The contribution of avoidable factors in doubling or halving the odds of hypertension.
Despite the well-known impact of fruit/vegetable consumption, physical activity, body mass index, waist-hip ratio, fasting blood glucose, and total cholesterol on blood pressure, the amount of exposure to these factors is required to halve or double the odds of hypertension is unknown, but it was investigated in this research. The data used in this study are derived from results of the seventh Iranian national STEPS survey involving 30,542 adults aged 18 years or older. The questionnaire measured non-communicable disease risk factors covered three different levels including behavioral characteristics, physical and biochemical measurements. The level of exposure to factors necessary to reach the odds ratio of 0.5 or odds ratio of 2.0 was obtained from the coefficients of the multiple logistic regression model. An OR of 0.5 corresponds to 7 servings of fruit and vegetable consumption daily and burning of 7175 kcal through physical activity at work or recreation daily. An OR of 2.0 corresponds to an increase in body mass index of about 11 kg/m2, an increase in the waist-hip ratio of about 18%, an increase in fasting blood glucose of about 77 mg/dl, and an increase in total cholesterol of about 134 mg/dl. The results of this study indicate how much fruit and vegetable and physical activity halve the odds of hypertension and how much increase in body mass index, the waist-hip ratio, fasting blood glucose, and total cholesterol can double the odds of hypertension. Such information may be useful for developing guidelines by policymakers.


Existence of nodal-arc and its evolution into Weyl-nodes in the presence of spin-orbit coupling in TaAs & TaP.
In this work, we report the existence ofnodal-arc, which acts as the building block of all the nodal-rings in TaAs & TaP. Thisnodal-arcis found to be capable of generating all the nodal-rings in these materials upon the application of space-group symmetry operations including time-reversal symmetry. The arcs are obtained to be dispersive with the energy spread of ∼109 (∼204) meV in TaAs (TaP). Also, the orbitals leading to bands-inversion and thus the formation ofnodal-arcsare found to be Ta-5d& As-4p(P-3p) in TaAs (TaP). The area of nodal-rings is found to be highly sensitive to the change in hybridization-strength, where the increase in hybridization-strength leads to the decrease in the area of nodal-rings. In the presence of spin-orbit coupling (SOC), all the points on these arcs get gaped-up and two pairs of Weyl-nodes are found to evolve from them. Out of the two pair, one is found to be situated close to the joining point of the two arcs forming a ring. This causes the evolution of each nodal-ring into three pairs of Weyl-nodes. The coordinates of these Weyl-nodes are found to be robust to the increase in SOC-strength from ∼ 0.7-3.5 eV. All the results are obtained at thefirst-principlelevel. This work provides a clear picture of the existence of nodal-arc due to accidental degeneracy and its evolution into Weyl-nodes under the effect of SOC.


Interleukin 7 receptor is required for myeloid cell homeostasis and reconstitution by hematopoietic stem cells.
Respiratory diseases are a leading cause of death worldwide, with vulnerability to disease varying greatly between individuals. The reasons underlying disease susceptibility are unknown, but there is often a variable immune response in lungs often. Recently, we identified a surprising novel role for the interleukin 7 receptor (IL7R), a primarily lymphoid-associated regulator, in fetal-specified, lung-resident macrophage development. Here, we report that traditional, hematopoietic stem cell-derived myeloid cells in the adult lung, peripheral blood, and bone marrow also depend on IL7R expression. Using single- and double-germline knockout models, we found that eosinophil numbers were reduced on deletion of IL7Rα. We then employed two Cre recombinase models in lineage tracing experiments to test whether these cells developed through an IL7Rα+ pathway. Despite the impact of IL7Rα deletion, IL7R-Cre labeled only a minimal fraction of eosinophils. We therefore examined the intrinsic versus extrinsic requirement for IL7R in the production of eosinophils using reciprocal hematopoietic stem cell transplantation assays. These assays revealed that extrinsic, but not eosinophil-intrinsic, IL7R is required for eosinophil reconstitution by HSCs in the adult lung. To determine which external factors may be influencing eosinophil development and survival, we performed a cytokine array analysis between wild-type and IL7Rα-deficient mice and found several differentially regulated proteins. These findings expand on our previous report that IL7R is required not only for proper lymphoid cell development and homeostasis, but also for myeloid cell homeostasis in tissues.


Changes in Online Illegal Drug Buying during COVID-19: Assessing Effects due to a Changing Market or Changes in Strain using a Longitudinal Sample Design.
This research uses longitudinal data to investigate if illegal online drug purchases changed over time during the COVID-19 pandemic, and if these changes were primarily driven by users adjusting to market conditions or by a heightened level of pandemic-induced strain that could drive a greater demand for drugs. Data were collected across four waves between fall 2019 and fall 2021 using an online survey. Data showed an increase in reported online drug purchases across the waves, but the online drug purchases remained consistent for the first year of the pandemic, but increased by approximately 44% between the fall 2020 and fall 2021 when over 13 percent of the sample admitted to buying illegal drugs online. Strain was also related to buying illegal drugs online as those respondents who made illegal online purchased had an average of 5.2 strain events in the past 12 months compared to only 2.4 events among those who did not report purchasing illegal drugs online. However, the influence of strain on online purchases remained consistent across time. These results suggest that the increase in online drug purchases was primarily driven by users adapting to changing market conditions rather than the cumulative strains associated with the pandemic producing a greater effect on purchases. Policy implications are also discussed.


