PyTMs: a useful PyMOL plugin for modeling common post-translational modifications.
Post-translational modifications (PTMs) constitute a major aspect of protein biology, particularly signaling events. Conversely, several different pathophysiological PTMs are hallmarks of oxidative imbalance or inflammatory states and are strongly associated with pathogenesis of autoimmune diseases or cancers. Accordingly, it is of interest to assess both the biological and structural effects of modification. For the latter, computer-based modeling offers an attractive option. We thus identified the need for easily applicable modeling options for PTMs. We developed PyTMs, a plugin implemented with the commonly used visualization software PyMOL. PyTMs enables users to introduce a set of common PTMs into protein/peptide models and can be used to address research questions related to PTMs. Ten types of modification are currently supported, including acetylation, carbamylation, citrullination, cysteine oxidation, malondialdehyde adducts, methionine oxidation, methylation, nitration, proline hydroxylation and phosphorylation. Furthermore, advanced settings integrate the pre-selection of surface-exposed atoms, define stereochemical alternatives and allow for basic structure optimization of the newly modified residues. PyTMs is a useful, user-friendly modelling plugin for PyMOL. Advantages of PyTMs include standardized generation of PTMs, rapid time-to-result and facilitated user control. Although modeling cannot substitute for conventional structure determination it constitutes a convenient tool that allows uncomplicated exploration of potential implications prior to experimental investments and basic explanation of experimental data. PyTMs is freely available as part of the PyMOL script repository project on GitHub and will further evolve. Graphical Abstract PyTMs is a useful PyMOL plugin for modeling common post-translational modifications.


Hematopoietic protection by dexamethasone or granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients treated with carboplatin and ifosfamide.
Based on preclinical studies, the authors undertook a pilot study to determine the hematologic and biologic effects of pretreatment with dexamethasone (Dex) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients receiving carboplatin and ifosfamide. Patients (n = 28) with metastatic solid tumors were randomized to receive pretreatment with Dex or GM-CSF or no pretreatment prior to courses 1 or 2 of carboplatin and ifosfamide. No alteration in dose of chemotherapy was allowed between course 1 and 2. Alterations of hematologic and nonhematologic toxicity and selected biologic parameters were compared between courses 1 and 2. Patients without any pretreatment demonstrated worsening hematologic toxicity in course 2 compared to course 1. In contrast, Dex pretreatment reduced hematopoietic toxicity and improved the absolute granulocyte count (AGC) and platelet count recovery times. For example, course 1 versus course 2 (with Dex pretreatment): AGC nadir (mm3) 153 versus 549 (p = 0.07), days AGC <500/mm3 7.8 versus 4.0 (p = 0.10), days to AGC recovery >1,500/mm3, 26 versus 22 (p = 0.034). Overall comparison between all five cohorts by analyses of variance demonstrated that intervention with Dex improved multiple hematopoietic toxicities, including AGC nadir (p = 0.015), and recovery times to AGC >1,500/mm3 (p = 0.07) and platelet count to >100,000/mm3 (p = 0.05). GM-CSF pretreatment did not worsen hematopoietic parameters after course 2 compared to course 1. Expected biologic effects of Dex and GM-CSF treatment were observed. Patients demonstrated an overall response rate of 32%, 1 complete response, and 8 partial responses. In patients with cancer, pretreatment with Dex or GM-CSF may significantly decrease the hematopoietic toxicity of chemotherapeutic agents.


Enablers and challenges of spatial omics, a melting pot of technologies.
Spatial omics has emerged as a rapidly growing and fruitful field with hundreds of publications presenting novel methods for obtaining spatially resolved information for any omics data type on spatial scales ranging from subcellular to organismal. From a technology development perspective, spatial omics is a highly interdisciplinary field that integrates imaging and omics, spatial and molecular analyses, sequencing and mass spectrometry, and image analysis and bioinformatics. The emergence of this field has not only opened a window into spatial biology, but also created multiple novel opportunities, questions, and challenges for method developers. Here, we provide the perspective of technology developers on what makes the spatial omics field unique. After providing a brief overview of the state of the art, we discuss technological enablers and challenges and present our vision about the future applications and impact of this melting pot.


Negative Emotion Differentiation Predicts Psychotherapy Outcome: Preliminary Findings.
Emotion differentiation (ED), the extent to which same-valenced emotions are experienced as distinct, is considered a valuable ability in various contexts owing to the essential affect-related information it provides. This information can help individuals understand and regulate their emotional and motivational states. In this study, we sought to examine the extent to which ED can be beneficial in psychotherapy context and specifically for predicting treatment response. Thirty-two prospective patients with mood and anxiety disorders completed four daily assessments of negative and positive emotions for 30 days before receiving cognitive-behavioral treatment. Depression, stress, and anxiety symptoms severity were assessed pre- and post-treatment using self-reports and clinical interviews. We conducted a series of hierarchical regression models in which symptoms change scores were predicted by ED while adjusting for the mean and variability. We found that negative ED was associated with greater self-reported treatment response (except for anxiety) when negative emotional variability (EV) was included in the models. Probing negative ED and EV's interactive effects suggested that negative ED was associated with greater treatment response (except for anxiety) for individuals with lower EV levels. Results were obtained while controlling for mean negative affect. Our findings suggest that negative ED can benefit psychotherapy patients whose negative emotions are relatively less variable. We discuss the meaning of suppression and interactive effects between affect dynamics and consider possible clinical implications.


Evaluation of optic canal anatomy and symmetry using CT.
We aim to describe the anatomy and symmetry patterns of the optic canal in patients having undergone maxillofacial CT imaging. In this retrospective chart review, we included all patients who received sinus and maxillofacial CT at the University of North Carolina hospitals between 2008 and 2016, without facial or cranial fractures or other medical conditions that would affect optic canal size. We measured the length of ≥75% enclosed canal, minimum cross-sectional area and minimum diameter bilaterally using iNtuition TeraRecon (Durham, North Carolina) and compared bilateral symmetry using a 20 % difference threshold. Each parameter above was compared among white, black, non-white and non-black patients. Of 335 patients, the mean canal length was 5.61±2.22 mm. The mean minimum area was 11.84±3.11 mm2. The mean minimum diameter was 3.28±0.55 mm. A total of 39.4% (132/335) of patients had asymmetric canal lengths, 18.8% (63/335) had asymmetric minimum areas, and 12.5% (42/335) had asymmetric minimum diameters. No differences were found between racial groups. The right optic canal was larger than the left (right: 12.12 mm vs left: 11.55 mm, p<0.0001). Optic canal asymmetry is not uncommon. It may affect risk of papilloedema severity, explain cases of unilateral or asymmetric papilloedema and possibly asymmetric glaucoma.


Influence of tropospheric ozone control on exposure to ultraviolet radiation at the surface.
Improving air quality by reducing ambient ozone (O(3)) will likely lower O(3) concentrations throughout the troposphere and increase the transmission of solar ultraviolet (UV) radiation to the surface. The changes in surface UV radiation between two control scenarios (nominally 84 and 70 ppb O(3) for summer 2020) in the Eastern two-thirds of the contiguous U.S. are estimated, using tropospheric O(3) profiles calculated with a chemistry-transport model (Community Multi-Scale Air Quality, CMAQ) as inputs to a detailed model of the transfer of solar radiation through the atmosphere (tropospheric ultraviolet-visible, TUV) for clear skies, weighed for the wavelengths known to induce sunburn and skin cancer. Because the incremental emission controls differ according to region, strong spatial variability in O(3) reductions and in corresponding UV radiation increments is seen. The geographically averaged UV increase is 0.11 ± 0.03%, whereas the population-weighted increase is larger, 0.19 ± 0.06%, because O(3) reductions are greater in more densely populated regions. These relative increments in exposure are non-negligible given the already high incidence of UV-related health effects, but are lower by an order of magnitude or more than previous estimates.


VARIATION IN OVIPOSITION PREFERENCE OF HELIOTHIS VIRESCENS IN RELATION TO MACROEVOLUTIONARY PATTERNS OF HELIOTHINE HOST RANGE.
When cotton, geranium, petunia, tobacco, tomato, and velvetleaf were presented simultaneously to strains of the Heliothine moth, Heliothis virescens (F.), from Arizona (AZ), Mississippi (MS), and North Carolina (NC), oviposition choices were similar, while a strain from the Virgin Islands (VI) was significantly different from both the AZ and MS strains. In the MS-VI six-host test, the VI strain laid a higher proportion of its eggs on tomato and a lower proportion of its eggs on petunia than did the MS strain. Since petunia and tomato are in the same plant family (Solanaceae), differences between the strains in host preference do not appear to involve traits common to all members of a plant family. In the AZ-VI six-host test, the AZ strain laid a higher percentage of its eggs on tobacco and lower percentages on geranium and velvetleaf (Malvaceae) than did the VI strain. The percentages of eggs laid on cotton (Malvaceae) by the two strains were not significantly different. When moths were placed in cages with only tobacco and geranium, the AZ strain again laid a higher percentage of its eggs on tobacco than did the VI strain. However, when host choice was restricted to tobacco and cotton or velvetleaf and cotton, no significant difference between strains was found. Reciprocal hybrids of the AZ and VI strains were intermediate to the parental stocks in their preference for tobacco over geranium, indicating that a genetic mechanism was responsible for oviposition preference. The relevance of these findings to seemingly rapid fluxes in host range among members of the Heliothinae is discussed.


Time-Resolved Laser-Induced Incandescence Measurements on Aerosolized Nickel Nanoparticles.
This work presents the first quantitative analysis of time-resolved laser-induced incandescence (TiRe-LII) measurements on aerosolized nickel nanoparticles in several gases and over a range of laser fluences. A measurement model composed of spectroscopic and heat transfer submodels is used to recover the particle size distribution parameters and the thermal accommodation coefficient (TAC). A qualitative analysis of the results reveals evidence of nonincandescent laser-induced emission temporally aligned with the laser pulse, and more laser energy is absorbed than can be accounted for from the modeled spectral absorption cross section of the nanoparticles. The TiRe-LII inferred particle size parameters were generally consistent with values found from ex situ transmission electron microscopy (TEM) analysis. The TACs for nickel nanoparticles in polyatomic gases were larger than those in monoatomic gases, which may indicate chemisorption.


