Domain mapping of the photoaffinity drug-binding sites in P-glycoprotein encoded by mouse mdr1b.
P-glycoprotein is an energy-dependent drug efflux pump with broad specificity for hydrophobic antitumor agents such as vinblastine, doxorubicin, and taxol. We have previously shown that [3H]azidopine and [125I] iodoaryl azidoprazosin, which are photoaffinity probes for the alpha 1-subunit of the L-type calcium channel and alpha 1-adrenergic receptor, respectively, specifically interact with P-glycoprotein, partially reverse multidrug resistance, and bind to a 6-kDa common domain in the 140-kDa P-glycoprotein molecule (Greenberger, L., Yang, C.-P. H., Gindin, E., and Horwitz, S. B. (1990) J. Biol. Chem. 265, 4394-4401). An immunological approach was used to identify the position of photoaffinity drug-binding domains in P-glycoprotein. Analysis was done with a series of site-specific rabbit polyclonal antibodies to peptides that mimic domains in the mouse mdr1b gene product. The antibodies were made against amino acid residues 269-284, 356-373, 665-682, 740-750, 907-924, and 1203-1222. Upon trypsin digestion, cleavage products of 95 and 55 kDa were obtained, which after further digestion migrated at 60 and 40 kDa, respectively. The 40-kDa fragment was recognized by the antibodies to residues 1203-1222 and 919-1276, while the 55-kDa fragment was recognized by these antibodies plus antibodies to residues 740-750 and 907-924. In contrast, the 95- and 60-kDa trypsin fragments were recognized only by the antibody to residues 269-284. The 55- and 40-kDa fragments, as well as the 95- and 60-kDa fragments, were major photolabeled species after digestion of P-glycoprotein. The previously identified 6-kDa photo-labeled P-glycoprotein fragment was within the 40-kDa trypsin fragment. These data suggest that there are two photoaffinity drug-binding domains in P-glycoprotein encoded by mouse mdr1b. The C-terminal site most likely resides within or in close proximity to putative transmembrane domains 11-12.


pH-Sensitive Polymeric Nanoparticles Fabricated by Dispersion Polymerization for the Delivery of Bioactive Agents.
Development of pH-responsive nanoparticles capable of rapid degradation in the acidic environments in the endosomes and lysosomes of tumor tissues but relatively more stable in the physiological pH (pH 7.4) is desirable. To show that the number of methoxy groups on the benzene ring of benzaldehyde bisacrylate acetal crosslinkers should affect the rate of hydrolysis of the crosslinkers and in vitro availability of the drug loaded into the nanoparticles. Three pH-sensitive acetal crosslinkers were synthesized and characterized by 1H NMR, 13C NMR, FT-IR and high resolution mass spectroscopy (HR-MS). The nanoparticles were fabricated by free-radical dispersion polymerization method. Hydrolysis studies were carried out on the crosslinkers and nanoparticles; drug release studies were done on docetaxel-loaded nanoparticles at pH 5.0 and pH 7.4. The statisitical experimental design was randomized complete block design followed by analyses of variance with F-test of significance. Pairwise comparison test was used to locate specific differences among parameters of the crosslinkers and the nanopaticles. Scanning electron micrographs showed the formation of spherical particles. Particle size analysis showed that the nanoparticles are within nanosize range with negative zeta potential. Data showed that the rate of hydrolysis and drug release were faster at pH 5.0 compared to pH 7.4. Hydrolysis and drug release studies were dependent on the structure of the acetals: Di(2-methacryloyloxyethoxy)- [2,4,6-trimethoxyphenyl] methane crosslinker showed the fastest rate of hydrolysis, followed by di(2- methacryloyloxyethoxy)-[2,4-dimethoxyphe-nyl] methane and di(2-methacryloyloxyethoxy)-[4-methoxyphenyl] methane. The pH-responsive nanoparticles are suitable for the delivery of bioactive agents, especially anticancer drugs.


Chronic renal allograft rejection and clinical trial design.
Both the choice of endpoints and the selection of patients will be critical study design features in randomized controlled trials needed to test the effectiveness of treatments for chronic renal allograft rejection. We examined the feasibility of carrying out clinical trials with different endpoints and patient inclusion criteria by analyzing data from a population of 627 cadaveric kidney transplant recipients who survived with a functioning allograft for at least six months. Among those who lost grafts to chronic rejection, decreases in renal function of 30% and 60% preceded graft loss by a median of only 1.1 and 0.7 years, respectively, suggesting that little would be gained in a clinical trial that used a predetermined reduction in renal function as a surrogate endpoint. Less clear is whether histologic changes could be used as a surrogate endpoint. At present, graft loss to chronic rejection and graft failure from any cause are the most reliable endpoints. Unfortunately, large numbers of patients are needed to demonstrate clinically relevant therapeutic effects on these endpoints. Limiting enrollment to patients who are at high risk for developing chronic rejection, by selecting patients who already have a decline in renal function, for example, may reduce the number of patients needed in a clinical trial. On the other hand, selecting patients with disease that is too advanced may diminish the effectiveness of therapy. In any case, it is impossible to accurately determine the number of patients needed for a definitive clinical trial without preliminary data demonstrating the expected magnitude of the treatment effect. Thus, well-designed pilot studies are needed to measure possible treatment effects before conducting large-scale clinical trials for chronic renal allograft rejection.


Enhancement of Antituberculosis Immunity in a Humanized Model System by a Novel Virus-Vectored Respiratory Mucosal Vaccine.
The translation of preclinically promising novel tuberculosis vaccines to ultimate human applications has been challenged by the lack of animal models with an immune system equivalent to the human immune system in its genetic diversity and level of susceptibility to tuberculosis. We have developed a humanized mice (Hu-mice) tuberculosis model system to investigate the clinical relevance of a novel virus-vectored (VV) tuberculosis vaccine administered via respiratory mucosal or parenteral route. We find that VV vaccine activates T cells in Hu-mice as it does in human vaccinees. The respiratory mucosal route for delivery of VV vaccine in Hu-mice, but not the parenteral route, significantly reduces the humanlike lung tuberculosis outcomes in a human T-cell-dependent manner. Our results suggest that the Hu-mouse can be used to predict the protective efficacy of novel tuberculosis vaccines/strategies before they proceed to large, expensive human trials. This new vaccine testing system will facilitate the global pace of clinical tuberculosis vaccine development.


Psychiatric home care: a new tool for crisis intervention.
The cost of psychiatric care has been rapidly increasing in recent years. Between 1984 and 1987, there was a 46 percent increase in psychiatric hospitals beds and a 60 percent increase in psychiatric units in general hospitals. This reflected a recognition by many health care systems that psychiatric patients were a good source of revenue. With this push toward more and more inpatient programs, crucial aspects of psychiatric care were left behind. Specifically, the limitations of inpatient therapy have not been recognized. Within the past five years, a new program has been developed and pioneered to use home care to prevent psychiatric hospitalizations and to also prevent the difficult transitions for psychiatric patients. Over a two-year period, this program was studied for its impact on the quality and cost of psychiatric care.


Partially hydrolyzed polyacrylamide: enhanced oil recovery applications, oil-field produced water pollution, and possible solutions.
Polymers, such as partially hydrolyzed polyacrylamide (HPAM), are widely used in oil fields to enhance or improve the recovery of crude oil from the reservoirs. It works by increasing the viscosity of the injected water, thus improving its mobility and oil recovery. However, during such enhanced oil recovery (EOR) operations, it also produces a huge quantity of water alongside oil. Depending on the age and the stage of the oil reserve, the oil field produces ~ 7-10 times more water than oil. Such water contains various types of toxic components, such as traces of crude oil, heavy metals, and different types of chemicals (used during EOR operations such as HPAM). Thus, a huge quantity of HPAM containing produced water generated worldwide requires proper treatment and usage. The possible toxicity of HPAM is still ambiguous, but its natural decomposition product, acrylamide, threatens humans' health and ecological environments. Therefore, the main challenge is the removal or degradation of HPAM in an environmentally safe manner from the produced water before proper disposal. Several chemical and thermal techniques are employed for the removal of HPAM, but they are not so environmentally friendly and somewhat expensive. Among different types of treatments, biodegradation with the aid of individual or mixed microbes (as biofilms) is touted to be an efficient and environmentally friendly way to solve the problem without harmful side effects. Many researchers have explored and reported the potential of such bioremediation technology with a variable removal efficiency of HPAM from the oil field produced water, both in lab scale and field scale studies. The current review is in line with United Nations Sustainability Goals, related to water security-UNSDG 6. It highlights the scale of such HPAM-based EOR applications, the challenge of produced water treatment, current possible solutions, and future possibilities to reuse such treated water sources for other applications.


Medical management of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop.
Primary hyperparathyroidism (PHPT) is a common endocrine disorder that is frequently asymptomatic. The 2002 International Workshop on Asymptomatic PHPT addressed medical management of asymptomatic PHPT and summarized the data on nonsurgical approaches to this disease. At the Third International Workshop on Asymptomatic PHPT held in May 2008, this subject was reviewed again in light of data that have since become available. We present the results of a literature review of advances in the medical management of PHPT. A series of questions was developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies evaluating the management of PHPT with bisphosphonates, hormone replacement therapy, raloxifene, and calcimimetics was conducted. Existing guidelines and recent unpublished data were also reviewed. All selected relevant articles were reviewed, and the questions developed by the International Task Force were addressed by the Consensus Panel. Bisphosphonates and hormone replacement therapy are effective in decreasing bone turnover in patients with PHPT and improving bone mineral density (BMD). Fracture data are not available with either treatment. Raloxifene also lowers bone turnover in patients with PHPT. None of these agents, however, significantly lowers serum calcium or PTH levels. The calcimimetic cinacalcet reduces both serum calcium and PTH levels and raises serum phosphorus. Cinacalcet does not, however, reduce bone turnover or improve BMD. Bisphosphonates and hormone replacement therapy provide skeletal protection in patients with PHPT. Limited data are available regarding skeletal protection in patients with PHPT treated with raloxifene. Calcimimetics favorably alter serum calcium and PTH in PHPT but do not significantly affect either bone turnover or BMD. Medical management of asymptomatic PHPT is a promising option for those who are not candidates for parathyroidectomy.