Identification of a HERV-K env surface peptide highly recognized in Rheumatoid Arthritis (RA) patients: a cross-sectional case-control study.
Endogenous retroviruses (HERV) are believed to be pathogenic in several autoimmune diseases. Among them, HERV-K viruses have been reported recently to be involved in the pathogenesis of rheumatoid arthritis (RA). In this study we have explored the role of humoral immune response against HERV-K as a potential pathogenetic mechanism in RA. Four different peptides from the extracellular portion of the env protein of HERV-K (env-su19-37 , env-su109-126 , env-su164-186 , env-su209-226 ) were selected by bioinformatic analysis on the basis of their putative immunogenicity. Indirect enzyme-linked immunosorbent assay (ELISA) was then carried out to quantify antibodies against those peptides on blood samples of 70 consecutive RA patients and 71 healthy controls (HC). Differences between the two groups were analysed using the Mann-Whitney test. Potential correlations between RA laboratory, clinical descriptors and immunoglobulin (Ig)G levels were explored by bivariate regression analysis. Serum autoantibodies against one of four tested peptides of HERV-K (env-su19-37 ) were significantly higher in RA than in HC (19 versus 3%, P = 0·0025). Subgroup analysis showed no association between anti-HERV-K peptide humoral response and clinical, serological and clinimetric RA disease descriptors. Serum from RA patients in our series reacted significantly against HERV-K env-su19-37 peptide in comparison to the general population suggesting a role for the HERV-K- related, secondary antigenic-driven immune response in the pathogenesis of RA. Further studies are needed to confirm these results and to explore the role of this HERV-K surface peptide as a potential therapeutic target.


Developmental malformations in cerebral structures in "endogenous psychoses".
The last decades have revealed several structural deviances in patients with so called "endogenous psychoses". Reasonably well established are the enlargement of the lateral ventricles and subtle structural deficits in temporobasal and orbital frontal structures (hypofrontality) in a majority of schizophrenic patients. It is the aim of this investigation to examine the cytoarchitecture of these important central structures, namely the entorhinal region and the orbitofrontal cortex (Brodmann area 11) which have been under meticulous investigation in our laboratories over decades (for review: Beckmann, 2000).


Distribution of serotonergic neurons and processes in the lamprey spinal cord.
The distribution of serotonin in the spinal cord in two species of lamprey, Ichthyomyzon unicuspis and Petromyzon marinus, was studied by indirect immunofluorescence techniques. Multipolar cell bodies containing serotonin-like immunoreactivity were found along the length of the spinal cord, along the midline and slightly ventral to the central canal. These cell bodies send a diffuse projection of processes throughout the spinal cord, including: (1) a dense projection to the ventral surface; (2) a strong projection to the ventromedial longitudinal fiber tracts; (3) a less intense projection to the dorsal longitudinal fiber tracts; and (4) a weak projection to the lateral fiber tracts. Lesion experiments showed that processes descending from the brain or rostral spinal cord provide a major projection to the lateral fiber tracts and smaller contributions to the dorsal and ventromedial fiber tracts. Fluorescent processes were also observed in the dorsal roots and serotonergic peripheral cell bodies were seen adjacent to the dorsal roots. Our results suggest that the serotonergic innervation of the lamprey spinal cord arises from three sources: spinal interneurons, descending tracts and peripheral (possibly sensory) input. This provides an anatomical substrate for our recent finding that serotonin modulates the central pattern generator for locomotion in the lamprey spinal cord.


Diagnosis of Streptococcus suis Meningoencephalitis with metagenomic next-generation sequencing of the cerebrospinal fluid: a case report with literature review.
Streptococcus suis meningoencephalitis is a zoonotic disease that mostly infects slaughterhouse workers. Rapid diagnosis of Streptococcus suis meningoencephalitis is critical for effective clinical management of this condition. However, the current diagnostic techniques are not effective for early diagnosis of this condition. To the best of our knowledge, the use of cerebrospinal fluid metagenomic next generation sequencing in the diagnosis of Streptococcus suis meningoencephalitis has been rarely reported. Here, we report a case of Streptococcus suis meningoencephalitis in a 51-year-old female patient. The patient had a history of long-term contact with pork and had a three-centimeter-long wound on her left leg prior to disease onset. Conventional tests, including blood culture, gram staining and cerebrospinal fluid culture, did not reveal bacterial infection. However, Streptococcus suis was detected in cerebrospinal fluid using metagenomic next generation sequencing. Metagenomic next generation sequencing is a promising approach for early diagnosis of central nervous system infections. This case report indicates that cases of clinical meningeal encephalitis of unknown cause can be diagnosed through this method.