[Research priorities and research topics for cardiovascular nursing: the Swiss Research Agenda for Nursing].
Cardiovascular diseases are worldwide a major challenge for the health care system and the number one reason for premature mortality and lost life years. Many accomplishments to reduce risk factors and improve treatment in acute and chronic disease and rehabilitation have been initiated by medical research but were also embraced by nursing research, which provided valuable knowledge about supporting risk factor modification and patients' self-management. Nursing research in the cardiovascular field has a long tradition in the US. In Europe cardiovascular nursing research also developed over the past decade, with increasing participation of Swiss nurse researchers. Efforts in this field of cardiovascular nursing have been made to convey projects in nursing research that help to enhance the health of the population sustainably and improve well-being in patients with acute and chronic courses of cardiovascular disease. Scientific knowledge is pivotal in developing evidence-based nursing interventions. Since both the German and the French speaking part of Switzerland have been lacking a literature-based and expert-supported agenda for nursing research, the aim of the Swiss Research Agenda for Nursing (SRAN) project was to develop an agenda providing researchers, funding agencies, and politics with orientation. This article takes the seven priorities of the SRAN project and links them to the topics of risk factor modification, rehabilitation programs, self-care, and patient education. The article presents the first agenda for cardiovascular nursing for the years 2007 to 2017. The agenda will serve to develop an action plan and to promote nursing research projects in the field of cardiovascular nursing in Switzerland.


Oral implants in patients receiving bisphosphonates: a review and update.
This review is made to establish the convenience of dental implant treatment in patients receiving bisphosphonates or programmed to receive such drugs, with a description of their mechanisms of action and the way in which they can affect the mandibular or maxillary bone of dental implant candidates. In turn, a description is provided of the key elements for evaluating the benefit-risk ratio in patients treated with bisphosphonates who require oral surgery. Clinicians must be aware of the potential risk of osteonecrosis in patients treated with bisphosphonates via the oral or intravenous route. When bisphosphonates are administered via the intravenous route, all invasive oral procedures (including implant surgery) are contraindicated, and should be avoided unless absolutely necessary. The indications are more controversial in the case of bisphosphonates administered via the oral route. There is little literature on the influence of oral bisphosphonates upon bone repair, and there are not many published cases of mandibular or maxillary osteonecrosis among patients that receive such medication. The use of bisphosphonates is becoming increasingly widespread, and the duration of such treatment is increasing. It would be of interest to design studies to evaluate the risk factors of maxillary osteonecrosis among dental implant patients receiving treatment with oral bisphosphonates, and to define biomarkers capable of indicating the level of risk in the event of oral surgery in patients receiving such drugs.


Association of different microbes and pathogenic factors in cases of infectious bovine keratoconjunctivitis in cattle from Eastern Kazakhstan.
Infectious bovine keratoconjunctivitis (IBK) causes a significant economic loss to cattle industries in many countries, including Kazakhstan. Although Moraxella bovis is recognized as an etiologic agent of IBK, other bacterial and viral agents have been suspected to play a role in the pathogenesis of this disease. This study aimed to evaluate samples collected from the eyes of IBK-affected cattle in Eastern Kazakhstan at different stages of IBK for the presence of Mor. bovis, Moraxella bovoculi, Mycoplasma bovis, Mycoplasma bovoculi, and Bovine Herpes Virus Type 1 (BHV-1) and to characterize Mor. bovoculi pilA gene sequence diversity from Mor. bovoculi positive samples. Individual ocular swabs (n = 168) were collected from cattle that had clinical signs of IBK during the summer of 2022 on farms in the Abay region of Kazakhstan. Eye lesion scores (1, 2, and 3) were assigned depending on the degree of ocular damage. Infectious bovine keratoconjunctivitis-associated organisms were detected using a multiplex real-time polymerase chain reaction assay. The Mor. bovoculi pilA gene was sequenced from Mor. bovoculi positive samples. Mycoplasma bovis and BHV-1 were not detected in any of the collected samples. Mycoplasma bovoculi was identified in the majority of samples overall, usually in mixed infection with Moraxella spp. Moraxella bovoculi was detected in 76.2% of animals and predominated in animals with eye lesion scores 2 and 3. Mycoplasma bovoculi was detected only in association with Mor. bovis and/or Mor. bovoculi in animals with eye lesion scores 2 and 3. Moraxella bovis was found in 57.7% of animals and was always identified in association with another organism. Sequencing of the pilA gene in 96 samples from Mor. bovoculi positive samples identified five PilA groups. The majority belonged to PilA group A. However, three new PilA groups were identified and designated PilA groups N, O, and P. The results indicate a high prevalence of Myc. bovoculi and Mor. bovoculi in eyes of cattle with IBK on livestock farms in Eastern Kazakhstan. Additional novel Mor. bovoculi PilA groups were identified.


[Unusual cervical cyst. Adenocarcinoma ex-pleomorphic adenoma of a minor salivary gland].
Cysts with an origin in a malignant tumour of the cervical region are rare. It is even more uncommon that the malignant tumour has its origin in a minor salivary gland as it is the malignant transformation of a pleomorphic adenoma. Some considerations are made regarding its localization, histopathology, diagnosis and therapeuthic attitude, as well as some advices to take into account in order to arrive to the diagnosis and correct treatment in similar cases to the one shown.


[Sonographic detectability of narcotic drug containers in the gastrointestinal tract. Experimental research in the dog].
A "body-pack" is a swallowed plastic or rubber container used by drug smugglers to carry drugs. We report our experience in diagnoses of such packs in vivo. We simulated the pack by stuffing a fingerstall of a latex handglove with a mixture of 10% barium powder and flour to render it radiopaque. Eight serial examinations were made. In each series, an adult Alsatian dog was fed upto 10 such "body-packs". The passage of these packs through the gastrointestinal tract was followed with ultrasound examinations made at 2, 24, and 48 hours postprandially. Immediately after each sonographic localisation of "body-pack" was made, an x-ray examination of the abdomen in this region was also carried out. Ultrasound correctly determined the position of the "body-pack" in 20 out of 24 examinations as compared to x-ray results. In 4 cases ultrasound could not confirm the location of the "pack".


Reliability of scores from physical activity monitors in adults with multiple sclerosis.
We examined the reliability of scores from physical activity monitors in a sample of 193 individuals with multiple sclerosis (MS) who wore a pedometer and an accelerometer for a 7-day period. There were no significant differences among days for the pedometer (p = .12) or the accelerometer (p = .15) indicating that week and weekend days can be analyzed in a single intra-class correlation (ICC) analytic model. The 7 days of monitoring yielded ICC estimates of .93 for both the pedometer and accelerometer, and a minimum of 3 days yielded a reliability of .80 for both the pedometer and accelerometer. Results indicated that physical activity monitor scores are reliable measures of physical activity for individuals with MS.


Endovis Nail versus Dynamic Hip Screw for Unstable Pertrochanteric Fractures: A Feasibility Randomised Control Trial including Patients with Cognitive Impairment.
A prospective, feasibility, randomised study was performed to compare intramedullary versus extramedullary fixation of unstable pertrochanteric fractures and to assess the feasibility of including patients with dementia. From July 2016 to November 2017, 60 consecutive patients with an unstable pertrochanteric (OTA/AO 31-A2) fracture were randomized to either receive a short cephalomedullary nail (Endovis EBA2, Citieffe) or a dynamic hip screw (DHS, Zimmer Biomet). Primary feasibility measures included randomisation, recruitment, and retention rates. Secondary outcomes included peri-operative parameters, patient-reported outcomes and radiographic outcomes. Patients were followed-up at two, four, and twelve weeks. There was no difference in the randomisation rate between patients with and without cognitive impairment. Significantly more patients without cognitive impairment attended the 12-week follow-up. The overall recruitment rate was 0.9 patients per week. Patients treated with the nail had less pain at 2 weeks and less neck collapse, medialisation, and leg shortening at all time points. The rest of secondary outcomes were similar. Patients with dementia can successfully be enrolled in a randomised trial on hip fractures. Patients treated with the Endovis nail had lower levels of pain at two weeks and better radiographic outcomes.


Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies.
To assess the efficacy and safety of tadalafil, a phosphodiesterase 5 (PDE5) inhibitor efficacious for erectile dysfunction and lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH), in population subgroups, using pooled data from 4 international, randomized, placebo-controlled studies in men with LUTS/BPH. The safety database included 1500 men randomized to tadalafil 5 mg once daily or placebo for 12 weeks. Changes in total International Prostate Symptom Score (IPSS), IPSS-quality of life index, and BPH impact index were examined overall, and changes in IPSS or adverse events (AEs) were examined across subgroups of interest. Treatment-group differences were assessed using analysis of covariance. Results of pooled data confirmed that tadalafil (N = 752) resulted in significant improvements from baseline vs placebo (N = 746) in IPSS (mean difference -2.3; P <.001), and also in BPH impact index and IPSS-quality of life index (both P <.001). Subgroup analyses demonstrated that IPSS improvements were significant regardless of baseline LUTS severity (IPSS <20/≥20), age (≤65/>65 years), recent previous use of α-blockers or PDE5 inhibitors, total testosterone level (<300/≥300 ng/dL), or prostate-specific antigen predicted prostate volume (<40/≥40 mL). [corrected] Rates of treatment emergent AEs were comparable between subgroups of baseline age (≤65/>65 years), previous PDE5 inhibitor use, and the presence or absence of pre-existing diabetes, hypertension, or cardiovascular disease (including hypertension), but somewhat higher for recent previous α-blocker use. In these pooled data analyses, tadalafil 5 mg improved LUTS/BPH across subgroups of age, LUTS severity, testosterone levels, and prostate volume. Rates of AEs were similar across the subgroups assessed.


[SURGICAL "NEVER EVENTS" IN THE ANTERIOR CERVICAL APPROACH].
This article deals with incidents which involved damages that could have been prevented. This includes patients who have been suffocated and have suffered irreversible damage, unfortunately, as far as we know, due to the powerlessness of the medical staff who did not act suitably. The disasters have happened as a result of upper respiratory airway obstruction by a blood clot (retropharyngeal hematoma) that developed as a complication after an anterior cervical surgery (spine/carotid artery) or after a sharp cervical injury. The main question that derives from the following cases is whether it was possible to prevent the unnecessary death and/or the severe ongoing disability of the patients by choosing a different form of medical treatment. We are dealing with common practical knowledge, while referring to the importance of the immediate concern about the airway of patients after an anterior cervical surgery both by the nursing and the treating medical staff and also, by the risk managers. Malpractice events are very important educational material for the medical and nursing staff in order to avoid such preventable cases. Right before our eyes, a real revolution is happening in terms of digital medicine. This revolution may change the current comprehension among physicians about medical decisions, diagnosis and treatment selection. All of the above is being done by the rare resource that we possess which is the human resource. However, the problem is that in many medical cases, for instance the ones mentioned in the article, the medical treatment method for the patient will not benefit from digital medicine, moreso, in those cases we depend on the human resource. The purpose of this work is mainly to make an intellectual-behavioral change among medical staff, nurses and physicians, in terms of complaints such as dysphagia or respiratory difficulties after anterior cervical surgery. Time has a crucial role in those emergency cases, therefore complete seriousness, caution and a rapid airway opening are demanded in the described circumstances.


