001) and post-Ebola (n = 568, P < 0.001) periods. The proportions of patients tested for HIV, found to be HIV-positive and started on antiretroviral therapy decreased as follows: pre-Ebola (respectively 72%, 15% and 34%), Ebola (69%, 14% and 30%) and post-Ebola (68%, 12% and 26%). Treatment success rates among TB patients were: 80% pre-Ebola, 69% Ebola (P < 0.001) and 73% post-Ebola (P < 0.001). Loss to follow-up was the main contributing adverse outcome. Conclusion: The principal negative effects of Ebola were the significant decreases in diagnoses of smear-positive PTB, the declines in HIV testing and antiretroviral therapy uptake and poor treatment success. Ways to prevent these adverse effects from recurring in the event of another Ebola outbreak need to be found.


Funding medical education: should we follow a different model to general higher education? Commentary.
There has been much recent discussion on the funding of medical education. There has also been much discussion about the funding of higher education more generally. The topics of discussion have included the rising costs of education; who should pay; the various potential models of funding; and how best to ensure maximum returns from investment. Medical education has largely followed the emerging models of funding for higher education. However there are important reasons why the funding models for higher education may not suit medical education. These reasons include the fact that medical education is as important to the public as it is to the learner; the range of funding sources available to medical schools; the strict regulation of medical education; and the fact that the privatisation and commercialisation of higher education may not been in keeping with the social goals of medical schools and the agenda of diversification within the medical student population.


Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling.
Loss-of-function (LOF) mutations in the endothelial cell (EC)-enriched gene endoglin (ENG) cause the human disease hereditary haemorrhagic telangiectasia-1, characterized by vascular malformations promoted by vascular endothelial growth factor A (VEGFA). How ENG deficiency alters EC behaviour to trigger these anomalies is not understood. Mosaic ENG deletion in the postnatal mouse rendered Eng LOF ECs insensitive to flow-mediated venous to arterial migration. Eng LOF ECs retained within arterioles acquired venous characteristics and secondary ENG-independent proliferation resulting in arteriovenous malformation (AVM). Analysis following simultaneous Eng LOF and overexpression (OE) revealed that ENG OE ECs dominate tip-cell positions and home preferentially to arteries. ENG knockdown altered VEGFA-mediated VEGFR2 kinetics and promoted AKT signalling. Blockage of PI(3)K/AKT partly normalized flow-directed migration of ENG LOF ECs in vitro and reduced the severity of AVM in vivo. This demonstrates the requirement of ENG in flow-mediated migration and modulation of VEGFR2 signalling in vascular patterning.


Patient-reported nausea after implementation of an enhanced recovery after surgery protocol for gynae-oncology patients.
This study aimed to analyze the adherence to strategies to prevent post-operative nausea and vomiting after implementation of an enhanced recovery after surgery (ERAS) protocol for gynae-oncology patients. Patient-reported nausea before and after ERAS was also studied. This prospective observational study included all patients undergoing laparotomy for a suspicious pelvic mass or confirmed advanced ovarian cancer before (pre-ERAS) and after the implementation of ERAS (post-ERAS) at Oslo University Hospital, Norway. Patients were a priori stratified according to the planned extent of surgery into two cohorts (Cohort 1: Surgery of advanced disease; Cohort 2: Surgery for a suspicious pelvic tumor). Clinical data including baseline characteristics and outcome data were prospectively collected. A total of 439 patients were included, 243 pre-ERAS and 196 post-ERAS. At baseline, 27% of the patients reported any grade of nausea. In the post-ERAS cohort, statistically significantly more patients received double post-operative nausea and vomiting prophylaxis (64% pre-ERAS vs 84% post-ERAS, p<0.0001). There was no difference in the need for rescue medication (82% pre-ERAS vs 79% post-ERAS; p=0.17) and no statistically significant difference between pre- and post-ERAS or between the surgical cohorts in patient-reported nausea of any grade on day 2. Patients who reported none/mild nausea on day 2 had significantly less peri-operative fluid administered during surgery than those who reported moderate or severe nausea (median 12.5 mL/kg/hour vs 16.5 mL/kg/hour, p=0.045) but, in multivariable analysis, fluid management did not remain significantly associated with nausea. Implementation of an ERAS protocol increased the adherence to post-operative nausea and vomiting prevention guidelines. Nausea, both before and after laparotomy, remains an unmet clinical need of gynae-oncology patients also in an ERAS program. Patient-reported outcome measures warrant further investigation in the evaluation of ERAS.


Everything About Pulse Oximetry-Part 2: Clinical Applications, Portable/Wearable Pulse Oximeters, Remote Patient Monitoring, and Recent Advances.
Purpose: Pulse oximetry is widely used in healthcare settings for both screening and continuous monitoring. In this article, it was aimed to review some aspects of pulse oximetry including clinical applications, portable devices, and recent advances in detail. Materials and Methods: The international and national reliable sources were used in the literature review for critical data analysis. A total of 31 articles including 19 prospective comparative clinical studies, 9 reviews, 1 meta-analysis, 1 retrospective study, and 1 experimental study were used for preparation of this part of the review. Results: In this part of the article, clinical applications of pulse oximeters, portable/wearable pulse oximeters, remote patient monitoring, and recent advances were all reviewed in detail. Conclusion: Pulse oximetry is a widely used and reliable noninvasive technique that provides useful information about blood oxygenation in individuals. This technique can guide oxygen therapy, reduce the occurrence of hypoxemia, and decrease the frequency of admissions to the intensive care unit, as well as arterial blood gas sampling. New multiwaveform sensors and advanced signal processing techniques can differentiate between different types of hemoglobin and may be useful for continuous measurement of total hemoglobin, as well as for detecting and providing information on blood loss and cardiac output.


Basic amino acids in the N-terminal half of the PB2 subunit of influenza virus RNA polymerase are involved in both transcription and replication.
The PB2 subunit of influenza virus RNA polymerase is known to be involved in the initiation of transcription of the virus genome via cap binding. However, other specific roles of PB2 for viral RNA synthesis are not well understood. Here, we demonstrate that basic residues, 124R, 142R, 143R, 268R and 331K/332R, in the N-terminal half of PB2 are important for the polymerase activity. Notably, R124A mutation remarkably reduced the synthesis of mRNA, cRNA and vRNA in vivo, which was in good agreement with the data obtained in vitro. Cross-linking studies suggested that a reduction of the polymerase activity in the R124A mutant was due to a significant decrease in binding to the viral RNA promoter. In the three-dimensional structure of the polymerase, 124R is visible through the NTP tunnel and is located close to the polymerase active site. We propose that 124R plays a key role in promoter binding during RNA synthesis.


