Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The population pharmacokinetics and limited sampling strategies for ciclosporin monitoring have been extensively studied in renal and liver transplant recipients. Little is known about the pharmacokinetics of ciclosporin in patients undergoing haematopoietic allogeneic stem cell transplantation (HSCT). • It is anticipated that there is a difference in pharmacokinetics in patients after kidney or liver transplantation compared with patients undergoing stem cell transplantation, because of mucositis and interacting drugs (e.g. fluconazole). • Data on the pharmacokinetics of ciclosporin and the relationship between its systemic exposure, as reflected by the area under the curve (AUC), and the biological effect as graft vs. host-disease (GVHD) prophylaxis and graft vs. tumour (GVT) response are scarce in patients after HSCT. WHAT THIS STUDY ADDS • A pharmacokinetic model was developed for orally and intravenously administered ciclosporin, enabling an adequate estimate of the systemic exposure of ciclosporin in patients after HSCT. A limited sampling strategy was tested that may serve as a tool to study the optimum systemic exposure (AUC) of ciclosporin in HSCT to prevent GVHD but establish adequate GVT response and to guide therapeutic drug monitoring. AIM To develop a population pharmacokinetic model of ciclosporin (CsA) in haematopoietic allogeneic stem cell transplantation to facilitate a limited sampling strategy to determine systemic exposure (area under the curve [AUC]), in order to optimize CsA therapy in this patient population. METHODS The pharmacokinetics of CsA were investigated prospectively in 20 patients following allogeneic haematopoietic stem cell transplantation (HSCT). CsA was given twice daily, as a 3 h i.v. infusion starting at day 1 of the conditioning scheme, and orally later on, when oral intake was well tolerated. Fluconazole was given as antimycotic prophylaxis. Pharmacokinetic parameter estimation was performed using nonlinear mixed effect modelling as implemented in the NONMEM program. A first order absorption model with lag time was compared with Erlang frequency distribution and Weibull distribution models. The influence of demographic variables on the individual empirical Bayesian estimates of clearance and distribution volume was tested. Subsequently two limited sampling strategies (LSS) were evaluated: posterior Bayesian fitting and limited sampling equations. RESULTS Twenty patients were included and 435 samples were collected after i.v. and oral administration of CsA. A two compartment model with first order absorption best described the data. Clearance (CL) was 21.9 l h(-1) (relative standard deviation [RSD]± 5.2%) with an inter-individual variability of 21%. The central volume of distribution (V(c) ) was 18.3 l (RSD ± 8.7%) with an inter-individual variability of 29%. Bioavailability (F) was 0.71 (RSD ± 9.9%) with and inter-individual variability of 25% and lag time (t(lag) ) was 0.44 h (RSD 5.5%). Weight, body surface area, haematocrit, albumin, ALAT and ASAT had no significant influence on pharmacokinetic parameters. The best multiple point combination for posterior Bayesian fitting, in terms of estimating systemic CsA exposure, appeared to be C0 + C2 + C3. Two selected LSS two time point equations and all selected three and four time point equations predicted de all AUC(0,12 h) within 15% bias and prediction. CONCLUSIONS The i.v. and oralcurves were best described with a two compartment model with first-order absorption with lag time. With the Bayesian estimators from this model, the area under the concentration-time curve in HSCT patients taking fluconazole can be estimated with only three blood samples (0, 2, 3 h) with a bias of 1% and precision of 4%.


Risk factors and outcomes of blood transfusions in adrenalectomy.
Blood transfusion has been shown to be associated with adverse long-term and short-term outcomes. We sought to evaluate the preoperative risk factors associated with blood transfusion and its effects on postoperative outcomes after adrenalectomy. We performed a retrospective analysis of 4735 adrenalectomies (3664 laparoscopic and 1071 open) from 2005-2012 using the National Surgical Quality Improvement Program database. Data on preoperative risk factors and postoperative morbidity and mortality were evaluated. Median age and body mass index were 54 y and 29.3 kg/m(2), respectively. Most patients were female (60.0%). Of the total, 60.6% patients had American Society of Anesthesiologists score ≥3. On multivariate analysis, increasing age (odds ratio [OR] = 1.02, P < 0.001), open adrenalectomy (OR = 14.0, P < 0.001), preoperative hematocrit <38% (OR = 2.96, P < 0.001), and operative time >150 min (OR: 3.69, P < 0.001) were associated with an increased need for intraoperative blood transfusions. The need for intraoperative blood transfusions was an independent predictor of postoperative complications including mortality (OR = 12.7, P < 0.001), overall morbidity (OR = 3.2, P < 0.001), serious morbidity (OR = 3.8, P < 0.001), wound complication (OR = 2.1, P = 0.006), cardiopulmonary complication (OR = 3.6, P < 0.001), septic complication (OR = 2.5, P = 0.007), reoperation (OR = 3.6, P < 0.001), and prolonged length of stay (OR = 4.3, P < 0.001). There was an independent and incremental increase (10%-20%) in the risk of morbidity and mortality with each unit of blood transfused (P < 0.01). Age, open surgery, preoperative anemia, American Society of Anesthesiologists score, and prolonged operative time are associated with an increased need for blood transfusions in laparoscopic and open adrenalectomy. Intraoperative transfusion was independently and incrementally associated with significant morbidity and mortality after laparoscopic and open adrenalectomy.


Theory of competitive adsorption-nucleation in polypeptide-mediated biomineralization.
The process of biomineralization occurs in various natural organisms with astonishing ease by the interplay between polymers and mineralization but eludes a fundamental understanding. In addressing how specific polymers direct selection of mineral morphologies and their growth kinetics, we present a new model based on a competition between adsorption of polymers onto selective interfaces and nucleation growth of minerals. The model is couched in the context of zinc oxide, crystallized from solutions containing polypeptides, where systematic experimental data are available. Adsorption of the polymer onto certain crystallographic planes leads to poisoning of the surfaces, and as a result these surfaces are arrested from further growth. By this mechanism, originally disfavored growth sectors are promoted to grow by suppressing the initial faster growing sectors. Our theory predicts the relative growth rates of different sectors altered by selective adsorption of polymers. Theoretical prediction of the dependence of the aspect ratio on polypeptide concentration is in agreement with experimental results, providing credence to the applicability of adsorption-nucleation models to polymer-mediated biomineralization.


Multiple victimization of Spanish adolescents: a multilevel analysis.
Multiple victimization in adolescence is an issue that has received little research attention. Furthermore, adolescents are particularly vulnerable to victimization in different contexts. The aim of this study is to analyze correlates of multiple victimization in three contexts (home, school, and street). The following forms of victimization were considered: stealing, hitting, insulting, threatening, blackmailing, and weapon intimidation. Multiple victimization correlates explored were: sex, age, public/private school, socioeconomic status, quality of family relationships, and antisocial behavior. A probabilistic sample of 1,908 adolescents (ages 13 to 18) was used. Multilevel analyses were conducted to separate correlates at the individual level from those operating at the contextual level. Results show that gender, quality of family relationships, and deviant behavior were related to multiple victimization in adolescence.


Stakeholder value-linked sustainability assessment: Evaluating remedial alternatives for the Portland Harbor Superfund Site, Portland, Oregon, USA.
Regulatory decisions on remediation should consider affected communities' needs and values, and how these might be impacted by remedial options; this process requires that diverse stakeholders are able to engage in a transparent consideration of value trade-offs and of the distribution of risks and benefits associated with remedial actions and outcomes. The Stakeholder Values Assessment (SVA) tool was developed to evaluate remedial impacts on environmental quality, economic viability, and social equity in the context of stakeholder values and priorities. Stakeholder values were linked to the pillars of sustainability and also to a range of metrics to evaluate how sediment remediation affects these values. Sediment remedial alternatives proposed by the US Environmental Protection Agency (USEPA) for the Portland Harbor Superfund Site were scored for each metric, based upon data provided in published feasibility study (FS) documents. Metric scores were aggregated to generate scores for each value; these were then aggregated to generate scores for each pillar of sustainability. In parallel, the inferred priorities (in terms of regional remediation, restoration, planning, and development) of diverse stakeholder groups (SGs) were used to evaluate the sensitivity and robustness of the values-based sustainability assessment to diverse SG priorities. This approach, which addresses social indicators of impact and then integrates them with indicators of environmental and economic impacts, goes well beyond the Comprehensive Environmental Response, Compensation and Liability Act's (CERCLA) 9 criteria for evaluating remedial alternatives because it evaluates how remedial alternatives might be ranked in terms of the diverse values and priorities of stakeholders. This approach identified trade-offs and points of potential contention, providing a systematic, semiquantitative, transparent valuation tool that can be used in community engagement. Integr Environ Assess Manag 2018;14:43-62. © 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).


Checkpoints controlling mitosis.
Each year many reviews deal with checkpoint control.((1-5)) Here we discuss checkpoint pathways that control mitosis. We address four checkpoint systems in depth: budding yeast DNA damage, the DNA replication checkpoint, the spindle assembly checkpoint and the mammalian G2 topoisomerase II-dependent checkpoint. A main focus of the review is the organization of these checkpoint pathways. Recent work has elucidated the order-of-function of several checkpoint components, and has revealed that the S phase, DNA damage and spindle assembly checkpoints each have at least two parallel branches. These steps forward have largely come from kinetic studies of checkpoint-defective mutants.


Klippel-Trenaunay Syndrome: a case report with brief review of literature.
Klippel-Tranuanay Syndrome is a rare sporadic disease characterized by clinical triad of capillary malformation; soft tissue and bony hypertrophy; and atypical varicosity. Although this syndrome was first described more than hundred years ago, exact incidence has not been estimated yet. Several theories have been postulated to describe its pathogenesis. Clinical presentation of this syndrome is protean ranging from minimal asymptomatic disease to life threatening bleeding and embolism. Management of this syndrome includes careful diagnosis, prevention and treatment of complications. We are presenting a case of Klippel-Tranuanay Syndrome in a 19-year-old male patient presenting with varicosity in lateral aspect of right leg. On careful examination other components of the syndrome were found. Patient was kept on yearly follow up. Usually patients with Klippel-Tranuanay Syndrome present with complication. This case shows that there is also a need for medical solutions in patients who seek advise for cosmetic reasons.


