Anergy in memory CD4+ T cells is induced by B cells.
Induction of tolerance in memory T cells has profound implications in the treatment of autoimmune diseases and transplant rejection. Previously, we reported that the presentation of low densities of agonist peptide/MHC class II complexes induced anergy in memory CD4(+) T cells. In the present study, we address the specific interaction of different types of APCs with memory CD4(+) T cells. A novel ex vivo anergy assay first suggested that B cells induce anergy in memory T cells, and an in vivo cell transfer assay further confirmed those observations. We demonstrated that B cells pulsed with defined doses of Ag anergize memory CD4 cells in vivo. We established that CD11c(+) dendritic cells do not contribute to anergy induction to CD4 memory T cells, because diphtheria toxin receptor-transgenic mice that were conditionally depleted of dendritic cells optimally induced anergy in memory CD4(+) T cells. Moreover, B cell-deficient muMT mice did not induce anergy in memory T cells. We showed that B2 follicular B cells are the specific subpopulation of B cells that render memory T cells anergic. Furthermore, we present data showing that anergy in this system is mediated by CTLA-4 up-regulation on T cells. This is the first study to demonstrate formally that B cells are the APCs that induce anergy in memory CD4(+) T cells.


Asymmetric division through a reduction of microtubule centering forces.
Asymmetric divisions are essential for the generation of cell fate and size diversity. They implicate cortical domains where minus end-directed motors, such as dynein, are activated to pull on microtubules to decenter asters attached to centrosomes, nuclei, or spindles. In asymmetrically dividing cells, aster decentration typically follows a centering phase, suggesting a time-dependent regulation in the competition between microtubule centering and decentering forces. Using symmetrically dividing sea urchin zygotes, we generated cortical domains of magnetic particles that spontaneously cluster endogenous dynein activity. These domains efficiently attract asters and nuclei, yielding marked asymmetric divisions. Remarkably, aster decentration only occurred after asters had first reached the cell center. Using intracellular force measurement and models, we demonstrate that this time-regulated imbalance results from a global reduction of centering forces rather than a local maturation of dynein activity at the domain. Those findings define a novel paradigm for the regulation of division asymmetry.


Clinical application and histological properties of autologous tissue-engineered skin equivalents using an acellular dermal matrix.
We developed a transplantable tissue-engineered skin equivalent composed of autologous cultured keratinocytes, fibroblasts, and a decellularized allogeneic dermis (acellular allogeneic dermal matrix; ADM) obtained from cadavers. In a process taking 3 weeks, cultured autologous keratinocytes from burn patients were expanded and then grown on ADMs. The tissue-engineered autologous skin equivalents (TESEs) were then transplanted in a one-stage procedure to the debrided third-degree burn wounds of 4 patients. The mean graft survival rate was 96%. Delayed graft loss and graft fragility were not observed. Histological and immunohistological findings indicated that the transplanted TESE had similar characteristics to normal human split-thickness skin grafts. These results suggest that the TESE using ADM can be used for permanent repair of full-thickness skin defects.


Management of Patients in the Context of Zika Virus: ACOG COMMITTEE OPINION SUMMARY, Number 784.
Zika virus is a flavivirus with the potential to cause serious adverse pregnancy and infant outcomes. Although rates of Zika virus infection have decreased in the United States, obstetrician-gynecologists and other health care providers should continue to assess their patients for potential exposure based on travel or sexual history and test symptomatic patients with possible exposure and pregnant women with ongoing exposure regardless of symptoms in accordance with the Centers for Disease Control and Prevention recommendations. Pregnant women and those planning a pregnancy should talk to their health care providers about potential risks before traveling to an area where current or past Zika virus transmission has occurred. Testing recommendations for pregnant women with possible Zika virus exposure differ based on the presence or absence of symptoms of Zika virus infection and the circumstances of possible exposure. If obstetrician-gynecologists or other health care providers identify a patient who has possibly been exposed to the Zika virus and may require testing, they should contact their local or state health department for assistance. Consultation with a maternal-fetal medicine specialist or an infectious disease specialist with expertise in the management of infectious diseases in pregnancy may be useful for pregnant women with possible maternal Zika virus infection or concerning fetal findings. Zika virus identification and follow-up care of infants born to women with possible exposure to Zika virus during pregnancy are critical and can ensure that appropriate intervention services are available to affected infants. Obstetrician-gynecologists and other obstetric care providers should have a system to ensure relevant information regarding a woman's Zika infection status is communicated to pediatric care providers.


Sixth Congresses of the Macedonian Society for Nephrology, Dialysis, Transplantation and Artificial Organs (MSNDTAO) - Stimulus for the Development of Nephrology in N. Macedonia.
The Macedonian Society for Nephrology, Dialysis, Transplantation and Artificial Organs (MSNDTAO) was established on September 1, 1992 in order to stimulate the development of nephrology and to unite experts from all professions interested in the research and treatment of kidney patients. Momir H. Polenakovic was elected President of MSNDTAO.The First congress of MSNTAO was held in Ohrid from October, 7 to 10, 1993 in hotel "Desaret" under the auspices of the first President of R. Macedonia, Kiro Gligorov. During the Congress, the Balkan Cities Association of Nephrology, Dialysis, Transplantation and Artificial Organs (BANTAO) was formed on October 9, 1993. The idea of cooperation with the Department of Nephrology from the Ege University, Izmir, R. Turkey was promoted. Some of the presented papers were published in the Proceedings "Nephrology '93" as a supplement to the Macedonian medical review. The "Doctrine for performing nephrological activity in the Republic of Macedonia" was also promoted.The Second congress of MSNDTAO was held in Struga, R. Macedonia from September, 6 to 10, 1997 together with the Second BANTAO Congress. Selected papers were printed in the Macedonian Medical Review.The Third congress of MSNDTAO was held from May, 30 to June 2, 2001 in Skopje, at the Macedonian Academy of Sciences and Arts (MASA). Proceedings of papers was also published.In 2011 M. H. Polenakovic was elected Honorary President of MSNDTAO for life, and Goce Spasovski was elected the current President of MSNDTAO.The Fourth congress of MSNDTAO was held in Ohrid from June, 21 to 24, 2012 together with the Fourth Meeting of the South-Eastern European Pediatric Nephrology Working Group (SEEPNWG).The Fifth congress of MSNDTAO was held from June, 9 to 12, 2016 in Skopje, at MASA together with the 6th Southeastern European Pediatric Nephrology Working Group (SEPNWG) Meeting and IPNA (International Pediatric Nephrology Association) Teaching Course. The VIII Macedonian-Croatian Nephrology Days were also held during the Congress.The Sixth congress of MSNDTAO was held from September, 26 to 29, 2019 along with the 15th BANTAO Congress, in Skopje, at MASA. The Congress also marked the 80th anniversary of the birth of M. H. Polenakovic.Apart from the participants from R. Macedonia, the congress was attended by renowned nephrologists from Europe and the world.A novelty of the last congresses was the organization of 9 CME (Continuing Medical Education) courses with famous lecturers. CME courses supported by the ERA-EDTA and / or the ISN were as follows: 2005 - Ohrid (BANTAO), 2006 - Skopje (MSNDTAO), 2009 - Skopje (MSNDTAO), 2010 - Skopje (ERA-EDTA - ESAO), 2011 Skopje (ERA-EDTA - EUTox group), 2012 - Ohrid (MSNDTAO), 2014 -Skopje (MSNDTAO), 2016 - Skopje (MSNDTAO), 2018 - Skopje (MSNDTAO - ERA-EDTA & ISN), 2019 - Skopje (BANTAO - ISN & ERA-EDTA).In addition to the congresses, MSNDTAO has held meetings with nephrological associations from the neighboring countries as Croatia, Serbia, Albania and Kosovo.The congresses of MSNDTAO contributed to the introduction and education of doctors in the diagnosis and treatment of kidney patients. They were a strong stimulus for the development of nephrology in R. Macedonia and beyond.


Acoustic landmarks drive delta-theta oscillations to enable speech comprehension by facilitating perceptual parsing.
A growing body of research suggests that intrinsic neuronal slow (<10 Hz) oscillations in auditory cortex appear to track incoming speech and other spectro-temporally complex auditory signals. Within this framework, several recent studies have identified critical-band temporal envelopes as the specific acoustic feature being reflected by the phase of these oscillations. However, how this alignment between speech acoustics and neural oscillations might underpin intelligibility is unclear. Here we test the hypothesis that the 'sharpness' of temporal fluctuations in the critical band envelope acts as a temporal cue to speech syllabic rate, driving delta-theta rhythms to track the stimulus and facilitate intelligibility. We interpret our findings as evidence that sharp events in the stimulus cause cortical rhythms to re-align and parse the stimulus into syllable-sized chunks for further decoding. Using magnetoencephalographic recordings, we show that by removing temporal fluctuations that occur at the syllabic rate, envelope-tracking activity is reduced. By artificially reinstating these temporal fluctuations, envelope-tracking activity is regained. These changes in tracking correlate with intelligibility of the stimulus. Together, the results suggest that the sharpness of fluctuations in the stimulus, as reflected in the cochlear output, drive oscillatory activity to track and entrain to the stimulus, at its syllabic rate. This process likely facilitates parsing of the stimulus into meaningful chunks appropriate for subsequent decoding, enhancing perception and intelligibility.


Preparing Copper Nanoparticles and Flexible Copper Conductive Sheets.
Nanotechnology is used in a wide range of fields, including medicine, cosmetics, and new material development, and is one of the most popular technologies in the field of flexible electronic products. For the present work, the chemical reduction method with environmentally friendly reducing agents was used to synthesize copper nanoparticles (CuNPs) with good dispersibility. The CuNPs were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), and ultraviolet-visible spectrophotometry (UV-vis). After the CuNPs were formed, the solvent, polymers, and additives were added to form copper ink. Finally, the prepared copper inks were applied to flexible polyethylene terephthalate (PET) substrate under low sintering temperature and the effects of sintering time and different concentrations of sintering agent on resistivity were investigated. The results show that the copper nanoparticles synthesized by secondary reduction were smaller, more uniform, and better dispersed than those formed by primary reduction. Ethylene glycol has reducing effects under high temperatures; therefore, the CuNPs formed using the mixed solvent were small and well dispersed. The copper ink was applied on the PET substrate, treated with a formic acid aqueous solution, and sintered at 130 °C for 60 min, and its resistivity was about 1.67 × 10-3 Ω cm. The proposed synthesizing method is expected to have potential applications in the flexible electronic products field.