[Nonoperative approach to injuries of the lateral collateral ligament of the ankle joint].
Patients in number of 185 were included in this study. All of them were treated nonoperatively. One group (64 patients) was treated with early mobilization treatment and the other one (121 patients) with three weeks cast immobilization. Checking examination was done twice: 5 weeks and one year after injury. Chi-square test was used for data processing. Patients treated with cast had shorter recovery, but three were not statistical differences. Positive ADS test one year after the injury (I group 4.7%, and II group 2.5%) was considered as poor result and so was functional instability a year after injury (positive Romberg test, I group 12%, and II group 6.6%). Repeated injury was poor result also. In the first group there were 13.33% repeated injuries and in the second 4.95%.


Activity of glycogen depolymerizing enzymes in extracts from brain tumor tissue (anaplastic astrocytoma and glioblastoma multiforme).
An approximately threefold increase in glycogenolytic activity of the neutral alpha-1,4-glucosidase and a twofold increase in the same activity of the acid isoform have been found in extracts of anaplastic astrocytoma and glioblastoma multiforme tumors of brain tissue. "Maltase activity" of the respective enzymes increased by 60-80% in both kinds of tumor extracts. However a significant decrease in a-amylase and almost complete disappearance of phosphorylase activities have also been found in both kinds of tumors.


A virtual screening method for prediction of the HERG potassium channel liability of compound libraries.
A computer-based method has been developed for prediction of the hERG (human ether-à-go-go related gene) K(+)-channel affinity of low molecular weight compounds. hERG channel blockage is a major concern in drug design, as such blocking agents can cause sudden cardiac death. Various techniques were applied to finding appropriate molecular descriptors for modeling structure-activity relationships: substructure analysis, self-organizing maps (SOM), principal component analysis (PCA), partial least squares fitting (PLS), and supervised neural networks. The most accurate prediction system was based on an artificial neural network. In a validation study, 93 % of the nonblocking agents and 71 % of the hERG channel blockers were correctly classified. This virtual screening method can be used for general compound-library shaping and combinatorial library design.


Reductive Aldol-type Reactions in the Synthesis of Pharmaceuticals.
The efficient chemo-, regio- and stereoselective formation of saturated carbon-carbon fragment is the critical challenge of organic synthesis; therefore, developing new methods for formation of these bonds is paramount. The rising interest for reductive aldol-type reactions is conditioned by its versatile applications, allowing the efficient formation of carbon-carbon bonds. The review aims to highlight the advantages and disadvantage of reductive aldol-type reactions to total synthesis of pharmaceutical substances in order to summarize knowledge and encourage further investigation of the field.


Translocation of group 1 capsular polysaccharide in Escherichia coli serotype K30. Structural and functional analysis of the outer membrane lipoprotein Wza.
The late steps in assembly of capsular polysaccharides (CPS) and their translocation to the bacterial cell surface are not well understood. The Wza protein was shown previously to be required for the formation of the prototype group 1 capsule structure on the surface of Escherichia coli serotype K30 (Drummelsmith, J., and Whitfield, C. (2000) EMBO J. 19, 57-66). Wza is a conserved outer membrane lipoprotein that forms multimers adopting a ringlike structure, and collective evidence suggests a role for these structures in the export of capsular polymer across the outer membrane. Wza was purified in the native form and with a C-terminal hexahistidine tag. WzaHis6 was acylated and functional in capsule assembly, although its efficiency was slightly reduced in comparison to the native Wza protein. Ordered two-dimensional crystals of WzaHis6 were obtained after reconstitution of purified multimers into lipids. Electron microscopy of negatively stained crystals and Fourier filtering revealed ringlike multimers with an average outer diameter of 8.84 nm and an average central cavity diameter of 2.28 nm. Single particle analysis yielded projection structures at an estimated resolution of 3 nm, favoring a structure for the WzaHis6 containing eight identical subunits. A derivative of Wza (Wza*) in which the original signal sequence was replaced with that from OmpF showed that the native acylated N terminus of Wza is critical for formation of normal multimeric structures and for their competence for CPS assembly, but not for targeting Wza to the outer membrane. In the presence of Wza*, CPS accumulated in the periplasm but was not detected on the cell surface. Chemical cross-linking of intact cells suggested formation of a transmembrane complex minimally containing Wza and the inner membrane tyrosine autokinase Wzc.


A note on familywise error rate for a primary and secondary endpoint.
Hung et al. (2007) considered the problem of controlling the type I error rate for a primary and secondary endpoint in a clinical trial using a gatekeeping approach in which the secondary endpoint is tested only if the primary endpoint crosses its monitoring boundary. They considered a two-look trial and showed by simulation that the naive method of testing the secondary endpoint at full level α at the time the primary endpoint reaches statistical significance does not control the familywise error rate at level α. Tamhane et al. (2010) derived analytic expressions for familywise error rate and power and confirmed the inflated error rate of the naive approach. Nonetheless, many people mistakenly believe that the closure principle can be used to prove that the naive procedure controls the familywise error rate. The purpose of this note is to explain in greater detail why there is a problem with the naive approach and show that the degree of alpha inflation can be as high as that of unadjusted monitoring of a single endpoint.


[Clinical comprehensive evaluation of Reyanning Mixture in treatment of acute upper respiratory tract infection (heat-toxin attacking lung syndrome)].
This study systematically sorted out the evidence data of the safety, effectiveness, economy, innovation, suitability, accessibility, and characteristics of traditional Chinese medicine(TCM) of Reyanning Mixture in the treatment of acute upper respiratory tract infection(heat-toxin attacking lung syndrome) with the qualitative and quantitative evaluation methods adopted. Based on evidence-based medicine, epidemiology, clinical medicine, evidence-based pharmacy, pharmacoeconomics, and health technology evalua-tion(HTA), the clinical value of Reyanning Mixture was evaluated using multi-criteria decision analysis(MCDA) model, Chinese patent medicine clinical evidence, and value evaluation software(CSC v2.0). The SRS monitoring data, Meta-analysis, and other safety evidence showed that the main adverse reactions of Reyanning Mixture were nausea, diarrhea, and rash, and no serious adverse reactions were found. The pharmacovigilance system was sound, and the system was perfect. There was no recall, notification, or interview for unqualified products. Based on the existing research, the evidence was sufficient, and the risk was controllable. Hence, its safety was grade A. Meta-analysis showed that in the treatment of acute upper respiratory tract infection, Reyanning Mixture combined with Amoxicillin Capsules was better than Amoxicillin Capsules alone in shortening the complete fever relief time and improving the cure rate. Besides, it was superior to Shuanghuanglian Granules in shortening the complete fever relief time, cough relief time, nasal congestion relief time, and pharyngeal congestion relief time. The Meta-analysis was conducted based on AMSTAR standard, and its ove-rall quality was proved good. The evidence quality in GRADE system evaluation was medium and low. The quality of evidence was medium, and the clinical value was obvious. Hence, its effectiveness was grade A. The results of pharmacoeconomic research showed that compared with Amoxicillin Capsules, Reyanning Mixture alone or in combination with Amoxicillin Capsules had cost-effectiveness advantages in the treatment of acute upper respiratory tract infection, and the results were stable in sensitivity analysis. According to the CASP economic evaluation checklist, the research problems were clear and the results were reliable. As revealed by the comprehensive evaluation, the evidence quality was sufficient and the result was clear. Its economy was grade B. Reyanning Mixture had multiple therapeutic targets like anti-virus, anti-bacteria, antipyresis, and anti-cough, with good clinical innovation. There were many innovative initiatives in ensuring drug supply, especially at the grass roots, drug safety, and effectiveness, and also multiple innovative contributions to production technology, quality control, scientific and technological research and development, and enterprise management and marketing. Therefore, its innovation was grade B. The dosage form of Reyanning was mixture, which made it convenient for storage and transportation. The usage was easy to be mastered and accepted by doctors and nurses, exhibiting good suitability for clinicians, nurses, pharmacists, and patients who received this drug and basically meeting the needs of clinical medication. The suitability was grade B. The average daily cost of this drug was 8.082 yuan, and the price was low. The treatment cost accounted for a small proportion of the annual disposable income of urban and rural residents, indicating that it was affordable. Reyanning Mixture was available in 31 provinces, cities and autonomous regions, covering 6 910 hospitals. The allocation of hospitals at all levels was more than 50%. There was no shortage or supply restriction of medicinal material resources. The annual production capacity was sufficient to meet the supply demand, so its accessibility was grade A. Reyanning Mixture, sourced from "pneumonia Ⅲ", has been subjected to a real-world study of its clinical application, with 4 367 cases involved, and the characteristic of TCM was grade B. The comprehensive evaluation results demonstrated that the clinical value score of Reyanning Mixture in the treatment of acute upper respiratory tract infection(heat-toxin attacking lung syndrome) was 0.80, making it rated class A. According to the Guidelines for Management of Comprehensive Clinical Evaluation of Drugs(trial version 2021), it is recommended to convert it into the relevant policy results of basic clinical medication management according to the procedures.