Down-regulation of increased signal transduction capacity in human cancer cells.
Signal transduction capacity in human cancer cells is constitutively up-regulated by the markedly increased steady-state activities of the three synthetic enzymes, PI kinase, PIP kinase and PLC, which catalyze the conversion of PI to the second messengers IP3 and DAG. This evidence is supported by the elevated concentration of IP3 in human colon, ovarian and breast carcinoma samples and rat hepatocellular carcinomas and sarcoma. The decrease in activities of the two specific phosphatases in the degradative pathway of signal transduction provides an amplified capacity for IP3 production. The elevated second messenger concentrations should lead to increased calcium release and protein kinase C activation. These biochemical alterations should confer selective biological advantages to cancer cells. The malignancy-linked rise in the activity of the signal transduction pathway can be down-regulated by drugs (tiazofurin, ribavirin, tamoxifen) or through inhibition of the kinases by flavonoids (quercetin, genistein) which lead to a reduction of IP3 concentration. As a result, carcinoma cells in culture stop proliferating and are destroyed. The stringent linkage of signal transduction with neoplasia provides novel targets for clinical chemotherapy.


A pair of circularly permutated PDZ domains control RseP, the S2P family intramembrane protease of Escherichia coli.
The sigma(E) pathway of extracytoplasmic stress responses in Escherichia coli is activated through sequential cleavages of the anti-sigma(E) protein, RseA, by membrane proteases DegS and RseP. Without the first cleavage by DegS, RseP is unable to cleave full-length RseA. We previously showed that a PDZ-like domain in the RseP periplasmic region is essential for this negative regulation of RseP. We now isolated additional deregulated RseP mutants. Many of the mutations affected a periplasmic region that is N-terminal to the previously defined PDZ domain. We expressed these regions and determined their crystal structures. Consistent with a recent prediction, our results indicate that RseP has tandem, circularly permutated PDZ domains (PDZ-N and PDZ-C). Strikingly, almost all the strong mutations have been mapped around the ligand binding cleft region in PDZ-N. These results together with those of an in vitro reaction reproducing the two-step RseA cleavage suggest that the proteolytic function of RseP is controlled by ligand binding to PDZ-N.


Detection of DNA hypermethylation in remote media of patients with colorectal cancer: new biomarkers for colorectal carcinoma.
Colorectal cancer is the third most common cancer and a major cause of cancer-related mortality. The lifetime risk to develop colorectal cancer is 6% in the Western world, and one third of the affected people will ultimately die from this disease. Colorectal carcinomas develop slowly over a period of several years. Therefore, identifying people with precancerous lesions holds the potential to reduce the incidence and mortality of colorectal cancer. Apart from mutations and chromosomal imbalances, inactivation of tumor suppressor genes by DNA hypermethylation has been recognized as an important mechanism driving colorectal carcinogenesis. In recent years, screening tests have been developed that rely on the detection of DNA hypermethylation in remote media to identify people suffering from asymptomatic colorectal cancers at early stages. Apart from their diagnostic value, methylation markers hold the potential to be used as prognostic markers. Here, we summarize the recent development of DNA methylation markers for colorectal cancer in remote media with regard to their diagnostic and prognostic value.


In vivo subchronic effects of ciguatoxin-related compounds, reevaluation of their toxicity.
Ciguatoxins are marine compounds that share a ladder-shaped polyether structure produced by dinoflagellates of the genus Gambierdiscus and Fukuyoa, and include maitotoxins (MTX1 and MTX3), ciguatoxins (CTX3C) and analogues (gambierone), components of one of the most frequent human foodborne illness diseases known as ciguatera fish poisoning. This disease was previously found primarily in tropical and subtropical areas but nowadays, the dinoflagellates producers of ciguatoxins had spread to European coasts. One decade ago, the European Food Safety Authority has raised the need to complete the toxicological available data for the ciguatoxin group of compounds. Thus, in this work, the in vivo effects of ciguatoxin-related compounds have been investigated using internationally adopted guidelines for the testing of chemicals. Intraperitoneal acute toxicity was tested for maitotoxin 1 at doses between 200 and 3200 ng/kg and the acute oral toxicity of Pacific Ciguatoxin CTX3C at 330 and 1050 ng/kg and maitotoxin 1 at 800 ng/kg were also evaluated showing not effects on mice survival after a 96 h observation period. Therefore, for the following experiments the oral subchronic doses were between 172 and 1760 ng/kg for gambierone, 10 and 102 ng/kg for Pacific Ciguatoxin CTX3C, 550 and 1760 ng/kg for maitotoxin 3 and 800, 2560 and 5000 ng/kg for maitotoxin 1. The results presented here raise the need to reevaluate the in vivo activity of these agents. Although the intraperitoneal lethal dose of maitotoxin 1 is assumed to be 50 ng/kg, without chemical purity identifications and description of the bioassay procedures, in this work, an intraperitoneal lethal dose of 1107 ng/kg was obtained. Therefore, the data presented here highlight the need to use a common procedure and certified reference material to clearly establish the levels of these environmental contaminants in food.


