Origin of lagrangian intermittency in drift-wave turbulence.
The Lagrangian velocity statistics of dissipative drift-wave turbulence are investigated. For large values of the adiabaticity (or small collisionality), the probability density function of the Lagrangian acceleration shows exponential tails, as opposed to the stretched exponential or algebraic tails, generally observed for the highly intermittent acceleration of Navier-Stokes turbulence. This exponential distribution is shown to be a robust feature independent of the Reynolds number. For small adiabaticity, algebraic tails are observed, suggesting the strong influence of point-vortex-like dynamics on the acceleration. A causal connection is found between the shape of the probability density function and the autocorrelation of the norm of the acceleration.


Quality assessment of child care services in primary health care settings of central karnataka (davangere district).
Infectious disease and malnutrition are common in children. Primary health care came into being to decrease the morbidity. Quality assessment is neither clinical research nor technology assessment. It is primarily an administrative device used to monitor performance to determine whether it continues to remain within acceptable bounds. To assess the quality of service in the delivery of child health care in a primary health care setting. To evaluate client satisfaction. To assess utilization of facilities by the community. Cross-sectional community-based study. Quality assessment was done by taking 30-50%, of the service provider. Client satisfaction was determined with 1 Immunization and child examination-90 clients each. Utilization of services was assessed among 478 households. Proportions, Likert's scale to grade the services and Chi-square. IMMUNIZATION SERVICE: Identification of needed vaccine, preparation and care was average. Vaccination technique, documentation, EPI education, maintenance of cold chain and supplies were excellent. Client satisfaction was good. Growth monitoring: It was excellent except for mother's education andoutreach educational session. Acute respiratory tract infection care: History, physical examination, ARI education were poor. Classification, treatment and referral were excellent. Client satisfaction was good. Diarrheal disease care: History taking was excellent. But examination, classification, treatment, ORT education were poor. Mothers education was not stressed by service providers. Service providers' knowledge do not go with the quality of service rendered. Physical examination of the child was not good. Except for immunization other services were average.


[Mesodermal (Muller) mixed ovarian tumor].
A case of mesodermal (Müller) mixed tumor of the ovary is described. The tumor consisted of the endometrial component with benign epithelial structures, stromal sarcoma, rhabdomyosarcoma, and elements of undifferentiated sarcoma. By its histological structure the tumor may be classified as one of the variants of mesodermal (Müller) mixed tumor of the heterologous adenosarcoma type.


Luman, a new member of the CREB/ATF family, binds to herpes simplex virus VP16-associated host cellular factor.
The human host cell factor (HCF) is expressed in a variety of adult and fetal tissues, and its gene is conserved in animals as diverse as mammals and insects. However, its only known function is to stabilize the herpes simplex virus virion transactivator VP16 in a complex with the cellular POU domain protein Oct-1 and cis-acting regulatory elements in promoters of immediate-early viral genes. To identify a cellular function for HCF, we used the yeast two-hybrid system to identify a cellular ligand for HCF. This protein, Luman, appears to be a cyclic AMP response element (CRE)-binding protein/activating transcription factor 1 protein of the basic leucine zipper superfamily. It binds CREs in vitro and activates CRE-containing promoters when transfected into COS7 cells. This activation of transcription was synergistically enhanced by the presence of CCAAT/enhancer-binding protein elements and inhibited by AP-1 elements in the promoter. In addition to a basic DNA binding domain, Luman possesses an unusually long leucine zipper and an acidic amino-terminal activation domain. These features in Luman are also present in what appear to be homologs in the mouse, Drosophila melanogaster, and Caenorhabditis elegans. Luman and VP16 appear to have similar mechanisms for binding HCF, as in vitro each competitively inhibited the binding of the other to HCF. In transfected cells, however, while VP16 strongly inhibited the ability of GAL-Luman to activate transcription from a GAL4 upstream activation sequence-containing promoter, Luman was unable to inhibit the activity of GAL-VP16. Luman appears to be a ubiquitous transcription factor, and its mRNA was detected in all human adult and fetal tissues examined. The possible role of HCF in regulating the function of this ubiquitous transcription factor is discussed.


Studies on the adsorption of chromium(VI) onto 3-Mercaptopropionic acid coated superparamagnetic iron oxide nanoparticles.
Chromium (Cr) in the form of Cr(VI) is deemed toxic in water due to its mutagenic and carcinogenic properties. For the successful removal of Cr(VI), we demonstrate a novel adsorbent consisting of superparamagnetic iron oxide nanoparticles (SPION) functionalized with 3-Mercaptopropionic acid (3-MPA). Fourier transform infrared spectroscopy (FT-IR) confirmed the functionalization of nanoparticles and presence of sulfonate groups. Batch adsorption experiments showed that the functionalized adsorbent recovered 45 mg of Cr(VI)/g of 3-MPA coated SPION at initial concentration of 50mg/L aqueous solution at pH 1 with less than 1% of Fe dissolution from SPION. The results from X-ray photoelectron spectroscopy confirmed that Cr(VI) chemisorbed onto the adsorbent. Hence, the XPS spectra did not indicate any reduction of Cr(VI) to Cr(III) upon adsorption. The adsorption data were better fitted for the Freundlich model. Moreover, the Cr(VI) adsorption kinetics on functionalized SPION followed a pseudo-second order rate, revealing chemisorption as the dominant mechanism. The high Cr(VI) removal, rapid adsorption kinetics and stability of adsorbent indicate that 3-MPA coated SPION could be an efficient adsorbent for the removal of Cr(VI).


Temporal distribution of peak running demands relative to match minutes in elite football.
The peak match running demands of football (soccer) have been quantified across time durations of 1-10 min, however, little is known as to when the peak match running demands occur within match play. Data were collected from 44 elite footballers, across 68 fixtures (Files = 413, mean ± SD; 11 ± 8 observations per player, range; 1-33), with peak match running demands quantified for each playing half at ten incremental rolling average durations (1 min rolling averages, 2 min rolling averages, etc.). Data were assessed if players completed the full match. Three measures of running performance were assessed total distance (TD), high-speed distance (> 19.8 km · h-1) (HSD) and average acceleration (AveAcc)], with the in-game commencement time of the peak running demands recorded. Descriptive statistics and normality were calculated for each rolling average duration, with the self-containment of shorter rolling average epochs within longer epochs also assessed (e.g. Do the 1 min peak running demands occur within the 10 min peak running demands). Peak TD and AveAcc demands occurred early in each half (median time = 7-17 min and 6-16 min, respectively). Conversely, peak HSD covered was uniformly distributed (Skewness = 0-0.5, Kurtosis = 1.7-2.0). There were low-moderate levels of self-containment for each peak match running period (10-51%), dependent upon metric. Peak match running demands for TD and AveAcc occurred at similar stages of a match where TD and acceleration volumes are typically greatest, whereas peak HSD demands appeared more unpredictable. These timings may help inform training prescriptions in preparation of athletes for competition.


Integrative Oncology's 30-Year Anniversary: What Have We Achieved? A North American Naturopathic Oncology Perspective.
In 1991 the U.S. Congress mandated that the National Institutes of Health (NIH) form the Office of Alternative Medicine to study alternative medical therapies, especially in oncology care. Shortly after, the National Cancer Institute (NCI) created its own division of complementary and alternative medicine (Office of Complementary and Alternative Medicine). At the genesis of the field 30 years ago, what were we hoping to see accomplished by now? In this article we take a look back at milestones, shortfalls and future directions. Exciting opportunities exist to direct our established subspeciality's future directions and we have made valuable advances the field of integrative oncology over the last 30 years: 1, IV high dose ascorbate has clinical research-based applications when used concurrently with some chemotherapeutic agents. 2. Whole body, extracorporeal and locoregional hyperthermia are being applied in treating solid tumors, including brain tumors. 3. PDL-1 tumor microenvironment testing and PDL-1 inhibitor immunotherapies have surprisingly excellent outcomes in a subgroup of cancer patients. 4. Tumor DNA sequencing (resected tumor and circulating tumor DNA in blood) has led to personalized precision targeted treatments. 5. Glucose metabolism's role in cancer progression is better understood and better therapies are available (e.g., intermittent fasting, metformin). 6. Medical cannabis has a larger role in treating chemotherapy-related side effects and shows promise for anti-proliferative effects. 8. Greater understanding has been gained of the interdependence and mutual regulation of processes in psychoneuroendocrinoimmunology (PNEI). The burgeoning field of PNEI has exponentially expanded the discussion of tumorigenesis, apoptosis, and introduced to the field the investigation of more holistic approaches to immune regulation and cancer care. 8. Psychedelic-assisted psychotherapy is gaining traction especially for cancer patients facing demoralization, existential and spiritual distress, anxiety, depression and trauma related to the diagnosis and treatment of their cancer. 9. Spiritual health of cancer patients is more commonly addressed and measurable with an NIH validated scale. 10. Mind-Body therapies are efficacious for reducing cancer-related distress and are included in many cancer care programs.


Coronary Artery Aneurysms in Kawasaki Disease: Risk Factors for Progressive Disease and Adverse Cardiac Events in the US Population.
The natural history of coronary artery aneurysms (CAA) after intravenous immunoglobulin (IVIG) treatment in the United States is not well described. We describe the natural history of CAA in US Kawasaki disease (KD) patients and identify factors associated with major adverse cardiac events (MACE) and CAA regression. We evaluated all KD patients with CAA at 2 centers from 1979 to 2014. Factors associated with CAA regression, maximum CA z-score over time (zMax), and MACE were analyzed. We performed a matched analysis of treatment effect on likelihood of CAA regression. Of 2860 KD patients, 500 (17%) had CAA, including 90 with CAA z-score >10. Most (91%) received IVIG within 10 days of illness, 32% received >1 IVIG, and 27% received adjunctive anti-inflammatory medications. CAA regression occurred in 75%. Lack of CAA regression and higher CAA zMax were associated with earlier era, larger CAA z-score at diagnosis, and bilateral CAA in univariate and multivariable analyses. MACE occurred in 24 (5%) patients and was associated with higher CAA z-score at diagnosis and lack of IVIG treatment. In a subset of patients (n=132) matched by age at KD and baseline CAA z-score, those receiving IVIG plus adjunctive medication had a CAA regression rate of 91% compared with 68% for the 3 other groups (IVIG alone, IVIG ≥2 doses, or IVIG ≥2 doses plus adjunctive medication). CAA regression occurred in 75% of patients. CAA z-score at diagnosis was highly predictive of outcomes, which may be improved by early IVIG treatment and adjunctive therapies.