Introduction to causal diagrams for confounder selection.
In respiratory health research, interest often lies in estimating the effect of an exposure on a health outcome. If randomization of the exposure of interest is not possible, estimating its effect is typically complicated by confounding bias. This can often be dealt with by controlling for the variables causing the confounding, if measured, in the statistical analysis. Common statistical methods used to achieve this include multivariable regression models adjusting for selected confounding variables or stratification on those variables. Therefore, a key question is which measured variables need to be controlled for in order to remove confounding. An approach to confounder-selection based on the use of causal diagrams (often called directed acyclic graphs) is discussed. A causal diagram is a visual representation of the causal relationships believed to exist between the variables of interest, including the exposure, outcome and potential confounding variables. After creating a causal diagram for the research question, an intuitive and easy-to-use set of rules can be applied, based on a foundation of rigorous mathematics, to decide which measured variables must be controlled for in the statistical analysis in order to remove confounding, to the extent that is possible using the available data. This approach is illustrated by constructing a causal diagram for the research question: 'Does personal smoking affect the risk of subsequent asthma?'. Using data taken from the Tasmanian Longitudinal Health Study, the statistical analysis suggested by the causal diagram approach was performed.


Gene signature of stromal cells which support dendritic cell development.
Spleen stromal cells are critical determinants of dendritic cell (DC) development in spleen. The spleen stromal line, namely STX3, supports DC differentiation in vitro from overlaid bone marrow cells while the lymph node stromal line, namely 2RL22, does not. Here we have characterised the hematopoietic support capacity of each stroma, and analysed lineage origin of the stromal cell lines by gene profiling using microarrays. Stromal co-culture experiments were performed using bone marrow cells as a source of hematopoietic progenitors. A characteristic immature myeloid-like CD11c(+)CD11b(+)CD86(+)MHC-II(/lo)B220()CD8alpha() DC is produced after 14 days in STX3 cocultures, while 2RL22 cocultures produce only monocyte/macrophage-like cells. No other hematopoietic cell type is produced. The STX3 and 2RL22 stroma were compared by transcriptome analysis utilising Affymetrix Murine U74Av2 genechips to identify gene expression related to differential hematopoietic support function. Data mining was used to determine cell surface marker expression reflecting endothelial cells and fibroblasts, as well as adhesion molecules contributing to the microenvironment. STX3 shows gene expression reflective of early endothelial cells, while 2RL22 expresses markers specific to fibroblasts. The expression of genes like Flt1, CD34, Mcam, and Eng distinguishes STX3 as an early immature endothelial cell lacking markers of angioblasts or hemangioblasts like Tal1/SCL, Tie1, Tie2, Kdr or Prom1/AC133. The absence of expression of genes like Vwf and Cd31 distinguishes STX3 from fully differentiated vascular endothelial cells. In contrast, the 2RL22 lymph node stroma specifically expresses genes related to fibroblastic-like cells like osteoblasts with expression of Vdr (Vitamin D receptor), and epithelial cells with expression of Krt13 (keratins). Gene expression data identifies STX3 as splenic endothelial cells, independently able to support the outgrowth of immature, myeloid DC-like cells from progenitors present in bone marrow, while 2RL22 lymph node fibroblastic cells provide support for development of monocytes/macrophages.


Fast quantification of extracellular vesicles levels in early breast cancer patients by Single Molecule Detection Array (SiMoA).
Preliminary reports suggest that extracellular vesicles (EVs) might be a promising biomarker for breast cancer (BC). However, the quantification of plasmatic levels of EVs is a complex task. To overcome these limitations, we developed a new, fast, and easy to use assay for the quantification of EVs directly in plasma based on the use of Single-Molecule Array (SiMoA). By using SiMoA to identify CD9+/CD63+ EVs, we analyzed plasma samples of 181 subjects (95 BC and 86 healthy controls, HC). A calibration curve, made of a serial dilution of lyophilized standards from human plasma, was used in each run to ensure the obtainment of quantitative results from the assay. In a subgroup of patients, EVs concentrations were estimated in plasma before and after 30 days from cancer surgery. Additional information on the size of EVs were also acquired using a Nanosight system to obtain a clearer understanding of the mechanism underlying the releases of EVs associated with the presence of cancer. The measured levels of EVs resulted significantly higher in BC patients (median values 1179.1 ng/µl vs 613.0 ng/µl, p < 0.0001). ROC curve was used to define the optimal cut-off level of the test at 1034.5 ng/µl with an AUC of 0.75 [95% CI 0.68-0.82]. EVs plasmatic concentrations significantly decreased after cancer surgery compared to baseline values (p = 0.014). No correlation was found between EVs concentration and clinical features of BC. SiMoA assay allows plasmatic EVs levels detection directly without any prior processing. EVs levels are significantly higher in BC patients and significantly decreases after cancer surgery.


Infrared image of venus at the time of pioneer venus probe encounter.
An image of the infrared emission from the Earth-facing hemisphere of Venus was obtained at the time the Pioneer Venus probes penetrated the atmosphere. The thermal structure of the atmosphere at the 85-millibar level included regions of rapidly varying polar features, a solar-related postdawn warm area, and a nonsolar-fixed nighttime warm area. The probes succeeded in entering each of these three thermal regions.


The multifaceted activities of AMPK in tumor progression--why the "one size fits all" definition does not fit at all?
AMP-activated kinase (AMPK) is a central cellular energetic biosensor and regulator of a broad array of cellular metabolic routes activated by nutrient deprivation, mitochondrial dysfunction, oxidative stress, and cytokines. The activation of AMPK maintains ATP levels in response to hypoxia, mitochondrial dysfunction, and shortage of essential metabolic fuels. Activated AMPK turns on energy sparing pathways and promotes antiapoptotic functions thereby permitting cells to survive extremely hostile conditions for prolonged periods of time. Cancer cells in solid tumors are generally subjected to such harsh conditions; however, they manage to efficiently survive and proliferate. This is likely due, in great part, to a peculiar form of metabolism that is heavily reliant on glycolysis and which promotes cancer cell adaptation and tumor progression. AMPK controls the influx and utilization of glucose by cancer cells and therefore has emerged as an attractive target to treat cancer. Investigations exploring this possibility demonstrated that activators or inhibitors of AMPK impact cancer cell viability and possibly cancer progression. For example, the AMPK activator metformin induces apoptosis in a variety of cancer cell lines and models. A major problem with many of the studies on metformin is that little effort has been invested in unraveling how metformin activates AMPK in the many contexts it has been tested. This is significant because many AMPK-independent effects of metformin have been documented. The notion that AMPK acts solely as a tumor suppressor also conflicts with findings that it confers resistance to nutrient deprivation, sustains NADPH levels in cancer cells, facilitates stress-induced gene transcription, promotes cell survival via antiapoptotic function upregulation, intermediates epithelial-to-mesenchymal transition, and increases malignant transformation. These are all recognized steps necessary for the successful evolution of tumors. This review highlights some of these findings and proposes that the role of AMPK in cancer should be reconsidered in light of the complex roles of AMPK under different metabolic conditions.


Crossover scaling of wavelength selection in directional solidification of binary alloys.
We simulate cellular and dendritic growth in directional solidification in dilute binary alloys using a phase-field model solved with adaptive-mesh refinement. The spacing of primary branches is examined for a wide range of thermal gradients and alloy compositions and is found to undergo a maximum as a function of pulling velocity, in agreement with experimental observations. We demonstrate that wavelength selection is unambiguously described by a nontrivial crossover scaling function from the emergence of cellular growth to the onset of dendritic fingers. This result is further validated using published experimental data, which obeys the same scaling function.


Limb salvage in antiphospholipid syndrome with repetitive arterial occlusions.
Outcomes of vascular surgery for patients with primary antiphospholipid syndrome (APS) presenting with acute limb ischaemia (ALI) are poor, with a high rate of postoperative arterial thrombosis and limb amputation. A primary antiphospholipid syndrome 42-year-old male patient presented with acute limb ischaemia. Timely endovascular thrombectomy successfully prevented irreversible tissue damage but failed to maintain this due to recurrent thrombosis. Intensive plasma exchange following repeated endovascular therapy (EVT) ameliorated this thrombotic event. Two weeks post-discharge, thrombotic arterial reocclusion led to readmission and repeated management. Following successful reperfusion, intensive immunosuppressive therapy and anticoagulant agents ensured that the patient was free from recurrent events during the next eight months. This case highlights the combination of endovascular thrombectomy and intensive plasma exchange for limb salvage in such cases.


The Texas health workforce benefit of military physician assistant program veterans.
Little is known about the benefits to society of the educational development of health personnel in the military who return to civilian life and continue their careers. The U.S. Department of Defense has produced physician assistants (PAs) since the early 1970s, and PA training is now consolidated into one location in Texas as the Interservice Physician Assistant Program (IPAP). We studied redistribution of PAs upon service departure to determine if IPAP attendance had an effect on the Texas PA workforce. The Texas Medical Board dataset of licensed PAs was examined to identify program attended, practice specialty by supervising physician designation, practice location, and primary care or specialty care practice designation. Primary care was defined as family medicine, general pediatrics, or general internal medicine. All other designations were classified as specialty practice. Of 6016 licensed Texas PAs, 425 (7.0%) reported attending a military PA training program. Of the 254 PAs in full-time civilian clinical practice, 148 (58.3%) reported practice in primary care settings, and 106 (41.7%) reported specialty clinical practice settings. With the average military officer retirement age of 47 years and the 2010 average U.S. retirement age of 64 years for men and 62 for women, an estimated 16 years of community workforce productivity is provided per veteran PA following completion of military service. We estimated over 47,000 outpatient visits are provided per PA following military service. The care provided can be measured as a positive return-on-investment of taxpayer-provided education.


Pacific kids DASH for health (PacDASH) randomized, controlled trial with DASH eating plan plus physical activity improves fruit and vegetable intake and diastolic blood pressure in children.
Pacific Kids DASH for Health (PacDASH) aimed to improve child diet and physical activity (PA) level and prevent excess weight gain and elevation in blood pressure (BP) at 9 months. PacDASH was a two-arm, randomized, controlled trial (ClinicalTrials.gov: NCT00905411). Eighty-five 5- to 8-year-olds in the 50th-99th percentile for BMI were randomly assigned to treatment (n=41) or control (n=44) groups; 62 completed the 9-month trial. Sixty-two percent were female. Mean age was 7.1±0.95 years. Race/ethnicity was Asian (44%), Native Hawaiian or Other Pacific Islander (28%), white (21%), or other race/ethnicity (7%). Intervention was provided at baseline and 3, 6 and 9 months, with monthly supportive mailings between intervention visits, and a follow-up visit at 15 months to observe maintenance. Diet and PA were assessed by 2-day log. Body size, composition, and BP were measured. The intervention effect on diet and PA, body size and composition, and BP by the end of the intervention was tested using an F test from a mixed regression model, after adjustment for sex, age, and ethnic group. Fruit and vegetable (FV) intake decreased less in the treatment than control group (p=0.04). Diastolic BP (DBP) was 12 percentile units lower in the treatment than control group after 9 months of intervention (p=0.01). There were no group differences in systolic BP (SBP) or body size/composition. The PacDASH trial enhanced FV intake and DBP, but not SBP or body size/composition.