Comparison of the clinical performance, contraceptive efficacy and acceptability of levonorgestrel-releasing IUD and Norplant-2 implants in China.
The levonorgestrel-releasing IUD (LNG-IUD, 20 micrograms/d) and the Norplant-2 implants were studied in a randomized comparative clinical trial with 200 women for one year. No pregnancy or expulsion occurred with the Norplant-2. In the LNG-IUD group, there was one pregnancy at the 12th month of use after an unnoticed expulsion. The net cumulative pregnancy and expulsion rates of LNG-IUD were 1.0 and 3.0. The removal rate due to menstrual disturbances in both LNG-IUD and Norplant-2 groups was 3.0. The use-related discontinuation rates were 9.0 and 3.0, and the continuation rates were 90.0 and 96.0, respectively. The differences were not statistically significant. Menstrual disturbance was the main side effect. It was improved after long time use, especially in the LNG-IUD group. After one year, the percentages of women with amenorrhea were 18.9 for the LNG-IUD and 8.3 for the Norplant-2. The menstrual blood loss was statistically significantly reduced in the LNG-IUD group, and blood haemoglobin concentration increased in both groups. The LNG-IUD and Norplant-2 are highly effective, safe, long-acting, and well accepted by the Chinese women.


Effects of t-butyl-4-hydroxyanisole and other phenolic antioxidants on tumoral cells and Trypanosoma parasites.
The antioxidant food additives 2(3)-tert-butyl-4-hydroxyanisole (BHA), 2,6-di(tert-butyl)-p-cresol (BHT) and the methyl and propyl esters of gallic acid inhibited Trypanosoma cruzi culture growth and oxygen consumption. The I50 values for growth and oxygen uptake with BHA were 0.284 and 0.400 and for BHT 0.083 and 0.235 mM, respectively. Moreover, BHA inhibited the respiration of several tumor cells, as well as of the procyclic and bloodstream trypomastigote forms of T. brucei brucei, with I50 in the range 0.29-0.52 mM. Inhibition of the parasites' oxygen uptake by BHA was not of the pure Michaelis-Menten type, but may be of a mixed form. It is postulated that these compounds are inhibitors because they resemble ubiquinone.


Evaluation of human health risks posed by carcinogenic and non-carcinogenic multiple contaminants associated with consumption of fish from Taihu Lake, China.
The present study estimated the human daily intake and uptake of organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), polycyclic aromatic hydrocarbons (PAHs), and toxic trace elements [mercury (Hg), chromium (Cr), cadmium (Cd), and arsenic (As)] due to consumption of fish from Taihu Lake, China, and the associated potential health risks posed by these contaminants. The health risks posed by the contaminants were assessed using a risk quotient of the fish consumption rate to the maximum allowable fish consumption rate considering the contaminants for carcinogenic and non-carcinogenic effect endpoints. The results showed that fish consumption would not pose non-cancer risks. However, some species would cause a cancer risk. Relative risks of the contaminants were calculated to investigate the contaminant which posed the highest risk to humans. As a result, in view of the contaminants for carcinogenic effects, As was the contaminant which posed the highest risk to humans. However, when non-carcinogenic effects of the contaminants were considered, Hg posed the highest risk. The risk caused by PBDEs was negligible. The results demonstrated that traditional contaminants, such as As, Hg, DDTs (dichlorodiphenyltrichloroethane and its metabolites), and PCBs, require more attention in Taihu Lake than the other target contaminants.


Nucleotide sequence of the gene for the large subunit of Rubisco from Cyanophora paradoxa--phylogenetic implications.
The gene (rbcL) for the large subunit (LSU) of Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) from Cyanophora paradoxa was cloned and the nucleotide sequence determined. Sequence homologies to rbcL genes from other sources clearly indicated a close phylogenetic relationship between the photosynthetic organelles of Cyanophora (cyanelles), green chloroplasts and cyanobacteria. Our data support the hypothesis that the cyanelles of Cyanophora may represent a closely related, but independent, side line to chloroplast evolution. Cyanelles and rhodoplasts or phaeoplasts seem not to be related.