A stand-alone mesoporous crystal structure model from in situ X-ray diffraction: nitrogen adsorption on 3D cagelike mesoporous silica SBA-16.
We present a modeling scheme to analyze cagelike silica mesoporous crystals based on in situ X-ray diffraction (XRD) data collected during gas adsorption-desorption (physisorption) processes. Nitrogen physisorption on a silica mesoporous crystal of SBA-16 was directly monitored by using synchrotron in situ powder XRD measurements conducted at SPring-8. SBA-16 is a well-ordered mesoporous silica in which three-dimensional interconnected cagelike primary mesopores are located at the body-centered cubic lattice points. In addition, the surrounding silica matrix contains random microporous and mesoporous intrawall porosities that are significantly influential to the diffusion properties, and thus important to be quantified for this media. The in situ XRD data exhibits seven Bragg reflections throughout the measurements, and the present method allows one to obtain the maximal and stand-alone information about the pore structure (for example, the mesopore size, the matrix density, the intrawall porosity, and pore surface roughness) together with the nitrogen film evolution in the primary mesopores and the intrawall pore-filling in the silica matrix. We furthermore observe a macroscopic amount of nitrogen adsorbed assuming the density of the fluid, and confirm that the XRD "isotherm" recalculated from the analysis result is consistent with the conventional nitrogen isotherm on a semi-quantitative level; however, these results suggest that the intrawall pores would have a greater contribution to the adsorption than considered based on the conventional isotherm analyses. The present method is readily extendable to any ordered mesopores wrapped by the wall matrix containing a certain intrawall porosity.


The parturient woman: can there be room for more than 'one person with full and equal rights inside a single human skin'?
The aim of the paper is to raise awareness around the legal and ethical issues involved in the enforcement of caesarean sections on non-consenting women. The paper considers the competing rights of mother and foetus in situations where a mother's wishes may result in harm or death to the foetus. In this light of various court decisions about enforcing caesarean sections, the paper examines the pertinent legal and ethical issues, recognising that health professionals need to operate within an explicit legal and ethical framework. Content. The arguments about a woman's right to autonomous decision-making and a foetus' absolute right to life are examined with the focus throughout being on the legal framework. The need for health professionals to work within this as well as to avoid the temptation to base individual clinical decisions or professional behaviour on subjective moral judgements is emphasized. The attitudes of the judiciary are considered along with recent legal developments. There is an analysis of the way in which established legal principle is sometimes circumvented to override a woman's right to autonomy. The part played by lawyers and health professionals in denying a woman's competence to consent in order to achieve an outcome of which they approve is critically appraised. The basis for the decisions in these cases is deconstructed, along with a discussion of the role of health professionals in contributing to the dilemmas highlighted. It is essential that nurses or midwives caring for pregnant women have a full understanding of the legal and ethical issues surrounding this complicated and emotive area and where they, as health professionals, fit within this. The subject matter is also a useful arena for debating such ethical and legal issues as capacity and competence to consent as well as the extent of the right of any patient to full autonomy.


[Frequent errors in neuro-otologic diagnosis].
A number of characteristic sources of error during the testing of vestibular function, originating from anamnesis, equipment and examination, are described. It is stressed that false-positive findings are often due to the influence of alcohol and that false-negative findings may be the result of tiredness or sedative drugs. With regard to the caloric test, it is recommended that water provides a better stimulus than air, and that the warm caloric stimulus is more valid than the cold caloric stimulus. Attention should be paid to the ENG-recorders, particularly to an adequate writing breadth, and to time constants. Different parameters in use for quantitative analysis of the intensity of vestibular reactions are discussed. If the findings are vague, repeated examination will often help to clarify matters. The regular use of Frenzel glasses is of great importance, since otherwise examination of the vestibular organs must be considered incomplete.


John Staige Davis: pioneer American plastic surgeon.
John Staige Davis was the first surgeon to devote his entire practice to plastic surgery and worked exclusively for its recognition as a specialty. He wrote the first American text on plastic surgery, published 78 papers on a wide range of subjects in plastic surgery, was the first to establish a formal training program in plastic surgery in 1924, and was the first Chairman of the American Board of Plastic Surgery.


A probable stellar solution to the cosmological lithium discrepancy.
The measurement of the cosmic microwave background has strongly constrained the cosmological parameters of the Universe. When the measured density of baryons (ordinary matter) is combined with standard Big Bang nucleosynthesis calculations, the amounts of hydrogen, helium and lithium produced shortly after the Big Bang can be predicted with unprecedented precision. The predicted primordial lithium abundance is a factor of two to three higher than the value measured in the atmospheres of old stars. With estimated errors of 10 to 25%, this cosmological lithium discrepancy seriously challenges our understanding of stellar physics, Big Bang nucleosynthesis or both. Certain modifications to nucleosynthesis have been proposed, but found experimentally not to be viable. Diffusion theory, however, predicts atmospheric abundances of stars to vary with time, which offers a possible explanation of the discrepancy. Here we report spectroscopic observations of stars in the metal-poor globular cluster NGC 6397 that reveal trends of atmospheric abundance with evolutionary stage for various elements. These element-specific trends are reproduced by stellar-evolution models with diffusion and turbulent mixing. We thus conclude that diffusion is predominantly responsible for the low apparent stellar lithium abundance in the atmospheres of old stars by transporting the lithium deep into the star.


Factors Affecting the Decision to Grant Consent for Organ Donation: A Survey of Adults in England.
Solid organ transplantation reduces both morbidity and mortality. Donation rates have increased by more than 60% in the last 6 years in the United Kingdom, largely through improved identification and management of potential donors. However, the next of kin (NoK) decline to consent in 43% of cases-the second highest rate in Europe. We aimed to define factors that influence decisions to consent for organ donation. This is an online survey of 1549 adult residents of England with results weighted to national demographics. Eighty percent would consider donating some or all of their organs. Religion, age, and ethnicity influenced this support. Concerns over body integrity, religion, and effects on the quality of care received reduce support. Only 48% recognized that NoK consent would be sought before any donation. Previous discussion and Organ Donor Register (ODR) enrollment both correlate with NoK consent: 87% would consent after discussion and ODR enrollment, 79% would consent after discussion alone, 55% would consent with ODR registration alone, and 29% would consent without either. Reported misconceptions inhibiting consent included a perceived inability to deregister from the ODR and that individuals were too old to donate. Those who did not wish to donate their own organs were more likely to overrule others' expressed wishes to donate. To ensure that organ donation occurs wherever appropriate, attention should focus primarily on determining an individual's wishes before death, ensuring that any misconceptions are corrected before a decision is made, promotion of ODR enrollment, and challenging those NoK who wish to overrule others' wishes.


Multimodality therapy for locally advanced and limited stage IV breast cancer: the impact of effective non-cross-resistance late-consolidation chemotherapy.
To determine the effectiveness of non-cross-resistant late-consolidation chemotherapy in locally advanced breast cancer (LABC) and stage IV breast cancer, we review our experience with two regimens. Between 1985 and 1991, we enrolled 56 patients with LABC, who were treated with a doxorubicin-based adjuvant regimen, followed by a late-consolidation non-cross-resistant regimen containing methotrexate, 5-fluorouracil, cisplatin, and cyclophosphamide. Between 1985 and 1996, a total of 45 patients with limited stage IV breast cancer underwent surgical excision of all evaluable disease, making them metastatic (stage IV) with no evaluable disease. Surgery was followed by a doxorubicin-containing regimen and then a late-consolidation non-cross-resistant regimen, which was either methotrexate, 5-fluorouracil, cisplatinum, and cyclophosphamide or 5-fluorouracil, mitomycin, etoposide, and cisplatin. Twenty-four patients with limited bone metastases that were unresectable were treated with a doxorubicin-containing regimen, radiation therapy to all sites of disease, and then one of the two late non-cross-resistant regimens. With a median follow-up of 84 months, 78% of patients with LABC are alive, and 68% are free of disease. After a median follow-up of 44 months, 53% of patients with stage IV with no evaluable disease are alive and free of disease. The use of non-cross-resistant late-consolidation chemotherapy is an effective strategy in the treatment of patients with LABC and selected patients with limited stage IV breast cancer.


Simple and efficient subtractive hybridization screening.
A method of subtractive hybridization screening is presented that does not rely on the availability of large amounts of poly(A)+ RNA. The usefulness of this method is demonstrated by the isolation of cDNA clones that are unique or present at enhanced levels in cDNA libraries derived from a psoriatic skin cell line. A very high level of enrichment for rare cDNA sequences is possible as shown by the isolation of cDNA clones present at a frequency of less than one in one hundred thousand (0.001%). This method is particularly useful in experimental systems where the amount of RNA available is limited.


Radiotherapy Enhancement for Human Pancreatic Carcinoma Using a Peptide-Gold Nanoparticle Hybrid.
Pancreatic ductal adenocarcinoma (PDAC) is radioresistant. Due to their strong X-ray absorption capacity, gold nanoparticles (AuNPs) have been used as radiosensitizers for cancer therapeutics. Herein, we describe a novel conjugate complex consisting of a peptide for targeting plectin-1 (PTP) specifically expressed on the PDAC cell membrane and AuNPs, termed AuNP-PTP, to be used for PDAC radiotherapy in vitro and in vivo. Previous studies revealed that compared with unmodified AuNPs, AuNP-PTP along with relevant low-energy X-ray irradiation of 6 MV at a dose of 2 Gy (RF) increased the targeting efficiency and induced apoptosis in treated PANC-1 cells and tumours. Importantly, extensive histopathological examination did not reveal evidence of acute or chronic injury in mice due to AuNPs or AuNP-PTP for up to six weeks despite the presence of X-ray exposure. The delicate AuNP-PTP hybrid provides a novel strategy to enhance radiotherapy efficiency in PDAC treatment.


