Primary Epstein-Barr virus infection in early childhood.
In a prospective study 43 consecutive children in hospital, aged between 6 months and 7 years and displaying at least one of the clinical signs of infectious mononucleosis (IM), were investigated for Epstein-Barr (EB) virus-specific IgM antibodies by an indirect immunofluorescence test. On this basis EB virus infection was considered confirmed in 8 patients, each of whom had IgM antibodies in the initial serum sample. In one additional patient, IgM antibodies were only detected in a second sample. The IgM antibodies disappeared with 3-11 weeks. Assessment of IgG antibodies had no diagnostic value in the acute phase of IM. Clinically the 3 youngest children, about 1 year of age, were diagnosed as having pneumonia or hepatitis, the 5 other consecutive patients as having IM. Hepatosplenomegaly was fairly frequently associated with IM, while sore throat, lymphadenopathy, and rash were often signs of other diseases. Only the oldest child had heterophil antibodies. Atypical lymphocytes (greater than 10%) were present in 4 of the 9 IM cases and were seen in children with other diseases as well. Our data stress the importance of measuring EB virus-specific IgM antibodies in order to diagnose IM in early childhood.


Human germ/stem cell-specific gene TEX19 influences cancer cell proliferation and cancer prognosis.
Cancer/testis (CT) genes have expression normally restricted to the testis, but become activated during oncogenesis, so they have excellent potential as cancer-specific biomarkers. Evidence is starting to emerge to indicate that they also provide function(s) in the oncogenic programme. Human TEX19 is a recently identified CT gene, but a functional role for TEX19 in cancer has not yet been defined. siRNA was used to deplete TEX19 levels in various cancer cell lines. This was extended using shRNA to deplete TEX19 in vivo. Western blotting, fluorescence activated cell sorting and immunofluorescence were used to study the effect of TEX19 depletion in cancer cells and to localize TEX19 in normal testis and cancer cells/tissues. RT-qPCR and RNA sequencing were employed to determine the changes to the transcriptome of cancer cells depleted for TEX19 and Kaplan-Meier plots were generated to explore the relationship between TEX19 expression and prognosis for a range of cancer types. Depletion of TEX19 levels in a range of cancer cell lines in vitro and in vivo restricts cellular proliferation/self-renewal/reduces tumour volume, indicating TEX19 is required for cancer cell proliferative/self-renewal potential. Analysis of cells depleted for TEX19 indicates they enter a quiescent-like state and have subtle defects in S-phase progression. TEX19 is present in both the nucleus and cytoplasm in both cancerous cells and normal testis. In cancer cells, localization switches in a context-dependent fashion. Transcriptome analysis of TEX19 depleted cells reveals altered transcript levels of a number of cancer-/proliferation-associated genes, suggesting that TEX19 could control oncogenic proliferation via a transcript/transcription regulation pathway. Finally, overall survival analysis of high verses low TEX19 expressing tumours indicates that TEX19 expression is linked to prognostic outcomes in different tumour types. TEX19 is required to drive cell proliferation in a range of cancer cell types, possibly mediated via an oncogenic transcript regulation mechanism. TEX19 expression is linked to a poor prognosis for some cancers and collectively these findings indicate that not only can TEX19 expression serve as a novel cancer biomarker, but may also offer a cancer-specific therapeutic target with broad spectrum potential.


Multi-level diffractive optics for single laser exposure fabrication of telecom-band diamond-like 3-dimensional photonic crystals.
We present a novel multi-level diffractive optical element for diffractive optic near-field lithography based fabrication of large-area diamond-like photonic crystal structure in a single laser exposure step. A multi-level single-surface phase element was laser fabricated on a thin polymer film by two-photon polymerization. A quarter-period phase shift was designed into the phase elements to generate a 3D periodic intensity distribution of double basis diamond-like structure. Finite difference time domain calculation of near-field diffraction patterns and associated isointensity surfaces are corroborated by definitive demonstration of a diamond-like woodpile structure formed inside thick photoresist. A large number of layers provided a strong stopband in the telecom band that matched predictions of numerical band calculation. SEM and spectral observations indicate good structural uniformity over large exposure area that promises 3D photonic crystal devices with high optical quality for a wide range of motif shapes and symmetries. Optical sensing is demonstrated by spectral shifts of the Gamma-Zeta stopband under liquid emersion.


A potential role for adjunctive omega-3 polyunsaturated fatty acids for depression and anxiety symptoms in recent onset psychosis: Results from a 16 week randomized placebo-controlled trial for participants concurrently treated with risperidone.
Omega-3 treatment studies for multi-episode schizophrenia or clinical high risk for conversion to psychosis states have had variable, and often negative, results. To examine adjunctive omega-3 treatment for recent onset psychosis, participants aged 15-40 years with recent onset schizophrenia-spectrum (n = 46) or bipolar (n = 4) disorders and current psychotic symptoms were treated for 16 weeks with risperidone and randomly-assigned omega-3 (EPA 740 mg and DHA 400 mg daily) or matching placebo. The primary outcome measure was the Brief Psychiatric Rating Scale (BPRS) total score. Mean lifetime antipsychotic exposure was 18.1 days. Length of time in treatment, risperidone dose and number of omega-3/placebo capsules taken did not differ between conditions. Longitudinal analysis of the total BPRS score revealed a trend level (p = 0.0826) treatment effect favoring omega-3 treatment. Lorazepam was an allowed concomitant medication. Among the subgroup (N = 23) who did not receive lorazepam, the treatment effect on BPRS total scores favoring omega-3 was significant (p = 0.0406) and factor scores analyses revealed a substantial decrease in depression-anxiety with omega-3 but no change with placebo (treatment-by-time interaction, p = 0.0184). Motor side effects did not differ between conditions. Analysis of Systematic Assessment for Treatment Emergent Events assessments revealed fewer adverse events overall with omega-3 compared with placebo with the largest differences between conditions (all favoring omega-3) on confusion, anxiety, depression, irritability, and tiredness/fatigue. These results suggest that omega-3 adjuvant treatment is a potential option for depression and anxiety symptoms of people with recent onset psychosis. Further research is needed to confirm this potential. Clinical trial registration: NCT01786239.


Reframing Recruitment: Evaluating Framing in Authorization for Research Contact Programs.
The changing clinical research recruitment landscape involves practical challenges but introduces opportunities. Researchers can now identify large numbers of eligible patients through electronic health record review and can directly contact those who have authorized contact. Applying behavioral science-driven strategies to design and frame communication could affect patients' willingness to authorize contact and their understanding of these programs. The ethical and practical implications of various strategies warrant empirical evaluation. We conducted an online survey (n = 1070) using a nationally-representative sample. Participants were asked to imagine being asked for authorization for research contact in clinic. They were randomly assigned to view one of three flyers: #1-neutral text flyer; #2-a positive text flyer; or #3-positive graphics-based flyer. Primary outcomes included likelihood of enrollment and comprehension of the program. Chi-Square tests and regression analyses were used to examine whether those who saw the positive flyers were more likely to enroll and had increased comprehension. Compared to the neutral flyer, individuals who received the positive text flyer were numerically more likely to enroll, but this was not statistically significant (24.2% v. 19.0%, p = 0.11). Individuals who received the positive graphics flyer were more likely to enroll (28.7% v. 19.0%, p = 0.002). After adjustment, individuals assigned to both novel flyers had increased odds of being likely to enroll (OR = 1.55 95%CI [1.04, 2.31] and OR = 1.95 95%CI [1.31, 2.91]). Flyer type did not affect overall comprehension (p = 0.21), and greater likelihood of enrollment was observed only in individuals with better comprehension. This study demonstrated that employing behavioral science-driven communication strategies for authorization for research contact had an effect on likelihood of hypothetical enrollment but did not significantly affect comprehension. Strategies using simple, positive language and visual tools may be effective and ethically appropriate. Further studies should explore how these and other approaches can help to optimize research recruitment.


Comparison of Different Intubation Methods in Difficult Airways during Simulated Cardiopulmonary Resuscitation with Continuous Chest Compression: A Randomized Cross-Over Manikin Trial.
Airway management is one of key elements of resuscitation. Endotracheal intubation is still considered the gold standard for airway management during resuscitation. The aim of the study was to compare success rates and intubation time of different endotracheal intubation methods during emergency intubation with difficult airways in the conditions of cardiopulmonary resuscitation in a standardized manikin model. The study was designed as a prospective, randomized, cross-over simulation study. It involved 46 paramedics with at least 5 years of experience in Emergency Medical Service. The participants performed endotracheal intubation under difficult airway conditions during continuous chest compression, implemented with the LUCAS3 chest compression system. Three methods of tracheal intubation were applied: (1) standard Macintosh laryngoscope without a bougie stylet; (2) standard laryngoscope and a standard bougie stylet; (3) standard laryngoscope and a new bougie stylet. The overall intubation success rate was 100% in the standard bougie and new bougie groups and lower (86.9%) when no bougie stylet was used (P=0.028). The intubation success rate with the 1st attempt equalled 91.3% for the new bougie group, 73.9% for standard bougie, and only 23.9% in the no-bougie group. The median intubation time was shortest in the new bougie group, where it amounted to 29 s (interquartile range [IQR]: 25-38); the time equalled 38s (IQR:31-44.5) in the standard bougie group and 47.5s (IQR:36-58) in the no-bougie group. The ease of use was lowest in the no-bougie group (85, IQR:63-88), average in the standard bougie group (44, IQR:30-51), and highest in the new bougie stylet group (32, IQR:19-41). In this manikin-based study, paramedics were able to perform endotracheal intubation with higher efficacy and in a shorter time using the new bougie stylet as compared with the standard bougie stylet.


[Pleomorphic xanthoastrocytoma--a case report].
Pleomorphic xanthoastrocytoma (PXA) is a very rare and special kind of astrocytoma. Most of the patients have a relatively favorable prognosis despite its bizarre and pleomorphic cells. A 13 year old girl with PXA in the right occipitoparietal region is reported. Under light microscope, the tumor was markedly pleomorphic; mitosis was occasionally encountered and necrosis was absent. Immunohistochemically, cytoplasm of the tumor cells was positive for GFAP stain. Under electron microscope, many tumor cells contained glial filaments and large lipid vacuoles. Pericellular basal laminae could be found about some tumor cells, indicating a possible origin from subpial astrocyte. The clinicopathologic features, histogenesis, differential diagnosis and prognosis of PXA are discussed with review of literature.