Acculturation and alcohol consumption in the Mexican American population of the southwestern United States: findings from HHANES 1982-84.
Data from the Southwestern sample of the Hispanic HANES are employed to evaluate the relationship of acculturation into the larger society with alcohol consumption. As in previous work, acculturation was not found to be related to alcohol consumption of Mexican American men, but was positively related to the consumption of younger Mexican American women. Among middle-aged women, acculturation was not important. However, we found evidence that middle-aged women might be turning to alcohol in response to marital disruption and poverty. In addition, middle-aged women who are not employed are less frequent drinkers but those who drink are heavier drinkers than employed women.


Beyond hands-on and hands-off: supervisory approaches and entrustment on the inpatient ward.
The concept of entrustment has garnered significant attention in medical specialties, despite variability in supervision styles and entrustment decisions. There is a need to further study the enactment of supervision on inpatient wards to inform competency-based assessment design. Attending physicians, while supervising on clinical teaching inpatient wards, were invited to describe a recent moment of enacting supervision with an internal medicine resident. Constructivist grounded theory guided data collection and analysis. Interview transcripts were analysed in iterative cycles to inform data collection. Constant comparison was used to build a theory of supervision from the identified themes. In 2016-2017, 23 supervisors from two Canadian universities with supervision reputations ranging from very involved to less involved participated in one or two interviews (total: 28). Supervisors were not easily dichotomised into styles based on behaviour because all used similar oversight strategies. Supervisors described adjusting between 'hands-on' (e.g. detail oriented) and 'hands-off' (e.g. less visible on ward) styles depending on the context. All also contended with the competing roles of clinical teacher and care provider. Supervisors made a distinction between the terms `entrust' and `trust', and did not grant complete entrustment to senior residents. We propose that a supervisor's perceived responsibility for the ward underlies adjustments between 'hands-on' (i.e. personal ward responsibility) and 'hands-off' (i.e. shared ward responsibility) styles. Our approaches to clinical supervision model combines this responsibility tension with the tension between patient care and teaching to illustrate four supervisory approaches, each with unique priorities influencing entrustment. Given the fluidity in supervision, documenting changes in oversight strategies, rather than absolute levels of entrustment, may be more informative for assessment purposes. Research is needed to determine if there is sufficient association between the supervision provided, the entrustment decision made and the supervisor's trust in a trainee to use these as proxies in assessing a trainee's competence.


Macular infarction following intravitreal bevacizumab for treatment of central retinal vein occlusion.
Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), is widely used for the treatment of macular edema associated with central retinal vein occlusion (CRVO). The authors present a series of three patients with CRVO who suffered apparent macular infarction within weeks of intravitreal administration of bevacizumab. Of the nearly 200 patients undergoing intravitreal injections of bevacizumab for this indication over a surveillance period of 3 years, this event occurred in three patients. This has not been described in the natural history of the disease and is associated with poor visual outcomes.


Identification of polymorphisms in the osteopontin gene and their associations with certain semen production traits of water buffaloes in the Brazilian Amazon.
The osteopontin gene may influence the fertility of water buffaloes because it is a protein present in sperm. The aim of this work was to identify polymorphisms in this gene and associate them with fertility parameters of animals kept under extensive grazing. A total of 306 male buffaloes older than 18 months, from two farms, one in the state of Amapá and the other in the state of Pará, Brazil were used in the study. Seven SNPs were identified in the regions studied. The polymorphisms were in gene positions 1478, 1513 and 1611 in the region 5'upstrem and positions 6690, 6737, 6925 and 6952 in the region amplified in intron 5. The SNPs were associated with the traits, namely scrotal circumference, scrotal volume, sperm motility, sperm concentration and sperm pathology. There were significant SNPs (p < 0.05) for all the traits. The SNP 6690 was significant for scrotal circumference, sperm concentration, sperm motility and sperm pathology and the SNP 6737 for scrotal volume. The genotype AA of SNP 6690 presented the highest averages for scrotal circumference, sperm concentration and motility and the lowest total number of sperm pathologies. For the scrotal volume trait, the animals with the largest volume were correlated with the presence of the genotype GG of SNP 6737. These results indicate a significance of the osteopontin gene as it seems to exert a substantial influence on the semen production traits of male buffaloes.


Ubiquitination system and autoimmunity: the bridge towards the modulation of the immune response.
The ubiquitination system comprises a highly specific and regulated post-translational mechanism by which the immune response can be modulated, setting the balance between immunity and tolerance. Proteolysis dependent and independent mechanisms have been implicated. Particularly, the role of ubiquitin ligases as modulators of central and peripheral tolerance has brought attention to this system as one of the key elements of a complex regulatory network designed to maintain an active surveillance system. Cbl-b, GRAIL and Itch are the main E3 ligases, considered as negative regulators of the immune response as part of the genetic program induced by the calcium/calcineurin pathway. Other key signaling pathways for the immune response, such as the NF-kappaB and TGF-beta signaling are prone to be modulated by these ubiquitin ligases. Diverse mechanisms have been implicated in the development of anergy associated to E3 ligases, among these, the setting for TCR responsiveness and repression of cytokine transcription are best well characterized. Also, a role as inductors of regulatory T cells has been evidenced for Cbl-b and GRAIL. The defective expression of some of these E3 ligases has been related to the development of autoimmune disease, in experimental murine and human models, remarking its possible pathogenic role.


Role of intrinsic synaptic circuitry in collicular sensorimotor integration.
The superficial gray layer of the superior colliculus contains a map that represents the visual field, whereas the underlying intermediate gray layer contains a vector map of the saccades that shift the direction of gaze. These two maps are aligned so that a particular region of the visual field is represented directly above the neurons that orient the highest acuity area of the retina toward that region. Although it has been proposed that the transmission of information from the visuosensory to the motor map plays an important role in the generation of visually guided saccades, experiments have failed to demonstrate any functional linkage between the two layers. We examined synaptic transmission between these layers in vitro by stimulating the superficial layer while using whole-cell patch-clamp methods to measure the responses of intermediate layer neurons. Stimulation of superficial layer neurons evoked excitatory postsynaptic currents in premotor cells. This synaptic input was columnar in organization, indicating that the connections between the layers link corresponding regions of the visuosensory and motor maps. Excitatory postsynaptic currents were large enough to evoke action potentials and often occurred in clusters similar in duration to the bursts of action potentials that premotor cells use to command saccades. Our results indicate the presence of functional connections between the superficial and intermediate layers and show that such connections could play a significant role in the generation of visually guided saccades.


Air pollution, temperature, and regional differences in lung cancer mortality in Japan.
In this study, the authors investigated regional differences in lung cancer mortality in Japan, and, based on data acquired between 1970 and 1990 for 47 Japanese prefectures, estimated the relationship between regional lung cancer mortality and air pollution and/or temperature. Investigators used data for nitrogen dioxide, sulfur dioxide, motor vehicle density, tobacco expenditure, and temperature as independent variables for age-adjusted lung cancer death rates. The age-adjusted lung cancer death rates were higher in the southern geographical block of Japan (i.e., approximately 1.2-fold in males and 1.1-fold in females) and in the northern block (approximately 1.2-fold in males) than in the central block. The regional differences in the age-adjusted lung cancer death rates were explained by nitrogen dioxide and temperature. Temperature caused a greater effect (regression coefficients) of nitrogen dioxide on the age-adjusted lung cancer death rates than did nitrogen dioxide alone in the southern block (i.e., approximately 1.3-fold in males and 1.2-fold in females). These results provide the first evidence of a possible synergistic interaction between air pollution and high temperature on lung cancer mortality.


Measured spectral bidirectional reflection properties of four vegetated surfaces.
Spectral bidirectional reflectance values are presented at the 0.52-microm wavelength based on measured values of the radiation field of four vegetated surfaces: savannah, bog, pasture land, and coniferous forest, which cover a wide range of natural vegetated canopies. The results are given as examples of the full set of bidirectional reflectance values which consists of data at seven wavelengths between 0.43microm and 2.20 microm for each of the four surfaces. (From July 1977, the full set of data is available from the author on request.) The data may be applied for calculations of the radiative transfer in the atmosphere with realistic ground properties instead of isotropic albedo values.


Draft Genome Sequences of Azole-Resistant and Azole-Susceptible Aspergillus turcosus Clinical Isolates Recovered from Bronchoalveolar Lavage Fluid Samples.
We present the draft genome sequences of two clinical strains of Aspergillus turcosus, one azole-susceptible (strain HMR-AF-23/LSPQ-01275) and the other azole-resistant (strain HMR-AF-1038/LSPQ-01280), isolated from bronchoalveolar lavage fluid of two adult patients. These two strains are the first reported clinical isolates of A. turcosus.


Regulation of interleukin-8 gene at a distinct site of its promoter by CCAAT enhancer-binding protein homologous protein in prostaglandin E2-treated human T cells.
For a long period of time, the transcription factor CCAAT/enhancer-binding protein homologous protein (CHOP) has been thought to inhibit transcriptional activity for its ability to interact with CCAAT enhancer-binding protein family factors, thus preventing their binding to DNA. We have previously shown that in human T lymphocytes the CHOP phosphorylation induced by prostaglandin E(2) (PGE(2))-increased interleukin-8 (IL-8) gene expression. Given the CHOP positive role in the regulation of transcription, here we have investigated the molecular mechanism(s) by which CHOP increases IL-8 gene activity under PGE(2) stimulus. Transfection experiments with mutants showed both that the CHOP transactivation domain is essential for IL-8 transcription and that the IL-8/activator protein 1 (AP-1) promoter mutated in NF-kappaB and NF-IL-6, but not in the AP-1 site, harbors essential CHOP-responsive elements. CHOP silencing confirmed its role in the IL-8 transcriptional regulation and protein production, whereas c-Jun small interfering RNA experiments showed that the PGE(2)-induced activation of IL-8 promoter is mainly c-Jun-independent. Moreover, PGE(2) induced CHOP-DNA complexes only when the entire IL-8/AP-1 promoter or the wild type sequences encompassing the AP-1 upstream region were employed. Mutations introduced in these sequences prevented the DNA-CHOP complex formation. The IL-8/AP-1 mutant promoter lacking the sequence immediately upstream the AP-1 site is PGE(2)-unresponsive. Finally, chromatin immunoprecipitation data confirmed in vivo that PGE(2) induces CHOP binding to the IL-8 promoter. Taken together, our results suggest that the increased expression of CHOP in response to PGE(2) exerts a positive transcriptional regulation of the IL-8 promoter mediated by direct binding to a novel consensus site.


