Regulation of apoptotic effects by erythrocarpine E, a cytotoxic limonoid from Chisocheton erythrocarpus in HSC-4 human oral cancer cells.
The aim of this study was to determine the cytotoxic and apoptotic effects of erythrocarpine E (CEB4), a limonoid extracted from Chisocheton erythrocarpus on human oral squamous cell carcinoma. Based on preliminary dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays, CEB4 treated HSC-4 cells demonstrated a cytotoxic effect and inhibited cell proliferation in a time and dose dependent manner with an IC(50) value of 4.0±1.9 µM within 24 h of treatment. CEB4 was also found to have minimal cytotoxic effects on the normal cell line, NHBE with cell viability levels maintained above 80% upon treatment. Annexin V-fluorescein isothiocyanate (FITC), poly-ADP ribose polymerase (PARP) cleavage and DNA fragmentation assay results showed that CEB4 induces apoptosis mediated cell death. Western blotting results demonstrated that the induction of apoptosis by CEB4 appeared to be mediated through regulation of the p53 signalling pathway as there was an increase in p53 phosphorylation levels. CEB4 was also found to up-regulate the pro-apoptotic protein, Bax, while down-regulating the anti-apoptotic protein, Bcl-2, suggesting the involvement of the intrinsic mitochondrial pathway. Reduced levels of initiator procaspase-9 and executioner caspase-3 zymogen were also observed following CEB4 exposure, hence indicating the involvement of cytochrome c mediated apoptosis. These results demonstrate the cytotoxic and apoptotic ability of erythrocarpine E, and suggest its potential development as a cancer chemopreventive agent.


Conserved Enzymatic Cascade for Bacterial Azoxy Biosynthesis.
Azoxy compounds exhibit a wide array of biological activities and possess distinctive chemical properties. Although there has been considerable interest in the biosynthetic mechanisms of azoxy metabolites, the enzymatic basis responsible for azoxy bond formation has remained largely enigmatic. In this study, we unveil the enzyme cascade that constructs the azoxy bond in valanimycin biosynthesis. Our research demonstrates that a pair of metalloenzymes, comprising a membrane-bound hydrazine synthase and a nonheme diiron azoxy synthase, collaborate to convert an unstable pathway intermediate to an azoxy product through a hydrazine-azo-azoxy pathway. Additionally, by characterizing homologues of this enzyme pair from other azoxy metabolite pathways, we propose that this two-enzyme cascade could represent a conserved enzymatic strategy for azoxy bond formation in bacteria. These findings provide significant mechanistic insights into biological N-N bond formation and should facilitate the targeted isolation of bioactive azoxy compounds through genome mining.


Papillary microcarcinoma of the thyroid among atomic bomb survivors: tumor characteristics and radiation risk.
: Radiation exposure is an established cause of clinical thyroid cancer, but little is known about radiation effects on papillary microcarcinoma (PMC) of the thyroid, a relatively common subclinical thyroid malignancy. Because the incidence of these small thyroid cancers has been increasing, it is important to better understand them and their relation to radiation. : PMCs were identified in a subset of 7659 members of the Life Span Study of atomic bomb survivors who had archived autopsy or surgical materials. We conducted a pathology review of these specimens and evaluated the histological features of the tumors and the association between PMCs and thyroid radiation dose. : From 1958 to 1995, 458 PMCs were detected among 313 study subjects. The majority of cancers exhibited pathologic features of papillary thyroid cancers. Overall, 81% of the PMCs were of the sclerosing variant and 91% were nonencapsulated, psammoma bodies that occurred in 13% and calcification was observed in 23%. Over 95% had papillary or papillary-follicular architecture and most displayed nuclear overlap, clear nuclei, and nuclear grooves. Several of these features increased with increasing tumor size, but no association was found with radiation dose. A significant radiation-dose response was found for the prevalence of PMCs (estimated excess odds ratio/Gy = 0.57; 95% confidence interval, 0.01-1.55), with the excess risk observed primarily among women. : Exposure to low-to-moderate doses of ionizing radiation appears to increase the risk of thyroid PMCs, even when exposure occurs during adulthood. Cancer 2010. (c) 2010 American Cancer Society.


Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice.
Adipose tissue inflammation is linked to the pathogenesis of insulin resistance. In addition to exerting death-promoting effects, the death receptor Fas (also known as CD95) can activate inflammatory pathways in several cell lines and tissues, although little is known about the metabolic consequence of Fas activation in adipose tissue. We therefore sought to investigate the contribution of Fas in adipocytes to obesity-associated metabolic dysregulation. Fas expression was markedly increased in the adipocytes of common genetic and diet-induced mouse models of obesity and insulin resistance, as well as in the adipose tissue of obese and type 2 diabetic patients. Mice with Fas deficiency either in all cells or specifically in adipocytes (the latter are referred to herein as AFasKO mice) were protected from deterioration of glucose homeostasis induced by high-fat diet (HFD). Adipocytes in AFasKO mice were more insulin sensitive than those in wild-type mice, and mRNA levels of proinflammatory factors were reduced in white adipose tissue. Moreover, AFasKO mice were protected against hepatic steatosis and were more insulin sensitive, both at the whole-body level and in the liver. Thus, Fas in adipocytes contributes to adipose tissue inflammation, hepatic steatosis, and insulin resistance induced by obesity and may constitute a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes.


Illustrations in the Journal of Craniofacial Surgery.
The aim of this study is to analyze the medical illustrations that appeared in the Journal of Craniofacial Surgery (JCFS) during the last 3 years (2016-2018).All illustrations in 2676 articles from 24 issues were analyzed.In total, 363 articles (13.6%) contained illustrations (for total of 589 illustrations), and 38 articles (1.4%) cited illustrations from other articles. The number of illustrations increased over time (152 in 2016, 181 in 2017, and 256 in 2018; P = 0.007). The signature of the illustrator appeared in 16.5% of the illustrations, and the illustrator's name was acknowledged in 7.6%. The most frequent contents of the 589 illustrations were surgical procedures (55.4%), followed by anatomy (34.1%). Among the 555 illustrations showing regions of the body, the most frequently illustrated region was the oral cavity (41.6%), followed by the eye and periorbital region (18.4%), the nose (12.4%), and the head (11.4%). Of the 555 illustrations showing tissue, the tissue most frequently depicted was bone (52.8%), followed by soft tissue (42.5%). The mean score for clarity of the intended message was 3.5 ± 1.2. The mean score for artistic skill was 3.2 ± 1.0.As the number of illustrations in JCFS increases, it is increasingly important that information on the illustrators be given. The journal editor should recommend that authors provide the illustrators' information. From the author's perspective, the best illustration is one that tells the story the author wants to convey to readers. Therefore, the crucial point is the expression of the author's goal, rather than the esthetics of the illustration.


Tissue response to silicone tubes used to repair human median and ulnar nerves.
Silicone tubes of appropriate sizes were used to enclose the injured zone of transsected ulnar and median nerves in the human forearm as an alternative to conventional microsurgical repair of the nerve trunk. A gap measuring 3-5 mm was left intentionally between the nerve ends inside the tube. The clinical early results from a prospective randomised study that compared these two principles have recently been presented. Seven patients (five men and two women), aged 15-49 years (median 20) were reexplored 12-44 months (median 22) after the initial procedure because of local discomfort from the tube in four patients. There was a new nerve structure bridging the former gap and in most cases it was impossible to distinguish the site of the injury. In all cases there was a thin capsule around the silicone tube that microscopically consisted of connective tissue with thin walls and no signs of inflammation, granuloma or macrophages (n = 4), while in two cases a mild foreign body reaction was seen at a single site (n = 1) or at patchy areas (n = 1). These results indicate that after more than one year there is a limited tissue reaction around silicone tubes used to repair median and ulnar nerves in humans.


Reusable bi-directional 3ω sensor to measure thermal conductivity of 100-μm thick biological tissues.
Accurate knowledge of the thermal conductivity (k) of biological tissues is important for cryopreservation, thermal ablation, and cryosurgery. Here, we adapt the 3ω method-widely used for rigid, inorganic solids-as a reusable sensor to measure k of soft biological samples two orders of magnitude thinner than conventional tissue characterization methods. Analytical and numerical studies quantify the error of the commonly used "boundary mismatch approximation" of the bi-directional 3ω geometry, confirm that the generalized slope method is exact in the low-frequency limit, and bound its error for finite frequencies. The bi-directional 3ω measurement device is validated using control experiments to within ±2% (liquid water, standard deviation) and ±5% (ice). Measurements of mouse liver cover a temperature ranging from -69 °C to +33 °C. The liver results are independent of sample thicknesses from 3 mm down to 100 μm and agree with available literature for non-mouse liver to within the measurement scatter.


Autosomal recessive inherited bleeding disorders in Pakistan: a cross-sectional study from selected regions.
Autosomal recessive bleeding disorders (ARBDs) include deficiencies of clotting factors I, II, V, VII, X, XI, XIII, vitamin K dependent clotting factors, combined factor V & VIII, Von Willebrand Disease (vWD) type 3, Glanzmann's thrombasthenia (GT) and Bernard-Soulier syndrome. Patients with primary bleeding disorders from all the major provincial capitals of Pakistan were screened for ARBDs. Prothrombin (PT), activated partial thromboplastin time (APTT), bleeding time (BT) and fibrinogen levels were measured. Cases with isolated prolonged APTT were tested for factors VIII and IX using factor assays This was followed by FXI:C level assessment in cases with normal FVIII and FIX levels. vWD was screened in patients with low FVIII levels. Factors II, V and X were tested in patients with simultaneous prolongation of PT and APTT. Peripheral blood film examination and platelet aggregation studies were performed to assess platelet disorders. Urea clot solubility testing was done to detect Factor XIII levels where platelet function tests were normal. Descriptive analysis was done using SPSS version 16. Of the 429 suspected bleeding disorder patients, 148 (35%) were diagnosed with hemophilia A and 211 (49.1%) patients had ARBDs. 70 patients (16.3%) remained undiagnosed. Out of 211 patients with ARBD; 95 (33.8%) had vWD type 3. Fibrinogen deficiency was found in 34 patients (12%), GT in 27 (9.6%), factor XIII deficiency in 13 (4.6%), factor VII deficiency in 12 (4.3%), factor V deficiency in 9 (3.2%). Eight patients (2.8%) had vitamin K-dependent clotting factor deficiency, Bernard-Soulier syndrome was diagnosed in seven patients (2.5%), factor X deficiency in 2 (0.7%), factor II deficiency in 2 (0.7%), factor XI deficiency and combined factor V and VIII deficiency in 1 (0.4%) patient each. vWD type 3 was the most common ARBD found in our sample of patients in Pakistan, followed by fibrinogen deficiency and GT in respective order.


