Effectiveness of a clinical intervention for MD/PhD students re-entering medical school.
For MD/PhD students, the transition to medical school following graduate research can be difficult. We developed a clinical intervention, the Clinical Preceptorship Program (CPP), for MD/PhD students at Vanderbilt to ease the transition to the core clinical clerkship year (the 3rd medical year) following graduate training. In this study, we determined whether the CPP prepared MD/PhD students adequately for medical school reentry. Clerkship grades were obtained for 680 medical students and 50 MD/PhD students for academic years 2004-2010. A student's unpaired t test was used to analyze differences between group grades. We did not detect significant differences in the grades of the MD versus MD/PhD students. No differences in individual clerkships were detected with the exception of the Surgery clerkship. These data suggest that the CPP intervention was successful in preparing MD/PhD students for the core clerkship year. Such a clinical intervention can be an effective preparation for MD/PhD students returning to medical school.


Fluorobenzoic acid coformers to improve the solubility and permeability of the BCS class IV drug naftopidil.
Crystalline salts of the low solubility and low permeability drug naftopidil were investigated with mono-, di-, tri-, and tetrafluorobenzoic acids as coformers to show that 245TFBA (2,4,5-trifluorobenzoic acid) is the optimal salt with faster dissolution and high permeability, thereby opening the study of fluorinated coformers in pharmaceutical cocrystals and salts.


Surface markers and cytotoxic activities of lymphocytes in monoclonal gammopathy of undetermined significance and untreated multiple myeloma. Increased phytohemagglutinin-induced cellular cytotoxicity and inverted helper/suppressor cell ratio are features common to both diseases.
To determine whether monoclonal gammopathy of undetermined significance (MGUS) resembles multiple myeloma (MM) with regard to phenotype and functional activity, 16 patients with MGUS and 16 with untreated MM were studied for surface markers and cytotoxic activities phytohemagglutinin-induced cellular cytotoxicity (PHA-ICC), antibody-dependent cellular cytotoxicity, natural killer (NK) activity. Our data showed a consistent immunological similarity between the two diseases. An increase in OKT8+ cells was evident in both patient groups and a significant reduction in the T4/T8 ratio, more pronounced in MM, was observed. Alterations in NK activity or ADCC were not found in MGUS or MM. A significant increase in PHA-ICC was demonstrated in the two diseases. The increase in PHA-ICC observed seems to be attributable to an increased frequency and/or lytic efficiency of PHA-ICC lymphoid effector cells. These data suggest that similar immunological alterations are common to the two diseases. The greater helper/suppressor ratio reduction observed in MM seems to be related to the more severe clonal proliferation in these patients.


Studies on the occurrence of circulating immune complexes in vascular diseases.
The presence of circulating immune complexes was studied in 347 samples of serum from 212 patients with various vascular diseases. Two quantitative methods (complement-consumption assay and C1q-solubility test) were used for the measurement of the concentration of the complexes. Immune complexes were detected in each group of patients tested (coronary arteriosclerosis, myocardial infarction, cerebral artery sclerosis, arteriosclerosis obliterans, phlebothrombosis, pulmonary infarction). A high proportion of positivity was recorded in myocardial infarction (in 43 patients out of the 94 tested) and in arteriosclerosis obliterans (7 out of 11 cases). The possible pathogenic role of the circulating immune complexes is discussed.


Therapeutic metastatic prostate cancer vaccines: lessons learnt from urologic oncology.
Therapeutic cancer vaccines have been recognized as a promising treatment option in clinical oncology for nearly three decades. However, despite many efforts, only one cancer vaccine - sipuleucel-T, activating the anti-PAP (prostatic acid phosphatase) immune response, has obtained Food and Drug Administration (FDA) approval. This review describes the most advanced research on the use of therapeutic cancer vaccines in the treatment of prostate cancer. In addition to sipuleucel-T, which was approved in urologic oncology in 2010, four cancer vaccines were and have been tested in phase III clinical trials in patients with metastatic castration resistant prostate cancer (mCRPC): GVAX (prostate cancer variant) containing irradiated prostate cancer cell, PPV peptide vaccine, PCVAC/PCa dendritic cell-based vaccine and PROSTVAC anti PSA (prostate-specific antigen) vaccine. This review compares the most promising and best-studied cancer vaccines: sipuleucel-T and PROSTVAC. Currently, both vaccines have been tested in combination with other therapeutic approaches, including check point inhibitors. It seems possible that the efficacy of sipuleucel-T and PROSTVAC could be increased in combination therapy with other medications.


The NPY/AgRP neuron and energy homeostasis.
Kennedy hypothesized nearly 50 y ago that negative feedback regulation of body fat stores involves hormones that circulate in proportion to adiposity and enter the brain, where they exert inhibitory effects on food intake and energy balance. Recent studies implicate leptin and insulin as 'adiposity signals' to the brain that promote negative energy balance in two ways: by inhibiting 'anabolic' hypothalamic neuronal circuits that stimulate food intake and promote weight gain, and by activating 'catabolic' pathways that reduce food intake and body weight. Chief among candidate 'anabolic' effector pathways is the NPY/AgRP neuron, found only in the hypothalamic arcuate nucleus. These neurons make peptides that potently stimulate food intake not only by increasing neuropeptide Y (NPY) signaling, but by reducing melanocortin signaling via the release of agouti-related peptide (AgRP), an endogenous melanocortin 3/4 receptor antagonist. Since NPY/AgRP neurons express receptors for leptin and insulin and are inhibited by these hormones, they are activated by a decrease of leptin or insulin signaling. Fasting, uncontrolled diabetes, and genetic leptin deficiency are examples of conditions in which food intake increases via a mechanism hypothesized to involve NPY/AgRP neurons. Data are reviewed which illustrate the role of these neurons in adaptive and maladaptive states characterized by hyperphagia and weight gain.


Concussion Care in the Emergency Department: A Prospective Observational Brief Report.
Emergency physicians are often the initial-and only-clinical providers for patients who have sustained a mild traumatic brain injury. This prospective observational study seeks to examine the practice patterns of clinicians in an academic Level I trauma center as they relate to the evaluation of patients who were presumed to be at high risk for mild traumatic brain injury. Specifically, we describe the frequency of a documented mild traumatic brain injury evaluation, diagnosis, and discharge education. This pilot study took place in a single academic Level I trauma and emergency care center during a 4-week period. Patients were identified by triage nurses, who determined whether they responded affirmatively to 2 questions that indicated a potential risk for mild traumatic brain injury. Data were abstracted from emergency department clinician documentation on identified patients to describe the frequency of a documented mild traumatic brain injury evaluation (history and physical examination), diagnosis, and discharge education among those who were identified to be at risk for a mild traumatic brain injury. Ninety-eight subjects were included in the present study. Documentation of a mild traumatic brain injury evaluation was present for less than 50% of patients, a final diagnosis of mild traumatic brain injury was included for 36 (37%; 95% confidence interval 27.8% to 46.7%), and discharge education was provided to 15 (15%; 95% confidence interval 9.2% to 21.4%). Of the 36 patients who received a documented mild traumatic brain injury diagnosis, 15 (41.5%; 95% confidence interval 26.7% to 57.9%) received mild traumatic brain injury-specific discharge education. This study suggests that the majority of patients at high risk for mild traumatic brain injury have no documentation of an evaluation for one. Also, patients with a mild traumatic brain injury diagnosis were unlikely to receive appropriate discharge education about it. Education and standardization are needed to ensure that patients at risk for mild traumatic brain injury receive appropriate evaluation and care.


Adhesion prevention by solutions of sodium carboxymethylcellulose in the rat. II.
In a rat model, sodium carboxymethylcellulose (SCMC) was compared with normal saline and 32% dextran 70 in the prevention of surgically induced intraperitoneal adhesions. The 32% dextran 70 was similar to normal saline in the initial prevention of adhesions, and both appeared less effective than SCMC. After lysis of the initial adhesions, SCMC was significantly more effective than 32% dextran 70 in the prevention of the reformation of adhesions. Possible mechanisms of action, complications of SCMC, and the need for further research in finding an ideal solution for use in adhesion prevention are discussed.


Diffusion analysis of valproate and trans-2-en-valproate in agar and in cerebral cortex of the rat.
The diffusion of valproate (VPA) and trans-2-en-valproate were studied in agar gel and in the cerebral cortex of the rat using pressure microejection and VPA-selective microelectrodes. From the agar measurements a free diffusion coefficient for VPA of 6.52 x 10(-6) cm2.s-1 and for trans-2-en-VPA of 5.25 x 10(-6) cm2.s-1 for 37 degrees C was determined. The tortuosity value in the cortex was 1.92 for VPA and 1.67 for trans-2-en-VPA. The tortuosity values suggest that VPA and trans-2-en-VPA diffuse mainly in the extracellular space of the brain.


Applying concepts from "rapid" and "agile" implementation to advance implementation research.
The translation of research findings into practice can be improved to maximize benefits more quickly and with greater flexibility. To expedite translation, researchers have developed innovative approaches to implementation branded as "rapid" and "agile" implementation. Rapid implementation has roots in precision medicine and agile implementation has roots in systems engineering and software design. Research has shown that innovation often derives from learning and applying ideas that have impacted other fields. This commentary examines "rapid" and "agile" approaches to implementation and provides recommendations to implementation researchers stemming from these approaches. Four key ideas are synthesized that may be broadly applicable to implementation research, including (1) adopting a problem orientation, (2) applying lessons from behavioral economics, (3) using adaptive study designs and adaptive interventions, and (4) using multi-level models to guide implementation. Examples are highlighted from the field where researchers are applying these key ideas to illustrate their potential impact. "Rapid" and "agile" implementation approaches to implementation stem from diverse fields. Elements of these approaches show potential for advancing implementation research, although adopting them may entail shifting scientific norms in the field.


Widespread endogenization of giant viruses shapes genomes of green algae.
Endogenous viral elements (EVEs)-viruses that have integrated their genomes into those of their hosts-are prevalent in eukaryotes and have an important role in genome evolution1,2. The vast majority of EVEs that have been identified to date are small genomic regions comprising a few genes2, but recent evidence suggests that some large double-stranded DNA viruses may also endogenize into the genome of the host1. Nucleocytoplasmic large DNA viruses (NCLDVs) have recently become of great interest owing to their large genomes and complex evolutionary origins3-6, but it is not yet known whether they are a prominent component of eukaryotic EVEs. Here we report the widespread endogenization of NCLDVs in diverse green algae; these giant EVEs reached sizes greater than 1 million base pairs and contained as many as around 10% of the total open reading frames in some genomes, substantially increasing the scale of known viral genes in eukaryotic genomes. These endogenized elements often shared genes with host genomic loci and contained numerous spliceosomal introns and large duplications, suggesting tight assimilation into host genomes. NCLDVs contain large and mosaic genomes with genes derived from multiple sources, and their endogenization represents an underappreciated conduit of new genetic material into eukaryotic lineages that can substantially impact genome composition.


Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02.
Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.


Comparison of two different metronidazole regimens in the treatment of Gardnerella vaginalis infection with or without trichomoniasis.
Gardnerella vaginalis infection confirmed by culture was treated either by a 2 g dose or divided doses of metronidazole in 100 and 200 female patients respectively. Both dosages were equally effective. We recommend a single dose of 2 g metronidazole in the treatment of Gard. vaginalis infection, particularly when association with trichomoniasis is confirmed or suspected.


Spatially and temporally regulated expression of the LIM class homeobox gene Hrlim suggests multiple distinct functions in development of the ascidian, Halocynthia roretzi.
Hrlim is a LIM class homeobox gene that was first isolated from the ascidian Halocynthia roretzi. To assess its roles in early development of the ascidian, spatial and temporal expression of Hrlim was examined by whole mount in situ hybridization. This revealed that transcription of Hrlim is activated at the 32-cell stage specifically in the endoderm lineage. Hrlim is also transiently expressed in all notochord precursor cells. Expression in the endoderm lineage continues through to the middle of gastrulation. After gastrulation, Hrlim is expressed in certain lineages that give rise to subsets of cells in the brain and spinal cord. Based on these observations, it is suggested that Hrlim plays multiple distinct roles in ascidian embryogenesis.


Vital Statistics: Estimating Injury Mortality in Kigali, Rwanda.
Globally, injury deaths largely occur in low- and middle-income countries. No estimates of injury associated mortality exist in Rwanda. This study aimed to describe the patterns of injury-related deaths in Kigali, Rwanda using existing data sources. We created a database of all deaths reported by the main institutions providing emergency care in Kigali—four major hospitals, two divisions of the Rwanda National Police, and the National Emergency Medical Service--during 12 months (Jan–Dec 2012) and analyzed it for demographics, diagnoses, mechanism and type of injury, causes of death, and all-cause and cause-specific mortality rates. There were 2682 deaths, 57% in men, 67% in adults >18 year, and 16% in children <5 year. All-cause mortality rate was 236/100,000; 35% (927) were due to probable surgical causes. Injury-related deaths occurred in 22% (593/2682). The most common injury mechanism was road traffic crash (cause-specific mortality rate of 20/100,000). Nearly half of all injury deaths occurred in the prehospital setting (47%, n = 276) and 49% of injury deaths at the university hospital occurred within 24 h of arrival. Being injured increased the odds of dying in the prehospital setting by 2.7 times (p < 0.0001). Injuries account for 22% of deaths in Kigali with road traffic crashes being the most common cause.Injury deaths occurred largely in the prehospital setting and within the first 24 h of hospital arrival suggesting the need for investment in emergency infrastructure. Accurate documentation of the cause of death would help policy makers make data-driven resource allocation decisions.


Bio-Inspired Highly Brilliant Structural Colors and Derived Photonic Superstructures for Information Encryption and Fluorescence Enhancement.
Inspired by the brilliant and tunable structural colors based on the large refractive index contrast (Δn) and non-close-packing structures of chameleon skins, ZnS-silica photonic crystals (PCs) with highly saturated and adjustable colors are fabricated. Due to the large Δn and non-close-packing structure, ZnS-silica PCs show 1) intense reflectance (maximal: 90%), wide photonic bandgaps, and large peak areas, 2.6-7.6, 1.6, and 4.0 times higher than those of silica PCs, respectively; 2) tunable colors by simply adjusting the volume fraction of particles with the same size, more convenient than the conventional way of altering particle sizes; and 3) a relatively low threshold of PC's thickness (57 µm) possessing maximal reflectance compared to that (>200 µm) of the silica PCs. Benefiting from the core-shell structure of the particles, various derived photonic superstructures are fabricated by co-assembling ZnS-silica and silica particles into PCs or by selectively etching silica or ZnS of ZnS-silica/silica and ZnS-silica PCs. A new information encryption technique is developed based on the unique reversible "disorder-order" switch of water-responsive photonic superstructures. Additionally, ZnS-silica PCs are ideal candidates for enhancing fluorescence (approximately tenfold), approximately six times higher than that of silica PC.


Increased nuchal translucency and pregnancy outcome: a retrospective study of 1063 consecutive singleton pregnancies in a single referral institution.
The goals of this study are to assess pregnancy outcome with increased nuchal translucency (NT) and to determine the risk of adverse pregnancy outcome in relation to the degree of increased NT. All singleton pregnancies with increased NT at the first screening ultrasound examination referred to the Department of Fetal Medicine at the Helsinki University Central Hospital during 2002 to 2007 were included. Pregnancy outcomes and short-term outcomes of the newborns were recorded and analyzed. Of the 1063 pregnancies, karyotype was normal in 834 (78%). The majority, 611 (73%), of euploid fetuses was in the lowest NT group (95th percentile--3.4 mm). Percentage of favorable outcome decreased from 92% in the lowest NT group (95th percentile--3.4 mm) to 18% in the highest NT group (≥6.5 mm). Structural defects or genetic disorders were observed in 74 (9%) of cases with normal karyotype, of which 43 (58%) resulted in live birth, 25 (34%) in termination of pregnancy, and 6 (8%) in miscarriage or perinatal death. Even minimal (95th percentile--3.4 mm) increase in NT thickness is associated with adverse pregnancy outcome also in euploid fetuses.


Analysis of Complex Carbohydrate Composition in Plant Cell Wall Using Fourier Transform Mid-Infrared Spectroscopy.
Fourier transform mid-infrared spectroscopy (FTIR) is a powerful tool for compositional analysis of plant cell walls. The infrared spectrum generates a fingerprint of a sample with absorption peaks corresponding to the frequency of vibrations between the bonds of the atoms making up the material. Here we describe a method focused on the use of FTIR in combination with principal component analysis (PCA) to characterize the composition of the plant cell wall. The FTIR method described here facilitates high-throughput identification of the major compositional differences across a large set of samples in a low-cost and non-destructive manner.


Fast and efficient removal of Reactive Black 5 from aqueous solution by a combined method of ultrasound and sorption process.
Removal of Reactive Black 5 (RB5) from aqueous solutions was carried by the sorption process in the presence and in the absence of ultrasound. Sorption of the dye on the solid phase was investigated in a series of batch sorption experiments to determine the influence of different parameters such as contact time, amount of sorbent and concentration of pollutant on the removal efficiency of RB5 with and without ultrasound. The experimental data were fitted properly to the Freundlich model and the isotherm constants were 28.2 and 7.4 for k(f) and 0.13 and 0.38 for 1/n in the presence and in the absence of ultrasound (20 kHz) respectively. The data were analyzed with different sorption kinetic models and were better fitted with a pseudo-second-order kinetic model. Two ultrasonic generators at 20 and 500 kHz were used for sonication of the system. This investigation also reveals that RB5 can be removed by higher frequency apparatus (500 kHz) without sorbent in about 60 min sonication. The rate of removal was higher at the higher frequency than at the lower one.


Reconstructing Middle and Upper Paleolithic human mobility in Portuguese Estremadura through laser ablation strontium isotope analysis.
Understanding mobility and landscape use is important in reconstructing subsistence behavior, range, and group size, and it may contribute to our understanding of phenomena such as the dynamics of biological and cultural interactions between distinct populations of Upper Pleistocene humans. However, studies using traditional strontium isotope analysis are generally limited to identifying locations of childhood residence or nonlocal individuals and lack the sampling resolution to detect movement over short timescales. Here, using an optimized methodology, we present highly spatially resolved 87Sr/86Sr measurements made by laser ablation multicollector inductively coupled plasma mass spectrometry along the growth axis of the enamel of two marine isotope stage 5b, Middle Paleolithic Neanderthal teeth (Gruta da Oliveira), a Tardiglacial, Late Magdalenian human tooth (Galeria da Cisterna), and associated contemporaneous fauna from the Almonda karst system, Torres Novas, Portugal. Strontium isotope mapping of the region shows extreme variation in 87Sr/86Sr, with values ranging from 0.7080 to 0.7160 over a distance of c. 50 km, allowing short-distance (and arguably short-duration) movement to be detected. We find that the early Middle Paleolithic individuals roamed across a subsistence territory of approximately 600 km2, while the Late Magdalenian individual parsimoniously fits a pattern of limited, probably seasonal movement along the right bank of the 20-km-long Almonda River valley, between mouth and spring, exploiting a smaller territory of approximately 300 km2. We argue that the differences in territory size are due to an increase in population density during the Late Upper Paleolithic.


Oleanolic acid rejuvenates testicular function through attenuating germ cell DNA damage and apoptosis via deactivation of NF-κB, p53 and p38 signalling pathways.
Inflammation can cause degenerative changes of reproductive function. Oleanolic acid (OA), the effective component from Ligustrum lucidum Ait., exhibits significantly anti-inflammation and antiageing activity. However, whether OA restores testicular dysfunction via inhibition of inflammation with ageing is unclear. Here, in a natural ageing rat model, we investigated the protection effects of OA and its mechanism of action. Eighteen-month-old Sprague Dawley (SD) rats were randomly divided into ageing control group and two OA-treated groups (5 and 25 mg/kg). Nine-month-old SD rats were used as adult controls. All rats were received either vehicle or OA for 6 months. Then, histomorphology, weight and index of testis, protein expression and immunohistochemistry were examined. Oleanolic acid significantly restored testicular morphology and improved testicular weight and index. Moreover, OA significantly inhibited phospho-NF-κB p65 and its downstream proinflammatory cytokines' expressions, including IL-1β, COX-2 and TNF-α in testis tissues. Similarly, OA remarkably inhibited IL-1β and TNF-α production. OA significantly attenuated germ cells' DNA damage and apoptosis. Such changes were accompanied by downregulation of γH2AX, p-P53 and Bax expressions, and upregulation of Bcl-2 and Bcl-2/Bax ratio. In addition, OA remarkably inhibited p38 signalling. Oleanolic acid effectively rejuvenates testicular function via attenuating germ cell DNA damage and apoptosis through deactivation of NF-κB, p53 and p38 signalling pathways.