Surface-Modified and Unmodified Calcite: Effects of Water and Saturated Aqueous Octanoic Acid Droplets on Stability and Saturated Fatty Acid Layer Organization.
A profound understanding of the properties of unmodified and saturated fatty acid-modified calcite surfaces is essential for elucidating their resistance and stability in the presence of water droplets. Additional insights can be obtained by also studying the effects of carboxylic acid-saturated aqueous solutions. We elucidate surface wettability, structure, and nanomechanical properties beneath and at the edge of a deposited droplet after its evaporation. When calcite was coated by a highly packed monolayer of stearic acid, a hydrophilic region was found at the three-phase contact line. In atomic force microscopy mapping, this region is characterized by low adhesion and a topographical hillock. The surface that previously was covered by the droplet demonstrated a patchy structure of about 6 nm height, implying stearic acid reorganization into a patchy bilayer-like structure. Our data suggest that during droplet reverse dispensing and droplet evaporation, pinning of the three-phase contact line leads to the transport of dissolved fatty carboxylic acid and possibly calcium bicarbonate Ca(HCO3)2 molecules to the contact line boundary. Compared to the surface of intrinsically hydrophobic materials, such as polystyrene, the changes in contact angle and base diameter during droplet evaporation on stearic acid-modified calcite are strikingly different. This difference is due to stearic acid reorganization on the surface and transport to the water-air interface of the droplet. An effect of the evaporating droplet is also observed on unmodified calcite due to dissolution and recrystallization of the calcite surface in the presence of water. In the case where a water droplet saturated with octanoic acid is used instead of water, the stearic acid-coated calcite remains considerably more stable. Our findings are discussed in terms of the coffee-ring effect.


A support vector machine model for the prediction of proteotypic peptides for accurate mass and time proteomics.
The standard approach to identifying peptides based on accurate mass and elution time (AMT) compares profiles obtained from a high resolution mass spectrometer to a database of peptides previously identified from tandem mass spectrometry (MS/MS) studies. It would be advantageous, with respect to both accuracy and cost, to only search for those peptides that are detectable by MS (proteotypic). We present a support vector machine (SVM) model that uses a simple descriptor space based on 35 properties of amino acid content, charge, hydrophilicity and polarity for the quantitative prediction of proteotypic peptides. Using three independently derived AMT databases (Shewanella oneidensis, Salmonella typhimurium, Yersinia pestis) for training and validation within and across species, the SVM resulted in an average accuracy measure of 0.8 with a SD of <0.025. Furthermore, we demonstrate that these results are achievable with a small set of 12 variables and can achieve high proteome coverage. http://omics.pnl.gov/software/STEPP.php. Supplementary data are available at Bioinformatics online.


Osmoregulation of the magnocellular neuroendocrine system during lactation.
Glucose utilization and Fos expression were used to compare responses of cerebral structures involved in osmoregulation in virgin and lactating rats given 0.15, 0.85, or 1.5 M NaCl subcutaneously. In virgin animals, glucose utilization increased (P < 0.05) in the supraoptic nuclei (SON), paraventricular nuclei (PVN), and neural lobe (NL) proportionally to the osmotic stimulus (0.15 M NaCl < 0.85 M NaCl < 1.5 M NaCl), whereas metabolism in the median preoptic nucleus (MPO) and median eminence (ME) increased only after 1.5 M NaCl. In lactating rats, enhanced utilization of glucose in response to osmotic stimulation was absent in the PVN (0.85 M NaCl), MPO, and ME or significantly (P < 0.01) reduced (SON, PVN, NL) compared with virgin animals. Glucose utilization in each structure correlated linearly with plasma osmolality but with a lower slope (P < 0.05) in lactating animals. Magnocellular neurons expressing Fos in the SON increased linearly with plasma osmolality and were more numerous (P < 0.05) in control lactating animals but increased less (P < 0.05) than in virgin rats after 0.85 M NaCl. The attenuated magnocellular response during lactation results from reduced afferent activation from osmosensitive forebrain sites.


GLI1+ progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic gonadal-like tissue.
As certain strains of mice age, hyperplastic lesions resembling gonadal tissue accumulate beneath the adrenal capsule. Gonadectomy (GDX) accelerates this heterotopic differentiation, resulting in the formation of wedge-shaped adrenocortical neoplasms that produce sex steroids. Stem/progenitor cells that reside in the adrenal capsule and retain properties of the adrenogonadal primordium are thought to be the source of this heterotopic tissue. Here, we demonstrate that GLI1+ progenitors in the adrenal capsule give rise to gonadal-like cells that accumulate in the subcapsular region. A tamoxifen-inducible Cre driver (Gli1-creERT2) and two reporters (R26R-lacZ, R26R-confetti) were used to track the fate of GLI1+ cells in the adrenal glands of B6D2F2 mice, a strain that develops both GDX-induced adrenocortical neoplasms and age-dependent subcapsular cell hyperplasia. In gonadectomized B6D2F2 mice GLI1+ progenitors contributed to long-lived adrenal capsule cells and to adrenocortical neoplasms that expressed Gata4 and Foxl2, two prototypical gonadal markers. Pdgfra, a gene expressed in adrenocortical stromal cells, was upregulated in the GDX-induced neoplasms. In aged non-gonadectomized B6D2F2 mice GLI1+ progenitors gave rise to patches of subcapsular cell hyperplasia. Treatment with GANT61, a small-molecule GLI antagonist, attenuated the upregulation of gonadal-like markers (Gata4, Amhr2, Foxl2) in response to GDX. These findings support the premise that GLI1+ progenitor cells in the adrenal capsule of the adult mouse give rise to heterotopic tissue.


[Progression of right internal carotid artery stenosis in ischemic stroke patient with autoimmune polyglandular syndrome: A case report].
A 40-year-old man who presented with left hemiparesis was admitted to our hospital. He had tachycardia and a fever. He had a 25-year history of insulin therapy for diabetes mellitus. Brain magnetic resonance (MR) images showed fresh infarction in the right hemisphere, and carotid ultrasonography showed stenosis of the right internal carotid artery (ICA). We determined that atherothrombotic brain infarction had likely occurred. After admission, the right ICA became narrow and finally occluded. Computed tomography revealed the presence of a thrombus in the right ICA, and gadolinium-enhanced MRA showed vasculitis of the ICA. In laboratory tests, his thyroid hormones were elevated. He was diagnosed with hyperthyroidism. After treatment, the tachycardia and high fever were improved. Because of a positive anti-glutamic acid decarboxylase antibody test result, he was diagnosed with insulin-dependent diabetes mellitus. We found that he had anti-phospholipid antibody syndrome because he was positive for anti-beta-glycoprotein I antibody. These findings suggested that his condition was autoimmune polyglandular syndrome type 3. He received prednisolone and warfarin. After 3 months, his neurological findings were improved; however, occlusion of the ICA remained. Autoimmunity was considered to be the cause of ICA occlusion. Ischemic stroke with autoimmune polyglandular syndrome is very rare and is associated with progressive carotid lesions in juvenile patients. It is necessary to diagnose and treat this condition as soon as possible.


DNA damage-dependent cell cycle checkpoints and genomic stability.
In response to genotoxic stress, which can be caused by environmental or endogenous genotoxic insults such as ionizing or ultraviolet radiation, various chemicals and reactive cellular metabolites, cell cycle checkpoints which slow down or arrest cell cycle progression can be activated, allowing the cell to repair or prevent the transmission of damaged or incompletely replicated chromosomes. Checkpoint machineries can also initiate pathways leading to apoptosis and the removal of a damaged cell from a tissue. The balance between cell cycle arrest and damage repair on one hand and the initiation of cell death, on the other hand, could determine if cellular or DNA damage is compatible with cell survival or requires cell elimination by apoptosis. Defects in these processes may lead to hypersensitivity to cellular stress, and susceptibility to DNA damage, genomic defects, and resistance to apoptosis, which characterize cancer cells. In this article, we have noted recent studies of DNA damage-dependent cell cycle checkpoints, which may be significant in preventing genomic instability.


Socioeconomic status and cancer survival.
Survival data from eight Cancer and Leukemia Group B (CALGB) protocols were examined for patients with lung cancer (N = 961), multiple myeloma (N = 577), gastric cancer (N = 231), pancreatic cancer (N = 174), breast cancer (N = 87), and Hodgkin's disease (N = 58). After accounting for differences in survival rate attributable to type of cancer, initial performance status, age, and 14 other protocol-specific prognostic indicators, the additional predictive value of socioeconomic status (SES) was evaluated. Race (white v non-white) was not a significant predictor of survival time, but income and education were. People with lower annual incomes (below $5,000 per year in the years 1977 to 1981) and those with lower educational level (grade school only) showed survival times significantly shorter than those with higher income or education, respectively. These survival differences were associated with, but could not be fully explained by, severity of disease at initial presentation. SES continued to exert a small but significant impact on cancer survival, even after controlling for all known prognostic variables. Economically and educationally disadvantaged cancer patients may require treatment programs that include education about treatment and compliance, even after an initial diagnosis is made and treatment is initiated. Because SES is related to survival independent of all known prognostic variables, it should be included in the data bases of clinical trial groups to provide a more accurate test of the effectiveness of new therapies.


New methods for picture reconstruction: recursive and causal techniques.
The methods proposed by Kashyap and Mittal [1], [2] for the reconstruction of pictures from projections are reformulated under a regression model. These reinterpretations are based on least-squares and Bayesian formulations of a statistical linear model and lead to the derivation of recursive and causal algorithms which are more efficient. Experimental results with simulation of the filters are also presented.


Complete sequence analysis of transgene loci from plants transformed via microprojectile bombardment.
A substantial literature exists characterizing transgene locus structure from plants transformed via Agrobacterium and direct DNA delivery. However, there is little comprehensive sequence analysis of transgene loci available, especially from plants transformed by direct delivery methods. The goal of this study was to completely sequence transgene loci from two oat lines transformed via microprojectile bombardment that were shown to have simple transgene loci by Southern analysis. In line 3830, transformed with a single plasmid, one major and one of two minor loci were completely sequenced. Both loci exhibited rearranged delivered DNA and flanking genomic sequences. The minor locus contained only 296 bp of two non-contiguous fragments of the delivered DNA flanked by genomic (filler) DNA that did not originate from the integration target site. Predicted recognition sites for topoisomerase II and a MAR region were observed in the transgene integration target site for this non-functional minor locus. Line 11929, co-transformed with two different plasmids, had a single relatively simple transgene locus composed of truncated and rearranged sequences from both delivered DNAs. The transgene loci in both lines exhibited multiple transgene and genomic DNA rearrangements and regions of scrambling characteristic of complex transgene loci. The similar characteristics of recombined fragments and junctions in both transgenic oat lines implicate similar mechanisms of transgene integration and rearrangement regardless of the number of co-transformed plasmids and the level of transgene locus complexity.