Influence of solvent quality on the mechanical strength of ethylcellulose oleogels.
Ethylcellulose (EC) is the only known food-grade polymer able to structure edible oils. The gelation process and gel properties are similar to those of polymer hydrogels, the main difference being the nature of the solvent. The present study examines the influence of solvent quality on the large deformation mechanical behavior of EC oleogels. Two alternative strategies for manipulating the mechanical response of these gels were evaluated; manipulating the bulk solvent polarity and the addition of surface active small molecules. Gel strength was positively correlated to solvent polarity when blending soybean oil with either mineral oil or castor oil. This behavior was attributed to the ability of the polar entities present in the oil phase to interact with the EC gel network. The addition of the small molecules oleic acid and oleyl alcohol resulted in a substantial enhancement in gel strength up to 10wt% addition, followed by a gradual decrease with increasing proportions. Binding interactions between EC and these molecules were successfully modeled using a Langmuir adsorption isotherm below 10wt% addition. Furthermore, the thermal behavior of stearic acid and stearyl alcohol also indicated a direct interaction between these molecules and the EC network. Differences in the mechanical behavior of gels prepared using refined, bleached, and deodorized canola or soybean oils, and those made with cold-pressed flaxseed oil could be attributed to both oil polarity, and the presence of minor components (free fatty acids). Shorter pulsed NMR T2 relaxation times were observed for stronger gels due to the more restricted mobility of the solvent when interacting with the polymer. This work has demonstrated the strong influence of the solvent composition on the mechanical properties of EC oleogels, which will allow for the tailoring of mechanical properties for various applications.


Clinical efficacy and safety of Zuranolone (SAGE-217) in individuals with major depressive disorder.
Major depressive disorder (MDD) is a common mental disorder with a high rate of morbidity and mortality. Dysfunctional signaling of gamma-aminobutyric acid (GABA) has been implicated in some studies in the etiology of MDD. Zuranolone (SAGE-217) is a novel, oral neuroactive steroid and an investigational positive allosteric modulator of synaptic and extrasynaptic GABAA receptors. Herein, we aimed to evaluate the efficacy and safety of Zuranolone in individuals with MDD. We reviewed seven studies including 1662 participants with MDD. Zuranolone was investigated as an oral, once-daily, 14-day treatment course. The results of our synthesis indicate that the antidepressant effects of Zuranolone are rapid, clinically meaningful, and replicated across multiple randomized clinical trials. In addition to replicated efficacy, Zuranolone is associated with an acceptable level of treatment-emergent adverse events and discontinuation without serious adverse events. It is believed that Zuranolone's antidepressant effects arise from its ability to enhance inhibitory GABAergic signaling by increasing synaptic and extrasynaptic GABAA activity and regulation of GABAA receptor expression. Taken together, preliminary evidence suggests the potential for antidepressant effects of Zuranolone. Zuranolone has been approved by FDA for postpartum depression, and is showing efficacy in major depressive disorder. Future research vistas should seek to determine the durability of this treatment approach as well as its effects on domain-specific outcomes (e.g., anhedonia, circadian rhythm, arousal systems) along with application in other diagnostic entities (e.g., bipolar depression).


"Hot spot" on gallium-67-citrate scan in renal cell carcinoma. Clinicopathologic and biochemical correlation.
A frontal tomographic whole-body gallium-67-citrate scan was performed on 30 patients with renal cell carcinoma. Positive gallium uptake by the kidney in 20 patients (66.7%) correlated well with the clinicopathologically higher stage and grade of the tumor and with abnormal values in prognostic indexes in the blood. Thus, a negative gallium uptake may be indicative of an improved clinical course and longer survival in patients with renal cell carcinoma.


Client and provider factors associated with integration of family planning services among maternal and reproductive health clients in Kigoma Region, Tanzania: a cross-sectional study, April-July 2016.
Integration of family planning (FP) services into non-FP care visits is an essential strategy for reducing maternal and neonatal mortality through reduction of short birth intervals and unplanned pregnancies. Cross-sectional surveys were conducted across 61 facilities in Kigoma Region, Tanzania, April-July 2016. Multilevel, mixed effects logistic regression analyses were conducted on matched data from providers (n = 330) and clients seeking delivery (n = 935), well-baby (n = 272), pregnancy loss (PL; n = 229), and other routine (postnatal, HIV/STI, other; n = 69) services. Outcomes of interest included receipt of FP information and a modern FP method (significance level p < 0.05). Clients had significantly greater odds of receiving FP information if the primary reason for seeking care was for PL versus (vs) any other types of care (aOR 1.97), had four or more pregnancies vs fewer (aOR 1.78), and had had a FP discussion with their partner vs no FP discussion (aOR 1.73). Clients had lower odds of receiving FP information if they were aged 40-49 vs 15-19 (aOR 0.50) and reported attending religious services at least weekly vs less frequently (aOR 0.61). Clients of providers who perceived that in-service training had helped vs had not helped job performance (aOR 2.27), and clients of providers having high vs low recent FP training index scores (aOR 1.58) had greater odds of receiving FP information. Clients had greater odds of receiving a modern method when they received information on two or more vs fewer methods (aOR 7.13), had had a FP discussion with their partner vs no discussion (aOR 5.87), if the primary reason for seeking care was for PL vs any other types of care (aOR 4.08), had zero vs one or more live births (aOR 3.92), made their own FP decisions vs not made own FP decisions (aOR 3.17), received FP information from two or more vs fewer sources (aOR 3.12), and were in the middle or high vs the low wealth tercile (aOR 1.99 and 2.30, respectively). Well-baby care clients, Other routine services clients, and married clients had significantly lower odds of receiving a method (aOR 0.14; aOR 0.08; and aOR 0.41, respectively) compared to their counterparts. Strategies that better integrate FP into routine care visits, encourage women to have FP discussions with their partners and providers, increase FP training among providers, and expand FP options and sources of information may help reduce the unmet need for FP, and ultimately lower maternal and neonatal mortality.