A reassessment of the importance of "low-count" bacteriuria in young women with acute urinary symptoms.
To determine whether a statistical association exists between "low-count" bacteriuria (> 10(2) to 10(4) colony-forming units/mL) and acute urinary symptoms in young women. Prospective, case-control study. Gynecology clinic at a student health center. Women with or without urinary or vaginal symptoms. History of urinary infections and sexual activity. Quantitative determination of bacteriuria and pyuria and bacterial species; urine leukocyte esterase test; specific gravity; creatinine levels; vaginal leukocytes; and in-vitro culture of urine. The frequency of recent sexual activity, pregnancies, and contraceptive practices was not statistically different between women with acute urinary symptoms and asymptomatic controls. Escherichia coli and Staphylococcus saprophyticus were the only microorganisms statistically associated with urinary symptoms and pyuria (P < 0.001). Low counts of these organisms were found in 10.2% of asymptomatic women. As the bacterial count increased, the association between these organisms and symptoms increased, and a step-wise increase occurred in the frequency and magnitude of pyuria, but the specific gravity and urine creatinine levels remained unchanged. Escherichia coli, even at low counts, grew well in the patients' own urine. Pyuria (> 20 leukocytes/mm3) was present in 19.6% of asymptomatic women and was associated with vaginal leukorrhea. "Low-count" bacteriuria was statistically more frequent among young women with urinary symptoms than among asymptomatic controls. The low counts could not be explained by dilution of the urine or failure of the bacteria to grow well in the patients' urine. These findings suggest that the infection was not established in the bladder urine and that "low-count" bacteriuria might be an early phase of urinary tract infection.


Intraoperative cytologic diagnosis of chordoid meningioma. A case report.
Chordoid meningioma is an uncommon supratentorial tumor in which a cordonal pattern on a mucofibrillar background covers areas of classic meningioma with a diffuse, meningeal, immunohistochemically reactive pattern. Its cytology has not been described before. A 45-year-old woman with headaches and a poorly defined, nondiplopic vision alteration underwent magnetic resonance imaging, which showed a tumor in the upper part of the left orbital cavity. An intraoperative squash smear showed closely knit, pseudosyncytial plates composed of medium-sized cells with homogeneous nuclei and nuclear pseudoinclusions. There were some physaliferouslike, loose cells without cytoplasmic vacuolation and a fairly abundant, metachromatic, pink to light purple background that was absent inside the plates. A diagnosis of meningioma with a possible chordoid pattern was made. No frozen intraoperative section was prepared. Histology showed 90% chordoid meningioma merging with areas of classic meningothelial meningioma and overall positivity for epithelial membrane antigen and vimentin. S-100 was negative. A reliable intraoperative cytologic diagnosis of chordoid meningioma can be made because the morphology is highly characteristic. Close cellular association and the cells' nuclear traits are expected in a meningioma. The metachromatic background can cause a false diagnosis of chordoma. However, there are some clear differences in the cells and their relation to the mucofibrillar matrix that make the diagnosis definitive.


Alyssum (Lobularia maritima) selectively attracts and enhances the performance of Cotesia vestalis, a parasitoid of Plutella xylostella.
The use of nectar-providing plants to nourish natural enemies of pest species has become a widely-used approach in conservation biological control to reduce pest damage without the indiscriminate use of insecticides. Choice of plant species is crucial to maximize benefits, but suitable species are yet to be identified for many important crop-pest systems. Here we explored the suitability of three candidate nectar plants for use in brassica vegetables to suppress the globally significant pest, Plutella xylostella L. (Lepidoptera: Plutellidae), using the widely-distributed parasitoid, Cotesia vestalis (Haliday) (Hymenoptera: Braconidae). Volatiles of alyssum (Lobularia maritima (L.) Desv) (Brassicaceae) were attractive to the parasitoid and access to flowering shoots increased adult longevity and realized fecundity of C. vestalis. Moreover, adult diamondback moth derived no benefit from this flower. In contrast, buckwheat (Fagopyrum esculentum Moench) (Polygonaceae), a species widely used in conservation biological control in other systems, increased the longevity and fecundity of both pest and parasitoid, rendering it less suitable. A third plant, heronsbill (Portulaca grandiflora Hook.) (Portulacaceae) denied benefit to the pest and promoted longevity of the parasitoid under no-choice conditions but did not improve fecundity and was repellent to female parasitoids under choice conditions. The contrasting effects of this set of plants illustrate the need to test multiple response variables and effects on both pest and natural enemy when seeking optimal nectar plants for use in a novel conservation biological control system.


[A case of AIDS with disseminated Mycobacterium kansasii infection in which Mycobacterium, avium complex was also detected from his sputum repeatedly].
A 43 year-old Japanese male was admitted to our hospital because of productive cough and fever. He was diagnosed as acquired immunodeficiency syndrome (AIDS) in 1994. Laboratory findings were as follows: WBC was 3200/microliter, CD4+ T lymphocyte count was 22/microliter. His chest X-ray film taken on admission showed infiltration with small cavity lesion in middle left lung field. Tuberculin skin reaction was negative. He was treated with isoniazid 0.4 g, rifampicin 0.45 g, and ethambutol 0.75 g each daily. Sputum smear was positive for acid fast bacilli. The cultured isolates were identified as Mycobacterium kansasii (M. kansasii) and Mycobacterium avium complex (MAC). Urine smear was also positive for acid fast bacilli. The cultured isolates were identified as M. kansasii. He was diagnosed as disseminated M. kansasii infection and suspected MAC infection. About one hundred days later, his chest X-ray film showed reticular shadow. His clinical symptoms improved and the sputum smear and culture converted to negative for acid fast bacilli. Based on these findings, his MAC discharge was considered not as MAC infection, but MAC colonization. He returned to the former hospital for AIDS treatment, and he died in August 1996.


Structural role of Gly(193) in serine proteases: investigations of a G555E (GLY193 in chymotrypsin) mutant of blood coagulation factor XI.
In serine proteases, Gly(193) is highly conserved with few exceptions. A patient with inherited deficiency of the coagulation serine protease factor XI (FXI) was reported to be homozygous for a Gly(555) --> Glu substitution. Gly(555) in FXI corresponds to Gly(193) in chymotrypsin, which is the numbering system used subsequently. To investigate the abnormality in FXI(G193E), we expressed and purified recombinant FXIa(G193E), activated it to FXIa(G193E), and compared its activity to wild type-activated FXI (FXIa(WT)). FXIa(G193E) activated FIX with approximately 300-fold reduced k(cat) and similar K(m), and hydrolyzed synthetic substrate with approximately 10-fold reduced K(m) and modestly reduced k(cat). Binding of antithrombin and the amyloid beta-precursor protein Kunitz domain inhibitor (APPI) to FXIa(G193E) was impaired approximately 8000- and approximately 100000-fold, respectively. FXIa(G193E) inhibition by diisopropyl fluoro-phosphate was approximately 30-fold slower and affinity for p-aminobenzamidine (S1 site probe) was 6-fold weaker than for FXIa(WT). The rate of carbamylation of NH(2)-Ile(16), which forms a salt bridge with Asp(194) in active serine proteases, was 4-fold faster for FXIa(G193E). These data indicate that the unoccupied active site of FXIa(G193E) is incompletely formed, and the amide N of Glu(193) may not point toward the oxyanion hole. Inclusion of saturating amounts of p-aminobenzamidine resulted in comparable rates of carbamylation for FXIa(WT) and FXIa(G193E), suggesting that the occupied active site has near normal conformation. Thus, binding of small synthetic substrates or inhibitors provides sufficient energy to allow the amide N of Glu(193) to point correctly toward the oxyanion hole. Homology modeling also indicates that the inability of FXIa(G193E) to bind antithrombin/APPI or activate FIX is caused, in part, by impaired accessibility of the S2' site because of a steric clash with Glu(193). Such arguments will apply to other serine proteases with substitutions of Gly(193) with a non-glycine residue.


Is minimally invasive orthopedic surgery safer than open? A systematic review of systematic reviews.
To assess the safety of minimally invasive surgery (MIS) for orthopedic spinal, upper limb and lower limb procedures, this systematic review of systematic reviews compared their complications with open procedures. A literature search was conducted electronically (PubMed, Cochrane library and Web of Science; May 8, 2021) without language restriction in the past five years. Reviews that consulted at least two databases, compared MIS with open orthopedic surgery, and reported the following: intraoperative, post-operative or total complications, function, ambulation, pain, hospital stay, reoperation rate and operation time were included. Article selection, quality assessment using AMSTAR-2, and data extraction were conducted in duplicate on predesigned forms. In each review, a subset analysis focusing on prospective cohort and randomized studies was additionally performed. CRD42020178171. The search yielded 531 articles from which 76 reviews consisting of 1104 primary studies were included. All reviews were assessed as being low quality. Compared to open surgery, MIS had fewer total, postoperative and intraoperative complications in 2/10, 2/11 and 2/5 reviews of spinal procedures respectively, 1/3, 1/4 and 1/2 reviews of upper limb procedures respectively, and 4/6, 2/7 and 0/2 reviews of lower limb procedures respectively. MIS had greater overall safety compared to open surgery in spinal procedures. In upper limb and lower limb procedures, MIS was not outright superior to open procedures in terms of safety hence a general preference of MIS is not justified on the premise of a better safety profile compared to open procedures.


Clinical challenges associated with the endovascular treatment of acute stroke in a patient with infective endocarditis.
Although stroke is common in infective endocarditis (IE), only 26 cases of thrombectomy have been reported to date for IE-related acute stroke. We report a 40-year-old man who presented with left middle cerebral artery occlusion of unknown cause. Multiple attempts of mechanical aspiration thrombectomy and stentrievers failed to recanalize the artery. Effective revascularization was eventually achieved by placing a self-expanding intracranial stent. Post-procedurally the patient was diagnosed with IE with mitral valve insufficiency, mandating emergent valvular replacement while the patient was still on tirofiban infusion. On follow-up, the patient had a modified Rankin's score of 0, had no recurrent stroke, and the intracranial stent remained patent yet stenosed. Based on the use of a self-expanding intracranial stent in the setting of IE, we discuss the consequences of the fibrotic and inflammatory content of the embolus and the associated high risk of intracranial hemorrhage which complicates clinical decision making.