Identification and quantification of drug-albumin adducts in serum samples from a drug exposure study in mice.
The formation of drug-protein adducts following the bioactivation of drugs to reactive metabolites has been linked to adverse drug reactions (ADRs) and is a major complication in drug discovery and development. Identification and quantification of drug-protein adducts in vivo may lead to a better understanding of drug toxicity, but is challenging due to their low abundance in the complex biological samples. Human serum albumin (HSA) is a well-known target of reactive drug metabolites due to the free cysteine on position 34 and is often the first target to be investigated in covalent drug binding studies. Presented here is an optimized strategy for targeted analysis of low-level drug-albumin adducts in serum. This strategy is based on selective extraction of albumin from serum through affinity chromatography, efficient sample treatment and clean-up using gel filtration chromatography followed by tryptic digestion and LC-MS analysis. Quantification of the level of albumin modification was performed through a comparison of non-modified and drug-modified protein based on the relative peak area of the tryptic peptide containing the free cysteine residue. The analysis strategy was applied to serum samples resulting from a drug exposure experiment in mice, which was designed to study the effects of different acetaminophen (APAP) treatments on drug toxicity. APAP is bioactivated to N-acetyl-p-benzoquinoneimine (NAPQI) in both humans and mice and is known to bind to cysteine 34 (cys34) of HSA. Analysis of the mouse serum samples revealed the presence of extremely low-level NAPQI-albumin adducts of approximately 0.2% of the total mouse serum albumin (MSA), regardless of the length of drug exposure. Due to the targeted nature of the strategy, the NAPQI-adduct formation on cys34 could be confirmed while adducts to the second free cysteine on position 579 of MSA were not detected.


Longitudinal changes in growth parameters are correlated with changes in pulmonary function in children with cystic fibrosis.
Nutritional status is associated with pulmonary health and survival in children with cystic fibrosis (CF). This study evaluated the weight gain pattern of children with CF in relation to the longitudinal trends of their pulmonary function. Our hypothesis was that children who experience continuous weight gain at a given rate will have better average forced expiratory volume in 1 second (FEV(1)) and change in FEV(1) than children who have weight gain patterns that deviate from this rate, even when total weight gain seems adequate. Prospectively collected data were examined in 319 children, aged 6 to 8, who were routinely followed at the Minnesota Cystic Fibrosis Center. One to 67 measurements of weight (kg), height (cm), and FEV(1) (mL) were taken per child during this 2-year period. The data were analyzed by repeated measure regression analysis and by growth pattern analysis. At baseline, a 1-kg higher initial weight was associated with a 55-mL higher average FEV(1). During the follow-up period, a 1-kg gain in weight was associated with an increase in FEV(1) by 32 mL. Children who had a steady weight gain tended to experience greater increases in FEV(1) than children who experienced periodic losses in weight. We established that children who weigh more and who gain weight at an appropriate and uninterrupted rate have a better FEV(1) trajectory. Aggressive nutritional support to maintain growth in these children may therefore improve FEV(1), which can be taken as a surrogate for better lung health, and may ultimately lead to better survival.


Is a tailored work-related support intervention feasible in everyday clinical practice? The experience of healthcare professionals and patients with cancer.
Work is valued as an important feature in life, however patients diagnosed with cancer can experience work-related problems. We developed a work-related support intervention to support those in need. The objective of this study was to evaluate the feasibility of the performed tailored GIRONA (Gastro Intestinal cancer patients Receiving Occupational support Near and After diagnosis) intervention and to describe the experiences of those receiving the work-related support and of those providing it. An online questionnaire was used to survey the feasibility of the intervention of the support recipients (patients diagnosed with gastrointestinal cancer) and the support providers (healthcare professionals including: oncology nurses and oncological occupational physicians). Five themes were covered: acceptability, demand, implementation, practicality and integration of Bowen's feasibility model. Twenty-three patients, 14 oncology nurses and 4 oncological occupational physicians, shared their experiences about the tailored work-related support intervention. This intervention was generally perceived as positive and feasible by the participants. Some patients received work-related support despite not experiencing severe problems; others mentioned that they received no such support even though they did need it. Despite positive experiences, there are some barriers to tackle, such as length of consultation, timing of the initiation of work-related support and embedding the oncological occupational physician within the clinical setting. According to the healthcare professionals involved, GIRONA is feasible, however some practical barriers were mentioned. The intervention was perceived as positive by both patients and healthcare professionals, but the tailored component could be further improved to better support those in need of work-related support.


Finite element modeling of ROPS in static testing and rear overturns.
Even with the technological advances of the last several decades, agricultural production remains one of the most hazardous occupations in the United States. Death due to tractor rollover is a prime contributor to this hazard. Standards for rollover protective structures (ROPS) performance and certification have been developed by groups such as the Society of Automotive Engineers (SAE) and the American Society of Agricultural Engineers (ASAE) to combat these problems. The current ROPS certification standard, SAE J2194, requires either a dynamic or static testing sequence or both. Although some ROPS manufacturers perform both the dynamic and static phases of SAE J2194 testing, it is possible for a ROPS to be certified for field operation using static testing alone. This research compared ROPS deformation response from a simulated SAE J2194 static loading sequence to ROPS deformation response as a result of a simulated rearward tractor rollover. Finite element analysis techniques for plastic deformation were used to simulate both the static and dynamic rear rollover scenarios. Stress results from the rear rollover model were compared to results from simulated static testing per SAE J2194. Maximum stress values from simulated rear rollovers exceeded maximum stress values recorded during simulated static testing for half of the elements comprising the uprights. In the worst case, the static model underpredicts dynamic model results by approximately 7%. In the best case, the static model overpredicts dynamic model results by approximately 32%. These results suggest the need for additional experimental work to characterize ROPS stress levels during staged overturns and during testing according to the SAE standard.


Anisotropic Interface Successive Assembly for Bowl-Shaped Metal-Organic Framework Nanoreactors with Precisely Controllable Meso-/Microporous Nanodomains.
Colloidal metal-organic framework (MOF) nanoparticles, with tailored asymmetric nanoarchitectures and hierarchical meso-/microporosities, have significant implications in high-performance nanocatalysts, nanoencapsulation carriers, and intricate assembly architectures. However, the methodology that could achieve precise control over the anisotropic growth of asymmetric MOF particles with tailored distributions of meso- and microporous regions has not yet been established. In this study, we introduce a facile anisotropic interface successive assembly approach to synthesize asymmetric core-shell MOF (ZIF-67) nanobowls with worm-like mesopores in the core and intrinsic micropores in the shell. Our synthesis pathway relies on anisotropic nucleation of mesoporous MOF nanohemispheres on emulsion interfaces through the cooperative assembly of surfactants and MOF precursors. This is followed by the growth of microporous MOF layers on both interfaces of mesoporous cores and emulsion droplets, resulting in a hierarchically porous core-shell nanostructure. By utilizing this multi-interface-driven approach, we enable the creation of diverse geometries and distributions of mesopores and micropores in asymmetric MOF nanoarchitectures. The obtained bowl-like meso-/microporous core-shell ZIF-67 particles exhibit enhanced catalytic activity for CO2 cycloaddition, attributed to reactant accumulation within the bowl-like architecture, active site accessibility in the open mesoporous core, and improved structural stability. Overall, our study provides insights and inspiration for exploring the intricate asymmetric nanostructures of hierarchically porous MOFs with diverse potential applications.


Defects in the Expression of Chloroplast Proteins Leads to H2O2 Accumulation and Activation of Cyclic Electron Flow around Photosystem I.
We describe a new member of the class of mutants in Arabidopsis exhibiting high rates of cyclic electron flow around photosystem I (CEF), a light-driven process that produces ATP but not NADPH. High cyclic electron flow 2 (hcef2) shows strongly increased CEF activity through the NADPH dehydrogenase complex (NDH), accompanied by increases in thylakoid proton motive force (pmf), activation of the photoprotective qE response, and the accumulation of H2O2. Surprisingly, hcef2 was mapped to a non-sense mutation in the TADA1 (tRNA adenosine deaminase arginine) locus, coding for a plastid targeted tRNA editing enzyme required for efficient codon recognition. Comparison of protein content from representative thylakoid complexes, the cytochrome bf complex, and the ATP synthase, suggests that inefficient translation of hcef2 leads to compromised complex assembly or stability leading to alterations in stoichiometries of major thylakoid complexes as well as their constituent subunits. Altered subunit stoichiometries for photosystem I, ratios and properties of cytochrome bf hemes, and the decay kinetics of the flash-induced thylakoid electric field suggest that these defect lead to accumulation of H2O2 in hcef2, which we have previously shown leads to activation of NDH-related CEF. We observed similar increases in CEF, as well as increases in H2O2 accumulation, in other translation defective mutants. This suggests that loss of coordination in plastid protein levels lead to imbalances in photosynthetic energy balance that leads to an increase in CEF. These results taken together with a large body of previous observations, support a general model in which processes that lead to imbalances in chloroplast energetics result in the production of H2O2, which in turn activates CEF. This activation could be from either H2O2 acting as a redox signal, or by a secondary effect from H2O2 inducing a deficit in ATP.


[Clinical and angiographic comparisons in stable stenocardia].
Comparative data of clinical, instrumental and coronarographic studies in 185 patients with ischaemic heart disease and stable angina pectoris are presented. It is concluded that in the evaluation of the severity of ischaemic heart disease along with the clinical data it behooves to give due consideration to the additional signs of chronic ischaemia of the myocardium: changes in repolarization on ECG at rest and after exercise, local disorders of the function of the left ventricle, disorders of lactic acid metabolism and cardiac rhythm.