Effect of the silybin-phosphatidylcholine complex (IdB 1016) on the development of mammary tumors in HER-2/neu transgenic mice.
Silybin, a main component of the milk thistle of Silybum marianum, has been reported to possess anticancer activity. We investigated the effects of IdB 1016, a complex of silybin with phosphatidylcholine, on the development of mammary tumors appearing spontaneously in HER-2/neu transgenic mice. The mechanisms involved in the antitumor effect of IdB 1016 were evaluated by studying the apoptosis, senescent-like growth arrest, intratumoral leukocyte infiltrate, and the expression of HER-2/neu and p53 in tumoral mammary glands from transgenic mice and in human breast SKBR3 tumor cells. The administration of IdB 1016 delayed the development of spontaneous mammary tumors, reduced the number and size of mammary tumor masses, and diminished lung metastasization in HER-2/neu transgenic mice. In tumoral mammary glands from IdB 1016-treated mice, a down-regulation of HER-2/neu gene expression was associated with an increased senescent-like growth arrest of tumor cells, and an increased infiltrate of neutrophils, CD4, and CD8 T cells. Both senescent-like growth arrest and apoptosis were significantly increased and were associated with a reduced p185(HER-2/neu) protein and an increased p53 mRNA in SKBR3 in vitro treated with IdB 1016 in comparison with control cells. The results show the antitumor effect of IdB 1016 in the development of spontaneous mammary tumors in HER-2/neu transgenic mice. The effect of IdB 1016 might be related to the down-regulation of HER-2/neu expression and the induction of senescent-like growth arrest and apoptosis through a p53-mediated pathway in tumor cells.


Mutual interference of Cu and Zn ions in Alzheimer's disease: perspectives at the molecular level.
While metal ions such as copper and zinc are essential in biology, they are also linked to several amyloid-related diseases, including Alzheimer's disease (AD). Zinc and copper can indeed modify the aggregation pathways of the amyloid-β (Aβ) peptide, the key component encountered in AD. In addition, the redox active copper ions do produce Reactive Oxygen Species (ROS) when bound to the Aβ peptide. While Cu(i) or Cu(ii) or Zn(ii) coordination to the Aβ has been extensively studied in the last ten years, characterization of hetero-bimetallic Aβ complexes is still scarce. This is also true for the metal induced Aβ aggregation and ROS production, for which studies on the mutual influence of the copper and zinc ions are currently appearing. Last but not least, zinc can strongly interfere in therapeutic approaches relying on copper detoxification. This will be exemplified with a biological lead, namely metallothioneins, and with synthetic ligands.


Response of myogenic and fibrogenic cells to cytochalasin B and to colcemid. I. Light microscope observations.
Cytochalasin B (CB) induces a biphasic retraction is some cell types. The rapid response that peaks in 30 min leads to the "dendritic" condition. Replicating myogenic and fibrogenic cells, as well as postmitotic myoblasts and myotubes, participate in this reaction. This is followed by a slower phase that requires 40 h for stabilization and leads to the fully "absorized" state. Only replicating myogenic and fibrogenic cells participate in this reaction. Postmitotic myoblasts and myotubes do not arborize but round up and float off into the medium. Pretreatment with Colcemid does not block the rapid response to CB, but does block arborization. CB-arborized cells exposed to Colcemid while in the presence of CB develop sufficient tension to pull themselves apart. If CB depolymerizes actin-like filaments, and if such filaments constitute the only contractile system in the cell, then it is difficult to visualize how cells in CB develop such tension. Colcemid induces twisting, birefringent bands in interphase- and metaphase-arrested myogenic and fibrogenic cells, and in postmitotic myotubes. Such bands are more evident when CB-arborized cells are removed from CB and allowed to relax in Colcemid. These birefringent bands assemble in the prescence of cycloheximide, and may constitute 20% of the volume of the cell.


RARβ regulates neuronal cell death and differentiation in the avian ciliary ganglion.
Programmed cell death during chicken ciliary ganglion (CG) development is mostly discussed as an extrinsically regulated process, guided either by the establishment of a functional balance between preganglionic and postganglionic activity or the availability of target-derived neurotrophic factors. We found that the expression of the gene coding for the nuclear retinoic acid receptor β (RARB) is transiently upregulated prior to and during the execution phase of cell death in the CG. Using retroviral vectors, the expression of RARB was knocked down during embryonic development in ovo. The knockdown led to a significant increase in CG neuron number after the cell death phase. BrdU injections and active caspase-3 staining revealed that this increase in neuron number was due to an inhibition of apoptosis during the normal cell death phase. Furthermore, apoptotic neuron numbers were significantly increased at a stage when cell death is normally completed. While the cholinergic phenotype of the neurons remained unchanged after RARB knockdown, the expression of the proneural gene Cash1 was increased, but somatostatin-like immunoreactivity, a hallmark of the mature choroid neuron population, was decreased. Taken together, these results point toward a delay in neuronal differentiation as well as cell death. The availability of nuclear retinoic acid receptor β (RARβ) and RARβ-induced transcription of genes could therefore be a new intrinsic cue for the maturation of CG neurons and their predisposition to undergo cell death.


Sodium Bicarbonate Supplementation Delays Neuromuscular Fatigue Without Changes in Performance Outcomes During a Basketball Match Simulation Protocol.
Ansdell, P and Dekerle, J. Sodium bicarbonate supplementation delays neuromuscular fatigue without changes in performance outcomes during a basketball match simulation protocol. J Strength Cond Res 34(5): 1369-1375, 2020-To investigate the development of neuromuscular fatigue during a basketball game simulation and to ascertain whether sodium bicarbonate (NaHCO3) supplementation attenuates any neuromuscular fatigue that persists. Ten participants ingested 0.2 g·kg of NaHCO3 (or an equimolar placebo dosage of sodium chloride [NaCl]) 90 and 60 minutes before commencing a basketball game simulation (ALK-T vs. PLA-T). Maximal voluntary isometric contractions (MVICs) of the knee extensors and potentiated high- (100 Hz) and low- (10 Hz) frequency doublet twitches were recorded before and after each match quarter for both trials. In addition, 15-m sprint times and layup completion (%) were recorded during each quarter. Maximal voluntary isometric contraction, 100- and 10-Hz twitch forces declined progressively in both trials (p ≤ 0.05) with a less pronounced decrease in MVIC during ALK-T (p < 0.01). Both 100- and 10-Hz twitch forces were also significantly greater in ALK-T (p ≤ 0.05). Fifteen-meter sprint time increased over the course of both trials (∼2%, p < 0.01); however, no significant condition or time effect was found for layup completion (p > 0.05). A basketball simulation protocol induces a substantial amount of neuromuscular (reduction in knee extensor MVICs) and peripheral fatigue with a concomitant increase in 15-m sprint time over the protocol. NaHCO3 supplementation attenuated the rate of fatigue development by protecting contractile elements of the muscle fibers. This study provides coaches with information about the magnitude of fatigue induced by a simulated basketball game and provides evidence of the efficacy of NaHCO3 in attenuating fatigue.


COVID-19 emergency: the influence of implicit attitudes, information sources, and individual characteristics on psychological distress, intentions to get vaccinated, and compliance with restrictive rules.
To limit the spread of the COVID-19 emergency, a massive vaccination program was implemented and restrictive measures were imposed on the population. However, the propensity to adhere to the vaccination program has struggled to take off. Moreover, complying with the restrictive rules and maintaining social distancing have been highly distressing for many individuals. Italian participants (N = 140, females = 65%, mean age = 29.50, SD = 10.80) were presented with an online survey consisting of multiple-choice questions and two single-category implicit association tests (SC-IATs). One SC-IAT evaluated the tendency of participants to automatically associate personal protective equipment (PPE) and vaccines with safety or danger; the other evaluated their tendency to automatically associate social situations with good or bad. Multiple-choice questions explored individual, social, and environmental factors that were expected to contribute to vaccine propensity, compliance with restrictive rules, and feelings of distress. Using scientific information sources was related to implicitly associating PPE and vaccines with safety, which in turn was associated with the propensity to get the vaccine. Moreover, being female, young, unsatisfied with social relationships, having suffered health and economic consequences due to the pandemic, and having negative implicit attitudes toward social situations contributed to increasing feelings of distress. Communication may contribute to individuals' behavior and preferences and it can also be associated with implicit attitudes, becoming consequently one of the main leverages to reduce vaccine hesitancy. Recovery programs should prioritize the development of interventions aimed at fostering psychological well-being through the enhancement of social contacts.


Diazoxide treatment for insulinoma: a national UK survey.
A survey of UK patients receiving the drug diazoxide, revealed 40 patients with insulinoma on this treatment. Mean age (+/- SD) was 67 +/- 18 years, and 74% were female. Duration of treatment was 7 +/- 6 years (range 1-22). Most (55%) patients were treated with diazoxide because of tumour non-localisation (including failed previous surgery). Metastatic disease (20%) and poor surgical risk (10%) were other indications. Side-effects (notably fluid retention and hirsutism) were common (47%) but not troublesome. Treatment was highly effective--59% were symptom free and 38% had only occasional symptoms. Only one patient had frequent hypoglycaemia despite treatment. We conclude that diazoxide is effective in the management of insulinoma. Side-effects are common but not problematic. Treatment should be considered for all patients not cured by surgery, or unsuitable for surgical treatment.


Loss control/risk management. A survey of the contribution of autopsy examination.
I surveyed 183 hospitals with medical school pathology residency affiliations regarding their recognition and use of the autopsy in loss control/risk management. Thirty physician-owned, medical society-created professional liability companies and nine other malpractice liability underwriters were also surveyed. The results generally supported my bias for increased use of autopsy information in the field of hospital-risk management. I also examined an opposing minority view. Autopsy surgeons' and hospital administrators' responses supported increased use of autopsies in loss control activities for the following reasons: to eliminate suspicion, to provide reassurance to families, to substitute facts for conjecture, to construct a better defense, to reduce the number of claims, and to improve the quality of care.


Electron deficiency but semiconductive diamond-like B2CN originated from three-center bonds.
B2CN was one of the synthesized light element compounds, which was expected to be superhard material with a metallic character due to its electron deficienct nature. However, in this work, we discovered two novel semiconducting superhard B2CN phases using particle swarm intelligence technique and first-principles calculations, which were reported to have three-dimensional and four coordinated covalent diamond-like structures. These two new phases were calculated to be dynamically stable at zero and high pressures, and can be deduced from the previously reported Pmma phase by pressure-induced structural phase transitions. More importantly, unlike the previously proposed metallic B2CN structures, these two new phases combine superhard (the calculated Vickers hardness reached ∼55 GPa) and semiconducting character. The semiconducting behavior of the newly predicted B2CN phases breaks the traditional view of the metallic character of the electron deficient diamond-like B-C-N ternary compounds. By a detail analyzation of the electron localization functions of these two new phases, three-center bonds were reported between some B, C and B atoms, which were suggested to be the primary mechanism that helps the compound overcome its electron-deficient nature and finally exhibit a semiconducting behavior.