Tips of the Trade #14. A guide for the proper placement of a above a cannulated Asnis screw above a sliding DHS hip screw.
Low fractures of the femoral neck are often treated by reduction and internal fixation with a sliding screw and plate. In base of the neck fractures, a supplemental cannulated screw should be used to prevent rotation of the femoral head and neck during sliding screw insertion. It is critical that the large sliding screw and the smaller supplemental screw are inserted in parallel alignment, without impinging upon each other. This article describes an easily manufactured guide that facilitates parallel placement of the screws and assures adequate clearance between the two screws.


Do you know the diagnostic importance of susceptibility-weighted imaging on MRI for patients with cerebral fat embolism?
If you suspect cerebral fat embolism (CFE) of the diagnosis for the patients who present with impaired consciousness and hypoxia following a fracture, susceptibility-weighted imaging should be included of head MRI imaging. We report a case of cerebral fat embolism (CFE) that could be identified only by susceptibility-weighted imaging (SWI). Collection and analysis of previous case reports of CFE revealed utilization of SWI in less than one third of suspected cases, despite its known diagnostic ability for CFE.


Effect of flexible sigmoidoscopy-based screening on colorectal cancer incidence and mortality: an updated systematic review and meta-analysis of randomized controlled trials.
Our objective was to estimate the effect of flexible sigmoidoscopy (FS)-based screening on colorectal cancer (CRC) incidence and mortality by conducting an updated meta-analysis of randomized controlled trials (RCTs). PubMed, Web of Science, Embase, and Cochrane Library searched for RCTs from database inception to December 2022. The methodological quality of the RCTs was assessed using the Cochrane Collaboration Risk of Bias Tool. RevMan 5.4 was used for this meta-analysis. Four RCTs involving 457, 871 patients were included. This meta-analysis revealed that FS-based screening was associated with a 20% relative risk reduction in CRC incidence [RR = 0.80; 95% CI (0.75, 0.86); P < 0.00001], and a 24% reduction in CRC mortality [RR = 0.76; 95% CI (0.70, 0.82); P < 0.00001]. In addition, this meta-analysis revealed that FS-based screening reduced the incidence[RR = 0.68; 95% CI (0.60, 0.77); P < 0.00001] and mortality[RR = 0.64; 95% CI (0.49, 0.83); P = 0.0007] of distal CRC, but had no significant effect on proximal colon cancer. FS-based screening appeared to be effective in reducing distal CRC incidence and mortality in patients at average risk compared to no intervention, but had no significant effect on proximal colon cancer.


Leucine-rich repeat-containing G protein-coupled receptor 5 expression in ductular reactions after chemotherapy for metastatic colorectal cancer.
Oval cells with ductular reactions (DR) in damaged liver are referred to as "intermediate hepatobiliary cells". In a preliminary study, we had found expression of the leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) known as a potential marker for stem cells in the small intestine and colon in DR in liver damaged by chemotherapy for metastatic colorectal cancer (CRC). The aim of this study was to confirm LGR expression in DR in damaged liver after chemotherapy. A total of 68 liver specimens obtained after surgical resection were stained with monoclonal antibodies for cytokeratin (CK)7, neural cell adhesion molecule (NCAM; a bile ductular and liver progenitor cell marker), CD133 (a candidate stem cell marker of hepatocellular carcinoma as well as CRC) and LGR5. Additionally, these mRNA levels were investigated according to the location in damaged liver after chemotherapy using microdissected specimens. We observed that LGR5 was expressed in DR with CD133, CK7 and NCAM expression. By contrast, LGR5, CD133 and NCAM were not expressed in mature bile ducts with CK7. In transcriptional analysis, LGR5 mRNA levels in fibrotic tissue including DR were higher compared with that in adjacent normal liver without significant difference. These findings suggest that LGR5 may be involved in maintaining DR in damaged liver.


Crystal structure of aqua-(nitrato-κO)dioxido{2-[3-(pyridin-2-yl-κN)-1H-1,2,4-triazol-5-yl-κN (4)]phenolato-κO}uranium(VI) aceto-nitrile monosolvate monohydrate.
In the title compound, [U(C13H9N4O)(NO3)O2(H2O)]·CH3CN·H2O, the U(VI) atom is seven-coordinated in a distorted penta-gonal-bipyramidal N2O5 manner by one tridentate triazole ligand, one monodentate nitrate anion and one water mol-ecule in the equatorial plane and by two uran-yl(VI) O atoms in the axial positions. In the crystal, the U(VI) complex mol-ecule is linked to the water and aceto-nitrile solvent mol-ecules through N-H⋯N, O-H⋯O and O-H⋯N hydrogen bonds, forming a sheet structure parallel to the bc plane. The sheets are further linked by an additional O-H⋯O hydrogen bond, forming a three-dimensional network.


Proenzyme to urokinase-type plasminogen activator in the mouse in vivo.
We have investigated whether urokinase-type plasminogen activator (u-PA) is present in the mouse in vivo as the proenzyme or as the active enzyme. u-PA in extracts of various murine tissues was of a one-polypeptide chain form with an electrophoretic mobility indistinguishable from purified proenzyme (pro-u-PA), as demonstrated by SDS-polyacrylamide gel electrophoresis under reducing conditions followed by immunoblotting. No 2-chain u-PA was detected in any of the extracts (detection limit 10% of that of one-chain u-PA). In bladder urine more than half of the u-PA was of the one-chain form. Together with previous immunocytochemical studies of the normal murine tissues and studies of the Lewis lung carcinoma, the present results indicate that in these tissues the one-chain proenzyme is the predominant form of u-PA in intracellular stores and for the first time demonstrates that at least in some cases the one-chain form constitutes a sizeable fraction of the u-AP in extracellular fluids in the intact organism.


[Fever after travel to the tropics].
Fever in travellers returning from the tropics may be caused not only by tropical infection but also by travel associated non-specific infections and cosmopolitan infective diseases. A rational out-patient step by step procedure needs clinical data and a small account of laboratory investigations. A parasitological screening is mandatory. The results refer to parasitological, bacterial or viral diseases. Epidemiological aspects of the travelled country and incubation periods of tropical or other diseases have to be considered. Plasmodium falciparum infection has to be excluded first because of vital damage. Following malaria (30%) respiratory infections (11%) are common. Fever as a symptom of non-infective disease occurred in 9%. Other diseases (typhus, Dengue fever, tuberculosis) are rare but have to be considered.


Expression of CD44 during early development of the chick embryo.
CD44, the major cell-surface receptor for hyaluronate, is expressed on many cell types to mediate different functions including cell activation, homing and adhesion. The early pattern of CD44 expression was determined in the avian embryo by using a specific monoclonal antibody in whole-mount and tissue sections. CD44 was first expressed on cephalic neural fold cells and later on by subpopulations of pre-and migratory cranial neural crest cells. Trunk neural crest cells did not express CD44. At the 18-20 somite stage, CD44 expressing cells were also localized in the caudal region of the embryo, in the mesoderm of the remaining primitive streak and in the caudal ectoderm and above the secondary neural tube during the process of cavitation. In addition, some hemopoietic cells present in the blood stream were also CD44 positive.


Cyclosporin A in the ocular fluids of uveitis patients following long-term systemic administration.
To determine the levels of cyclosporin A (CsA) in tears and the anterior segment of the eye following long-term oral intake for autoimmune diseases. Subjects taking oral CsA to treat relapsing autoimmune ocular inflammation were included in this study. All of the patients had been quiescent for at least 6 months. In patients scheduled for cataract extraction (group A), the CsA levels in the blood, aqueous humour and anterior capsule of the lens were determined. In subjects not requiring surgical intervention (group B), CsA was measured in tears and blood. The samples were analysed using turbulent flow chromatography coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). There were 19 subjects in group A and 43 subjects in group B. CsA was detectable in all of the tear samples with a mean value of 22.4 +/- 20.2 ng/ml and there was a significant positive correlation between the CsA levels in tears and blood (P = 0.012). CsA was not detected in any of the surgical samples. LC-MS/MS proved very sensitive for detecting CsA in low-volume biological samples. CsA was present in human tears in proportion to the blood level after an average of 12 hours from the last oral intake.


Regional development and seasonality of communicable diseases in rural Andhra Pradesh, India.
This paper explores the seasonality of morbidity due to communicable diseases in Guntur district in Andhra Pradesh, India. The district has been divided into development regions using cluster analysis. Seasonality of selected communicable diseases is then compared with the levels of development. It is shown that seasonality is most pronounced in the least developed region of the district. In the most developed region, seasonality of morbidity is low. The paper supports the general hypothesis that there is a decreased seasonality of illness as development takes place.


Small grain and semi-dwarf 3, a WRKY transcription factor, negatively regulates plant height and grain size by stabilizing SLR1 expression in rice.
OsWRKY36 represses plant height and grain size by inhibiting gibberellin signaling. Plant height and grain size are important agronomic traits affecting yield in cereals, including rice. Gibberellins (GAs) are plant hormones that promote plant growth and developmental processions such as stem elongation and grain size. WRKYs are transcription factors that regulate stress tolerance and plant development including height and grain size. However, the relationship between GA signaling and WRKY genes is still poorly understood. Here, we characterized a small grain and semi-dwarf 3 (sgsd3) mutant in rice cv. Hwayoung (WT). A T-DNA insertion in the 5'-UTR of OsWRKY36 induced overexpression of OsWRKY36 in the sgsd3 mutant, likely leading to the mutant phenotype. This was confirmed by the finding that overexpression of OsWRKY36 caused a similar small grain and semi-dwarf phenotype to the sgsd3 mutant whereas knock down and knock out caused larger grain phenotypes. The sgsd3 mutant was also hyposensitive to GA and accumulated higher mRNA and protein levels of SLR1 (a GA signaling DELLA-like inhibitor) compared with the WT. Further assays showed that OsWRKY36 enhanced SLR1 transcription by directly binding to its promoter. In addition, we found that OsWRKY36 can protect SLR1 from GA-mediated degradation. We thus identified a new GA signaling repressor OsWRKY36 that represses GA signaling through stabilizing the expression of SLR1.