Improved cholesterol phenotype analysis by a model relating lipoprotein life cycle processes to particle size.
Increased plasma cholesterol is a known risk factor for cardiovascular disease. Lipoprotein particles transport both cholesterol and triglycerides through the blood. It is thought that the size distribution of these particles codetermines cardiovascular disease risk. New types of measurements can determine the concentration of many lipoprotein size-classes but exactly how each small class relates to disease risk is difficult to clear up. Because relating physiological process status to disease risk seems promising, we propose investigating how lipoprotein production, lipolysis, and uptake processes depend on particle size. To do this, we introduced a novel model framework (Particle Profiler) and evaluated its feasibility. The framework was tested using existing stable isotope flux data. The model framework implementation we present here reproduced the flux data and derived lipoprotein size pattern changes that corresponded to measured changes. It also sensitively indicated changes in lipoprotein metabolism between patient groups that are biologically plausible. Finally, the model was able to reproduce the cholesterol and triglyceride phenotype of known genetic diseases like familial hypercholesterolemia and familial hyperchylomicronemia. In the future, Particle Profiler can be applied for analyzing detailed lipoprotein size profile data and deriving rates of various lipolysis and uptake processes if an independent production estimate is given.


Potential clinical applications for high-dose nutritional antioxidants.
High but well-tolerated doses of the nutritional antioxidants selenium and vitamins E and C have significant immunostimulant, anti-inflammatory, and anti-carcinogenic effects which are well documented in the existing biomedical literature. In addition, these antioxidants help to protect the structural integrity of ischemic or hypoxic tissues, and may have useful anti-thrombotic actions as well. Supplementation with high-dose nutritional antioxidants may eventually gain a broad role in the prevention, treatment, or palliation of cancer, cardiovascular disease, infection, inflammatory disorders, and certain diabetic complications.


Arthroscopic subacromial decompression: results in advanced impingement syndrome.
A study group composed of 25 shoulders in 24 patients underwent arthroscopic subacromial decompression for advanced impingement syndrome. There were no full thickness rotator cuff tears, biceps tendon ruptures, significant acromioclavicular arthrosis, or evidence of glenohumeral instability. Twenty men and four women ranging in age from 18 to 63 years (mean age 37) with dominant arm involvement in 17/24 were evaluated for an average follow-up of 20.3 months (range 14-32) postoperatively. Operative results were based on the UCLA shoulder rating scale. Eighty-eight percent of the cases (22/25) had good or excellent results. Twelve percent had fair results (3/25). There were no poor results. The average UCLA pain score improved from 2.6 preoperative (constant pain) to 7.8 postoperative (occasional pain). Ninety-two percent of the patients were satisfied, said they were better, and that they would have the surgery again. Arthroscopic subacromial decompression is recommended as an alternative to open anterior acromioplasty in advanced impingement syndrome.


Ctp1 protein-DNA filaments promote DNA bridging and DNA double-strand break repair.
The Ctp1 protein in Schizosaccharomyces pombe is essential for DNA double-strand break (DSB) repair by homologous recombination. Fission yeast Ctp1 and its budding yeast (Sae2) and human (CtIP) homologs control Mre11-Rad50-Nbs1 nuclease complex activity and harbor DNA-binding and -bridging activities. However, the molecular basis for Ctp1-DNA transactions remains undefined. Here, we report atomic force microscopy (AFM) imaging of S. pombe Ctp1-DNA complexes revealing that Ctp1 polymerizes on dsDNA molecules and forms synaptic filaments that bridge two dsDNA strands. We observed that Ctp1 DNA filaments are typified by an average filament length of ∼180 bp of dsDNA and a Ctp1 tetramer footprint of ∼15 bp. Biochemical results characterizing Ctp1 variants with impaired DNA-binding or -bridging properties were consistent with Ctp1-mediated DNA bridging requiring the intact and correctly folded Ctp1 tetramer. Furthermore, mutations altering Ctp1 oligomerization and DNA bridging in vitro conferred cell sensitivity to DSB-producing agents. Together, these results support an important role for Ctp1-regulated DNA strand coordination required for DNA DSB repair in S. pombe.


Evidence of elemene injection combined radiotherapy in lung cancer treatment among patients with brain metastases: A systematic review and meta-analysis.
This review evaluates the effectiveness and safety of elemene injection combined radiotherapy in the treatment of lung cancer with brain metastases. A systematic literature research was conducted from EMBASE, Cochrane Library, PubMed, Chinese biomedical database, Chinese scientific journal database, China knowledge resource integrated database, and WanFang Database from established to July 2016 without language restriction. The Cochrane Collaboration tool was used to evaluate the risk of bias. All statistical analyses were conducted with STATA (version 14.0) and RevMan (version 5.3). Eleven randomized controlled trials (765 patients) were included for determining the effectiveness and safety of elemene combined with radiotherapy in the treatment of lung cancer with brain metastases. Objective response rate (ORR) [odds ratio (OR) = 2.89, 95% confidence interval (95% CI) 2.04-4.08, P < .00001] and symptoms (OR = 4.06, 95% CI 2.00-8.25, P = .0001) improved more in the elemene-based combination treatment group than in the radiotherapy-alone control group. The Karnofsky Performance Status (KPS) score was used to measure patients' improvement rate. The patients who were treated with elemene-based combination with radiotherapy were higher than those patients who were treated with radiotherapy alone (OR = 3.51, 95% CI 2.20-5.61, P < .00001]. The incidence of bone marrow suppression (OR = 0.27, 95% CI 0.11-0.68, P = .006) and leukopenia (OR = 0.23, 95% CI 0.12-0.46, P < .00001) decreased in the elemene-based combination treatment group by radiotherapy significantly. The elemene injection combined radiotherapy in the treatment of lung cancer with brain metastases appears to improve the treatment response rate and alleviated symptoms. The combined treatment has showed positive impact to reduce adverse reactions and improve quality of life.


Immunogenic profiling in mice of a HIV/AIDS vaccine candidate (MVA-B) expressing four HIV-1 antigens and potentiation by specific gene deletions.
The immune parameters of HIV/AIDS vaccine candidates that might be relevant in protection against HIV-1 infection are still undefined. The highly attenuated poxvirus strain MVA is one of the most promising vectors to be use as HIV-1 vaccine. We have previously described a recombinant MVA expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (referred as MVA-B), that induced HIV-1-specific immune responses in different animal models and gene signatures in human dendritic cells (DCs) with immunoregulatory function. In an effort to characterize in more detail the immunogenic profile of MVA-B and to improve its immunogenicity we have generated a new vector lacking two genes (A41L and B16R), known to counteract host immune responses by blocking the action of CC-chemokines and of interleukin 1beta, respectively (referred as MVA-B DeltaA41L/DeltaB16R). A DNA prime/MVA boost immunization protocol was used to compare the adaptive and memory HIV-1 specific immune responses induced in mice by the parental MVA-B and by the double deletion mutant MVA-B DeltaA41L/DeltaB16R. Flow cytometry analysis revealed that both vectors triggered HIV-1-specific CD4(+) and CD8(+) T cells, with the CD8(+) T-cell compartment responsible for >91.9% of the total HIV-1 responses in both immunization groups. However, MVA-B DeltaA41L/DeltaB16R enhanced the magnitude and polyfunctionality of the HIV-1-specific CD4(+) and CD8(+) T-cell immune responses. HIV-1-specific CD4(+) T-cell responses were polyfunctional and preferentially Env-specific in both immunization groups. Significantly, while MVA-B induced preferentially Env-specific CD8(+) T-cell responses, MVA-B DeltaA41L/DeltaB16R induced more GPN-specific CD8(+) T-cell responses, with an enhanced polyfunctional pattern. Both vectors were capable of producing similar levels of antibodies against Env. These findings revealed that MVA-B and MVA-B DeltaA41L/DeltaB16R induced in mice robust, polyfunctional and durable T-cell responses to HIV-1 antigens, but the double deletion mutant showed enhanced magnitude and quality of HIV-1 adaptive and memory responses. Our observations are relevant in the immune evaluation of MVA-B and on improvements of MVA vectors as HIV-1 vaccines.


ICTV Virus Taxonomy Profile: Potyviridae.
The Potyviridae is the largest family of RNA plant viruses, members of which have single-stranded, positive-sense RNA genomes and flexuous filamentous particles 680-900 nm long and 11-20 nm wide. There are eight genera, distinguished by the host range, genomic features and phylogeny of the member viruses. Genomes range from 8.2 to 11.3 kb, with an average size of 9.7 kb. Most genomes are monopartite but those of members of the genus Bymovirus are bipartite. Some members cause serious disease epidemics in cultivated plants. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Potyviridae, which is available at www.ictv.global/report/potyviridae.


Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse, and recurrence.
In 1988, the MacArthur Foundation Research Network on the Psychobiology of Depression convened a task force to examine the ways in which change points in the course of depressive illness had been described and the extent to which inconsistency in these descriptions might be impeding research on this disorder. We found considerable inconsistency across and even within research reports and concluded that research on depressive illness would be well served by greater consistency in the definition change points in the course of illness. We propose an internally consistent, empirically defined conceptual scheme for the terms remission, recovery, relapse, and recurrence. In addition, we propose tentative operational criteria for each term. Finally, we discuss ways to assess the usefulness of such operational criteria through reanalysis of existing data and the design and conduct of new experiments.