The advancement of human serum albumin-based molecular probes for molecular imaging.
Human serum albumin (HSA) is an abundant protein in blood and tissue fluids and has been used as a carrier for drug delivery. HSA can improve the pharmacokinetic profiles of drugs, such as extending the blood half-life of existing drugs and reducing toxic side effects. At the same time, more and more molecular imaging probes conjugated or fused with HSA have been studied to achieve higher specificity and better pharmacokinetic performance. These molecular probes can be attached to HSA covalently or non-covalently. They can also be fused with HSA as a fusion protein or coupled with HSA in vivo. Importantly, HSA conjugated probes have been applied to many imaging modalities such as the single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), positron emission tomography (PET) and optical imaging alone or in combination with more than one modality. Besides in vivo molecular imaging, HSA conjugated probes can be used for molecular therapeutics, image-guided therapy, such as photodynamic imaging and photodynamic therapy (PDI/PDT). Some potential problems also need to be considered when using of HSA based probe strategy which are discussed in detail in the paper. Overall, HSA based probe design represents a very useful and powerful strategy for developing more molecular probes for theranostics of diseases.


Application of high-performance liquid chromatography based measurements of lipophilicity to model biological distribution.
Octanol-water partition coefficients are the most widely used measure of lipophilicity in modelling biological partition/distribution. It has long been recognised that the retention of a compound in reversed-phase liquid chromatography is governed by its lipophilicity/hydrophobicity, and thus shows correlation with an octanol-water partition coefficient. A great number of publications have reported the efforts made to adjust HPLC conditions to measure surrogate octanol-water partition coefficients. However, there is no general consensus in this field. HPLC provides a platform to measure various types of lipophilicity that can provide relevant information about the compounds' property. In this way HPLC can be more valuable than just a surrogate for octanol-water partition. Chromatography using biomimetic stationary phases may provide better insight for biological partition/distribution processes. The research in this field is still ongoing and a large variety of HPLC conditions have been suggested. This review will outline approaches to overcoming the difficulties of standardisation and describe different theoretical approaches for comparison of HPLC lipophilicity data obtained under various conditions, along with the relation of these results to biological partition/distribution.


Insulin and oral agents for managing cystic fibrosis-related diabetes.
The Cystic Fibrosis Foundation recommends both short-term and long-acting insulin therapy when cystic fibrosis-related diabetes has been diagnosed. Diagnosis is based on: an elevated fasting blood glucose level greater than 6.94 mmol/liter (125 mg/deciliter); or oral glucose tolerance tests greater than 11.11 mmol/liter (200 mg/deciliter) at two hours; or symptomatic diabetes for random glucose levels greater than 11.11 mmol/liter (200 mg/deciliter); or glycated hemoglobin levels of at least 6.5%. To establish the effectiveness of insulin and oral agents for managing diabetes in people with cystic fibrosis in relation to blood sugar levels, lung function and weight management. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also handsearched abstracts from pulmonary symposia and the North American Cystic Fibrosis Conferences.Date of the most recent search of the Group's Cystic Fibrosis Trials Register: 18 February 2016. Randomized controlled trials comparing all methods of diabetes therapy in people with diagnosed cystic fibrosis-related diabetes. Two authors independently extracted data and assessed the risk of bias in the included studies. The searches identified 22 trials (34 references). Four trials (200 participants) are included: one short-term single-center trial (n = 7) comparing insulin with oral repaglinide and no medication in people with cystic fibrosis-related diabetes and normal fasting glucose; one long-term multicenter trial (n = 100, 74 of whom had cystic fibrosis-related diabetes) comparing insulin with oral repaglinide and placebo; one long-term multicenter trial (n = 73) comparing insulin with oral repaglinide; and one 12-week single-center trial (n = 20) comparing the long-acting insulin glargine to short-term neutral protamine Hagedorn insulin.Two trials with data for the comparison of insulin to placebo did not report any significant differences between groups for the primary outcomes of blood glucose levels, lung function and nutritional status. This was also true for the single trial with data for the comparison of repaglinide to placebo. Two trials (one lasting one year and one lasting two years) contributed data for the comparison of insulin versus repaglinide. There were no significant differences for the primary outcomes at any time point, except at one year (in the two-year trial) when the insulin group had significant improvement in z score for body mass index compared to the repaglinide group. The single trial comparing glargine to neutral protamine Hagedorn insulin also did not report any significant differences in the review's primary outcomes. A few cases of hypoglycemia were seen in three out of the four trials (none in the longest trial), but these events resolved without further treatment.There was an unclear risk of bias from randomization and allocation concealment in two of the four included trials as the authors did not report any details; in the remaining two studies details for randomization led to a low risk of bias, but only one had sufficient details on allocation concealment to allow a low risk judgement, the second was unclear. There was a high risk from blinding for all trials (except for the comparison of oral repaglinide versus placebo) due to the nature of the interventions. Complete data for all outcomes were not available from any trial leading to a high risk of reporting bias. The amounts of insulin and repaglinide administered were not comparable and this may lead to bias in the results. None of the included trials were powered to show a significant improvement in lung function. This review has not found any significant conclusive evidence that long-acting insulins, short-acting insulins or oral hypoglycemic agents have a distinct advantage over one another in controlling hyperglycemia or clinical outcomes associated with cystic fibrosis-related diabetes. While some cystic fibrosis centers use oral medications to help control diabetes, the Cystic Fibrosis Foundation (USA) clinical practice guidelines support the use of insulin therapy and this remains the most widely-used treatment method. Randomized controlled trials specifically related to controlling diabetes with this impact on the course of pulmonary disease process in cystic fibrosis continue to be a high priority.There is no demonstrated advantage yet established for using oral hypoglycemic agents over insulin, and further trials need to be evaluated to establish whether there is clear benefit for using hypoglycemic agents. Agents that potentiate insulin action, especially agents with additional anti-inflammatory potential should be further investigated to see if there may be a clinical advantage to adding these medications to insulin as adjuvant therapy.


Bird fancier's lung: a state-of-the-art review.
Bird fancier's lung (BFL) resulting from avian antigen exposure is a very common form of hypersensitivity pneumonitis. Its pathogenesis is modified by genetic polymorphisms located within the major histocompatibility complex, and also by smoking, which may decrease serum antibody response to inhaled antigen. Acute, subacute, and chronic presentations of BFL are recognized, but often overlap clinically. Continued antigen exposure in the chronic phase portends a worse prognosis. Chronic bronchitis symptoms may be part of the BFL clinical spectrum, and rhinitis may suggest an allergic component. The diagnosis of BFL is enhanced by a high index of suspicion of exposure to avian antigen, recurrent symptomatic episodes occurring 4-8 h after exposure, inspiratory "velcro" crackles on auscultation, weight loss, and positive IgG precipitins to the antigen. Characteristic findings on high-resolution computed tomography of the chest include centrilobular nodules, ground-glass opacification, and mosaicism due to air trapping. Bronchoalveolar lavage will classically show >25% lymphocytosis, a CD4/CD8 ratio of <1.0 and >1% mast cells in the acute phase. Lung biopsies, if obtained in the subacute phase of the disease, typically show loosely formed granulomas, giant cells, a lymphoplasmacytic interstitial infiltrate, and possibly some degree of fibrosis. In some patients, usual interstitial pneumonia or fibrotic non-specific interstitial pneumonia patterns may be seen on surgical biopsy. Skin testing, serological testing, and bronchial provocation tests for BFL frequently suffer from a lack of standardization. Effective treatment for BFL consists mainly of antigen avoidance, as corticosteroids likely do not alter long-term prognosis. Lung transplantation can be considered for progressive chronic disease refractory to medical measures.


(n-3) PUFA alter raft lipid composition and decrease epidermal growth factor receptor levels in lipid rafts of human breast cancer cells.
To determine the mechanism by which the (n-3) fatty acids (FA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) decrease proliferation and induce apoptosis in MDA-MB-231 human breast cancer cells, we examined the effects of EPA and DHA on the lipid composition of lipid rafts as well as epidermal growth factor receptor (EGFR) raft localization and phosphorylation. (n-3) FA (a combination of EPA and DHA) inhibited (P < 0.05) the growth of MDA-MB-231 cells by 48-62% in the presence and absence, respectively, of linoleic acid (LA). More EPA and DHA were incorporated into lipid rafts isolated from MDA-MB-231 cells after treatment with (n-3) FA compared with cells treated with LA (P < 0.05). EPA and DHA treatment decreased (P < 0.05) lipid raft sphingomyelin, cholesterol, and diacylglycerol content and, in the absence of LA, EPA and DHA increased (P < 0.05) raft ceramide levels. Furthermore, there was a marked decrease in EGFR levels in lipid rafts, accompanied by increases in the phosphorylation of both EGFR and p38 mitogen-activated protein kinase (MAPK), in EPA+DHA-treated cells (P < 0.05). As sustained activation of the EGFR and p38 MAPK has been associated with apoptosis in human breast cancer cells, our results indicate that (n-3) FA modify the lipid composition of membrane rafts and alter EGFR signaling in a way that decreases the growth of breast tumors.


Hepatic osteodystrophy in chronic cholestasis: evidence for a multifactorial etiology.
Children with cholestatic liver disease have been thought to develop hepatic osteodystrophy resulting from vitamin D and calcium malabsorption, resulting in secondary hyperparathyroidism and osteomalacia or rickets. However, treatment with vitamin D has not always proven successful in improving the bone disturbance. The aim of our study was to determine the role of vitamin D deficiency in the pathogenesis of hepatic osteodystrophy. We studied five patients, three female and two male, ages 0.9-19 yr, with biopsy-proven chronic cholestatic liver disease and previously low serum levels of vitamin D despite oral intake of vitamin D preparations. Patients were admitted to the Clinical Research Center for 8 days for sunlight deprivation and ultraviolet light substitution and for determinations of serum 25-hyroxyvitamin D(25(OH)) D2 and -D3, osteocalcin, and type I collagen telopeptide (ICTP), the last two being markers of bone formation and resorption, respectively. Samples were taken on admission, at discharge, and 1 month later. Results demonstrated low serum levels of osteocalcin and normal circulating levels of ICTP. Admission serum 25(OH)D2 levels were uniformly low or undetectable and remained so. Admission levels of circulating 25(OH)D3 were normal or low and did not rise during ultraviolet light therapy or subsequent resumption of oral vitamin D therapy and remained low 1 month later. These results indicate that in the face of low-normal to low total 25(OH)D levels, the low osteocalcin and normal ICTP levels suggest that decreased bone formation and not increased bone resorption is the main determinant of bone loss in a subset of children with chronic cholestatic liver disease.