Is the clinical efficacy of epidural diamorphine concentration-dependent when used as analgesia for labour?
The physicochemical properties of diamorphine (3,6-diacetylmorphine) enhance its bioavailability compared with more lipid-soluble opioids when administered into the epidural space. However, the influence of concentration, volume or mass on the clinical efficacy of diamorphine is not known. In this double-blind, randomized, prospective study, 62 women in active labour and </=5 cm cervical dilatation were recruited to determine whether the mode of action of diamorphine in the epidural space is concentration-dependent. After insertion of a lumbar epidural catheter, patients received epidural diamorphine 3 mg either as a high-volume, low-concentration solution (group A) or a low-volume, high-concentration solution (group B). The concentration of diamorphine was determined by the response of the previous patient in the same group using up-down sequential allocation. Pain corresponding to the previous contraction was assessed using a 100-mm visual analogue score and effective analgesia was defined as </=10 mm within 30 min of epidural injection. There was no significant difference in EC50 for diamorphine between the groups: the difference was 15.0 microg ml(-1) (95% CI -40.3 to 10.3). The EC50 for group A was 237.5 microg ml(-1) (95% CI 221.2 to 253.8) and the EC50 for group B was 252.5 microg ml(-1) (95% CI 232.2 to 272.8). The EC50 ratio was 0.95 (95% CI 0.87 to 1.06). The groups exhibited parallelism (P=0.98). The overall EC50 for all data was 244.2 microg ml(-1) (95% CI 230.8 to 257.2). We conclude that diamorphine provides analgesia in labour by a concentration-dependent effect.


Electromagnetic thermotherapy for deep organ ablation by using a needle array under a synchronized-coil system.
Thermal ablation by using electromagnetic thermotherapy (EMT) has been a promising cancer modality in recent years. It has relatively few side effects and has therefore been extensively investigated for a variety of medical applications in internal medicine and surgery. The EMT system applies a high-frequency alternating electromagnetic field to heat up the needles which are inserted into the target tumor to cause tumor ablation. In this study, a new synchronized-coil EMT system was demonstrated, which was equipped with two synchronized coils and magnetic field generators to provide a long-range, penetrated electromagnetic field to effectively heat up the needles. The heating effect of the needles at the center of the two coils was first explored. The newly designed two-section needle array combined with the synchronized-coil EMT system was thus demonstrated in the in vitro and in vivo animal experiments. Experimental data showed that the developed system is promising for minimally invasive surgery since it might provide superior performance for thermotherapy in cancer treatment.


Molecular and cellular control points in pediatric liver injury and repair.
Several exciting areas of cellular and molecular biology of the liver have led to a better understanding of the mechanisms of pediatric liver injury and repair. Soon these advances will lead to treatment options for specialized areas of pediatric hepatology. Most of the current goals of surgical therapy lead to either successful hepatic resection for tumors or biliary decompression for atresia. We have come to accept the unfortunate fact that ongoing chronic liver disease ultimately leads to replacement by transplantation. The purpose of this article is to demonstrate areas of recent basic science advancement, directly related to pediatric liver disease, that may provide opportunities and new strategies to obviate the progression from early injury to end-stage liver disease or to augment repair of the injured liver.


Liver depot gene therapy for Pompe disease.
Gene therapy for Pompe disease has advanced to early phase clinical trials, based upon proof-of-concept data indicating that gene therapy could surpass the benefits of the current standard of care, enzyme replacement therapy (ERT). ERT requires frequent infusions of large quantities of recombinant human acid α-glucosidase (GAA), whereas gene therapy involves a single infusion of a vector that stably transduces tissues to continuously produce GAA. Liver-specific expression of GAA with an adeno-associated virus (AAV) vector established stable GAA secretion from the liver accompanied by receptor-mediated uptake of GAA, which corrected the deficiency of GAA and cleared the majority of accumulated glycogen in the heart and skeletal muscle. Liver depot gene therapy was equivalent to ERT at a dose of the AAV vector that could be administered in an early phase clinical trial. Furthermore, high-level expression of GAA has decreased glycogen stored in the brain. A unique advantage of liver-specific expression stems from the induction of immune tolerance to GAA following AAV vector administration, thereby suppressing anti-GAA antibodies that otherwise interfere with efficacy. A Phase I clinical trial of AAV vector-mediated liver depot gene therapy has been initiated based upon promising preclinical data (NCT03533673). Overall, gene therapy promises to address limits of currently available ERT, if clinical translation currently underway is successful.


Metastatic renal cell carcinoma without evidence of a primary renal tumour.
Although metastases are common in patients with renal cell carcinoma (rcc), it is extremely rare for patients to present with metastatic rcc (mrcc) without evidence of a primary mass in the kidney. Two cases of mrcc with no detectable primary renal mass are reported here. Both patients had bilateral native kidneys in situ and no significant prior urologic history. The first patient presented with a hip fracture and was found to have multiple radiologic bony and lung metastases. Biopsy of a mass involving the pubic bone demonstrated clear cell mrcc. Multiple scans by computed tomography (ct) and confirmatory imaging by magnetic resonance demonstrated no renal mass. This first patient had disease stabilization for 18 months on sunitinib and was still alive at last follow-up. The second patient was diagnosed with clear-cell mrcc after thickened synovium was discovered and biopsied during a knee arthroplasty. Multiple scans by ct in this second patient demonstrated no primary renal mass. Sunitinib and radiotherapy to the knee lesion were initiated, but unfortunately, the patient deteriorated clinically and passed away from disease progression shortly after diagnosis. Because of the rare nature of these cases, a standardized course of action has not yet been established. However, we hypothesize that it is reasonable to manage metastases in these patients by following established mrcc protocols.


[Basophil activation test using flow cytometry in Hymenoptera venom allergy].
The basophil activation test (TAB) clearly shows evidence to Hymenoptera venoms. Comparison of the TAB value with the clinical history allows fixation of a threshold that will anticipate the type of clinical reaction by the TAB value. For the technique of TAB 3 dilutions are used. The basophil activation values produce a threshold for each dilution. For the first dilution the threshold is 50% activation: below this threshold, 70% of patients would have a local or systemic reaction and above this threshold, 70% of patients would have a systemic allergic reaction.


Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study.
Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma. In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0-2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing. Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60-72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61-72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0-8·5; 165 [67%] of 246 patients had an event) in the melflufen group and 4·9 months (4·2-5·7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64-0·98]; p=0·032), at a median follow-up of 15·5 months (IQR 9·4-22·8) in the melflufen group and 16·3 months (10·1-23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1-25·6) at a median follow-up of 19·8 months (IQR 12·0-25·0) in the melflufen group and 25·0 months (95% CI 18·1-31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8-23·7; HR 1·10 [95% CI 0·85-1·44]; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia). Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Oncopeptides AB.


An investigation of the photon energy dependence of the EPR alanine dosimetry system.
The electron paramagnetic resonance (EPR) alanine dosimetry system is based on EPR measurements of radicals formed in alanine by ionizing radiation. The system has been studied to determine its energy dependence for photons in the 10-30 MV region relative to those of 60Co and to find out if the system would be suitable for dosimetry comparisons. The irradiations were carried out at the National Research Council, Ottawa, Canada and the doses ranged from 8 to 54 Gy. The EPR measurements were performed at the University of Oslo, Norway. The ratio of the slope of the alanine reading versus dose-to-water curve for a certain linac photon beam quality and the corresponding slope for a reference 60Co gamma-radiation gives an experimental measure of the relative dose-to-water response of the EPR alanine dosimetry system. For calculating the linear regression coefficients of these alanine reading versus dose curves, the method of weighted least squares was used. This method is assumed to produce more accurate regression coefficients when applied to EPR dosimetry than the common method of standard least squares. The overall uncertainty on the ratio of slopes was between 0.5 and 0.6% for all three linac energies. The relative response for all the linac beams compared to cobalt was less than unity: by about 0.5% for the 20 and 30 MV points but by more than 1% for the 10 MV point. The given standard uncertainties negate concluding that there is any significant internal variation in the measured response as a function of beam quality between the three linac energies. Thus, we calculated the average dose response for all three energies and found that the alanine response is 0.8% (+/-0.5%) lower for high energy x-rays than for 60Co gamma-rays. This result indicates a small energy dependence in the alanine response for the high-energy photons relative to 60Co which may be significant. This result is specific to our dosimetry system (alanine with 20% polyethylene binder pressed into a particular shape) including its waterproofing sleeve of PMMA (2 mm thick); however, we expect that this result may apply to other similar detectors.


Sensitivity and specificity of alternative screening methods for systematic reviews using text mining tools.
To evaluate the impact of text mining (TM) on the sensitivity and specificity of title and abstract screening strategies for systematic reviews (SRs). Twenty reviewers each evaluated a 500-citation set. We compared five screening methods: conventional double screen (CDS), single screen, double screen with TM, combined double screen and single screen with TM, and single screen with TM. Rayyan, Abstrackr, and SWIFT-Review were used for each TM method. The results of a published SR were used as the reference standard. The mean sensitivity and specificity achieved by CDS were 97.0% (95% confidence interval [CI]: 94.7, 99.3) and 95.0% (95% CI: 93.0, 97.1). When compared with single screen, CDS provided a greater sensitivity without a decrease in specificity. Rayyan, Abstrackr, and SWIFT-Review identified all relevant studies. Specificity was often higher for TM-assisted methods than that for CDS, although with mean differences of only one-to-two percentage points. For every 500 citations not requiring manual screening, 216 minutes (95% CI: 169, 264) could be saved. TM-assisted screening methods resulted in similar sensitivity and modestly improved specificity as compared to CDS. The time saved with TM makes this a promising new tool for SR.