Temporal processing in poor adult readers.
The aim of this study was to investigate the relationships between two different temporal processing tasks and word identification performance in skilled, dyslexic and poor adult readers. In Experiment 1 spatial and temporal sequencing tasks were conducted. It was found that adult dyslexics were significantly less accurate than skilled readers across all conditions in the temporal sequencing task, and when higher numbers of stimuli were presented in the spatial task. Experiment 2 replicated Experiment 1 in the temporal sequencing task and also found that poor readers had significantly higher motion coherence thresholds than those found in the skilled reader group. Ten percent of the variance in coherence thresholds was accounted for by performance on the temporal sequencing task. Multiple regression analyses determined that performance on the two temporal tasks could explain seventy percent of the variance in word identification scores, with the temporal sequencing task making the larger independent contribution. Experiment 3 replicated the findings of Experiment 2, while taking into account IQ, verbal memory and processing speed. Three things were concluded. First, the temporal tasks measure different aspects of temporal processing. The contribution to performance of higher-level perceptual and attentional components of the temporal sequencing task accounts for the relatively weak correlation found between the two measures. While sensory sensitivity to motion is measured at MT, the involvement of this area and PPC in higher-level perceptual and attentional processes is suggested by the findings of this study. Second, the association between temporal sequencing and reading skills may provide a stronger link between neural processing and poor reading skills than basic sensory processing measures alone, suggesting that a sensory magnocellular (M) system deficit cannot fully explain the relationship found between reading and visual neural processing. Third, problems with rapid sequential processing are predicted to be a generalised problem in poor adult readers, whether they are formally classified as dyslexic, or are poor performers on measures of word identification. Temporal processing may follow a distribution similar to that found for word identification skills.


[Effect of the molecular structure of anthracycline compounds on their intercalation into DNA].
Kinetics of interaction of rubomycin, carminomycin, and their C9-analogues with deoxyribonucleic acid have been studied by the stop - flow method. Possible reasons of nonexponentiality of the kinetic curves are discussed. The rate constants of direct and reverse intercalation of the drugs between DNA base pairs were determined and relatively small differences found for various drugs. These data and of equilibrium binding studies of interaction of the antibiotics and their analogs with DNA led to conclusion that C9-modification of anthracyclines has little effect on the binding process. That was confirmed by quantum-mechanic calculations of potential energy of interaction between various anthracycline aglicones and DNA base-pairs.


Spatiotemporal and kinematic adjustments in master runners may be associated with the relative physiological effort during running.
Master runners maintain a similar running economy to young runners, despite displaying biomechanical characteristics that are associated with a worse running economy. This apparent paradox may be explained by a greater physiological effort-i.e., percentage of maximal oxygen uptake (VO2-max)-that master runners perform at a given speed. Moreover, age-related responses to non-exhaustive sustained running are yet underexplored. The aims of this study were, therefore, to examine if biomechanical adjustments in master runners are physiological-effort dependent, and to explore the age-related biomechanical changes during a non-exhaustive sustained run. Young (23.9 ± 6; n = 12) and master (47.3 ± 6.9; n = 12) runners performed a sustained 30-minute treadmill run matched for relative physiological effort (70% VO2-max), while spatiotemporal and lower-limb kinematic characteristics were collected during the 1st and 30th minute. Group differences were observed in step/stride length, knee touch-down angle, and knee stiffness. However, both groups of runners had a similar step frequency, vertical center of mass oscillation, and knee range of motion. Age-related adjustment in these latter characteristics may thus not be an inevitable result of the aging process but rather a strategy to maintain running economy. The relative physiological effort of runners should, therefore, be considered when examining age-related adjustments in running biomechanics.


Brain parenchyma penetration by intrathecal nonionic iopamidol.
Iopamidol, a nonionic, water-soluble contrast medium, has been recently recommended for myelography. As with other such media, the extent of parenchymal penetration is of interest in relation to the genesis of clinical complications. In this study the degree and depth of brain penetration of intrathecal iopamidol, using an iodine concentration of 280 mg l/ml, were compared at 15 and 60 min in adult greyhound dogs using coronal computed tomographic scanning of the brain after removal. A significant but patchy penetration corresponding to the cortical sulci was demonstrated at 15 min, while by 60 min there had been a further increase in the distribution and concentration of the contrast medium. Comparing the present study with a previous series using metrizamide and methylglucamine iothalamate at a similar iodine concentration (280 mg l/ml), no significant difference in the depth or degree of penetration at 60 min was found between the three contrast media, indicating a similar rate of diffusion across the cerebrospinal fluid/brain interface. Therefore, any difference in neurotoxicity is not explained by a reduced concentration of contrast medium due to variation in the rate of diffusion across this interface.


Shades of a color. Illusion or reality?
Attaining the highest clinical level in esthetic and cosmetic dentistry necessitates the development of artistic skills; of balancing illusion with reality. The shade of a tooth is a combination of color and light and varies in different light conditions. Understanding the differences in color shades is the basis to creating illusions. Understanding light and color, and the reality of illusions, allows the clinician to design and sculpt a smile, to modify a flawed display artistically so that patients may perceive it as natural and more attractive, and to design laminates and veneers, class III, class IV, and cervical cavities.


Non-high-density lipoprotein cholesterol is associated more closely with albuminuria in Chinese type 2 diabetic patients with normal renal function, compared with traditional lipid parameters.
Urinary albumin excretion rate (UAER) is a remarkable index reflecting the progression of kidney disease in diabetic subjects. The link between UAER and lipid metabolism is still unclear. The correlation of Apolipoprotein B (ApoB) to albuminuria has been investigated. The National Cholesterol Education Program-Adult Treatment Panel III recommends that clinicians consider non-high-density lipoprotein cholesterol (non-HDL-c) as a surrogate marker for ApoB. We sought to evaluate the relationship of UAER with lipid profile, especially with non-HDL-c in type 2 diabetic patients without renal dysfunction. A total of 507 type 2 diabetic patients with normal renal function participated in this study. Demographic and anthropometric data were collected; 24-hour urine samples were collected for UAER measurement. Blood samples were collected for lipid parameters and HbA1c measurement. The patients with albuminuria had greater levels of non-HDL-c and ApoB. The frequencies of albuminuria among the four quartiles of lipid parameters, ie, triglycerides, total cholesterol, non-HDL-c, and ApoB, demonstrated significantly linearly increasing (P for trend <.01). After adjustment, UAER was significantly correlated with total cholesterol, triglycerides, ApoB, and non-HDL-c but not with low-density lipoprotein cholesterol (LDL-c) or lipoprotein(a) [Lp(a)]. Stepwise regression analysis showed that age (β = .255, P = .000), systolic blood pressure (β = .261, P = .000), non-HDL-c (β = .164, P = .000), and duration of diabetes (β = .105, P = .024) were independently correlated with UAER in diabetic patients without renal dysfunction. Compared with the lipid parameters of total cholesterol, triglycerides, HDL-c, LDL-c, ApoB, Apolipoprotein A-I (ApoA-I), and Lp(a), non-HDL-c was more closely associated with albuminuria in Chinese type 2 diabetic patients without impaired renal function.


ERG deletions in childhood acute lymphoblastic leukemia with DUX4 rearrangements are mostly polyclonal, prognostically relevant and their detection rate strongly depends on screening method sensitivity.
ERG-deletions occur recurrently in acute lymphoblastic leukemia, especially in the DUX4-rearranged subtype. The ERG-deletion was shown to positively impact prognosis of patients with IKZF1-deletion and its presence precludes assignment into IKZF1 plus group, a novel high-risk category on AIEOP-BFM ALL trials. We analyzed the impact of different methods on ERG-deletion detection rate, evaluated ERG-deletion as a potential marker for DUX4-rearranged leukemia, studied its associations with molecular and clinical characteristics within this leukemia subtype, and analyzed its clonality. Using single-nucleotide-polymorphism array, genomic polymerase chain reaction (PCR) and amplicon-sequencing we found ERG-deletion in 34% (16 of 47), 66% (33 of 50) and 78% (39 of 50) of DUX4-rearranged leukemia, respectively. False negativity of ERG-deletion by single-nucleotide-polymorphism array caused IKZF1 plus misclassification in 5 patients. No ERG-deletion was found outside the DUX4-rearranged cases. Within DUX4-rearranged leukemia, the ERG-deletion was associated with higher total number of copy-number aberrations, and, importantly, the ERG-deletion positivity by PCR was associated with better outcome [5-year event-free survival (EFS), ERG-deletion-positive 93% vs. ERG-deletion-negative 68%, P=0.022; 5-year overall survival (OS), ERG-deletion-positive 97% vs. ERG-deletion-negative 75%, P=0.029]. Ultra-deep amplicon-sequencing revealed distinct co-existing ERG-deletions in 22 of 24 patients. In conclusion, our data demonstrate inadequate sensitivity of single-nucleotide-polymorphism array for ERG-deletion detection, unacceptable for proper IKZF1 plus classification. Even using more sensitive methods (PCR/amplicon-sequencing) for its detection, ERG-deletion is absent in 22-34% of DUX4-rearranged leukemia and does not represent an adequately sensitive marker of this leukemia subtype. Importantly, the ERG-deletion potentially stratifies the DUX4-rearranged leukemia into biologically/clinically distinct subsets. Frequent polyclonal pattern of ERG-deletions shows that late origin of this lesion is more common than has been previously described.


Sleep of children with attention deficit hyperactivity disorder: actigraphic and parental reports.
The objectives of this study were to characterize the sleep of children with attention deficit hyperactivity disorder (ADHD), using actigraphy and parental questionnaires, and examine the potentially moderating role of psychostimulant medication and psychiatric comorbidity. Children with ADHD significantly differed from controls on parental and actigraphic measures of sleep, with parental reports indicating more severe sleep disturbances, and actigraphic recordings of longer sleep onset latency, lower sleep efficiency, and lower total sleep time. Both medicated and unmedicated ADHD subgroups differed from the control group on sleep measures, but did not differ from each other. Only the subgroup with comorbid psychiatric symptoms differed from the control group on actigraphic measures. The presence of psychiatric comorbidity, but not psychostimulant medication use, was associated with more severe sleep disturbances. The main implication of these findings is that clinicians should systematically attend to sleep disturbances in children with ADHD, particularly when other psychiatric symptoms are also present.


Diagnosis of coronary vasospasm in patients with clinical presentation of unstable angina pectoris using ergonovine echocardiography.
Although coronary vasospasm can contribute to the development of unstable angina, the definite diagnostic method has not been established. The purpose of this study was to determine if ergonovine echocardiography (detection of regional wall motion abnormality during bedside ergonovine challenge) after angiographic confirmation of insignificant fixed disease would be useful and safe in detecting coronary vasospasm in patients with unstable angina. After control of chest pain with medications in patients admitted to the coronary care unit under the tentative diagnosis of unstable angina, diagnostic coronary angiography was performed. All patients with normal or insignificant fixed disease underwent ergonovine echocardiography after discontinuation of medications for 4+/-1 days. Among 208 consecutive patients enrolled for this study, 75% (156 of 208) showed significant fixed disease in the angiography. Ergonovine echocardiography was performed in 52 patients with insignificant disease, and coronary vasospasm was documented in 33 (63%, 33 of 52). No serious procedure-related arrhythmia or myocardial infarction occurred. Esophageal motility disorder and hypertrophic cardiomyopathy were diagnosed in 6 and 3 patients, respectively. Chest pain of undetermined etiology was the final diagnosis at discharge in 10 patients (5%, 10 of 208); among them chest pain redeveloped in 2 patients, and repeated ergonovine echocardiography revealed positive results. Our data suggest that among patients with the clinical presentation of unstable angina, coronary vasospasm is the main cause of myocardial ischemia in a considerable number of patients with a normal or near-normal angiogram, and ergonovine echocardiography after confirmation of absence of significant fixed disease is useful and safe for noninvasive diagnosis of coronary vasospasm in this setting.