The Polysomnographical Meaning of Changed Sleep Quality-A Study of Treatment with Reduced Time in Bed.
Reports of poor sleep are widespread, but their link with objective sleep (polysomnography-PSG) is weak in cross-sectional studies. In contrast, the purpose of this study was to investigate the association between changes in subjective and objective sleep variables using data from a study of the reduction in time in bed (TIB). One sleep recording was carried out at baseline and one at treatment week 5 (end of treatment) (N = 34). The Karolinska Sleep Quality Index improved and was correlated with improvement in sleep efficiency (r = 0.41, p < 0.05) and reduction in TIB (r = -0.47, p < 0.01) and sleep latency (r = 0.36, p < 0.05). The restorative sleep index showed similar results. Improvements in the insomnia severity index (ISI) essentially lacked correlations with changes in the PSG variables. It was suggested that the latter may be due to the ISI representing a week of subjective sleep experience, of which a single PSG night may not be representative. It was concluded that changes in the subjective ratings of sleep are relatively well associated with changes in the PSG-based sleep continuity variables when both describe the same sleep.


The association of opioid use with incident lower extremity fractures in spinal cord injury.
To determine the association between opioid use and lower extremity fracture risk in men with spinal cord injury (SCI). Retrospective cohort study. Veterans Affairs Healthcare System. In total, 7447 male Veterans with a history of a traumatic SCI identified from the Veterans Affairs (VA) Spinal Cord Dysfunction Registry (SCD) from September 2002 through October 2007 and followed through October 2010. Incident lower extremity fractures by use of opioids. In individuals identified from the VA SCD Registry 2002-2007, opioid use was quite common, with approximately 70% of the cohort having received a prescription for an opioid. Overall, there were 892 incident lower extremity fractures over the time period of this study (597 fractures in the opioid users and 295 fractures in the non-opioid users). After adjusting for covariates, there was a statistically significant relationship between opioid use and increased risk for lower extremity fractures (hazard ratio 1.82 (95% confidence interval 1.59-2.09)). Shorter duration of use (<6 months) and higher doses were positively related to fracture risk (P < 0.0001). Opioid use is quite common in SCI and is associated with an increased risk for lower extremity fractures. Careful attention to fracture prevention is warranted in patients with SCI, particularly upon initiation of an opioid prescription and when higher doses are used.


Production of novel antioxidative phenolic amides through heterologous expression of the plant's chlorogenic acid biosynthesis genes in yeast.
Phenolic esters like chlorogenic acid play an important role in therapeutic properties of many plant extracts. We aimed to produce phenolic esters in baker's yeast, by expressing tobacco 4CL and globe artichoke HCT. Indeed yeast produced phenolic esters. However, the primary product was identified as N-(E)-p-coumaroyl-3-hydroxyanthranilic acid by NMR. This compound is an amide condensation product of p-coumaric acid, which was supplied to the yeast, with 3-hydroxyanthranilic acid, which was unexpectedly recruited from the yeast metabolism by the HCT enzyme. N-(E)-p-coumaroyl-3-hydroxyanthranilic acid has not been described before, and it shows structural similarity to avenanthramides, a group of inflammation-inhibiting compounds present in oat. When applied to mouse fibroblasts, N-(E)-p-coumaroyl-3-hydroxyanthranilic acid induced a reduction of intracellular reactive oxygen species, indicating a potential therapeutic value for this novel compound.


[Streptococcus pyogenes and the brain: living with the enemy].
Streptococcus pyogenes (or group A beta hemolytic streptococcus) is a pathogenic bacterium that can give rise to a range of invasive and autoimmune diseases, although it is more widely known as the cause of tonsillitis. It is particularly interesting to note that this germ only causes disease in humans. For many years it has been acknowledged that it can cause an autoimmune brain disease (Sydenham s chorea). Yet, the spectrum of post streptococcal brain disorders has recently been extended to include other movement disorders such as tics or dystonia. A number of systematic psychiatric studies have shown that certain emotional disorders generally accompany the movement disorder (particularly, obsessive compulsive disorder). The proposed pathogenetic mechanism is that of a neuronal dysfunction in which antibodies play a mediating role. The antibodies that are produced after the streptococcal infection cross react with neuronal proteins, and more especially so in individuals with a propensity. This represents a possible model of immunological mimicry and its potential importance with respect to certain idiopathic disorders such as Tourette syndrome and obsessive compulsive disorder.


Introverted and yet effective? A faceted approach to the relationship between leadership and extraversion.
Extraversion and its facets of assertiveness and sociability were identified as stable predictors for leader emergence and effectiveness. However, recent research suggested that extraversion may lie in the eyes of the beholder; it might not be the leader's possession but their followers' attribution of the trait that shapes these criteria of leader success. In our study, we reverse-engineered this relationship and assessed the effects of effective leadership behaviors on personality perceptions. More specifically, we created scenarios of a leader responding to coordination challenges with passive-avoidant, transactional, or transformational leadership behaviors. We presented 204 participants with these scenarios and assessed how extraverted, assertive, and sociable they perceived the leader to be. Interestingly, and not fully meeting our expectations, ascriptions of extraversion and its facets of assertiveness and sociability did not directly relate to the effectiveness of the behaviors, as the moderately effective transactional leadership style garnered the highest ascriptions of extraversion and its facets. Further, ascriptions of extraversion to the transformational behavior of intellectual stimulation were remarkably low, matched only by the laissez-faire dimension of the passive-avoidant leadership style. We integrate and contrast these unexpected but explainable findings with current research, discuss potential associations between introversion and empowering leadership practices and provide suggestions for future discourse, illustrating the potential of investigating the presence of an introverted leadership advantage in the workplace of tomorrow.


Management of Familial Adenomatous Polyposis in Children and Adolescents: Position Paper From the ESPGHAN Polyposis Working Group.
Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, characterized by the development of hundreds to thousands of adenomas in the colorectum, with implications in children and adolescents. Almost all adult patients will develop colorectal cancer if they are not identified and treated early enough. Identifying and screening for FAP commences in adolescence. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the adenomatous polyposis (APC) gene. This European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) position paper provides a guide for diagnosis, assessment, and management of FAP in children and adolescents.This is the first position paper regarding FAP published by ESPGHAN. Literature from PubMed, Medline, and Embase was reviewed and in the absence of evidence, recommendations reflect the opinion of paediatric and adult experts involved in the care of polyposis syndromes. Because many of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, these of the recommendations are supported on expert opinion. This position paper will instruct on the appropriate management and timing of procedures in children and adolescents with FAP.


Location, function, and nucleotide sequence of a promoter for bacteriophage T3 RNA polymerase.
The major promoters for bacteriophage T3 RNA polymerase on the T3 genome have been mapped by DNA.RNA filter hybridization. One promoter is located in a 300-base-pair Hpa I restriction fragment near the genetic "left" end of T3 DNA. The sequence in the vicinity of the major initiation site of transcription in this region has been determined. A part of the (-)strand sequence is 5' T-A-T-T-T-A-C-C-C-T-C-A-C-T-A-A-A-G-+1 G-G-A-A-U 3'. Comparison of this sequence with the prototype 23-base-pair promoter sequence for bacteriophage T7 RNA polymerase shows a striking pattern of homology and divergence. Between positions -9 and +4, the sequences are virtually identical, whereas between positions -17 and -10, the sequences are quite different. It is postulated that these sequence subsets may perform different functions in transcription initiation by the phage RNA polymerases.


Design and formulation of mebeverine HCl semisolid formulations for intraorally administration.
Gel formulations of mebeverine hydrochloride (MbHCl) containing hydroxypropylmethylcellulose (HPMC), metolose (MTL), and poloxamer 407 (PLX) were prepared to be used in the treatment of different oral painful conditions. HPMC was used as a mucoadhesive gel base while MTL and PLX were used to prepare sol-gel thermosensitive gels. MTL and PLX formulations showed proper sol-gel transition temperature for intraoral application. Formulations were evaluated in terms of their viscosity, mechanical properties, mucoadhesivity, stability, and in vitro drug release. The formulation prepared with 2% of HPMC K100M provided the highest viscosity at room temperature. However, the viscosity of HPMC-PLX mixture showed a significant increase at body temperature. The greatest mucoadhesion was also noted in HPMC-PLX combinations. Texture profile analysis exhibited the differences of the adhesion, hardness, elasticity, cohesiveness, and compressibility of the formulations. The release profiles of MbHCl were obtained, and non-Fickian release was observed from all the formulations. The formulations were stored at different temperature and relative humidity. No significant changes were observed at the end of the 3 months. HPMC-PLX formulation of MbHCl was chosen for in vivo studies, and it remained longer than dye solution on the rabbit's intraoral mucosal tissue. It was found worthy of further clinical evaluation.


Implicit Maternal Intuition Confidence Is Associated With Maternal Well-Being Across Cultures.
The transition to motherhood involves the experience of each individual mother and child, as well as the burden of cultural expectations. Social desirability demands may impede self reports of difficulties during the transition to motherhood when using traditional explicit measures. One core component of maternal role attainment is a mother's confidence in her own intuitive knowledge of her child. This brief report presents two studies that examine a "low technology" implicit measure of maternal intuition confidence that is based within a more general decision confidence paradigm. Study 1 examined the association of both implicit and explicit maternal intuition confidence with depressive symptoms, life satisfaction, and maternal identity satisfaction in a United States sample of mothers. The implicit measure contributed to variance in each of the outcome measures, above and beyond an explicit measure. Study 2 explored the association of implicit maternal intuition confidence with life satisfaction and maternal identity satisfaction in Brazil, China, India, the United States and the United Kingdom. Across all samples, implicit maternal intuition confidence was significantly associated with satisfaction with life. However, it was significantly associated with maternal identity satisfaction only in the two individualistic countries (the United States and the United Kingdom), but not in the three collectivist countries.