Allergic airway inflammation is differentially exacerbated by daytime and nighttime ultrafine and submicron fine ambient particles: heme oxygenase-1 as an indicator of PM-mediated allergic inflammation.
Ambient particulate matter (PM) originates from a range of sources and differs in composition with respect to season, time of day, and particle size. In this study, ambient PM samples in the ultrafine and submicrometer fine range were tested for the potential to exacerbate a murine model of allergic airway inflammation when exposure occurs solely during allergic sensitization, but not during subsequent allergen challenge. Temporally resolved and size-segregated PM samples were used to understand how summer or winter, day or night, and ambient ultrafine and submicrometer fine particle size influence PM's ability to exacerbate allergic inflammation. PM was collected in urban Fresno, CA. BALB/c mice were exposed to PM and house dust mite allergen (HDM) via intranasal aspiration on d 1, 3, and 5. HDM challenge occurred on d 12-14, with inflammation assessed 24 h following final challenge. While season or particle size did not predict allergic inflammation, daytime ultrafine and submicrometer fine particles significantly increased total cellular inflammation, specifically lymphocyte and eosinophil infiltration, compared to allergic controls. Further studies examined PM-mediated changes within the lung during the period where allergen sensitization occurred by measuring direct effects of PM on pulmonary oxidative stress and inflammation. Pulmonary levels of heme oxygenase-1 (HO-1), a biomarker of oxidative stress, but not cellular inflammation, demonstrated a remarkable correlation with the degree of allergic inflammation in animals sensitized to allergen and PM concomitantly, suggesting acute PM-mediated HO-1 levels may serve as a predictive indicator of a particle's ability to exacerbate allergic airway inflammation.


Deficiency of Retinoblastoma gene in mouse embryonic stem cells leads to genetic instability.
Genetic instability has been recognized as a hallmark of human cancers. Retinoblastoma (Rb) tumor suppressor protein has an essential role in modulating cell cycle progression. However, there is no direct evidence supporting its role in maintaining genetic stability. Here, we developed a sensitive method to examine the level of chromosome instability by using retrovirus carrying both positive and negative selectable markers that integrated randomly into individual chromosomes, and the frequency of loss of this selectable chromosomal marker (LOM) in normal mammalian cells was measured. Our results showed that normal mouse embryonic stem (ES) cells had a very low frequency of LOMs, which was less than 10(-8)/cell/generation. In Rb-/- mouse ES cells, the frequency was increased to approximately 10(-5)/cell/generation, whereas in Rb+/- ES cells, the frequency was approximately 10(-7)/cell/generation. LOMs was mediated mainly through chromosomal mechanisms and not through point mutations. These results, therefore, revealed that Rb, with a haploinsufficiency, plays a critical role in the maintenance of chromosome stability. The mystery of why Rb heterozygous carriers have early-onset tumor formation with high penetrance can be, at least, partially explained by this novel activity.


The Role of Vitamin K in Cholestatic Liver Disease.
Vitamin K (VK) is a ligand of the pregnane X receptor (PXR), which plays a critical role in the detoxification of xenobiotics and metabolism of bile acids. VK1 may reduce the risk of death in patients with chronic liver failure. VK deficiency is associated with intrahepatic cholestasis, and is already being used as a drug for cholestasis-induced liver fibrosis in China. In Japan, to treat osteoporosis in patients with primary biliary cholangitis, VK2 formulations are prescribed, along with vitamin D3. Animal studies have revealed that after bile duct ligation-induced cholestasis, PXR knockout mice manifested more hepatic damage than wild-type mice. Ligand-mediated activation of PXR improves biochemical parameters. Rifampicin is a well-known human PXR ligand that has been used to treat intractable pruritus in severe cholestasis. In addition to its anti-cholestatic properties, PXR has anti-fibrotic and anti-inflammatory effects. However, because of the scarcity of animal studies, the mechanism of the effect of VK on cholestasis-related liver disease has not yet been revealed. Moreover, the application of VK in cholestasis-related diseases is controversial. Considering this background, the present review focuses on the effect of VK in cholestasis-related diseases, emphasizing its function as a modulator of PXR.


Neuronavigation in interventional MR imaging. Prospective stereotaxy.
A practical MR imaging-based guidance/control methodology has been developed successfully and validated for improving the performance of stereotactic neurosurgerical procedures such as brain lesion biopsy. The use of the device and method in 40 routine MR-guided procedures has revealed its potential as an alternative approach. Superior to the traditional stereotactic systems, which rely on the old images, the new method, based on prospective guidance, can provide good and acceptable targeting accuracy in the presence of brain shift. Furthermore, the use of MR monitoring of the overall neurosurgical procedure provides another independent assurance for the success of a complicated surgery. The advantages of the new surgical guidance system and method are simple and compatible with the existing capabilities of conventional MR scanners. More importantly, it allows a more effective surgical guidance in the presence of brain shift during the typical neurosurgery. Another important advantage of the guidance method and device is the performance of a truly MR-guided neurosurgical procedure in a conventional, short bore high field MR scanner. Surgical procedures using the guidance system and method have been accepted by radiologists and neurosurgeons as an attractive MR-based stereotactic approach. It can be expected that this guidance scheme will be a useful addition to the MR-based stereotactic system for neurosurgery, and animal research, in which cumbersome stereotactic frames have been used.


A luminescent single-molecule magnet of dimetallofullerene with cage-dependent properties.
It is important to explore luminescent single-molecule magnets (SMMs) to promote their application in high-density data storage. Herein, we report two dimetallofullerenes of DyEr@C82 isomers, which exhibit cage-dependent single-molecule magnet behavior and photoluminescence properties. DyEr@C82 isomers were characterized with a Cs and C3v cage symmetry by UV-vis-NIR spectroscopy and single-crystal X-ray diffraction analysis. Magnetic results revealed that DyEr@C3v-C82 displays SMM behavior below 3 K, whereas DyEr@Cs-C82 is a paramagnet. In addition, photoluminescence (PL) was also observed for both of these two isomers, whose peak patterns are different. Theoretical calculations revealed the presence of a one-electron-two-center Dy-Er bond in these two isomers, and different electronic structures of DyEr@Cs-C82 and DyEr@C3v-C82, which agrees well with the experimental results. These results show that dimetallofullerenes are promising magneto-luminescent materials with varied properties.


Targeted therapy in combination with gemcitabine in non-small cell lung cancer.
Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and cisplatin are commonly used in the treatment of many solid tumors, although the impact of chemotherapy is limited in metastatic non-small cell lung cancer. However, in clinical practice, there is a minority of patients who can attain long-term survival. Upregulation of mRNA transcripts has been linked to chemoresistance, and in some instances, mRNA expression has been correlated with polymorphisms. Cisplatin resistance is directly linked to the nucleotide excision repair system, specifically to the transcription-coupled nucleotide excision repair pathway that involves genes that are deficient in rare inborn disorders such as Cockayne syndrome and xeroderma pigmentosum. Overexpression of ERCC1 correlates with poor survival in gemcitabine/cisplatin-treated non-small cell lung cancer patients. At the preclinical level, ERCC1 and XPD mRNA expression correlate with each other, and overexpression of XPD causes selective cisplatin resistance in human tumor cell lines. XPD polymorphisms have been associated with lower DNA repair capacity. In our experience, time to progression is significantly higher in gemcitabine/cisplatin-treated patients with the Lys751Gln genotype (9.6 months) than in those with the Lys751Lys genotype (4.2 months; P =.03). Other polymorphisms involved in parallel DNA repair systems may well provide the same information, indicating a high degree of biologic redundancy. The overexpression of the subunit M1 of ribonucleotide reductase (RRM1) has been linked to gemcitabine resistance in our retrospective assessment. Preliminary findings that a subset of gemcitabine/cisplatin-treated patients with low ERCC1 and RRM1 mRNA levels show a significantly longer survival and highlight the possibilities of individually tailored chemotherapy.


Epidemiology and characterisation of carbapenem-non-susceptible Pseudomonas aeruginosa in a large intensive care unit in Jakarta, Indonesia.
The aim of this study was to describe the epidemiology and clinical impact of carbapenem-non-susceptible Pseudomonas aeruginosa (CNPA) in intensive care units (ICUs) of the national referral hospital of Indonesia. Adult patients admitted to ICUs were prospectively included. Pseudomonas aeruginosa were from clinical cultures and systematic screening. Environmental niches and healthcare workers (HCWs) were also screened. Susceptibility was determined phenotypically and the presence of carbapenemase genes was determined by PCR. Multiple loci variable-number tandem repeat analysis (MLVA) and multilocus sequence typing (MLST) were used for genotyping. Of the patients included in the study, 17/412 (4.1%) carried CNPA on admission and 34/395 (8.6%) became positive during their ICU stay. The acquisition rate was 18/1000 patient-days at risk. Of 16 environmental isolates, 12 (75.0%) were CNPA. HCWs screened negative. Acquisition of CNPA was associated with longer ICU stay (adjusted hazard ratio = 1.89, 99% confidence interval 1.12-3.13). Mortality was >40% among patients with CNPA versus <30% among those without CNPA (P = 0.019). Moreover, 83/119 (69.7%) CNPA carried either blaVIM (n = 36), blaIMP (n = 23) or blaGES-5 (n = 24). Four sequence types (STs) dominated (ST235, ST823, ST446 and ST357). Five major MLVA clusters were distinguished, two belonging to ST235 and the other three to ST823, ST446 and ST357. CNPA are introduced into these ICUs and some strains expand clonally among patients and the environment, creating endemic CNPA. VIM-, IMP- and GES-5 genes are prevalent. CNPA acquisition was associated with prolonged ICU stay and may affect ICU survival.