Chromosomal localization of the human and mouse hyaluronan synthase genes.
We have recently identified a new vertebrate gene family encoding putative hyaluronan (HA) synthases. Three highly conserved related genes have been identified, designated HAS1, HAS2, and HAS3 in humans and Has1, Has2, and Has3 in the mouse. All three genes encode predicted plasma membrane proteins with multiple transmembrane domains and approximately 25% amino acid sequence identity to the Streptococcus pyogenes HA synthase, HasA. Furthermore, expression of any one HAS gene in transfected mammalian cells leads to high levels of HA biosynthesis. We now report the chromosomal localization of the three HAS genes in human and in mouse. The genes localized to three different positions within both the human and the mouse genomes. HAS1 was localized to the human chromosome 19q13.3-q13.4 boundary and Has1 to mouse Chr 17.HAS2 was localized to human chromosome 8q24.12 and Has2 to mouse Chr 15. HAS3 was localized to human chromosome 16q22.1 and Has3 to mouse Chr 8. The map position for HAS1 reinforces the recently reported relationship between a small region of human chromosome 19q and proximal mouse chromosome 17. HAS2 mapped outside the predicted critical region delineated for the Langer-Giedion syndrome and can thus be excluded as a candidate gene for this genetic syndrome.


Water bath hyperthermia is a simple therapy for psoriasis and also stimulates skin tanning in response to sunlight.
An eight week trial, involving superficial hyperthermia delivered biweekly via simple water bath immersion, was tested for its ability to clear mild to moderate psoriatic lesions. Seven patients were treated and three cases rapidly improved. In the remaining patients, the treatment frequency was increased to alternate days; two cases improved significantly, one patient showed a partial response, and the fourth had no visible change (this was the only patient taking concurrent drug therapy--etretinate). In addition to resolving psoriatic lesions, water bath hyperthermia also reduced edema (swelling) and relieved pruritus (itching) in all patients, both during the treatment period and for up to several months after lesions had returned. Lesion reappearance occurred within one to three months after the last heat treatment. We retreated one patient and produced a second complete remission. These results indicate that simple repetitive water bath hyperthermia alone is effective in the treatment of psoriatic lesions in heatable locations. An unexpected side effect was enhanced melanin content (tanning) in all areas where hyperthermia treated skin was exposed to sunlight.


Coordinated regulation of hyaluronan and aggrecan content in the articular cartilage of immobilized and exercised dogs.
To study the influence of joint loading and immobilization on articular cartilage hyaluronan concentration and histological distribution in the knee joints of young dogs subjected to 11 weeks' immobilization by splinting, and 15 weeks' running exercise at a rate of 40 km/day. The amount of hyaluronan in articular cartilage was determined by a competitive binding assay using a biotinylated hyaluronan binding complex (HABC) of aggrecan and link protein. Histologic sections were stained for the localization of hyaluronan with the HABC probe. Extracted proteoglycans were characterized by sodium dodecyl sulfate agarose gel electrophoresis. Immobilization significantly reduced the concentration of hyaluronan in all sites studied (tibial and femoral condyles, patellar surface of femur). The proportion of hyaluronan to total uronic acid (mainly from aggrecan) remained unchanged because of a concurrent decrease in aggrecan. The ratio of hyaluronan and aggrecan remained constant also in runners. The staining pattern of free hyaluronan in the tissue sections and the electrophoretic mobility of the extracted proteoglycans were not affected by the different loading regimes. Reduced joint loading due to splint immobilization significantly decreases both hyaluronan and aggrecan in the articular cartilage. The remarkably parallel changes in aggrecan and hyaluronan content suggest that joint loading exerts a coordinated influence on their metabolism.


Catheter-related thrombosis: lifeline or a pain in the neck?
Central venous catheters (CVCs) are used extensively in cancer patients for the administration of therapy and phlebotomy. An important complication of CVCs is the development of catheter-related thrombosis (CRT), which becomes symptomatic in approximately 5% of the patients. Several factors, such as insertion location and position of the catheter tip, increase the risk of CRT. Prevention of CRT with systemic anticoagulant prophylaxis has largely been ineffective. In addition, the optimal diagnostic strategy and anticoagulant treatment are unclear due to the lack of well-designed studies. The most recent American College of Chest Physicians guidelines recommend (color) Doppler ultrasound more than venography as the initial diagnostic test in patients with suspected arm thrombosis. Only if the ultrasound is negative and clinical suspicion is high is further testing with D-dimer, serial ultrasound, or venography advocated. In case of CRT, removal of the catheter is not necessary if it is functional and needed for chemotherapy. Anticoagulant treatment of CRT consists of treatment with low-molecular-weight heparin (LMWH) followed by vitamin K antagonists for at least 3 months. Whether long-term treatment with LMWH is more effective than vitamin K antagonists in cancer patients with CRT is unknown, but LMWH may be advocated following the recommendations in lower limb thrombosis and cancer. In addition, the effect of new anticoagulants in CRT has not been studied.


Primary care physician supply and children's health care use, access, and outcomes: findings from Canada.
To describe the relationship of primary care physician (PCP) supply for children and measures of health care access, use, and outcomes. We conducted a population-based, cross-sectional study of all Ontario children from 2003 to 2005. We used health administrative data to calculate county-level supply (full-time equivalents [FTEs]) of PCPs. We modeled the relationship of supply to (1) recommended primary care visits, (2) emergency department (ED) use, and (3) ambulatory care-sensitive condition admissions and adjusted for neighborhood income. We used population-based surveys to describe access. The county-level PCP supply ranged from 1720 to 4720 children per FTE. Of the children, 45.4% live in the highest-supply areas (<2000 children per FTE) and 8% in the lowest-supply areas (>3000 children per FTE). Compared with high-supply counties, the lowest had significantly lower rates of primary care visits (2716 vs 7490 per 1000) and higher proportions of newborns without early follow-care (58.2% vs 14.5%). Low-supply areas had higher rates of ED visits (440 vs 179 per 1000) and admissions. A stepwise gradient existed for every decrease in supply for most measures. Self-reported access barriers were most evident in areas with >3500 children per FTE (32.8% without a physician). Under universal insurance there are differences in access to, and outcomes of, primary care related to local physician supply after controlling for neighborhood income. The most pronounced effect is on primary and ED care use, but there are implications for acute and chronic disease control. Physician distribution is a critical issue to address in policies to improve access to care.


Adjustable Bilateral Superior Oblique Tendon Advancement for Bilateral Fourth Nerve Palsy.
Bilateral fourth nerve palsy may be symmetric or asymmetric with combined vertical and excylotropic deviations and so there may be an advantage to independent adjustment of vertical and torsional components. We report a surgical technique that allows such independent adjustment. Retrospective interventional case series. Fifteen patients, aged 17-73 years, underwent adjustable bilateral superior oblique tendon advancements for bilateral fourth nerve palsy: 11 symmetric (≤2 prism diopters [pd] hyperdeviation in straight-ahead gaze) and 4 asymmetric. Motor alignment was assessed with double Maddox rods and prism and alternate cover tests preoperatively, pre- and postadjustment, and 6 weeks postoperatively. Preoperative torsion ranged from 7 to 30 degrees excyclotropia (mean 17 ± 7 degrees) and hyperdeviation from 0 to 10 pd. Preadjustment torsion ranged from 5 degrees excyclotropia to 40 degrees incyclotropia, and hyperdeviation from 0 to 8 pd. Twelve of the 15 patients (80%) were adjusted to a target of 0 pd hyperphoria and 10 degrees incyclotropia (actual mean 9 degrees incyclotropia, range 2-13 degrees incyclotropia). At 6 weeks postoperatively there was expected excyclodrift (to mean 4 degrees excyclotropia, range 0 degrees incyclotropia to 15 degrees excyclotropia), but 13 (87%) had 5 degrees or less excyclotropia and 14 (93%) had 2 pd or less hyperdeviation. Mean torsional correction from preoperative to preadjustment was 31 ± 14 degrees (P < .0001), and from preoperative to 6 weeks was 13 ± 6 degrees (P < .0001). Adjustable bilateral superior oblique tendon advancement allows independent control of torsional and vertical components of the deviation, and therefore may be useful in cases of bilateral superior oblique palsy.


Serum matrix metalloproteinase-9 activity is dysregulated with disease progression in the mutant SOD1 transgenic mice.
Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal neurodegenerative disorder characterized by progressive deterioration of motor neurons in the spinal cord, brainstem, and cerebral cortex. Matrix metalloproteinase-9 (MMP-9) is proposed to be a biomarker for ALS due to a potential pathological role in the disease. However, despite numerous studies, it is still unclear whether there is a direct correlation between MMP-9 expression in serum and progression of disease. Therefore, we used a TgSOD1(G93A) mouse with a low transgene copy number. This model shows slow disease progression analogous to human ALS and provides a useful model to study biomarker expression at different stages of disease. Using zymography, we found that serum MMP-9 activity was significantly elevated in animals showing early signs of disease when compared to the younger, pre-symptomatic animals. This was followed by a decrease in MMP-9 activity in TgSOD1(G93A) mice with end-stage disease. These results were confirmed in serum of a high copy number strain of TgSOD1(G93A) mice with rapid progression. MMP-9 expression was changed accordingly in spinal motor neurons, glia and neuropil, suggesting a spinal cord contribution to blood MMP-9 activity. Serum MMP-2 activity followed a similar profile as the MMP-9 in these two models. These data indicate that circulating MMP-9 is altered throughout the course of disease progression in mice. Further studies in human ALS may validate the suitability of serum MMP-9 activity as a biomarker for early stage disease.


Novel chemical method for the preparation of nucleic acids for nonisotopic hybridization.
A novel chemical method was used to prepare biotin-labeled nucleic acids for nonisotopic hybridization. The method involves the transamination of unpaired cytosine residues in polynucleotides with sodium bisulfite and ethylenediamine. Primary amino groups on the cytosine derivatives are then reacted with biotinyl-e-aminocaproic acid N-hydroxysuccinimide ester. Biotinylated probes hybridized with 1 to 2 pg of nitrocellulose filter-bound DNA and were visualized with a colorimetric detection technique. This method is simpler and less expensive than other methods for the preparation of nonisotopic probes. In addition, it is more versatile since the chemically modified bases can potentially react with other "indicator" molecules or proteins such as an enzyme. The specificity for unpaired cytosine residues is another advantage which could allow for the selective labeling of a specific region of a double-stranded nucleic acid. This improved labeling method should lead to the wider application of hybridization techniques in diagnostic microbiology and basic research in infectious diseases.