Is the transfer factor a relevant tool to assess the soil-to-plant transfer of radionuclides under field conditions?
The radiological impact of radionuclides released to the terrestrial environment is usually predicted with mathematical models in which the transfer of radionuclides from soil to the plant is described with the transfer factor (TF). This paper questions the validity of the protocols proposed by the International Atomic Energy Agency to measure TF in the field and in greenhouses conditions. We grew maize (Zea mays L.) both in the field after a surface application of radionuclides ((54)Mn, (57)Co, (65)Zn, and (134)Cs) and in a greenhouse with the same soil that has received the same fertilization and that had been previously sieved and homogeneously labeled with the same radionuclides before being repacked in pots. The analysis of the displacement of radionuclides in the field soil profile showed a higher concentration of the surface-applied radionuclides in the preferential flow path (PFP) in comparison to the soil matrix indicating that they infiltrated heterogeneously in the soil profile due to the structure-induced non-uniform water flow. A significantly higher recovery of (57)Co and (134)Cs was observed in the plants grown in the field soil, whereas no differences in the recovery of (54)Mn and (65)Zn between the two experiments were detected. These results suggest that (i) under field conditions the soil-to-plant transfer of radionuclides that co-exist as stable elements present at low concentrations in the soil and in the plant is higher than that measured under greenhouse conditions and (ii) the implicit assumption made when calculating the TF (that radionuclides are homogeneously distributed in the soil profile) is not valid, thereby preventing the calculation of an average concentration to obtain the TF parameter.


Ribulose-1,5-bisphosphate carboxylase/oxygenase from Zea mays: amino-acid sequence of the small subunit.
The amino-acid sequence of the small subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase from Zea mays has been determined by alignment of peptides generated by digestion with trypsin, chymotrypsin, staphylococcal protease and thermolysin. The protein-chemically determined structure is in complete agreement with the nucleotide-derived sequence as published recently (Matsuoka et al. (1987) J. Biochem. 102, 673-676), but in addition possesses, however, sixteen experimentally verified dimorphies at various positions and possibly nine more for which evidence is tentatively pointing to two (or more) different expressed nuclear genes for the small subunit. These protein dimorphies represent a protein family corresponding to a gene family, the components of which have not been separated. The closest homologous polypeptide is the small subunit from wheat.


Lymphotoxin-alphabeta heterotrimers are cleaved by metalloproteinases and contribute to synovitis in rheumatoid arthritis.
Tumor necrosis factor-superfamily (TNF-SF) members, lymphotoxin (LT)-alpha and LTbeta, are proinflammatory cytokines associated with pathology in rheumatoid arthritis. LTalpha3 homotrimers are secreted, whereas LTalpha(1)beta(2) heterotrimers are expressed on the surface of activated lymphocytes. As many TNF-SF members are actively cleaved from cell membranes, we determined whether LTalphabeta heterotrimers are also cleaved, and are biologically active in rheumatoid arthritis (RA) patients. LTalphabeta heterotrimers were detected in culture supernatants from activated human T-helper (Th) 0, Th1, and Th17 cells, together with LTalpha3 and TNFalpha. The heterotimers were actively cleaved from the cell surface by ADAM17 metalloproteinase (MMP) and MMP-8, and cleavage was inhibited by TAPI-1, a TNF-alpha converting enzyme (TACE) inhibitor. Soluble LTalphabeta was detected in serum from both normal donors and RA patients, and was elevated in synovial fluid from RA patients compared to osteoarthritis (OA) patients. Levels of LTalphabeta in RA patient synovial fluid correlated with increased TNFalpha, IL-8, IL-12, IL-1beta, IFN-gamma, and IL-6 cytokines. Moreover, recombinant LTalpha1beta2-induced CXCL1, CXCL2, IL-6, IL-8, VCAM-1, and ICAM-1 from primary synovial fibroblasts isolated from RA patients. Therefore, soluble LTalphabeta in synovial fluid is associated with a proinflammatory cytokine milieu that contributes to synovitis in RA.


[Clinical application of retrosigmoid approach for BONEBRIDGE implantation after auricle reconstruction using expanded postauricular flap].
Objective: To explore the safety and reliability of retrosigmoid approach BONEBRIDGE implantation in patients with auricle reconstruction using skin expansion flap. Methods: A retrospective analysis was conducted on 43 congenital aural atresia cases (43 ears) who underwent BONEBRIDGE implantation from September 2019 to January 2023 in Beijing Tongren Hospital. 30 males and 13 females were included in this work. The implantation age was 9-36 years old (median age=10 y/o). All cases underwent auricle reconstruction surgery using the posterior ear flap expansion method, with 36 cases using the single expanded postauricular flap method and 7 cases using two-flap method. BONEBRIDGE implant surgery was performed during the third stage of auricle reconstruction or after all stages. The hearing improvements were evaluated by comparing the changes in pure tone hearing threshold and speech recognition rate of patients before and after BONEBRIDGE implantation. Routine follow-up was conducted to observe the hearing results and complications. SPSS 14.0 software was applied for data statistical analysis. Results: All 43 patients healed well and had no surgical complications when discharge. The average bone conduction hearing threshold after surgery was (8.2±6.6) dBHL, and there was no statistically significant difference compared to the preoperative [(8.1±5.7) dBHL] (P=0.95). After surgery, the threshold of hearing assistance with power on was significantly lower than that without hearing assistance [(32.8±4.6) dBHL vs (60.5±5.5) dBHL], and the difference was statistically significant (P<0.001). The speech recognition rate of monosyllable words, disyllabic words and short sentences in quiet environment increased to 72%, 84%, and 98% respectively. The differences were statistically significant (P<0.001). The speech recognition rate of monosyllabic words, disyllabic words, and short sentences in noise environment was significantly increased by 70%, 80%, and 92% respectively (P<0.001). After a follow-up of 4 to 47 months (median=24 months), the hearing results were stable and the aesthetic outcomes were satisfying. One patient had delayed hematoma around coil of the implant. After aspiration and compressed dressing for one week, hematoma was not recurrent. Conclusion: For patients after auricle reconstruction using expanded postauricular flap, the preference of retrosigmoid approach is a good choice in terms of safety and reliability of operation, as well as aesthetic appearance.