Proteomics technique opens new frontiers in mobilome research.
A large proportion of the genome of most eukaryotic organisms consists of highly repetitive mobile genetic elements. The sum of these elements is called the "mobilome," which in eukaryotes is made up mostly of transposons. Transposable elements contribute to disease, evolution, and normal physiology by mediating genetic rearrangement, and through the "domestication" of transposon proteins for cellular functions. Although 'omics studies of mobilome genomes and transcriptomes are common, technical challenges have hampered high-throughput global proteomics analyses of transposons. In a recent paper, we overcame these technical hurdles using a technique called "proteomics informed by transcriptomics" (PIT), and thus published the first unbiased global mobilome-derived proteome for any organism (using cell lines derived from the mosquito Aedes aegypti). In this commentary, we describe our methods in more detail, and summarise our major findings. We also use new genome sequencing data to show that, in many cases, the specific genomic element expressing a given protein can be identified using PIT. This proteomic technique therefore represents an important technological advance that will open new avenues of research into the role that proteins derived from transposons and other repetitive and sequence diverse genetic elements, such as endogenous retroviruses, play in health and disease.


Fruit development and ripening orchestrating the biosynthesis and regulation of Lycium barbarum polysaccharides in goji berry.
Lycium barbarum polysaccharides (LBPs) are the primary bioactive components in fruits of L. barbarum, commonly known as goji berry. Despite significant progress in understanding the chemical structures and health benefits of LBPs, the biosynthesis and regulation of LBPs in goji berry remains largely unknown. In this study, physiological indicators, including LBPs, were monitored in goji berry during fruit development and ripening (FDR), suggesting that pectin might be the major component of LBPs with increased content reaching 235.8 mg/g DW. Proteomic and transcriptomic analysis show that 6410 differentially expressed genes (DEGs) and 2052 differentially expressed proteins (DEPs) were identified with overrepresentation of flavonoids and polysaccharides-related gene ontology (GO) terms and KEGG pathways. Weighted gene co-expression network analysis (WGCNA) showed that LBPs coexpress with genes involved in pectin biosynthesis (LbGALS3, LbGATL5, LbQUA1, LbGAUT1/4/7, LbRGGAT1, LbRRT1/7, and LbRHM2), modification (LbSBT1.7), and regulation (LbAP2, LbGL2 LbTLP2, LbERF4, and LbTTG2), as well as with novel transcription factors (LbSPL9 and LbRIN homologs) and glycosyltransferases. Transgenic hairy roots overexpressing LbRIN validated that LbRIN modulate the expression of WGCNA-predicted regulators, including LbERF4, LbTTG2, and LbSPL9. These findings suggest that the biosynthesis and regulation of LBPs is conserved partially to those in Arabidopsis pectin. Taken together, this study provides valuable insights into the biosynthesis and regulation of LBPs, which can facilitate future studies on synthetic biology applications and genetic improvement of LBPs.


PCM1 recruits Plk1 to the pericentriolar matrix to promote primary cilia disassembly before mitotic entry.
Primary cilia, which emanate from the cell surface, exhibit assembly and disassembly dynamics along the progression of the cell cycle. However, the mechanism that links ciliary dynamics and cell cycle regulation remains elusive. In the present study, we report that Polo-like kinase 1 (Plk1), one of the key cell cycle regulators, which regulate centrosome maturation, bipolar spindle assembly and cytokinesis, acts as a pivotal player that connects ciliary dynamics and cell cycle regulation. We found that the kinase activity of centrosome enriched Plk1 is required for primary cilia disassembly before mitotic entry, wherein Plk1 interacts with and activates histone deacetylase 6 (HDAC6) to promote ciliary deacetylation and resorption. Furthermore, we showed that pericentriolar material 1 (PCM1) acts upstream of Plk1 and recruits the kinase to pericentriolar matrix (PCM) in a dynein-dynactin complex-dependent manner. This process coincides with the primary cilia disassembly dynamics at the onset of mitosis, as depletion of PCM1 by shRNA dramatically disrupted the pericentriolar accumulation of Plk1. Notably, the interaction between PCM1 and Plk1 is phosphorylation dependent, and CDK1 functions as the priming kinase to facilitate the interaction. Our data suggest a mechanism whereby the recruitment of Plk1 to pericentriolar matrix by PCM1 plays a pivotal role in the regulation of primary cilia disassembly before mitotic entry. Thus, the regulation of ciliary dynamics and cell proliferation share some common regulators.


Data-informed decision-making for life-saving commodities investments in Malawi: A qualitative case study.
During the last 15 years, Malawi has made remarkable progress in reducing child mortality. However, maternal and newborn mortality remains persistently high. To help address these entrenched challenges, the Reproductive, Maternal, Newborn and Child Health (RMNCH) Trust Fund provided short-term catalytic financing of $11.5 million (2013-2016) to support country plans to advance the RMNCH and commodity agenda. (1) To document how Malawi (ministries, partners, working groups) used evidence to inform decision-making and RMNCH investments, (2) To identify barriers to utilizing information and evidence in the planning and prioritization process at national and sub-national levels, and (3) To assess the utility of the RMNCH Landscape Synthesis, which uses existing information to review life-saving RMNCH commodities and services. This was a qualitative case study utilizing a Rapid Appraisal (RA) approach, where semi-structured interviews were conducted with staff members from UN agencies, development partners and the Ministry of Health (MoH) at national and district level. The analysis enlists a framework approach for manual qualitative content analysis. Led by the MoH, the RMNCH Trust Fund grant proposal utilized an evidence-based and equity-focused process for prioritization of investments. Data-informed decision-making permeates similar commodity-focused working groups. However, common health information system (HIS) weaknesses, such as data quality and collection burden, persist and are more prevalent at district-level. The collation of evidence in the RMNCH Landscape Synthesis was a useful and sustainable tool to support planning. The evidence-based, equity-focused decision-making process for the RMNCH Trust Fund proposal provides an effective model for inter-agency investment prioritization. Strengthening data-informed decision-making will require financial and political commitments to HIS and capacity building for data use, particularly at the district-level. New initiatives (e.g. Health Data Collaborative and QED Network to Improve Quality of Care) provide opportunities to further improve evidence-informed decision-making.


QTc and R-R intervals in victims of the sudden infant death syndrome.
Electrocardiograms obtained during sleep within the first and/or fourth week postnatally were available on eight infants who subsequently died of the sudden infant death syndrome (SIDS). The corrected QT (QTc) and R-R intervals were compared with controls for the purpose of evaluating their relevance for SIDS. The QTc interval in controls increased with age and tended to be longer during sleep without rapid eye movements. The R-R interval decreased with age. None of the SIDS victims was found to have a prolonged QTc interval. However, the R-R interval during rapid eye movement epochs was significantly shorter in future SIDS victims compared with controls. These data were interpreted as being inconsistent with the congenital variants of the long-QT hypothesis but compatible with the growing conviction that infants who die of SIDS have a chronic underlying abnormality that has subtle manifestations within the immediate postnatal period.


RPR-115135, a new non peptidomimetic farnesyltransferase inhibitor, induces G0/G1 arrest only in serum starved cells.
A new non peptidomimetic farnesyltransferase inhibitor, RPR-115135, was studied in an isogenic cell model system consisting of human colon cancer HCT-116 line. HCT-116 cells were transfected with an empty control pCMV vector or with a dominant-negative mutated p53 transgene to disrupt p53 function. Growth inhibitory effects of RPR-115135 were evaluated on cells growing under different conditions (serum starvation, serum starvation and recovery, nocodazole treatment). The cytotoxic activity of RPR-115135 was independent of the cell cycle status of the target cells. Addition of RPR-115135 only to cells exposed to reduced serum conditions (0.1% FCS) resulted in an enhanced ability of HCT-116 cells to arrest in the G0/G1 phase. This arrest response appeared independent of p53/p21cip1/waf-1 function. A reduction of Cyclin A protein amount by RPR-115135 was observed in both clones. These latter results suggest that RPR-115135 might down-regulate the cell cycle factor that would normally impede G0/G1 arrest.


Benchmarking computational methods to identify spatially variable genes and peaks.
Spatially resolved transcriptomics offers unprecedented insight by enabling the profiling of gene expression within the intact spatial context of cells, effectively adding a new and essential dimension to data interpretation. To efficiently detect spatial structure of interest, an essential step in analyzing such data involves identifying spatially variable genes. Despite researchers having developed several computational methods to accomplish this task, the lack of a comprehensive benchmark evaluating their performance remains a considerable gap in the field. Here, we present a systematic evaluation of 14 methods using 60 simulated datasets generated by four different simulation strategies, 12 real-world transcriptomics, and three spatial ATAC-seq datasets. We find that spatialDE2 consistently outperforms the other benchmarked methods, and Moran's I achieves competitive performance in different experimental settings. Moreover, our results reveal that more specialized algorithms are needed to identify spatially variable peaks.


Incidence and outcomes of antenatally detected congenital hydronephrosis.
Antenatally detected urinary tract abnormalities (ADUTA) are increasingly recognized. Our aims were to determine the incidence and outcomes of antenatally diagnosed congenital hydronephrosis in a large cohort. We recorded the number of total deliveries over 4 years at King Abdulaziz University Hospital (KAUH) between January 2008 and December 2011 from the number of nursery and neonatal intensive care unit (NICU) admissions. We reviewed the records of 18 853 deliveries between January 2008 and December 2011 at KAUH, Saudi Arabia. ADUTA were recorded, and their postnatal medical records were reviewed for demographic and radiological data. ADUTA were diagnosed in 327 fetuses (1.7%). The commonest pathology was congenital hydronephrosis (n=313, 95.7%). Cystic renal anomalies were reported in 4 babies (1.2%), and 10 children (3.1%) were reported to have other renal anomalies, including duplex kidneys or a single kidney. A total of 240 babies with congenital hydronephrosis were followed up. Hydronephrosis resolved in 99 children (41.2%) within 2 months of birth. A total of 29 subjects had underlying renal anomalies (12.1%), including vesicoureteral reflux (n=12, 5%), pelvi-ureteric junction obstruction (n=14, 5.8%), and posterior urethral valve (n=3, 1.3%). The best predictor for nonresolving congenital hydronephrosis and underlying anatomical abnormalities was the anteroposterior diameter on the first postnatal scan. A cut-off point of 5 mm was found to be 83% sensitive in predicting nonresolving hydronephrosis, while 7 mm was 88% sensitive and 10 mm was 94% sensitive. Congenital hydronephrosis is the commonest ADUTA. A large percentage resolved within 2 months of birth, but underlying anatomical abnormalities were found in 12.1%. All babies with antenatally detected hydronephrosis should be examined by ultrasound postnatally but further radiological investigations should only be performed for persistent significant AP dilatation >=10 mm.