Ilizarov tibial lengthening in the skeletally immature patient.
We wished to examine the effectiveness of tibial lengthening using a two ring Ilizarov frame in skeletally immature patients. This is a potentially biomechanically unstable construct which risks the loss of axial control. We retrospectively reviewed a consecutive series of 24 boys and 26 girls, with a mean age of 8.6 years (4 to 14), who underwent 52 tibial lengthening procedures with a mean follow-up of 4.3 years (4.0 to 16.9). Tibial alignment was measured before and after treatment using joint orientation lines from the knee and a calculation of the oblique plane axis. The mean percentage length gain was 20% (13 to 31) with a mean bone-healing index (BHI) of 34 days per centimetre (20 to 54). Age at surgery and location of the osteotomy site showed a strong relationship as the location of the osteotomy migrated more proximally with age. However, no significant correlation was found between BHI and the position of the osteotomy. The coronal and sagittal joint orientation of the lengthened tibias were within the normal range in 67% and 92% of cases, respectively. The oblique plane angulation calculation revealed a statistically significant change pre- to post-operatively in both magnitude (p < 0.05) and direction (p < 0.01), but without clinical consequence. The majority of complications were minor (n = 40 in 27 patients; 1.48 complications per segment lengthened) with no residual disability reported. Two-ring tibial lengthening is effective in maintaining segmental alignment, efficient in callous production and relatively comfortable for the patient with few significant complications. Cite this article: Bone Joint J 2016;98-B:1276-82.


Ectopic recurrent craniopharyngioma of the frontal bone.
Ectopic recurrence of craniopharyngioma is a rare phenomenon after transcranial resection of the primary tumor. The authors present a case of ectopic recurrent adamantinomatous craniopharyngioma of the frontal bone resected 16 years after initial transcranial resection of the primary tumor. The lesion was first radiographically described 12 years after surgery and was adjacent to the osteosynthesis plate that had been implanted at the craniotomy site. The recurrent craniopharyngioma was totally resected via a lateral eyebrow approach. No infiltration of the meninges or the brain was detected. Only 50 cases of ectopic recurrent craniopharyngioma have been described to date, with the present case being the first one with recurrence located at the skull bone. So far 2 mechanisms have been described: contamination with tumor cells alongside the surgical tract and spreading via CSF and the subarachnoid space. The authors reviewed the literature, provided the largest collection of cases so far, and performed basic statistical analysis regarding ectopic recurrence. Pediatric and adult patients as well as male and female ones are affected equally by this phenomenon. The mean time of ectopic recurrence after initial surgery was 7.1 years. Ectopic recurrence, although rare, should always be considered in a patient with a newly diagnosed intracranial lesion who has undergone transcranial craniopharyngioma resection before.


Management of Atopic Eczema in primary care.
Introduction : Atopic eczema (AE) is a common inflammatory skin dermatosis that is increasing in prevalence. However, it can present in various clinical presentations, which leads to challenges in the diagnosis and treatment of the condition, especially in a primary care setting. The Clinical Practice Guidelines on the Management of Atopic Eczema was developed by a multidisciplinary development group and approved by the Ministry of Health Malaysia in 2018. It covers the aspects of diagnosis, severity assessment, treatment, and referral.


Effect of Monthly High-Dose Vitamin D Supplementation on Cardiovascular Disease in the Vitamin D Assessment Study : A Randomized Clinical Trial.
Cohort studies have reported increased incidence of cardiovascular disease (CVD) among individuals with low vitamin D status. To date, randomized clinical trials of vitamin D supplementation have not found an effect, possibly because of using too low a dose of vitamin D. To examine whether monthly high-dose vitamin D supplementation prevents CVD in the general population. The Vitamin D Assessment Study is a randomized, double-blind, placebo-controlled trial that recruited participants mostly from family practices in Auckland, New Zealand, from April 5, 2011, through November 6, 2012, with follow-up until July 2015. Participants were community-resident adults aged 50 to 84 years. Of 47 905 adults invited from family practices and 163 from community groups, 5110 participants were randomized to receive vitamin D3 (n = 2558) or placebo (n = 2552). Two participants retracted consent, and all others (n = 5108) were included in the primary analysis. Oral vitamin D3 in an initial dose of 200 000 IU, followed a month later by monthly doses of 100 000 IU, or placebo for a median of 3.3 years (range, 2.5-4.2 years). The primary outcome was the number of participants with incident CVD and death, including a prespecified subgroup analysis in participants with vitamin D deficiency (baseline deseasonalized 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL). Secondary outcomes were myocardial infarction, angina, heart failure, hypertension, arrhythmias, arteriosclerosis, stroke, and venous thrombosis. Of the 5108 participants included in the analysis, the mean (SD) age was 65.9 (8.3) years, 2969 (58.1%) were male, and 4253 (83.3%) were of European or other ethnicity, with the remainder being Polynesian or South Asian. Mean (SD) baseline deseasonalized 25(OH)D concentration was 26.5 (9.0) ng/mL, with 1270 participants (24.9%) being vitamin D deficient. In a random sample of 438 participants, the mean follow-up 25(OH)D level was greater than 20 ng/mL higher in the vitamin D group than in the placebo group. The primary outcome of CVD occurred in 303 participants (11.8%) in the vitamin D group and 293 participants (11.5%) in the placebo group, yielding an adjusted hazard ratio of 1.02 (95% CI, 0.87-1.20). Similar results were seen for participants with baseline vitamin D deficiency and for secondary outcomes. Monthly high-dose vitamin D supplementation does not prevent CVD. This result does not support the use of monthly vitamin D supplementation for this purpose. The effects of daily or weekly dosing require further study. clinicaltrials.gov Identifier: ACTRN12611000402943.


Essential role of Cenexin1, but not Odf2, in ciliogenesis.
Primary cilia are microtubule-based solitary sensing structures on the cell surface that play crucial roles in cell signaling and development. Abnormal ciliary function leads to various human genetic disorders, collectively known as ciliopathies. Outer dense fiber protein 2 (Odf2) was initially isolated as a major component of sperm-tail fibers. Subsequent studies have demonstrated the existence of many splicing variants of Odf2, including Cenexin1 (Odf2 isoform 9), which bears an unusual C-terminal extension. Strikingly, Odf2 localizes along the axoneme of primary cilia, whereas Cenexin1 localizes to basal bodies in cultured mammalian cells. Whether Odf2 and Cenexin1 contribute to primary cilia assembly by carrying out either concerted or distinct functions is unknown. By taking advantage of odf2-/- cells lacking endogenous Odf2 and Cenexin1, but exogenously expressing one or both of these proteins, we showed that Cenexin1, but not Odf2, was necessary and sufficient to induce ciliogenesis. Furthermore, the Cenexin1-dependent primary cilia assembly pathway appeared to function independently of Odf2. Consistently, Cenexin1, but not Odf2, interacted with GTP-loaded Rab8a, localized to the distal/subdistal appendages of basal bodies, and facilitated the recruitment of Chibby, a centriolar component that is important for proper ciliogenesis. Taken together, our results suggest that Cenexin1 plays a critical role in ciliogenesis through its C-terminal extension that confers a unique ability to mediate primary cilia assembly. The presence of multiple splicing variants hints that the function of Odf2 is diversified in such a way that each variant has a distinct role in the complex cellular and developmental processes.


[The enzyme systems of the epithelial and subepithelial layers of the rat small intestine after the transposition of its sections].
At different times after the transposition of the jejunum and ileum of rats bidirectional changes in the mass and activity of digestive enzymes were observed not only in the epithelial but also in the subepithelial layers of various parts of the small intestine and in the duodenal mucosa. The greatest increase in the mucosal mass was revealed in the duodenum. The activity of membrane enzymes changed insignificantly in the epithelial and subepithelial layers. The activity of cytosolic peptidases was increased to the greatest extent in the subepithelial layers of the small intestine, especially at the early terms after surgical interventions. It is concluded, that the enzyme systems (particularly, peptidase) of the subepithelial layers of the small intestine are an integral part of the enzymatic barrier and perform an important protective function.


Annoyance with aircraft noise in local recreational areas and the recreationists' noise situation at home.
Few socioacoustic studies have examined the effect of noise on outdoor recreationists. Most studies concentrate on one setting of the everyday life of a noise-exposed population, which mainly has been the residential setting. This article relates annoyance with aircraft noise in outdoor recreational areas to the recreationists' noise situation at home. In conjunction with the relocation of the main airport of Norway in 1998, field studies were conducted before and after the change in one area near the old airport (1930 survey respondents), and one area near the new airport (1001 survey respondents). Multivariate linear regression analyses of the relationship between annoyance and aircraft noise exposure (LAeq for the aircraft events) in the recreational areas were conducted, controlled for noise annoyance at home, or aircraft noise exposure at home, the situation (before/ after the change), context- and demographic variables. People more highly annoyed at home tended to be more annoyed than others while in the recreational areas. A significant effect of aircraft noise exposure at home on annoyance in the recreational setting was not found. More research is warranted regarding the relationship between noise exposure at home and outdoor recreational demands.