Computer Modelling of Wrist Biomechanics: Translation into Specific Tasks and Injuries.
The carpus is a complicated and functionally challenged mechanical system, advancements in the understanding of which have been compromised by the recognition that there is no standard carpal mechanical system and no typical wrist. This paper covers components of a larger project that seeks to develop a kinetic model of wrist mechanics to allow reverse analysis of the specific biomechanical controls or rules of a specific patient's carpus. Those rules, unique to each patient, could be used to create a forward synthesis mathematical model to reproduce the individual's anatomical motion in a virtual environment. Based on the previous observations, the carpus essentially moves with only two degrees of freedom-pitch (flexion/extension) and yaw (radial deviation/ulnar deviation)-while largely preventing roll (pronation/supination). The objective of this paper is, therefore, to present the background and justification to support the rules-based motion (RBM) concept, which states that the motion of a mechanical system, such as the wrist, is the net interplay of four rules: morphology, constraint, interaction, and load. The stable central column theory (SCCT) of wrist mechanics applies the concept of RBM to the carpus, and by using a reverse engineering computational analysis model, a consistent pattern of isometric constraints was identified, creating a "two-gear four-bar" linkage. This study assessed the motion of the carpus using a 3D (three-dimensional) dynamic visualization model. The hypothesis was that the pattern and direction of motion of the proximal row and the distal row with respect to the immediately cephalad carpal bones or radius would be similar in all directions of wrist motion. To identify the unique motion segments, 3D models were created from five normal wrists that underwent CT scanning in multiple positions of radial and ulnar deviation as well as flexion and extension. Each carpal row (proximal and distal) was animated in a virtual environment with the cephalad carpal bones or radius held immobile. The rotational axis and position of each bone and each row were then compared in sagittal (flexion-extension) and coronal (radial and ulnar deviation) motion. The carpus appeared to have only two degrees of freedom, and yet was stable in those arcs with the loads applied proximally in the forearm. The proximal row moved in a singular arc, but with a varying extent during sagittal and coronal motion. The isometric constraints were consistent in both directions. The distal row moved on an axis formed by a pivot joint laterally (between the trapezium and scaphoid) and a saddle joint medially (between hamate and triquetrum). The sagittal and coronal alignment of this axis changed as the proximal row moved. This created a distinct pattern of row motion to achieve the various required positions of wrist function. On wrist radial deviation, the scaphoid (with the proximal row) was flexed and the distal row was extended, whereas, in wrist flexion, the scaphoid flexed (with the proximal row) and so did the distal row. The pattern was reversed in the opposite wrist movements. While the general direction of motion of each row was consistent, the extent was quite variable. This review supports the SCCT of carpal mechanics and the carpus acting as a twogear four-bar linkage, as well as the concept of RBM as a means to understand the biomechanics of the wrist, and how this is translated into specific functional tasks. More sophisticated 3D modelling will be required to further understand the specifics of carpal motion; however, reverse engineering of the specific rules that define each individual wrist can also be applied to a mathematical model to provide a "what if" test of particular surgical interventions for a variety of wrist injuries. The use of quantitative 3D Computed Tomography Scan (CT) analysis, surgical planning and virtual surgical intervention allows potential surgical solutions to be applied to a computer model of an injured wrist to test the possible outcomes and prognosis of a proposed treatment.


[Is a history of hypnosis possible?].
One cannot develop the history of a scientific object called "hypnosis" without investigating its historicity and, at the same time, its scientific status. We cannot elaborate one, but several accounts, corresponding to the different strategies of time, according to whether one holds the position of science historian, historian, historian of ideas, psychologist, or psychoanalyst.


Urological management of indinavir-associated acute renal failure in HIV-positive patients.
Indinavir, a protease inhibitor that is commonly used to treat HIV infection, may cause crystal formation within the renal tubules when urine pH is above 3.5. Crystallization in the urine may lead to intrarenal crystal deposition and acute renal failure (ARF). To establish the beneficial urological management of acute renal failure caused by indinavir treatment of HIV/AIDS patients. Five HIV positive patients (four men, one woman) with a mean age of 32 years (range 28-36 years) were referred to our Department of Urology from an AIDS outpatient Clinic, because of the development of postrenal acute renal failure with continuously elevated creatinine and urea plasma levels after indinavir therapy. Among the initial therapeutic maneuvers, indinavir administration was interrupted for 1 week while bilateral double-J ureteral stents were inserted in all the HIV/AIDS patients, during the first 24-72 h to secure upper-tract drainage. Concurrently urine has been acidified by oral administration of the amino acid L: -methionine and oral fluid intake was increased. All the patients responded well to the treatment and their renal function was effortlessly restored to normal within a few days. HIV-positive patients receiving indinavir therapy might be complicated by acute renal failure, mainly due to intrarenal crystal deposition (tubules) or urolithiasis (postrenal obstruction). This adverse effect may simply manage by the discontinuation of indinavir administration, urine acidification, as well as the possible early insertion of bilateral double-J ureteral stents.


Distribution, Fate, Inhalation Exposure and Lung Cancer Risk of Atmospheric Polycyclic Aromatic Hydrocarbons in Some Asian Countries.
A large-scale monitoring program, the Asia Soil and Air Monitoring Program (Asia-SAMP), was conducted in five Asian countries, including China, Japan, South Korea, Vietnam, and India. Air samples were collected using passive air samplers with polyurethane foam disks over four consecutive 3-month periods from September 2012 to August 2013 to measure the seasonal concentrations of 47 polycyclic aromatic hydrocarbons (PAHs), including 21 parent and 26 alkylated PAHs, at 176 sites (11 background, 83 rural, and 82 urban). The annual concentrations of total 47 PAHs (∑47PAHs) at all sites ranged from 6.29 to 688 ng/m(3) with median of 82.2 ng/m(3). Air concentrations of PAHs in China, Vietnam, and India were greater than those in Japan and South Korea. As expected, the air concentrations (ng/m(3)) were highest at urban sites (143 ± 117) followed by rural (126 ± 147) and background sites (22.4 ± 11.4). Significant positive correlations were found between PAH concentrations and atmosphere aerosol optical depth. The average benzo(a)pyrene equivalent concentration (BaPeq) was 5.61 ng/m(3). It was estimated that the annual BaPeq concentrations at 78.8% of the sampling sites exceeded the WHO guideline level. The mean population attributable fraction (PAF) for lung cancer due to inhalation exposure to outdoor PAHs was on the order 8.8‰ (0.056-52‰) for China, 0.38‰ (0.007-3.2‰) for Japan, 0.85‰ (0.042-4.5‰) for South Korea, 7.5‰ (0.26-27‰) for Vietnam, and 3.2‰ (0.047-20‰) for India. We estimated a number of lifetime excess lung cancer cases caused by exposure to PAHs, which the concentrations ranging from 27.8 to 2200, 1.36 to 108, 2.45 to 194, 21.8 to 1730, and 9.10 to 720 per million people for China, Japan, South Korea, Vietnam, and India, respectively. Overall, the lung cancer risk in China and Vietnam were higher than that in Japan, South Korea, and India.


Understanding the mechanism of action of poly(amidoamine)s as endosomolytic polymers: correlation of physicochemical and biological properties.
Bioresponsive poly(amidoamine)s (PAA)s are currently under development as endosomolytic polymers for intracellular delivery of proteins and genes. Here for the first time, small-angle neutron scattering (SANS) is used to systematically investigate the pH-dependent conformational change of an endosomolytic polymer, the PAA ISA 23. The radius of gyration of the ISA23 was determined as a function of pH and counterion, the aim being to correlate changes in polymer conformation with membrane activity assessed using a rat red blood cell haemolysis assay. With decreasing pH, the ISA23 radius of gyration increased to a maximum (R(g) approximately 80 A) around pH = 3, before subsequently decreasing once more. At high pH and therefore high ionic strengths, the polymer is negatively charged and adopts a rather compact structure (R(g) approximately 20 A), presumably with the dissociated carboxylic groups on the exterior of the polymer coil. At low pH, the coil again collapses (R(g) < 20 A), presumably due to the effects of the high ionic strength. It is concluded that the nature of the salt form has no direct bearing on the size of the polymer coil, but it does indirectly determine the prevailing pH and, hence, polymer conformation. Pulsed-gradient spin-echo NMR measurements were in good agreement with the SANS estimates of the radius of gyration, although ISA23 polydispersity does complicate the data interpretation/comparison. These results support the proposed mode of action of PAAs, namely a coil expansion on passing from a neutral pH (extracellular) to an acidic pH (endosomal and lysosomal) environments. The results do, however, suggest that the charge on the polymer shows a closer correlation with the haemolysis activity rather than the polymer conformation.