Lotus Leaf Derived NiS/Carbon Nanofibers/Porous Carbon Heterogeneous Structures for Strong and Broadband Microwave Absorption.
Developing composite materials with the synergistic effects of heterogeneous structures and multiple components is considered as a promising strategy to achieve high-performance electromagnetic wave (EMW) absorbers. To further satisfy the demand of broadband and strong microwave absorption, a novel NiS/carbon nanofibers (CNFs)/porous carbon composite is successfully synthesized by hydrothermal and chemical vapor deposition using lotus leaves as a biomass carbon source. A few carbon nanotubes (CNTs) and uniformly dispersed Ni nanocrystals have also been found in the hybrid. Benefiting from the porous structure derived from lotus leaves, the combination of dielectric NiS, conductive carbon nanomaterials, and magnetic Ni nanoparticles, together with the three-dimensional conductive network of CNFs and CNTs, the remarkable EMW absorption properties with a minimum reflection loss up to -67.65 dB have been achieved at merely 2.32 mm. Besides, the widest effective absorption band can reach 5.9 GHz with a thin thickness of 2.07 mm, covering almost the entire Ku band. In addition, under the incident angle of 31°, the radar cross-section reduction value of LNSF-600 can reach 42.88 dBm2. Therefore, this work provides an efficient and facile method for manufacturing outstanding biomass-derived EMW absorbers.


Approaches for discovering novel bioactive small molecules targeting autophagy.
In recent years, development of novel bioactive small molecules targeting autophagy has been implicated for autophagy-related disease treatment. Screening new small molecules regulating autophagy allows for the discovery of novel autophagy machinery and therapeutic agents. Areas covered: Two major screening methods for novel autophagy modulators are introduced in this review, namely target based screening and phenotype based screening. With increasing attention focused on chemical compound libraries, coupled with the development of new assay systems, this review attempts to provide an efficient strategy to explore autophagy biology and discover small molecules for the treatment of autophagy-related diseases. Expert opinion: Adopting an appropriate autophagy screening strategy is important for developing small molecules capable of treating neurodegenerative diseases and cancers. Phenotype based screening and target based screening were both used for developing effective small molecules. However, each of these methods has many pros and cons. An efficient approach is suggested to screen for novel lead compounds targeting autophagy, which could provide new hits with better efficiency and rapidity.


Platelet Activation in Human Immunodeficiency Virus Type-1 Patients Is Not Altered with Cocaine Abuse.
Recent work has indicated that platelets, which are anucleate blood cells, significantly contribute to inflammatory disorders. Importantly, platelets also likely contribute to various inflammatory secondary disorders that are increasingly associated with Human Immunodeficiency Virus Type-1 (HIV) infection including neurological impairments and cardiovascular complications. Indeed, HIV infection is often associated with increased levels of platelet activators. Additionally, cocaine, a drug commonly abused by HIV-infected individuals, leads to increased platelet activation in humans. Considering that orchestrated signaling mechanisms are essential for platelet activation, and that nuclear factor-kappa B (NF-κB) inhibitors can alter platelet function, the role of NF-κB signaling in platelet activation during HIV infection warrants further investigation. Here we tested the hypothesis that inhibitory kappa B kinase complex (IKK) activation would be central for platelet activation induced by HIV and cocaine. Whole blood from HIV-positive and HIV-negative individuals, with or without cocaine abuse was used to assess platelet activation via flow cytometry whereas IKK activation was analyzed by performing immunoblotting and in vitro kinase assays. We demonstrate that increased platelet activation in HIV patients, as measured by CD62P expression, is not altered with reported cocaine use. Furthermore, cocaine and HIV do not activate platelets in whole blood when treated ex vivo. Finally, HIV-induced platelet activation does not involve the NF-κB signaling intermediate, IKKβ. Platelet activation in HIV patients is not altered with cocaine abuse. These results support the notion that non-IKK targeting approaches will be better suited for the treatment of HIV-associated inflammatory disorders.


Lock-in and pulsed thermography for solar cell testing.
Inspection of solar cells is an important part of their production process because even small defects can cause a significant drop of a whole photovoltaic module performance. LED illuminated lock-in (LEDILIT) and flash-pulse thermographic techniques (FPT) were compared in this study. Lock-in methods are more commonly used for solar cell inspection. The aim of the study was to discover if the FPT is the appropriate method for inspection of defects of multicrystalline solar cells. Experimental setup, inspection results, and advantages/disadvantages of both methods are presented. It is demonstrated that the LEDILIT is the suitable technique for inspection of defects connected with a photovoltaic effect. Local shunts, cracks, and artificial laser-made defects were detected. Only some of the most significant shunts and laser-made defects were identified by the FPT. However, the FPT inspection is much faster than the LEDILIT. The FPT was also able to indicate an inhomogeneity at a bottom layer of a cell, which was not connected with a photovoltaic effect and not revealed by the LEDILIT.


Longitudinal study of racial and ethnic differences in developing end-stage renal disease among aged medicare beneficiaries.
Diabetes and hypertension are the leading causes of renal failure. This study investigated racial differences in developing ESRD by participants' diabetes and hypertension status. This longitudinal study included 1,306,825 Medicare beneficiaries who were aged > or =66 yr at the study start and followed up to 10 yr from January 1, 1993, for the development of ESRD or death. During the 10 yr, 0.93 patients per 100 received ESRD treatment. After adjustment for age and gender, among patients with diabetes, black patients were 2.4 to 2.7 times and other races/ethnicities 1.6 to 1.7 times more likely than white patients to develop ESRD. Among hypertensive patients, black patients were 2.5 to 2.9 and others 1.7 to 1.8 times more likely than white patients to develop ESRD. Among patients with neither diabetes nor hypertension, black patients were 3.5 and others 2.0 times more likely. Black men with diabetes were 1.9 to 2.1 and women 2.5 to 3.4 times more likely than their white counterparts to develop ESRD. Hypertensive black men were 2.1 to 2.2 and women 2.8 to 3.6 times more likely to develop ESRD. The same findings were noted in women of other races/ethnicities. Compared with white counterparts, mortality was higher for black patients in all cohorts but lower among patients with ESRD. Although they are leading causes for renal failure, diabetes and hypertension do not cause racial differences in developing ESRD. Minority women especially are at greater risk for ESRD than white women. Further studies are needed to determine whether earlier initiation of dialysis is a factor in higher ESRD incidence among minorities.


Gamma-hydroxybutyrate increases brain resting-state functional connectivity of the salience network and dorsal nexus in humans.
According to the triple network hypothesis the brain is equipped with three core neurocognitive networks: the default mode (DMN), the salience (SN), and the central executive (CEN) network. Moreover, the so called dorsal nexus, has met growing interest as it is a hub region connecting these three networks. Assessment of resting-state functional connectivity (rsFC) of these networks enables the elucidation of drug-induced brain alterations. Gamma-hydroxybutyrate (GHB) is a GHB/GABA-B receptor agonist that induces a paradoxical state of mixed stimulation and sedation at moderate doses, which makes it a valuable tool to investigate neural signatures of subjective drug effects. Employing a placebo-controlled, double-blind, randomized, cross-over design, we assessed the effects of GHB (35 mg/kg p. o.) in 19 healthy male subjects on DMN-, SN-, CEN-, and dorsal nexus-rsFC measured by functional magnet resonance imaging and applying independent component as well as seed-based analyses, while subjective drug effects were investigated using visual analog scales (VAS). Subjectively, GHB increased VAS ratings of a general drug effect, stimulation, and sedation. Intrinsic DMN-, and CEN-rsFC remained largely unchanged under GHB, but the drug increased SN-DMN-rsFC and SN-dorsal nexus-rsFC, while dorsal nexus-rsFC was reciprocally increased to both the SN (right anterior insula) and to the CEN (right middle frontal gyrus). Increased sedation significantly predicted the observed SN-dorsal nexus-rsFC. In conclusion, GHB generates a unique stimulant/sedative subjective state that is paralleled by a complex pattern of increased functional connectivity encompassing all three core neurocognitive networks of the brain, while increased SN-dorsal nexus-rsFC was demonstrated to be a potential signature of the sedative component of the drug effect.


[Toward a dialectic concept in psychiatry].
It is intended to define dialectics, and then to follow its evolution from its origin in the pre-Socratic philosophy up to its culmination in Hegel. It is then postulated its importance for the better understanding of the vital history, of the endogenous or functional psychoses and of the classical types of personality in its relation with the fundamental psychopathological structures. With respect to the first one, dialectic thinking would allow to understand vital history as the unfolding in time of a consciousness that is being splinted in contradictions of increasing tension up to its resolution in a failure (disease) or in a synthesis that implies a step forward in the maturation, plenitude or wisdom. With respect to the second one, the great psychoses could be seen as dialectic polarities, both within themselves (mania versus depression, type I versus type II of Crow), and of a group with respect of the other (affective diseases versus schizophrenic diseases). What is schizophrenic and what is depressive appear as polar ones both in the previous personality and in the outbreaking situations, both in the symptomatology as in the evolution. In the third place, dialectics would also allow to conceive the most classic types of personality as ordered in polarities (schizoid-depressive, hysterical-obsessive), in which the poles simultaneously attract and repel themselves, so that each one can be seen as a positivity with respect to the other one. The deviation towards a pole of the alternative does not need to be seen as a lack, but as a dynamic displacement of the existence against the other pole of the alternative. Finally, the author proposes a scheme on the interrelation between the mentioned four structures and the more frequent psychiatric syndromes.