Dissection of carotid sinus hypersensitivity: the timing of vagal and vasodepressor effects and the effect of body position.
We assessed the timing of vagal and sympathetic factors that mediate hypotension during CSM (carotid sinus massage) in patients with carotid sinus hypersensitivity. We hypothesized that a fall in cardiac output would precede vasodepression, and that vasodepression would be exaggerated by head-up tilt. We performed pulse contour analyses on blood pressure recordings during CSM in syncope patients during supine rest and head-up tilt. In a subset we simultaneously recorded muscle sympathetic nerve activity supine. During supine rest, systolic blood pressure decreased from 150±7 to 107±7 mmHg (P<0.001) and heart rate from 64±2 to 39±3 beats/min (P<0.01). Cardiac output decreased with heart rate to nadir (66±6% of baseline), 3.1±0.4 s after onset of bradycardia. In contrast, total peripheral resistance reached nadir (77±3% of baseline) after 11±1 s. During head-up-tilt, systolic blood pressure fell from 149±10 to 90±11 mmHg and heart rate decreased from 73±4 to 60±7 beats/min. Compared with supine rest, cardiac output nadir was lower (60±8 compared with 83±4%, P<0.05), whereas total peripheral resistance nadir was similar (81±6 compared with 80±3%). The time to nadir from the onset of bradycardia did not differ from supine rest. At the onset of bradycardia there was an immediate withdrawal of muscle-sympathetic nerve activity while total peripheral resistance decay occurred much later (6-8 s). The haemodynamic changes following CSM have a distinct temporal pattern that is characterized by an initial fall in cardiac output (driven by heart rate), followed by a later fall in total peripheral resistance, even though sympathetic withdrawal is immediate. This pattern is independent of body position.


Aphasia disorders outcome after stroke.
Aphasia is considered to be the most difficult disorders of speech-language communication, and is often companion by all forms of cerebrovascular disease. To determine the outcome of aphasia disorder a year after a stroke and stroke type influence on the outcome of aphasia disorders. We analyzed one-year outcome of aphasia disorders in patients who had a first stroke. Patients were tested by a speech pathologist with the International test for aphasia, immediately after admission and one year after the stroke. All patients that were hospitalized during treatment had a speech therapy and only a small number of patients were realsed from hospital. Out of 74 patients with aphasia who were discharged from hospital within one year 20 patients died and 2 patients did not respond to control clinical treatment review. Analysis of the remaining 52 respondents determined that out of the 10 patients with global aphasia 8 (80%) evolved into another aphasia syndrome, and two (20%) remained unchanged in form. In most cases, global aphasia was transformed in mixed non fluent aphasia (4 of 10 patients or 40%), and in two cases (20%) global aphasia was transformed in Broca aphasia. Broca aphasia (n = 20) in other forms evolved in 9 patients (45%), and 11 patients (55%) remained unchanged in form. Anomic aphasia had 11 patients (78.6%) which remained unchanged in form, while 3 (21.4%) evolved into an Alexia agraphia. Full recovery was noted in two patients (3.84%). Type of stroke did not affect the outcome of aphasia disorders. Out of the 52 analyzed patients after hospitalization, unfortunately, only 11 (21.2%) had some kind of speech pathology treatment after leaving the hospital. One year after the stroke severe aphasia evolved into a lighter form in a significant number of patients. Most often anomic aphasia remained (34.6%), followed by Broca (25%) and Conductive aphasia (7.7%). Type of stroke does not affect the outcome of aphasia disorders. Unfortunately only a small number of patients (21.2%) continued with aphasia speech therapy after leaving the hospital.


Resveratrol: potential as anticancer agent.
Cancer is one of the leading causes of deaths in the world. Current chemotherapeutic agents are associated with serious side effects in patients therefore researchers are trying to find an alternative agent that is effective against cancer as well as less toxic. Resveratrol (3,5,4'-trihydroxystilbene), commonly found in red wine and grape skins, is a phytoalexin agent that was originally extracted from the roots of Polygonum cuspidatum. Resveratrol is believed to work as a chemopreventive agent by producing its effect on cell apoptosis, antiproliferation, and anti-inflammation. To determine whether resveratrol is effective as an anticancer agent. A systematic review was performed by searching various databases for primary, secondary, and tertiary references. Databases included PubMed, EBSCO, Cochrane, AccessPharmacy, and StatRef by using key terms of "resveratrol," "cancer," and "anticancer." Review search looked at both animal and human studies limited within 10 years. The major mechanisms of actions through which resveratrol works include proapoptotic, antiproliferation, and anti-inflammation. Numerous in vitro and in vivo studies have supported these mechanisms thus warranting further research in human studies for resveratrol's anticancer effects. Pharmacokinetic human studies suggest good tolerability in healthy subjects, although they have low absorptive characteristics. Resveratrol appears to have anticancer effects. Additionally, these studies indicate that resveratrol's chemoprevention effect is dose and duration dependent. It has synergistic effect with anticancer drugs in vitro. Further human studies need to be done.


Modeling the larvae dispersion of sun coral in the Brazil current off Cape Frio: A cyclonic eddy scenario.
The study aims to understand the dispersal patterns of non-indigenous Tubastraea spp. (Sun Coral) larvae in the Brazil Current (BC), specifically in the Cape Frio recurrent cyclonic eddy (CFE) scenario. For this, the Regional Ocean Model System was used to simulate the hydrodynamic fields in a high-resolution nested grid, where a model of lagrangian floats, in a good approximation of the larvae properties and considering massive planulation events, was coupled with surface larval release from the Campos Basin area. The simulation was representative of mesoscale features compared to similar studies, ARGO vertical profiles and a py-eddy-track algorithm was used to obtain eddy variables, such as radius, rotational and translational velocities. These parameters are fundamental to access when an eddy tends to trap or not the water, heat and plankton in its interior. CFE turned out to be highly nonlinear, with a strong tendency to trap larvae in its core, acting as a dispersal constrictor when compared with the organisms in the axis of the higher speed of BC. A strong negative correlation (-0.75) was found between the days that larvae were inside the eddy and their distance from the origin. None of the 48,000 larvae released during simulated experiment a 16-day spawning event reached the coast. There are two different patterns for the dispersal, one along the shelf break and another, with higher larval density, off from the 1000 m isobath. The CFE's presence allows larvae to remain in the same region for longer periods, although in offshore areas. Therefore, as there is considerable availability of fixed substrates on oil rig structures, larvae could settle on them resulting in a possible inter-platforms connectivity between populations of Tubastraea spp. Also, regions in the CFE that present downward vertical velocities (downwelling), may move young larvae to depths of about 60 m suggesting that subsurface colonizations are possible due to specific dynamics of propagating cyclonic eddies. So, identifying the main factors that affect the dispersion of propagules is essential to subsidize management policies for controlling bioinvasion associated with exploitation of hydrocarbon resources in offshore areas.


Consensus amplification and novel multiplex sequencing method for S segment species identification of 47 viruses of the Orthobunyavirus, Phlebovirus, and Nairovirus genera of the family Bunyaviridae.
A reverse transcription-PCR (RT-PCR) assay was designed, according to previously determined and newly derived genetic data, to target S genomic segments of 47 viruses, including 29 arthropod-borne human pathogens, of the family Bunyaviridae. The analytical sensitivity of the presented assay was evaluated through its application to RNAs extracted from quantitated dilutions of bunyaviruses of interest. Additionally, the assay's analytical specificity was determined through the evaluation of RNAs extracted from selected bunyaviruses and other representative arthropod-borne viruses isolated from a diverse group of host species and temporal and geographic origins. After RT-PCR amplification, DNAs amplified from bunyaviruses of interest were subjected to a novel multiplex sequencing method to confirm bunyavirus positivity and provide preliminary, species-level S segment identification. It is our goal that this assay will be used as a tool for identification and characterization of emergent arthropod-borne bunyavirus isolates of medical import as well as related viruses of the family Bunyaviridae that have not been associated with human illness.


Effect of arachidonic acid on specific binding of [3H]naloxone to opioid receptors.
The effects of arachidonic acid (AA) on binding of [3H]naloxone to the agonist and antagonist configurations of opioid receptors were investigated in rat brain. Equilibrium binding parameters of the agonist and antagonist configurations of the receptors were evaluated from homologue displacement data in the presence or absence of AA. Addition of AA at a concentration of 0.6 mM (1.5 mumole/mg of protein) reduced by 22% and 53% the maximal number of binding sites (Bmax) respectively in the absence or presence of 100 mM NaCl. Binding affinity (KD) was not altered significantly (P < 0.05) either in the presence or absence of 100 mM NaCl and AA. We conclude that AA mediated reduction in [3H]naloxone specific binding was chiefly due to a decrease in the number of binding sites.


Management of complex spine surgery.
The main objective of this article is to present the updated data regarding the perioperative management of patients undergoing major spine surgery in an era where the surgical techniques are changing and there is a high demand for these surgeries in older and high-risk patients. Preoperative assessment and stabilization is now more structured protocol and it is based on a multidisciplinary approach to the patient. The Enhanced Recovery After Surgery (ERAS) programs and the Perioperative Surgical Home on major spine surgery are not yet fully evidence based but it seems that the use of a perioperative optimization of patients and use of a drugs' bundle is more effective than using single drugs or interventions on the postoperative pain reduction and faster recovery from surgery. Fluid and pain-control protocols combined with an accurate blood management represent the key to success. A tailored approach to patients undergoing major spine surgeries seems to be effective improving the outcome and quality of life of patients. Future studies should aim to understand which elements of the ERAS can be improved to allow the patient to have a long-term good outcome. VIDEO ABSTRACT.


GABA and glutamate neurons in the VTA regulate sleep and wakefulness.
We screened for novel circuits in the mouse brain that promote wakefulness. Chemogenetic activation experiments and electroencephalogram recordings pointed to glutamatergic/nitrergic (NOS1) and GABAergic neurons in the ventral tegmental area (VTA). Activating glutamatergic/NOS1 neurons, which were wake- and rapid eye movement (REM) sleep-active, produced wakefulness through projections to the nucleus accumbens and the lateral hypothalamus. Lesioning the glutamate cells impaired the consolidation of wakefulness. By contrast, activation of GABAergic VTA neurons elicited long-lasting non-rapid-eye-movement-like sleep resembling sedation. Lesioning these neurons produced an increase in wakefulness that persisted for at least 4 months. Surprisingly, these VTA GABAergic neurons were wake- and REM sleep-active. We suggest that GABAergic VTA neurons may limit wakefulness by inhibiting the arousal-promoting VTA glutamatergic and/or dopaminergic neurons and through projections to the lateral hypothalamus. Thus, in addition to its contribution to goal- and reward-directed behaviors, the VTA has a role in regulating sleep and wakefulness.