Trauma histories, substance use coping, PTSD, and problem substance use among sexual assault victims.
Sexual assault history is associated with higher risk of problem drinking and drug use in women, yet little is known about mechanisms linking trauma histories in general to women's drinking or drug use problems. This study examined how various types of trauma, substance use coping, and PTSD relate to past-year problem drinking and drug use in women who experienced sexual assault. Data from a large, diverse sample of women who had experienced adult sexual assault were analyzed with structural equation modeling to test a theoretical model of the relationship between trauma types, substance use coping, PTSD symptoms, and past-year drinking and drug use (N=1863). Results show that PTSD symptoms fully mediated the association between non-interpersonal trauma and the use of substances to cope. However, the association between both interpersonal trauma and child sexual abuse severity on substance use to cope was only partially mediated by PTSD symptoms. In turn, use of substances to cope fully mediated the relationship between PTSD and problem drug use as well as partially mediated the effect of PTSD on problem drinking. These results suggest that different trauma types and substance use coping may be important risk factors distinguishing sexually assaulted women who develop PTSD and problematic substance use from those who do not. Identifying women's histories of different traumas may help to identify those at greater risk for substance use problems.


A walk in the park? Characterizing gait-related artifacts in mobile EEG recordings.
Brain activity during natural walking outdoors can be captured using mobile electroencephalography (EEG). However, EEG recorded during gait is confounded with artifacts from various sources, possibly obstructing the interpretation of brain activity patterns. Currently, there is no consensus on how the amount of artifact present in these recordings should be quantified, or is there a systematic description of gait artifact properties. In the current study, we expand several features into a seven-dimensional footprint of gait-related artifacts, combining features of time, time-frequency, spatial, and source domains. EEG of N = 26 participants was recorded while standing and walking outdoors. Footprints of gait-related artifacts before and after two different artifact attenuation strategies (after artifact subspace reconstruction (ASR) and after subsequent independent component analysis [ICA]) were systematically different. We also evaluated topographies, morphologies, and signal-to-noise ratios (SNR) of button-press event-related potentials (ERP) before and after artifact handling, to confirm gait-artifact reduction specificity. Morphologies and SNR remained unchanged after artifact attenuation, whereas topographies improved in quality. Our results show that the footprint can provide a detailed assessment of gait-related artifacts and can be used to estimate the sensitivity of different artifact reduction strategies. Moreover, the analysis of button-press ERPs demonstrated its specificity, as processing did not only reduce gait-related artifacts but ERPs of interest remained largely unchanged. We conclude that the proposed footprint is well suited to characterize individual differences in gait-related artifact extent. In the future, it could be used to compare and optimize recording setups and processing pipelines comprehensively.


Infarction and circulation in cerebrum. Effect of recanalization and/or collateral circulation on the lesion and prognosis.
Findings of computed tomography (CT) and angiography in supratentorial cerebral infarction associated with complete stroke were compared with regard to prognosis. It was found that the extent of low-density areas on CT was perfectly in accordance with the areas of occluded arteries on angiograms. However, the low-density areas on CT were always smaller than the areas involved angiographically when early recanalization and/or collateral circulation were carried out within 2 to 3 days of onset. It was also found that smaller low-density areas only had favorable effect. We concluded that the prognosis was better with early recanalization and/or collateral circulation, despite the general acceptance of its poor prognostic implication.


Further toxicologic studies with commercial and candidate flame retardant chemicals. Part II.
A number of commercial and candidate flame retardants were studied with regard to their toxicity to goldfish, inhibition of cholinesterase, inhibition of acetyl choline binding to its receptor and insecticidal properties. Several of the flame retardants were notably toxic to fish. Some of the compounds showed modest inhibition of cholinesterase and/or microsomal oxidases, but none inhibited acetyl choline receptor binding. Whereas several of the flame retardants showed little or no insecticidal properties when added alone to a housefly diet, piperonyl butoxide greatly synergised their toxicity to houseflies.


A PC-based system for visual evoked potential studies.
An interactive PC-based computer controlled system is described that can be used for collection and analysis of data of Visual Evoked Potentials (VEPs). Visual stimuli are generated on a high-resolution color monitor driven by an Enhanced Graphics Adaptor (EGA). The VEP waveforms are digitized by an A/D converter at a sampling rate of 1 KHz and stored on a hard disk for further analysis. The analysis software includes both time and frequency analysis routines as well as some innovative techniques for the use of the VEPs as a diagnostic measure for various diseases.