Normalized maximum intensity time ratio maps and morphological descriptors for assessment of malignancy in MR mammography.
Effectiveness of morphological descriptors based on normalized maximum intensity-time ratio (nMITR) maps generated using a 3 x 3 pixel moving mask on dynamic contrast-enhanced magnetoresistance (MR) mammograms are studied for assessment of malignancy. After a rough indication of volume of interest on the nMITR maps, lesions are automatically segmented. Two-dimensional (2D) convexity, normalized complexity, extent, and eccentricity as well as three-dimensional (3D) versions of these descriptors and contact surface area ratio are computed. On a data set consisting of dynamic contrast-enhanced MR DCE-MR mammograms from 51 women that contain 26 benign and 32 malignant lesions, 3D convexity, complexity, and extent are found to reflect aggressiveness of malignancy better than 2D descriptors. Contact surface area ratio which is easily adaptable to different imaging resolutions is found to be the most significant and accurate descriptor (75% sensitivity, 88% specificity, 89% positive predictive values, and 74% negative predictive values).


Structural approaches to explain the selectivity of COX-2 inhibitors: is there a common pharmacophore?
The identification and characterisation of the isoenzyme cyclooxygenase 2 (COX-2) stimulated investigations to develop efficient non-steroidal anti-inflammatory drugs with reduced side effects compared to standard NSAIDs. This review will focus on the structural features needed to achieve COX-2 selectivity. Five structural classes can be identified together with a class bearing little or no resemblance to one another in their molecular structure. The most interesting point is the very distinct structure/activity relationship. On the one hand only minor modifications to a particular compound induce a drastic change in its COX selectivity and on the other hand the structural prerequisites in terms of molecular shape, lipophilicity, electron density, flexibility, polarity and H-bonding dynamics allow a wide range of diversity.


Comparative evaluation of antibacterial efficacy of conventional glass-ionomer cement and bulk-fill alkasite material when combined with doxycycline and double antibiotic paste containing ciprofloxacin and metronidazole against Streptococcus mutans and Lactobacillus spp.: An in vitro study.
Glass-ionomer cement (GIC) have been indispensable to pediatric dentistry. Along with these, newer materials like bulk-fill alkasite cement (Cention N) are popularizing. In spite of this, the search is still on for the "ideal" bioactive material which could provide a therapeutic edge. In light of this, incorporation of antibiotics in GIC or newer materials like bulk-fill alkasite cement (Cention N) would provide a novel alternative material to the dentists. The study was aimed at comparing the antibacterial efficacy of conventional glass-ionomer cement (CGIC) and bulk-fill alkasite cement (Cention N) with doxycycline (DOX) and double antibiotic paste (DAP) containing metronidazole and ciprofloxacin (1.5% w/w) on Streptococcus mutans and Lactobacillus. Agar well diffusion method was followed, in which material discs of 10 mm were made and inserted into the wells. Inhibition zones were calculated after incubation for 24 h at 37°C with zone interpretation scale. A highly significant statistical correlation was found between antibacterial efficacy of the control groups (CGIC and bulk-fill alkasite cement [Cention N]) without antibiotics as compared to the experimental group (CGIC and bulk-fill alkasite cement [Cention N] with DOX and DAP), P = 0.0001 and P = 0.0006 for the CGIC group and P = 0.0147 and P = 0.0080 for the Cention N group (P < 0.05). Incorporation of antibiotics significantly enhanced the antibacterial efficacy of CGIC and bulk-fill alkasite cement (Cention N).


Effects of aging on cerebral vasospasm after subarachnoid hemorrhage in rabbits.
The effects of aging on cerebral vasospasm after subarachnoid hemorrhage (SAH) remain to be elucidated. The aim of this study was to clarify age-related differences of vasospasm and of papaverine reactivity in the responses of basilar arteries after SAH in rabbits. Rabbits receiving a single injection of arterial blood into the cisterna magna were divided into 3 groups: young (2 to 3 months old), adult (6 to 9 months old), and old (20 to 40 months old). Vertebrobasilar angiograms were obtained before SAH and 1, 2, 4, and 7 days after SAH. Papaverine was administrated selectively via the vertebral artery on day 2, and serial angiography was performed for up to 2 hours. Vessel structures were assessed with light microscopy on days 1, 2, 4, and 7 after SAH and at 10, 30, and 60 minutes after papaverine infusion. Mortality from SAH in old rabbits was 40%, whereas that of young and adult rabbits was 0%. Angiograms revealed that SAH induced maximal constriction of the basilar arteries on day 2 in all age groups, and the constrictions were significantly increased with age at all time points investigated. The degree of dilatation of spastic basilar arteries after intra-arterial papaverine administration significantly decreased with age. Duration of the efficacy of papaverine became significantly shorter with age. Vessel diameter returned to the preinfusion value approximately 120, 60, and 30 minutes after infusion in young, adult, and old rabbits, respectively. Light microscopy in old rabbits showed luminal narrowing and corrugation of the internal elastic lamina not only in the basilar arteries but also in small arteries and intraparenchymal arterioles. This study suggests that aging increases the degree of vasospasm in rabbits. The impaired reactivity to papaverine with aging might imply the early transition of the aged vessel to the papaverine-resistant chronic stage.


A PDI family network acts distinctly and coordinately with ERp29 to facilitate polyomavirus infection.
Endoplasmic reticulum (ER)-to-cytosol membrane transport is a decisive infection step for the murine polyomavirus (Py). We previously determined that ERp29, a protein disulfide isomerase (PDI) member, extrudes the Py VP1 C-terminal arm to initiate ER membrane penetration. This reaction requires disruption of Py's disulfide bonds. Here, we found that the PDI family members ERp57, PDI, and ERp72 facilitate virus infection. However, while all three proteins disrupt Py's disulfide bonds in vitro, only ERp57 and PDI operate in concert with ERp29 to unfold the VP1 C-terminal arm. An alkylated Py cannot stimulate infection, implying a pivotal role of viral free cysteines during infection. Consistent with this, we found that although PDI and ERp72 reduce Py, ERp57 principally isomerizes the virus in vitro, a reaction that requires viral free cysteines. Our mutagenesis study subsequently identified VP1 C11 and C15 as important for infection, suggesting a role for these residues during isomerization. C11 and C15 also act together to stabilize interpentamer interactions for a subset of the virus pentamers, likely because some of these residues form interpentamer disulfide bonds. This study reveals how a PDI family functions coordinately and distinctly to promote Py infection and pinpoints a role of viral cysteines in this process.


The evolution of DNA sequences in Escherichia coli.
It is proposed that certain families of transposable elements originally evolved in plasmids and functioned in forming replicon fusions to aid in the horizontal transmission of non-conjugational plasmids. This hypothesis is supported by the finding that the transposable elements Tn3 and gamma delta are found almost exclusively in plasmids, and also by the distribution of the unrelated insertion sequences IS4 and IS5 among a reference collection of 67 natural isolates of Escherichia coli. Each insertion sequence was found to be present in only about one-third of the strains. Among the ten strains found to contain both insertion sequences, the number of copies of the elements was negatively correlated. With respect to IS5, approximately half of the strains containing a chromosomal copy of the insertion element also contained copies within the plasmid complement of the strain.


Immune interaction between SARS-CoV-2 and Mycobacterium tuberculosis.
SARS-CoV-2 and Mycobacterium tuberculosis (Mtb) are major infectious causes of death, with meta-analyses and population-based studies finding increased mortality in co-infected patients simultaneously diagnosed with COVID-19 and tuberculosis (TB). There is a need to understand the immune interaction between SARS-CoV-2 and Mtb which impacts poor outcomes for those co-infected. We performed a PubMed and preprint search using keywords [SARS-CoV-2] AND [tuberculosis] AND [Immune response], including publications after January 2020, excluding reviews or opinions. Abstracts were evaluated by authors for inclusion of data specifically investigating the innate and/or acquired immune responses to SARS-CoV-2 and Mtb in humans and animal models, immunopathological responses in co-infection and both trials and investigations of potential protection against SARS-CoV-2 by Bacille Calmette Guérin (BCG). Of the 248 articles identified, 39 were included. Incidence of co-infection is discussed, considering in areas with a high burden of TB, where reported co-infection is likely underestimated. We evaluated evidence of the clinical association between COVID-19 and TB, discuss differences and similarities in immune responses in humans and in murine studies, and the implications of co-infection. SARS-CoV-2 and Mtb have both been shown to modulate immune responses, particularly of monocytes, macrophages, neutrophils, and T cells. Co-infection may result in impaired immunity to SARS-CoV-2, with an exacerbated inflammatory response, while T cell responses to Mtb may be modulated by SARS-CoV-2. Furthermore, there has been no proven potential COVID-19 clinical benefit of BCG despite numerous large-scale clinical trials.


Gut microbes shape microglia and cognitive function during malnutrition.
Fecal-oral contamination promotes malnutrition pathology. Lasting consequences of early life malnutrition include cognitive impairment, but the underlying pathology and influence of gut microbes remain largely unknown. Here, we utilize an established murine model combining malnutrition and iterative exposure to fecal commensals (MAL-BG). The MAL-BG model was analyzed in comparison to malnourished (MAL mice) and healthy (CON mice) controls. Malnourished mice display poor spatial memory and learning plasticity, as well as altered microglia, non-neuronal CNS cells that regulate neuroimmune responses and brain plasticity. Chronic fecal-oral exposures shaped microglial morphology and transcriptional profile, promoting phagocytic features in MAL-BG mice. Unexpectedly, these changes occurred independently from significant cytokine-induced inflammation or blood-brain barrier (BBB) disruption, key gut-brain pathways. Metabolomic profiling of the MAL-BG cortex revealed altered polyunsaturated fatty acid (PUFA) profiles and systemic lipoxidative stress. In contrast, supplementation with an ω3 PUFA/antioxidant-associated diet (PAO) mitigated cognitive deficits within the MAL-BG model. These findings provide valued insight into the malnourished gut microbiota-brain axis, highlighting PUFA metabolism as a potential therapeutic target.