Pre- or postoperative interscalene block and/or general anesthesia for arthroscopic shoulder surgery: a retrospective observational study.
Arthroscopic shoulder surgery can be performed with an interscalene brachial plexus block (ISBPB) alone, ISBPB combined with general anesthesia (GA), or GA alone. Postoperative pain is typically managed with opioids; however, both GA and opioids have adverse effects which can delay discharge. This retrospective study compares the efficacy of four methods of anesthesia management for arthroscopic shoulder surgery. Charts of all patients who underwent shoulder surgery by a single surgeon from 2012-2015 were categorized by analgesic regimen: GA only (n = 177), single-shot ISBPB only (n = 124), or pre- vs postoperative ISBPB combined with GA (ISBPB + GA [n = 72] vs GA + ISBPB [n = 52], respectively). The primary outcome measure was the time to discharge from the postanesthesia care unit (PACU). Mean (SD) time in the PACU ranged from 70.5 (39.9) min for ISBPB only to 111.2 (56.9) min for GA only. Use of ISBPB in any combination and regardless of timing resulted in significantly reduced PACU time, with a mean drop of 27.2 min (95% confidence interval [CI], 17.3 to 37.2; P < 0.001). The largest mean pairwise difference was between GA only and ISBPB only, with a mean difference of 40.7 min (95% CI, 25.5 to 55.8; P < 0.001). Use of ISBPB also reduced pain upon arrival at the PACU and, in some cases, upon discharge from the PACU (i.e., ISBPB only but not ISBPB + GA compared with GA). An ISBPB (alone or prior to GA) also reduced analgesic requirements. Previously reported benefits of an ISBPB for arthroscopic shoulder surgery are confirmed. Postoperative ISBPBs may also be beneficial for reducing pain and opioid requirements and could be targeted for patients in severe pain upon emergence. A sufficiently powered randomized-controlled trial could determine the relative efficacy, safety, and associated financial implications associated with each method.


Nobiletin and 3'-Demethyl Nobiletin Activate Brown Adipocytes upon β-Adrenergic Stimulation.
Brown adipose tissue (BAT) specifically regulates energy expenditure via heat production. Nobiletin (NOB), a natural polymethoxylated flavone present in citrus fruits, can activate thermogenesis in the BAT of high-fat diet-induced obese mice. The activity of BAT is directly regulated by β-adrenergic stimulation. In this study, we report the effects of NOB on BAT activation using β-adrenergic agonists. We observed that when HB2 brown adipocyte cell lines are stimulated with β-adrenergic agonists, NOB enhances the expression of uncoupling protein 1 (UCP1), which is associated with the mitochondrial energy metabolism in these cells. Moreover, NOB increases the mRNA expression of the brown adipokines neuregulin-4 (Nrg4) and fibroblast growth factor-21 (FGF-21) and the secretion of FGF-21. These results suggest that NOB can enhance the thermogenic functions of brown adipocytes and promote brown adipokine secretion due to enhanced β-adrenergic stimulation. In addition, 3'-demethyl nobiletin (3'-DMN), an NOB CYP-enzyme metabolite, can increase UCP1 mRNA expression. Both NOB and 3'-DMN significantly promoted mitochondrial membrane potential in HB2 adipocytes following β-adrenergic stimulation. Therefore, we believe that NOB could be a promising candidate for activating BAT under β-adrenergic stimulation and preventing the onset of obesity.


Pyrido-pyrimidine derivative CYC10424 inhibits glycosaminoglycan changes on vascular smooth muscle-derived proteoglycans and reduces lipoprotein binding.
Cardiovascular disease is a major cause of mortality with the underlying process being atherosclerosis. Modified proteoglycans bind low-density lipoproteins (LDL), a critical initial step in the atherosclerotic cascade, representing a potential therapeutic target. Platelet-derived growth factor (PDGF) stimulates proteoglycan synthesis and is strongly implicated in atherogenesis. In human vascular smooth muscle cells (VSMCs), CYC10424 (Cytopia Research Ltd), a pyrido-pyrimidine derivative, dose-dependently decreased PDGF-mediated radiolabel incorporation into proteoglycans associated with an increase in electrophoretic mobility by SDS-PAGE. PDGF stimulated increases in both chemically-cleaved and xyloside-associated glycosaminoglycan (GAG) chain size, which were inhibited in the presence of CYC10424 by size exclusion chromatography (Sepharose CL-6B). CYC10424 treatment inhibited the PDGF effect to increase the 6:4 position sulfation ratio of monosulfated disaccharides by fluorophore-assisted carbohydrate electrophoresis. Proteoglycans derived from cells treated with CYC10424 had a decreased binding affinity and capacity to human LDL by gel mobility shift assay. CYC10424 and related compounds are possible candidates as therapeutic agents for the prevention of lipid deposition as characteristic of diseases such as atherosclerosis.


The relationship between histologic chorioamnionitis and decidual macrophage polarization and their influence on outcomes of neonates born before the 32nd gestational week.
To explore the relationship between histologic chorioamnionitis (HCA) and decidual macrophage (DM) polarization and their influence on outcomes of neonates born before the 32nd gestational week. Eighty-four neonates and their placentas were included in this retrospective case-control study and divided into two groups: with and without HCA present (HCA + and HCA-). Neonatal, maternal, and placental risk factors were explored and their influence on neonatal outcomes was examined. We used CD68 and iNOS as markers for polarized DMs type 1 (M1) and CD163, CD206 and arginase (Arg-1) for polarized DMs type 2 (M2). HCA was present in 47 (56%) cases, and 37 (44%) cases were without the present HCA. There was no statistically significant difference in neonatal risk factors between the two groups (HCA + and HCA-). Higher rates of HCA (p = .042) were observed in mothers who received antepartum corticosteroid therapy. The frequency of vaginal deliveries in HCA + pregnancies was significantly higher than in HCA- pregnancies where deliveries by cesarean section were more frequently observed (p < .001). M2 DM were more abundant in the HCA + group (p = .035). Multiple regression model assessed the association between the presence of HCA, M1, and M2 DM with ROP stages. It has been observed that HCA is a risk factor for ROP stages (β coefficient = 0.34, rpartial = 0.246, p = .024). With the logistic regression model, the association between the presence of HCA, M1, and M2 DM with neonatal nCPAP respiratory support and necrotizing enterocolitis (NEC) was assessed. The presence of M2 macrophages in decidua is an independent risk factor for neonatal nCPAP respiratory support (coefficient -0.07, OR = 0.928, 95% CI 0.87-0.99, p = .024) and the presence of M1 macrophages in decidua increases the risk for NEC (coefficient 0.010, OR = 1.0108, 95% CI 1.00-1.02, p = .032). The significantly more abundant presence of M2 DM was detected in HCA + placentas and their association with the increased risk for neonatal nCPAP respiratory support was observed. On the contrary, the presence of M1 DM increases the risk for NEC. The presence of HCA is a risk factor for ROP stages.


Three-dimensional printer-assisted reduction genioplasty; surgical guide fabrication.
Genioplasty is a common operation to enhance function and appearance of the chin, the most prominent part of the lower third of the face, which has major impact on character impressions and facial beauty. However, since transference of preconfigured accurate treatment plans to patients during operation is difficult, sometimes it can be challenging, especially for inexperienced surgeons. This article represents a simplified technique to perform reduction genioplasty by utilizing a customized genioplasty guide manufactured with three-dimensional printing technology. This approach is helpful to achieve more precise and safer outcomes with fewer complications.


No secondary impact of ivermectin mass drug administration for onchocerciasis elimination on the prevalence of scabies in northwestern Ethiopia.
Mass drug administration (MDA) is among the five major strategies that are currently in use to control, eliminate or eradicate Neglected Tropical Diseases (NTDs). Optimising MDA to control multiple NTDs maximises impact. The objective of this study is to estimate the secondary impact of ivermectin MDA for onchocerciasis on the prevalence of scabies. This quasi-experimental study was conducted in Ayu Guagusa district, northwestern Ethiopia. Scabies prevalence was estimated in surveys before the MDA, at 6 and 12 months afterwards. The sample size was 1437 people from a panel of 381 randomly selected study households. Multistage sampling was employed in randomly selecting six kebeles (the lowest administrative unit) with respective gotes (small villages) and households. All members of the selected households were invited to participate in the study and participants who were available in all three surveys formed a cohort. Scabies prevalence was similar prior to the MDA (13.4%, 95% CI 11.7 to 15.2%) and 6 months after (11.7%, 95% CI 10.1 to 13.2%) but was substantially greater at 12 months (22.1%, 95% CI 20.1 to 24.1%). The 6-month incidence and disappearance rates were 10.8% (95% CI 8.8 to 13.2%) and 82.6% (95% CI 75.0 to 88.6%), respectively. Ivermectin MDA for onchocerciasis was not observed to have a secondary impact on the prevalence of scabies over the follow-up period of 12 months.


Cage model of polar fluids: Finite cage inertia generalization.
The itinerant oscillator model describing rotation of a dipole about a fixed axis inside a cage formed by its surrounding polar molecules is revisited in the context of modeling the dielectric relaxation of a polar fluid via the Langevin equation. The dynamical properties of the model are studied by averaging the Langevin equations describing the complex orientational dynamics of two bodies (molecule-cage) over their realizations in phase space so that the problem reduces to solving a system of three index linear differential-recurrence relations for the statistical moments. These are then solved in the frequency domain using matrix continued fractions. The linear dielectric response is then evaluated for extensive ranges of damping, dipole moment ratio, and cage-dipole inertia ratio and along with the usual inertia corrected microwave Debye absorption gives rise to significant far-infrared absorption with a comb-like structure of harmonic peaks. The model may be also regarded as an extension of Budó's [J. Chem. Phys. 17, 686 (1949)] treatment of molecules containing rotating polar groups to include inertial effects.


Chronic Pruritus of Unknown Origin: Clinical Profile and Disease-Related Burden.
Chronic pruritus of unknown origin is established when no underlying origin for pruritus can be determined. This retrospective cohort study aimed to determine the clinical profile and disease-related burden of chronic pruritus of unknown origin. A total of 263 patients (female/male: 154/109, median age 55 years) were included. Moderate to severe itch intensities were recorded (median average itch: 5.5/10, n = 200; median worst itch: 7.5/10, n = 199). In most cases pruritus lasted longer than 1 year (77.6%), occurred daily (68.2%), occurred in attacks (72.8%), and was often accompanied by dysaesthesias, such as burning, tingling and stinging. Quality of life was moderately impaired, while 22.2% and 12.4% of patients showed pathological anxiety and depression scores. Scratch lesions were associated with higher intensities of itch and greater impairment of quality of life, while women were more burdened by the disease than men. Chronic pruritus of unknown origin may occur at any age and the majority of patients endure severe itch with substantial disease-related burden.


Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials.
Two identical, phase 3, randomized, double-blind, placebo-controlled trials evaluated the efficacy and safety of plecanatide in patients with irritable bowel syndrome with constipation (IBS-C). Adults meeting Rome III criteria for IBS-C were randomized (1:1:1) to placebo or plecanatide (3 or 6 mg) for 12 weeks. The primary efficacy end point was the percentage of overall responders (patients reporting ≥30% reduction from baseline in worst abdominal pain plus an increase of ≥1 complete spontaneous bowel movement (CSBM)/week from baseline in the same week for ≥6 of 12 treatment weeks). Safety was assessed by adverse events (AEs). Overall, 2189 individuals were randomized across the two studies and 1879 completed the studies. Demographic and baseline characteristics were similar across treatment groups and between studies. The percentage of overall responders in Study 1 was 30.2% and 29.5% for plecanatide 3 and 6 mg, respectively, vs. 17.8% placebo (P < 0.001 for each dose vs. placebo), and in Study 2 was 21.5% (P = 0.009) and 24.0% (P < 0.001) for plecanatide 3 and 6 mg, respectively, compared to 14.2% for placebo. The percentage of sustained efficacy responders (overall responders plus weekly responders for ≥2 of last 4 weeks of the 12-week treatment period) was significantly greater for both doses of plecanatide vs. placebo across both studies. All secondary end points (stool frequency/consistency, straining, abdominal symptoms) showed statistically significant improvements compared with placebo. The most common AE was diarrhea (3 mg, 4.3%; 6 mg, 4.0%; placebo, 1.0%). Discontinuation due to diarrhea was infrequent (3 mg, 1.2%; 6 mg, 1.4%; placebo, 0). Plecanatide significantly improved both abdominal pain and constipation symptoms of IBS-C with minimal associated side effects and high levels of tolerability.


Molecular Mechanism for PACAP 38-Induced Neurite Outgrowth in PC12 Cells.
The present research investigates the molecular mechanism of neurite outgrowth (protrusion elongation) under pituitary adenylate cyclase-activating polypeptide (PACAP) 38 treatments using a rat adrenal-derived pheochromocytoma cell line-PC12. This study specifically looks into the regulation of PACAP38-induced collapsing response mediator protein 2 (CRMP2) previously identified in a mouse brain ischemia model and which could be recovered by PACAP38 treatment. Previously, DNA microarray analysis revealed that PACAP 38-mediated neuroprotection involved not only CRMP2 but also pathways related to glycogen synthase kinase-3β (GSK-3β) and other signaling components. Thus, to clarify whether CRMP2 acts directly on PACAP38 or through GSK-3β as part of the mechanism of PACAP38-induced neurite outgrowth, we observed neurite outgrowth in the presence of GSK-3β inhibitors and activators. PC12 cells were treated with PACAP38 being added to the cell culture medium at concentrations of 10-7 M, 10-8 M, and 10-9 M. Post PACAP38 treatment, immunostaining was used to confirm protrusion elongation of the PC12 cells, while RT-PCR, two-dimensional gel electrophoresis in conjunction with Western blotting, and inhibition experiments were performed to confirm the expression of the PACAP gene, its receptors, and downstream signaling components. Our data show that neurite protrusion elongation by PACAP38 (10-7 M) in PC12 cells is mediated through the PAC1-R receptor as demonstrated by its suppression by a specific inhibitor PA-8. Inhibitor experiments suggested that PACAP38-triggered neurite protrusion follows a GSK-3β-regulated pathway, where the AKT and cAMP/ERK pathways are involved and where the inhibition of Rho/Roc could enhance neurite protrusion under PACAP38 stimulation. Although we could not yet confirm the exact role and position of CRMP2 in PACAP38-mediated PC12 cell elongation, it appears that its phosphorylation and dephosphorylation have a correlation with the neurite protrusion elongation through the interplay of CDK5, which needs to be investigated further.


Amelioration of dextran sulfate sodium-induced colitis in mice by oral administration of beta-caryophyllene, a sesquiterpene.
beta-Caryophyllene (BCP), a naturally occurring plant sesquiterpene, was examined for anti-inflammatory activity in a mouse model of experimental colitis induced by dextran sulfate sodium (DSS). Colitis was induced by exposing male BALB/c mice to 5% DSS in drinking water for 7 days. BCP in doses of 30 and 300 mg/kg was administered orally once a day, beginning concurrently with exposure to DSS. The body weight and colon length were measured, and histological damage and myeloperoxidase (MPO) activity as well as inflammatory cytokines were assessed in both serum and colonic tissue after 7 days of treatment with DSS. The DSS treatment damaged the colonic tissue, increased MPO activity and inflammatory cytokines, lowered the body weight, and shortened the length of the colon. Oral administration of BCP at 300 mg/kg significantly suppressed the shortening of colon length and slightly offset the loss of body weight. BCP treatment (300 mg/kg) also significantly reduced the inflammation of colon and reversed the increase in MPO activity that had been induced by exposure to DSS. Further, BCP significantly suppressed the serum level of IL-6 protein (a 55% reduction) as well as the level of IL-6 mRNA in the tissue. These results demonstrate that BCP ameliorates DSS-induced experimental colitis, and may be useful in the prevention and treatment of colitis.


CDK11 negatively regulates Wnt/β-catenin signaling in the endosomal compartment by affecting microtubule stability.
Objectives: Improper activation of Wnt/β-catenin signaling has been implicated in human diseases. Beyond the well-studied glycogen synthase kinase 3β (GSK3β) and casein kinase 1 (CK1), other kinases affecting Wnt/β-catenin signaling remain to be defined. Methods:To identify the kinases that modulate Wnt/β-catenin signaling, we applied a kinase small interfering RNA (siRNA) library screen approach. Luciferase assays, immunoblotting, and real-time polymerase chain reaction (PCR) were performed to confirm the regulation of the Wnt/β-catenin signaling pathway by cyclin-dependent kinase 11 (CDK11) and to investigate the underlying mechanism. Confocal immunofluorescence, coimmunoprecipitation (co-IP), and scratch wound assays were used to demonstrate colocalization, detect protein interactions, and explore the function of CDK11. Results: CDK11 was found to be a significant candidate kinase participating in the negative control of Wnt/β-catenin signaling. Down-regulation of CDK11 led to the accumulation of Wnt/β-catenin signaling receptor complexes, in a manner dependent on intact adenomatosis polyposis coli (APC) protein. Further analysis showed that CDK11 modulation of Wnt/β-catenin signaling engaged the endolysosomal machinery, and CDK11 knockdown enhanced the colocalization of Wnt/β-catenin signaling receptor complexes with early endosomes and decreased colocalization with lysosomes. Mechanistically, CDK11 was found to function in Wnt/β-catenin signaling by regulating microtubule stability. Depletion of CDK11 down-regulated acetyl-α-tubulin. Moreover, co-IP assays demonstrated that CDK11 interacts with the α-tubulin deacetylase SIRT2, whereas SIRT2 down-regulation in CDK11-depleted cells reversed the accumulation of Wnt/β-catenin signaling receptor complexes. CDK11 was found to suppress cell migration through altered Wnt/β-catenin signaling. Conclusions: CDK11 is a negative modulator of Wnt/β-catenin signaling that stabilizes microtubules, thus resulting in the dysregulation of receptor complex trafficking from early endosomes to lysosomes.


Flocking of two unfriendly species: The two-species Vicsek model.
We consider the two-species Vicsek model (TSVM) consisting of two kinds of self-propelled particles, A and B, that tend to align with particles from the same species and to antialign with the other. The model shows a flocking transition that is reminiscent of the original Vicsek model: it has a liquid-gas phase transition and displays micro-phase-separation in the coexistence region where multiple dense liquid bands propagate in a gaseous background. The interesting features of the TSVM are the existence of two kinds of bands, one composed of mainly A particles and one mainly of B particles, the appearance of two dynamical states in the coexistence region: the PF (parallel flocking) state in which all bands of the two species propagate in the same direction, and the APF (antiparallel flocking) state in which the bands of species A and species B move in opposite directions. When PF and APF states exist in the low-density part of the coexistence region they perform stochastic transitions from one to the other. The system size dependence of the transition frequency and dwell times show a pronounced crossover that is determined by the ratio of the band width and the longitudinal system size. Our work paves the way for studying multispecies flocking models with heterogeneous alignment interactions.


The diversity of major histocompatibility complex class II DRB1 gene in sheep breeds from Xinjiang, China.
Exon 2 of the ovine leukocyte antigen OLA-DRB1 locus was examined in sheep from the Xinjiang Karakul Ram and Bashibai populations, and three generations of hybrids were derived from a cross between Bashibai and Altai Argali wild sheep. This identified 12 novel alleles and 30 previously reported alleles. A neighbor-joining tree of the amino acid sequences of these 42 alleles revealed allelic clusters shared across the study populations. There were significant differences in allelic frequency between Karakul Ram and Bashibai sheep. DRB1*K18cC was the most frequent allele in Kararul Ram with a frequency of 21.2%, while DRB1*2F10c8 (13.2%) and DRB1*0803 (13.2%) were the most frequent alleles found in Bashibai sheep; the alleles DRB1*2F16c2, DRB1*1601, and DRB1*0803 occurred most frequently in F1, F2, and F3 populations, with frequencies of 17.6%, 14.3%, and 20%, respectively. Although many alleles were shared by Bashibai and hybrid sheep, some alleles differed between them, especially in the F1 generation of the Bashibai × Altai Argali cross. The hybrid-specific alleles indicated the introgression of Altai Argali alleles into hybrid flocks. A population tree based on the OLA-DRB1 allelic frequency in each population indicated that the Bashibai sheep and three hybrid populations were similar, with Karakul Ram being genetically distinct.


Unstable periodic solutions embedded in a shell model turbulence.
An approach to intermittency of a shell model turbulence is proposed from the viewpoint of dynamical systems. We detected unstable solutions of the Gledzer-Ohkitani-Yamada shell model and studied their relation to turbulence statistics. One of the solutions has an unstable periodic orbit (UPO), which shows an intermittency where the scaling exponents of the structure function have a nonlinear dependence on its order, quite similar to that of turbulence solution at the same parameter values. The attractor in the phase space is found to be well approximated by a continuous set of solutions generated from the UPO through a one-parameter phase transformation, which implies that the intermittency of the shell model turbulence is described by this UPO.


Genetic diversity of species Fowl aviadenovirus D and Fowl aviadenovirus E.
Complete genomes of eight reference strains representing different serotypes within the species Fowl aviadenovirus D (FAdV-D) and Fowl aviadenovirus E (FAdV-E) were sequenced. The sequenced genomes of FAdV-D and FAdV-E members comprise 43 287 to 44 336 bp, and have a gene organization identical to that of an earlier sequenced FAdV-D member (strain A-2A). Highest diversity was noticed in the hexon and fiber genes and ORF19. All genomes sequenced in this study contain one fiber gene. Phylogenetic analyses and G+C content support the division of the genus Aviadenovirus into the currently recognized species. Our data also suggest that strain SR48 should be considered as FAdV-11 instead of FAdV-2 and similarly strain HG as FAdV-8b. The present results complete the list of genome sequences of reference strains representing all serotypes in species FAdV-D and FAdV-E.