DNA repair in the c-myc proto-oncogene locus: possible involvement in susceptibility or resistance to plasmacytoma induction in BALB/c mice.
This report describes an unexpected difference in the efficiency of removal of UV-induced DNA damage in the c-myc locus in splenic B lymphoblasts from two inbred strains of mice. In cells from plasmacytoma-resistant DBA/2N mice, 35% of UV-induced damage in the regulatory and 5' flank of c-myc is removed by 12 h. However, in cells from plasmacytoma-susceptible BALB/cAn mice, damage is not removed from this region. In the protein-encoding region and 3' flank of c-myc as well as in two dihydrofolate reductase gene fragments, UV damage is repaired with similar efficiency in B lymphoblasts from both strains of mice. Furthermore, in the protein-encoding portion and 3' flank of c-myc, damage is selectively removed from only the transcribed strand. No repair is detected in the nontranscribed strand. In contrast, DNA repair in the 5' flank of c-myc is not strand specific; in DNA from DBA/2N cells, UV damage is rapidly removed from both the transcribed and nontranscribed strands. In BALB/cAn cells no repair was detected in either strand in the 5'flank, consistent with the results with double-stranded, nick-translated probes to this region of c-myc. In addition to the repair studies, we have detected post-UV-damage formation: in most of the genes studied, we find that additional T4 endonuclease-sensitive sites are formed in the DNA 2 h after irradiation. Our findings provide new insights into the details of gene-specific and strand-specific DNA repair and suggest that there may be close links between DNA repair and B-cell neoplastic development.


Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor.
The product of the von Hippel-Lindau gene, pVHL, targets the alpha subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF) for polyubiquitination in the presence of oxygen. The binding of pVHL to HIF is governed by the enzymatic hydroxylation of conserved prolyl residues within peptidic motifs present in the HIFalpha family members. By using a biochemical purification strategy, we have identified a human homolog of Caenorhabditis elegans Egl9 as a HIF prolyl hydroxylase. In addition, we studied the activity of a structurally diverse collection of low molecular weight inhibitors of procollagen prolyl 4-hydroxylase as potential inhibitors of the HIF hydroxylase. A model compound of this series stabilized HIF in a variety of cells, leading to the increased production of its downstream target, vascular endothelial growth factor.


Plasmon-Polaron Coupling in Conjugated Polymer on Infrared Nanoantennas.
We propose and demonstrate a novel type of coupling between polarons in a conjugated polymer and localized surface plasmons in infrared (IR) nanoantennas. The near-field interaction between plasmons and polarons is revealed by polarized photoinduced absorption measurements, probing mid-IR polaron transitions, and infrared-active vibrational modes of the polymer, which directly gauge the density of photogenerated charge carriers. This work proves the possibility of tuning the polaronic properties of organic semiconductors with plasmonic nanostructures.


Risk of second cancer after ion beam radiotherapy: insights from animal carcinogenesis studies.
Purpose: To review recent studies to better understand the risk of second cancer after ion beam radiotherapy and to clarify the importance of animal radiobiology therein. Results: Risk of developing second cancer after radiotherapy is a concern, particularly for survivors of childhood tumors. Ion beam radiotherapy is expected to reduce the risk of second cancer by reducing exposure of normal tissues to radiation. Large uncertainty lies, however, in the choice of relative biological effectiveness (RBE) of high linear energy transfer (LET) radiation (e.g. carbon ions and neutrons) in cancer induction, especially for children. Studies have attempted to predict the risk of second cancer after ion beam radiotherapy based on an assessment of radiation dose, the risk of low LET radiation, and assumptions about RBE. Animal experiments have yielded RBE values for selected tissues, radiation types, and age at the time of irradiation; the results indicate potentially variable RBE which depends on tissues, ages, and dose levels. Animal studies have also attempted to identify genetic alterations in tumors induced by high LET radiation. Conclusions: Estimating the RBE value for cancer induction is important for understanding the risk of second cancer after ion beam radiotherapy. More comprehensive animal radiobiology studies are needed.


Pre-pubertal children and exercise in hot and humid environments: a brief review.
The ability of pre-pubertal children to regulate their body temperature under thermoneutral environments is similar to that of an adult albeit via differing routes. However, this ability is challenged when exposed to extreme environments. Thermoregulatory responses of pre-pubertal children differ from adults via adaptations that occur during growth and maturation and disadvantage children when exercising in hot and humid environments. When ambient temperatures exceed that of the skin, an influx of thermal energy from the environment increases thermal stress. When coupled with exercise, the increased thermal stress results in reduced physical performance and an increased risk of developing heat-related illness. Evidence suggesting the severity of heat-related illness is greater in pre-pubertal children than adults is inconclusive because age-related differences in thermoregulatory responses are attributed to either morphologic or functional changes. Additionally, the majority of research on pre-pubertal children exercising in the heat has been maturational or comparative studies with adults conducted in the near absence of convective cooling, complicating extrapolation to field-based environments. However, current consensus is that pre-pubertal children are disadvantaged when exercising in extreme temperatures and that care should be taken in preparing for and conducting sporting activities in hot and humid environments for pre-pubertal children. Key pointsPre-pubertal children's ability to thermoregulate when exposed to hot and humid environments is deficient compared to adults.Research into the severity of heat-related illness in pre-pubertal children is inconclusive.Discretion should be used in applying findings from indoor studies to outdoor activities due to the influence of the velocity of circulating air on thermoregulation.


Human cortical regions activated by wide-field visual motion: an H2(15)O PET study.
1. Several areas in the monkey dorsal visual pathway, including the dorsal part of the medial superior temporal area, have been found to contain cells responding to movements of a wide visual field and are suggested to be involved in analyzing self-induced motion information. In the present study, positron emission tomography was used to localize human cortical regions responding to wide-field visual motion. Changes in regional cerebral blood flow (rCBF) were measured when subjects maintained fixation and viewed low-contrast (0.15 log units brighter than the background) dots subtending 80 x 80 degrees and moving either coherently or incoherently. Brain foci were localized after activity in a fixation-only paradigm was subtracted from that in the two moving dot paradigms. 2. Both the coherent and incoherent movements significantly activated the primary/secondary visual cortex and surrounding visual areas in the cuneus and superior occipital gyrus. Subtraction of images between the coherent and incoherent movements showed that the activity caused by the two types of movement was comparable in these early visual cortical regions. 3. In the lateral occipitotemporoparietal cortex, the coherent movement specifically activated two separate areas; a posterior focus was located at the border of the right occipitotemporal gyri, and a dorsoanterior focus was located bilaterally in the temporoparietal cortex. The incoherent movement did not activate these regions. 4. A fine anatomic localization using individual magnetic resonance images was performed for the bilateral activation in the temporoparietal cortex, which was found to be located mainly in the depth of the inferior parietal lobule and a small portion of the superior and middle temporal gyri. 5. Both the coherent and incoherent movements activated a part of the superior parietal lobule located within the intraparietal sulcus (Brodmann area 7). The bilateral foci activated by the coherent movement were located more anteriorly than the focus activated by the incoherent movement. Subtraction images between the coherent and incoherent movements, however, did not reveal any significant rCBF increases in the superior parietal lobule. 6. Several other cortical regions known to be involved in visuospatial and visuomotor functions were also activated by the coherent movement, including the frontal eye field (Brodmann area 8) and premotor cortex (Brodmann area 6) in the frontal lobe. 7. The posteriorly located activation at the border of occipito-temporal gyri corresponds to the homologue of the middle temporal area reported in previous activation studies using small to medium-sized motion stimuli. The bilateral activation in the inferior parietal lobule appeared to rely on wide-field motion stimulation.


The possible association of Chlamydia pneumoniae infection with nasal polyps.
The objective of this study was to investigate the possible etiologic role of Chlamydia pneumoniae infection in nasal polyps. This prospective clinical study was undertaken enrolling 30 patients with nasal polyps, and 30 age and sex-matched control subjects from whom epithelial material was obtained during endoscopic surgery. IgG specific ELISA was used to determine seropositivity, and indirect immunoflorescence to determine C. pneumoniae in the biopsy material. C. pneumoniae specific IgG antibodies were found to be positive in 16 (53.3%) of the patients with nasal polyps, and 9 (22%) of the control subjects (P = 0.065). Indirect immunofluorescence results indicate that there was a significant difference between groups; 16 (53.3%) patients in the study group and 8 (26.6%) patients in the control group were found to be positive (P = 0.034). We found no correlation with cigarette smoking. Our results indicated that Chlamydia pneumoniae is possibly associated with the presence of nasal polyps. However, these results remain to be confirmed with further studies using other techniques, and the underlying mechanism should be defined.


[VEGF and central nervous system diseases].
Vascular endothelial growth factor (VEGF or VEGF-A) is a hypoxia induced angiogenic growth factor that is potent in neurotrophy,neuroprotection, anti-apoptosis and cell proliferation. Recent reports suggest that VEGF is related to many central nervous system diseases, such as cerebral ischemic disease, Alzheimer's disease and Parkinson's disease. Further study of the relationship between VEGF and central nervous system diseases,and investigation of VEGF related drugs will shed light on a new way for treatment of central nervous system diseases.


Parapneumonic pleural effusions caused by Streptococcus pneumoniae serotype 3 in children immunized with 13-valent conjugated pneumococcal vaccine.
During 2012, Streptococcus pneumoniae serotype 3 was identified by polymerase chain reaction in 15 out of 20 (75%) pleural fluid specimens from children with pneumococcal pneumonia complicated by parapneumonic pleural effusion in Greece. One-third of these children had been immunized with the 13-valent conjugated pneumococcal vaccine after the age of 12 months, according to the national immunization schedule.