Treatment approaches to major depressive disorder relapse. Part 2: reinitiation of antidepressant treatment.
Anecdotal reports concerning mood disorder patients suggest restarting drug treatment in patients who prematurely discontinue it may be associated with a diminished chance of response upon rechallenge. We evaluated the likelihood of response to reinitiation of fluoxetine treatment in patients relapsing after switching to placebo during a long-term efficacy study of two different dosing regimens of fluoxetine. Patients who met the DSM-IV major depressive disorder criteria with modified HAMD17 scores > or =18 and CGI-Severity scores > or =4 were treated with open-label 20 mg/day fluoxetine for 13 weeks in a multicenter US study. Responders (n = 501) were randomized to placebo, 20 mg fluoxetine daily, or 90 mg enteric-coated fluoxetine weekly for 25 weeks of double-blind continuation treatment. Patients relapsing during the continuation phase were offered 25 weeks of double-blind rescue treatment during which the study medication dose was increased as follows: (1) patients on placebo had treatment with fluoxetine 20 mg/ day reinitiated; (2) patients on fluoxetine 20 mg/day had their dose increased to 40 mg/day, and (3) patients on a 90-mg weekly dose had their dose increased to 90 mg twice a week. Only the results of the rescue phase for the group who relapsed while on continuation treatment with placebo are reported here. Analyses included percentage of responders (50% reduction of modified HAMD17 and CGI-Severity < or =2) and assessments of change from baseline to endpoint (HAMD, CGI-Severity). Safety measures included assessment of vital signs, laboratory measures, and treatment-emergent adverse events. Of 122 patients assigned to placebo, 57 (47%) relapsed during continuation treatment. Fifty-five (96%) of these elected to enter double-blind rescue treatment. Overall, patients who relapsed upon switching to placebo responded well to reinitiation of fluoxetine (62%). The mean modified HAMD17 score decreased from 20 to less than 9 and was maintained for up to 6 months. Thirty-eight percent of patients either did not respond or initially responded but again relapsed after reinitiation of medication. This study suggests that patients who, after an initial response to fluoxetine, relapse upon switching to placebo have a relatively high probability of responding to the reinitiation of fluoxetine treatment. These results challenge the view that the efficacy of an agent prematurely discontinued is diminished when such an agent is restarted. They also generally support reinitiation of the same antidepressant as a 'first-line' treatment strategy in patients who relapsed after stopping a previously effective antidepressant.


Recognition and binding of the human selenocysteine insertion sequence by nucleolin.
Prokaryotic and eukaryotic cells cotranslationally incorporate the unusual amino acid selenocysteine at a UGA codon, which conventionally serves as a termination signal. Translation of selenoprotein gene transcripts in eukaryotes depends upon a "selenocysteine insertion sequence" in the 3'-untranslated region. We have previously shown that DNA-binding protein B specifically binds this sequence element. We now report the identification of nucleolin as a partner in the selenoprotein translation complex. In RNA electromobility shift assays, nucleolin binds the selenocysteine insertion sequence from the human cellular glutathione peroxidase gene, competes with binding activity from COS cells, and shows diminished affinity for probes with mutations in functionally important, conserved sequence elements. Antibody to nucleolin interferes with the gel shift activity of COS cell extract. Antibody to DNA-binding protein B co-extracts nucleolin from HeLa cell cytosol, and the two proteins co-sediment in glycerol gradient fractions of ribosomal high salt extracts. Thus, nucleolin appears to join DNA-binding protein B and possibly other partners to form a large complex that links the selenocysteine insertion sequence in the 3'-untranslated region to other elements in the coding region and ribosome to translate the UGA "stop" codon as selenocysteine.


Effects of ascorbic acid on alkaline phosphatase activity and hormone responsiveness in the osteoblastic osteosarcoma cell line UMR-106.
L-ascorbic acid at physiological concentrations (10 micrograms/ml) increased alkaline phosphatase activity in the osteoblastlike rat osteosarcoma cell line, UMR-106. The increase was dose-dependent and detectable at 6 hours after the addition of 100 micrograms/ml ascorbic acid to the medium. Treatment of the cells with 100 micrograms/ml ascorbic acid potentiated the response of cAMP to both PTH and PGE1, while cell growth was inhibited. Furthermore, the number of colonies formed by the cells grown in the soft agar was significantly reduced by increasing concentrations of ascorbic acid. These results indicate that ascorbic acid might play some role in the differentiation of osteoblasts.


Sonographic diagnosis and outcome of hepatic artery thrombosis after orthotopic liver transplantation in adults.
The objective of our study was to determine the timing and frequency of symptomatic hepatic artery thrombosis in an adult orthotopic liver transplant population, the sensitivity of Doppler sonography for this diagnosis, and the clinical and sonography outcomes in this population. The subjects included all adult recipients with orthotopic liver transplants during a 10.5-year period. A retrospective review of all cases of hepatic artery thrombosis detected on angiography or at surgery was correlated with sonography findings at diagnosis. Clinical and sonography outcomes were recorded. Patients were divided into early (< 1 week) and late hepatic artery thrombosis groups. Hepatic artery thrombosis was considered primary or secondary due to treatment of other hepatic artery complications. Of 522 transplants, 25 (4.8%) developed hepatic artery thrombosis that was primary in 18 (3.5%), with five early (1.0%) and 13 late (2.5%), and secondary in seven (1.3%). Sensitivities of sonography compared with angiography were 100% for detection of early hepatic artery thrombosis and 72.7% for late hepatic artery thrombosis. Seventeen patients (68%) with an episode of hepatic artery thrombosis are currently alive, 11 of whom have irreversible hepatic artery thrombosis; in 10 of the 11 cases, sonography showed that collateral arterial flow had developed. The mean survival was 51.4 months in the patients with irreversible hepatic artery thrombosis, eight of whom had documented biliary or septic complications (or both). Hepatic artery thrombosis is uncommon after liver transplantation in adults. Sonography is extremely sensitive for the detection of hepatic artery thrombosis in symptomatic patients during the immediate postoperative period. Sonography becomes less sensitive as the interval between transplantation and diagnosis of hepatic artery thrombosis increases due to collateral arterial flow. Patients with irreversible hepatic artery thrombosis typically develop interval arterial collaterals that can be seen on sonography. Biliary and septic complications are common but usually are self-limited.


Aqueous-Methanol Extracts of Orange-Fleshed Sweet Potato (Ipomoeabatatas) Ameliorate Oxidative Stress and Modulate Type 2 Diabetes Associated Genes in Insulin Resistant C2C12 Cells.
Edible plants such as sweet potato are sources of natural antioxidants that can be exploited in the management and treatment of insulin resistance. This present study investigated the effects of the extracts of an orange-fleshed sweet potato on oxidative stress biomarkers (glutathione status and lipid peroxidation) and activities of antioxidant enzymes (catalase, CAT and glutathione peroxidase, GPx) in palmitate-induced insulin resistant C2C12 cells. The intracellular antioxidant status of the cells was also measured using Ferric reducing antioxidant power (FRAP) and Trolox equivalent antioxidant capacity (TEAC) assays. Furthermore, this study determined the effect of the extracts on the regulation of some type 2 diabetes associated genes; glucose transporter 4 (glut4), Nuclear respiratory factor 1 (nrf1), Myocyte enhanced factor 2A (mef2a), Carnitine palmitoyltransferase 1 (cpt1) and Acetyl-CoA carboxylase 2 (acc2). The results showed a significant (p < 0.05) increase in intracellular GSH level, a significant reduction in the level of malonaldehyde and a significant improvement in the intracellular antioxidant status upon treatment of the insulin resistant cells with the extracts. The extracts were also able to positively modulate the expression levels of the type 2 diabetes associated genes. On the other hand, HPLC-MS analysis of the extracts showed the presence of polyphenols which could have contributed to the bioactivity of the extracts through their antioxidant effects.


[The analysis of results of laboratory analyses considering the circannual rhythms].
The technique of cosinor-analysis was applied to study the oncological dynamics of hormonal and lipid status, activity of peroxide oxidation of lipids in 580 healthy males and females residing in the Western Siberia. The clear circannual rhythm of gluco-corticoid function of suprarenal glands, insular apparatus and activity of thyroid system, lipid metabolism and half-year periodicity, of activity of lipids peroxide oxidation are detected. The statistically significant differences of number of indicators in various phases of circannual rhythm are established.


Association between intake of sugar-sweetened beverages and circulating 25-hydroxyvitamin D concentration among premenopausal women.
Intake of sugar-sweetened beverages has increased in North America and seems to have several adverse health effects possibly through decreased circulating 25-hydroxyvitamin D (25(OH)D) concentrations. The aim of this cross-sectional study was to evaluate the association between sugar-sweetened beverages intake and 25(OH)D concentrations among premenopausal women. Intake of sugar-sweetened beverages including colas, other carbonated beverages and sweet fruit drinks was assessed using a validated food frequency questionnaire among 741 premenopausal women. Plasma concentrations of 25(OH)D were quantified by radioimmunoassay. The association between sugar-sweetened beverages intake and 25(OH)D concentrations was evaluated using multivariate generalized linear models and Spearman correlations. A higher intake of colas was associated with lower mean 25(OH)D levels (67.0, 63.7, 64.7 and 58.5 nmol/L for never, <1, 1-3 and >3 servings/week, respectively; r = -0.11 (p = 0.004)). A correlation was observed between intake of other carbonated beverages and 25(OH)D concentrations but was not statistically significant (r = -0.06 (p = 0.10)). No association was observed between intake of sweet fruit drinks and 25(OH)D concentrations. This study suggests that high intake of colas may decrease 25(OH)D levels in premenopausal women. Considering the high consumption of these drinks in the general population and the possible consequences of vitamin D deficiency on health, this finding needs further investigation.


Plasma uridine changes in cancer patients treated with the combination of dipyridamole and N-phosphonacetyl-L-aspartate.
Dipyridamole (DP) and N-phosphonacetyl-L-aspartate (PALA) act synergistically in vitro against many cell lines and in vivo against human ovarian carcinoma xenografts. We have conducted a phase I clinical trial of DP p.o. (50 mg/m2, every 6 h) in combination with PALA (starting at 500 mg/m2 i.v. with 300-mg dose escalations). Sixty-five patients were entered into this study, and we have established the maximum tolerated dose of PALA to be 4.5 g/m2 when combined with DP, which is approximately 80% of the previously reported maximum tolerated dose for PALA alone. The observed toxicities of DP plus PALA were mild and were similar to those reported for PALA alone. Bone marrow toxicities were not evident at any PALA dose. Ten patients with a mean pretreatment plasma uridine concentration of 3.49 +/- 1.28 (SD) microM had their plasma uridine reduced to 2.29 +/- 0.70 microM 9 h after DP p.o. A peak plasma DP concentration of 1.86 +/- 0.99 microM was achieved approximately 2 h after p.o. dosing. Nine patients who had a reduced plasma uridine concentration of 2.46 +/- 0.61 microM after 1 week of DP had their plasma uridine further reduced by PALA to 0.87 +/- 0.23 microM 7 h post-PALA. Daily plasma uridine measurements in two patients during their DP treatment confirmed the previously described pattern for Day 1, but the data suggest a slight recovery (15%) in plasma uridine by Day 2. Daily sampling in two other patients after a single PALA dose of 4.2 g/m2 showed that their plasma uridine declined 5 h after the PALA dose and remained depressed for 6 days in one patient and 11 days in the other. These results suggest that DP worked in synergy with PALA to lower circulating uridine in cancer patients. The mechanism for the ability of DP to reduce plasma uridine is not known, but there is evidence that DP can inhibit cellular efflux of uridine as well as its uptake. DP may reduce plasma nucleoside pools in addition to blocking nucleoside salvage and therefore have general applicability in other chemotherapy regimens.