Metformin improves fibroblast metabolism and ameliorates arthrofibrosis in rats.
Emerging studies have suggested an essential role of fibroblast metabolic reprogramming in the pathogenesis of arthrofibrosis. The metabolic modulator metformin appears to be a therapeutic candidate for fibrotic disorders. However, whether metformin could alleviate arthrofibrosis has not been defined. In this study we have determined if treatment with metformin has beneficial effect on arthrofibrosis and its underlying mechanism. Articular capsule samples were collected from patients with/without arthrofibrosis to perform gene and protein expression analysis. Arthrofibrosis animal model was established to examine the anti-fibrotic effect of metformin. Cell culture experiments were conducted to determine the mechanism by which metformin inhibits fibroblast activation. We found that glycolysis was upregulated in human fibrotic articular capsules. In an arthrofibrosis animal model, intra-articular injection of metformin mitigated inflammatory reactions, downregulated expression of both fibrotic and glycolytic markers, improved range of motion (ROM) of the joint, and reduced capsular fibrosis and thickening. At the cellular level, metformin inhibited the activation of fibroblasts and mitigated the abundant influx of glucose into activated fibroblasts. Interestingly, metformin prompted a metabolic shift from oxidative phosphorylation to aerobic glycolysis in activated fibroblasts, resulting in the anti-fibrotic effect of metformin. Metformin decreased glycolysis, causing a metabolic shift toward aerobic glycolysis in activated fibroblasts and has beneficial effect on the treatment of arthrofibrosis.The translational potential of this article: The findings of this study demonstrated the therapeutic effect of metformin on arthrofibrosis and defined novel targets for the treatment of articular fibrotic disorders.


Pulsed EPR studies of a bacterial sulfite-oxidizing enzyme with pH-invariant hyperfine interactions from exchangeable protons.
Variable-frequency pulsed electron paramagnetic resonance studies of the molybdenum(V) center of sulfite dehydrogenase (SDH) clearly show couplings from nearby exchangeable protons that are assigned to a Mo(V)OH(n) group. The hyperfine parameters for these exchangeable protons of SDH are the same at both low and high pH and similar to those for the high-pH forms of sulfite oxidases (SOs) from eukaryotes. The SDH proton parameters are distinctly different from the low-pH forms of chicken and human SO.


Conventional sunscreen application does not lead to sufficient body coverage.
This study aimed to assess sunscreen application habits and relative body coverage after single whole body application. Fifty-two healthy volunteers were asked to use the test product once, following their usual sunscreen application routine. Standardized UV photographs, which were evaluated by Image Analysis, were conducted before and immediately after product application to evaluate relative body coverage. In addition to these procedures, the volunteers completed an online self-assessment questionnaire to assess sunscreen usage habits. After product application, the front side showed significantly less non-covered skin (4.35%) than the backside (17.27%) (P = 0.0000). Females showed overall significantly less non-covered skin (8.98%) than males (13.16%) (P = 0.0381). On the backside, females showed significantly less non-covered skin (13.57%) (P = 0.0045) than males (21.94%), while on the front side, this difference between females (4.14%) and males (4.53%) was not significant. In most cases, the usual sunscreen application routine does not provide complete body coverage even though an extra light sunscreen with good absorption properties was used. On average, 11% of the body surface was not covered by sunscreen at all. Therefore, appropriate consumer education is required to improve sunscreen application and to warrant effective sun protection.


Immune tolerance induction with highly purified plasma-derived factor VIII containing von Willebrand factor in hemophilia A patients with high-responding inhibitors.
We retrospectively evaluated the efficacy of immune tolerance induction (ITI) in a homogenous cohort of eight patients with constitutive severe hemophilia A with high-responding factor VIII (FVIII) inhibitors using Facteur VIII-LFB/Factane, a highly purified FVIII concentrate containing von Willebrand factor (VWF).


[Genetics analysis of microsatellite instability in patients from hereditary nonpolyposis colorectal cancer (HNPCC) families].
Microsatellite instability (MSI) is due to defective DNA mismatch repair and is characteristic of HNPCC tumours. The role of MSI in familial predisposition to colorectal cancer was investigated in this study by microsatellite analysis among familial cases. PCR-based microsatellite analysis was performed in blood obtained from 30 members from HNPCC families. Blood samples age matched healthy individuals (n = 28) served as control. MSI was studied at five loci containing single- or dinucleotide repeat sequences and mapping to different chromosomal locations: BAT-25 (at locus 4q12), BAT-26 (2p16), D2S123 (2p16-p21), D5S346 (5q21-q22) and D17S250 (17q11.2-q12). MSI frequency was higher in member of HNPCC families (40%) than in control (10.7%) cases. Out of the 30 samples tested, 12 were found to be MSI positive, 9 MSI high and 3 MSI low. The present study suggest that microsatellite instability seem to be a risk factor of colorectal cancer in subjects belonged to HNPCC families with high incidence of this cancer.


Primary care access decreases nonurgent hospital visits for indigent diabetics.
The objective was to determine the relationship between the source of primary care and utilization of health services among public hospital walk-in clinic patients. A group of 218 adults with diabetes mellitus presenting to a walk-in hospital clinic was followed prospectively with baseline and 3-, 6-, and 12-month surveys; baseline and 6-month hemoglobin A1Cs; and chart reviews. Sites of care, acquisition of primary care, and report of four diabetes services were recorded. Individuals with a visit to a primary care site by 3 months after enrollment had more primary care visits and fewer walk-in clinic visits over the subsequent 9 months than those without one. Those with a primary care visit within 3 months of enrollment received more of the four diabetes services during the study year than those without. Access to primary care was associated with decreased utilization of nonurgent episodic care services and better quality of diabetes care.


Ethnic differences in renal responses to furosemide.
Blacks have a greater tendency to retain Na than whites. The present study sought evidence for ethnic differences in parameters reflective of Na uptake by the Na,K,2Cl cotransporter in the thick ascending limb, namely, the urine concentration and urinary excretion of certain cations before and after furosemide administration (40 mg IV). Subjects were healthy (ages 18 to 36 years). During the preceding overnight period, urine volume was lower, and osmolality was higher in blacks than in whites, an ethnic difference that disappeared when water intake was restricted to infused normal saline (60 mL/h). Plasma vasopressin levels were higher in black males than in other sex/ethnic groups. Baseline urinary excretion rates of K, Ca, and Mg were significantly lower in blacks than in whites. After furosemide (0 to 1 hour), K and Ca excretion rates increased, but the proportionate ethnic difference decreased from 44% to 22% and from 22% to 10%, respectively, consistent with blacks having more basal Na,K,2Cl cotransporter activity to inhibit. During a later postfurosemide period (1 to 5 hours), urinary concentrations of Ca and Mg recovered more slowly in blacks, consistent with greater reuptake in the thick ascending limb. In summary, there were distinct ethnic differences in renal handling of Ca and Mg basally and in response to furosemide that were consistent with a more active Na,K,2Cl cotransporter in the thick ascending limb in blacks. An increase in vasopressin levels appeared to explain greater urine concentrations in black males but not black females.