SNAI2/SLUG and estrogen receptor mRNA expression are inversely correlated and prognostic of patient outcome in metastatic non-small cell lung cancer.
Epithelial-mesenchymal transition (EMT) is involved in important malignant features of cancer cells, like invasion, metastatic potential, anti-apoptotic and stem-cell like phenotypes. Among several transcription factors, SNAI2/SLUG is supposed to play an essential role for EMT. Paraffin embedded tumor samples from 63 patients with metastatic non-small cell lung cancer, enrolled in a randomized phase II trial, were prospectively collected, 53 samples qualified for further analysis. Automated RNA extraction from paraffin and RT-quantitative PCR was used for evaluation of SNAI2/SLUG, estrogen receptor 1 (ESR1) and matrix-metalloproteinases (MMP) mRNA expression. Clinical features like age, gender, performance status, histological subtype and stage were similarly distributed among SNAI2/SLUG positive and negative patients. SNAI2/SLUG was significantly, inversely correlated with ESR1 mRNA expression (p < 0.0001). In contrast, MMP2 (p = 0.387), MMP7 (p = 0.396) and MMP9 mRNA expression (p = 0.366) did not correlate with SNAI2/SLUG. Patients with high SNAI2/SLUG expression (grouped by median expression) had a worse outcome. Median overall survival in patients with high SNAI2/SLUG expression was 5.7 months versus 11.6 months with low SNAI2/SLUG expression (p = .038). Inversely, patients with high ESR1 expression (grouped by median expression) had an improved median OS with 10.9 months vs. 5.0 months in the low expression group (p = .032). In multivariate analysis, SNAI2/SLUG2 (p = .022) and ESR1 (p = .017) separately were independent prognostic factors for survival. SNAI2/SLUG is prognostic of patients' outcome. The strong inverse correlation with ESR1 indicates a significant impact of estrogen receptor pathway regarding these malignant features.


A Giant Pseudo-Aneurysm on the Anastomosis Site for a Redo Bentall Operation due to Behçet Disease Treated by Thoracic Endovascular Aortic Aneurysm Repair with a Custom-Made Stent Graft.
A 34-year-old man who had undergone aortic valve replacement 8 years ago underwent an additional Bentall operation due to mechanical valve dehiscence 2 years later. Subsequently, he was diagnosed with Behçet disease and Batter syndrome. A week after being hospitalized again due to chest pain and dyspnea, a large pseudo-aneurysm was detected on computed tomography. Because of the excessively large size of the pseudo-aneurysm, surgical treatment seemed very risky. Therefore, we planned to perform thoracic endovascular aortic repair (TEVAR) and treated him successfully. However, the patient experienced recurrence of the same symptoms 4 months later, and was found to have type IV endoleak. He received a TEVAR procedure again, and it was successful.


Alcohol use beliefs and behaviors among high school students.
To identify specific alcohol use beliefs and behaviors among local high school students; to determine whether relationships exist between alcohol use and various sociodemographic and lifestyle behaviors; and to assist in the development and implementation of alcohol abuse prevention programs. This cross-sectional study involved the completion of a questionnaire by 1236 Grade 9-13 students (86% response rate) from 62 randomly selected classrooms in three Canadian urban schools. Data analyzed here are part of a larger lifestyle survey. A total of 24% of students reported never having tasted alcohol, 22% have tasted alcohol but do not currently drink, 39% are current moderate drinkers, 11% are current heavy drinkers (five or more drinks on one occasion at least once a month), and 5% did not answer. Reasons stated most often for not drinking were "bad for health" and "upbringing," while reasons stated most often for drinking were "enjoy it" and "to get in a party mood." Student drinking patterns were significantly related to gender, ethnicity, grade, and the reported drinking habits of parents and friends. Older male adolescents who describe their ethnicity as Canadian are at higher risk for heavy drinking than students who are younger or female, or identify their ethnicity as European or Asian. Current heavy drinkers are at higher risk than other students for engaging in other high-risk behaviors such as drinking and driving, being a passenger in a car when the driver is intoxicated, and daily smoking. Heavy alcohol use in adolescents remains an important community health concern. Older self-described Canadian and Canadian-born male adolescents are at higher risk for heavy drinking. Current and heavy drinking rises significantly between Grades 9 and 12. Students who drink heavily are more likely to drink and drive, to smoke daily, and to have friends and parents who drink alcohol.


Not just snot: local inflammatory profiles in patients with aspirin-exacerbated respiratory disease differ from patients with aspirin-tolerant chronic rhinosinusitis.
IL-5, CCL2, and CXCL8 in sinus mucous are higher in patients with AERD relative to aspirin-tolerant patients with CRS These mediators are pleiotropic, leading to widescale inflammatory processes contributing to AERD AERD is not only a T2 disease but heterogeneous: this may explain the refractory nature of AERD.


Proposition for the biochemical mechanism occurring in the sucrose isomerase active site.
Sucrose conversion by sucrose isomerase from Protaminobacter rubrum, Serratia plymuthica and Erwinia rhapontici was investigated in the presence of different monosaccharides in the reaction mixture. These conditions led to inhibitory effects and to glucosyl transfer of the glucose moiety of sucrose to the exogen monosaccharide. Comparison of the structure of the different inhibitors and acceptors has allowed us to suppose the binding of the sucrose molecule into the active site, and thereafter, to propose the possible biochemical reactions leading to the formation of different products from sucrose. This study also underlines the close homologies between these enzymes.


A Novel Classification and Scoring Method Based on Immune-Related Transcription Factor Regulation Patterns in Gastric Cancer.
Transcription factors (TFs) play a crucial role in tumorigenesis and anti-tumor immunity. However, the potential role of large-scale transcription factor regulation patterns in the progression in gastric cancer (GC) is unknown. We comprehensively assessed the relevance of immune-related TF (IRTF) regulation patterns in anti-tumor immunity and immunotherapy in 1,136 gastric cancer (GC) patients, and evaluated the IRTF score based on IRTF regulation patterns using random forests. Two distinct IRTF regulation patterns were identified, which demonstrating the distinct characteristics in clinical phenotypes, tumor immune microenvironment (TIME), immunogenicity and prognosis in GC. Subsequently, the IRTF score was established to quantify the IRTF regulation pattern for each GC patient. Analysis of large conventional therapy cohorts showed low IRTF score was associated with a better prognosis. In addition, analysis of multiple immunotherapy cohorts showed low IRTF score was also linked to enhanced response to immunotherapy. TF regulation patterns were found to play an important role in the complex immune regulatory relationships in GC. Evaluation of the IRTF regulation patterns in patients will enhance our understanding of immune specificities, and thus, provide effective strategies for personalized therapy.


The 24-month metabolic benefits of the healthy living partnerships to prevent diabetes: A community-based translational study.
Large-scale clinical trials and translational studies have demonstrated that weight loss achieved through diet and physical activity reduced the development of diabetes in overweight individuals with prediabetes. These interventions also reduced the occurrence of metabolic syndrome and risk factors linked to other chronic conditions including obesity-driven cancers and cardiovascular disease. The Healthy Living Partnerships to Prevent Diabetes (HELP PD) was a clinical trial in which participants were randomized to receive a community-based lifestyle intervention translated from the Diabetes Prevention Program (DPP) or an enhanced usual care condition. The objective of this study is to compare the 12 and 24 month prevalence of metabolic syndrome in the two treatment arms of HELP PD. The intervention involved a group-based, behavioral weight-loss program led by community health workers monitored by personnel from a local diabetes education program. The enhanced usual care condition included dietary counseling and written materials. HELP PD included 301 overweight or obese participants (BMI 25-39.9kg/m2) with elevated fasting glucose levels (95-125mg/dl). At 12 and 24 months of follow-up there were significant improvements in individual components of the metabolic syndrome: fasting blood glucose, waist circumference, HDL, triglycerides and blood pressure and the occurrence of the metabolic syndrome in the intervention group compared to the usual care group. This study demonstrates that a community diabetes prevention program in participants with prediabetes results in metabolic benefits and a reduction in the occurrence of the metabolic syndrome in the intervention group compared to the enhanced usual care group.


Foot surface area database and estimation formula.
The purpose of this study is to establish a foot surface area (FSA) database and estimation formula based on 3-D foot scan data. For each gender, 135 subjects stratified in five statures and three body weights were drawn. The foot was measured using a high-resolution 3-D foot scanner, of which the precision and accuracy is within 1%. The FSA was computed by the triangular mesh summation method and five 1-D foot measurements were extracted automatically to be used as candidate estimators for FSA estimation formula. The results of the FSA measurements are tabulated on fifteen strata for the Male, the Female and the Total (the two genders combined). The comparison of these FSA measurements with previous studies shows that previous studies underestimated the FSA approximately 4.06% for the Total (for the Male, 6.93%; for the Female, 0.82%). Regression analyses using these five 1-D foot measurements were performed. The results show that foot-length and ball-girth are effective estimators of FSA for the total (FSA=1.043 x foot-length x ball-girth, R(2)=95.4%). A test on the necessity of gender-specific formula indicated that no gender-specific formula is needed, and the formula for the total is good for both genders.


Gene expression profiles in esophageal adenocarcinoma.
The incidence of esophageal adenocarcinoma (EAC) has risen dramatically in the last two decades. As with other malignancies, changes in gene expression play a key role in the development and progression of these tumors. Microarray analysis was used to study gene expression of 12,000 genes in EAC specimens. Adenocarcinoma tissue samples (n = 10) and controls of normal stomach (n = 6) and esophageal (n = 7) mucosa were collected fresh, then rapidly frozen in liquid nitrogen. The messenger ribonucleic acid (mRNA) from the samples was isolated, reverse transcribed, and used to generate biotin-labeled mRNA fragments, which were hybridized to Affymetrix U95 gene chips (AME Bioscience, Norway) for analysis. Additional samples analyzed included tissue containing dysplastic Barrett's epithelium from three patients, metastatic lymph nodes from two patients with EAC, one squamous carcinoma, and two esophageal cancer cell lines. Samples were segregated into groups with similar patterns of gene expression using clustering algorithms and gene sets that differentiated tumors from normal tissue were generated. There were 150 genes that were fourfold up regulated and 183 genes that were fourfold down regulated in the esophageal adenocarcinoma specimens, as compared to normal esophageal mucosa tissue controls. Using paired specimens (n = 5) and the paired t-test (p Value of 0.05) as a filter, only 64 genes were fourfold up regulated and 110 were fourfold down regulated. These groups included cytoskeletal, cell adhesion, tumor suppressor, and signal transduction genes. Hierarchical clustering segregated the samples into the expected divisions. The esophageal cancer cell lines, OE19 and OE33, clustered separately from the EAC specimens. Extremely high gene expression levels of the ERBB2 gene, seen in the microarray analysis of the 2 cell lines, correlated with amplification of the gene determined by Southern blotting. Gene expression patterns from a small subset of genes distinguish EAC specimens from normal controls. This technique can rapidly identify genes for targeted chemotherapeutic approaches to cancer treatment.