Development Considerations for Nanocrystal Drug Products.
Nanocrystal technology has emerged as a valuable tool for facilitating the delivery of poorly water-soluble active pharmaceutical ingredients (APIs) and enhancing API bioavailability. To date, the US Food and Drug Administration (FDA) has received over 80 applications for drug products containing nanocrystals. These products can be delivered by different routes of administration and are used in a variety of therapeutic areas. To aid in identifying key developmental considerations for these products, a retrospective analysis was performed on the submissions received by the FDA to date. Over 60% of the submissions were for the oral route of administration. Based on the Biopharmaceutics Classification System (BCS), most nanocrystal drugs submitted to the FDA are class II compounds that possess low aqueous solubility and high intestinal permeability. Impact of food on drug bioavailability was reduced for most nanocrystal formulations as compared with their micronized counterparts. For all routes of administration, dose proportionality was observed for some, but not all, nanocrystal products. Particular emphasis in the development of nanocrystal products was placed on the in-process tests and controls at critical manufacturing steps (such as milling process), mitigation and control of process-related impurities, and the stability of APIs or polymorphic form (s) during manufacturing and upon storage. This emphasis resulted in identifying challenges to the development of these products including accurate determination of particle size (distribution) of drug substance and/or nanocrystal colloidal dispersion, identification of polymorphic form (s), and establishment of drug substance/product specifications.


[General tumor pathology and pathophysiology].
The clinical behaviour of malignancies is characterized by four stages of progressive development: local, locoregional, mono- or oligotop-distant, and disseminated-distant. In the first three stages surgery is the most effective means of treatment. The possibility of tumor cell dissemination and implantation within the surgical area determines the methods of oncological surgery (no touch, wide margins of clearance, en bloc resection together with lymph node dissection).


Priming Th1 immunity to viral core particles is facilitated by trace amounts of RNA bound to its arginine-rich domain.
Particulate hepatitis B core Ag (C protein) (HBcAg) and soluble hepatitis B precore Ag (E protein) (HBeAg) of the hepatitis B virus share >70% of their amino acid sequence and most T and B cell-defined epitopes. When injected at low doses into mice, HBcAg particles prime Th1 immunity while HBeAg protein primes Th2 immunity. HBcAg contains 5-20 ng RNA/microg protein while nucleotide binding to HBeAg is not detectable. Deletion of the C-terminal arginine-rich domain of HBcAg generates HBcAg-144 or HBcAg-149 particles (in which >98% of RNA binding is lost) that prime Th2-biased immunity. HBcAg particles, but not truncated HBcAg-144 or -149 particles stimulate IL-12 p70 release by dendritic cells and IFN-gamma release by nonimmune spleen cells. The injection of HBeAg protein or HBcAg-149 particles into mice primes Th1 immunity only when high doses of RNA (i.e., 20-100 microg/mouse) are codelivered with the Ag. Particle-incorporated RNA has thus a 1000-fold higher potency as a Th1-inducing adjuvant than free RNA mixed to a protein Ag. Disrupting the particulate structure of HBcAg releases RNA and abolishes its Th1 immunity inducing potency. Using DNA vaccines delivered intradermally with the gene gun, inoculation of 1 microg HBcAg-encoding pCI/C plasmid DNA primes Th1 immunity while inoculation of 1 microg HBeAg-encoding pCI/E plasmid DNA or HBcAg-149-encoding pCI/C-149 plasmid DNA primes Th2 immunity. Expression data show eukaryotic RNA associated with HBcAg, but not HBeAg, expressed by the DNA vaccine. Hence, codelivery of an efficient, intrinsic adjuvant (i.e., nanogram amounts of prokaryotic or eukaryotic RNA bound to arginine-rich sequences) by HBcAg nucleocapsids facilitates priming of anti-viral Th1 immunity.


Artificial intelligence-assisted interpretation of systolic function by echocardiogram.
Precise and reliable echocardiographic assessment of left ventricular ejection fraction (LVEF) is needed for clinical decision-making. Recently, artificial intelligence (AI) models have been developed to estimate LVEF accurately. The aim of this study was to evaluate whether an AI model could estimate an expert read of LVEF and reduce the interinstitutional variability of level 1 readers with the AI-LVEF displayed on the echocardiographic screen. This prospective, multicentre echocardiographic study was conducted by five cardiologists of level 1 echocardiographic skill (minimum level of competency to interpret images) from different hospitals. Protocol 1: Visual LVEFs for the 48 cases were measured without input from the AI-LVEF. Protocol 2: the 48 cases were again shown to all readers with inclusion of AI-LVEF data. To assess the concordance and accuracy with or without AI-LVEF, each visual LVEF measurement was compared with an average of the estimates by five expert readers as a reference. A good correlation was found between AI-LVEF and reference LVEF (r=0.90, p<0.001) from the expert readers. For the classification LVEF, the area under the curve was 0.95 on heart failure with preserved EF and 0.96 on heart failure reduced EF. For the precision, the SD was reduced from 6.1±2.3 to 2.5±0.9 (p<0.001) with AI-LVEF. For the accuracy, the root-mean squared error was improved from 7.5±3.1 to 5.6±3.2 (p=0.004) with AI-LVEF. AI can assist with the interpretation of systolic function on an echocardiogram for level 1 readers from different institutions.


Capacity of Human Dental Follicle Cells to Differentiate into Neural Cells In Vitro.
The dental follicle is an ectomesenchymal tissue surrounding the developing tooth germ. Human dental follicle cells (hDFCs) have the capacity to commit to differentiation into multiple cell types. Here we investigated the capacity of hDFCs to differentiate into neural cells and the efficiency of a two-step strategy involving floating neurosphere-like bodies for neural differentiation. Undifferentiated hDFCs showed a spindle-like morphology and were positive for neural markers such as nestin, β-III-tubulin, and S100β. The cellular morphology of several cells was neuronal-like including branched dendrite-like processes and neurites. Next, hDFCs were used for neurosphere formation in serum-free medium containing basic fibroblast growth factor, epidermal growth factor, and B27 supplement. The number of cells with neuronal-like morphology and that were strongly positive for neural markers increased with sphere formation. Gene expression of neural markers also increased in hDFCs with sphere formation. Next, gene expression of neural markers was examined in hDFCs during neuronal differentiation after sphere formation. Expression of Musashi-1 and Musashi-2, MAP2, GFAP, MBP, and SOX10 was upregulated in hDFCs undergoing neuronal differentiation via neurospheres, whereas expression of nestin and β-III-tubulin was downregulated. In conclusion, hDFCs may be another optimal source of neural/glial cells for cell-based therapies to treat neurological diseases.


Dioxane-involving reaction for the synthesis of 3-aryl-1-(2-(vinyloxy)ethoxy)isoquinolines catalyzed by AgOTf.
Dioxane was found to be involved in the reaction of 2-(arylethynyl)benzaldehydes and 3-aminopyrazine-2-carbohydrazide, and underwent a ring-opening reaction catalyzed by AgOTf. This domino type procedure provided an efficient method for the synthesis of 3-aryl-1-(2-(vinyloxy)ethoxy)isoquinolines in good yields via the loss of a molecule of 3-aminopyrazine-2-carboxamide.


Can targeted HIV testing campaigns alter health-seeking behaviour?
This paper describes the evaluation of 'gimme 5 minutes' a multimedia HIV testing campaign aimed at gay and bisexual men in London particularly targeting those of Black and South European Origin and those under the age of 25 years old using peer images. The text linked a summary of the key issues of a pre-test discussion with detailed information on how to access testing at a specified testing centre (campaign clinic). The number and demographics of men who reported sex with men (MSM) testing at the campaign clinic were monitored and compared with those testing at two other central London clinics. There was a 4.5-fold rise (p < 0.001) in MSM testing at the campaign clinic. Increases were proportionately greater in the sub-populations targeted with peer images: South European origin, 14-fold rise (p < 0.001), Black origin, 6.5-fold rise (p = 0.003), and MSM under 25 years old, 9.5-fold rise (p < 0.001). There were no significant changes in the number of MSM testing for HIV at the two other central London clinics studied. The results suggest that including detailed information about accessing testing services may be a vital ingredient in the success of media campaigns focusing on HIV testing.


Biochemical function of selenium and its relation to vitamin E.
Glutathione peroxidase (glutathione:H2O2 oxidoreductase, E.C. 220.127.116.11), isolated from ovine and bovine erythrocytes, has recently been shown to contain 4 selenium atoms per mole, an average of 1 Se per protein subunit of about 22,000 molecular weight. Selenium deficiency in the rat, chick and sheep causes dramatic decreases in the activity of this enzyme in the tissues, but certain sites such as liver are affected more than others. Decreases in glutathione peroxidase correlate with lesions caused by selenium deficiency and appear useful in diagnosing selenium deficiency. Glutathione peroxidase is an important enzyme in destroying H2O2 and organic hydroperoxides such as lipid hydroperoxides. It therefore guards against oxidative damage to the cell membranes and other oxidant-sensitive sites in the cell. While this selenium-dependent system destroys lipid hydroperoxides and other peroxides, vitamin E is believed to protect against oxidant damage to membranes by preventing the formation of lipid hydroperoxides. A scheme is proposed, based on oxidant damage and its prevention, which accounts for the interaction between selenium, vitamin E, unsaturated lipids, sulfur-containing amino acids, and cell damaging agents such as oxidant stressors and toxicants such as silver and tri-o-cresyl phosphate. The background for such a scheme is reviewed.


[Retroperitoneal extraskeletal myxoid chondrosarcoma].
Extraskeletal myxoid chondrosarcoma is a rare soft tissue tumor included by WHO in the group of tumors of uncertain differentiation because well formed cartilage is rarely seen in its setting; moreover some of the immunophenotype features of the tumor are still controversial. The reciprocal translocation t(9;22)(q22;q12) has recently been identified in many cases, and this chromosomal aberration is currently considered high specific of this tumor. We report the case of a 75-year-old female submitted to radical nephrectomy for a voluminous kidney tumor with radiological evidence of extrarenal extension. Grossly the lesion was set in the perirenal fat tissue. Histological examination revealed a malignant mesenchimal tumor with myxoid f eatures and areas of chondroid differentiation consistent with the diagnosis of extraskeletal myxoid chondrosarcoma. According with the diagnosis the tumor showed focal positivity to NSE by immunohistochemistry. Differentiated cartilage is seen in extraskeletal myxoid chondrosarcoma in about 30% of the cases. Our case is then interesting not only for the rare site of tumor location but also for the extension of chondroid differentiation areas found on histologic examination in the tumor setting. Moreover immunohistochemistry showed focal positivity of the neoplastic cells for NSE, according with recent studies demonstrating expression of some neural/neuroendocrine markers in extrascheletal myxoid chondrosarcoma.