Pre- and post-weaning scours in southeastern Australia: A survey of 22 commercial pig herds and characterisation of Escherichia coli isolates.
Diarrhoeal diseases in piglets caused by Escherichia coli are responsible for substantial losses each year in the Australian pig industry. A cross-sectional survey was conducted (September 2013-May 2014) across 22 commercial pig herds located in southeastern Australia: NSW (n = 9); VIC (n = 10); and SA (n = 3), to estimate the prevalence of E. coli associated diarrhoea in pre- and post-weaned piglets and to identify key risk factors associated with E. coli disease. A questionnaire on management and husbandry practices was included. Faecal samples (n = 50 from each herd) were tested for the presence of β-haemolytic E. coli. Species level identification was confirmed by matrix-assisted laser desorption / ionisation time-of-flight mass spectrometry (MALDI-TOF/MS). ETEC virulence and enterotoxin genes (F4, F5, F6, F18, F41, STa, STb and LT) were screened for by multiplex PCR. This study assessed 60 potential risk factors for E. coli disease in post-weaned piglets, with 2 key factors-recent disease events and the presence of bedding, statistically associated with the presence of post-weaning scours. The prevalence of diarrhea in pre-weaned pens was 17% (16/93), compared with 24% (24/102) in post-weaned pens. The most prevalent β-haemolytic ETEC genes were F18 (32%) and STb (32%) but isolates were more likely to contain F4:STb (11 of 22 herds, 23%), than F18:STb (5 of 22 herds, 6%). These findings indicate that recent disease events that have occurred within the last 12 months, and by the use of bedding or not maintaining fresh bedding can have significant impacts on piglet diarrhoea.


Suggestive evidence of a multi-cytokine resistin pathway in humans and its role on cardiovascular events in high-risk individuals.
In cells and tissues resistin affects IL-1β, IL-6, IL-8, IL-12 and TNF-α expression, thus suggesting the existence of a multi-cytokine "resistin pathway". We investigated whether such pathway does exist in humans and, if so, if it is associated with cardiovascular risk factors and with major adverse cardiovascular events (MACE). Serum cytokines were measured in 280 healthy subjects from the Gargano Study 2 (GS2) whose BMI, waist circumference, HOMAIR, triglycerides, HDL-cholesterol, systolic and diastolic blood pressure data were available and in 353 patients with type 2 diabetes and coronary artery disease from the Gargano Heart Study (GHS)-prospective design (follow-up 5.4 ± 2.5 years; 71 MACE). In GS2, cytokines mRNA levels in white blood cells were also measured. In GS2, resistin mRNA was correlated with all cytokines expression (all p < 0.001), but IL-12B. Consistently, serum resistin was correlated with all serum cytokines (all p < 0.001), but IL-12. Expression (eRPS) and serum (sRPS) resistin pathway scores (excluding IL-12) were each other correlated (p < 0.001) and both associated with cardiovascular risk factors (all p < 0.01). In GHS, sRPS was independently associated with MACE (HR = 1.44, 95% CI = 1.10-1.90). Our data indicate the existence of a resistin pathway, which is associated with cardiovascular risk factors and which strongly and independently predicts MACE.


Efficacy of Juzentaihoto for Tumor Immunotherapy in B16 Melanoma Metastasis Model.
Introduction. Medical care for Japanese cancer patients includes Western and Kampo medicines, and treatments with juzentaihoto (JTT) reportedly prevent cancer metastasis and recurrence. In this study, we examined the effects of JTT on natural killer (NK) cell activity and metastasis in combined treatments with anti-PD-1 antibody in a mouse model of melanoma metastasis. Methods. C57BL/6 male mice were intravenously injected with B16 melanoma cells (B16 cell) and were given chow containing 3% JTT. In subsequent in vivo experiments, we assessed serum cytokine levels and tumor colony formation in the lungs. Additionally, we assessed NK cell activity in ex vivo experiments. Results. JTT significantly suppressed B16 cell metastasis, whereas injection of anti-asialo-GM1 antibody into mice abrogated the inhibitory actions of JTT. JTT significantly increased interleukin- (IL-) 12 and interferon- (IFN-) γ levels in serum and induced NK cell activity. It increased the inhibitory actions of the anti-PD-1 antibody on B16 cell metastasis. Discussion. These data suggest that JTT inhibits B16 cell metastasis by inducing NK cell activity. Additionally, combination therapy with JTT and anti-PD-1 antibody increased treatment response rates for B16 melanoma.


Angina pectoris after recovery from an acute coronary event--the role of psychological factors in Japanese vs North American patients.
To determine whether specific psychological characteristics are associated with angina pectoris in clinically stable patients 1 to 6 months after recovery from an acute coronary event, a battery of tests was administered to 92 Japanese and 646 North American participants (22% females) in the Multicenter Study of Myocardial Ischemia. Of these 738 patients, 541 had originally suffered acute myocardial infarction, 188 had unstable angina, and 9 were admitted for other acute ischemic events. At the time of enrollment, an average of 2.7 months after the index event, 205 patients reported having had anginal symptoms during the preceding months. Compared to those who did not report angina, these patients scored higher on a modified Autonomic Perception Questionnaire (p = 0.04) and lower on the Internal Health Locus of Control Scale (p = 0.004). These differences were generalized across the Japanese and North American cohorts. These results indicate that in these patients, angina pectoris was associated with an increased awareness of a wide range of physical symptoms and a decreased sense of personal control over one's own health and prognosis.


Effect of microstructure on thermal conductivity of Cu, Ag thin films.
Thin film type materials are widely used in modern industries, such as semiconductor devices, functional superconductors, machining tools, and so on. The thermal properties of material in semiconductor are very important factors for stable operation because the heat generated during device operation may increase clock frequency. Even though thermal properties of thin films may play a major role in assessing reliability of parts, the measurement methods of thin film thermal properties are generally known to be complex to devise. In this study, a temperature distribution method was applied for the measurement of thermal conductivity of Cu and Ag thin film on borosilicate glass substrate. Cu and Ag thin films were deposited on borosilicate glass using thermal evaporation processes. To measure the thermal conductivity changes according to the microstructure of metallic thin film, the processing variables for the Cu and Ag thin film deposition were changed. To minimize the effect of film thickness, the film thickness was fixed to the thickness of approximately 500 nm throughout experiments. The thermal conductivities of thin films were measured to be much lower than those of bulk materials. Thin film with larger grain size showed higher thermal conductivity probably due to the lower number density of grain boundary. Weidman-Franz law could be applied to thin films produced in this study. Thermal conductivity was also estimated from the resistivity of thin film and Lorenz number of bulk material.


Influence of protein formulation and carrier solution on asymmetrical flow field-flow fractionation: a case study of the plant-produced recombinant anthrax protective antigen pp-PA83.
Asymmetrical flow field-flow fractionation (afFFF) was used to investigate the properties of a plant-produced anthrax toxin protective antigen, pp-PA83. The afFFF fractogram consisted of two main peaks with molar masses similar to the molecular mass of pp-PA83 monomer. afFFF carrier solutions strongly influenced the ratio and the intensity of the two main peaks. These differences indicate that conformation changes in the pp-PA83 molecule occurred during the afFFF analysis. Similar fractograms were obtained for different pp-PA83 formulations when the afFFF carrier solution and the protein formulation were the same (or very similar). The data show that in specific cases, afFFF could be used to study protein conformation and document the importance of studying the influence of the carrier solution on afFFF.