Acceptability and feasibility of telehealth outpatient video-link consultations: A national cross-sectional survey of surgeons prior to the COVID-19 pandemic.
This study explored use and perceived barriers to the use of post-operative video-link telehealth among a sample of Australian surgeons shortly before the COVID-19 pandemic. During 2019-2020, a survey was mailed to RACS or RANZCOG Fellows. Cross-sectional survey. A total of 907 surgeons practising in Australia completed the survey. The study-specific survey assessed telehealth use in the last 3 months and the perceived barriers and enablers to the use of post-operative teleconsultations, across the domains: quality of care; convenience and efficiency; legal/regulatory issues; financial issues and technological issues. Twenty-five percent of eligible surgeons returned the survey, with n = 763 pre-pandemic responses included in analyses. Approximately one-quarter (26%) of surgeons had used telehealth post-operatively with patients in the last 3 months. The most frequently endorsed barriers to use related to quality of care: 'I cannot undertake a patient examination' and 'I cannot provide the same level of care as during an in-person consultation'; and convenience and efficiency: 'Teleconsultations are more difficult to arrange'. Surgeons who had recently used telehealth were less likely to endorse most barriers. Younger age, awareness of Medicare telehealth reimbursement and working in neurosurgery, urology, paediatric surgery and plastic and reconstructive surgery (compared to general surgery) were associated with recent telehealth use by surgeons. Some surgeons' perceived barriers to telehealth pre-COVID may be overcome by COVID-19-related telehealth uptake and familiarisation. However, many barriers will need to be addressed to ensure that telehealth adoption is sustained beyond the pandemic.


Anatomic and functional results of ventral biological mesh rectopexy for posterior pelvic floor disorders.
Ventral mesh rectopexy (VMR) is the gold standard for rectal prolapse surgery, but the type of mesh reinforcement is still a matter of debate. The aim of this study was to assess the anatomic and functional results of a single center cohort of patients receiving ventral rectopexy with biological mesh compared to a reference group who had implantation of synthetic mesh. We also assessed the predictive factors for recurrence. Seventy patients (2015-2021) were included in the biological mesh group and were compared to a reference group of 345 patients operated on with a synthetic mesh (2004-2017). In the biological mesh group, the mean age of patients was 65 years (53-72). The main disorders of the posterior pelvic floor were rectal prolapse (30 cases) or rectocele (37 cases). Two patients had solitary rectal ulcer syndrome and one had internal prolapse. VMR was performed by a laparoscopic approach with robotic assistance in 93%. After a median follow-up of 12 (4.5-23) months, the anatomic recurrence rate was 10%. The median satisfaction score assessed in a telephone interview by a semi-quantitative scale from 0 to 10 was 7. Compared to the synthetic group, neither the morbidity rate (Dindo>2) (0.6% synthetic versus 1.4% biological mesh), nor the recurrence rate (12% synthetic versus 10% biological (ns) with an average interval of 13.5 versus 14 months, respectively) were statistically significantly different. VMR with biological mesh represents an alternative to synthetic mesh. Despite its resorbable nature, biological mesh does not seem to increase the risk of recurrence and offers satisfying functional results after a medium term follow-up.


Patent nasopalatine ducts after rapid maxillary expansion.
Patent nasopalatine ducts connecting the oral and nasal cavities are a rare developmental anomaly that has not been reported in the orthodontic literature. Only 36 cases of unilateral, central, or bilateral patent nasopalatine ducts are documented since the first publication in 1881. Some patients with this condition exhibit clinical symptoms, but not all elect to have definitive treatment with surgical repair or chemical ablation. This report describes the appearance of nasopalatine ducts in an adolescent male after rapid maxillary expansion [corrected]


One Anastomosis Gastric Bypass Versus Roux-en-Y Gastric Bypass for Obesity: a Systematic Review and Meta-Analysis of Randomized Clinical Trials.
We aim to compare the efficacy and safety outcomes of one anastomosis gastric bypass (OAGB) with Roux-en-Y gastric bypass (RYGB). We searched Ovid Medline, Ovid Embase, and the Cochrane Library from inception to May 14, 2019, without language restrictions, for randomized clinical trials comparing OAGB with RYGB in obesity. Quality of included trials was assessed by Cochrane Collaboration's tool; quality of evidence was evaluated by GRADE approach. The primary outcome was excess body mass index (BMI) loss at 2 years. We identified 206 reports; after exclusions, three trials with a total of 733 patients were eligible for analysis. Compared with RYGB, OAGB was associated with more excess BMI loss at 2 years (mean difference (MD), 10.22; 95% CI, 3.05 to17.40; I2 = 95%; low-quality evidence), with benefit seen in OAGB using non-obese patients (MD, 17.10; 95% CI, 15.76 to18.44; P for interaction = 0.007 ) and no benefit in OAGB using standard length of biliopancreatic limb (MD, 6.49; 95% CI, - 1.09 to 14.08). Moreover, individuals allocated to OAGB compared with RYGB had a higher remission rate of type 2 diabetes(T2D) (risk ratio (RR), 1.13; 95% CI, 1.01 to 1.27; I2 = 0%). No statistically significant difference was found between the two surgical groups in adverse events. OAGB is possibly associated with more body weight loss compared with RYGB in patients with obesity, despite the low quality of evidence caused by inconsistent of the effect of biliopancreatic limb length in OAGB group. This benefit appears to be confined to OAGB using the extended length of the biliopancreatic limb but not to OAGB using the standard length of the biliopancreatic limb, compared with RYBG. Additional large clinical studies are needed to assess the impact of limb length in OAGB.


The prevalence of stress urinary incontinence in patients with cystic fibrosis: an under-recognized problem.
To identify the prevalence of stress urinary and fecal incontinence in patients with cystic fibrosis (CF) and investigate any correlation between CF severity and the incidence and degree of incontinence. An initial postal questionnaire was used to identify patients with an incontinence problem, followed by a detailed interview-administered questionnaire assessing the type of incontinence and the impact of the incontinence on patients and the management of their CF. The correlation between CF severity and the incidence and severity of incontinence was also analysed. All patients aged 5-18 years attending the CF service at The Respiratory and Urology departments of a University Teaching Hospital were invited to participate. There was no therapeutic intervention. Stress urinary incontinence was present in 31% of girls and 2.2% of boys, with fecal incontinence in four girls. The youngest patient with incontinence was 9 years old. Of the patients, 78% found their incontinence a problem and 44% had hidden the problem from parents and carers. There was no correlation between incontinence and the severity of CF as measured by the forced expiratory volume in 1s. Urinary incontinence is common in girls with CF and in many cases it is a hidden problem. These patients need to be identified so they can receive appropriate management, instead of suffering in silence.


Interferon but not MxB inhibits foamy retroviruses.
Foamy viruses (FV) are retroviruses that are widely distributed in primate and non-primate animal species. We tested here FV with capsids of simian and non-simian origin for sensitivity to interferon-β (IFN-β). Our data show significant inhibition of FV by IFN-β early in infection of human HOS and THP-1 but not of HEK293T cells. The post-entry restriction of FV was not mediated by the interferon-induced MxB protein that was recently identified as a capsid-interacting restriction factor targeting Human immunodeficiency virus (HIV) before integration. Neither the ectopic expression of MxA or MxB in HEK293T cells nor the lack of MxB expression in CRISPR/CAS MxB THP-1 knockout cells impacted the infection of the tested FV. IFN-β treated THP-1 and THP-1 KO MxB cells showed the same extend of restriction to FV. Together, the data demonstrate that IFN-β inhibits FV early in infection and that MxB is not a restriction factor of FV.


Arsenic release and transformation in co-combustion of biomass and coal: Effect of mineral elements and volatile matter in biomass.
After the co-combustion of tobacco stem/black bean straw/wheat straw/millet straw/corn stalk/rice straw and coal, it was found that all tested biomass in this study could inhibit arsenic release, but only rice straw promoted arsenic release. When the acid washed biomass was mixed with coal during combustion, the release of arsenic increased. When mineral metals (Na, K, Mg, Ca, Al and Fe) and Si elements were added to the coal, the mineral metals inhibited arsenic release. However, the release of arsenic was increased when the silicon content in biomass was high. The volatiles in the biomass also promoted the release of arsenic during co-combustion. The arsenic in the ash generated from co-combustion was mainly in the sulphide-bound state. Co-combustion of biomass and coal reduced the occurrence of an exchangeable state in the ash, and also significantly reduce the possibility of leaching.


Functional and genetic characterization of calmodulin from the dimorphic and pathogenic fungus Paracoccidioides brasiliensis.
Calmodulin (CaM) modulates intracellular calcium signalling and acts on several metabolic pathways and gene expression regulation in many eukaryotic organisms including human fungal pathogens, such as Candida albicans and Histoplasma capsulatum. The temperature-dependent dimorphic fungus Paracoccidioides brasiliensis is the aetiological agent of paracoccidioidomycosis (PCM). The mycelium (M) to yeast (Y) transition has been shown to be essential for establishment of the infection, although the precise molecular mechanisms of dimorphism in P. brasiliensis are still unknown. In this work, several inhibitory drugs of the Ca(2+)/calmodulin signalling pathway were tested to verify the role of this pathway in the cellular differentiation process of P. brasiliensis. EGTA and the drugs calmidazolium (R24571), trifluoperazine (TFP), and W7 were able to inhibit the M-Y transition. We have cloned and characterized the calmodulin gene from P. brasiliensis, which comprises 924 nucleotides and five introns that are in a conserved position among calmodulin genes.