Do the estrogen receptors 1 gene variants influence the temperament and character inventory scores in suicidal attempters and healthy subjects?
Several studies investigated possible associations between single nucleotide polymorphisms and the temperament and character inventory (TCI) scores. The possible association between TCI scores and the estrogen receptors 1 (ESR1) polymorphisms, which are expressed in cerebral regions that are involved in the development of temperament and character, has not been investigated yet. The aim of the present study is to investigate possible associations between specific ESR1 polymorphisms and TCI scores. Two hundred eighty-nine healthy subjects and 111 suicide attempters were enrolled in the study. All subjects compiled TCI. Rs827421, rs1913474, rs1801132, rs722207, rs974276, and rs910416 in ESR1 were genotyped. Rs722207 was associated with Harm Avoidance (HA) in the healthy sample (P = 0.003). Further associations have been found for two HA subscales, HA2 and HA3, in the healthy sample. Additionally, the haplotype rs722207-rs974276 showed an association with HA (P = 0.0003) and HA2 (P = 0.0002) in the global sample and in healthy volunteers and HA3 showed an association in the global sample. Our study showed a moderate association between ESR1 variants and TCI scores. The main finding concerns the association between rs722207 and HA in the healthy sample. Further research is needed to replicate our findings and to investigate further ESR1 polymorphisms.


Distribution and numbers of mucous glands in the horse trachea.
Horses commonly suffer from respiratory diseases associated with excess secretions in the airway lumen, some of which are presumably derived from airway mucous glands. However, these structures have been little investigated in the horse. Accordingly, we describe here the number, distribution and size of equine tracheal mucous glands, and compare the data with similar information for other mammalian species. Two types of gland acini were present. In the thick connective tissue, up to 400 microm beneath the epithelium, gland acini were grouped in thin sheets that, in cross-section, averaged 20 microm thick and were up to 4.0 mm in length. However, it is probable that most sheets had maximal diameters much less than 4.0 mm. Between 400 to 900 microm below the epithelium, the connective tissue was much more diffuse, and glands were larger and more globular. Gland volume in the ventral portion was approximately 1.7 microl/cm2 of mucosal surface, and approximately 1.1 microl/cm2 in the dorsal portion. Glands were somewhat more abundant between, rather than over, the cartilaginous rings, but the difference between the 2 locations was not marked. Mucous gland openings were small (20 microm diameter) and very unevenly distributed, generally occurring about 100 microm apart in longitudinal rows of about 5. Average frequency of openings in the ventral portions of 3 tracheas was approximately 1.0/mm2 of mucosal surface. The volume of individual glands was therefore approximately 17 nl. Although the frequency of gland openings in the horse trachea is similar to that for the tracheas of other large mammalian species, horse tracheal gland volume was only about 15% that of the other species. Therefore, the excess 'mucous' secretions seen in equine recurrent airway obstruction and other respiratory diseases are unlikely to be caused by comparatively high levels of airway mucous gland secretion. Instead, they may be caused mainly by hyperplasia of the mucus-producing cells of the surface epithelium or by vascular transudation.


[Erythrocyte membrane transport of tyrosine and tryptophan and plasma level of MHPG in depressive disorders].
Both plasma MHPG level and red blood cell membrane transports (TM) of L-tyrosine (L-TYR) and L-tryptophan (L-TRY) were evaluated in 29 depressed patients and compared to 16 control subjects. On the basis of MHPG plasmatic levels, we were able to define two subgroups in the depressed population showing a biological homogeneity: in the first one, both MHPG level and TYR TM decreased, while in the second one neither of these indices were disturbed. These biological features were not related to the nosographic subgroups. Bipolar depressed subjects showed a decrease in both MHPG and TYR TM; unipolar depressed subjects exhibited a decrease in both MHPG and TYR TM associated to an increase in TRY TM, whereas no change was found in dysthymic disorders. The time course of MHPG and MT were desynchronized if followed during the antidepressant treatment. At day 7, MHPG level increased significantly, while clinical improvement showed a normalisation of MHPG and TYR TM.


Postoperative treatment of carvedilol following low dose landiolol has preventive effect for atrial fibrillation after coronary artery bypass grafting.
Postoperative atrial fibrillation (AF) is the most common complication after coronary artery bypass grafting (CABG). We have reported that the intra- and perioperative administration of landiolol has a preventive effect on postoperative AF in the early postoperative period after CABG surgery. The purpose of this study was to investigate the prophylactic effect of postoperative treatment with carvedilol following landiolol against postoperative AF. We reviewed all patients who underwent CABG from December 2005 and February 2009. Fifty-three patients underwent scheduled isolated CABG and were divided two groups; carvedilol group (n = 31), and control group (n = 22). Incidences of postoperative AF were noted. There was no statistical difference between the two groups with regard to the occurrence of AF after CABG. The maximum ventricular rate of AF was significantly lower in the carvedilol group than in the control group. All patients with AF in the control group needed treatment for tachycardia, but this was not necessary in the carvedilol group. Postoperative treatment with carvedilol following landiolol has the effect of preventing tachycardia during AF after coronary artery bypass grafting.


Towards functional proteomics of membrane protein complexes in Synechocystis sp. PCC 6803.
The composition and dynamics of membrane protein complexes were studied in the cyanobacterium Synechocystis sp. PCC 6803 by two-dimensional blue native/SDS-PAGE followed by matrix-assisted laser-desorption ionization time of flight mass spectrometry. Approximately 20 distinct membrane protein complexes could be resolved from photoautotrophically grown wild-type cells. Besides the protein complexes involved in linear photosynthetic electron flow and ATP synthesis (photosystem [PS] I, PSII, cytochrome b6f, and ATP synthase), four distinct complexes containing type I NAD(P)H dehydrogenase (NDH-1) subunits were identified, as well as several novel, still uncharacterized protein complexes. The dynamics of the protein complexes was studied by culturing the wild type and several mutant strains under various growth modes (photoautotrophic, mixotrophic, or photoheterotrophic) or in the presence of different concentrations of CO2, iron, or salt. The most distinct modulation observed in PSs occurred in iron-depleted conditions, which induced an accumulation of CP43' protein associated with PSI trimers. The NDH-1 complexes, on the other hand, responded readily to changes in the CO2 concentration and the growth mode of the cells and represented an extremely dynamic group of membrane protein complexes. Our results give the first direct evidence, to our knowledge, that the NdhF3, NdhD3, and CupA proteins assemble together to form a small low CO2-induced protein complex and further demonstrate the presence of a fourth subunit, Sll1735, in this complex. The two bigger NDH-1 complexes contained a different set of NDH-1 polypeptides and are likely to function in respiratory and cyclic electron transfer. Pulse labeling experiments demonstrated the requirement of PSII activity for de novo synthesis of the NDH-1 complexes.


Stargardt's type maculopathy in a patient with 11778 Leber's optic neuropathy.
A 13-year-old boy presented with a 2-month history of blurred vision. Visual acuity was 20/200 in both eyes. Ophthalmoscopic examination revealed normal discs and "beaten bronze atrophy" in the maculae. Subsequently, progressive vision loss with optic atrophy occurred over the next few years. Fluorescein angiographic findings were compatible with Stargardt's maculopathy. Because his cousin developed sequential vision loss diagnosed as Leber's hereditary optic neuropathy, molecular genetic analysis was performed on blood mitochondrial DNA (mtDNA) from our patient, his cousin with vision loss, and another three asymptomatic cousins. The results showed that they all harbored homoplasmic G to A point mutations at nucleotide position 11778 of the ND4 gene in mtDNA.


Social work, technology, and ethical practices: a review and evaluation of the national association of social workers' technology standards.
Information and communication technologies (ICTs) are becoming essential to social work practice by providing increased treatment possibilities and reducing barriers to service. While recognizing the importance of ICTs in practice, social work practitioners have had concerns about ethical use. In response, NASW compiled the Standards for Technology and Social Work Practice. While the guidelines set the groundwork, they were not embedded in a process that would allow them to adapt to the swift pace of ICT changes. This article reviews the current Standards, evaluates how these have been implemented by practitioners, and offers suggestions for updates.


Distribution pattern and prevalence of haematological cancers among adults in Abakaliki, South-Eastern Nigeria.
Haematological cancers are clonal diseases of the blood and blood-forming organs, with the distribution pattern not known in our locality. This study aimed to describe the distribution pattern and prevalence of haematological cancers among adults in Abakaliki, Nigeria. This was an 8-year retrospective study in which the hospital records/case notes of adult patients diagnosed and managed for haematological cancers from May 2012 to April 2020 were reviewed. Data obtained were analysed with the SPSS software, version 20. One hundred and thirty-five cases of haematological cancers were included in the study, with 72 (53.4%) males and 63 (46.6%) females and male-to-female ratio of 1.1:1. The age range was 18-82 years, with a mean age of 49 ± 17 years. Lymphoid malignancies predominate more than myeloid (101 [74.8%] vs. 34 [25.2%]). The leukaemias were more predominant than the lymphomas and myeloma accounting for 48.2%, 36.3% and 7.4%, respectively. Chronic leukaemias were more common than the acute leukaemias with chronic lymphocytic leukaemia (CLL) being the most common accounting for 24.4% of haematological cancers. In general, non-Hodgkin's lymphoma (NHL) was the most common haematologic cancer accounting for 35 (25.9%), followed by CLL 33 (24.4%), chronic myeloid leukaemia (CML) 17 (12.6%), Hodgkin's lymphoma (HL) 14 (10.4%) and multiple myeloma (MM) 10 (7.4%). Others include acute lymphoblastic leukaemia (ALL) 9 (6.7%) and acute myeloblastic leukaemia (AML) 6 (4.4%). Myelodysplastic syndrome (MDS) and polycythaemia vera (PV), each contributed 3% while myelofibrosis (MF) and essential thrombocythaemia (ET) contributed 1.5% and 0.7%, respectively. This study has shown that haematological cancers are not uncommon in our locality with NHL being the most common, followed by CLL, CML, HL, MM, ALL, AML, MDS, PV. MF and ET in that order. The burden of haematological cancers in Ebonyi State, Nigeria is therefore significant and should be prioritised in health-care policy formulation and management.


Effect of FliK mutation on the transcriptional activity of the {sigma}54 sigma factor RpoN in Helicobacter pylori.
Helicobacter pylori is a motile Gram-negative bacterium that colonizes and persists in the human gastric mucosa. The flagellum gene regulatory circuitry of H. pylori is unique in many aspects compared with the Salmonella/Escherichia coli paradigms, and some regulatory checkpoints remain unclear. FliK controls the hook length during flagellar assembly. Microarray analysis of a fliK-null mutant revealed increased transcription of genes under the control of the sigma(54) sigma factor RpoN. This sigma factor has been shown to be responsible for transcription of the class II flagellar genes, including flgE and flaB. No genes higher in the flagellar hierarchy had altered expression, suggesting specific and localized FliK-dependent feedback on the RpoN regulon. FliK thus appears to be involved in three processes: hook-length control, export substrate specificity and control of RpoN transcriptional activity.