Combination of BMP-2 and 5-AZA is advantageous in rat bone marrow-derived mesenchymal stem cells differentiation into cardiomyocytes.
Bone morphogenetic protein-2 (BMP-2) has a crucial role in the development of cardiogenesis, and is used in inducing bone marrow mesenchymal stem cells (BMMSCs) to differentiate into cardiomyocytes. We have examined a combination of BMP-2 and 5-azacytidine (5-AZA) in inducing these differentiation effects. BMMSCs were collected and purified from bone marrow of 4-week-old Sprague-Dawley (SD) rats by density-gradient centrifugation and differential attachment. The fourth passage subculture of BMMSCs, selected by cytometry for purity and identification, was divided into four groups: a control group, BMP-2 treated, 5-AZA treated, and a combination of BMP-2 and 5-AZA treatment. Expression of cardiac Troponin I (cTnI) and Connexin 43 (CX-43) in BMMSCs after induction were detected by immunofluorescence and Western blot. Flow cytometry analysis was used for differentiation rates and apoptosis of induced BMMSCs, through the expression of cardiac Troponin T (cTnT) and Annexin V-FITC & PI kit, respectively. BMP-2 can ameliorate apoptosis of BMMSCs caused by 5-AZA and promote the differentiation of BMMSCs into cardiomyocyte-like cells. Thus a combination of BMP-2 and 5-AZA can significantly improve the cardiac differentiation with fewer cell damage effects, making it a safe and effective method of induction in vitro.


Effects of pH and corn steep liquor variability on mannitol production by Lactobacillus intermedius NRRL B-3693.
Lactobacillus intermedius NRRL B-3693 produced mannitol, lactic acid, and acetic acid when grown on fructose at 37 degrees C. The optimal pH for mannitol production from fructose by the heterofermentative lactic acid bacterium (LAB) in pH-controlled fermentation was at pH 5.0. It produced 160.7 +/- 1.1 g mannitol in 40 h with a volumetric productivity of 4.0 g l(-1) h(-1) in a simplified medium containing 250 g fructose, 50 g corn steep liquor (CSL), and 33 mg MnSO(4) per liter. However, the mannitol production by the LAB was severely affected by the variability of CSL. The supplementation of CSL with soy peptone (5 g/l), tryptophan (50 mg/l), tryptophan (50 mg/l) plus tyrosine (50 mg/l), or commercial protease preparation (2 ml/100 g of CSL) enhanced the performance of the inferior CSL and thus helped to overcome the nutrient limitations.


Enhanced Label-Free Nanoplasmonic Cytokine Detection in SARS-CoV-2 Induced Inflammation Using Rationally Designed Peptide Aptamer.
Rapid and precise serum cytokine quantification provides immense clinical significance in monitoring the immune status of patients in rapidly evolving infectious/inflammatory disorders, examplified by the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. However, real-time information on predictive cytokine biomarkers to guide targetable immune pathways in pathogenic inflammation is critically lacking, because of the insufficient detection range and detection limit in current label-free cytokine immunoassays. In this work, we report a highly sensitive localized surface plasmon resonance imaging (LSPRi) immunoassay for label-free Interleukin 6 (IL-6) detection utilizing rationally designed peptide aptamers as the capture interface. Benefiting from its characteristically smaller dimension and direct functionalization on the sensing surface via Au-S bonding, the peptide-aptamer-based LSPRi immunoassay achieved enhanced label-free serum IL-6 detection with a record-breaking limit of detection down to 4.6 pg/mL, and a wide dynamic range of ∼6 orders of magnitude (values from 4.6 to 1 × 106 pg/mL were observed). The immunoassay was validated in vitro for label-free analysis of SARS-CoV-2 induced inflammation, and further applied in rapid quantification of serum IL-6 profiles in COVID-19 patients. Our peptide aptamer LSPRi immunoassay demonstrates great potency in label-free cytokine detection with unprecedented sensing capability to provide accurate and timely interpretation of the inflammatory status and disease progression, and determination of prognosis.


Molecular aspects in HPV-dependent laryngeal and oropharyngeal carcinoma.
Human papillomavirus (HPV)-mediated cervical carcinogenesis represents a well analyzed model of viral implication in epithelial malignant transformation. Mechanisms of high risk (HR) HPV-related infection seem to demonstrate a similar action regarding its implication in head and neck (HN) carcinomas, predominantly in squamous cell carcinoma (SCC) histological type. The prevalence of HR HPV subtypes - mainly HPV16 - is characterized by a broad geographic heterogeneity. Furthermore, HPV-associated HNSCCs demonstrate differences regarding sexual, molecular, epidemiological, and prognostic features compared to alcohol and tobacco dependent ones. Based on these differences, HPV-derived HNSCC appear to be a specific well-defined entity mostly affecting young to middle-aged - male mainly - non-smokers. This is a strong reason of detecting an increased HR-HPV DNA levels -due to viral transmission - in oropharyngeal and laryngeal anatomic regions. Additionally, different response rates to chemoradiation and targeted therapeutic regimens are another significant field for handling these SCC malignancies in the corresponding patients. In the current special article we explored the role of HPV-related carcinogenesis in oropharyngeal and laryngeal SCC focused on the latest molecular aspects.


Cryogenic Preamplifiers for Magnetic Resonance Imaging.
Pursuing the ultimate limit of detection in magnetic resonance imaging (MRI) requires cryogenics to decrease the thermal noise of the electronic circuits. As cryogenic coils for MRI are slowly emerging cryogenic preamplifiers are required to fully exploit their potential. A cryogenic preamplifier operated at 77 K is designed and implemented for C imaging at 3 T (32.13 MHz), using off-the-shelves components. The design is based on a high electron mobility transistor (ATF54143) in a common source configuration. Required auxiliary circuitry for optimal cryogenic preamplifier performance is also presented consisting of a voltage regulator (noise free supply voltage and optimal power consumption), switch, and trigger (for active detuning during transmission to protect the preamplifier). A gain of 18 dB with a noise temperature of 13.7 K is achieved. Performing imaging experiments in a 3 T scanner showed an 8% increased signal-to-noise ratio from 365 to 399 when lowering the temperature of the preamplifier from 296 to 77 K while keeping the coil at room temperature. This paper thus enables the merger of cryogenic coils and preamplifiers in the hopes of reaching the ultimate limit of detection for MRI.


Colonoscopy performed by a family physician. A case series of 751 procedures.
Colonoscopy, including biopsy and polypectomy, is a procedure not commonly performed by primary care physicians. The purpose of this research was to present a large case series of colonoscopic procedures performed by a family physician in a rural practice. A chart review of every colonoscopy procedure performed by a family physician over a 7-year period determined the demographic characteristics, indications, findings, and complications for each procedure. A total of 751 colonoscopies were performed on 555 patients (347 women and 208 men), with a mean age of 53.8 years. In 91.5% of procedures, the cecum was intubated. The most common indications for colonoscopy were bleeding (49.9%), polyp follow-up (20.9%) abdominal pain (11.7%), diarrhea (11.6%), and abnormal findings on flexible sigmoidoscopy (8.4%). Three hundred sixteen benign polyps were discovered and removed by either biopsy or polypectomy. There were 184 adenomatous colorectal polyps found in 134 (17.8%) colonoscopies. Of these 184 adenomatous polyps, 106 (58%) were potentially within reach of the flexible sigmoidoscope. Only three adenocarcinomas were discovered during the entire study period. There was only one major procedural complication: a patient experienced blood oozing from a polypectomy stump; cautery stopped the bleeding, and the patient was hospitalized overnight, with no further intervention or transfusion required. There were five other self-limited complications, including adverse reactions to sedation and infiltration at the intravenous site. Colonoscopy with polypectomy that was safely and competently performed in a solo rural practice adds to the evidence that experienced family physicians can provide this important service to their community.