Undetectable postoperative cortisol does not always predict long-term remission in Cushing's disease: a single centre audit.
An undetectable postoperative serum cortisol has been regarded as a definition of cure in Cushing's disease. However, we noted disease recurrence amongst patients with Cushing's disease despite undetectable postoperative cortisol levels, and this led us to audit our data. We have also previously assessed surgical outcome for acromegaly and microprolactinoma for a single surgeon. The aims of this study were two-fold: (i) to investigate the treatment and surgical outcome of patients with Cushing's disease. In particular, we wished to compare the data with outcome for other pituitary tumours in our centre; and (ii) to determine whether undetectable cortisol following surgery is predictive of long-term cure for Cushing's disease. We performed a retrospective audit of 97 patients; mean age 39.1 (range: 14-82) years, 78/97 (80.4%) female, mean follow-up 92 months (range: 6 months to 29 years), with Cushing's disease seen in our unit between 1969 and 1998. We documented diagnostic investigation, immediate surgical outcome and disease recurrence in these patients. All patients had elevated urinary free cortisol (mean 1270.6 nmol/l, range: 327-3245 nmol/l). In total, 95.5% of patients did not suppress with low-dose dexamethasone suppression testing. Hypokalaemia (K < 3.2 mmol/l) was present in 15.6% of patients; 17.5% of patients did not show cortisol suppression with high-dose dexamethasone and 15.8% of patients did not show an ACTH rise of > 50% following corticotrophic releasing hormone (CRH) administration. There was no significant (> 3) gradient in ACTH or cortisol following CRH during inferior petrosal sinus sampling in 27.3% of patients who had the test. A pituitary tumour was demonstrated on imaging in 55.8% of patients; 10.3% were macroadenomas. Mortality rate following trans-sphenoidal surgery was 1%. Following surgery, the immediate postoperative remission rate (undetectable postoperative cortisol) was 68.5%. However, 11.5% of these patients developed disease recurrence during a mean follow-up period of 36.3 months. Considering microadenomas, Cushing's disease patients had an immediate postoperative remission rate of 63.2% which is significantly lower (P < 0.05) compared to a remission rate of 91.1% in acromegaly. Additionally, new postoperative gonadotrophin deficiency (13.9%) and TSH deficiency (25.8%) was higher in patients with Cushing's disease compared to patients with acromegaly or microprolactinoma. Immediate postoperative remission rates improved from 50% in the first decade of a surgeon's career to consistently above 60% in the second and third decades, demonstrating a trend which may be attributed to surgical experience. (i) Despite strict criteria for immediate postoperative remission and recurrence, undetectable postoperative cortisol is not always predictive of long-term remission. (ii) Despite an aggressive surgical approach, immediate postoperative remission rates for Cushing's disease are lower compared to other microadenomas. The development of new pituitary hormonal deficiency following surgery is also commoner than that seen amongst other microadenomas. These data have important implications for the follow-up of patients with Cushing's disease.


Comparison of ketamine/propofol (ketofol) and etomidate/fentanyl (etofen) combinations for procedural sedation and analgesia in the emergency department: An observational study.
The primary aim of this study was to report the vital signs, hemodynamic parameters and pain scores of the patients who have received procedural sedation and analgesia (PSA) with either ketofol (combination of ketamine and propofol) or etofen (combination of etomidate and fentanyl) and compare the proportion of patients with airway or respiratory adverse events (AEs) requiring an intervention and calculate the relative risk of AEs with each combination. This study is a prospective observational study with survey analysis. All patients received procedural sedation and analgesia (PSA) with either ketofol (combination of ketamine and propofol) or etofen (combination of etomidate and fentanyl) were prospectively observed. Vital and hemodynamic parameters and pain scores of the patients were recorded by automated equipment and visual analog scale (VAS) charts. 112 patients were enrolled, 55 received ketofol and 57 received etofen. All patients with a respiratory AE (n = 27) observed to receive a respiratory intervention. Respiratory AE rate and proportion of patient who required a respiratory intervention were significantly higher with ketofol (p = 0.0029). Overall AE rate, and rates of desaturation, emergence reaction were also significantly higher in ketofol group. Etofen is a promising combination for the PSA of adult patients with lower respiratory AE and intervention rates and with better hemodynamic profile.


Inflammatory mediators convert anandamide into a potent activator of the vanilloid type 1 transient receptor potential receptor in nociceptive primary sensory neurons.
The endogenous ligand, anandamide activates at least two receptors on nociceptors; the excitatory vanilloid type 1 transient receptor potential receptor, the activity of which is indispensable for the development and maintenance of inflammatory heat hyperalgesia, and the inhibitory cannabinoid 1 receptor, the activity of which reduces that pathological pain sensation. Recent data are equivocal on whether increasing anandamide levels at the peripheral terminals of nociceptors in pathological conditions increases or decreases inflammatory heat hyperalgesia. Here, by using the cobalt-uptake technique we examined whether vanilloid type 1 transient receptor potential receptor activity evoked by 10 nM-100 microM anandamide is increased or decreased in inflammatory conditions. An inflammatory milieu for cultured rat primary sensory neurons was established by incubating the cells in the presence of the inflammatory mediators, bradykinin and prostaglandin E2. Anandamide, similarly to the archetypical vanilloid type 1 transient receptor potential receptor agonist, capsaicin induced concentration-dependent cobalt-uptake in a proportion of neurons. However, the potency of anandamide was significantly lower than that of capsaicin. While pre-incubation of cultures with bradykinin and prostaglandin E2 alone did not evoke cobalt-entry, the inflammatory mediators potentiated the effect of both capsaicin and anandamide. Application of the competitive vanilloid type 1 transient receptor potential receptor antagonist, capsazepine, or inhibitors of protein kinase A, protein kinase C or phospholipase C inhibited the anandamide-evoked cobalt-uptake both in the presence and absence of bradykinin and prostaglandin E2. These findings show that inflammatory mediators significantly increase the excitatory potency and efficacy of anandamide on vanilloid type 1 transient receptor potential receptor, thus, increasing the anandamide concentration in, or around the peripheral terminals of nociceptors might rather evoke than decrease inflammatory heat hyperalgesia.


Desflurane or isoflurane for paediatric ENT anaesthesia. A comparison of intubating conditions and recovery profile.
The inhaled anaesthetic desflurane is characterized by a rapid wash-in and wash-out and may be useful for short paediatric ENT procedures. Therefore, this study was designed to compare the effects of desflurane or isoflurane on intubating conditions and recovery characteristics in paediatric ENT patients. In this prospective, randomised investigation, we studied 44 children scheduled for ENT surgery, aged 4-12 yr and classified ASA I-II. After thiopentone induction (5-8 mg/kg) the lungs were ventilated by face mask and the vaporizer was dialed to 1 MAC (age-adapted) of desflurane of isoflurane. A reduced dose of vecuronium (0.05 mg/kg) was administered, and intubating conditions were rated 3 min later. Following tracheal intubation, 50% nitrous oxide were added, and the concentration of desflurane or isoflurane was adjusted according to clinical needs. At the end of surgery all anaesthetics were discontinued simultaneously and recovery times were recorded. Intubating conditions were rated significantly better for desflurane (excellent or good 20 of 22) than for isoflurane (12 of 22). Recovery times were significantly shorter for desflurane than for isoflurane (mean +/- SE): spontaneous ventilation 4.0 +/- 0.5 min vs. 6.0 +/- 0.7 min, extubation 8.4 +/- 0.7 vs. 11.4 +/- 1.1 min and arrival at PACU 11.5 +/- 0.8 vs. 16.6 +/- 1.5 min. No airway complications (coughing, laryngospasm, or desaturation < 97%) were noted for either anaesthetic. Following an intravenous induction improved intubating conditions, shorter recovery times and the lack of airway complications make desflurane a suitable alternative to isoflurane for paediatric ENT anaesthesia.


Design and optimization of selective azaindole amide M1 positive allosteric modulators.
Selective activation of the M1 receptor via a positive allosteric modulator (PAM) is a new approach for the treatment of the cognitive impairments associated with schizophrenia and Alzheimer's disease. A novel series of azaindole amides and their key pharmacophore elements are described. The nitrogen of the azaindole core is a key design element as it forms an intramolecular hydrogen bond with the amide N-H thus reinforcing the bioactive conformation predicted by published SAR and our homology model. Representative compound 25 is a potent and selective M1 PAM that has well aligned physicochemical properties, adequate brain penetration and pharmacokinetic (PK) properties, and is active in vivo. These favorable properties indicate that this series possesses suitable qualities for further development and studies.


Letter to the Editor: The Case for Publicly Funded Headache Surgery in Germany.
Headache surgery has become a considerable therapeutic option in headache treatment and is of rising interest in the German medical sector. This viewpoint outlines the need for reimbursement of headache surgery in the German healthcare system and demonstrates its cost-effectiveness. Using state-of-the-art patient selection algorithms, the authors found headache surgery to be cost-effective within 7.2 to 6.3 years. Of note, the approach presented is not limited to the German healthcare system.


Multiple myeloma in a murine syngeneic model:modulation of growth and angiogenesis by a monoclonal antibody to kininogen.
Multiple myeloma (MM), a B-cell malignancy characterized by proliferation of monoclonal plasma cells remains incurable. Murine plasma cell tumors share common features with human MM. We used two cell lines (B38 and C11C1) derived from P3X63Ag8 myeloma cells. The new cell lines were implanted subcutaneously in the strain of origin (Balb/c mice) and used as a model to monitor the effects of C11C1 monoclonal antibody (mAb) to kininogen (HK). We assessed their behavior by intraperitoneal and subcutaneous implantation, by implanting them together and by treating B38-MM with purified mAb C11C1. We evaluated growth, microvascular density (MVD), and cellular expression of urokinase-type plasminogen activator-receptor (uPAR), fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), bradykinin-1 receptor (B1R), bradykinin-2 receptor (B2R) and HK. We found that both MM-cell-lines are uPAR positive, that mAb C11C1 inhibits its own tumor growth in vivo, slows down B38-MM growth rate when both MM are implanted together and when mAb C11C1 is injected intraperitoneally. MAb C11C1-treated-MM showed decreased MVD and HK binding in vivo without FGF-2, B1R or B2R expression changes. We propose that the B38-extramedullary-myeloma-model is a useful tool to study the interactions of this hematopoietic tumor and its environment and that mAb C11C1 may improve the efficacy of conventional MM treatment with minimal side effects.


A novel approach for identifying and addressing case-mix heterogeneity in individual participant data meta-analysis.
Case-mix heterogeneity across studies complicates meta-analyses. As a result of this, treatments that are equally effective on patient subgroups may appear to have different effectiveness on patient populations with different case mix. It is therefore important that meta-analyses be explicit for what patient population they describe the treatment effect. To achieve this, we develop a new approach for meta-analysis of randomized clinical trials, which use individual patient data (IPD) from all trials to infer the treatment effect for the patient population in a given trial, based on direct standardization using either outcome regression (OCR) or inverse probability weighting (IPW). Accompanying random-effect meta-analysis models are developed. The new approach enables disentangling heterogeneity due to case mix from that due to beyond case-mix reasons.