Monoclonal antibodies to human vitamin K-dependent protein S.
Monoclonal antibodies to human protein S have been prepared using established hybridoma technology. One antibody was isolated that binds protein S only when Ca2+ is present; others bind antigen equally well in the presence or absence of EDTA. Other antibodies display a diminished affinity for protein S in the presence of EDTA. Purified immunoglobulins from cell lines displaying Ca2+ dependence were immobilized and used to purify protein S from fractions obtained by barium precipitation of citrated plasma, ammonium sulfate fractionation, and chromatography on diethylaminoethanol (DEAE)-Sephadex and dextran sulfate agarose. Essentially homogeneous protein S was isolated from the barium-citrate-adsorbed, 35% ammonium-sulfate-soluble proteins using a totally Ca2+-dependent antibody and EDTA elution. Protein S and several substances of higher mol wt were bound directly from plasma by a partially Ca2+-dependent antibody and were eluted partially with EDTA and NaCl and finally with NaSCN. The largest and most abundant of the high mol wt materials is likely protein S-complement C4b-binding protein complex. The immunoaffinity-isolated protein S was found to be indistinguishable from conventionally isolated protein S in terms of activity, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) mobility, and by high-performance liquid chromatography (HPLC). These studies establish reagents that can probe the structure of protein S and isolate protein S in its free and complexed forms.


Examining the impact of 45 minutes of daily physical education on cognitive ability, fitness performance, and body composition of African American youth.
Increased importance on academic achievement has resulted in many school districts focusing on improved academic performance leading to reductions in physical education time. The purpose was to examine the effects of 45 minutes of daily physical education on the cognitive ability, fitness performance and body composition of African American elementary and middle school youth. Participants completing the informed consent in grades 2nd to 8th were included in the study. A pre/posttest design was used with repeated measures analysis of variance. Experimental and control school participants were pretested on the cognitive measures (ie, Fluid Intelligence and Perceptual Speed) and Fitnessgram® physical fitness test items (eg, aerobic capacity, muscular strength and muscular endurance, body composition) in September 2009 and posttested in May 2010. Experimental elementary and middle school participants observed significantly greater improvements compared with control elementary and middle school participants on 7 of 16 fitness and body composition measures and on 8 of 26 cognitive measures. These fitness, body composition, and cognitive improvement differences were more noticeable among elementary and middle school females. Providing 45 minutes of daily physical education can perhaps increase cognitive ability while increasing fitness and decreasing the prevalence of overweight and obese youth.


Detection and quantification of small right-to-left shunts by the phase-plane method.
In six anesthetized dogs 70 indicator-dilution curves and phase-plane plots were recorded. Indocyanine green was injected into the superior vena cava and sampled through a dichromatic cuvette densitometer from the femoral artery. Dye-dilution curves were recorded from dogs with normal cardiovascular systems and repeated after right-to-left shunts of different magnitude were surgically produced. The percent of blood shunting was calculated according to standard indicator-dilution equations and also by means of oximetric determination of blood samples. They were compared with shunt estimates based on phase-plane loop measurements. Good correlation was found with standard indicator-dilution procedures (r = 0.890) but not with oximetry (r = 0.466). The phase plane shows its utility in the detection and evaluation of small right-to-left shunts. These shunts affect the initial portion of the phase plane and the alterations appear to be more evident than in the corresponding concentration-vs.-time curves.


Sea blue histiocytosis: a common abnormality of the bone marrow in myelodysplastic syndromes.
To determine whether myelodysplastic syndromes (MDS) are associated with sea blue histiocytosis in the bone marrow. A retrospective review of bone marrow aspirates from 35 patients presenting consecutively with MDS and from 20 patients with each of the following: normal marrow appearance (routine staging for non-Hodgkin's lymphoma), polycythaemia rubra vera, immune thrombocytopenic purpura (ITP), chronic myeloid leukaemia (CML) in chronic phase. Sea blue histiocytes were present in the marrow in 12 of 35 cases of MDS and occurred in large numbers in three of these cases. Sea blue histiocytes varied in the degree of cytoplasmic granularity and some cells were intermediate in appearance between classic sea blue histiocytes and pseudo-Gaucher cells. Sea blue histiocyte granules additionally stained positively with Sudan black and periodic acid schiff. Sea blue histiocytes occurred only in the presence of marrow hypercellularity. Their presence did not correlate with FAB subtype, degree of dyserythropoeisis, or megakaryocyte numbers. No sea blue histiocytes were found in the normal marrow or polycythaemia cases. In ITP sea blue histiocytes were seen in two of 20 cases and in chronic myeloid leukaemia in eight of 20 cases. Sea blue histiocytes are a common cytological feature in the bone marrow of patients with MDS. As other disorders frequently associated with marrow sea blue histiocytes are relatively rare MDS is probably the most common cause of this phenomenon in a northern European population.


[Synthesis of soluble proinsulin in a cell-free protein synthesis system].
Proinsulin (Pins) is the precursor of insulin. The expression of proinsulin in Escherichia coli forms inclusion body, so that the recombinant protein should be processed with multiple steps to form active insulin. With the development in biotechnology, cell-free protein synthesis (CFPS) system is becoming a valuable tool in protein expression by decoupling the cell growth with protein production, which allows it to express proteins that would interfere with cell physiology. In this study, we synthesized soluble proinsulin in CFPS system in order to establish a new approach for both insulin expression and delivery. The soluble proinsulin was successfully expressed in CFPS system by fusing proinsulin with two types of fluorescent protein. The expression of Pins-mCherry was confirmed by Western blotting analysis, and the Pins-eGFP titer was (12.28±3.45) μg/mL in CFPS system. These results implicated that the proinsulin was expressed partially in soluble form. Here, for the first time, we successfully expressed soluble proinsulin in CFPS system by fluorescent protein fusion. These results provide useful information in developing new insulin expression and delivery method.


Carbohydrate structures of the human-immunodeficiency-virus (HIV) recombinant envelope glycoprotein gp120 produced in Chinese-hamster ovary cells.
The present paper describes the structures of the N-linked oligosaccharides of the human-immunodeficiency-virus (HIV) envelope glycoprotein gp120 (cloned from the HTLV-III B isolate and expressed as a secreted fusion protein after transfection of Chinese-hamster ovary cells), which is known to bind with high affinity to human T4-lymphocytes. Oligosaccharides were released from peptide by hydrazinolysis, fractionated by paper electrophoresis, high-performance lectin-affinity chromatography and Bio-Gel P-4 column chromatography, and their structures determined by sequential exoglycosidase digestions in conjunction with methylation analysis. The glycoprotein was found to be unique in its diversity of oligosaccharide structures. These include high-mannose type and hybrid type, as well as four categories of complex-type chains: mono-, bi-, tri- and tetra-antennary, with or without N-acetyl-lactosamine repeats, and with or without a core-region fucose residue. Among the sialidase-treated oligosaccharides, no less than 29 structures were identified as follows: (formula; see text) where G is galactose, GN is N-acetylglucosamine, M is mannose, F is fucose, and '+/- ' means that residues are present in a proportion of chains. The actual number of oligosaccharide structures is much greater, since before desialylation there was evidence that, among the hybrid and complex-type chains, all but 6% contained sialic acid at the C-3 position of terminal galactose residues, and partially sialylated forms of the bi- and multi-antennary chains were present. Detailed evidence for the proposed oligosaccharide sequences will be published as a supplementary paper [T. Mizuochi, M. W. Spellman, M. Larkin, J. Solomon, L. J. Basa & T. Feizi (1988) Biomed. Chromatogr., in the press].


A low-cost and portable wrist exoskeleton using EEG-sEMG combined strategy for prolonged active rehabilitation.
Hemiparesis is a common consequence of stroke that severely impacts the life quality of the patients. Active training is a key factor in achieving optimal neural recovery, but current systems for wrist rehabilitation present challenges in terms of portability, cost, and the potential for muscle fatigue during prolonged use. To address these challenges, this paper proposes a low-cost, portable wrist rehabilitation system with a control strategy that combines surface electromyogram (sEMG) and electroencephalogram (EEG) signals to encourage patients to engage in consecutive, spontaneous rehabilitation sessions. In addition, a detection method for muscle fatigue based on the Boruta algorithm and a post-processing layer are proposed, allowing for the switch between sEMG and EEG modes when muscle fatigue occurs. This method significantly improves accuracy of fatigue detection from 4.90 to 10.49% for four distinct wrist motions, while the Boruta algorithm selects the most essential features and stabilizes the effects of post-processing. The paper also presents an alternative control mode that employs EEG signals to maintain active control, achieving an accuracy of approximately 80% in detecting motion intention. For the occurrence of muscle fatigue during long term rehabilitation training, the proposed system presents a promising approach to addressing the limitations of existing wrist rehabilitation systems.


Uterine Corpus Metastasis From Rectal Adenocarcinoma Detected Using 18F-FDG PET/CT.
We report an unusual case of uterine corpus metastasis from rectal adenocarcinoma detected using F-FDG PET/CT. A 47-year-old woman was diagnosed with rectal adenocarcinoma and treated with surgery and radiochemotherapy 3 years ago. During follow-up, she presented with lower abdomen pain and elevated tumor markers, but ultrasonography findings were unremarkable. We performed an F-FDG PET/CT scan, which showed intense F-FDG avidity in the myometrium of the uterine corpus. Uterine corpus metastasis was suspected, and complementary MRI and diagnostic curettage histopathology confirmed uterine metastasis from rectal adenocarcinoma.