Monte Carlo analysis of a new model-based method for insulin sensitivity testing.
Insulin resistance (IR), or low insulin sensitivity, is a major risk factor in the pathogenesis of type 2 diabetes and cardiovascular disease. A simple, high resolution assessment of IR would enable earlier diagnosis and more accurate monitoring of intervention effects. Current assessments are either too intensive for clinical settings (Euglycaemic Clamp, IVGTT) or have too low resolution (HOMA, fasting glucose/insulin). Based on high correlation of a model-based measure of insulin sensitivity and the clamp, a novel, clinically useful test protocol is designed with: physiological dosing, short duration (<1 h), simple protocol, low cost and high repeatability. Accuracy and repeatability are assessed with Monte Carlo analysis on a virtual clamp cohort (N=146). Insulin sensitivity as measured by this test has a coefficient of variation (CV) of CV(SI)=4.5% (90% CI: 3.8-5.7%), slightly higher than clamp ISI (CV(ISI)=3.3% (90% CI: 3.0-4.0%)) and significantly lower than HOMA (CV(HOMA)=10.0% (90% CI: 9.1-10.8%)). Correlation to glucose and unit normalised ISI is r=0.98 (90% CI: 0.97-0.98). The proposed protocol is simple, cost effective, repeatable and highly correlated to the gold-standard clamp.


Matrix protein of rabies virus is responsible for the assembly and budding of bullet-shaped particles and interacts with the transmembrane spike glycoprotein G.
To elucidate the functions of rhabdovirus matrix (M) protein, we determined the localization of M in rabies virus (RV) and analyzed the properties of an M-deficient RV mutant. We provide evidence that M completely covers the ribonucleoprotein (RNP) coil and keeps it in a condensed form. As determined by cosedimentation experiments, not only the M-RNP complex but also M alone was found to interact specifically with the glycoprotein G. In contrast, an interaction of G with the nucleoprotein N or M-less RNP was not observed. In the absence of M, infectious particles were mainly cell associated and the yield of cell-free infectious virus was reduced by as much as 500,000-fold, demonstrating the crucial role of M in virus budding. Supernatants from cells infected with the M-deficient RV did not contain the typical bullet-shaped rhabdovirus particles but instead contained long, rod-shaped virions, demonstrating severe impairment of the virus formation process. Complementation with M protein expressed from plasmids rescued rhabdovirus formation. These results demonstrate the pivotal role of M protein in condensing and targeting the RNP to the plasma membrane as well as in incorporation of G protein into budding virions.


[Molecular mechanism and mental function of postnatal neurogenesis].
Postnatal neurogenesis has been observed in two brain regions: the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus, among vertebrates including human. Accumulating evidence has indicated the molecular mechanisms commonly underlying embryonic and adult neurogenesis. Genetic factors essential for neural development, i.e., Pax6, Fabp7, Sox2, Wnt3, Notch1, etc., are also expressed in adult neurogenic regions. Adult neurogenesis, however, is distinct from embryonic neurogenesis in that the former is activity dependent; environmental stimulation modulates the entire processes of adult neurogenesis. In the hippocampus, physical exercise and cognitive stimuli robustly increase the proliferation of precursor cells, whereas physical/psychosocial stress decreases the proliferation of newborn neurons. Thus, adult neurogenesis is intriguingly regulated by several genetic and environmental factors. Reduction in hippocampal neurogenesis during the infantile and adult stages has been observed in some animal models of mental illness such as schizophrenia and major depression, implicating that postnatal neurogenesis may contribute to a part of the symptoms of mental illness. In this review, we describe the molecular mechanisms and functional significance of postnatal neurogenesis.


Safety and efficacy of ipilimumab to treat advanced melanoma in the setting of liver transplantation.
Ipilimumab is a first-in-class immunological checkpoint blockade agent and monoclonal antibody against Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) that has demonstrated survival benefit and durable responses in patients with metastatic melanoma. To date, solid organ transplant recipients have been excluded from clinical trials with cancer immunotherapies on the basis of their concurrent treatment with immunosuppressive agents. We present the first case to our knowledge of a patient with advanced cutaneous melanoma receiving ipilimumab status post orthotopic liver transplantation with a partial response. Transaminitis was observed 4 months after administration of ipilimumab that resolved with close observation. No evidence of graft rejection has been observed to date. This case advocates for further investigation of the safety and efficacy of cancer immunotherapies in solid organ transplant recipients.


Sap-flux density measurement methods: working principles and applicability.
Sap-flow measurements have become increasingly important in plant science. Since the early experiments with dyes, many methods have been developed. Most of these are based on the application of heat in the sapwood which is transported by the moving sap. By measuring changes in the temperature field around the heater, sap flow can be derived. Although these methods all have the same basis, their working principles vary widely. A first distinction can be made between those measuring the sap-flow rate (gh-1) such as the stem heat balance and trunk sector heat balance method and those measuring sap-flux density (cm3cm-2h-1). Within the latter, the thermal dissipation and heat field deformation methods are based on continuous heating, whereas the compensation heat pulse velocity, Tmax, heat ratio, calibrated average gradient and Sapflow+ methods are based on the application of heat pulses. Each of these methods has its advantages and limitations. Although the sap-flow rate methods have been adequately described in previous reviews, recent developments in sap-flux density methods prompted a synthesis of the existing but scattered literature. This paper reviews sap-flux density methods to enable users to make a well founded choice, whether for practical applications or fundamental research questions, and to encourage further improvement in sap-flux density measurement techniques.


Optical fibers for endoscopic high-power Er:YAG laserosteotomy.
The highest absorption peaks of the main components of bone are in the mid-infrared region, making Er:YAG and CO2 lasers the most efficient lasers for cutting bone. Yet, studies of deep bone ablation in minimally invasive settings are very limited, as finding suitable materials for coupling high-power laser light with low attenuation beyond 2 μm is not trivial. The first aim of this study was to compare the performance of different optical fibers in terms of transmitting Er:YAG laser light with a 2.94-μm wavelength at high pulse energy close to 1 J. The second aim was to achieve deep bone ablation using the best-performing fiber, as determined by our experiments. In our study, various optical fibers with low attenuation (λ = 2.94 μm) were used to couple the Er:YAG laser. The fibers were made of germanium oxide, sapphire, zirconium fluoride, and hollow-core silica, respectively. We compared the fibers in terms of transmission efficiency, resistance to high Er:YAG laser energy, and bending flexibility. The best-performing fiber was used to achieve deep bone ablation in a minimally invasive setting. To do this, we adapted the optimal settings for free-space deep bone ablation with an Er:YAG laser found in a previous study. Three of the fibers endured energy per pulse as high as 820 mJ at a repetition rate of 10 Hz. The best-performing fiber, made of germanium oxide, provided higher transmission efficiency and greater bending flexibility than the other fibers. With an output energy of 370 mJ per pulse at 10 Hz repetition rate, we reached a cutting depth of 6.82 ± 0.99 mm in sheep bone. Histology image analysis was performed on the bone tissue adjacent to the laser ablation crater; the images did not show any structural damage. The findings suggest that our prototype could be used in future generations of endoscopic devices for minimally invasive laserosteotomy.


Neonatal deaths and injuries.
It is rare for babies to die or be injured during birth in Norway. We aimed to investigate whether maternity care was inadequate in cases reported to the Norwegian Board of Health Supervision and to single out areas in maternity care where there is potential for improvement. The material consists of cases reported to the Norwegian Board of Health Supervision in the three-year period 2006-2008 in which babies died or were severely injured during delivery. We recorded data on: maternity unit, fetal monitoring, delivery method, personnel involved and type of inadequate maternity care. The material consists of 81 cases. Babies died during or after deliver in 58 cases and were severely injured in 23 cases. The health trusts reported 42 of these events to the Board of Health Supervision; the remainder were reported by the patient ombudsman or the parents. There was inadequate fetal monitoring in 68 % of the births and delayed delivery in 67 %. A gynaecological specialist was not called for 44 % of the births. The number of cases of injuries in relation to the number of deliveries reported to the Board of Health Supervision was significantly higher for small maternity units (< 1000 births per year) than for larger units. Doctors and midwives need a better knowledge of fetal monitoring. Maternity units must develop sound procedures for singling out high-risk births, use of fetal monitoring, calling for a doctor and reporting to the Board of Health Supervision. Exercises in dealing with acute situations should be held. Small maternity units appear to be most vulnerable to adverse events.


Physiological concentrations of bile salts inhibit recovery of ischemic-injured porcine ileum.
We have previously shown rapid in vitro recovery of barrier function in porcine ischemic-injured ileal mucosa, attributable principally to reductions in paracellular permeability. However, these experiments did not take into account the effects of luminal contents, such as bile salts. Therefore, the objective of this study was to evaluate the role of physiological concentrations of deoxycholic acid in recovery of mucosal barrier function. Porcine ileum was subjected to 45 min of ischemia, after which mucosa was mounted in Ussing chambers and exposed to varying concentrations of deoxycholic acid. The ischemic episode resulted in significant reductions in transepithelial electrical resistance (TER), which recovered to control levels of TER within 120 min, associated with significant reductions in mucosal-to-serosal (3)H-labeled mannitol flux. However, treatment of ischemic-injured tissues with 10(-5) M deoxycholic acid significantly inhibited recovery of TER with significant increases in mucosal-to-serosal (3)H-labeled mannitol flux, whereas 10(-6) M deoxycholic acid had no effect. Histological evaluation at 120 min revealed complete restitution regardless of treatment, indicating that the breakdown in barrier function was due to changes in paracellular permeability. Similar effects were noted with the application of 10(-5) M taurodeoxycholic acid, and the effects of deoxycholic acid were reversed with application of the Ca(2+)-mobilizing agent thapsigargin. Deoxycholic acid at physiological concentrations significantly impairs recovery of epithelial barrier function by an effect on paracellular pathways, and these effects appear to be Ca(2+) dependent.


Nuclear export competence of pre-40S subunits in fission yeast requires the ribosomal protein Rps2.
Ribosome biogenesis is an evolutionarily conserved pathway that requires ribosomal and nonribosomal proteins. Here, we investigated the role of the ribosomal protein S2 (Rps2) in fission yeast ribosome synthesis. As for many budding yeast ribosomal proteins, Rps2 was essential for cell viability in fission yeast and the genetic depletion of Rps2 caused a complete inhibition of 40S ribosomal subunit production. The pattern of pre-rRNA processing upon depletion of Rps2 revealed a reduction of 27SA(2) pre-rRNAs and the concomitant production of 21S rRNA precursors, consistent with a role for Rps2 in efficient cleavage at site A(2) within the 32S pre-rRNA. Importantly, kinetics of pre-rRNA accumulation as determined by rRNA pulse-chases assays indicated that a small fraction of 35S precursors matured into 20S-containing particles, suggesting that most 40S precursors were rapidly degraded in the absence of Rps2. Analysis of steady-state RNA levels revealed that some pre-40S particles were produced in Rps2-depleted cells, but that these precursors were retained in the nucleolus. Our findings suggest a role for Rps2 in a mechanism that monitors pre-40S export competence.