Placebo in epilepsy.
Placebos impact epilepsy in a number of ways. Through randomized clinical trials, explicit clinical use, and also through implicit clinical use, placebos play a role in epilepsy. This chapter will discuss the reasons placebo is used, the determinants of placebo response in epilepsy, observations about placebo specific to epilepsy, and ways in which clinical trial design is impacted by placebo.


Stroke Thrombolysis Protocol Shortens "Door-to-Needle Time" and Improves Outcomes-Experience at a Tertiary Care Center in Qatar.
To assess the effect of acute thrombolysis protocol on "door-to-needle time" (DTN) and improvement in outcome following acute stroke (AS). The charts of all patients receiving intravenous (IV) thrombolysis for AS between January 2008 and June 2015 were reviewed for DTN, complications, and clinical outcome. Good prognosis was defined as modified Rankin Scale (mRS) score of less than 2 at 90 days. In January 2014, a protocol for faster DTN was introduced. We reviewed the prognosis before and after the introduction of the new protocol. Up to 204 patients received IV recombinant tissue plasminogen activator (r-tPA) (mean age 52.5 ± 12.4 years). Mean door-to-CT time improved from 42.5 ± 41.1 to 27.1 ± 26.3 minutes (P < .001); DTN improved from 83.26 ± 47.7 to 47.09 ± 25.7 minutes (P < .001). Complications were reduced from 15.7% to 8.8% (P = .14). The mRS score of less than or equal to 2 improved from 47.1% to 73.3% at 90 days (P = .001). After implementing new protocol, thrombolysis rate increased to 11.8% in 2014 (before 3.3% in 2011, 4.9% in 2012, and 4.4% in 2013), P < .0001. NIHSS (National Institutes of Health Stroke Scale) score at admission (P = .002), hypodensity on initial CT brain (P = .041), protocol implementation (P = .014), and reduced length of stay (P = .004) were associated with outcome at 90 days (mRS score ≤2). Implementation of specific protocols to reduce DTN in patients receiving IV r-tPA leads to reduction in complications and improves outcome.


Thymoquinone reduces hepatic glucose production in diabetic hamsters.
The aim of this study was to elucidate the mechanisms underlying the glucose lowering effects of thymoquinone in streptozotocin (STZ)-induced diabetic hamsters in terms of hepatic glucose production. Diabetes was induced by intraperitoneal injection of 65 mg/kg body weight of STZ. Treatment with thymoquinone commenced 4 weeks after induction of diabetes at a daily dose of 50 mg/kg body weight by gastric gauge. Blood glucose and glycated hemoglobin levels were significantly reduced depending on periods of the treatment. Thirty days after commencement of thymoquinone-treatment, hepatocytes were isolated using collagenase to determine liver glucose production. Glucose production after 2 h incubation of the isolated hepatocytes with gluconeogenic precursors (alanine, glycerol and lactate) was significantly lower in hamsters treated with thymoquinone as compared to that in vehicle controls. The results of this study demonstrate that the antidiabetic action of thymoquinone is at least partially mediated through a decrease in hepatic gluconeogenesis.


A multiple retinoic acid antagonist induces conotruncal anomalies, including transposition of the great arteries, in mice.
The morphogenetic mechanisms that are responsible for the transposition of the great arteries are still largely unknown, mainly because this malformation is very difficult to experimentally reproduce. The aim of the present study was to test the effect of BMS-189453, a retinoic acid antagonist, on murine heart morphogenesis. We administered this drug at 5 mg/kg body weight (twice, at a 12-h interval) to pregnant mice on 6.25/6.75 days postcoitum (dpc) (Group A), 6.75/7.25 dpc (Group B), 7.25/7.75 dpc (Group C), 7.75/8.25 dpc (Group D), or 8.25/8.75 dpc (Group E). At birth, the anatomical features of fetuses were evaluated by stereomicroscopic examination. In Group A (18 fetuses), cardiovascular anatomy was normal in 10 (56%) cases, and 8 (44%) fetuses presented with transposition of the great arteries. In Group B, no fetuses were obtained. In Group C (78 fetuses), cardiovascular anatomy was normal in 19 (24%) cases, while 59 (76%) mice presented with various types of cardiac defects, including 48 transpositions of the great arteries (61%). In Group D (80 fetuses), cardiac defects were seen in 22 (27%) mice: 14 of these (17%) were transpositions of the great arteries. In Group E (72 fetuses), cardiovascular anatomy was normal in all cases. Of 248 fetuses analyzed, 87% presented with thymic aplasia or hypoplasia, and 20% presented with meroanencephalia and/or rachischisis. Transposition of the great arteries can be consistently reproduced in mice by administration of a retinoic acid competitive antagonist on 7.5 dpc.


Introduction to nanoscale quantum technologies.
An introduction to the Nanoscale themed collection on emerging quantum technologies at the nanoscale, featuring high-quality research on quantum materials and devices for computing, sensing, imaging and communication.


Positioning of actin filaments and tension generation in skinned muscle fibres released after stretch beyond overlap of the actin and myosin filaments.
Skinned fibres from frog semitendinosus muscle were stretched in relaxing solution from a sarcomere length of 2.5 microns to greater sarcomere lengths, and then shortened back to the original length. Fibres could be stretched up to sarcomere lengths of 3.3 microns, and reshortened fully. If the original stretch was to a sarcomere length greater than 3.3 microns, the extent of recovery was dependent on the magnitude of the stretch and the number of times the stretch/shorten cycle was repeated. When the original stretch was to sarcomere lengths beyond overlap of the thick and thin filaments, the thin filaments did not re-enter the thick filament array but buckled at the A-I junction. If these fibres were subsequently activated and contracted, the thin filaments re-entered the thick filament array, taking up approximately their former positions, and allowing reduced development of isometric tension.


Partial response to dabrafenib and trametinib in relapsed BRAF V600E-Mutated multiple myeloma and possible mechanisms of resistance.
BRAF V600E mutations are detected in 3%-10% of patients with multiple myeloma (MM) and are associated with more aggressive disease, higher frequency of extramedullary growth and shorter survival. Monotherapy with the BRAF inhibitor vemurafenib has been disappointing in MM. In patients with BRAF-mutated melanoma, MEK and BRAF inhibition has been a successful approach. Here we describe a very good partial response and possible mechanisms of resistance to a combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib in a patient with BRAF V600E-mutant refractory MM.


Environmental consequences of treating cattle with the antiparasitic drug ivermectin.
Ivermectin (22,23-dihydroavermectin B1) is a recently discovered, persistent, broad-spectrum, antiparasitic drug of unpredecented potency which is now routinely administered to cattle, horses, sheep and pigs in many countries. In cattle, it is an efficient control for parasitic gastrointestinal and respiratory tract nematodes, warble fly, mites, lice and ticks. However, most of the ivermectin dose is ultimately eliminated in the faeces of the treated animals where it has been shown to have an insecticidal effect on the larvae of economically important, dung-breeding, haematophagous Diptera. Nevertheless, the effects of excreted ivermectin on the cowpat fauna as a whole and the wider consequences of such effects have not previously been considered. In field trials reported here, the faeces of calves fitted with rumenal boluses delivering ivermectin at 40 micrograms per kg per day, failed to degrade in the normal way and this failure was associated with the absence of dung-degrading insects. Faeces from placebo-treated controls contained a characteristic dung-degrading invertebrate community and were largely degraded within 100 days. These results indicate that the increasing widespread use of ivermectin may have important environmental consequences for pastureland.


Effects of testosterone and its metabolites in relation to androgen-binding activity in murine submandibular salivary glands.
The relative potencies of testosterone (T), testosterone propionate (TP) and other related steroids (5 alpha-dihydrotestosterone, DHT; 5 alpha-androstane-3 alpha, 17 beta-diol, alpha-diol; 5 alpha-androstane-3 beta, 17 beta-diol, beta-diol) in restoring some morphological and functional characteristics of submandibular gland (SMG) were investigated in castrated mice. The steroids restored to near-control values the glandular weight and total protein content, alpha-diol and TP being the most effective compounds tested; with regard to proteolytic activity stimulation, beta-diol was more effective than DHT. The alpha-diol metabolite was unique in significantly increasing DNA synthesis. In competition studies, alpha-diol and beta-diol were ineffective in displacing the specifically bound [3H]-R1881 from the SMG androgen-binding macromolecules. Thus T can elicit its effects on SMG without the need of prior conversion to DHT; there must be alternative, receptor-independent mechanisms whereby alpha- and beta-diol exert trophic/metabolic effects on murine SMG.


A patient navigation initiative to improve access to breast cancer care in Cali, Colombia.
Patient navigation is the logistical and emotional support necessary to achieve diagnostic and treatment compliance. It can improve time to diagnosis, initiation of treatment, and patient satisfaction, as well as reduce the cost of treatment. Colombia has a well-defined Cancer Control Plan, but its implementation is lacking. To implement the first patient navigation initiative in Colombia, as part of a pilot program for the early detection of breast cancer. The process involved assessing and addressing the barriers faced by women to access breast health care by providing training for health personnel, strengthening primary health care providers, and coordinating diverse level institutions for the provision of services. This led to the design and implementation of a navigation strategy focused on the needs of patients in Cali, Colombia and the involvement of the local health system to provide such services. Time to diagnosis was significantly reduced; research advanced by the Colombian National Institute of Cancerology shows that the average time between the first medical consultation and diagnosis was 91 days (CI 95%: 82-97 days), while this study carried out the same process in an average of 30 days, but patients still had issues with continuity of treatment due to financial strain between healthcare providers and insurers. Navigation, however, manages to overcome many of these problems by assisting women in the clinical and administrative care processes and seeking well-being for the beneficiaries. In addition, patient navigation helped identify critical failures in care, such as fragmentation of care and excessive bureaucracy. The navigation process improved data collection and established agreements to simplify and make the delivery of care more efficient. In addition, it generated partnerships between service providers and insurers. While several barriers and poor understanding of the navigation process still exist, a navigation program can help implement a Cancer Control Plan.