[Surgical treatment of appendicular peritonitis in children].
The article is based on the results of 10-year use of the method of aspiration drainage of the abdominal cavity in the treatment of 980 children with purulent peritonitis of appendicular origin. The authors used only a polymer tube to drain the cavity of the true pelvis and in principle did not resort to intraoperative irrigation of the abdominal cavity, postoperative lavage, and intraperitoneal injection of antibiotics. Postoperative complications were recognized in the early stages of development and were treated by nonoperative methods on the main. The number of relaparotomies was 0.83% of the total number of operations for appendectomy. The described method meets the principles of pediatric surgery most fully, is more sparing than the other methods, and the authors recommend it for wide introduction into practice.


Tracking Bacterial Chromosome Dynamics with Microfluidics-Based Live Cell Imaging.
In bacteria, chromosomes are highly organized within the limited volume of the cell to form a nucleoid. Recent application of microscopy and chromosome conformation capture techniques have together provided a comprehensive understanding of the nature of this organization and the role of factors such as the structural maintenance of chromosomes (SMC) proteins in the establishment and maintenance of the same. In this chapter, we outline a microfluidics-based approach for live cell imaging of Escherichia coli chromosome dynamics in wild-type cells. This assay can be used to track the activity of the SMC complex, MukBEF, on DNA and assess the impact of perturbations such as DNA damage on chromosome organization and segregation.


Complex microbial nitrogen-cycling networks in three distinct anammox-inoculated wastewater treatment systems.
Microbial nitrogen removal mediated by anaerobic ammonium oxidation (anammox) are cost-effective, yet it is time-consuming to accumulate the slow-growing anammox bacteria in conventional wastewater treatment plants (WWTPs). Inoculation of anammox enriched pellets is an effective way to establish anammox and achieve shortcut nitrogen removal in full-scale WWTPs. However, little is known about the complex microbial nitrogen-cycling networks in these anammox-inoculated WWTPs. Here, we applied metagenomic and metatranscriptomic tools to study the microbial nitrogen removal in three conventional WWTPs, which have been inoculated exogenous anammox pellets, representing partial-nitrification anammox (PNA) and nitrification-denitrification nitrogen removal processes. In the PNA system of Bali (BL), ammonia was partially oxidized by ammonia-oxidizing bacteria (AOB) Nitrosomonas and the oxidized nitrite and the remaining ammonium were directly converted to N2 by anammox bacteria Ca. Brocadia and Ca. Kuenenia. In the nitrification-denitrification system of Wenshan (WS), ammonia-oxidizing archaea (AOA) Thaumarchaeota unexpectedly dominated the nitrifying community in the presence of AOB Nitrosomonas. Meanwhile, the biomass yield of Ca. Brocadia was likely inhibited by the high biodegradable organic compound input and limited by substrate competitions from AOA, AOB, complete ammonia oxidizers (comammox) Nitrospira, nitrite-oxidizing bacteria (NOB) Nitrospira, and heterotrophic denitrifiers. Unexpectedly, comammox Nitrospira was the predominant nitrifier in the presence of AOB Nitrosomonas in the organic carbon-rich nitrification-denitrification system of Linkou (LK). These results clearly showed that distinct active groups were working in concert for an effective nitrogen removal in different WWTPs. This study confirmed the feasibility of anammox application in ammonium-rich systems by direct inoculation of the exogenous anammox pellets and improved our understanding of microbial nitrogen cycling in anammox-driven conventional WWTPs from both physiochemical and omics perspectives.


Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis.
Small cell lung cancer (SCLC) is a pulmonary neuroendocrine cancer with very poor prognosis and limited effective therapeutic options. Most patients are diagnosed at advanced stages, and the exact reason for the aggressive and metastatic phenotype of SCLC is completely unknown. Despite a high tumor mutational burden, responses to immune checkpoint blockade are minimal in patients with SCLC. This may reflect defects in immune surveillance. Here we illustrate that evading natural killer (NK) surveillance contributes to SCLC aggressiveness and metastasis, primarily through loss of NK-cell recognition of these tumors by reduction of NK-activating ligands (NKG2DL). SCLC primary tumors expressed very low level of NKG2DL mRNA and SCLC lines express little to no surface NKG2DL at the protein level. Chromatin immunoprecipitation sequencing showed NKG2DL loci in SCLC are inaccessible compared with NSCLC, with few H3K27Ac signals. Restoring NKG2DL in preclinical models suppressed tumor growth and metastasis in an NK cell-dependent manner. Likewise, histone deacetylase inhibitor treatment induced NKG2DL expression and led to tumor suppression by inducing infiltration and activation of NK and T cells. Among all the common tumor types, SCLC and neuroblastoma were the lowest NKG2DL-expressing tumors, highlighting a lineage dependency of this phenotype. In conclusion, these data show that epigenetic silencing of NKG2DL results in a lack of stimulatory signals to engage and activate NK cells, highlighting the underlying immune avoidance of SCLC and neuroblastoma. SIGNIFICANCE: This study discovers in SCLC and neuroblastoma impairment of an inherent mechanism of recognition of tumor cells by innate immunity and proposes that this mechanism can be reactivated to promote immune surveillance.


Civil society organisations and global health initiatives: problems of legitimacy.
Civil society organisations (CSOs) have a prominent role in global health initiatives such as The Global Fund to Fight AIDS, Tuberculosis and Malaria (the Global Fund) and, in the United States, the President's Emergency Plan for AIDS Relief (PEPFAR). They are increasingly consulted by international organisations and, in some cases like the Global Fund, are involved in decision-making. They are also increasingly seen as crucial agents in delivering health interventions on the ground. Some donors prefer to channel funds through CSOs in developing countries than through perceived to be corrupt or inefficient government agencies. This paper examines this growing role and the arguments put forward to justify their increasing influence, particularly in HIV/AIDS initiatives. It analyses the main challenges to CSOs' legitimacy and outlines key responses to these challenges. It concludes by suggesting a number of research priorities that might help to evaluate the impact of CSOs in global health initiatives.


New insights of aquaporin 5 in the pathogenesis of high altitude pulmonary edema.
High altitude pulmonary edema (HAPE) affects individuals and is characterized by alveolar flooding with protein-rich edema as a consequence of blood-gas barrier disruption. In this study, we hypothesized that aquaporin 5 (AQP5) which is one kind of water channels may play a role in preservation of alveolar epithelial barrier integrity in high altitude pulmonary edema (HAPE). Therefore, we established a model in Wildtype mice and AQP5 -/- mice were assingned to normoxic rest (NR), hypoxic rest (HR) and hypoxic exercise (HE) group. Mice were produced by training to walk at treadmill for exercising and chamber pressure was reduced to simulate climbing an altitude of 5000 m for 48 hours. Studies using BAL in HAPE mice to demonstrated that edema is caused leakage of albumin proteins and red cells across the alveolarcapillary barrier in the absence of any evidence of inflammation. In this study, the Lung wet/dry weight ratio and broncholalveolar lavage protein concentrations were slightly increased in HE AQP5 -/- mice compared to wildtype mice. And histologic evidence of hemorrhagic pulmonary edema was distinctly shown in HE group. The lung Evan's blue permeability of HE group was showed slightly increased compare to the wildtype groups, and HR group was showed a medium situation from normal to HAPE development compared with NR and HE group. Deletion of AQP5 slightly increased lung edema and lung injury compared to wildtype mice during HAPE development, which suggested that the AQP5 plays an important role in HAPE formation induced by high altitude simulation.


Biodegradation of 1,2,3-trichloropropane through directed evolution and heterologous expression of a haloalkane dehalogenase gene.
Using a combined strategy of random mutagenesis of haloalkane dehalogenase and genetic engineering of a chloropropanol-utilizing bacterium, we constructed an organism that is capable of growth on 1,2,3-trichloropropane (TCP). This highly toxic and recalcitrant compound is a waste product generated from the manufacture of the industrial chemical epichlorohydrin. Attempts to select and enrich bacterial cultures that can degrade TCP from environmental samples have repeatedly been unsuccessful, prohibiting the development of a biological process for groundwater treatment. The critical step in the aerobic degradation of TCP is the initial dehalogenation to 2,3-dichloro-1-propanol. We used random mutagenesis and screening on eosin-methylene blue agar plates to improve the activity on TCP of the haloalkane dehalogenase from Rhodococcus sp. m15-3 (DhaA). A second-generation mutant containing two amino acid substitutions, Cys176Tyr and Tyr273Phe, was nearly eight times more efficient in dehalogenating TCP than wild-type dehalogenase. Molecular modeling of the mutant dehalogenase indicated that the Cys176Tyr mutation has a global effect on the active-site structure, allowing a more productive binding of TCP within the active site, which was further fine tuned by Tyr273Phe. The evolved haloalkane dehalogenase was expressed under control of a constitutive promoter in the 2,3-dichloro-1-propanol-utilizing bacterium Agrobacterium radiobacter AD1, and the resulting strain was able to utilize TCP as the sole carbon and energy source. These results demonstrated that directed evolution of a key catabolic enzyme and its subsequent recruitment by a suitable host organism can be used for the construction of bacteria for the degradation of a toxic and environmentally recalcitrant chemical.


Transforming their lives: post-traumatic growth experience in Chinese women with breast cancer-a grounded theory study.
Our research sought to explore post-traumatic growth experience among Chinese women with breast cancer. Constructivist grounded theory methodology was utilised to understand Chinese women's post-traumatic growth experience. 24 women with breast cancer were recruited from China. Data was collected through semi-structured, interviews. Three categories were developed from the data: renewing self-perception, encountering changes in relationships, and altering philosophical values and beliefs. The unique manifestations of post-traumatic growth highlight the need for development and adaption of the post-traumatic growth inventory to reduce cultural biases within the assessment tool and incorporate new culturally appropriate items.