Assessment of Neonatal Intensive Care Unit Practices and Preterm Newborn Gut Microbiota and 2-Year Neurodevelopmental Outcomes.
In very preterm newborns, gut microbiota is highly variable with major dysbiosis. Its association with short-term health is widely studied, but the association with long-term outcomes remains unknown. To investigate in preterm newborns the associations among practice strategies in neonatal intensive care units (NICUs), gut microbiota, and outcomes at 2 years. EPIFLORE is a prospective observational cohort study that includes a stool sample collection during the fourth week after birth. Preterm newborns of less than 32 weeks of gestational age (GA) born in 2011 were included from 24 NICUs as part of the French nationwide population-based cohort, EPIPAGE 2. Data were collected from May 2011 to December 2011 and analyzed from September 2016 to December 2018. Eight NICU strategies concerning sedation, ventilation, skin-to-skin practice, antibiotherapy, ductus arteriosus, and breastfeeding were assessed. A NICU was considered favorable to a practice if the percentage of that practice in the NICU was more than the expected percentage. Gut microbiota was analyzed by 16S ribosomal RNA gene sequencing and characterized by a clustering-based method. The 2-year outcome was defined by death or neurodevelopmental delay using a Global Ages and Stages questionnaire score. Of 577 newborns included in the study, the mean (SD) GA was 28.3 (2.0) weeks, and 303 (52.5%) were male. Collected gut microbiota was grouped into 5 discrete clusters. A sixth cluster included nonamplifiable samples owing to low bacterial load. Cluster 4 (driven by Enterococcus [n = 63]), cluster 5 (driven by Staphylococcus [n = 52]), and cluster 6 (n = 93) were significantly associated with lower mean (SD) GA (26.7 [1.8] weeks and 26.8 [1.9] weeks, respectively) and cluster 3 (driven by Escherichia/Shigella [n = 61]) with higher mean (SD) GA (29.4 [1.6] weeks; P = .001). Cluster 3 was considered the reference. After adjustment for confounders, no assisted ventilation at day 1 was associated with a decreased risk of belonging to cluster 5 or cluster 6 (adjusted odds ratio [AOR], 0.21 [95% CI, 0.06-0.78] and 0.19 [95% CI, 0.06-0.62], respectively) when sedation (AOR, 10.55 [95% CI, 2.28-48.87] and 4.62 [1.32-16.18], respectively) and low volume of enteral nutrition (AOR, 10.48 [95% CI, 2.48-44.29] and 7.28 [95% CI, 2.03-26.18], respectively) was associated with an increased risk. Skin-to-skin practice was associated with a decreased risk of being in cluster 5 (AOR, 0.14 [95% CI, 0.04-0.48]). Moreover, clusters 4, 5, 6 were significantly associated with 2-year nonoptimal outcome (AOR, 6.17 [95% CI, 1.46-26.0]; AOR, 4.53 [95% CI, 1.02-20.1]; and AOR, 5.42 [95% CI, 1.36-21.6], respectively). Gut microbiota of very preterm newborns at week 4 is associated with NICU practices and 2-year outcomes. Microbiota could be a noninvasive biomarker of immaturity.


Creation of a functional heterogeneous vesicle array via DNA controlled surface sorting onto a spotted microarray.
Membrane protein microarrays are expected to play a key role in the future of drug screening and discovery. The authors present a method for the creation of functional heterogeneous vesicle arrays via DNA controlled surface sorting. Complexes of streptavidin and biotinylated DNA are spotted onto a biomolecule- and cell-resistant surface of biotinylated poly(L-lysine)-grafted-poly(ethylene glycol). Two kinds of vesicles functionalized with either the membrane-binding protein annexin A5 or loaded with bovine serum albumin, are tagged with DNA, mixed together, and guided to predefined spots on the surface. The authors show that the spotted complexes remain active and selective and that the background is resistant towards nonspecific adsorption of the vesicles and the proteins.


BOAT: Basic Oligonucleotide Alignment Tool.
Next-generation DNA sequencing technologies generate tens of millions of sequencing reads in one run. These technologies are now widely used in biology research such as in genome-wide identification of polymorphisms, transcription factor binding sites, methylation states, and transcript expression profiles. Mapping the sequencing reads to reference genomes efficiently and effectively is one of the most critical analysis tasks. Although several tools have been developed, their performance suffers when both multiple substitutions and insertions/deletions (indels) occur together. We report a new algorithm, Basic Oligonucleotide Alignment Tool (BOAT) that can accurately and efficiently map sequencing reads back to the reference genome. BOAT can handle several substitutions and indels simultaneously, a useful feature for identifying SNPs and other genomic structural variations in functional genomic studies. For better handling of low-quality reads, BOAT supports a "3'-end Trimming Mode" to build local optimized alignment for sequencing reads, further improving sensitivity. BOAT calculates an E-value for each hit as a quality assessment and provides customizable post-mapping filters for further mapping quality control. Evaluations on both real and simulation datasets suggest that BOAT is capable of mapping large volumes of short reads to reference sequences with better sensitivity and lower memory requirement than other currently existing algorithms. The source code and pre-compiled binary packages of BOAT are publicly available for download at http://boat.cbi.pku.edu.cn under GNU Public License (GPL). BOAT can be a useful new tool for functional genomics studies.


Interstitial pneumonia with autoimmune features.
Some patients with idiopathic interstitial pneumonias (IIPs) have clinical features that suggest autoimmune process but not fulfill established criteria for connective tissue disease (CTD). Different terms and criteria have been proposed to describe these patients, which includes undifferentiated connective tissue disease (UCTD), lung dominant connective tissue disease (LD-CTD), and autoimmune-featured interstitial lung disease (AIF-ILD). To marshal these ununiform classification criteria, the "European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease" proposed a consensus regarding the nomenclature and classification criteria for patients with IIP and features of autoimmunity with the term "interstitial pneumonia with autoimmune features" (IPAF). It was reported that patients with IPAF accounted for 7.3%∼34.1% of patients with interstitial lung disease (ILD). Survival, rate of progressing to CTD, appropriate treatment, and treatment response are not yet elucidated. Furthermore, it is not determined whether IPAF is a distinct category of ILD or simply a part of IIP. These questions should be elucidated by future prospective cohort studies. Hopefully, rheumatologists should participate in not only clinical trials but also in multidisciplinary discussions for IPAF.


Incorporation of HPMCAS during loading of glibenclamide onto mesoporous silica improves dissolution and inhibits precipitation.
Mesoporous silica has emerged as an enabling formulation for poorly soluble active pharmaceutical ingredients (APIs). Unlike other formulations, mesoporous silica typically does not inhibit precipitation of supersaturated API therefore, a suitable precipitation inhibitor (PI) should be added to increase absorption from the gastrointestinal (GI) tract. However, there is limited research about optimal processes for combining PIs with silica formulations. Typically, the PI is added by simply blending the API-loaded silica mechanically with the selected PI. This has the drawback of an additional blending step and may also not be optimal with regard to release of drug and PI. By contrast, loading PI simultaneously with the API onto mesoporous silica, i.e. co-incorporation, is attractive from both a performance and practical perspective. The aim of this study was to demonstrate the utility of a co-incorporation approach for combining PIs with silica formulations, and to develop a mechanistic rationale for improvement of the performance of silica formulations using the co-incorporation approach. The results indicate that co-incorporating HPMCAS with glibenclamide onto silica significantly improved the extent and duration of drug supersaturation in single-medium and transfer dissolution experiments. Extensive spectroscopic characterization of the formulation revealed that the improved performance was related to the formation of drug-polymer interactions already in the solid state; the immobilization of API-loaded silica on HPMCAS plates, which prevents premature release and precipitation of API; and drug-polymer proximity on disintegration of the formulation, allowing for rapid onset of precipitation inhibition. The data suggests that co-incorporating the PI with the API is appealing for silica formulations from both a practical and formulation performance perspective.


Cognitive behavioral therapy of obsessive-compulsive disorder.
Until the mid-1960s, obsessive-compulsive disorder (OCD) was considered to be treatment-resistant, as both psychodynamic psychotherapy and medication had been unsuccessful in significantly reducing OCD symptoms. The first real breakthrough came in 1966 with the introduction of exposure and ritual prevention. This paper will discuss the cognitive behavioral conceptualizations that influenced the development of cognitive behavioral treatments for OCD. There will be a brief discussion of the use of psychodynamic psychotherapy and early behavioral therapy, neither of which produced successful outcomes with OCD. The main part of the paper will be devoted to current cognitive behavioral therapy (CBT) with an emphasis on variants of exposure and ritual or response prevention (EX/RP) treatments, the therapy that has shown the most empirical evidence of its efficacy.


Direct interaction of the novel Nox proteins with p22phox is required for the formation of a functionally active NADPH oxidase.
Nox1 and Nox4, homologues of the leukocyte NADPH oxidase subunit Nox2 (gp91phox) mediate superoxide anion formation in various cell types. However, their interactions with other components of the NADPH oxidase are poorly defined. We determined whether a direct interaction of Nox1 and Nox4 with the p22phox subunit of the NADPH oxidase occurs. Using confocal microscopy, co-localization of p22phox with Nox1, Nox2, and Nox4 was observed in transiently transfected vascular smooth muscle cells (VSMC) and HEK293 cells. Plasmids coding for fluorescent fusion proteins of p22phox and the Nox proteins with cyan- and yellow-fluorescent protein (cfp and yfp, respectively) were constructed and expressed in VSMC and HEK293 cells. The cfp-tagged p22phox expression level increased upon cotransfection with Nox1 or Nox4. Protein-protein interaction between the fluorescent fusion proteins of p22phox and the Nox partners was observed using the fluorescence resonance energy transfer technique. Immunoprecipitation of native Nox1 from human VSMC revealed co-precipitation of p22phox. Immunoprecipitation from transfected HEK293 cells revealed co-precipitation of native p22phox with yfp-tagged Nox1, Nox2, and Nox4. Following mutation of a histidine (corresponding to the position 115 in human Nox2) to leucine, this interaction was abolished. Transfection of rat p22phox (but not Noxo1 and Noxa1) increased the radical generation in cells expressing Nox4. We provide evidence that p22phox directly interacts with Nox1 and Nox4, to form an superoxide-generating NADPH oxidase and demonstrate that mutation of the potential heme binding site in the Nox proteins disrupts the complex formation of Nox1 and Nox4 with p22phox.