Reprogramming adult human dermal fibroblasts to islet-like cells by epigenetic modification coupled to transcription factor modulation.
In this article, we describe novel conditions for culture, expansion, and transdifferentiation of primary human dermal fibroblasts (hDFs) to induce expression of transcription factors (TFs) and hormones characteristic of the islets of Langerhans. We show that histones associated with the insulin gene are hyperacetylated and that insulin gene DNA is less methylated in islet cells compared to cells that do not express insulin. Using two compounds that alter the epigenetic signature of cells, romidepsin (Romi), a histone deacetylase inhibitor, and 5-Azacytidine (5-AzC), a chemical analogue of cytidine that cannot be methylated, we show that hDFs exhibit a distinctive regulation of expression of TFs involved in islet development as well as of induction of glucagon and insulin. Overexpression of Pdx1, a TF important for islet differentiation, and silencing of musculoaponeurotic fibrosarcoma oncogene homolog B, a TF that is expressed in mature glucagon-producing cells, result in induction of insulin to a higher level compared to Romi and 5-AzC alone. The cells obtained from this protocol exhibit glucose-stimulated insulin secretion and lower blood glucose levels of diabetic mice. These data show that fully differentiated nonislet-derived cells could be made to transdifferentiate to islet-like cells and that combining epigenetic modulation with TF modulation leads to enhanced insulin expression.


The metR binding site in the Salmonella typhimurium metH gene: DNA sequence constraints on activation.
Transcription of the metH gene in Salmonella typhimurium and Escherichia coli is positively regulated by the metR gene product, a DNA binding protein. The interaction between the MetR activator protein and the S. typhimurium metH control region was investigated. In vitro gel mobility shift assays and DNase I protection assays established that the MetR protein binds to and protects a 24-bp sequence in the metH promoter region from DNase I attack. This region includes the proposed metR recognition sequence 5'-TGAANNNNNCTCA-3'. Single-base-pair changes were introduced into the proposed MetR recognition sequence within the promoter region of a metH-lacZ gene fusion by oligonucleotide-directed mutagenesis. Two classes of mutations were identified. In the first class, the mutations caused reduced activation of the metH-lacZ fusions that correlated with reduced MetR binding. In the second class, activation of the metH-lacZ fusion was reduced, yet there was no appreciable reduction in MetR binding, indicating that the presence of bound MetR is not sufficient for activation of metH-lacZ gene expression. These two classes of mutations in the DNA binding site are grouped spatially, suggesting that the proposed MetR recognition sequence can be divided into two functional domains, one for binding and the other for activation.


The impact of brain atrophy on the outcomes of mechanical thrombectomy.
Pre-existing brain atrophy may affect the outcomes of patients treated with mechanical thrombectomy (MT) for large-vessel-occlusion because it is an indicator of low brain reserve. We performed a systematic literature review to assess the impact of brain atrophy on MT-related clinical outcomes. We conducted a systematic search of PubMed, MEDLINE, EMBASE, and Cochrane Library databases from inception to March 2021 using keywords with Boolean operators("brain atrophy"; "atrophy"; "white matter"; and "thrombectomy"). Articles published in English that evaluated the impact of pre-existing brain atrophy on outcomes of MT-treated acute ischemic stroke were eligible for inclusion. Four articles were included. Brain atrophy index was a predictor of mortality (odds ratio [OR]:1.81-1.87, 95% confidence interval [CI]:1.16-2.93) after adjustments for age and white matter lesions. Global cortical atrophy scale was an independent predictor of futile recanalization (OR 1.15, 95% CI 1.08-1.22) in multivariate-adjusted logistic regression. Automated measurement of CSF identified increasing volumes associated with reduced 3-month functional independence and higher modified Rankin scale scores. STandards for ReportIng Vascular changes on Neuroimaging criteria for brain atrophy were associated with unfavorable outcome in ordinal-shift analysis (OR 2.72, 95% CI 1.25-5.91). The few studies available highlight heterogeneity of neuroimaging methodologies for assessing brain atrophy and difficulty addressing the multiple confounders involved in clinical outcomes. More consistent, accurate investigation is needed before proposing brain atrophy as a possible parameter to improve patient selection for MT. Brain atrophy is associated with many of the clinical confounders frequently present in patients with acute ischemic stroke. Heterogeneity in classification methodologies for brain atrophy and complexity analyzing multiple clinical confounders make it difficult to assess the true impact of this radiological finding on MT-related outcomes.


Redox-Responsive Pickering Emulsions Based on Silica Nanoparticles and Electrochemical Active Fluorescent Molecules.
In this paper, we report a novel redox-responsive water-in-oil Pickering emulsion stabilized by negatively charged silica nanoparticles in combination with a trace amount of redox switchable fluorescent molecule ferrocene azine (FcA), in which ferrocene serves as a redox-sensitive group and anthryl unit serves as a fluorescence emission center. By alternately adding oxidants and reducing agents at a moderate condition, the amphiphilicity of silica nanoparticles changes because of the adsorption of Fc+A and the desorption of FcA on the silica surface. On the one hand, the stability of emulsions can be transformed between stable and unstable at ambient temperature via redox trigger and the regulation process can be cycled at least three times. On the other hand, the fluorescent intensity of the FcA molecule can be regulated by redox stimuli; thus, the change in fluorescent behavior of the emulsion droplets is observed upon redox cycles, which makes it useful in the fluorescent label of stimuli-responsive Pickering emulsions. This work provides a deep understanding of the regulation mechanism of Pickering emulsions upon redox stimuli and opens the new way for in situ fluorescent label of stimulus-responsive Pickering emulsions without introducing additional fluorescent molecules.


A symmetry mismatch at the site of RNA packaging in the polymerase complex of dsRNA bacteriophage phi6.
The polymerase complex of the enveloped double-stranded RNA (dsRNA) bacteriophage phi6 fulfils a similar function to those of other dsRNA viruses such as Reoviridae. The phi6 complex comprises protein P1, which forms the shell, and proteins P2, P4 and P7, which are involved in RNA synthesis and packaging. Icosahedral reconstructions from cryo-electron micrographs of recombinant polymerase particles revealed a clear dodecahedral shell and weaker satellites. Difference imaging demonstrated that these weak satellites were the sites of P4 and P2 within the complex. The structure determined by icosahedral reconstruction was used as an initial model in an iterative reconstruction technique to examine the departures from icosahedral symmetry. This approach showed that P4 and P2 contribute to structures at the 5-fold positions of the icosahedral P1 shell which lack 5-fold symmetry and appear in variable orientations. Reconstruction of isolated recombinant P4 showed that it was a hexamer with a size and shape matching the satellite. Symmetry mismatch between the satellites and the shell could play a role in RNA packaging akin to that of the portal vertex of dsDNA phages in DNA packaging. This is the first example of dsRNA virus in which the structure of the polymerase complex has been determined without the assumption of icosahedral symmetry. Our result with phi6 illustrates the symmetry mismatch which may occur at the sites of RNA packaging in other dsRNA viruses such as members of the Reoviridae.


Combined experimental and theoretical study on the Raman and Raman optical activity signatures of pentamethylundecane diastereoisomers.
The synthesis and the separation of the four stereoisomers of 2,4,6,8,10-pentamethylundecane (PMU) are described together with their characterization by Raman spectroscopy. In parallel, theoretical calculations of the Raman and vibrational Raman optical activity (VROA) spectra are reported and analyzed in relation with the recorded spectra. A very good agreement is found between the experimental and theoretical spectra. The Raman spectra are also shown to be less affected by the change of configuration than the VROA spectra. Nevertheless, by studying the overlap between the theoretical Raman spectra, we show clear relationships between the spectral fingerprints and the structures displaying a mixture of the TGTGTGTG conformation of the (4R,6s,8S)-PMU (isotactic compound) with the TTTTTTTT conformation of the (4R,6r,8S)-PMU (syndiotactic compound). Then, the fingerprints of the VROA spectra of the five conformers of the (4R,8R)-PMU have been related to the fingerprints of the regular (TG)(N) isotactic compound as a function of the torsion angles. Since the (TT)(N) syndiotactic compound has no VROA signatures, the VROA spectroscopy is very sensitive to the helical structures, as demonstrated here.


[Fascioliasis and brucellosis in same patient].
Brucellosis is a zoonotic infectious disease that can affect many organs and systems and leads to very different clinical circumstances. Brucellosis is rare in association with various infectious agents. Fascioliasis is a zoonotic disease caused by Fasciola hepatica, popularly referred to as a large leaf-shaped liver fluke. This case is a 39-year-old male patient, and his complaints began a week ago, which were chills, fever, abdominal pain, nausea, vomiting, weakness, sweating, and widespread pain. The patient was considered brucellosis in the preliminary diagnosis. Rose Bengal test and Wright test (1/640) were detected as positive. Due to patients having elevated liver enzymes, abdominal ultrasound was taken. A liver lesion was seen with abdominal ultrasound. So, abdominal computed tomography (CT) was taken. The CT result report came in the form that at the left lobe of the liver segment 2, largely necrosis that showed no contrast enhancement, approximately 61x63 mm in size (compatible with fascioliasis) is viewed. The patient's IHA test results, required for fascioliasis, were detected as 1/320 positive. Especially for zoonotic diseases in areas with high endemicity, it should be considered that more than one infectious agent can be present together in high-risk patients.