Improvement of start-up and nitrogen removal of the anammox process in reactors inoculated with conventional activated sludge using biofilm carrier materials.
The start-up of the anaerobic ammonium oxidation (anammox) process in three up-flow column reactors seeded with common mixed activated sludge and added with three materials, sponge (R1), sponge + volcanic rock (R2) and sponge + charcoal (R3), as carriers for biofilm formation were comparatively investigated in this study. The supplement of volcanic rock and charcoal could significantly shorten the start-up time of the anammox process, which primarily occurred in the activity-enhanced phase, with ammonium and nitrite removal efficiencies stabilized above 92.5% and 93.4% after an operation period of 145, 105 and 121 d for R1, R2 and R3, respectively. After the successful anammox start-up, R2 performed significantly better in TN removal (p < .05), achieving an average rate of 91.0% and 191.5 g N m-3 d-1 compared to R1 of 88.4% and 172.1 g N m-3 d-1, and R3 of 89.9% and 180.1 g N m-3 d-1 in the steady running phase. The ratios of consumed [Formula: see text] and generated [Formula: see text]/consumed [Formula: see text] after anammox start-up were lower than the theoretical values, probably suggesting the simultaneous existences of anammox, denitrification as well as nitrification processes in the reactors. A reddish brown biofilm was wrapped on the carriers and morphological detection of biofilm displayed the presentations of thick and compact floc aggregates and some filamentous bacteria on the sponge, and spherical-, ovoid- and shortrod-shaped microorganisms on the volcanic rock and charcoal. Using porous material as carrier for biofilm development is an effective strategy for practical application of the anammox reactor.


Worldwide prevalence of tocophobia in pregnant women: systematic review and meta-analysis.
Tocophobia is defined as a severe fear of pregnancy and childbirth. There is increasing evidence that tocophobia may have short-term and long-term adverse effects on mother and baby. We performed a systematic review and meta-analysis to determine the global prevalence of tocophobia in pregnancy. Relevant articles were identified through searching six relevant databases: MEDLINE, CINAHL, Pubmed, PsycINFO, Maternity & Infant Care and Scopus between 1946 and April 2016. We used search terms for tocophobia prevalence in pregnant women that we agreed on with a medical librarian. There were no language restrictions. Two review authors independently assessed data for inclusion, extracted data and assessed quality using a standardized appraisal tool. Meta-analysis was performed to determine the overall pooled-prevalence of tocophobia. Several subgroup and sensitivity analyses were conducted. Thirty-three studies were included in the systematic review from 18 countries of which data from 29 studies were used in the meta-analysis of 853 988 pregnant women. Definition of tocophobia varied, whereas prevalence rates ranged between 3.7 and 43%. The overall pooled prevalence of tocophobia, using a random-effects model, was 14% (95% CI 0.12-0.16). Significant heterogeneity was observed (I2 = 99.25%, p = 0.00), which was not explained in subgroup analyses including tocophobia definition used, screening trimester and parity. The prevalence of tocophobia is estimated at 14% and appears to have increased in recent years (2000 onwards). Considerable heterogeneity (99.25%) was noted that may be attributed to lack of consensus on the definition of tocophobia, so our results should be interpreted with caution.


Genetic analysis and fine mapping of a dynamic rolled leaf gene, RL10(t), in rice (Oryza sativa L.).
A dynamically rolled leaf mutant (rl10) was identified from a spontaneous mutation in an Oryza sativa L. subsp. indica line, II-32B. The leaf chlorophyll content of rl10 is higher than that of the wild type. Genetic analysis using 3 F2 segregating populations derived from crosses between rl10 and the rice lines Mian5B, II-32B, and D62B, respectively, confirmed that the rolled leaf trait of rl10 is controlled by a single recessive gene. Of 719 SSR primer pairs that showed polymorphism between D62B and rl10, 151 were adopted to map the RL10(t) gene using an F2 segregating population of the cross rl10 x D62B, which contained 352 recessive plants. RL10(t) was primarily mapped on the long arm of chromosome 9, 5.09 cM from marker RM105 and 5.13 cM from marker RM3912. Using a novel set of 22 primer pairs between RM105 and RM3912, RL10(t) was further mapped between markers rlc3 (0.72 cM in distance) and rlc12 (0.1 cM in distance) using an F2/F3 population containing 1172 recessive individuals. Mapped position analysis and homology analysis of the 20 genes within the 194-kb region between these 2 markers both indicated that a gene encoding a Myb-like domain transcription factor with homology to Arabidopsis KANADI (annotated in PAC clone AP005904) is the most probable candidate for RL10(t). This study enables further investigation of whether KANADI-like Myb genes are involved in leaf polarity modeling in monocots, as they are in dicots.


Local competition and metapopulation processes drive long-term seagrass-epiphyte population dynamics.
It is well known that ecological processes such as population regulation and natural enemy interactions potentially occur over a range of spatial scales, and there is a substantial body of literature developing theoretical understanding of the interplay between these processes. However, there are comparatively few studies quantifying the long-term effects of spatial scaling in natural ecosystems. A key challenge is that trophic complexity in real-world biological communities quickly obscures the signal from a focal process. Seagrass meadows provide an excellent opportunity in this respect: in many instances, seagrasses effectively form extensive natural monocultures, in which hypotheses about endogenous dynamics can be formulated and tested. We present amongst the longest unbroken, spatially explict time series of seagrass abundance published to date. Data include annual measures of shoot density, total above-ground abundance, and associated epiphyte cover from five Zostera marina meadows distributed around the Isles of Scilly, UK, from 1996 to 2011. We explore empirical patterns at the local and metapopulation scale using standard time series analysis and develop a simple population dynamic model, testing the hypothesis that both local and metapopulation scale feedback processes are important. We find little evidence of an interaction between scales in seagrass dynamics but that both scales contribute approximately equally to observed local epiphyte abundance. By quantifying the long-term dynamics of seagrass-epiphyte interactions we show how measures of density and extent are both important in establishing baseline information relevant to predicting responses to environmental change and developing management plans. We hope that this study complements existing mechanistic studies of physiology, genetics and productivity in seagrass, whilst highlighting the potential of seagrass as a model ecosystem. More generally, this study provides a rare opportunity to test some of the predictions of ecological theory in a natural ecosystem of global conservation and economic value.


State-of-the art endoscopic imaging in lung cancer: should specialties collide or concur?
Endoscopic ultrasound has been recently established as a routine diagnostic and staging procedure in lung cancer patients, mainly because of the possibility of tissue sampling. Transesophageal endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) represents a method which not only allows the visualization of the upper gastrointestinal tract, but also offers good visualisation of the posterior and inferior mediastinum. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) permits the assessment of the tumors in the anterior mediastinum. Based on previously published literature, it is obvious that this minimally invasive procedure now offers the possibility of tissue diagnosis in mediastinal masses including primary tumours or secondary lesions from both benign and malignant diseases.


Junctional transmission in fast- and slow-twitch mammalian motor units.
The phenomena of facilitation and tetanic potentiation of end-plate potentials (EPPs) were investigated in the predominantly fast-twitch extensor digitorum longus (EDL) and the predominantly slow-twitch soleus (Sol) muscles of the rat, using extra- and intracellular recording methods. When the quantal content of the EPPs was reduced to average values of 2-3, facilitation and potentiation could be studied in both muscles without the masking effects of neuromuscular depression. Under these conditions, the facilitation and potentiation at the neuromuscular junctions of EDL were different from those at the junctions of Sol. The potentiation during sustained activation was higher in EDL than in Sol at stimulation frequencies varying between 10 and 100 Hz. The same tendency was found for the facilitation measured by paired stimuli; the facilitation in EDL was generally higher than in Sol with interpulse intervals between 300 and 10 ms. The dependence of facilitation and potentiation on the stimulation frequency was also different in EDL and Sol. As the interpulse interval decreased from 200 to 25 ms, the facilitation in Sol increased more steeply than in EDL, whereas with further decrease from 25 to 10 ms, the facilitation in Sol did not increase at all, whereas the facilitation in EDL exhibited a substantial increase. The same general pattern was observed for potentiation: the potentiation in Sol increased more steeply than in EDL between 10 and 40 Hz (100- to 25-ms intervals) and more moderately than in EDL between 40 and 100 Hz (25- to 10-ms intervals). Another paradigm, repetitive short trains, induced a progressive increase in potentiation at the neuromuscular junctions of both muscles. The cumulative effect of potentiation was more prominent in EDL than in Sol. The differences in potentiation between EDL and Sol were also evident from intracellular recordings. These recordings also revealed that the amplitude of miniature EPPs remained unaltered in both muscles before and during the stimulus trains. Comparisons of the EPPs elicited before and at the end of tetanic trains revealed that the onset time of the EPPs was delayed in Sol but not in EDL during the train. This latency shift was also observed in the focally recorded nerve terminal potentials and end-plate currents in Sol, but not in EDL. The differences in facilitation and potentiation between EDL and Sol may be due to heterogeneities of the transmitter release machinery of their nerve terminals or differences in the capability of their presynaptic nerves to conduct action potentials at high frequencies.(ABSTRACT TRUNCATED AT 400 WORDS)


N-procalcitonin: central effects on feeding and energy homeostasis in rats.
Procalcitonin (PCT), the precursor of calcitonin (CT), is a 116-amino-acid peptide, but PCT itself has no known activity. However, although the C cells of the thyroid gland are the dominant source of circulating CT, PCT and its free bioactive amino-terminal fragment (N-PCT) have been localized in adipocytes and neuroendocrine cells as well as in some hypothalamic regions of primary importance in the regulation of feeding and energy balance. These findings together with the coelaboration of N-PCT and CT, and N-PCT's sequence conservation during evolution, suggest that N-PCT has a critical, and as yet undefined, physiological function. We demonstrate here that intracerebroventricular administration of N-PCT significantly decreased food intake and body weight gain for at least 48 h in conscious, freely moving, and unstressed rats fed ad libitum. These effects were accompanied by a transitory increase in body temperature and a decrease in locomotor activity. Moreover, after intracerebroventricular N-PCT administration, Fos protein, a marker of neuronal activation, was found in regions of primary importance in the integration of hormonal signals for energy homeostasis and feeding. In contrast, ip administration of N-PCT did not elicit any anorectic or catabolic effects. Furthermore, PCT was found in key feeding areas such as the arcuate nucleus of free-feeding rats, and its level was significantly reduced after fasting. These results suggest that N-PCT can function as an endogenous ligand for the CT receptor and may act as a catabolic signaling molecule in the central regulation of feeding behavior and energy homeostasis.