Upward transtentorial herniation, hydrocephalus, and cerebellar edema in hypertensive encephalopathy.
Edema of the cerebellum with secondary obstructive hydrocephalus is a rare presentation of hypertensive encephalopathy. The authors report an unusual case of isolated posterior fossa swelling with upward transtentorial herniation and hydrocephalus causing neurologic deterioration. These patients are often initially evaluated by a neurologist because of the acute neurologic symptoms. Prompt diagnosis with aggressive blood pressure control may obviate the need for emergent cerebrospinal fluid (CSF) diversion. This is a case report of a 26-year-old man who presented to the emergency room with confusion and somnolence over a 2-day period. His initial blood pressure was 175/110 mmHg. On examination he was disoriented, with a Glasgow Coma Scale score of 12 points, opening his eyes only to loud verbal stimuli, verbalizing inappropriately, and he was only able to follow simple commands. Neuroimaging revealed edema of the cerebellar folia with noncommunicating hydrocephalus and upward transtentorial herniation. Differential diagnoses of posterior fossa tumor, rhombencephalitis, and hypertensive encephalopathy were entertained. A thorough literature review is included with the discussion of this case. The patient underwent emergent ventriculostomy for CSF drainage and prompt blood pressure control with nitroprusside. After 48 hours of CSF drainage and correction of his hypertension, his neurologic examination normalized. Repeat imaging revealed near resolution of the obstructive hydrocephalus and cerebellar edema. Isolated edema of the cerebellum with upward transtentorial herniation and obstructive hydrocephalus is a rare presentation of hypertensive encephalopathy and should be considered in patients with an acute hypertensive crisis and mental status changes. This entity responds to prompt blood pressure control; however, emergent ventriculostomy by a neurosurgical team should be entertained for neurologic deterioration secondary to significant obstructive hydrocephalus, as illustrated in this case.


GASTRECTOMY IN OCTOGENARIANS WITH GASTRIC CANCER: IS IT FEASIBLE?
The octogenarian population is expanding worldwide and demand for gastrectomy due to gastric cancer in this population is expected to grow. However, the outcomes of surgery with curative intent in this age group are poorly reported and it is unclear what matters most to survival: age, clinical status, disease´s stage, or the extent of the surgery performed. Evaluate the results of gastrectomy in octogenarians with gastric cancer and to verify the factors related to survival. From prospective database, patients aged 80 years or older with histologically confirmed adenocarcinoma who had undergone gastrectomy with curative intent were selected. Factors related to postoperative complications and survival were studied. Fifty-one patients fulfilled the inclusion criteria. A total of 70.5% received subtotal gastrectomy and in 72.5% D1 lymphadenectomy was performed. Twenty-five (49%) had complications, in eleven major complications occurred (seven of these were clinical complications). Hospital length of stay was longer (8.5 vs. 17.8 days, p=0.002), and overall survival shorter (median of 1.4 vs. 20.5 months, p=0.009) for those with complications. D2 lymphadenectomy and the presence of postoperative complications were independent factors for worse overall survival. Octogenarians undergoing gastrectomy with curative intent have high risk for postoperative clinical complications. D1 lymphadenectomy should be the standard of care in these patients.


Avoiding Pitfalls in the Statistical Analysis of Heterogeneous Tumors.
Information about tumors is usually obtained from a single assessment of a tumor sample, performed at some point in the course of the development and progression of the tumor, with patient characteristics being surrogates for natural history context. Differences between cells within individual tumors (intratumor heterogeneity) and between tumors of different patients (intertumor heterogeneity) may mean that a small sample is not representative of the tumor as a whole, particularly for solid tumors which are the focus of this paper. This issue is of increasing importance as high-throughput technologies generate large multi-feature data sets in the areas of genomics, proteomics, and image analysis. Three potential pitfalls in statistical analysis are discussed (sampling, cut-points, and validation) and suggestions are made about how to avoid these pitfalls.


Ocular motor abnormalities in ataxia telangiectasia.
Although abnormal eye movements are a prominent feature of ataxia telangiectasia, the characteristics of the oculomotor dysfunction in the disease have been reported only in small groups of patients. We have examined eye movements clinically in 56 patients with ataxia telangiectasia, and obtained electrooculographic recordings of eye movements in 33 subjects. Deficits were observed in the eye movement systems that stabilize images on the retina, including pursuit, gaze holding, convergence, vestibular and optokinetic slow phases, and cancellation of vestibular slow phases. Abnormalities in the systems that maintain fixation and shift gaze were also prominent, including abnormal reflexive and voluntary saccades (characterized by prolonged latency, hypometric amplitude, and the use of head movements to initiate gaze shifts), impaired fixation, and a reduction in vestibular and optokinetic quick phases. The abnormalities in image stabilization most likely result from dysfunction in the cerebellar flocculus and paraflocculus. The basis of the saccadic and fixation disturbance is less certain but may be the result of abnormal supranuclear control of the superior colliculus resulting from dysfunction in the cerebellar vermis or the basal ganglia.


L-CAM expression induces fibroblast-epidermoid transition in squamous carcinoma cells and down-regulates the endogenous N-cadherin.
SCC9 cells, derived from a squamous carcinoma of the tongue, were shown to lack E-cadherin but express alpha- and beta-catenins and N-cadherin. These cells also lack plakoglobin expression, do not assemble desmosomes and exhibit the typical morphology and growth properties of transformed cells. The N-cadherin expressed in SCC9 cells has properties similar to other classical cadherins, including interactions with the catenins. We transfected SCC9 cells with a full-length cDNA for L-CAM (liver cell adhesion molecule), the functional chicken homologue of E-cadherin. The exogenously expressed L-CAM formed complexes with catenins and the cytoskeleton and induced a morphological transition from fibroblastoid to epithelioid, conferred density-dependent growth inhibition, increased aggregation ability, and increased synthesis and stability of alpha- and beta-catenins. Coincident with these phenotypic changes, we detected a significant reduction in the level of endogenous N-cadherin, primarily as a result of rapid degradation of this protein in L-CAM-expressing cells. These results show the abnormal expression of N-cadherin in these transformed epidermoid cells, demonstrate the dynamics of the relationship between two cadherins, and provide a model system for the functional analysis of the tumor suppressor activity of E-cadherin in carcinomas.


Osteoporosis in acute fractures of the cervical spine: the role of opportunistic CT screening.
Recently published data make it possible to generate estimates of bone mineral density (BMD) by using CT attenuation; this innovation can save time and reduce costs. Although advanced age is associated with reduced BMD, especially in patients with a fracture of C-2, relatively few patients ever undergo formal dual x-ray absorptiometry studies. To the authors' knowledge, this is the first study to assess the utility of this technique in elucidating BMD in patients with an acute fracture of the cervical spine. Patients who presented to a Level I trauma center with an acute fracture of the cervical spine and underwent abdominal (or L-1) CT scanning either at admission or in the 6 months before or after the injury were evaluated. Using a picture-archiving and communication system, the authors generated regions of interest of similar size in the body of L-1 (excluding the cortex) and computed mean values for CT attenuation. The values derived were compared with threshold values, which differentiate between osteoporotic and nonosteoporotic states; age-stratified groups were also compared. Of the 91 patients whose data were reviewed, 51 were < 65 years old (mean 43.2 years) and 40 were ≥ 65 years old (mean 80.9 years). The overall mean CT attenuation values (in Hounsfield units [HU]), stratified according to age, were 193.85 HU for the younger cohort and 117.39 HU for the older cohort; the result of a comparison between these two values was significant (p < 0.001). Using opportunistic CT scanning, this study demonstrates the relative frequency of osteoporosis in acute fractures of the cervical spine. It also objectively correlates overall BMD with the known higher frequency of C-2 fractures in older patients. This technique harnesses the presence of opportunistic CT scans of the abdomen, which potentially reduces the need for the extra time and cost that may be associated with dual x-ray absorptiometry scanning.


What does it cost the patient to see the doctor?
Against a background of increasing demands on limited resources, there will be an emphasis on undertaking studies that relate benefits of an intervention to the costs that are incurred in their production. Patient costs are an important, but often overlooked, part of an economic exercise and include transport costs, loss of employment, and loss of leisure time. This paper highlights the theoretical difficulties inherent in deriving patient costs and suggests a pragmatic framework to derive unit costs in these areas. We demonstrate that these costs are not inconsiderable when compared with the cost of a general practitioner consultation.


Development of an aggregate-selective, human-derived α-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models.
Aggregation of α-synuclein (α-syn) is neuropathologically and genetically linked to Parkinson's disease (PD). Since stereotypic cell-to-cell spreading of α-syn pathology is believed to contribute to disease progression, immunotherapy with antibodies directed against α-syn is considered a promising therapeutic approach for slowing disease progression. Here we report the identification, binding characteristics, and efficacy in PD mouse models of the human-derived α-syn antibody BIIB054, which is currently under investigation in a Phase 2 clinical trial for PD. BIIB054 was generated by screening human memory B-cell libraries from healthy elderly individuals. Epitope mapping studies conducted using peptide scanning, X-ray crystallography, and mutagenesis show that BIIB054 binds to α-syn residues 1-10. BIIB054 is highly selective for aggregated forms of α-syn with at least an 800-fold higher apparent affinity for fibrillar versus monomeric recombinant α-syn and a strong preference for human PD brain tissue. BIIB054 discriminates between monomers and oligomeric/fibrillar forms of α-syn based on high avidity for aggregates, driven by weak monovalent affinity and fast binding kinetics. In efficacy studies in three different mouse models with intracerebrally inoculated preformed α-syn fibrils, BIIB054 treatment attenuated the spreading of α-syn pathology, rescued motor impairments, and reduced the loss of dopamine transporter density in dopaminergic terminals in striatum. The preclinical data reported here provide a compelling rationale for clinical development of BIIB054 for the treatment and prevention of PD.