Non-surgical management of rectal cancer. Series of 68 cases, long follow up in two leading centres in Argentina.
The non-surgical management in a selected group of rectal cancer patients has shown promising results with adequate follow up. describing the results of the non-surgical management in patients with complete clinical response, with a close follow up. Between 2006 and 2015, patients with rectal cancer, stages I-III, without metastasis, treated with neoadjuvant CRT/CT, who had clinical complete response were included. CCR was defined through digital palpation, endoscopy-based criteria and MRI. Follow up was set according to institutional guidelines. 68 patients were included. Initial stage was assessed with MRI in 55/68 pts and EUS 11/68. Considering the recurrence risk factors 57.6% (29/68) were T2-3ab N0, 3.3% (2/68) were T4N0, 29% (20/68) were T3-4 N1-2, with 39.7% with positive MRC. Mean distance to the anal margin was 3cm. Chemoradiation included radiotherapy at 50.4cGy, and concurrent capecitabine. In 22% a fluoropirimidine and oxaliplatin-based schema was used as induction therapy. Median follow up was 37.5 months and response assessment time 9 weeks (5-19). Eleven patients recurred, 6 endoluminally, 3 developed mesorectal recurrence, and two distant failure. Five years DFS and OS were 76.3% and 93.8%. conservative management was feasible with close follow up in leading cancer centres. In this series, DFS and OS were comparable to the data already reported in the literature.


Size-dependent placental retention effect of liposomes in ICR pregnant mice: Potential superiority in placenta-derived disease therapy.
The great challenge in developing safe medications for placenta-derived diseases is to reduce or eliminate fetal drug exposure while still providing the necessary therapeutic effect. Rapid advances in nanotechnology have brought opportunities for the therapy of placenta-derived disease through accumulating the drug in the placenta while reducing its placental penetration. Among various nanocarriers, liposomes are regarded as an ideal type of carrier for placental drug delivery due to their biosafety and biodegradability. However, their placental retention effect with different particle sizes has not been studied. This research aimed to explore a suitable size of liposomes for placenta drug delivery. Cy 5 dye was chosen as a model molecule for tracing the distribution of three different-sized liposomes (∼80 nm, 200 nm, and 500 nm) in ICR pregnant mice. The stability, cytotoxicity, and cellular uptake study of Cy 5-loaded liposomes were performed. The in vivo fluorescence studies on ICR pregnant mice suggested that the particle size of liposomes was positively correlated with the degree of liposome aggregation in the placenta. The ratio of fluorescence in the placenta and fetus section (P/F value) was proposed to evaluate the placental retention effect of different-sized liposomes. The results showed that the liposomes with 500 nm had the highest P/F value and thus exhibited the strongest placental retention effect and the weakest placental penetration ability. Moreover, liquid chromatography-mass spectrometry analysis confirmed the reliability of the fluorescence section analysis in exploring the placental retention effect of nanovehicles. In general, this study introduced a simple and intuitive method to evaluate the placental retention effect of nanoplatforms and defined a suitable size of liposomes for placenta-derived disease drug delivery.


Accuracy of high-resolution computed tomography in revealing fallopian canal fracture of patients with traumatic facial paralysis.
To investigate accuracy of high-resolution computed tomography (HRCT) of temporal bone in revealing fallopian canal fracture among the patients with traumatic facial paralysis. HRCT of temporal bone with cross-sectional scanning and multi-planar reformation (MPR) was performed on 31 patients with traumatic facial paralysis, and fracture sites of fallopian canal revealed by HRCT were retrospectively analyzed and compared with surgical findings. HRCT of temporal bone showed fracture of fallopian canal at geniculate ganglion in 25 cases, at tympanic segment in 15 cases, at labyrinthine segment in 5 cases, at pyramid segment in 2 cases, and at mastoid segment in one case, while surgical findings revealed that fracture involved geniculate ganglion in 27 cases, labyrinthine segment in 5, tympanic segment in 19, pyramid segment in 12, and mastoid segment in 9; the sensitivity of HRCT of temporal bone to detect fracture at such sites was 88.9%, 100%, 52.6%, 16.7% and 11.1%, respectively, and the specificity was 96.0%, 100%, 66.7%, 100% and 100%, respectively. HRCT of temporal bone was able to accurately reveal fracture of fallopian canal at geniculate ganglion and labyrinthine segment in the vast majority cases, but severely underestimated fracture at pyramid segment and mastoid segment of fallopian canal.


Rationale and Design of the Left Atrial Pressure Monitoring to Optimize Heart Failure Therapy Study (LAPTOP-HF).
Daily measurements of left atrial pressure (LAP) may be useful for guiding adjustments in medical therapy that prevent clinical decompensation in patients with severe heart failure (HF). LAPTOP-HF is a prospective, multicenter, randomized, controlled clinical trial in ambulatory patients with advanced heart failure in which the safety and clinical effectiveness of a physician-directed patient self-management therapeutic strategy based on LAP measured twice daily by means of an implantable sensor will be compared with a control group receiving optimal medical therapy. The trial will enroll up to 730 patients with New York Heart Association functional class III symptoms and either a hospitalization for HF during the previous 12 months or an elevated B-type natriuretic peptide level, regardless of ejection fraction, at up to 75 investigational centers. Randomization to the treatment group or control group will be at a 1:1 ratio in 3 strata based on the ejection fraction (EF > or ≤35%) and the presence of a de novo CRT device indication. LAPTOP-HF will provide essential information about the role of implantable LAP monitoring in conjunction with a new HF treatment paradigm across the spectrum of HF patients.