Ferritin immunosensing on microfabricated electrodes based on the integration of immunoprecipitation and electrochemical signaling reactions.
A signal registration strategy from micropatterned immunosensors that converts antigen-antibody binding reactions into electrochemical signals was demonstrated. An array-type micropatterned gold electrode on a silicon wafer was fabricated, containing two electrode geometries of rectangular (100 microm x 500 microm) and circular (r. 50 microm) types, exhibiting electrochemical characteristics of bulk and micro-electrodes, respectively. Ferritin was employed as a model analyte for immunosensing because it has an advantageous molecular structure for functionalization to the sensing interface, and is regarded as a general marker protein for tumors and cancer recurrence. With the fabricated and ferritin-functionalized immunosensors, biospecific interactions were performed with antiferritin antiserum and secondary antibody samples, followed by electrochemical signaling via an immunoprecipitation reaction by the label enzyme. Under the optimized affinity-surface construction steps and reaction conditions, both types of microfabricated electrodes exhibited well-defined calibration results as a function of the protein concentration in antiserum samples. Furthermore, circular-type micropatterned immunoelectrodes exhibited voltammetric characteristics of microelectrodes, which is advantageous in terms of sensor operation under a fixed potential and low signal drift during the signaling reaction compared with the bulk-type electrodes. The results support that the employed signaling method with the proposed immunosensor configuration is fit for sensor miniaturization and integration to future biomicrosystems.


The effect of urethral stricture on male fertility in Ife.
Twenty patients with Urethral stricture disease presenting with difficulty in micturition, azoospermia, and oligospermia were studied. Only 5% of our patients could firmly claim to be fertile at the time of presentation with a rise to 80% fertility rate at the end of management. Fifteen percent did not notice any change in their status. Surgical approach claimed better result over conservative management because of other complications following gonococcal infections. The need for a close forensic analysis in the determination of paternity in all cases of Urethral strictures was stressed while a treatment protocol of graft urethroplasty in all cases of traumatic rupture and dilatation in cases following inflammatory lesions of the urethra was established.


The fatty acid beta-oxidation pathway is important for decidualization of endometrial stromal cells in both humans and mice.
Embryo implantation and development requires the endometrial stromal cells (ESCs) to undergo decidualization. This differentiation process requires glucose utilization, and blockade of the pentose phosphate pathway inhibits decidualization of ESCs both in vitro and in vivo. Glucose and fatty acids are energy substrates for many cell types, and fatty acid beta-oxidation is critical for embryo implantation. Here, we investigated whether beta-oxidation is required for decidualization of ESCs. As assessed by marker gene expression, decidualization of human primary ESCs was blocked by reducing activity of carnitine calmitoyltransferase I, the rate-limiting enzyme in beta-oxidation, either by short hairpin RNA-mediated silencing or by treatment with the inhibitor etomoxir. Ranolazine (RAN), a partial beta-oxidation inhibitor, blocked early decidualization of a human ESC line. However, decidualization resumed after several days, most likely due to a compensatory up-regulation of GLUT1 expression and an increase in glucose metabolism. Simultaneous inhibition of the beta-oxidation pathway with RAN and the pentose phosphate pathway with glucosamine (GlcN) impaired in vitro decidualization of human ESCs more strongly than inhibition of either pathway alone. These findings were confirmed in murine ESCs in vitro, and exposure to RAN plus GlcN inhibited decidualization in vivo in a deciduoma model. Finally, intrauterine implantation of time-release RAN and GlcN pellets reduced pup number. Importantly, pup number returned to normal after the end of the pellet-active period. This work indicates that both fatty acids and glucose metabolism pathways are important for ESC decidualization, and suggests novel pathways to target for the design of future nonhormonal contraceptives.


The surgical management of osteomyelitis: with special reference to a surgical classification.
Bone infection requires a multifaceted approach that may be more clearly defined by a pathophysiologic and pathoanatomic classification. Seven types of bone infection are described, which differ by pathophysiology. Anatomically, infection may involve nonmedullary bone tissues, medullary bone, or the epiphyseal growth plate. Treatment can be prescribed accordingly. The isolation and persistence of bone infection usually requires invasion of the septic space by a surgical approach. By this means, bacterial colonization is denied and vascular return can reclaim the tissue domain. Bone infection is difficult to eradicate, yet a proficient surgical approach to sepsis can restore skeletal health and form.


Cost as a barrier to accessing dental care: findings from a Canadian population-based study.
The aim of this study is to determine the demographic and socioeconomic characteristics of Canadians who report cost barriers to dental care. An analysis of data collected from the 2007/09 Canadian Health Measures Survey was undertaken from a sample of 5,586 Canadian participants aged 6-79. Cost barriers to dental care were operationalized through two questions: "In the past 12 months, have you avoided going to a dental professional because of the cost of dental care?" and "In the past 12 months, have you avoided having all the dental treatment that was recommended because of the cost?" Logistic regressions were conducted to identify relationships between covariates and positive responses to these questions. Approximately 17.3 percent of respondents had avoided a dental professional because of cost within the previous year, and 16.5 percent had declined recommended dental treatment because of cost. Adjusted estimates demonstrate that respondents with lower incomes and without dental insurance were over four times more likely to avoid a dental professional because of cost and approximately two and a half times more likely to decline recommended dental treatment because of cost. Nearly one out of five Canadians surveyed reported cost barriers to dental care. This study provides valuable baseline information for future studies to assess whether financial barriers to dental care are getting better or worse for Canadians.


Cost-Utility of Elbasvir/Grazoprevir in Patients with Chronic Hepatitis C Genotype 1 Infection.
To evaluate the cost-utility of treatment with elbasvir/grazoprevir (EBR/GZR) regimens compared with ledipasvir/sofosbuvir (LDV/SOF), ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (3D ± RBV), and sofosbuvir/velpatasvir (SOF/VEL) in patients with chronic hepatitis C genotype (GT) 1 infection. A Markov cohort state-transition model was constructed to evaluate the cost-utility of EBR/GZR ± RBV over a lifetime time horizon from the payer perspective. The target population was patients infected with chronic hepatitis C GT1 subtypes a or b (GT1a or GT1b), stratified by treatment history (treatment-naive [TN] or treatment-experienced), presence of cirrhosis, baseline hepatitis C virus RNA (< or ≥6 million IU/mL), and presence of NS5A resistance-associated variants. The primary outcome was incremental cost-utility ratio for EBR/GZR ± RBV versus available oral direct-acting antiviral agents. One-way and probabilistic sensitivity analyses were performed to test the robustness of the model. EBR/GZR ± RBV was economically dominant versus LDV/SOF in all patient populations. EBR/GZR ± RBV was also less costly than SOF/VEL and 3D ± RBV, but produced fewer quality-adjusted life-years in select populations. In the remaining populations, EBR/GZR ± RBV was economically dominant. One-way sensitivity analyses showed varying sustained virologic response rates across EBR/GZR ± RBV regimens, commonly impacted model conclusions when lower bound values were inserted, and at the upper bound resulted in dominance over SOF/VEL in GT1a cirrhotic and GT1b TN noncirrhotic patients. Results of the probabilistic sensitivity analysis showed that EBR/GZR ± RBV was cost-effective in more than 99% of iterations in GT1a and GT1b noncirrhotic patients and more than 69% of iterations in GT1b cirrhotic patients. Compared with other oral direct-acting antiviral agents, EBR/GZR ± RBV was the economically dominant regimen for treating GT1a noncirrhotic and GT1b TN cirrhotic patients, and was cost saving in all other populations.


[Role of optokinetic stimulation in realizing vestibulospinal reflexes].
This paper presents data about the effect of optokinetic stimulation (OKS) on vestibulospinal reflexes and discusses mechanisms of interaction of the vestibular, optic and proprioceptive sensors during their combined stimulation. The vestibulospinal reflexes were investigated using a 2-minute step test and simultaneous OKS that was produced by a portable optokinetic drum mounted on the head of the test subject. During the tests optokinetic nystagmus was recorded and the angle of body rotation relative to the initial position was measured. It was found that during the step test the body turned along the OKS direction, i. e. towards the slow component of optokinetic nystagmus. During leftward OKS the angle of rotation was larger than during rightward OKS: 406.4 +/- 75.9 deg and 207.5 +/- 40.7 deg, respectively. During leftward OKS loss of equilibrium was recorded 4.5 times more often than during rightward OKS. It has been demonstrated that the capacity to track stimuli moving to the left is lower than that to pursue stimuli moving to the right. It has been shown that there is a correlation between the rate of the optokinetic nystagmus slow phase and the angle of body rotation during the step test. It has been concluded that optokinetic nystagmus can be used as an informative parameter when measuring statokinetic stability in response to multisensory stimulation.


Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease.
Some patients with inflammatory bowel disease (IBD) who were under mesalamine treatment develop adverse reactions called "mesalamine allergy," which includes high fever and worsening diarrhea. Currently, there is no method to predict mesalamine allergy. Pharmacogenomic approaches may help identify these patients. Here we analyzed the genetic background of mesalamine intolerance in the first genome-wide association study of Japanese patients with IBD. Two independent pharmacogenetic IBD cohorts were analyzed: the MENDEL (n = 1523; as a discovery set) and the Tohoku (n = 788; as a replication set) cohorts. Genome-wide association studies were performed in each population, followed by a meta-analysis. In addition, we constructed a polygenic risk score model and combined genetic and clinical factors to model mesalamine intolerance. In the combined cohort, mesalamine-induced fever and/or diarrhea was significantly more frequent in ulcerative colitis vs Crohn's disease. The genome-wide association studies and meta-analysis identified one significant association between rs144384547 (upstream of RGS17) and mesalamine-induced fever and diarrhea (P = 7.21e-09; odds ratio = 11.2). The estimated heritability of mesalamine allergy was 25.4%, suggesting a significant correlation with the genetic background. Furthermore, a polygenic risk score model was built to predict mesalamine allergy (P = 2.95e-2). The combined genetic/clinical prediction model yielded a higher area under the curve than did the polygenic risk score or clinical model alone (area under the curve, 0.89; sensitivity, 71.4%; specificity, 90.8%). Mesalamine allergy was more common in ulcerative colitis than in Crohn's disease. We identified a novel genetic association with and developed a combined clinical/genetic model for this adverse event.