Pretreatment of rice straw by newly isolated fungal consortium enhanced lignocellulose degradation and humification during composting.
The slow decomposition rate of the reluctant structure of lignocellulose in agricultural waste is the great limitation of composting processes, which can be averted by pretreatment-strategies. This study focused on the impacts of pretreating rice straw using a consortium of newly isolated fungal species on lignocellulose degradation and humic substances during composting. Fungal pretreatment had a significant impact on lignocellulose degradation (84%) of rice straw by producing higher lignocellulytic enzymes than chemical pretreatments (79%) or the control (61%). The compost with fungal pretreated rice straw (FPT) showed significantly high composting temperature in the late mesophilic stage, which enhanced the degradation of lignocellulose. The fluorescence excitation emission spectroscopy revealed that significantly more humic acid-like compounds were formed in FPT. These findings suggest that fungal pretreatment is a feasible method to accelerate straw degradation and humification.


Exercise Preserves Physical Function in Prostate Cancer Patients with Bone Metastases.
The presence of bone metastases has excluded participation of cancer patients in exercise interventions and is a relative contraindication to supervised exercise in the community setting because of concerns of fragility fracture. We examined the efficacy and safety of a modular multimodal exercise program in prostate cancer patients with bone metastases. Between 2012 and 2015, 57 prostate cancer patients (70.0 ± 8.4 yr; body mass index, 28.7 ± 4.0 kg·m) with bone metastases (pelvis, 75.4%; femur, 40.4%; rib/thoracic spine, 66.7%; lumbar spine, 43.9%; humerus, 24.6%; other sites, 70.2%) were randomized to multimodal supervised aerobic, resistance, and flexibility exercises undertaken thrice weekly (EX; n = 28) or usual care (CON; n = 29) for 3 months. Physical function subscale of the Medical Outcomes Study Short-Form 36 was the primary end point as an indicator of patient-rated physical functioning. Secondary end points included objective measures of physical function, lower body muscle strength, body composition, and fatigue. Safety was assessed by recording the incidence and severity of any adverse events, skeletal complications, and bone pain throughout the intervention. There was a significant difference between groups for self-reported physical functioning (3.2 points; 95% confidence interval, 0.4-6.0 points; P = 0.028) and lower body muscle strength (6.6 kg; 95% confidence interval, 0.6-12.7; P = 0.033) at 3 months favoring EX. However, there was no difference between groups for lean mass (P = 0.584), fat mass (P = 0.598), or fatigue (P = 0.964). There were no exercise-related adverse events or skeletal fractures and no differences in bone pain between EX and CON (P = 0.507). Multimodal modular exercise in prostate cancer patients with bone metastases led to self-reported improvements in physical function and objectively measured lower body muscle strength with no skeletal complications or increased bone pain. ACTRN12611001158954.


Decreased DHRS2 expression is associated with HDACi resistance and poor prognosis in ovarian cancer.
Histone deacetylases (HDACs) have been linked to a variety of cancers, and HDAC inhibitors (HDACi) are a promising class of drugs that have demonstrated anti-cancer effects. However, we have little knowledge regarding the selection and application of HDAC inhibitors to the personalized treatment of ovarian cancer (OC). Here, we report a correlation between the high expression of HDACs and poor outcomes in OC patients, which reveals that HDACi are a class of agents that show great promise for the treatment of OC. Furthermore, we found that HDACi increased both the mRNA and protein levels of DHRS2, which has been shown to be closely linked to HDACi sensitivity when it is highly expressed, especially in ovarian cancer cells. Consistently, we found that suppression of DHRS2 reduced the sensitivity of OC cells to HDAC inhibitors via attenuation of the inhibitory effects of HDAC inhibitors on Mcl-1 in vitro. Our study demonstrated that DHRS2 expression was decreased in OC tissues and that high expression of DHRS2 was correlated with better outcomes in OC patients. In addition, DHRS2 expression was closely related to the effects of chemotherapy. Our study reveals the role of DHRS2 in cell apoptosis induced by HDAC inhibitors and explores the clinical attributes of DHRS2 in OC from a new perspective, suggesting that OC patients with high DHRS2 expression may benefit from treatment with HDAC inhibitors.


Neglecting Plasma Protein Binding in COVID-19 Patients Leads to a Wrong Interpretation of Lopinavir Overexposure.
Boffito et al. recalled the critical importance to correctly interpret protein binding. Changes of lopinavir pharmacokinetics in coronavirus disease 2019 (COVID-19) are a perfect illustration. Indeed, several studies described that total lopinavir plasma concentrations were considerably higher in patients with severe COVID-19 than those reported in patients with HIV. These findings have led to a reduction of the dose of lopinavir in some patients, hypothesizing an inhibitory effect of inflammation on lopinavir metabolism. Unfortunately, changes in plasma protein binding were never investigated. We performed a retrospective cohort study. Data were collected from the medical records of patients hospitalized for COVID-19 treated with lopinavir/ritonavir in intensive care units or infectious disease departments of Toulouse University Hospital (France). Total and unbound concentrations of lopinavir, C reactive protein, albumin, and alpha-1-acid glycoprotein (AAG) levels were measured during routine care on the same samples. In patients with COVID-19, increased total lopinavir concentration is the result of an increased AAG-bound lopinavir concentration, whereas the unbound concentration remains constant, and insufficient to reduce the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral load. Although international guidelines have recently recommended against using lopinavir/ritonavir to treat severe COVID-19, the description of lopinavir pharmacokinetics changes in COVID-19 is a textbook case of the high risk of misinterpretation of a total drug exposure when changes in protein binding are not taken into consideration.


Basilar artery dissection treated by Neuroform stenting: fungal stent infection.
The authors describe a case of basilar artery dissection treated with Neuroform stenting. This new treatment modality for basilar artery dissection may be safer than anticoagulation in patients with subarachnoid hemorrhage. However, complications associated with stenting should be taken into careful consideration. These complications include thromboembolism and stent infection. This 36-year-old white male underwent Neuroform stenting of basilar artery dissection and subsequently developed bilateral pontine infarct and fungal stent infection. This is worrisome in an otherwise healthy 36-year-old. Thromboembolism is a well-known phenomenon with endovascular stenting that may be improved with evolution in stent technology. Fungal infection of Neuroform stent in a patient with no history of immunocompromised status is of major concern. The patient subsequently underwent successful treatment of stent infection through parenteral antifungal agent. This case report highlights the potential pitfalls of Neuroform stenting of basilar artery dissection and potential methods by which to avert these complications. Further evolution in stent technology may help prevent further complications involving Neuroform stenting of basilar artery dissection. In addition, the successful treatment of stent infection through parenteral agent demonstrates the increasing efficacy of novel antifungal agent in the treatment of these infections.


Photosystem II core quenching in desiccated Leptolyngbya ohadii.
Cyanobacteria living in the harsh environment of the desert have to protect themselves against high light intensity and prevent photodamage. These cyanobacteria are in a desiccated state during the largest part of the day when both temperature and light intensity are high. In the desiccated state, their photosynthetic activity is stopped, whereas upon rehydration the ability to perform photosynthesis is regained. Earlier reports indicate that light-induced excitations in Leptolyngbya ohadii are heavily quenched in the desiccated state, because of a loss of structural order of the light-harvesting phycobilisome structures (Bar Eyal et al. in Proc Natl Acad Sci 114:9481, 2017) and via the stably oxidized primary electron donor in photosystem I, namely P700+ (Bar Eyal et al. in Biochim Biophys Acta Bioenergy 1847:1267-1273, 2015). In this study, we use picosecond fluorescence experiments to demonstrate that a third protection mechanism exists, in which the core of photosystem II is quenched independently.


Validity of the Eating Disorders Examination-Questionnaire when used with adolescents with bulimia nervosa and atypical bulimia nervosa.
To validate the online questionnaire form of the Eating Disorders Examination (EDE-Q) against the interview version (EDE) in a clinic and community sample of adolescents with bulimia nervosa (BN) or atypical BN (eating disorder not otherwise specified with bulimic features - EDNOS-BN). Adolescents with BN (N=58) or EDNOS-BN (N=37) completed the EDE over the telephone and the EDE-Q online. There were moderate to high correlations between the attitudinal scales. Eating was rated as more pathological on the EDE-Q than the EDE, except dietary restraint. As in research among adults, agreement between the two measures was low regarding binge eating episodes, but better for vomiting episodes. When compared with the EDE, the EDE-Q attitudinal scales were more valid for BN than for EDNOS-BN patients, and more valid for the clinic sample. The online version of the EDE-Q has partial validity for use with adolescents. The EDE-Q might be reporting a more accurate description of current status, as it avoids possible filtering and approval aspects.


Conditions for dipyridamole potentiation of skeletal muscle active hyperemia.
The effects of dipyridamole on active hyperemia were evaluated in dog gracilis muscles undergoing sustained isometric contractions. Muscles were stimulated to contract for 5, 15, 25, and 50 s at 20% maximal tension (20% Tmax) or for 10 s at 100% Tmax during intra-arterial infusion of either saline or dipyridamole (1 microM). In two separate groups of dogs, muscles were stimulated to contract under free-flow or restricted-flow (ischemic) conditions. In the later group, blood flow was reduced to 50% of precontraction level during the period of contraction. Dipyridamole increased resting vascular conductance by about 45%; however, it did not affect the change in vascular conductance resulting from muscle contraction. The recovery time for active hyperemia following free-flow contractions at 20% Tmax was not altered by dipyridamole. However, dipyridamole increased the recovery time following 50 s of restricted-flow contraction (20% Tmax) and 10 s of 100% Tmax contractions by 46 and 169%, respectively. These results suggest that adenosine contributes to active hyperemia following sustained ischemic contractions at 20% Tmax and contractions at 100% Tmax but not from contractions at 20% Tmax where blood flow is allowed to increase freely.