A retrospective analysis of usefulness of impulse oscillometry system in the treatment of asthma.
Bronchial asthma (BA) has different phenotypes, and it requires a clinically effective subtype classification system. The impulse oscillometry system (IOS) is an emerging technique device used in respiratory functional tests. However, its efficacy has not been validated. Therefore, this study aimed to assess the relationship between BA and the IOS parameters, and the difference in the therapeutic effects of inhaled corticosteroids (ICSs) among the subtype classifications was evaluated using the IOS. Of the 245 patients with bronchial asthma who were screened, 108 were enrolled in this study. These patients were divided based on three subtypes according to the IOS result as follows: central predominant type (n = 34), peripheral predominant type (n = 58), and resistless type (n = 16). Then, the following ICSs were randomly prescribed in daily medical care: coarse-particle ICS (fluticasone propionate [FP]), fine-particle ICS (mometasone furoate [MF]), and moderate-particle ICS (budesonide [BUD]). The treatment effects were assessed using the Asthma Health Questionnaire (AHQ) and the Asthma Control Test (ACT) and were compared among the three subtypes. In the central predominant type, the AHQ score of the MF group was significantly higher than that of the FP group (15.4 vs. 3.6, p < 0.01) and the BUD group (15.4 vs. 8.8, p < 0.05); the ACT score of the FP group was significantly higher than that of the MF and BUD groups (24.3 vs. 21.7, 22.3, respectively, p < 0.05) at 4 weeks after treatment. In the peripheral predominant type, the AHQ score of the FP group was significantly higher than that of the MF group (14.1 vs. 3.4, p < 0.05); the ACT score of the FP group was lower than that of the MF and BUD groups (22.8 vs. 24.6, 24.4, respectively, p < 0.01) at 4 weeks after treatment. An association was observed between IOS subtype classification and ICS particle size in terms of therapeutic efficacy in BA. This result indicates that the IOS could be an effective tool in the selection of ICS and the evaluation of the BA phenotype.


Effects of aerobic exercise on blood pressure and lipids in overweight hypertensive postmenopausal women.
Menopause may increase risk of hypertension and abnormal lipid profile. The aim of the study was to examine the effects of morning and afternoon aerobic exercises on hypertension and lipids in overweight hypertensive postmenopausal women. Forty five women aged from 49 to 60 years were randomly assigned into three groups. Group (A) 15 patients received medicine, (B) 15 patients performed morning aerobic exercises and received medicine, and group (C) 15 patients performed afternoon aerobic exercises and received medicine. Blood pressure measurement and lipid profile tests were performed before and after the study. The results showed that there was a statistical significant difference among all groups in systolic and diastolic blood pressure, favoring group C. Also there was a statistical significant difference among all groups in lipid levels, favoring group C. Therefore, it can be concluded that morning aerobic exercises were more effective in reducing the blood pressure and lipids than afternoon exercises in overweight hypertensive postmenopausal women.


Brain mapping in sedated infants and young children with passive-functional magnetic resonance imaging.
Functional magnetic resonance imaging (fMRI) in pediatric patients presents a unique set of problems due to the need for patient compliance, the frequent need for sedation and an early developmental status. A new method for using fMRI in sedated infants and young children is presented using passive stimuli focused on visual, sensorimotor and language functions. All of these stimuli are presented such that no patient interaction is required. Eight sedated children undergoing diagnostic MRI scans of the brain participated in these passive fMRI procedures. Cortical regions were identified using standard techniques applied to the blood-oxygen-level-dependent signal which is the basis for fMRI. The results support the feasibility of brain mapping in sedated children with passive fMRI techniques.


Single-Crystal Investigation, Hirshfeld Surface Analysis, and DFT Study of Third-Order NLO Properties of Unsymmetrical Acyl Thiourea Derivatives.
In the current research work, unsymmetrical acyl thiourea derivatives, 4-((3-benzoylthioureido)methyl)cyclohexane-1-carboxylic acid (BTCC) and methyl 2-(3-benzoylthioureido)benzoate (MBTB), have been synthesized efficiently. The structures of these crystalline thioureas were unambiguously confirmed by single-crystal diffractional analysis. The crystallographic investigation showed that the molecular configuration of both compounds is stabilized by intramolecular N-H···O bonding. The crystal packing of BTCC is stabilized by strong N-H···O bonding and comparatively weak O-H···S, C-H···O, C-H···π, and C-O···π interactions, whereas strong N-H···O bonding and comparatively weak C-H···O, C-H···S, and C-H···π interactions are responsible for the crystal packing of MBTB. The noncovalent interactions that are responsible for the crystal packing are explored by the Hirshfeld surface analysis for both compounds. The void analysis is performed to find the quantitative strength of crystal packing in both compounds. Additionally, state-of-the-art applied quantum chemical techniques are used to further explore the structure-property relationship in the above-entitled molecules. The optimization of molecular geometries showed a reasonably good correlation with their respective experimental structures. Third-order nonlinear optical (NLO) polarizability calculations were performed to see the advanced functional application of entitled compounds as efficient NLO materials. The average static γ amplitudes are found to be 27.30 × 10-36 and 102.91 × 10-36 esu for the compounds BTCC and MBTB, respectively. The γ amplitude of MBTB is calculated to be 3.77 times larger, which is probably due to better charge-transfer characteristics in MBTB. The quantum chemical analysis in the form of 3-D plots was also performed for their frontier molecular orbitals and molecular electrostatic potentials for understanding charge-transfer characteristics. We believe that the current investigation will not only report the new BTCC and MBTB compounds but also evoke the interest of the materials science community in their potential use in NLO applications.


A three-group comparison of acute-onset dizzy, long-term dizzy and non-dizzy older patients in primary care.
The hypothesis of increased cardiovascular risk contributing to chronic dizziness has been discussed controversially so far. We investigated older patients suffering from acute (<6 months), chronic (≥ 6 months) or no dizziness, in terms of their cardiovascular risk and other impairments. A cross-sectional three-group comparison of 257 patients (65+) presenting at family medicine surgeries in Germany was performed. Measures of cardiovascular risk, including overall scores, scores of quality of life (SF-12), activities of daily living (ADL), depression (GDS), dizziness handicap (DHI) and patients' needs (DiNA), as well as comorbidity and medication, were compared in univariate and multivariate logistic regression analysis. In univariate analysis, systolic and diastolic blood pressure were significantly lower in the dizziness groups. The overall cardiovascular risk was not increased in dizzy patients. Anxiety was strongly associated with dizziness, whereas other associations were of marginal importance. In multivariate analysis, age (OR 1.10, 95% CI 1.03-1.17), female gender (OR 2.07, 95% CI 1.01-4.26) and anxiety (OR 2.50, 95% CI 1.03-6.05) were associated with acute dizziness, whereas only female gender was significant in chronic dizziness (OR 1.96, 95% CI 1.02- 3.75). Comparing all dizzy patients with the non-dizzy group, lower systolic blood pressure was also significantly associated with dizziness. Results from our sample suggest that low systolic blood pressure is more important for dizziness in older patients than increased cardiovascular risk. Acute-onset and long-term dizzy patients were comparable in many aspects, which makes this classification less clinically important.


Health Improvements Have Been More Rapid and Widespread in China than in India: A Comparative Analysis of Health and Socioeconomic Trends from 1960 to 2011.
We examined differences between China and India in key health and socioeconomic indicators, including life expectancy, infant and child mortality, non-communicable disease mortality from cancer, cardiovascular diseases (CVD), and diabetes, Human Development Index, Gender Inequality Index, material living conditions, and health expenditure. Data on health and social indicators came from various World Health Organization and United Nations databases on global health and development statistics, including the GLOBOCAN cancer database. Mortality trends were modeled by log-linear regression, and differences in rates and relative risks were tested for statistical significance. Although both countries have made marked improvements, India lags behind China on several key health indicators. Differential rates of mortality decline during 1960-2009 have led to a widening health gap between China and India. In 2009 the infant mortality rate in India was 50 deaths per 1,000 live births, 3 times greater than the rate for China. Sixty-six out of 1,000 Indian children died before reaching their 5th birthday, compared with 19 children in China. China's life expectancy is 9 years longer than India's. Life expectancy at birth in India increased from 42 years in 1960 to 65 years in 2009, while life expectancy in China increased from 47 years in 1960 to 74 years in 2009. Major health concerns for China include high rates of stomach, liver, and lung cancer, CVD, and smoking prevalence. Globally, India ranked 90th and China 102nd in life satisfaction. India's less favorable health profile compared to China is largely attributable to its higher rates of mortality from communicable diseases and maternal and perinatal conditions. Further health gains can be achieved by reducing social inequality, greater investments in human development and health services, and by prevention and control of chronic-disease risks such as hypertension, smoking, obesity, and physical inactivity.


Sitagliptin plus pantoprazole can restore but not maintain insulin independence after clinical islet transplantation: results of a pilot study.
Resuming insulin use due to waning function is common after islet transplantation. Animal studies suggest that gastrointestinal hormones, including gastrin and incretins may increase β-cell mass. We tested the hypothesis that pantoprazole plus sitagliptin, would restore insulin independence in islet transplant recipients with early graft insufficiency and determined whether this would persist after a 3-month washout. Single-centre, uncontrolled, open label study of sitagliptin 100 mg daily plus pantoprazole 40 mg twice daily for 6 months. After 6 months of treatment, two of eight participants (25%) achieved the primary endpoint, defined as HbA1C < 42 mmol/mol (6%), fasting plasma glucose < 7.0 mmol, C-peptide > 0.5 nmol and no insulin use. There was a significant reduction in mean insulin dose, but no change in HbA1C or weight. There were no changes in the acute insulin response to arginine, the mixed meal tolerance test or blinded continuous glucose monitoring. After the washout, no participants met the primary endpoint and HbA1C increased from 45 ± 8 mmol/mol (6.3 ± 0.7%) to 51 ± 6 mmol/mol (6.8 ± 0.6%) (P < 0.05). Two participants had mild-moderate transient gastrointestinal side effects. There were no episodes of hypoglycaemia. Sitagliptin plus pantoprazole is well tolerated and safe and may restore insulin independence in some islet transplant recipients with early graft insufficiency, but this was not sustained when treatment was withdrawn. A larger, controlled trial is required to confirm the effectiveness of this combination to achieve insulin independence and to confidently exclude any persistent benefit for graft function. (Clinical Trials Registry No.: NCT00768651).