ABR examinations: the why, what, and how.
The American Board of Radiology (ABR) has provided certification for diagnostic radiologists and other specialists and subspecialists for more than 75 years. The Board certification process is a tangible expression of the social contract between the profession and the public by which the profession enjoys the privilege of self-regulation and the public is assured that it can expect medical professionals to put patients' interests first, guarantees the competence of practitioners, and guards the public health. A primary tool used by the ABR in fulfilling this responsibility is the secure proctored examination. This article sets forth seven standards based on authoritative sources in the field of psychometrics (the science of mental measurements), and explains in each case how the ABR implements that standard. Readers are encouraged to understand that, despite the multiple opinions that may be held, these standards developed over decades by experts using the scientific method should be the central feature in any discussion or critique of examinations given for the privilege of professional practice and for safeguarding the public well-being.


First-in-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with Follicular and Other CD20+ Non-Hodgkin Lymphomas.
In this phase I study (NCT01307267), we evaluated safety, pharmacokinetics, clinical activity, and pharmacodynamics of treatment with utomilumab plus rituximab in patients with relapsed/refractory follicular lymphoma (FL) and other CD20+ non-Hodgkin lymphomas (NHL). Primary objectives were to assess treatment safety and tolerability for estimating the MTD, using a modified time-to-event continual reassessment method, and selecting the recommended phase II dose (RP2D). Sixty-seven patients received utomilumab (0.03-10.0 mg/kg every 4 weeks) and rituximab (375 mg/m2 weekly) in the dose-escalation groups or utomilumab (1.2 mg/kg every 4 weeks) plus rituximab in the dose-expansion cohort. No patient experienced dose-limiting toxicity. The MTD for utomilumab in combination with rituximab was not reached and estimated to be ≥10 mg/kg every 4 weeks. The majority of the utomilumab treatment-related adverse events (AE) were grade 1 to 2; the most common AE was fatigue (16.4%). The pharmacokinetics of utomilumab in combination with rituximab was linear in the 0.03 to 10 mg/kg dose range. A low incidence (1.5%) of treatment-induced antidrug antibodies against utomilumab was observed. The objective response rate was 21.2% (95% CI, 12.1%-33.0%) in all patients with NHL, including four complete and 10 partial responses. Analysis of paired biopsies from a relapsed/refractory FL patient with complete response showed increased T-cell infiltration and cytotoxic activity in tumors. Biomarker correlations with outcomes suggested that clinical benefit may be contingent on patient immune function. Utomilumab in combination with rituximab demonstrated clinical activity and a favorable safety profile in patients with CD20+ NHLs.


Collaboration in the presence of an electronic health record.
Recent laws in the United States incent healthcare practices to adopt electronic health records (EHRs). While there is extensive research related to EHRs generally, there is a dearth of EHR research specific to collaborative care settings. This study reports responses from 101 collaborative care offices who completed a 13-question online survey. The mixed-methods analysis provides insights as to the satisfaction, obstacles, and solutions to interdisciplinary collaboration in the presence of an EHR. Respondents reported highest satisfaction with medical billing, interdisciplinary communication, and scheduling. Satisfaction was lower as it relates to time consumption, difficult learning curve, creation of appointment notes, and health registries. This research reveals varied and conflicting approaches to addressing confidentiality and HIPAA within the EHR. Recommendations for improving EHR to better support collaborative care include the addition of modules common in mental health-specific EHR, enhanced tracking of mental health outcomes, templates for joint appointments, and improvements in population-based registry functions.


Proteolytic events of wound-healing--coordinated interactions among matrix metalloproteinases (MMPs), integrins, and extracellular matrix molecules.
During wound-healing, cells are required to migrate rapidly into the wound site via a proteolytically generated pathway in the provisional matrix, to produce new extracellular matrix, and, subsequently, to remodel the newly formed tissue matrix during the maturation phase. Two classes of molecules cooperate closely to achieve this goal, namely, the matrix adhesion and signaling receptors, the integrins, and matrix-degrading and -processing enzymes, the matrix metalloproteinases (MMPs). There is now substantial experimental evidence that blocking key molecules of either group will prevent or seriously delay wound-healing. It has been known for some time now that cell adhesion by means of the integrins regulates the expression of MMPs. In addition, certain MMPs can bind to integrins or other receptors on the cell surface involved in enzyme activation, thereby providing a mechanism for localized matrix degradation. By proteolytically modifying the existing matrix molecules, the MMPs can then induce changes in cell behavior and function from a state of rest to migration. During wound repair, the expression of integrins and MMPs is simultaneously up-regulated. This review will focus on those aspects of the extensive knowledge of fibroblast and keratinocyte MMPs and integrins in biological processes that relate to wound-healing.


Prospects for using nonconventional feeds in diets for Awassi dairy sheep in Syria.
High feed costs are major obstacles for resource-poor dairy sheep farmers in West Asia, along with large fluctuation in grain and straw prices. Farmers need low-cost diets using locally available feeds that can provide sufficient milk of good quality. Two experimental trials were conducted on Awassi milking ewes to evaluate nonconventional and balanced low-cost diets against the traditional unbalanced diet used by farmers (control) on the total yields (milk, fat, protein, and total solids) and milk composition (fat, protein, total solids, and lactose), an important indicator of milk quality. The first trial was conducted at the research station of the International Center for Agricultural Research in the Dry Areas (ICARDA, Aleppo, Syria) to test 6 low-cost balanced diets using locally available feeds and agro byproducts against the control diet. Each diet was tested on 8 ewes that were kept on pasture as a basal diet, but received different supplements, including barley, wheat bran and nonconventional feeds (urea-treated wheat straw, molasses, sugar beet pulp, and cotton seed cake). Five balanced diets enhanced the total yields of milk, fat, protein, and total solids, in 2 cases, significantly. These diets increased total milk yield by 17.7 to 50.2% and decreased supplement feeding costs by 43% compared with the control. However, milk composition remained unaffected. The second trial was conducted on 3 different farms in northern Syria to assess in each farm a low-cost balanced diet on milking ewes (n=15) in comparison to the farmer's control (n=15). The balanced diet was a modification requested by farmers of the best performing diet in the on-station trial. Confirming the first trial's research results, the balanced diet outperformed the control in total yields; for instance, it increased total milk yield by 28 to 40% and raised net income by 30%, without affecting milk composition. Both trials showed that using locally available nonconventional feedstuffs, such as molasses, integrated into balanced dairy sheep diets can decrease feed costs of resource-poor farmers, while enhancing total yields of milk and milk constituents without compromising milk quality components. This will greatly improve the profitability of dairy sheep production in dry areas.


Intra- and extracellular markers in interstitial transudate of perfused rat hearts.
The interstitial transudate was investigated in isolated perfused rat hearts. Capillary permeability and the kinetics of interstitial uptake and release were characterized using four different marker molecules (mol wt 522 to 2 X 10(6)). The half-time (t1/2) values (less than 30 to 170 s) and the interstitial concentration after 30 min (100-44% of arterial concentration) reflected the order and inverse order of their molecular weights, respectively. Creatine kinase (CK) and glutathione (GSH) were measured during control state, hypoxia, and anoxia, followed by reoxygenation. Interstitial concentrations of CK and GSH were higher by a factor of 100 and 8, respectively, compared with the venous effluent. During hypoxia (PO2 = 110 mmHg, i.e., O2 supply = 30% of demand) and reoxygenation there was a significant increase only in the interstitial (not venous) release of CK and GSH, which was further increased during anoxia. Ischemia (75 min) and reperfusion cause no interstitial release of lysosomal (acid phosphatase) and mitochondrial (glutamate dehydrogenase) enzymes despite a massive loss of cytosolic enzymes. Examination of the interstitial transudate allows characterization of capillary transfer and provides a very sensitive measure of sarcolemmal release phenomena.


The ligurian human immunodeficiency virus clinical network: a web tool to manage patients with human immunodeficiency virus in primary care and multicenter clinical trials.
In recent years, Highly-Active Anti-Retroviral Therapies (HAARTs) have modified the Human Immunodeficiency Virus (HIV) life-cycle and the disease is now considered chronic. Consequently, a longitudinal and complex follow-up is now required for HIV positive patients during their lifetime. Moreover, patients often encounter various complications due to comorbidities, related to the immunodeficiency state and HAARTs' side effects. Thus, HIV positive patients are involved in multicenter clinical trials (MCTs) to improve treatments and discover a preventive vaccine. Therefore, physicians require proper instruments to access comprehensive patient data for managing patients during follow-ups, and tools for data collection and analysis in MCTs. The Ligurian HIV Clinical Network aims to provide physicians with a Web-tool to administrate HIV positive patients' data within primary-care and to reuse the collected clinical information to perform MCTs in Northern Italy. The key aspect of the system is a relational database which allows the storage of various types of clinical information (eg, related to HIV, cardiovascular, or hepatic diseases) in multiple formats. The modular design of the database permits a rapid insertion of new parameters without requiring any changes in the database structure. Furthermore, codes from biomedical ontologies controlled vocabularies ("Logical Observation Identifier Names and Codes", and "International Classification of Diseases 9") and ontologies ("Systematized Nomenclature of Medicine Clinical Terms"), units and normality ranges used by all partners participating in the project were collected to achieve a complete semantic interoperability. Accordingly, data can be automatically normalized through the z score formula and physicians can extract and correctly compare information with external statistical tools. Moreover, to respect patients' privacy and legal issues, a local identifier, determined through an HASH cryptography algorithm, is assigned to each patient during the registration process. The database is managed by a user-friendly Web-platform which allows quick access to information during medical examinations and the reusing of the collected data for present and future MCTs. Furthermore, a bidirectional middleware was created in order to import/export information through HL7 messaging. Hence, data can be manually entered by physicians or automatically collected within HL7-compliant Hospital Information systems. Presently, the direct storage of patients' information from the San Paolo Hospital (Savona, Italy), and San Martino and Galliera hospitals in Genoa is in a test phase. Currently, 8 centers of Infectious Diseases (located in Liguria and Piedmont) are participating in the project and almost 400 HIV positive patients have been recorded in the system. Patient data has been used for primary care and research purposes. Currently, there are 4 on-going MCTs and preliminary results have already been presented at International HIV congresses. The Web-platform allows effective management, sharing and reuse of information within primary care and clinical research. In the future it is planned to share the clinical information from this network with other HL7-compliant workgroups and to extend the platform to other infective diseases (eg, hepatitis).