Synthesis and properties of the monomethyl ester of meso-dimercaptosuccinic acid and its chelates of lead (II), cadmium(II), and mercury(II).
The monomethyl ester of meso-dimercaptosuccinic acid (MoMeDMSA) and its chelates with lead(II), cadmium(II), and mercury(II) have been synthesized. The mercury(II) chelate of MoMeDMSA is formed by the coordination of the two sulfur atoms in MoMeDMSA, whereas the lead(II) and cadmium(II) chelates are formed by the coordination of one sulfur and one oxygen atom. The solubilities of the chelates are pH dependent; the mercury(II) chelate dissolves when the uncoordinated carboxylic acid dissociates, but the lead(II) and cadmium(II) chelates are solubilized only after the uncoordinated mercapto group is dissociated. The cadmium(II) chelate is dimeric and the lead(II) and mercury(II) chelates are monomeric at the concentrations and conditions used in this study. The acid dissociation constants of the chelating agent and the uncoordinated groups in its metal chelates have been determined in 50% v/v methanol-water. These acid-base properties in addition to the polarity of the chelating agent contribute to the effectiveness in the in vivo mobilization of intracellular in vivo deposits of cadmium. The biliary excretion of cadmium in rats increased by a factor of 173 upon administration of the relatively toxic, nonpolar dimethyl ester of DMSA whereas the administration of the less toxic, more polar monomethyl ester increased the biliary excretion of cadmium by a factor of 63. On the other hand, meso-DMSA which is highly polar and less toxic is known to be without effect on biliary excretion of cadmium. The monomethyl DMSA, therefore, appears to have properties that are intermediate between those of DMSA and its dimethyl ester, as far as both chelating properties and biliary excretion of cadmium are concerned.


[Prolonged changes in hormonal homeostasis after brief circulatory arrest in the small intestine].
It has been established that temporary cessation of blood circulation in the rat small intestine induces alterations in the levels of thyroid and glucocorticoid hormones. These alterations are of the wavy character and can be traced up to 2 weeks after the operation that correlates with duration of previously found functional biochemical, and morphological changes.


Influence of the 5' noncoding region of hepatitis A virus strain GBM on its growth in different cell lines.
Previous sequence analysis of consecutive passages of the hepatitis A virus (HAV) strain GBM/WT in human embryonic kidney cells (HEK cells), human embryonic lung fibroblasts (HFS cells) and in FRhK-4 cells (foetal rhesus monkey kidney cells) pointed to a host cell dependent cell culture adaptation of GBM/WT in HFS cells involving mutations in the 5' noncoding region (5'NCR). Multiple nucleotide changes occurred in the 5'NCR of the GBM genome after the cell line used for virus passage was changed from HEK cells to HFS cells. In contrast, no mutations in the 5'NCR occurred during the first 20 passages of GBM/WT in FRhK-4 cells. In order to analyse the influence of the 5'NCR on host cell specific adaptation of HAV strain GBM in different cell cultures, GBM/HM175 chimeras were constructed which contained 5'NCRs from different GBM variants by replacing the 5'NCR of the infectious clone pHAV/7. Parallel transfection assays in FRhK-4 and HFS cells, performed with transcripts from the chimeric GBM/HM175 constructs, showed that the 5'NCR of the GBM variant GBM/HFS is essential for virus growth in HFS cells. The GBM/HM175 chimeric RNA, which contained the 5'NCR of GBM/HFS, exclusively, was able to produce infectious virus after transfection of HFS cells. The growth of the different GBM/HM175 chimeras in FRhK-4 cells, in contrast, did not seem to be strongly influenced by a specific sequence of the 5'NCR.


Allograft reconstruction of the acetabulum in revision hip surgery.
Acetabular deficiencies seen in revision hip arthroplasty require special attention. Custom components, space-filling cement, relocation of the hip center higher on ilium, and resection arthroplasties have all been used. Allograft reconstruction of acetabular defects has many attractive features, but methods of fixation, long-term success rates, and problems of graft resorption and implant loosening present significant questions. This article presents a classification system for acetabular defects and a surgical technique for correcting them. The results of 218 cementless acetabular reconstructions are reviewed and show the importance of the acetabular rim. When the rim is intact, 97% of reconstructions will remain stable, and 78% of allografts used will consolidate. When the acetabular rim is deficient, special techniques using bulk allograft and internal fixation must be used in order to avoid long-term graft resorption and implant loosening.


Non-Gaussian Resistance Fluctuations in Gold-Nanoparticle-Based Gas Sensors: An Appraisal of Different Evaluation Techniques.
Volatile organic compounds, such as formaldehyde, can be used as biomarkers in human exhaled breath in order to non-invasively detect various diseases, and the same compounds are of much interest also in the context of environmental monitoring and protection. Here, we report on a recently-developed gas sensor, based on surface-functionalized gold nanoparticles, which is able to generate voltage noise with a distinctly non-Gaussian component upon exposure to formaldehyde with concentrations on the ppm level, whereas this component is absent, or at least much weaker, when the sensor is exposed to ethanol or to pure air. We survey four different statistical methods to elucidate a non-Gaussian component and assess their pros and cons with regard to efficient gas detection. Specifically, the non-Gaussian component was clearly exposed in analysis using level-crossing parameters, which require nothing but a modest computational effort and simple electronic circuitry, and analogous results could be reached through the bispectrum function, albeit with more intense computation. Useful information could be obtained also via the Lévy-stable distribution and, possibly, the second spectrum.


Development and Evaluation of a Global Burnout Index Derived from the Use of the Copenhagen Burnout Inventory in Portuguese Physicians.
The Copenhagen Burnout Inventory was developed to overcome what some authors have proposed as potential limitations of existing burnout measures. Specifically, the Copenhagen Burnout Inventory measures the main component of burnout (i.e. exhaustion) in three domains: personal-, work- and patient-related. Additionally, some authors have argued the necessity to have available a global burnout index. This study followed a cross-sectional design in a sample of Portuguese physicians (n = 1348). A confirmatory factor analyses was conducted and the Copenhagen Burnout Inventory´s three-factor structure was tested. In addition, a model with a 2nd order factor was tested with the goal of achieving a one-factor structure that would allow a global burnout index. The confirmatory factor analyses showed a good model fit for both the three-factor and one-factor model, having the latter a significant better fit. The Copenhagen Burnout Inventory showed good psychometric properties for both structures, with good reliability according to Chronbach`s alphas and average variance extracted between factors. The Copenhagen Burnout Inventory I was statistically and positively correlated with depression, anxiety and stress symptoms, as well as rumination, and negatively correlated with life satisfaction. The current study shows that the Copenhagen Burnout Inventory is a psychometrically valid measure of burnout in Portuguese physicians, and contributes with an instrument able to produce a global index of burnout. This measure provides comprehensive information on different dimensions associated with the development of burnout, as well as presents a global burnout score. Results show that participants who had more burnout also presented higher levels of depressive, anxiety and stress symptoms, as well as present more ruminative thinking, and less life satisfaction. The Copenhagen Burnout Inventory is a psychometrically valid measure of burnout that allows for exploratory studies on the overall level of exhaustion, thus making it possible the comparison between groups in a way that is not restricted to occupation specific aspects.


Vulvar Paget's disease. Is immunocytochemistry helpful in assessing the surgical margins?
From January 1977 to December 1988, 19 patients with biopsy-proven Paget's disease of the vulva underwent simple or radical vulvectomy at the University of Miami/Jackson Memorial Medical Center. All vulvectomy specimens were evaluated immunocytochemically for the expression of carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA) and low-molecular-weight keratins 8 and 18 (LMK), both in areas containing neoplastic cells and in histologically negative surgical margins. Neoplastic Paget's cells stained positively for CEA in all cases; they were positive for EMA and LMK in 18 and 17 cases, respectively. In all eight cases with underlying in situ or invasive carcinomas, CEA, EMA and LMK were localized in the underlying tumors as well. None of the histologically proven negative margins reacted for CEA, EMA or LMK on immunocytochemistry. CEA appears to be a valuable immunocytochemical marker for extramammary Paget's disease; EMA and LMK are also expressed by the majority of such cases. None of these markers, however, is of added value in identifying Paget's cells in surgical margins if those margins appear negative on routine hematoxylin-and-eosin staining.


[Stress prevention programs--strategies, techniques, effectiveness. Part I. National and international activities to prevent stress at work].
Work stress is nowadays one of the major world-wide problems because of its negative impact on health and socio-economic consequences. Therefore, many organizations, established to protect occupational health and safety, include stress-related issues into their preventive activities. This article is the first part of a broader review of approaches to work stress prevention and existing practices in Europe. It presents anti-stress interventions elaborated and implemented at international and national levels, such as: legal and research initiatives, educational actions, supporting the development of knowledge of occupational stress, and promoting the idea of healthy work place.


What is so special about male adolescent sexual offending? A review and test of explanations through meta-analysis.
We tested special and general explanations of male adolescent sexual offending by conducting a meta-analysis of 59 independent studies comparing male adolescent sex offenders (n = 3,855) with male adolescent non-sex offenders (n = 13,393) on theoretically derived variables reflecting general delinquency risk factors (antisocial tendencies), childhood abuse, exposure to violence, family problems, interpersonal problems, sexuality, psychopathology, and cognitive abilities. The results did not support the notion that adolescent sexual offending can be parsimoniously explained as a simple manifestation of general antisocial tendencies. Adolescent sex offenders had much less extensive criminal histories, fewer antisocial peers, and fewer substance use problems compared with non-sex offenders. Special explanations suggesting a role for sexual abuse history, exposure to sexual violence, other abuse or neglect, social isolation, early exposure to sex or pornography, atypical sexual interests, anxiety, and low self-esteem received support. Explanations focusing on attitudes and beliefs about women or sexual offending, family communication problems or poor parent-child attachment, exposure to nonsexual violence, social incompetence, conventional sexual experience, and low intelligence were not supported. Ranked by effect size, the largest group difference was obtained for atypical sexual interests, followed by sexual abuse history, and, in turn, criminal history, antisocial associations, and substance abuse. We discuss the implications of the findings for theory development, as well as for the assessment, treatment, and prevention of adolescent sexual offending.


Iowa survey of waterborne 222Rn concentrations in private wells.
The major objective of the survey was to describe the distribution of waterborne 222Rn concentrations in Iowa's private well-water supplies. Well-water samples were obtained and analyzed for 222Rn from a random sample of 352 Iowa wells. The well-water 222Rn concentrations for the well sites were lognormally distributed and ranged from background concentrations to 87 Bq L-1, with a median value of 12 Bq L-1. The arithmetic mean 222Rn concentration for the sites was 16 Bq L-1 +/- 13 Bq L-1. The geometric mean 222Rn concentration was 12 Bq L-1 with a geometric standard deviation of 2.2. Over half of the samples (52%) exceeded 11 Bq L-1. Both well depth and indoor air 222Rn screening levels correlated with waterborne 222Rn concentrations; however, these correlations had very little predictive value. Glacial drift aquifers tended to have the highest 222Rn concentrations, although there was significant variance of 222Rn concentrations within all the aquifer classifications. In light of the estimate that 370 Bq L-1 of 222Rn in water may lead to 37 mBq L-1 in indoor air, the contribution of well-water derived indoor air 222Rn is minimal compared to ground sources in Iowa.