Promiscuity of Peptides Presented in HLA-DP Molecules from Different Immunogenicity Groups Is Associated With T-Cell Cross-Reactivity.
In the context of HLA-DP-mismatched allogeneic stem cell transplantation, mismatched HLA-DP alleles can provoke profound allo-HLA-DP-specific immune responses from the donor T-cell repertoire leading to graft-versus-leukemia effect and/or graft-versus-host disease in the patient. The magnitude of allo-HLA-DP-specific immune responses has been shown to depend on the specific HLA-DP disparity between donor and patient and the immunogenicity of the mismatched HLA-DP allele(s). HLA-DP peptidome clustering (DPC) was developed to classify the HLA-DP molecules based on similarities and differences in their peptide-binding motifs. To investigate a possible categorization of HLA-DP molecules based on overlap of presented peptides, we identified and compared the peptidomes of the thirteen most frequently expressed HLA-DP molecules. Our categorization based on shared peptides was in line with the DPC classification. We found that the HLA-DP molecules within the previously defined groups DPC-1 or DPC-3 shared the largest numbers of presented peptides. However, the HLA-DP molecules in DPC-2 segregated into two subgroups based on the overlap in presented peptides. Besides overlap in presented peptides within the DPC groups, a substantial number of peptides was also found to be shared between HLA-DP molecules from different DPC groups, especially for groups DPC-1 and -2. The functional relevance of these findings was illustrated by demonstration of cross-reactivity of allo-HLA-DP-reactive T-cell clones not only against HLA-DP molecules within one DPC group, but also across different DPC groups. The promiscuity of peptides presented in various HLA-DP molecules and the cross-reactivity against different HLA-DP molecules demonstrate that these molecules cannot be strictly categorized in immunogenicity groups.


Configurable IoT Open-Source Hardware and Software I-V Curve Tracer for Photovoltaic Generators.
Photovoltaic (PV) energy is a renewable energy resource which is being widely integrated in intelligent power grids, smart grids, and microgrids. To characterize and monitor the behavior of PV modules, current-voltage (I-V) curves are essential. In this regard, Internet of Things (IoT) technologies provide versatile and powerful tools, constituting a modern trend in the design of sensing and data acquisition systems for I-V curve tracing. This paper presents a novel I-V curve tracer based on IoT open-source hardware and software. Namely, a Raspberry Pi microcomputer composes the hardware level, whilst the applied software comprises mariaDB, Python, and Grafana. All the tasks required for curve tracing are automated: load sweep, data acquisition, data storage, communications, and real-time visualization. Modern and legacy communication protocols are handled for seamless data exchange with a programmable logic controller and a programmable load. The development of the system is expounded, and experimental results are reported to prove the suitability and validity of the proposal. In particular, I-V curve tracing of a monocrystalline PV generator under real operating conditions is successfully conducted.


Ketamine reduces remifentanil-induced postoperative hyperalgesia mediated by CaMKII-NMDAR in the primary somatosensory cerebral cortex region in mice.
Remifentanil is commonly used clinically for perioperative pain relief, but it may induce postoperative hyperalgesia. Low doses of ketamine have remained a common choice in clinical practice, but the mechanisms of ketamine have not yet been fully elucidated. In this study, we examined the possible effects of ketamine on calcium/calmodulin-dependent protein kinase II α (CaMKIIα) and N-methyl-d-aspartate receptor (NMDAR) subunit NR2B in a mouse model of remifentanil-induced postoperative hyperalgesia (RIPH) in the primary somatosensory cerebral cortex (SI) region. The paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were used to assess mechanical allodynia and thermal hyperalgesia, respectively, before and after intraoperative remifentanil administration. Before surgery, mice received intrathecal injections of the following drugs: ketamine, NMDA, BayK8644 (CaMKII activator), and KN93 (CaMKII inhibitor). Immunofluorescence was performed to determine the anatomical location and expression of activated CaMKIIα, phosphorylated CaMKIIα (p-CaMKIIα). Additionally, western blotting was performed to assess p-CaMKIIα and NMDAR expression levels in the SI region. Remifentanil decreased the PWMT and PWTL at 0.5 h, 2 h, and 5 h and increased p-CaMKIIα expression in the SI region. Ketamine increased the PWMT and PWTL and reversed the p-CaMKIIα upregulation. Both BayK8644 and NMDA reversed the effect of ketamine, decreased the PWMT and PWTL, and upregulated p-CaMKIIα expression. In contrast, KN93 enhanced the effect of ketamine by reducing hyperalgesia and downregulating p-CaMKIIα expression. These results suggested that ketamine reversed RIPH by inhibiting the phosphorylation of CaMKIIα and the NMDA receptor in the SI region in mice.


Neurokinin-1 receptor immunoreactivity in the nucleus of the solitary tract in the hamster.
Substance P (SP) modulates the activity of taste-responsive neurons in the gustatory zone of the nucleus of the solitary tract (NST) in the hamster. The distribution of the neurokinin-1 (NK1) receptor (i.e. the SP receptor) was mapped and compared with the distribution of SP immunoreactivity to identify the sites of ligand-receptor interactions. NK1-immunoreactive puncta and somata were located mostly in the rostral lateral, upper half of the rostral central and medial NST subnuclei. These subnuclei also contained intense SP-immunoreactive puncta, and are known to receive substantial inputs via gustatory and somatosensory afferent fibers. The ventral subnucleus, which is involved in visceromotor reflexes accompanying ingestion, contained little NK1 or lighter SP-immunoreactivity. These findings suggest that SP modulates taste activity destined for the ascending gustatory pathway at the level of the first central synapse in the gustatory pathway.


Sphingosine-1-phosphate in Endothelial Cell Recellularization Improves Patency and Endothelialization of Decellularized Vascular Grafts In Vivo.
S1P has been shown to improve the endothelialization of decellularized vascular grafts in vitro. Here, we evaluated the potential of tissue-engineered vascular grafts (TEVGs) constructed by ECs and S1P on decellularized vascular scaffolds in a rat model. Rat aorta was decellularized mainly by 0.1% SDS and characterized by histology. Rat ECs, were seeded onto decellularized scaffolds, and the viability of the ECs was evaluated by biochemical assays. Then, we investigated the in vivo patency rate and endothelialization for five groups of decellularized vascular grafts (each n = 6) in a rat abdominal aorta model for 14 days. The five groups included (1) rat allogenic aorta (RAA); (2) decellularized RAA (DRAA); (3) DRAA with S1P (DRAA/S1P); (4) DRAA with EC recellularization (DRAA/EC); and (5) DRAA with S1P and EC recellularization (DRAA/EC/S1P). In vitro, ECs were identified by the uptake of Dil-Ac-LDL. S1P enhanced the expression of syndecan-1 on ECs and supported the proliferation of ECs on decellularized vascular grafts. In vivo, RAA and DRAA/EC/S1P both had 100% patency without thrombus formation within 14 days. Better endothelialization, more wall structure maintenance and less inflammation were noted in the DRAA/EC/S1P group. In contrast, there was thrombus formation in the DRAA, DRAA/S1P and DRAA/EC groups. S1P could inhibit thrombus formation to improve the patency rate of EC-covered decellularized vascular grafts in vivo and may play an important role in the construction of TEVGs.


Controlled shielding and deshielding of gene delivery polyplexes using hydroxyethyl starch (HES) and alpha-amylase.
The non-viral delivery of nucleic acids faces many extracellular and intracellular hurdles on the way from injection site to the site of action. Among these, aggregation in the blood stream and rapid elimination by the mononuclear phagocytic system (MPS) represent strong obstacles towards successful development of these promising therapeutic modalities. Even the state-of-the-art solutions using PEGylation show low transfection efficiency due to limited uptake and hindered endosomal escape. Engineering the carriers with sheddable coats reduces aggregation and phagocytosis due to the effective shielding, while the controlled deshielding at the desired site of action enhances the uptake and intracellular release. This work reports for the first time the use of hydroxyethyl starch (HES) for the controlled shielding/deshielding of polyplexes. HES, with different molar masses, was grafted to polyethylenimine (PEI) and characterized using (1)H NMR, colorimetric copper-assay, and SEC. HES-PEI conjugates were used to generate polyplexes with the luciferase-expressing plasmid DNA pCMVluc, and were characterized by DLS and zeta potential measurements. Deshielding was tested in vitro by zeta potential measurements and, erythrocyte aggregation assay upon addition of α-amylase (AA) to the HES-decorated particles. The addition of AA led to gradual increase in the zeta potential of the nanoparticles over 0.5 to 1h and to a higher aggregation tendency for erythrocytes due to the degradation of the HES-coat and exposure of the polyplexes' positive charge. In vitro transfection experiments were conducted in 2 cell-lines±AA in the culture medium. The amylase-treated HES-decorated complexes showed up to 2 orders of magnitude higher transfection levels compared to the untreated HES-shielded particles, while AA had no effect on the transfection of PEG-coated or uncoated polyplexes. Finally, flow cytometry showed that the addition of AA increased the amount of delivered DNA per cell for the HES-shielded polyplexes. This study shows that decorating nanoparticles with HES can be a promising tool for the controlled shielding/deshielding of polyplexes.


[Influence of trabecular microstructure modeling on finite element analysis of dental implant].
To analyze the influence of trabecular microstructure modeling on the biomechanical distribution of implant-bone interface with a three-dimensional finite element mandible model of trabecular structure. Dental implants were embeded in the mandibles of a beagle dog. After three months of the implant installation, the mandibles with dental implants were harvested and scaned by micro-CT and cone-beam CT. Two three-dimensional finite element mandible models, trabecular microstructure(precise model) and macrostructure(simplified model), were built. The values of stress and strain of implant-bone interface were calculated using the software of Ansys 14.0. Compared with the simplified model, the precise models' average values of the implant bone interface stress increased obviously and its maximum values did not change greatly. The maximum values of quivalent stress of the precise models were 80% and 110% of the simplified model and the average values were 170% and 290% of simplified model. The maximum and average values of equivalent strain of precise models were obviously decreased, and the maximum values of the equivalent effect strain were 17% and 26% of simplified model and the average ones were 21% and 16% of simplified model respectively. Stress and strain concentrations at implant-bone interface were obvious in the simplified model. However, the distributions of stress and strain were uniform in the precise model. The precise model has significant effect on the distribution of stress and strain at implant-bone interface.