No-slip boundary conditions and forced flow in multiparticle collision dynamics.
Multiparticle collision dynamics (MPCD) is a particle-based fluid simulation technique that is becoming increasingly popular for mesoscale fluid modeling. However, some confusion and conflicting results persist in literature regarding several important methodological details, in particular the enforcement of the no-slip condition and thermostatting in forced flow. These issues persist in simple flows past stationary boundaries, which we exclusively focus on here. We discuss the parametrization of MPCD fluids and its consequences for fluid-solid boundaries in great detail, and show that the method of virtual particles proposed by Lamura et al. and adopted by many others is required only for parameter choices that lead to viscosities dominated by collisional contributions. We test several implementations of the virtual particle method and discuss how to completely eliminate slip at stationary boundaries. We also show that stochastic boundary reflection rules are inherently problematic for forced flow and suggest a possible remedy. Finally, we discuss the most robust way to achieve forced flow and evaluate several thermostatting methods in the process. All discussion is limited to solid objects that do not move as a result of collisions with MPCD particles (i.e., walls). However, the results can be extended to solutes that experience forces and torques due to interactions with MPCD particles (e.g., colloids). The detailed analysis presented for this simple case provides the level of rigor and accuracy to the MPCD method required for the study of more complex systems.


IKKepsilon phosphorylation of estrogen receptor alpha Ser-167 and contribution to tamoxifen resistance in breast cancer.
IKKepsilon has recently been identified as a breast cancer oncogene. Elevated levels of IKKepsilon are associated with cell survival and growth. Here, we show that IKKepsilon interacts with and phosphorylates estrogen receptor alpha (ERalpha) on serine 167 in vitro and in vivo. As a result, IKKepsilon induces ERalpha transactivation activity and enhances ERalpha binding to DNA. Cyclin D1, a major target of ERalpha, is transcriptionally up-regulated by IKKepsilon in a phospho-ERalpha-Ser-167-dependent manner. Further, overexpression of IKKepsilon induces tamoxifen resistance, whereas knockdown of IKKepsilon sensitizes cells to tamoxifen-induced cell death. These data suggest that ERalpha is a bona fide substrate of IKKepsilon and IKKepsilon plays an important role in tamoxifen resistance. Thus, IKKepsilon represents a critical therapeutic target in breast cancer.


Expression of genes involved in excitatory neurotransmission in anoxic crucian carp (Carassius carassius) brain.
The crucian carp, Carassius carassius, survives months without oxygen. During anoxia it needs to keep energy expenditure low, particularly in the brain, with its high rate of ATP use related to neuronal activity. This could be accomplished by reducing neuronal excitability through altered expression of genes involved in excitatory neurotransmission. Through cloning and the use of a recently developed real-time RT-PCR approach, with an external RNA control for normalization, we investigated the effect of 1 and 7 days of anoxia (12 degrees C) on the expression of 29 genes, including 8 3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor subunits, 6 N-methyl-d-aspartate (NMDA) receptor subunits, 7 voltage-gated sodium and calcium channels, 4 glutamate transporters, and 4 genes involved in NMDA receptor-mediated neuroplasticity. The subunits of the majority of the gene families had expression profiles similar to those observed in the mammalian brain and showed remarkably stable expression during anoxia. This suggests that the genes may have similar functions in crucian carp and mammals, and that the excitatory abilities of the crucian carp brain are retained during anoxia. Although the data generally argue against profound neural depression ("channel arrest"), NMDA receptor subunit (NR) expression showed features that could mediate reduced neural excitability. Primarily, the NR2 subunit expression, which was dominated by NR2B and NR2D, resembled that seen in hypoxia-tolerant neonatal rats, and decreased anoxic expression of NR1, NR2C, and NR3A indicated reduced numbers of functional NMDA receptors. We also report the full-length sequence of crucian carp NR1 mRNA and a novel NR1 splice cassette introducing an N-glycosylation site into the extracellular S1S2 domain.


Kinetic study of the thermal dehydration of borogypsum.
In Turkey, a large amount of borogypsum waste is discharged by the economically important boric acid industry. Calcination of this waste provides a promising technique not only for recovering an economic value but also for reducing its environmental impact. The aim of this work is to study the thermal behavior of borogypsum, which contains gypsum crystals, boron oxide and some impurities under nonisothermal conditions in air atmosphere by using thermogravimetry and differential thermal analysis techniques (TG-DTA). Experiments were carried out at temperatures ranging from ambient to 773 K at different heating rates. The temperatures of conversion from gypsum to hemihydrate and anhydrite states were determined. Various methods were used to analyze the TG and DTA data for determination of reaction kinetics. The activation energy and frequency factor were calculated for dehydration of borogypsum. Activation energy values of the main dehydration reaction of borogypsum were calculated to be approximately 95-114 kJ mol(-1).


[A case of acute autonomic, sensory and motor neuropathy with swelling and gadolinium enhancement of bilateral trigeminal nerve on MRI and dissociation between superficial and deep sensation disturbance].
We report a case of a 46-year old man with acute autonomic, sensory and motor neuropathy (AASMN). He developed severe orthostatic hypotension, anuria,anhydrosis, tonic pupil with dysarthria, dysphagia, jaw claudication, and dysesthesia and sharp pain several days after symptom of upper respiratory infection. Neurological examination revealed severely decreased superficial sensation with normal deep sensation. Brain MRI findings showed bilateral trigeminal nerve swelling with gadolinium (Gd) enhancement. His motor and sensory symptoms and MRI abnormality were improved after the administration of intravenous immunoglobulin and intravenous methylprednisolone therapy; however his autonomic symptoms scarcely reacted to these immunotherapies. As long as we investigated in AASMN cases, bilateral trigeminal nerve swelling with Gd enhancement and dissociation between superficial and deep sensation disturbance have not reported, suggesting that the present case mainly disrupted C nerve fibers distributing postganglionic autonomic and temperature-pain sensory nerves.


Degree of blood safety of voluntary non-remunerated versus replacement blood donations: A multi-centre study of the large cohort of blood donors from two provinces of Pakistan.
Voluntary non-remunerated blood donors (VNRBDs) are recognized as being crucial for the safety and sustainability of national blood supplies. Systems based on replacement donors (RDs) pose high risks of transfusion transmissible infections (TTIs). Currently, only 10%-13% of blood donations are voluntary in Pakistan. No large-scale studies have been conducted to objectively evaluate the impact of the mode of donation on the frequency of TTIs, a gap this study aimed to fill. The study was conducted at the Indus Hospital, Karachi. Data from a total of 591,820 blood donations were included from 1 October 2017 to 30 May 2021 and evaluated for type of donations and results of TTI testing, primarily performed on Architect i2000SR (Abbott). The TTIs tested include hepatitis B virus, hepatitis C virus, human immunodeficiency virus, syphilis and malaria. A total of 477,938 (80.7%) RDs and 113,882 (19.3%) VNRBDs were screened. Among these, 53,590 (9.06%) were positive for TTIs. There were 10.2% positive RDs (10.08-10.25 95% confidence interval [CI]) while 4.4% in VNRBDs (4.29-4.53 95% CI). Co-infections were observed in 2367 (0.4%) RDs, while 159 (0.02%) in VNRBDs. Geographically, the highest frequency of TTIs was observed in semi-urban areas of Sindh (11.2%) and Punjab (9.6%). A site-wise comparison of TTIs in RD versus VNRBD showed significant differences (p-value 0.00). RDs are associated with higher frequencies of TTIs, compared with VNRBD. However, the study was unable to assess whether the significant difference was related to individual risk or repeat/first time status of the donors. Other important variables affecting frequency are the catchment area of the blood donors in Pakistan. Urban areas have less prevalence than semi-urban areas.


Diagnostic challenges in non-cirrhotic portal hypertension - porto sinusoidal vascular disease.
Non-cirrhotic portal hypertension consists of a group of diseases characterized by signs and complications of portal hypertension, which differ from cirrhosis through histological alterations, hemodynamic characterization and, clinical outcome. Because of the similarities in clinical presentation and imaging signs, frequently these patients, and particularly those with porto-sinusoidal vascular disease (PSVD), are misdiagnosed as having liver cirrhosis and thus raising difficulties in their diagnosis. The most challenging differentiation to be considered is between PSVD and cirrhosis and, although not pathognomonic, liver biopsy is still the standard of diagnosis. Although they still require extended validation before being broadly used, new non-invasive methods for the diagnosis of porto-sinusoidal vascular disease, like transient elastography, contrast-enhanced ultrasound or metabolomic profiling, have shown promising results. Another issue is the differentiation between PSVD and chronic extrahepatic portal vein obstruction, especially now when it is known that 40% of patients suffering from PSVD develop portal vein thrombosis. In this particular case, once the portal vein thrombosis occurred, the diagnosis of PSVD is impossible according to the current guidelines. Moreover, so far, the differentiation between PSVD and sinusoidal obstruction syndrome has not been clear so far in particular circumstances. In this review we highlighted the diagnostic challenges regarding the PSVD, as well as the current techniques used in the evaluation of these patients.


Traditional Chinese Medicine for Acute Myocardial Infarction in Western Medicine Hospitals in China.
Amid national efforts to improve the quality of care for people with cardiovascular disease in China, the use of traditional Chinese medicine (TCM) is increasing, yet little is known about its use in the early management of acute myocardial infarction (AMI). We aimed to examine intravenous use of TCM within the first 24 hours of hospitalization (early IV TCM) for AMI. Data come from the China Patient-centered Evaluative Assessment of Cardiac Events Retrospective Study of Acute Myocardial Infarction, restricted to a large, representative sample of Western medicine hospitals throughout China (n=162). We conducted a chart review of randomly sampled patients with AMI in 2001, 2006, and 2011, comparing early intravenous TCM use across years, predictors of any early intravenous TCM use, and association with in-hospital bleeding and mortality. From 2001 to 2011, early intravenous TCM use increased (2001: 38.2% versus 2006: 49.1% versus 2011: 56.1%; P<0.01). Nearly all (99%) hospitals used early intravenous TCM. Salvia miltiorrhiza was most commonly prescribed, used in one third (35.5%) of all patients admitted with AMI. Patients receiving any early intravenous TCM, compared with those who did not, were similar in age and sex and had fewer cardiovascular risk factors. In multivariable hierarchical models, admission to a secondary (versus tertiary) hospital was most strongly associated with early intravenous TCM use (odds ratio: 2.85; 95% confidence interval: 1.98-4.11). Hospital-level factors accounted for 55% of the variance (adjusted median odds ratio: 2.84). In exploratory analyses, there were no significant associations between early intravenous TCM and in-hospital bleeding or mortality. Early intravenous TCM use for AMI in China is increasing despite the lack of evidence of their benefit or harm. There is an urgent need to define the effects of these medications because they have become a staple of treatment in the world's most populous country. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01624883.