Gender, hospitalization and mental disorders among homeless people compared with the general population in Stockholm.
The aim was to study the prevalence of mental disorders among homeless men and women admitted for inpatient treatment in hospitals. Hospital care utilization of homeless people, 1364 men and 340 women, was compared with a control group consisting of 3750 men and 1250 women from the general population, 1996-2002. Homeless women ran a higher risk for mental disorders than women in the population [risk ratio (RR) 20.88]; their risk was also higher than the risk for homeless men (RR 1.20). Younger homeless women had the highest risk (RR 2.17). Alcohol use disorders were equally common among homeless men and women, but women had more drug use disorders (RR 1.32). Women had higher risk of schizophrenia (RR 2.79), and personality disorders (RR 2.73). When adjustment was made for substance use disorders, no increased risk for mental disorder was found in the homeless group. The elevated risk for mental disorders among the homeless was mainly related to substance use problems. Younger homeless women had the highest risk of mental disorder.


[The spleen in non-malignant haematological disorders].
The spleen functions as a filter of the circulating blood, removing aging or abnormal red blood cells, intraerythrocyte inclusions as well as foreign particals. As the spleen is composed of lymphocytic tissue, circulatory elements and mononuclear phagocytic cells it plays an important role in the nonspecific as well as the specific immune response. Additionally, the spleen serves as a reservoir for circulating blood cells, especially platelet sequestration by the spleen is well do cumented. The spleen produces blood cells during fetal development and in certain haematological disorders such as myelofibrosis. The destruction of red blood cells within the splenic cords releases iron in the circulation, which is recycled and used to manufacture new erythrocytes in the bone marrow. In several non-malignant haematological disorders antibody-coated cells are cleared from the circulation by phagocytic cells of the spleen. This involves erythrocytes in autoimmunhaemolytic anaemias, platelets in immunthrombocytopenia and neutrophils in Felty syndrome. In hereditary spherocytosis the spleen destroys the resulting defective, spherical red cells. In pyruvate kinase deficiency impaired production of adenosine triphosphate leads to destruction of red blood cells in the spleen or in the liver. In sickle cell anaemia the defective erythrocytes cause sludging and thrombosis in small vessels with infarcts for instance in the spleen, which over time can result in autosplenectomy. In thalassaemia major abnormal haemoglobin forms protein precipitates in the red cells with development of a severe hypochromic anaemia with haemolysis and intramedullary inef fective erythropoiesis. Therapeutic splenectomy can be an option in all of these mentioned non-malignant haematological disorders. The rationale and the pathophysiology of its role in thrombotic thrombocytopenic purpura is probably at least well understood. The use of new and effective drugs such as the monoclonal antibody rituximab or thrombopoietin agonists in immunthrombocytopenia as well as the option of a laparoscopic rather than an open splenectomy have changed our view on benefits and risks of splenectomy in recent years. To minimize these risks such as overwhelming postsplenectomy infection or abdominal vein thrombosis, prophylactic vaccination, postoperative thromboembolism prophylaxis and patient education is mandatory.


Socio-economic inequality in health service utilisation: Does accounting for seasonality in health-seeking behaviour matter?
Seasonal variation exists in disease incidence. The variation could occur across the different regions in a country. This paper argues that using national household data that are not adjusted for seasonal and regional variations in disease incidence may not be directly suitable for assessing socio-economic inequality in annual outpatient service utilisation, including for cross-country comparison. In fact, annual health service utilisation may be understated or overstated depending on the period of data collection. This may lead to miss-estimation of socio-economic inequality in health service utilisation depending, among other things, on how health service utilisation, across geographical areas, varies by socio-economic status. Using a nationally representative dataset from South Africa, the paper applies a seasonality index that is constructed from the District Health Information System, an administrative dataset, to annualise public outpatient health service visits. Using the concentration index, socio-economic inequality in health service visits, after accounting for seasonal variations, was compared with that when seasonal variations are ignored. It was found that, in some cases, socio-economic inequality in outpatient health service visits depends on the socio-economic distribution of the seasonality index. This may justify the need to account for seasonal and geographical variations.


A Comparison of Natural Orifice Versus Transabdominal Specimen Extraction Following Laparoscopic Total Colectomy.
Natural orifice surgery has been increasingly used in colon surgery since the early 2000s. However, it is rarely used for total colectomy. In this study, we aimed to retrospectively compare natural orifice specimen extraction (NOSE) with transabdominal specimen extraction in patients undergoing laparoscopic total colectomy. Twenty-six patients who underwent laparoscopic total colectomy between 2013 and 2017 were enrolled and the patients were divided into two groups: NOSE (n = 13) and transabdominal group (n = 13). The patients' demographic characteristics, perioperative and postoperative outcomes, pathology results, visual analog scale scores, and cosmetic scores were compared. There was no significant difference between the two groups in terms of demographic characteristics as well as perioperative and postoperative outcomes, including complications. Benign pathologies were more common in the NOSE group (85% versus 15%, P = .001). The pain scores of the postoperative first, second, and third days were significantly lower in the NOSE group 4.1 ± 2.1 versus 7.1 ± 1.3 (P = .005), 3.7 ± 2.2 versus 6.0 ± 1.5 (P = .003), and 2.2 ± 2.0 versus 4.1 ± 0.9 (P = .03), respectively. As expected, the mean cosmetic score was significantly better in the NOSE group (8.3 ± 1.5 versus 6.7 ± 1.8, P = .02). NOSE combined with laparoscopic total colectomy provided better patient comfort in benign diseases and small-sized malignant diseases.


An expanded modern coexistence theory for empirical applications.
Understanding long-term coexistence of numerous competing species is a longstanding challenge in ecology. Progress requires determining which processes and species differences are most important for coexistence when multiple processes operate and species differ in many ways. Modern coexistence theory (MCT), formalised by Chesson, holds out the promise of doing that, but empirical applications remain scarce. We argue that MCT's mathematical complexity and subtlety have obscured the simplicity and power of its underlying ideas and hindered applications. We present a general computational approach that extends our previous solution for the storage effect to all of standard MCT's spatial and temporal coexistence mechanisms, and also process-defined mechanisms amenable to direct study such as resource partitioning, indirect competition, and life history trade-offs. The main components are a method to partition population growth rates into contributions from different mechanisms and their interactions, and numerical calculations in which some mechanisms are removed and others retained. We illustrate how our approach handles features that have not been analysed in the standard framework through several case studies: competing diatom species under fluctuating temperature, plant-soil feedbacks in grasslands, facilitation in a beach grass community, and niche differences with independent effects on recruitment, survival and growth in sagebrush steppe.


Estrogen modulates parathyroid hormone-induced fibronectin production in human and rat osteoblast-like cells.
Fibronectin (FN) is an important constituent of the extracellular matrix in bone. Its hormonal regulation in this tissue has not been extensively studied. We, therefore, examined the effects of PTH, estrogen, and transforming growth factor beta on the production of FN by human and rat osteoblast-like cells. Confluent cells were stabilized for 48 h under estrogen-replete (10(-9) M 17 beta-estradiol) conditions and then continued under these same conditions or withdrawn from estrogen for varying periods of time. PTH over the range 10(-11)-(10(-8) M caused a dose-dependent increase in FN production [P < 0.001 by analysis of variance (ANOVA)] such that at the highest dose, FN production was increased 11-fold. Estrogen withdrawal for 96 h caused a significant diminution in PTH-induced FN production (P < 0.005 by two-way ANOVA). Estrogen withdrawal over the of period 48-144 h caused a progressive diminution in PTH-induced FN production such that differences in mean values for estrogen-replete vs. deficient conditions were greater at 144 than 48 h (P < 0.05). The estrogen effect was titratable over the range 10(-11)-10(-9) M, and the inactive congener 17 alpha-estradiol failed to prevent the inhibitory effect of estrogen withdrawal on PTH-induced FN production. Interestingly, estrogen withdrawal had absolutely no effect on transforming growth factor-beta-induced FN production. Northern analysis demonstrated no effect of PTH on steady-state FN messenger RNA levels in Saos-2 cells under either estrogen-replete or estrogen-deficient conditions, suggesting that PTH effects an increase in FN production via a posttranscriptional mechanism in these cells. We conclude that PTH stimulates FN production in human and rat osteoblast-like cells, and under estrogen-deficient conditions this effect is significantly diminished. The modulatory effect of estrogen is not a universal phenomenon because transforming growth factor-beta-induced FN production is unaffected by estrogen withdrawal.


New mechanistic explanation for the localization of ulcers in the rat duodenum: role of iron and selective uptake of cysteamine.
Cysteamine, a coenzyme A metabolite, induces duodenal ulcers in rodents. Our recent studies showed that ulcer formation was aggravated by iron overload and diminished in iron deficiency. We hypothesized that cysteamine is selectively taken up in the duodenal mucosa, where iron absorption primarily occurs, and is transported by a carrier-mediated process. Here we report that cysteamine administration in rats leads to cysteamine accumulation in the proximal duodenum, where the highest concentration of iron in the gastrointestinal tract is found. In vitro, iron loading of intestinal epithelial cells (IEC-6) accelerated reactive oxygen species (ROS) production and increased [(14)C]cysteamine uptake. [(14)C]Cysteamine uptake by isolated gastrointestinal mucosal cells and by IEC-6 was pH-dependent and inhibited by unlabeled cysteamine. The uptake of [(14)C]cysteamine by IEC-6 was Na(+)-independent, saturable, inhibited by structural analogs, H(2)-histamine receptor antagonists, and organic cation transporter (OCT) inhibitors. OCT1 mRNA was markedly expressed in the rat duodenum and in IEC-6, and transfection of IEC-6 with OCT1 siRNA decreased OCT1 mRNA expression and inhibited [(14)C]cysteamine uptake. Cysteamine-induced duodenal ulcers were decreased in OCT1/2 knockout mice. These studies provide new insights into the mechanism of cysteamine absorption and demonstrate that intracellular iron plays a critical role in cysteamine uptake and in experimental duodenal ulcerogenesis.