Synergistic effect of exercise and statins on femoral strength in rats.
It is now widely recognized that in order to optimize bone health in the later years, bone healthy behaviors should begin at a young age and continue throughout life. Prescribed orally to lower lipid levels in adults of all ages, statins have also been shown to stimulate bone formation in vitro by promoting bone morphogenic protein-2 (BMP-2) activity and to stimulate bone formation in vivo. Weight bearing exercise is well known to stimulate bone formation through a mechanism whereby mechanical loading is 'sensed' by the mechano-sensors leading to a cascade of events involving the activation of osteoblasts. For individuals with high cholesterol levels, both of these interventions are recommended throughout adult life. Since statins and exercise stimulate bone formation via different mechanisms, we hypothesized that exercise in combination with oral simvastatin synergistically increases bone mineral density and strength. Mature adult female, Sprague Dawley rats were divided into 4 groups: control (n=9), statin only (n=8), exercise only (n=11), and statin plus exercise (n=11). Simvastatin was given to the two groups at a dose of 10 mg/kg/day in standard rat chow for the entire 5 week period. All rats ate the same mass of food. The two exercise groups ran on a treadmill with progressively greater speeds and time, ending on week 5 at 30 m/min for 60 min. After 5 weeks, rats were euthanized, and excised femurs were scanned for areal bone mineral density (BMD) and tested by three point bending to obtain the following performance measures: maximum force (strength), stiffness, and work-to-fracture. Only the group treated with statins and exercise showed a positive effect on the biomechanical performance of the femurs. Compared to controls, this group had increased maximum force, stiffness, moment of inertia, and BMD. Linear regression analysis revealed that the increased performance was related to increased BMD. We conclude that the combination of oral statins and appropriate exercise increases bone strength better than either individual treatment and may provide optimal protection against osteoporosis.


Cyclooxygenase-2 (COX-2) overexpression in childhood brain tumors.
The overexpression of COX enzymes has been demonstrated in human neoplasms at various sites, including the colon, gastrointestinal tract, lung, skin and recently in brain tumors. In this study, COX-2 receptor overexpression in primary childhood brain tumors was determined and the distribution pattern of COX-2 receptors was examined. A sensitive, 4-step, alkaline phosphatase conjugated antigen detection technique was used and a specific monoclonal antibody for medulloblastomas/ primitive neuroectodermal tumors (MEDs/PNETs), anaplastic, high-grade astrocytomas (ASTRs) and in glioblastoma multiformes (GMs) was employed. All of the 14 MEDs/PNETs observed demonstrated high levels of immunoreactivity (overexpression), with the highest immunostaining intensity (grades A and B). However, of the 14 subtypes of astrocytic tumors examined, the COX-2 receptor expression level did not even approach those of the MEDs/PNETs levels. However, significant differences were found when comparing low grade pilocytic ASTRs to high grade anaplastic ASTRs and glioblastomas. In two low grade pilocytic ASTRs, the expression level never exceeded 20%, while in high grade glial tumors (6 anaplastic ASTRs and 6 GMs) 30 to 50% of the tumor cells overexpressed COX-2 receptors, documenting an increase in COX-2 receptor overexpression with the increasing grade of the astrocytic tumor. In view of these findings, it would appear likely that COX-2 inhibitors may represent a chemo-preventive tool in treating childhood brain tumors, which are the leading cause of solid tumor cancer death in children under the age of 20.


Factor XI/ADAMTS13 complexes are quantitatively insignificant in human plasma.
Reportedly, complexes between factor XI and ADAMTS13 are detected with a commercial ADAMTS13/FXI ELISA kit in plasma and are decreased in thrombotic thrombocytopenic purpura (TTP). Using this kit, control and TTP patient plasma contained varying amounts of signal (25-670% of a reference plasma) but no signal was observed for mixtures of recombinant enzymes, suggesting little interaction. ADAMTS13/FXI complexes were undetectable by immunoprecipitation or gel filtration chromatography in control plasma or mixtures of recombinant proteins. These results suggest that ADAMTS13/FXI complexes are insignificant in plasma and unlikely to affect the function of either protein during normal hemostasis or in TTP.


[Brain deformation caused by hyperplasia molar teeth (macrodonts) in the Japanese field vole (Microtus montebelli)].
Protrusion of hyperplastic upper molar teeth (macrodonts) into the cranial cavity was observed in the Japanese field vole. Protrusions of the upper molars occurred on both sides, but were large on the left than on the right. The teeth invaded the cranial cavity and brain parenchyma. Large concavities on the ventral side of the brain were interposed between the lateral olfactory tract and the optic tract. Invation by one macrodont reached the basal nuclei, hypothalamic and thalamic nuclei. The brain was deformed bilaterally, and nearly the entire olfactory bulb, globus pallidus, internal capsule, and lateral preoptic nucleus, and a portion of the hypothalamus, thalamus and anterior commissure were absent on the left side.


Outcome analysis of prenatally detected ureteroceles associated with multicystic dysplasia.
We assessed the outcome of a nonoperative approach in infants with prenatally detected ureteroceles associated with multicystic dysplasia. A retrospective analysis of all infants with ureteroceles referred for evaluation of prenatally hydronephrosis was conducted. Ultrasound, cystogram and scintigraphy findings were tabulated. Clinical outcomes including infections and the need for surgical intervention were assessed. We identified 5 female and 3 male infants with prenatally detected ureteroceles and associated multicystic dysplasia. There were 4 cases with renal duplication and 4 with single systems. All infants were treated expectantly. One infant had a single urinary tract infection. The multicystic dysplastic moiety involuted by age 18 months in all children. The ureterocele collapsed in 3 children and remained stable in the remainder. None of the children required surgical intervention with a median and mean followup of 36 months (range 14 to 54). We identified a subset of prenatally diagnosed ureteroceles that had a benign clinical course and did not require surgical intervention with available followup. Careful evaluation and interpretation of postnatal studies will allow identification and observational management of this unique subset of ureteroceles associated with multicystic dysplasia and absence of hydroureteronephrosis.


Calorie restriction in nonhuman primates: mechanisms of reduced morbidity and mortality.
Long term chronic calorie restriction (CR) of adult nonhuman primates significantly reduces morbidity and increases median age of death. The present review is focused upon an ongoing study of sustained adult-onset calorie restriction, which has been underway for 15 years. Monkeys, initially calorie restricted at about 10 years of age, are now approximately 25 years old. The median life span of these restricted monkeys is increasing, now exceeding that of ad libitum (AL)-fed monkeys. In our laboratory, maximum life span for AL-fed monkeys appears to be about 40 years. Thus, whether CR can also increase maximal life span, as it does in rodents, cannot be determined for at least another 15 years. The earliest detectable positive benefit on morbidity in these monkeys was previously reported as the prevention of obesity. Current evidence, as reviewed here, suggests that much obesity-associated morbidity is also mitigated by sustained calorie restraint in nonhuman primates. Furthermore, probably because of the prevention of obesity, diabetes has also been prevented. Recent findings include the identification of extraordinary changes in the glycogen synthesis pathway, and on the phosphorylation of glycogen synthase in response to insulin. This calorie restriction-induced prevention of morbidity does not require excessive leanness, but is clearly present when body fat is within the normal range of 10 to 22%, and this is likely to be true in humans as well.


Chest-wall contouring surgery in female-to-male transgender patients: A one-center retrospective analysis of applied surgical techniques and results.
Chest-wall contouring surgery is an important part of the gender reassignment process that contributes to strengthening the self-image and facilitating living in the new gender role. Here, we analyze the surgical techniques used in our clinic and report the results. Female-to-male transgender patients (n = 57) undergoing chest-wall contouring surgery at Tampere University Hospital between January 2003 and April 2015 were enrolled in the study. Breast appearance was evaluated and either a concentric circular approach or a transverse incision technique was used for mastectomy. Patient characteristics and data regarding the technique and postoperative results were collected and analyzed retrospectively. In addition to the transgender diagnosis, 40.4% of the patients had another psychiatric diagnosis. For mastectomy, a concentric circular approach was used in 50.9% and a transverse incision approach in 49.1% of the patients. In the transverse incision group, 21.4% of the patients underwent pedicled mammaplasty and 78.6% mastectomy with a free nipple-areola complex graft. Compared with the transverse incision group, breasts were smaller (p < 0.001) and body mass index value was lower in the concentric circular group (p = 0.001). One-third of the patients had complications (hematoma, infection, seroma, fistula, or partial necrosis of nipple-areola complex) and the reoperation rate was 8.8%. Hematoma was the most frequent reason for reoperation. Corrections were required for the scar in 14.0% of the patients, the contour in 28.0%, the areola in 15.8%, and the nipple in 5.3%. Secondary corrections were needed more often in the concentric circular (55.2%) than in the transverse incision group (25.0%; p = 0.031). The larger the breast, poorer the skin quality, and greater the amount of excess skin, the longer the required incision and resulting scar is for mastectomy of female-to-male patients. Hematoma is the most common reason for acute reoperation and secondary corrections are often needed.


Thickness-Dependent Crystallization of Ultrathin Antimony Thin Films for Monatomic Multilevel Reflectance and Phase Change Memory Designs.
Phase change materials, with more than one reflectance and resistance states, have been a subject of interest in the fields of phase change memories and nanophotonics. Although most current research focuses on rather complex phase change alloys, e.g., Ge2Sb2Te5, recently, monatomic antimony thin films have aroused a lot of interest. One prominent attractive feature is its simplicity, giving fewer reliability issues like segregation and phase separation. However, phase transformation and crystallization properties of ultrathin Sb thin films must be understood to fully incorporate them into future memory and nanophotonics devices. Here, we studied the thickness-dependent crystallization behavior of pulsed laser-deposited ultrathin Sb thin films by employing dynamic ellipsometry. We show that the crystallization temperature and phase transformation speed of as-deposited amorphous Sb thin films are thickness-dependent and can be precisely tuned by controlling the film thickness. Thus, crystallization temperature tuning by thickness can be applied to future memory and nanophotonic devices. As a proof of principle, we designed a heterostructure device with three Sb layers of varying thicknesses with distinct crystallization temperatures. Measurements and simulation results show that it is possible to address these layers individually and produce distinct and multiple reflectance profiles in a single device. In addition, we show that the immiscible nature of Sb and GaSb could open up possible heterostructure device designs with high stability after melt-quench and increased crystallization temperature. Our results demonstrate that the thickness-dependent phase transformation and crystallization dynamics of ultrathin Sb thin films have attractive features for future memory and nanophotonic devices.