Living with a peripherally inserted central catheter: the perspective of cancer outpatients-a qualitative study.
The aim of this study was to describe the experience of using a peripherally inserted central catheter (PICC) in cancer sufferers receiving outpatient treatment. A qualitative, phenomenological study was performed. Purposeful sampling methods were used. Data collection methods included semi-structured interviews and researcher field notes. Thematic analysis was used to analyze data. The study was conducted following the Consolidated Criteria for Reporting Qualitative Research guidelines. Eighteen patients (61% women, mean age 58 years) participated. They spent a mean duration of 155 days with the line in place. Two themes were identified with different subgroups. The theme "Living with a PICC line," including the subthemes "Benefits" and "Disadvantages," displays how the implantation is experienced by patients in a dichotomous manner. This highlighted both the beneficial and negative aspects of the implantation. The second theme was "Adapting to life with the catheter" and comprised three subthemes: "Advantages," "Lifestyle modifications," and "Overall assessment of the peripherally inserted central catheter," which shows how patients gradually accept the catheter by adapting their lifestyle. Over time, most patients considered having a PICC line to be a positive experience that they would recommend to other patients, as they found that it did not alter their quality of life. These results can be applied in Oncology Units for developing specific protocols for patients.


Optimization of in vitro conditions for bovine subcutaneous and intramuscular preadipocyte differentiation.
The objective of these experiments was to develop an in vitro cell culture system for differentiation of bovine preadipocytes, which will permit examination of differences in differentiation between intramuscular (i.m.) and subcutaneous (s.c.) bovine preadipocytes. Stromal-vascular cells from bovine i.m. and s.c. adipose depots were isolated and cultured. Clonally derived s.c. preadipocytes were used to determine the ability of insulin, bovine serum lipids, octanoate, acetic acid, dexamethasone (DEX), and troglitazone (TRO) to elicit differentiation of these cells when added to serum-free medium. Addition of 10 and 20 microL/mL of a commercially available serum lipids supplement to low-glucose Dulbecco's modified Eagle's medium containing 280 nM insulin increased glycerol-3-phosphate dehydrogenase (GPDH) activity (P < 0.01). Inclusion of 1.25 to 10 microM TRO to medium containing 280 nM insulin and 20 microL/ mL serum lipids supplement also increased GPDH activity (P < 0.001) compared with 0 microM TRO. The combination of 280 nM insulin, 1 mM octanoate, and 10 mM acetic acid, with 48 h exposure to 0.25 microM DEX caused morphological differentiation in a small number of cells but did not stimulate GPDH activity (P = 0.99). When used together, 280 nM insulin, 20 microL/mL of serum lipids supplement, 40 microM TRO, and 0.25 microM DEX stimulated differentiation compared with the aforementioned treatment (P < 0.001). Omission of TRO or insulin from this medium reduced GPDH activity by 68% (P < 0.001), whereas removal of DEX tended to reduce GPDH activity (P = 0.06). Preadipocytes from s.c. (n = 3) and i.m. (n = 2) adipose tissues of 3 steers were used to determine the effects of TRO on differentiation using the established conditions. Forty to sixty microM TRO enhanced differentiation compared with 0 microM TRO (P < 0.02) in both depots. No depot differences in response to TRO were detected (P = 0.32). These data demonstrate that bovine preadipocytes are capable of differentiation in response to combinations of insulin, serum lipids, DEX, and TRO. Although TRO enhanced differentiation of bovine preadipocytes, no differential effects of TRO on the differentiation of s.c. and i.m. cells were detected.


Biosimilars and the extrapolation of indications for inflammatory conditions.
Extrapolation is the approval of a biosimilar for use in an indication held by the originator biologic not directly studied in a comparative clinical trial with the biosimilar. Extrapolation is a scientific rationale that bridges all the data collected (ie, totality of the evidence) from one indication for the biosimilar product to all the indications originally approved for the originator. Regulatory approval and marketing authorization of biosimilars in inflammatory indications are made on a case-by-case and agency-by-agency basis after evaluating the totality of evidence from the entire development program. This totality of the evidence comprises extensive comparative analytical, functional, nonclinical, and clinical pharmacokinetic/pharmacodynamic, efficacy, safety, and immunogenicity studies used by regulators when evaluating whether a product can be considered a biosimilar. Extrapolation reduces or eliminates the need for duplicative clinical studies of the biosimilar but must be justified scientifically with appropriate data. Understanding the concept, application, and regulatory decisions based on the extrapolation of data is important since biosimilars have the potential to significantly impact patient care in inflammatory diseases.


Injectable paracetamol in children: yet more cases of 10-fold overdose.
Intravenous paracetamol injection is associated with a risk of 10-fold overdose. This is due to confusion between normal dose prescription in milligrams and administration in millilitres of injectable solution (containing 10 mg per ml). Reports of overdose show that the consequences can be severe, due to the hepatic toxicity of paracetamol, which may be fatal if the error is not detected rapidly enough for antidote (acetylcysteine) administration. In practice, injectable paracetamol should only be prescribed when oral administration is not possible. Care must be taken when calculating the dose to be administered, and the calculation must be double checked before the drug is administered.


Ureteroscopic management of upper tract urothelial carcinoma (UTUC) in patients with Lynch Syndrome (hereditary nonpolyposis colorectal cancer syndrome).
To report our experience with ureteroscopic laser ablation of upper tract urothelial carcinoma (UTUC) in patients with Lynch Syndrome (LS), as defined by a documented germline mutation in the MSH-2 gene. To increase awareness among urologists about UTUC in this unique patient population and refer to genetic counselling when appropriate. Demographic, clinical and pathological data on 13 consecutive patients with UTUC and documented MSH-2 mutation comprising 15 involved renal units were retrospectively collected. Ureteroscopic evaluations involved biopsy and laser treatment with combination holmium/neodymium yttrium aluminum garnet (YAG) lasers. Tumours were graded from 1 to 3 according to the 1973 World Health Organisation classification by a single pathologist evaluating cell block preparations. The mean patient age at initial presentation was 56.5 years, with six of 13 patients having metachronous bilateral UT disease. The mean follow-up was 59 months with a mean number of surveillances of 12. Of 15 affected renal units, 10/15 (67%) of initial tumours involved the ureter with mean lesion size of 17.5 mm, while five of 15 (33%) involved the intrarenal collecting system with mean lesion size of 25 mm. Ureteroscopy cleared 13/15 (87%) lesions and four of those 13 (31%) needed staged procedures. Renal preservation rate was 14/15 (93%) with one nephroureterectomy and one segmental ureterectomy performed. One patient developed metastatic UTUC after 40 months surveillance. No patient presented with bladder tumours but seven of the 13 (54%) developed them within 10 months of the initial ureteroscopy. Patients with LS who develop UTUC present at younger ages and appear to be more likely to have bilateral UT disease over their lifetimes vs sporadic UTUC patients. Ureteroscopic laser ablation offers a good renal preservation rate with reasonable cancer control in patients willing to undergo endoscopic surveillance. Development of new bladder tumours is common.