Capacity for stochastic self-renewal and differentiation in mammalian spermatogonial stem cells.
Mammalian spermatogenesis is initiated and sustained by spermatogonial stem cells (SSCs) through self-renewal and differentiation. The basic question of whether SSCs have the potential to specify self-renewal and differentiation in a cell-autonomous manner has yet to be addressed. Here, we show that rat SSCs in ex vivo culture conditions consistently give rise to two distinct types of progeny: new SSCs and differentiating germ cells, even when they have been exposed to virtually identical microenvironments. Quantitative experimental measurements and mathematical modeling indicates that fate decision is stochastic, with constant probability. These results reveal an unexpected ability in a mammalian SSC to specify both self-renewal and differentiation through a self-directed mechanism, and further suggest that this mechanism operates according to stochastic principles. These findings provide an experimental basis for autonomous and stochastic fate choice as an alternative strategy for SSC fate bifurcation, which may also be relevant to other stem cell types.


Salt-induced changes in cardiac phosphoproteome in a rat model of chronic renal failure.
Heart damage is widely present in patients with chronic kidney disease. Salt diet is the most important environmental factor affecting development of chronic renal failure and cardiovascular diseases. The proteins involved in chronic kidney disease -induced heart damage, especially their posttranslational modifications, remain largely unknown to date. Sprague-Dawley rats underwent 5/6 nephrectomy (chronic renal failure model) or sham operation were treated for 2 weeks with a normal-(0.4% NaCl), or high-salt (4% NaCl) diet. We employed TiO2 enrichment, iTRAQ labeling and liquid-chromatography tandem mass spectrometry strategy for phosphoproteomic profiling of left ventricular free walls in these animals. A total of 1724 unique phosphopeptides representing 2551 non-redundant phosphorylation sites corresponding to 763 phosphoproteins were identified. During normal salt feeding, 89 (54%) phosphopeptides upregulated and 76 (46%) phosphopeptides downregulated in chronic renal failure rats relative to sham rats. In chronic renal failure rats, high salt intake induced upregulation of 84 (49%) phosphopeptides and downregulation of 88 (51%) phosphopeptides. Database searches revealed that most of the identified phospholproteins were important signaling molecules such as protein kinases, receptors and phosphatases. These phospholproteins were involved in energy metabolism, cell communication, cell differentiation, cell death and other biological processes. The Search Tool for the Retrieval of Interacting Genes analysis revealed functional links among 15 significantly regulated phosphoproteins in chronic renal failure rats compared to sham group, and 23 altered phosphoproteins induced by high salt intake. The altered phosphorylation levels of two proteins involved in heart damage, lamin A and phospholamban were validated. Expression of the downstream genes of these two proteins, desmin and SERCA2a, were also analyzed.


Staff's perception of adolescent aggressive behaviour in four European forensic units: a qualitative interview study.
Aggressive behaviour among patients is extremely common in forensic adolescent psychiatry compromising the safety of the treatment milieu and posing a treatment challenge to the staff. The staff's perception of aggression is likely to contribute to the aggression management practices among disturbed adolescents. To examine staff's perceptions of adolescent aggressive behaviour and factors contributing it. Qualitative interviews were conducted in four adolescent forensic units in four European countries. Data was analysed using qualitative content analysis. Aggressive behaviour was perceived to be verbal and physical in nature with various levels of severity. Several factors were perceived to contribute to aggressive acts, including adolescents' early life experiences. Participants mainly shared perceptions of adolescent aggressive behaviour in the four units studied. The study provides new international knowledge about how staff perceive adolescent aggressive behaviour in the forensic setting. The shared understanding of adolescents' aggressive behaviour enables the implementation of safe, ethically sound and more consistent aggression management in clinical forensic practice. Reduced occurrence of aggression may improve the therapeutic milieu of the unit and may strengthen the staff's occupational health.


Expression profiling of maternal plasma and placenta microRNAs in preeclamptic pregnancies by microarray technology.
Preeclampsia (PE) is one of the leading causes of maternal and fetal morbidity and mortality, occurring usually in the second half of pregnancy and affecting approximately 5-8% of pregnancies in the world. miRNAs play critical role in the regulation of placental development processes. We aimed to determine specific novel miRNAs for early diagnosis of preeclampsia which is one of the most dangerous pregnancy diseases. In this study 72 samples, maternal age 22 ≤ and ≤36, have been analyzed; maternal plasma and placental miRNAs were isolated from 18 severe preeclampsia (sPE) patients and 18 controls, respectively. Profiling of human miRNAs (1368 probe) was performed in samples with Agilent v16 microarrays for detection of the differences in miRNA expression between two groups. The results were validated by using TaqMan RT-qPCR method. The analysis indicated that 406 of these miRNAs in all placentas and 42 of these miRNAs in all maternal plasma were expressed. The relative expression analysis has shown that 12 miRNAs (p < 0.05 and >2-fold) in maternal plasma were differentially expressed in PE and control group. However, five miRNAs were validated by qRT-PCR. Once validated miRNAs have been searched in databases for their target genes and function, it has been shown that there are some preeclampsia related pathways as a target such as angiogenesis, cardiovascular, hypertension, placental abruption and preeclampsia disorders. Differentially expressed and validated plasma miRNAs might be used as notable biomarkers for non-invasive early diagnosis of preeclampsia and treatment of disease.


[Epidemiology, mechanisms of cancerogenesis and prevention of neoplasms].
Primary prevention is the priority in cancer fighting. Smoking control is the most important measure in primary prevention of cancer. Dietary factor is also essential. Modification of diet with an increase in consumption of fresh fruit and vegetables, low-calory products, intensification of physical activity and lowering of body mass produce a reduction in the incidence of cancer of the stomach, large bowel, breast, corpus uteri, prostate. Prevention of infection including vaccination is the most efficient method for prevention of cancer of the liver, cervix uteri, some leukemias and lymphomas, H. pylori associated stomach cancer. Control of environmental hazards such as intensive ultraviolet radiation, ionizing radiation, air and soil pollution decrease the rate of skin cancer, melanoma, etc. The progress in molecular biology allows to modify carcinogenesis at each stage of cancer. Cancer risk assessment can be based not only on the knowledge of carcinogenicity of environmental factor and its dose but also on the information about individual genetic susceptibility. Information about carcinogen-specific somatic genetic damage (finger prints) and tumor-specific molecular changes in oncogenes and tumor suppressor genes can be used for identification of causative factors and early preclinical molecular diagnosis of cancer.


Varifocal diffractive lenses for multi-depth microscope imaging.
Flat optical elements enable the realization of ultra-thin devices able to either reproduce or overcome the functionalities of standard bulky components. The fabrication of these elements involves the structuration of material surfaces on the light wavelength scale, whose geometry has to be carefully designed to achieve the desired optical functionality. In addition to the limits imposed by lithographic design-performance compromises, their optical behavior cannot be accurately tuned afterward, making them difficult to integrate in dynamic optical systems. Here we show the realization of fully reconfigurable flat varifocal diffractive lens, which can be in-place realized, erased and reshaped directly on the surface of an azopolymer film by an all-optical holographic process. Integrating the lens in the same optical system used as standard refractive microscope, results in a hybrid microscope capable of multi-depth object imaging. Our approach demonstrates that reshapable flat optics can be a valid choice to integrate, or even substitute, modern optical systems for advanced functionalities.


Evaluation of Nafamostat as Chemoprophylaxis for SARS-CoV-2 Infection in Hamsters.
The successful development of a chemoprophylaxis against SARS-CoV-2 could provide a tool for infection prevention that is implementable alongside vaccination programmes. Nafamostat is a serine protease inhibitor that inhibits SARS-CoV-2 entry in vitro, but it has not been characterised for chemoprophylaxis in animal models. Clinically, nafamostat is limited to intravenous delivery and has an extremely short plasma half-life. This study sought to determine whether intranasal dosing of nafamostat at 5 mg/kg twice daily was able to prevent the airborne transmission of SARS-CoV-2 from infected to uninfected Syrian Golden hamsters. SARS-CoV-2 RNA was detectable in the throat swabs of the water-treated control group 4 days after cohabitation with a SARS-CoV-2 inoculated hamster. However, throat swabs from the intranasal nafamostat-treated hamsters remained SARS-CoV-2 RNA negative for the full 4 days of cohabitation. Significantly lower SARS-CoV-2 RNA concentrations were seen in the nasal turbinates of the nafamostat-treated group compared to the control (p = 0.001). A plaque assay quantified a significantly lower concentration of infectious SARS-CoV-2 in the lungs of the nafamostat-treated group compared to the control (p = 0.035). When taken collectively with the pathological changes observed in the lungs and nasal mucosa, these data are strongly supportive of the utility of intranasally delivered nafamostat for the prevention of SARS-CoV-2 infection.


High-power, high repetition rate picosecond and femtosecond sources based on Yb-doped fiber amplification of VECSELs.
Picosecond pulses at gigahertz repetition rates from two different passively mode-locked VECSELs are amplified to high powers in cascaded ytterbium doped fiber amplifiers. Small differences in pulse durations between the two VECSELs led to amplification in different nonlinear regimes. The shorter 0.5 ps pulses could be amplified to 53 W of average power in the parabolic pulse regime. This was confirmed by excellent pulse compression down to 110 fs. The VECSEL producing longer 4.6 ps pulses was amplified in an SPM dominated regime up to 200 W of average power but with poor recompressed pulse quality.


Between Concealing and Revealing Intersexed Bodies: Parental Strategies.
Parents of intersex children are perceived in many studies as hopeless, highly dependent on the medical system, and as gate keepers of normative gendered bodies. In this article, we challenge these perceptions and argue that parents of intersex children are problematically positioned between their children's needs for care and well-being and the socialmedical forces that aim to "normalize" them. Their in-between position leads them to establish different parental strategies within and outside of traditional sex/gender norms. We focus on three intertwined parental strategy frameworks: bodily dialogue, sex/gender framing, and concealing/revealing practices, and describe how, in each of these strategic frameworks, the parents maneuver, act in accordance with or against, react to, and challenge the medical system, social interactions, and the sex/gender paradigm. This is a comparative study based on narrative interviews with 22 parents of intersex children in Germany and Israel.