Open Reduction and Internal Fixation of a Middle-Third Clavicle Fracture with a Superior Plate.
Open reduction and internal fixation has become a reliable technique to treat complex middle-third clavicle fractures (AO/OTA B-15). Nonoperative treatment of these fractures may result in higher rates of symptomatic malunion, nonunion, dissatisfaction with cosmetic appearance, and even dysfunction and muscular weakness. Risk factors such as substantial displacement or comminution, far lateral fractures, fractures in the elderly, open fractures, or those occurring in polytrauma scenarios are appropriate indications for surgery. The aim of the procedure is to reconstitute the initial curvature and length of the clavicle, restore a normal connection from the arm to the axial skeleton, and provide stable fixation of the proximal and distal fragments, to allow an immediate full range of motion during rehabilitation. The procedure includes the following steps. Step 1: Place the patient in a beach-chair, semi-sitting position.Step 2: Make a transverse skin incision along the anteroinferior aspect of the clavicle.Step 3: Expose the fracture site, identify and prepare the fragments unless they are comminuted, and preserve soft-tissue attachments to the extent possible.Step 4: Reduce the fragments by direct or indirect manipulation, and maintain the reduction with clamps, Kirschner wires, or mini-fragment plates. Consider bridging comminuted zones to allow secondary fracture-healing.Step 5: Apply a contoured plate to the superior or anterior surface of the clavicle, and obtain at least 6 cortices of fixation on each side with strategic nonlocking and locking screws. The working length of the plate is more important than the number of screws or cortices.Step 6: Obtain a single intraoperative anteroposterior radiograph of the clavicle.Step 7: Separately close the wound in layers (deltotrapezial fascia, platysma, and skin). Apply sterile dressings and a sling. The patient is discharged home on the same day if the injury is isolated, and a full range of motion of the affected shoulder is allowed immediately. The patient is expected to regain full function and strength of the arm once healing occurs.


Role of magnetic resonance neurography in intercostal neuralgia; diagnostic utility and efficacy.
To evaluate the utility and efficacy of MR neurography (MRN) in the diagnostic work-up for intercostal neuralgia and to assess the treatment course and outcomes in MRN-imaged clinically suspected intercostal neuropathy cases of chronic chest and abdominal wall pain syndromes. Following a retrospective cross-sectional study, a consecutive series of patients who underwent MRN of torso for suspected intercostal neuralgia were included. Patient demographics, pain location/level/duration, previous work-up for the same indication, MRN imaging results, and MRN cost per patient were recorded. An inter-reader reliability assessment was performed on the MRN findings using Cohen's weighted κ analysis. Post-MRN treatment choice, as well as success rates of MRN directed perineural injections and surgical management were also evaluated. A total of 28 patients (mean ± SD age, 48.3 ± 18.0 years, female/male = 3.0) were included. Pain and/or numbness in the right upper quadrant were the most common complaints. The mean maximum pain level experienced was 7.4 ± 2.5 on a 1 (lowest pain level) - 10 (highest pain level) visual analog scale. The duration of pain before MRN work-up was 36.9 ± 37.9 months. The patients had seen an average of 5 ± 2.8 physicians for such syndromes. 20 (71%) patients had one or multiple other imaging studies for prior work-up. MRN identified positive intercostal nerve abnormality in 19 cases with clinical symptoms of intercostal neuralgia. From the inter-reader reliability assessment, a Cohen's weighted κ value of 0.78 was obtained. The costs of work-up was about one-third with MRN for diagnostic purposes with less financial and psychological harm. Among the MRN-positive cases, 9/19 patients received perineural injections, of which 6 reported improvement after their first round, lasting an average of 41.1 ± 83 days. Among the nine MRN-negative cases, two received perineural injections, of which none reported improvement. Surgical management was mostly successful with a positive outcome in six out of seven operated cases (85.7%). MRN is useful in diagnostic algorithm of intercostal neuralgia and MRN-positive cases demonstrate favorable treatment response to perineural injections and subsequent surgical management. The use of MRN in intercostal neuralgia is an application that has not been previously explored in the literature. This study demonstrates that MRN offers superior visualization of pathology in intercostal neuralgia and confirms that treatment directed at MRN identified neuropathy results in good outcomes while maintaining cost efficiency.


Optimal outcome measures for detecting clinical benefits of early reperfusion: insights from the DEFUSE Study.
There is no consensus regarding which clinical outcome scales are the most sensitive indicators of early reperfusion in patients with acute stroke. Patients with acute stroke enrolled in the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) study with a perfusion-/diffusion-weighted imaging mismatch at baseline magnetic resonance imaging were studied. Prespecified secondary outcome measures were evaluated at both 30 and 90 days after treatment with intravenous tissue plasminogen activator. A nonparametric recursive partitioning algorithm was also used to identify the optimal dichotomous splits for differentiating patients who experienced early reperfusion from those who did not. In all, 34 of the 74 patients enrolled in DEFUSE met the inclusion criteria for this study. Statistically significant benefits of reperfusion were documented on multiple outcome measures. The most powerful predefined outcome measure was improvement in the National Institutes of Health Stroke Scale (NIHSS) score of greater than or equal to 11 points between baseline and day 90 and/or a day-90 NIHSS score of 0 to 1 (odds ratio 22.5, P = .0021). The recursive partitioning algorithm analysis identified an improvement of greater than or equal to 10 on the NIHSS score between baseline and 30 days and an NIHSS score of less than or equal to 2 at 30 days as optimal end points. For patients with stroke and a perfusion-/diffusion-weighted imaging mismatch treated with intravenous tissue plasminogen activator at 3 to 6 hours, a substantial change in the baseline NIHSS score (> or =10 points) is a potent discriminator of patients who experience early reperfusion from those who do not. In addition, an NIHSS score of less than or equal to 2 appears to be an excellent end point for phase II studies of reperfusion therapies.


A sensitive method for the quantification of short-chain fatty acids by benzyl chloroformate derivatization combined with GC-MS.
Short-chain fatty acids (SCFAs) were identified as critical markers in the diagnosis of chronic and metabolic diseases, but a sensitive and stable method to determine SCFAs in feces is a challenge for analysts due to the high volatility. Herein, a sensitive and accurate method to determine SCFAs adopting precolumn derivatization coupled with gas chromatography-mass spectrometry (GC-MS) has been developed. Benzyl chloroformate (BCF) was chosen as the reaction reagent and emulsified derivatization was applied to homogenize the reaction system. Higher sensitivity, wider application and satisfactory derivatization efficiency were obtained using the developed method. An excellent method validation showed a good linearity ranging from 0.9947 to 0.9998. At the same time, the intra-day and inter-day precision were achieved in the range of 0.56% to 13.07%. The lower limits of detection of all target analytes varied from 0.1 to 5 pg. The recovery ranged from 80.87% to 119.03%, and storage stability under three different conditions was also determined. This method was also successfully applied to the analysis of SCFAs in mice fecal samples to illustrate the significant differences between normal and type 2 diabetes mellitus mice.


Quantitative phosphoproteomics of murine Fmr1-KO cell lines provides new insights into FMRP-dependent signal transduction mechanisms.
Fragile X mental retardation protein (FMRP) is an RNA-binding protein that has a major effect on neuronal protein synthesis. Transcriptional silencing of the FMR1 gene leads to loss of FMRP and development of Fragile X syndrome (FXS), the most common known hereditary cause of intellectual impairment and autism. Here we utilize SILAC-based quantitative phosphoproteomics to analyze murine FMR1(-) and FMR1(+) fibroblastic cell lines derived from FMR1-KO embryos to identify proteins and phosphorylation sites dysregulated as a consequence of FMRP loss. We quantify FMRP-related changes in the levels of 5,023 proteins and 6,133 phosphorylation events and map them onto major signal transduction pathways. Our study confirms global downregulation of the MAPK/ERK pathway and decrease in phosphorylation level of ERK1/2 in the absence of FMRP, which is connected to attenuation of long-term potentiation. We detect differential expression of several key proteins from the p53 pathway, pointing to the involvement of p53 signaling in dysregulated cell cycle control in FXS. Finally, we detect differential expression and phosphorylation of proteins involved in pre-mRNA processing and nuclear transport, as well as Wnt and calcium signaling, such as PLC, PKC, NFAT, and cPLA2. We postulate that calcium homeostasis is likely affected in molecular pathogenesis of FXS.


Antibiotics, bacteria, and antibiotic resistance genes: aerial transport from cattle feed yards via particulate matter.
Emergence and spread of antibiotic resistance has become a global health threat and is often linked with overuse and misuse of clinical and veterinary chemotherapeutic agents. Modern industrial-scale animal feeding operations rely extensively on veterinary pharmaceuticals, including antibiotics, to augment animal growth. Following excretion, antibiotics are transported through the environment via runoff, leaching, and land application of manure; however, airborne transport from feed yards has not been characterized. The goal of this study was to determine the extent to which antibiotics, antibiotic resistance genes (ARG), and ruminant-associated microbes are aerially dispersed via particulate matter (PM) derived from large-scale beef cattle feed yards. PM was collected downwind and upwind of 10 beef cattle feed yards. After extraction from PM, five veterinary antibiotics were quantified via high-performance liquid chromatography with tandem mass spectrometry, ARG were quantified via targeted quantitative polymerase chain reaction, and microbial community diversity was analyzed via 16S rRNA amplification and sequencing. Airborne PM derived from feed yards facilitated dispersal of several veterinary antibiotics, as well as microbial communities containing ARG. Concentrations of several antibiotics in airborne PM immediately downwind of feed yards ranged from 0.5 to 4.6 μg/g of PM. Microbial communities of PM collected downwind of feed yards were enriched with ruminant-associated taxa and were distinct when compared to upwind PM assemblages. Furthermore, genes encoding resistance to tetracycline antibiotics were significantly more abundant in PM collected downwind of feed yards as compared to upwind. Wind-dispersed PM from feed yards harbors antibiotics, bacteria, and ARGs.