Point and interval estimation in two-stage adaptive designs with time to event data and biomarker-driven subpopulation selection.
In personalized medicine, it is often desired to determine if all patients or only a subset of them benefit from a treatment. We consider estimation in two-stage adaptive designs that in stage 1 recruit patients from the full population. In stage 2, patient recruitment is restricted to the part of the population, which, based on stage 1 data, benefits from the experimental treatment. Existing estimators, which adjust for using stage 1 data for selecting the part of the population from which stage 2 patients are recruited, as well as for the confirmatory analysis after stage 2, do not consider time to event patient outcomes. In this work, for time to event data, we have derived a new asymptotically unbiased estimator for the log hazard ratio and a new interval estimator with good coverage probabilities and probabilities that the upper bounds are below the true values. The estimators are appropriate for several selection rules that are based on a single or multiple biomarkers, which can be categorical or continuous.


The preparation of anisotropic hybrid nanostructures based on CdSe and CdS by the ligand combination method.
CdSe and CdS nanoparticles (NPs) are type I II-VI semiconductor materials with excellent optical properties. Usually various shapes of these NPs show a strong emission only from a CdSe or CdS single domain, while the emission from a CdSe core combined with a CdS shell is effectively suppressed due to the ultrafast hole relaxation from the CdS shell into the CdSe core. Therefore, the design and synthesis of heteronanostructures based on CdSe or CdS is of paramount importance in designing the ways of integrating these useful semiconductor materials into complex hybrid structures. Here we demonstrate the ligand-combination inducing growth method to prepare anisotropic core-shell (semiconductor-semiconductor) heteronanostructures, as well as anisotropic Au-semiconductor heteronanostructures. The NPs' anisotropic shape was confirmed by tilting a grid in TEM and their elemental composition was ascertained using EDX mapping in STEM mode. Furthermore, the photoluminescence excitation spectra were studied showing potential applications based on their unique optical properties. We believe that the mechanism investigation, the synthetic control, the obtained novel hybrid nanostructures and their optical properties will open doors to future studies on heterostructures based on semiconductors.


Interprofessional Education on Adverse Childhood Experiences for Associate Degree Nursing Students.
The health impact of adverse childhood experiences (ACEs) is significant. Nurses need knowledge and must work in multidisciplinary teams to address this problem. This study examined the effects of an interprofessional education (IPE) activity with nonhealth care students on associate degree nursing (ADN) students' ACEs knowledge and perspectives on IPE. The mixed-methods approach used a quasi-experimental pretest-posttest design with an intervention and control group and thematic analysis of focus group data. Readiness for Interprofessional Learning scale mean scores indicated positive baseline IPE perspectives. Scores changed minimally for most measures in both the intervention and control groups on posttest. However, four major relevant themes related to ACEs knowledge and two related to interprofessional learning were identified. IPE with nonhealth care students is an effective way to teach ADN students about ACEs and infuse interprofessional learning in a nonuniversity setting. However, outcomes are best captured with qualitative data. [J Nurs Educ. 2018;57(2):101-105.].


Silk Fibroin Separators: A Step Toward Lithium-Ion Batteries with Enhanced Sustainability.
Battery separators based on silk fibroin (SF) have been prepared aiming at improving the environmental issues of lithium-ion batteries. SF materials with three different morphologies were produced: membrane films (SF-F), sponges prepared by lyophilization (SF-L), and electrospun membranes (SF-E). The latter materials presented a suitable porous three-dimensional microstructure and were soaked with a 1 M LiPF6 electrolyte. The ionic conductivities for SF-L and SF-E were 1.00 and 0.32 mS cm-1 at 20 °C, respectively. A correlation between the fraction of β-sheet conformations and the ionic conductivity was observed. The electrochemical performance of the SF-based materials was evaluated by incorporating them in cathodic half-cells with C-LiFePO4. The discharge capacities of SF-L and SF-E were 126 and 108 mA h g-1, respectively, at the C/2-rate and 99 and 54 mA h g-1, respectively, at the 2C-rate. Furthermore, the capacity retention and capacity fade of the SF-L membrane after 50 cycles at the 2C-rate were 72 and 5%, respectively. These electrochemical results show that a high percentage of β-sheet conformations were of prime importance to guarantee excellent cycling performance. This work demonstrates that SF-based membranes are appropriate separators for the production of environmentally friendlier lithium-ion batteries.


Topical minoxidil: its use in treatment of male pattern baldness.
This review outlines the findings associated with topical minoxidil use. Approximately one-third of the treated patients will obtain terminal hair growth using a 2 to 3% solution twice a day. Patients should receive treatment for a minimum of six months to evaluate the drug's efficacy. Factors associated with patients who obtained new hair growth include: a thinning versus absolute baldness, treatment initiated at a relatively younger age, and hair growth noted within three months. Following a positive growth response, there may be a reduction in new hair growth gained with minoxidil use for more than one year. Stopping the medication is associated with an exacerbation of hair loss. Currently, patients with hypertension, cardiovascular disease, or any serious systemic illness should be excluded from therapy. Patients should be monitored every four to six months, or sooner with any complaints. Initial evaluation should include monitoring of the blood pressure, pulse, electrocardiogram and serum lipid determinations.


Electron-Transfer/Higher-Energy Collision Dissociation (EThcD)-Enabled Intact Glycopeptide/Glycoproteome Characterization.
Protein glycosylation, one of the most heterogeneous post-translational modifications, can play a major role in cellular signal transduction and disease progression. Traditional mass spectrometry (MS)-based large-scale glycoprotein sequencing studies heavily rely on identifying enzymatically released glycans and their original peptide backbone separately, as there is no efficient fragmentation method to produce unbiased glycan and peptide product ions simultaneously in a single spectrum, and that can be conveniently applied to high throughput glycoproteome characterization, especially for N-glycopeptides, which can have much more branched glycan side chains than relatively less complex O-linked glycans. In this study, a redefined electron-transfer/higher-energy collision dissociation (EThcD) fragmentation scheme is applied to incorporate both glycan and peptide fragments in one single spectrum, enabling complete information to be gathered and great microheterogeneity details to be revealed. Fetuin was first utilized to prove the applicability with 19 glycopeptides and corresponding five glycosylation sites identified. Subsequent experiments tested its utility for human plasma N-glycoproteins. Large-scale studies explored N-glycoproteomics in rat carotid arteries over the course of restenosis progression to investigate the potential role of glycosylation. The integrated fragmentation scheme provides a powerful tool for the analysis of intact N-glycopeptides and N-glycoproteomics. We also anticipate this approach can be readily applied to large-scale O-glycoproteome characterization. Graphical Abstract .