Medical treatment of non-streptococcal recurrent tonsillitis.
Forty patients with a history of recurrent non-beta-hemolytic streptococcal tonsillitis (RNST) participated in a prospective randomized study comparing penicillin and clindamycin in the treatment of acute non-group A streptococcal infection. The efficiency of each antibiotic was evaluated according to its ability to alleviate acute infection and prevent recurrence. Surface tonsillar cultures were obtained both before and ten days after the termination of therapy, and specimens were processed for aerobic and anaerobic bacteria. Beta-lactamase-producing bacteria (BLPB) were present in 36 (90%) tonsillar cultures. Thirty-one BLPB were isolated in 17 patients before penicillin therapy and 42 BLPB were recovered from 19 after such treatment. Thirty-three BLPB were recovered in 19 patients before clindamycin therapy, after which four BLPB were isolated in three patients (P less than .05). From the second day posttherapy onward, significantly fewer patients who received clindamycin had fever, pharyngeal injection, and sore throat. In a 1-year follow-up period, recurrent tonsillitis was noted in 13 of the patients who received penicillin and in two treated with clindamycin (P less than .001). The data clearly demonstrate the superiority of clindamycin therapy over penicillin in patients with RNST.


Inhibitory effect of glucocorticosteroids on anti-IgE-induced histamine release from human basophilic leukocytes: evidence for a dual mechanism of action.
Anti-IgE-induced histamine release from human leukocytes is inhibited when the cells before challenge are cultured overnight in the presence of glucocorticoids (GCSs). The present report suggests that the GCSs might exert their effect by at least a dual mechanism of action. Histamine release was induced by a suboptimum concentration of anti-IgE. When the release recorded in the presence of the steroid is plotted against the release recorded in its absence, the data points of several experiments fit a regression line characterized by two parameters: its slope and its intercept with the abscissa. Structure-activity examination with selected GCSs indicates that the orders of potency for affecting these two parameters are not identical. Furthermore, pulse experiments suggest that the cells require different times of contact with the steroid to express inhibition according to the two parameters. The removal of adherent cells or platelets did not markedly affect the degree of leukocyte histamine release or its inhibition by a given GCS, suggesting that the steroid interacts directly with the basophil. Finally, steroid-induced inhibition was not affected by the putative phospholipase A2-inhibitor p-bromophenacylbromide (BPB) or the 5-lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA).


Control of induced infestations of three African multihost tick species with sustained-release ivermectin.
The efficacy of ivermectin, released intraruminally from a 28-day-delivery device was evaluated in two titration studies against induced infestations of adult Rhipicephalus appendiculatus, R. evertsi and Hyalomma truncatum on cattle. Cattle were given a sufficient number of devices to release ivermectin at approximately 20, 40, 60 or 80 micrograms kg-1 day-1 at a steady-state rate 7-28 days after administration. Tick mortality was recorded, engorged female ticks were weighed and individually incubated, and reproductive data were recorded to determine a reproductive index for the species at various dose levels. Mortality of male and female ticks compared to that of controls was directly related to the daily dose of ivermectin, as was the number of ticks not engorging. Ticks fed on ivermectin-treated cattle had a smaller mass when engorged and laid smaller egg-masses, both absolutely and as a proportion of engorged mass. The index of reproduction of R. appendiculatus was reduced by more than 99.9% at 20 micrograms kg-1 day-1, and the reproductive indices of R. evertsi and H. truncatum were reduced by more than 99.9% at dose rates of 40 micrograms kg-1 day-1 and above. Practical implications of the application of sustained-release ivermectin for the control of multihost ticks and tick-borne diseases are discussed.


A method for estimating lateral diffusion coefficients in membranes from steady-state fluorescence quenching studies.
The Stern-Volmer theory, in which the quantum yield ratio (Io/I) depends linearly on the quencher concentration, will typically be inapplicable to fluorescence quenching in membranes. Numerical analysis shows that diffusion-controlled quenching results in a nonlinear concentration dependence for diffusion coefficients less than or of the order of 10(-6) cm2 s-1 and probe fluorescence lifetimes in the region of 10-100 ns. Lateral diffusion coefficients in membranes are typically overestimated an order of magnitude or more by the Stern-Volmer theory. An alternative empirical method is presented, which represents nonlinear concentration curves by a single parameter linear approximation determined by a least-squares analysis. The fitting parameter, P, depends on the interaction distance, the membrane thickness, the maximum extent of quenching and, in the case of biexponential probe fluorescence decay, the fluorescence kinetic parameters. P is presented in tabular form for a useful range of these parameters. The method is used to estimate diffusion coefficients for plastoquinone and plastoquinol from pyrene fluorescence quenching in soya bean phosphatidylcholine liposomes. It is found that the diffusion coefficients are nearly equal and in the region of 1.3-3.5 X 10(-7) cm2 s-1 for interaction radii of 1.5-0.5 nm, respectively.


Axon growth in embryonic chick and quail retinal whole mounts in vitro.
Whole retinae of 4- to 10-day-old chick and quail embryos were spread on membrane filters and kept in culture for up to 4 days. Axon growth during culture was demonstrated by silver staining, anterograde labeling of fibers with RITC, time-lapse recording, and SEM. Fiber growth was observed in specimens from chick embryos up to 7 days old, with a growth maximum at E6 and from quail embryos up to E6 with the maximum at E5. Newly growing axons followed the optic fiber pattern already existing and, like axons in vivo, grew predominantly toward the optic fissure. Directional and orientational adaptation of newly growing axons to the preexisting fibers increased with the donor age. Retinae from donors up to E5 in chick and up to E4 in quail showed a high proportion of axons which crossed the optic fissure during the culture period and invaded the opposite retinal fiber layer. These fibers showed a correct radial orientation while growing in the opposite direction to normal. Likewise, in cultures from these young donors some fibers grew out initially in the diametrically opposite direction to normal toward the tissue periphery. Since all of the wrongly directed axons grew at the same rate as normal and adapted correctly to the already formed axon pattern, this suggests independent signals for the direction and orientation of growing fibers. Treatment of mounted retinae with collagenase or trypsin removed the vitreal retinal surface, leaving the existing axon pattern intact. Subsequently, new axons grew profusely in culture, but lost both their orientational and directional characteristics.


Machine learning-based diagnostic method of pre-therapeutic 18F-FDG PET/CT for evaluating mediastinal lymph nodes in non-small cell lung cancer.
We aimed to find the best machine learning (ML) model using 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for evaluating metastatic mediastinal lymph nodes (MedLNs) in non-small cell lung cancer, and compare the diagnostic results with those of nuclear medicine physicians. A total of 1329 MedLNs were reviewed. Boosted decision tree, logistic regression, support vector machine, neural network, and decision forest models were compared. The diagnostic performance of the best ML model was compared with that of physicians. The ML method was divided into ML with quantitative variables only (MLq) and adding clinical information (MLc). We performed an analysis based on the 18F-FDG-avidity of the MedLNs. The boosted decision tree model obtained higher sensitivity and negative predictive values but lower specificity and positive predictive values than the physicians. There was no significant difference between the accuracy of the physicians and MLq (79.8% vs. 76.8%, p = 0.067). The accuracy of MLc was significantly higher than that of the physicians (81.0% vs. 76.8%, p = 0.009). In MedLNs with low 18F-FDG-avidity, ML had significantly higher accuracy than the physicians (70.0% vs. 63.3%, p = 0.018). Although there was no significant difference in accuracy between the MLq and physicians, the diagnostic performance of MLc was better than that of MLq or of the physicians. The ML method appeared to be useful for evaluating low metabolic MedLNs. Therefore, adding clinical information to the quantitative variables from 18F-FDG PET/CT can improve the diagnostic results of ML. • Machine learning using two-class boosted decision tree model revealed the highest value of area under curve, and it showed higher sensitivity and negative predictive values but lower specificity and positive predictive values than nuclear medicine physicians. • The diagnostic results from machine learning method after adding clinical information to the quantitative variables improved accuracy significantly than nuclear medicine physicians. • Machine learning could improve the diagnostic significance of metastatic mediastinal lymph nodes, especially in mediastinal lymph nodes with low 18F-FDG-avidity.


Assessment of exposures and potential risks to the US adult population from the leaching of elements from gold and ceramic dental restorations.
Using data from the 2001 to 2004 US National Health and Nutrition Examination Survey (NHANES) on the number and placement of tooth restorations in adults, we quantified daily doses due to leaching of elements from gold (Au) alloy and ceramic restorative materials. The elements with the greatest leaching rates from these materials are often the elements of lowest proportional composition. As a result, exposure due to wear will predominate for those elements of relatively high proportional composition, while exposure due leaching may predominate for elements of relatively low proportional composition. The exposure due to leaching of silver (Ag) and palladium (Pd) from Au alloys exceeded published reference exposure levels (RELs) for these elements when multiple full surface crowns were present. Six or more molar crowns would result in exceeding the REL for Ag, whereas three or more crowns would be necessary to exceed the REL for Pd. For platinum (Pt), the majority of tooth surfaces, beyond just molar crowns, would be necessary to exceed the REL for Pd. Exposures due to leaching of elements from ceramic dental materials were less than published RELs for all components examined here, including having all restorations composed of ceramic.


Prediction of acute kidney injury, sepsis and mortality in children with urinary CXCL10.
To determine the associations of urinary CXC motif chemokine 10 (uCXCL10) with AKI, sepsis and pediatric intensive care unit (PICU) mortality in critically ill children, as well as its predictive value for the aforementioned issues. Urinary CXCL10 levels were serially measured in 342 critically ill children during the first week after PICU admission. AKI diagnosis was based on the criteria of KDIGO. Sepsis was diagnosed according to the surviving sepsis campaign's international guidelines for children. Fifty-two (15.2%) children developed AKI, 132 (38.6%) were diagnosed with sepsis, and 30 (12.3%) died during the PICU stay. Both the initial and peak values of uCXCL10 remained independently associated with AKI, sepsis, septic AKI and PICU mortality. The AUCs of the initial uCXCL10 for predicting AKI, sepsis, septic AKI and PICU mortality were 0.63 (0.53-0.72), 0.62 (0.56-0.68), 0.75 (0.64-0.87) and 0.77 (0.68-0.86), respectively. The AUCs for prediction by using peak uCXCL10 were as follows: AKI 0.65 (0.56-0.75), sepsis 0.63 (0.57-0.69), septic AKI 0.76 (0.65-0.87) and PICU mortality 0.84 (0.76-0.91). Urinary CXCL10 is independently associated with AKI and sepsis and may be a potential indicator of septic AKI and PICU mortality in critically ill children. Urinary CXC motif chemokine 10 (uCXCL10), as an inflammatory mediator, has been proposed to be a biomarker for AKI in a specific setting. AKI biomarkers are often susceptible to confounding factors, limiting their utility as a specific biomarker, especially in heterogeneous population. This study revealed that uCXCL10 levels are independently associated with increased risk for AKI, sepsis, septic AKI and PICU mortality. A higher uCXCL10 may be predictive of septic AKI and PICU mortality in critically ill children.