Chronic multimorbidity among older adults in rural South Africa.
The rapid ageing of populations around the world is accompanied by increasing prevalence of multimorbidity. This study is one of the first to present the prevalence of multimorbidity that includes HIV in the complex epidemiological setting of South Africa, thus filling a gap in the multimorbidity literature that is dominated by studies in high-income or low-HIV prevalence settings. Out of the full sample of 5059 people aged 40+, we analysed cross-sectional data on 10 conditions from 3889 people enrolled in the Health and Ageing in Africa: A longitudinal study of an INDEPTH Community in South Africa (HAALSI) Programme. Two definitions of multimorbidity were applied: the presence of more than one condition and the presence of conditions from more than one of the following categories: cardiometabolic conditions, mental disorders, HIV and anaemia. We conducted descriptive and regression analyses to assess the relationship between prevalence of multimorbidity and sociodemographic factors. We examined the frequencies of the most prevalent combinations of conditions and assessed relationships between multimorbidity and physical and psychological functioning. 69.4 per cent (95% CI 68.0 to 70.9) of the respondents had at least two conditions and 53.9% (52.4-55.5) of the sample had at least two categories of conditions. The most common condition groups and multimorbid profiles were combinations of cardiometabolic conditions, cardiometabolic conditions and depression, HIV and anaemia and combinations of mental disorders. The commonly observed positive relationships between multimorbidity and age and decreasing wealth were not observed in this population, namelydue to different epidemiological profiles in the subgroups, with higher prevalence of HIV and anaemia in the poorer and younger groups, and higher prevalence of cardiometabolic conditions in the richer and older groups. Both physical functioning and well-being negatively associated with multimorbidity. More coordinated, long-term integrated care management across multiple chronic conditions should be provided in rural South Africa.


Antigen-binding cells in normal mouse thymus.
The thymus of a normal adult mouse contains lymphocytic cells with a large number of antigen-binding receptors. Binding of the antigen by these cells is specific and can be inhibited by cross-reactive materials. It is possible that the interaction of thymocytes with antibody-forming precursor cells, required in the primary immune response to certain antigens, is mediated by these specific antigen-binding cells of the thymus.


Polymer fullerene solution phase behaviour and film formation pathways.
We report the phase behaviour of polymer/fullerene/solvent ternary mixtures and its consequence for the morphology of the resulting composite thin films. We focus particularly on solutions of polystyrene (PS), C60 fullerene and toluene, which are examined by static and dynamic light scattering, and films obtained from various solution ages and thermal annealing conditions, using atomic force and light microscopy. Unexpectedly, the solution phase behaviour below the polymer overlap concentration, c*, is found to be described by a simple excluded volume argument (occupied by the polymer chains) and the neat C60/solvent miscibility. Scaling consistent with full exclusion is found when the miscibility of the fullerene in the solvent is much lower than that of the polymer, giving way to partial exclusion with more soluble fullerenes (phenyl-C61-butyric acid methyl ester, PCBM) and a less asymmetric solvent (chlorobenzene), employed in photovoltaic devices. Spun cast and drop cast films were prepared from PS/C60/toluene solutions across the phase diagram to yield an identical PS/C60 composition and film thickness, resulting in qualitatively different morphologies in agreement with our measured solution phase boundaries. Our findings are relevant to the solution processing of polymer/fullerene composites (including organic photovoltaic devices), which generally require effective solubilisation of fullerene derivatives and polymer pairs in this concentration range, and the design of well-defined thin film morphologies.


How does the duration of consults vary for upper respiratory tract infections in general practice where an antibiotic has been prescribed?
There is limited data on the duration of consults resulting in the prescription of antibiotics for upper respiratory tract infections (URTIs) in general practice. To explore how demographic factors influence consult duration where antibiotics have been prescribed for URTI in Australian general practice. 2985 URTI-specific presentations were identified from a national study of patients who were prescribed an antibiotic after presenting to general practice between June and September 2017. Consult duration was analysed to assess for any variation in visit length based on demographic factors. The overall median consult duration was 11.42 minutes [interquartile range (IQR) 7.95]. Longer consult duration was associated with areas of highest socio-economic advantage where patients living in postcodes of Index of Relative Socio-economic Advantage and Disadvantage (IRSAD) Quintile 5 (highest 20% on the IRSAD) had significantly longer consults [median 13.12 (IQR 8.01)] than all other quintiles (P < 0.001). Females [11.75 (IQR 8.13)] had significantly longer consults than males [10.87 (IQR 7.57); P < 0.001]. Clinics based in State C and State F had significantly shorter consults when compared with all other included states and territories (P < 0.001) and shorter consult duration was associated with visits on Sundays [median 8.18 (IQR 5.04)]. There is evidence for the association of demographic and temporal factors with the duration of consultations for URTIs where an antibiotic has been prescribed. These factors warrant further research.


[35S]sadopine, a novel high affinity, high specific activity, L-type Ca2+ channel probe: characterization of two equipotent diastereomers with opposite allosteric properties.
A novel 35S-labeled dihydropyridine (DHP), 1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)-pyridine-3,5-dic arboxyl-3- [2-(N-tert-butoxycarbonyl-L-[35S]methionyl)-aminoethyl]-ester-5-ethyl ester, ([35S]sadopine) (800-1400 Ci/mmol), the respective (+)- and (-)-diastereomers, and unlabeled (+/- )-, (-)-, and (+)-sadopine were synthesized. [35S]Sadopine is an excellent high affinity, high specific activity radioligand to label selectively the DHP receptor of L-type Ca2+ channels in tissue sections as well as in membrane fragments. Both diastereomers bind to the DHP receptors in a saturable and reversible manner, with equal, subnanomolar, dissociation constants. Despite their similar affinities, (+)- and (-)-sadopine differ with respect to their kinetic properties [the association and dissociation rate constants are 10-fold higher for (+)-[35S]sadopine at 22 degrees] and their allosteric modulation of the phenylaklylamine or benzothiazepine binding domain. (+)-Sadopine is a negative but (-)-sadopine a positive allosteric modulator of (-)-[N-methyl-3H]LU49888 or (+)-cis-[3H] diltiazem binding at 30 degrees. Both diastereomers act as L-type Ca2+ channel blockers in cardiac and smooth muscle cells. Computer-based analysis of the electrostatic potentials of the two diastereomers and calculation of the interaction energies with a hypothetical DHP receptor model predicted not only the similar affinities of (+)- and (-)-sadopine but also their Ca2+ channel-blocking effects. The temperature-dependent allosteric differences between the diastereomers suggest that two distinct conformational states of the DHP receptor are stabilized in vitro, both corresponding to a nonconducting state of the channel. Our data indicate that access to the DHP receptor site, but not binding affinity, is a function of the opposite stereochemistry of the sadopine diastereomers. Therefore, labeled and unlabeled (+)- and (-)-sadopine will be useful probes to further characterize the molecular basis of DHP-Ca2+ channel interaction and the pharmacological and physiological significance of the different allosteric conformations of the channel induced by Ca2+ channel-active drugs.


Dual Trajectories of Cigarette Smoking and Smokeless Tobacco Use From Adolescence to Midlife Among Males in a Midwestern US Community Sample.
Identifying trajectories of tobacco use is critical for understanding its natural history and targeting interventions, but research on trajectories of smokeless tobacco and dual use of smokeless tobacco and cigarettes is very limited. This study identified tobacco use trajectories from adolescence to midlife and tested correlates of trajectory group membership. This study included all male participants in a longitudinal study who reported cigarette smoking or smokeless tobacco use in 1987, 1993, 1999, 2005, or 2011 (N = 2230). Group-based trajectory analyses were conducted with zero-inflated Poisson models. Analysis of covariance was used to test adolescent health beliefs associated with trajectory group membership. Five smoking trajectory groups were identified: (1) consistent abstinence from cigarettes; (2) late onset intermittent, then cessation; (3) early onset regular, then cessation; (4) delayed onset regular, then cessation; and (5) consistent regular. Four smokeless tobacco trajectory groups were identified: (1) early onset, then cessation; (2) consistent abstinence from smokeless tobacco; (3) late onset, escalating; and (4) consistent regular. The proportion of participants in trajectory groups representing dual use was low. Adolescent beliefs favorable to smoking and smokeless tobacco were associated with membership in consistent regular use groups. The prevalence of dual use of cigarettes and smokeless tobacco was low, and there was little evidence to suggest switching between tobacco products. Participants who held more positive beliefs about smoking and smokeless tobacco as adolescents were more likely to be consistent regular users of cigarettes and smokeless tobacco into adulthood.


Variations in chromosomes 9 and 6p21.3 with risk of non-Hodgkin lymphoma.
There is growing evidence linking genetic variations to non-Hodgkin lymphoma (NHL) etiology. To complement ongoing agnostic approaches for identifying susceptibility genes, we evaluated 488 candidate gene regions and their relation to risk for NHL and NHL subtypes. We genotyped 6,679 tag single nucleotide polymorphisms (SNPs) in 947 cases and 826 population-based controls from a multicenter U.S. case-control study. Gene-level summary of associations were obtained by computing the minimum P value ("minP test") on the basis of 10,000 permutations. We used logistic regression to evaluate the association between genotypes and haplotypes with NHL. For NHL subtypes, we conducted polytomous multivariate unconditional logistic regression (adjusted for sex, race, age). We calculated P-trends under the codominant model for each SNP. Fourteen gene regions were associated with NHL (P < 0.01). The most significant SNP associated with NHL maps to the SYK gene (rs2991216, P-trend = 0.00005). The three most significant gene regions were on chromosome 6p21.3 (RING1/RXRB; AIF1; BAT4). Accordingly, SNPs in RING1/RXRB (rs2855429), AIF1 (rs2857597), and BAT4 (rs3115667) were associated with NHL (P-trends ≤ 0.0002) and both diffuse large B-cell and follicular lymphomas (P-trends < 0.05). Our results suggest potential importance for SYK on chromosome 9 with NHL etiology. Our results further implicate 6p21.3 gene variants, supporting the need for full characterization of this chromosomal region in relation to lymphomagenesis. Gene variants on chromosome 9 may represent a new region of interesting for NHL etiology. The independence of the reported variants in 6p21.3 from implicated variants (TNF/HLA) supports the need to confirm causal variants in this region.


High-performance computing service over the internet for intraoperative image processing.
This paper presents a framework for a cluster system that is suited for high-resolution image processing over the Internet during surgery. The system realizes high-performance computing (HPC) assisted surgery, which allows surgeons to utilize HPC resources remote from the operating room. One application available in the system is an intraoperative estimator for the range of motion (ROM) adjustment in total hip replacement (THR) surgery. In order to perform this computation-intensive estimation during surgery, we parallelize the ROM estimator on a cluster of 64 PCs, each with two CPUs. Acceleration techniques such as dynamic load balancing and data compression methods are incorporated into the system. The system also provides a remote-access service over the Internet with a secure execution environment. We applied the system to an actual THR surgery performed at Osaka University Hospital and confirmed that it realizes intraoperative ROM estimation without degrading the resolution of images and limiting the area for estimations.