Persistent hiccups due to aripiprazole in an adolescent with obsessive compulsive disorder responding to dose reduction and rechallenge.
Our case involves persistent hiccup arising in an adolescent with obsessive compulsive disorder (OCD) who was using aripiprazole as an augmentation to fluoxetine and whose hiccups remitted with dose reduction and rechallenge. Treatment suggested that aripiprazole might lead to hiccups. Antipsychotics are also used for the treatment of hiccups, but recent case reports suggest that they cause hiccups as well. Within 12 h of taking 5 mg aripiprazole, the 13-year-old girl began having continuous hiccups, which lasted for 3-4 h. The hiccups resolved when the dose of aripiprazole was reduced to 2.5 mg. To achieve augmentation, aripiprazole was replaced with risperidone 0.5 mg/day for 1 month, but excess sedation was observed. As a result, aripiprazole was restarted at a dose of 2.5 mg/day, and 1 week later, it was increased to 5 mg/every other day. No hiccups were observed.


Development of the Canadian Spinal Cord Injury Best Practice (Can-SCIP) Guideline: Methods and overview.
Spinal cord injury (SCI) is a life-altering injury that leads to a complex constellation of changes in an individual's sensory, motor, and autonomic function which is largely determined by the level and severity of cord impairment. Available SCI-specific clinical practice guidelines (CPG) address specific impairments, health conditions or a segment of the care continuum, however, fail to address all the important clinical questions arising throughout an individual's care journey. To address this gap, an interprofessional panel of experts in SCI convened to develop the Canadian Spinal Cord Injury Best Practice (Can-SCIP) Guideline. This article provides an overview of the methods underpinning the Can-SCIP Guideline process. The Can-SCIP Guideline was developed using the Guidelines Adaptation Cycle. A comprehensive search for existing SCI-specific CPGs was conducted. The quality of eligible CPGs was evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. An expert panel (n = 52) convened, and groups of relevant experts met to review and recommend adoption or refinement of existing recommendations or develop new recommendations based on evidence from systematic reviews conducted by the Spinal Cord Injury Research Evidence (SCIRE) team. The expert panel voted to approve selected recommendations using an online survey tool. The Can-SCIP Guideline includes 585 total recommendations from 41 guidelines, 96 recommendations that pertain to the Components of the Ideal SCI Care System section, and 489 recommendations that pertain to the Management of Secondary Health Conditions section. Most recommendations (n = 281, 48%) were adopted from existing guidelines without revision, 215 (36.8%) recommendations were revised for application in a Canadian context, and 89 recommendations (15.2%) were created de novo. The Can-SCIP Guideline is the first living comprehensive guideline for adults with SCI in Canada across the care continuum.


Does timing of targeted therapy for metastatic renal cell carcinoma impact treatment toxicity and surgical complications? A comparison of primary and adjuvant approaches.
To compare surgical complications and tyrosine kinase inhibitor (TKI)-toxicities in patients who underwent primary cytoreductive nephrectomy (CN) followed by adjuvant TKI therapy versus those who underwent neoadjuvant TKI therapy prior to planned CN for metastatic renal cell carcinoma (mRCC). Two-center retrospective analysis. Sixty-one mRCC patients underwent TKI therapy with sunitinib between July 2007 to January 2014. Patients were divided into three groups: primary CN followed by adjuvant TKI (n = 27, Group 1), neoadjuvant TKI prior to CN (n = 21, Group 2), and primary TKI alone (no surgery, n = 13, Group 3). Primary outcome was frequency and severity of surgical complications (Clavien). Secondary outcome was frequency and severity of TKI-related toxicities (NIH Common Toxicity Criteria). Multivariable analysis was carried out for factors associated with complications. There were no significant differences in demographics, ECOG status, and median number TKI cycles (p = 0.337). Mean tumor size (cm) was larger in Group 3 (12.8) than Group 2 (8.9) and Group 1 (9.3), p = 0.014. TKI-related toxicities occurred in 100%, 90.5%, and 88.9% in Group 3, Group 2, and Group 1 (p = 0.469). There was no difference in incidence of high grade (p = 0.967) and low grade (p = 0.380) TKI-toxicities. Overall surgical complication rate was similar between Group 2 (47.6%) and Group 1 (33.3%), p = 0.380. Group 2 had more high grade surgical complications (28.6%) than Group 1 (0%), p = 0.004. Multivariable analysis demonstrated increasing age was independently associated with development of surgical complications (HR 1.059, p = 0.040). Patients receiving neoadjuvant TKI therapy prior to CN experienced more high grade surgical complications than patients who underwent primary CN. Potential for increased high grade surgical complications requires further investigation and may impact pretreatment counseling.


[Sarcoma botryoides in the pediatric vagina--a soft tissue sarcoma with good prognosis].
Although rare, sarcoma botryoides of the vagina in infants is a highly aggressive soft tissue tumour. Former opinions suggesting exenterative surgery and radiation to improve the dismal outcome in these young children, are outdated. Due to balanced therapies (topical tumourectomy, chemotherapy and radiation adjusted to tumour stage) cure of these sarcomas may be expected dependent on tumour stage, localisation and response to chemotherapy. The rate of complete remissions has increased in recent years. We report on an eighteen-month old girl with complete remission of tumour stage IIA who had been treated according to the CWS 91 protocol. Diagnosis and treatment were performed in March 1994 at the age of six months. We observed the patient in complete remission for 8 months (till September 1995).


Type 1 interferons: A target for immune-mediated inflammatory diseases (IMIDs).
The improved understanding of the molecular basis of innate immunity have led to the identification of type I interferons (IFNs), particularly IFN-α, as central mediators in the pathogenesis of several Immune-mediated inflammatory diseases (IMIDs) such as systemic lupus erythematosus (SLE), systemic sclerosis, inflammatory myositis and Sjögren's syndrome. Here, we review the main data regarding the opportunity to target type I IFNs for the treatment of IMIDs. Type I IFNs and their downstream pathways can be targeted pharmacologically in several manners. One approach is to use monoclonal antibodies against IFNs or the IFN-receptors (IFNARs, such as with anifrolumab). The downstream signaling pathways of type I IFNs also contain several targets of interest in IMIDs, such as JAK1 and Tyk2. Of these, anifrolumab is licensed and JAK1/Tyk2 inhibitors are in phase III trials in SLE. Targeting IFN-Is for the treatment of SLE is already a reality and in the near future may prove useful in other IMIDs. IFN assays will find a role in routine clinical practice for the care of IMIDs as further validation work is completed and a greater range of targeted therapies becomes available.


A preliminary study of the effects of a single session of Swedish massage on hypothalamic-pituitary-adrenal and immune function in normal individuals.
Massage therapy is a multi-billion dollar industry in the United States with 8.7% of adults receiving at least one massage within the last year; yet, little is known about the physiologic effects of a single session of massage in healthy individuals. The purpose of this study was to determine effects of a single session of Swedish massage on neuroendocrine and immune function. It was hypothesized that Swedish Massage Therapy would increase oxytocin (OT) levels, which would lead to a decrease in hypothalamic-pituitary-adrenal (HPA) activity and enhanced immune function. The study design was a head-to-head, single-session comparison of Swedish Massage Therapy with a light touch control condition. Serial measurements were performed to determine OT, arginine-vasopressin (AVP), adrenal corticotropin hormone (ACTH), cortisol (CORT), circulating phenotypic lymphocytes markers, and mitogen-stimulated cytokine production. This research was conducted in an outpatient research unit in an academic medical center. Medically and psychiatrically healthy adults, 18-45 years old, participated in this study. The intervention tested was 45 minutes of Swedish Massage Therapy versus a light touch control condition, using highly specified and identical protocols. The standardized mean difference was calculated between Swedish Massage Therapy versus light touch on pre- to postintervention change in levels of OT, AVP, ACTH, CORT, lymphocyte markers, and cytokine levels. Compared to light touch, Swedish Massage Therapy caused a large effect size decrease in AVP, and a small effect size decrease in CORT, but these findings were not mediated by OT. Massage increased the number of circulating lymphocytes, CD 25+ lymphocytes, CD 56+ lymphocytes, CD4 + lymphocytes, and CD8+ lymphocytes (effect sizes from 0.14 to 0.43). Mitogen-stimulated levels of interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, and IFN-γ decreased for subjects receiving Swedish Massage Therapy versus light touch (effect sizes from -0.22 to -0.63). Swedish Massage Therapy decreased IL-4, IL-5, IL-10, and IL-13 levels relative to baseline measures. Preliminary data suggest that a single session of Swedish Massage Therapy produces measurable biologic effects. If replicated, these findings may have implications for managing inflammatory and autoimmune conditions.


[Histories of induced abortion among adolescents from Teresina in the State of Piauí, Brazil].
This paper analyses the methods, techniques and support networks taken by adolescents to perform illegal abortions. It is a descriptive and cross-sectional study involving interviews with 30 adolescents who had been hospitalized for uterine curettage in two public hospitals in Teresina between June and November 2011. Informed consent was given orally, and the interviews were recorded after the confirmation of the induced abortion. The adolescents were between 14 and 17 years old, single, and predominantly lived with their parents in urban areas, had little schooling and recorded a gestational age of 12 weeks. Between 3 and 6 tablets of Cytotec were taken orally and/or vaginally by 28 (94%) adolescents, and they were rushed to the hospital due to severe cramping, vaginal bleeding or both. They either bought Cytotec alone (43%, 13), or with the help of a friend or partner (40%, 12). Cytotec was sold to them in ordinary pharmacies, by the owner (45%, 13) or clerk (55%, 55), who provided instructions for use. They went to the hospital with their mother (40%, 12) or a girl friend (30%, 9). Three (10%) adolescents developed serious complications. The study revealed that Cytotec is the main method used to perform illegal abortions among adolescents.


Dystonia in the black and Puerto Rican population.
Dystonia among Black and Puerto Rican patients has been reported to be a rare occurrence. Two such patients have been presented. An attempt was made to discover other cases by utilizing a mail survey. This has documented the rarity of dystonia in those ethnic groups.


Structural basis of immune evasion at the site of CD4 attachment on HIV-1 gp120.
The site on HIV-1 gp120 that binds to the CD4 receptor is vulnerable to antibodies. However, most antibodies that interact with this site cannot neutralize HIV-1. To understand the basis of this resistance, we determined co-crystal structures for two poorly neutralizing, CD4-binding site (CD4BS) antibodies, F105 and b13, in complexes with gp120. Both antibodies exhibited approach angles to gp120 similar to those of CD4 and a rare, broadly neutralizing CD4BS antibody, b12. Slight differences in recognition, however, resulted in substantial differences in F105- and b13-bound conformations relative to b12-bound gp120. Modeling and binding experiments revealed these conformations to be poorly compatible with the viral spike. This incompatibility, the consequence of slight differences in CD4BS recognition, renders HIV-1 resistant to all but the most accurately targeted antibodies.