The role of nucleotides in apoptotic cell clearance: implications for disease pathogenesis.
Apoptosis occurs in many tissues, during both normal and pathogenic processes. Normally, apoptotic cells are rapidly cleared, either by neighboring or recruited phagocytes. The prompt clearance of apoptotic cells requires that the apoptotic cells announce their presence through the release of chemotactic factors, known as "find-me" signals, to recruit phagocytes to the site of death, and through the exposure of so-called "eat-me" signals, which are ligands for phagocytic uptake. The importance of prompt apoptotic cell clearance is revealed by findings that decreasing the efficiency of engulfment results in the persistence of apoptotic cells, which is often associated with chronic inflammation and autoimmunity. Additionally, the proper clearance of apoptotic cells is actively anti-inflammatory, which is thought to play a crucial role in immunologic tolerance. Therefore, defects associated with clearance of apoptotic cells may contribute to the pathogenesis of several inflammatory diseases, including autoimmunity and atherosclerosis. Here, we review the role of nucleotides in the apoptotic cell clearance process and discuss their implications for disease pathogenesis.


Density Affects the Nature of the Hexatic-Liquid Transition in Two-Dimensional Melting of Soft-Core Systems.
We find that both continuous and discontinuous hexatic-liquid transitions can happen in the melting of two-dimensional solids of soft-core disks. For three typical model systems, Hertzian, harmonic, and Gaussian-core models, we observe the same scenarios. These systems exhibit reentrant crystallization (melting) with a maximum melting temperature T_{m} happening at a crossover density ρ_{m}. The hexatic-liquid transition at a density smaller than ρ_{m} is discontinuous. Liquid and hexatic phases coexist in a density interval, which becomes narrower with increasing temperature and tends to vanish approximately at T_{m}. Above ρ_{m}, the transition is continuous, in agreement with the Kosterlitz-Thouless-Halperin-Nelson-Young theory. For these soft-core systems, the nature of the hexatic-liquid transition depends on density (pressure), with the melting at ρ_{m} being a plausible transition point from discontinuous to continuous hexatic-liquid transition.


Older people in the emergency department: a literature review.
Emergency departments (EDs) play a unique role in healthcare systems throughout the world by providing acute interventions for older patients with acute/emergency and multiple health problems. The aim of this review was to identify studies that focused on older patients admitted to EDs and to determine the reasons for the visits. The literature review was based on a comprehensive search of electronic databases. Inclusion criteria were original research written in English; published 2002-2012; focused on older people; reasons for ED visit; and factors that affect the discharge process and those associated with a repeat ED visit. Other literature reviews and studies unrelated to the ED context, and studies examining patients aged ≥65 years, were excluded. Content analysis was performed. Twenty-five studies were identified and critically evaluated. The highest proportion of older people visited the ED because of multiple health conditions. The reasons for the visits were cardiovascular, mental health, musculoskeletal and abdominal conditions; adverse drug reactions; dermatological, neurological and respiratory conditions; poor health status; accidents; and the influence of time factors such as time of day, week or season. Factors that affected the discharge process were unresolved problems, health risk identification, aftercare instructions, medication prescribed at discharge and patient's residence before ED admission. Factors associated with repeat ED visits were sociodemographic characteristics, social problems, health problems, need for systematic health assessment, healthcare service use and inadequacy of care provided. The current review showed that older people are the main population visiting EDs; important factors required for planning and providing nursing care for older people in EDs were identified. More research is needed to determine how EDs support older people and their families. The findings of the current review identified that older people visit ED quite often because of different reasons. Discharge process and repeat visits may be influenced by various factors. To ensure quality nursing care in ED nurses need to be aware why do older people visit the ED, what factors may influence discharge and what factors are associated with repeat ED visits.


Prediction of the performance of pre-packed purification columns through machine learning.
Pre-packed columns have been increasingly used in process development and biomanufacturing thanks to their ease of use and consistency. Traditionally, packing quality is predicted through rate models, which require extensive calibration efforts through independent experiments to determine relevant mass transfer and kinetic rate constants. Here we propose machine learning as a complementary predictive tool for column performance. A machine learning algorithm, extreme gradient boosting, was applied to a large data set of packing quality (plate height and asymmetry) for pre-packed columns as a function of quantitative parameters (column length, column diameter, and particle size) and qualitative attributes (backbone and functional mode). The machine learning model offered excellent predictive capabilities for the plate height and the asymmetry (90 and 93%, respectively), with packing quality strongly influenced by backbone (∼70% relative importance) and functional mode (∼15% relative importance), well above all other quantitative column parameters. The results highlight the ability of machine learning to provide reliable predictions of column performance from simple, generic parameters, including strategic qualitative parameters such as backbone and functionality, usually excluded from quantitative considerations. Our results will guide further efforts in column optimization, for example, by focusing on improvements of backbone and functional mode to obtain optimized packings.


Dispositional factors, coping and adaptation during menopause.
The objective of the study was to examine the direct and indirect influences of dispositional factors, namely optimism, health-related hardiness (HRH) and sense of coherence (SOC), on the symptom experiences of peri- and postmenopausal women. Indirect effects of dispositional factors were examined via attitudes to the menopause and coping (emotion-versus problem-focused). A survey methodology was employed to assess the research objective for 176 peri- and postmenopausal women recruited from menopause clinics and family planning centers in Queensland, Australia. Emotional stability of the subjects was statistically controlled to eliminate any possible confounding effect on symptom reporting. The results indicated that optimism and SOC affect menopausal health directly, as evidenced by fewer symptoms reported by women scoring highly on these dispositions. Any indirect effect of HRH, optimism and SOC appears to be exerted via problem-focused coping rather than emotion-focused coping or through attitudes. It was concluded that dispositional factors are important to the experience of the menopause and how women adapt to their midlife transition. Psychologists and professionals working in menopause clinics may need to promote feelings of optimism and a sense of coherence in menopausal women, to facilitate better adaptation to this important transitional phase in women's lives.


Viral encephalitis masquerading as a fulminant anticholinergic toxidrome.
Emergency physicians are well versed in the recognition and management of certain poisonings which present with characteristic toxidromes. We present a case of a young pharmacy student who presented with altered mental status, tachycardia, facial flushing, dilated pupils, and dry skin and mucous membranes presumably due to anticholinergic poisoning. She improved with a combination of benzodiazepines and the acetylcholinesterase inhibitor physostigmine. However, following resolution of her initial symptoms, she became ill again and the subsequent neurologic evaluation revealed a diencephalic lesion consistent with a viral encephalitis. The acute anticholinergic signs and symptoms resulted from this lesion in an area of large cholinergic outflow. Although recognition and management of her acute anticholinergic findings were appropriate, they were not the manifestations of an acute anticholinergic ingestion.


Comparative study between culture media employed in sterility test.
The sterility test aims at the contact of a product with a culture medium, as a way of detecting the possible presence of viable microorganisms in products which have been submitted to a sterilization process and/or to aseptic processing. Since the official introduction of the methodology, in 1932, several culture media have been proposed and adopted, in a constant attempt to offer conditions which support the growth of as many contaminants as possible. This work aimed at a comparative evaluation of the efficiency of microbial contaminants detection in the different types of culture media employed in sterility tests. The study led to the conclusion that the culture media recommended by the pharmacopoeia compendia, soybean casein digest and fluid thioglycollate, present the best results in microorganisms detection. Besides, the microbial strains, as well as microbial suspension density, recommended by the main pharmacopoeias to verify culture media growth promoting capacity, have also proved suitable for use.


Clinical Outcomes of Treatment Strategies for Postoperative Plate Fracture and In Situ Fracture of the Femoral Shaft.
To investigate the treatment and clinical efficacy of postoperative plate fracture and in situ fracture of the femoral stem. We have retrospectively analyzed the clinical data, revised surgery information, and clinical efficacy of patients with postoperative plate fracture of the femoral stem in our hospital. A total of 33 cases were included whose original fractures were located in the upper and cadaveric femur and treated with paralleling intramedullary pins for revision surgery, as well as patients whose original fractures were located in the lower femur which were fixed with retrograde intramedullary nailing or anatomical locking and compression splints in the distal femur. For the selection of bone grafting, the original fracture site with Fernadez-Esteve scab grades I and II was treated with an autologous iliac bone graft. Postoperatively, patients were evaluated for fracture healing time, the clinical outcome of the affected limb, and complications in the iliac bone donor area. All patients were followed up until fracture healing, and all patients achieved clinical healing with a healing rate of 100% and a mean healing time of 6.3 months. No internal fixation failure such as rebreakage or loosening of the internal fixation occurred in all patients during the follow-up period. According to the Tohner-Wrnch criteria, 23 cases were excellent, 10 cases were good, and 0 cases were poor, with an excellent rate of 100%. Complications in the autologous iliac bone donor area amounted to 36.7%. For patients with original fractures located in the upper femoral segment or cadre, it is recommended to perform revision surgery with a paralleling intramedullary pin, while patients with original fractures located in the lower femoral segment are fixed with the retrograde intramedullary nailing or an anatomical type of distal femoral locking and compression splint. Patients with postoperative plate fractures of the femoral stem do not require routine autologous bone grafting for revision surgery.


Novel anti-inflammatory interleukin-35 as an emerging target for antiatherosclerotic therapy.
Atherosclerosis has been widely recognized as a slow progressing inflammatory disease of the aorta and other large caliber arterial vessels. Accumulating evidence suggest that interleukin (IL)-35 can represent an attractive target for future anti-atherosclerotic therapy due to several atheroprotective properties. First, immunosuppressive and anti-inflammatory activity of this cytokine could be beneficial against vascular inflammation. Second, IL-35 can suppress a variety of T cells including proinflammatory Th1 and Th17 cells and probably dendritic cells. Third, IL-35 supports proliferation of regulatory T cells (Tregs), increases their inhibitory function, and induces a new set of Tregs called inducible IL-35-producing Tregs (iTr35 cells). Fourth, this cytokine promotes production of antiinflammatory cytokines such as IL-10 and down-regulates expression of proinflammatory cytokines such as IL-17. Finally, IL-35 is inducible. The fact that IL-35 could be induced by simple compounds such as chemical chaperons may provide advances in developing new efficient strategies for treatment of atherosclerosis. However, it is necessary to test IL-35-inducing factors in order to understand mechanisms of induction and then select the most optimal one. Probably, constructing of humanized antibodies that mimic IL-35 function may provide benefits for advanced atheroprotective therapy.