Regulatory Roles of Anoctamin-6 in Human Trabecular Meshwork Cells.
Trabecular meshwork (TM) cell volume is a determinant of aqueous humor outflow resistance, and thereby IOP. Regulation of TM cell volume depends on chloride ion (Cl-) release through swelling-activated channels (ICl,Swell), whose pore is formed by LRRC8 proteins. Chloride ion release through swelling-activated channels has been reported to be regulated by calcium-activated anoctamins, but this finding is controversial. Particularly uncertain has been the effect of anoctamin Ano6, reported as a Ca2+-activated Cl- (CaCC) or cation channel in other cells. The current study tested whether anoctamin activity modifies volume regulation of primary TM cell cultures and cell lines. Gene expression was studied with quantitative PCR, supplemented by reverse-transcriptase PCR and Western immunoblots. Currents were measured by ruptured whole-cell patch clamping and volume by electronic cell sizing. Primary TM cell cultures and the TM5 and GTM3 cell lines expressed Ano6 3 to 4 orders of magnitude higher than the other anoctamin CaCCs (Ano1 and Ano2). Ionomycin increased cell Ca2+ and activated macroscopic currents conforming to CaCCs in other cells, but displayed significantly more positive mean reversal potentials (+5 to +12 mV) than those displayed by ICl,Swell (-14 to -21 mV) in the same cells. Nonselective CaCC inhibitors (tannic acid>CaCCinh-A01) and transient Ano6 knockdown strongly inhibited ionomycin-activated currents, ICl,Swell and the regulatory volume response to hyposmotic swelling. Ionomycin activates CaCCs associated with net cation movement in TM cells. These currents, ICl,Swell, and cell volume are regulated by Ano6. The findings suggest a novel clinically-relevant approach for altering cell volume, and thereby outflow resistance, by targeting Ano6.


"Conversational Advice": A mixed-methods analysis of medical residents' experiences co-managing primary care patients with behavioral health providers.
When integrated behavioral health clinicians (IBHCs) and residents co-manage patients, residents may learn new approaches. We aimed to understand the effect of co-management on residents' behavioral health (BH) management learning. Residents completed a web-based survey enquiring: whether co-management included a shared visit and/or face-to-face meeting with an IBHC, whether residents received feedback from the IBHC, and what they learned. Qualitative responses were coded thematically using a constant comparative method. Among 117 respondents (overall response rate 72%, 117/163), from five residencies recruited from 40 residencies with BH integration, residents were significantly more likely to receive feedback if they had a shared visit with the patient and an IBHC (yes 69% vs. no 33%; adjusted OR 3.0, 95% CI 1.2-7.6). Residents reported three major learning themes: interpersonal communication skills awareness, BH skills awareness, and newly adopted attitudes toward BH. Residents who received feedback were more likely to report themes of interpersonal communication skills awareness (yes 26.6% vs. no 9.4%). BH integration promotes increased feedback for residents practicing face-to-face co-management with IBHCs, and a positive influence regarding residents' attitudes and perceived skills. Residency programs can meaningfully improve residents' learning by promoting face-to-face co-management with IBHCs.


Effects of Electroacupuncture on Alleviating Prostatodynia and Inflammation in Rats with Chronic Nonbacterial Prostatitis.
Chronic prostatitis (CP) is a common urinary disease characterized by a complex sequence of symptoms including prostatodynia, which results in significant physical pain and mental burden to affected patients. Currently, CP has no standard treatment. Thus, physical therapy electroacupuncture (EA) which has been successful in treating several inflammation-related pain conditions was used to determine its effect on rats with CP. Rats were castrated and treated with beta-estradiol for 28 days for CP modeling, and EA was initiated one week after. Following three weeks of treatment, pain-related behavioral testing, mechanical withdrawal threshold, and potential histopathological mechanisms were examined. EA treatment produced a significant antinociceptive effect, effectively increasing the pain threshold of CP rats, and the biochemical results revealed significantly lowered prostatic specific antigen levels. Histopathological results also demonstrated that EA exerted protective properties on prostate morphological changes, as well as decreased inflammation cytokines and oxidative stress molecular expressions in prostate tissue. Furthermore, EA alleviated microglial and astrocyte activation in the dorsal horn of the spinal cord, decreasing CXC motif ligand 1 expressions in activated spinal astrocytes. In conclusion, it was demonstrated that EA alleviated CP-induced pain, which was partly achieved by the downregulation of inflammation, oxidative stress, and spinal cord glial activation.


Subunit-specific mutational analysis of residue N348 in HIV-1 reverse transcriptase.
N348I in HIV-1 reverse transcriptase (RT) confers resistance to zidovudine (AZT) and nevirapine. Biochemical studies demonstrated that N348I indirectly increases AZT resistance by decreasing the frequency of secondary ribonuclease H (RNase H) cleavages that reduce the RNA/DNA duplex length of the template/primer (T/P) and diminish the efficiency of AZT-monophosphate (MP) excision. By contrast, there is some discrepancy in the literature in regard to the mechanisms associated with nevirapine resistance: one study suggested that it is due to decreased inhibitor binding while others suggest that it may be related to the decreased RNase H cleavage phenotype. From a structural perspective, N348 in both subunits of RT resides distal to the enzyme's active sites, to the T/P binding tract and to the nevirapine-binding pocket. As such, the structural mechanisms associated with the resistance phenotypes are not known. Using a novel modelled structure of RT in complex with an RNA/DNA T/P, we identified a putative interaction between the β14-β15 loop in the p51 subunit of RT and the RNA template. Substitution of the asparagine at codon 348 in the p51 subunit with either isoleucine or leucine abrogated the observed protein-RNA interaction, thus, providing a possible explanation for the decreased RNase H phenotype. By contrast, alanine or glutamine substitutions exerted no effect. To validate this model, we introduced the N348I, N348L, N348A and N348Q mutations into RT and purified enzymes that contained subunit-specific mutations. N348I and N348L significantly decreased the frequency of secondary RNase H cleavages and increased the enzyme's ability to excise AZT-MP. As predicted by the modelling, this phenotype was due to the mutation in the p51 subunit of RT. By contrast, the N348A and N348Q RTs exhibited RNase H cleavage profiles and AZT-MP excision activities similar to the wild-type enzyme. All N348 mutant RTs exhibited decreased nevirapine susceptibility, although the N348I and N348L mutations conferred higher fold resistance values compared to N348A and N348Q. Nevirapine resistance was also largely due to the mutation present in the p51 subunit of RT. This study demonstrates that N348I-mediated AZT and nevirapine resistance is due to the mutation in the p51 subunit of RT.


Cyanobacterial bloom significantly boosts hypolimnelic anammox bacterial abundance in a subtropical stratified reservoir.
The degradation of freshwater quality induced by cyanobacterial blooms is a major global environmental concern. Microbially driven nitrogen removal could alleviate eutrophication to some degree in freshwater ecosystems. However, the response of anaerobic ammonium oxidizing (anammox) bacterial communities to cyanobacterial blooms remains poorly understood, especially in reservoir ecosystems. Here we compared the dynamics of anammox bacterial communities during and after a cyanobacterial bloom in a subtropical reservoir. Our data showed that a cyanobacterial bloom triggered a significant increase in bottom anammox bacterial abundance. During the bloom period, anammox bacterial abundance in bottom waters was 9-fold and 52-fold higher compared with non-bloom stratification and mixing periods, respectively. The community composition of anammox bacteria in surface waters changed substantially accompanied by the disappearance of the cyanobacterial bloom, and a shift of dominance from unidentified anammox genera to Ca. Brocadia was observed. Although Ca. Brocadia was always predominant in both middle and bottom waters, the non-bloom period had more unique taxa than the bloom period. Cyanobacterial bloom-related changes in environmental conditions (e.g. NH4-N and total organic carbon) and water stratification together influenced the distribution and dynamics of anammox bacteria. Altogether, our study lays the basis for a better understanding of the breakdown of cyanobacterial blooms in a stratified reservoir.


Integrating medical abortion into safe abortion services: experience from three pilot sites in South Africa.
South Africa's Choice on Termination of Pregnancy Act of 1996 provides for safe termination of pregnancy (TOP) in designated facilities in the public and private health sectors. In 2001, mifepristone-misoprostol medical abortion was approved for TOP up to 56 days, but this method is not yet available in the public sector. Information on the operational requirements for integrating mifepristone-misoprostol medical abortion into South Africa's public sector safe abortion services is required to guide policy decisions. This study trained health workers to provide medical abortion to 290 women attending three TOP sites. Prospective data were collected to ascertain women's experience of the method, pregnancy outcome, women's and provider's acceptability of the method, and the operational requirements for providing medical abortion. Twenty-nine (10%) women were lost to follow-up; 261 (90%) women had a confirmed abortion outcome, of whom 93% had a complete abortion. Given the option, the vast majority of women opted to use misoprostol at home. No serious side effects were reported; pain (66%), and heavy bleeding (67%) were the most common side effects. Most (96%) women were very satisfied with the experience. Health providers were satisfied with providing medical abortion and recommended its introduction to complement existing surgical TOP services. This study demonstrates that integration of medical abortion into public sector services is feasible. The results of this study will guide policy decisions about integrating medical abortion into South Africa's public sector safe abortion services, within the context of the existing enabling legislative framework.


Rapid adhesion of nerve cells to muscle fibers from adult rats is mediated by a sialic acid-binding receptor.
Single viable muscle fibers isolated from adult rats by collagenase digestion rapidly bind dissociated spinal neurons or PC-12 cells but not a variety of other cells tested. The adhesion process is calcium-independent, temperature-sensitive, and is not blocked by pretreating cells with inhibitors of energy metabolism or actin polymerization. Adhesion is mediated by a carbohydrate-binding protein and can be inhibited by N-acetylneuraminic acid or mucin, a glycoprotein with high sialic acids content. The hapten inhibitors do not dissociate cells if added after aggregation has occurred. Experiments to block adhesion by pretreatment of cells with either neuraminidase or mucin show that the sialic acids-rich moiety is on the nerve cells, while its receptor is on the muscle fibers.