Effect of etomidate on intra-ocular pressure.
Etomidate, a new short-acting non-barbiturate hypnotic, was administered to 40 patients between the ages of 12 years and 65 years. Intra-ocular pressure was measured before and after etomidate injection using a Schiotz tonometer. A significant reduction of intra-ocular pressure was found to follow etomidate injection in spite of the often associated myoclonic movements. The mechanism of reduction of intra-ocular pressure has not been determined in this study. It is suggested that etomidate will be a useful intravenous induction agent where elevation of intra-ocular pressure is undesirable.


Role of mitochondria in the mechanisms of glutamate toxicity.
Current data on glutamate-induced functional and morphological changes in mitochondria correlating with or being a result of their membrane potential changes are reviewed. The important role of Ca2+, Na+, and H+ in the potentiation of such changes is considered. It is assumed that glutamate-induced loss of mitochondrial potential is mediated by Ca2+ overload resulting in the induction of nonspecific permeability of the inner mitochondrial membrane.


Serum Copper, Zinc, and Iron Levels in Patients with Alzheimer's Disease: A Meta-Analysis of Case-Control Studies.
Background: Many publications have investigated the association between metal ions and the risk of Alzheimer's disease (AD), but the results were ambiguous. Aims: The objective of this study was to assess the association between the serum levels of metals (copper/zinc/iron) and the risk of AD via meta-analysis of case-control studies. Methods: We screened literatures published after 1978 in the Pubmed, Embase, Cochrane library, Web of Science and ClinicalTrials.gov. Electronic databases. By using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review of the 407 publications, there are 44 of these publications met all inclusion criteria. The Review Manager 5.3 software was used to calculate available data from each study. Results: Consistent with the conclusions of other meta-analysis, our results demonstrated serum copper levels were significantly higher [MD = 9.27, 95% CI (5.02-13.52); p < 0.0001], and the serum zinc levels were significantly lower in AD patients than in healthy controls [MD = -6.12, 95% CI (-9.55, -2.69); p = 0.0005]. Serum iron levels were significantly lower in AD patients than in healthy controls after excluded two studies [MD = -13.01, 95% CI (-20.75, -5.27); p = 0.001]. Conclusion: The results of our meta-analysis provided rigorous statistical support for the association of the serum levels of metals and the risk of AD, suggesting a positive relationship between the serum copper levels and AD risk, and a negative relationship between the serum zinc/iron levels and AD risk.


N-terminal Leu-enkephalin rearrangements.
The synthesis of H-Tyr-Gly-Gly-Phe-Leu-OH (Leu-enkephalin), endogenus peptide with opiate-like activity, and two rearrangements concerning Leu-enkephalin N-terminus are described.


Is a low fat diet the optimal way to cut energy intake over the long-term in overweight people?
Successful weight loss depends on maintaining a sustained negative energy balance. This can be achieved on diets with a normal (40% energy) fat content as well as on low fat diets. Using a 'modified fat' (MF) diet enriched with monounsaturated fat (MUFA), body weight may be lost either by calorie counting, or by allowing ad libitum food intake with careful food selection. In the latter approach high energy, high MUFA foods (predominantly olive oil, but also may include nuts and avocado) should contribute no more than 20% total energy to the diet, and other foods should be selected to minimise meal energy density. This can be achieved simply by the consumption of a wide variety of vegetables and whole grain cereal foods. It is also important to restrict foods high in saturated fat and to encourage regular exercise. Such a 'modified fat' low energy diet designed for weight loss should also contribute numerous health benefits in relation to improved metabolic control in Type 2 diabetes and reduced cardiovascular disease risk (as the diet is not only rich in MUFA but also in a range of dietary antioxidants and other bio-active phytochemicals).


Role of bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 activator, in aldosterone- and salt-induced renal injury.
The aim of this study was to investigate the renoprotective effect of bardoxolone methyl (BM), a nuclear factor erythroid 2-related factor 2 (Nrf2) activator with an antioxidant effect, in a salt-sensitive hypertension model induced by aldosterone (Ald) and salt. Tubulointerstitial damage with urinary liver-type fatty acid-binding protein (L-FABP) was evaluated using human L-FABP chromosomal transgenic (L-FABP+/-) male mice. The mice in the Ald group (n=7) received systemic Ald infusions via an osmotic minipump and were given 1% NaCl water for 35 days. Those in the Ald-BM group (n=8) were administered BM intraperitoneally in addition to an injection of Ald and salt. The dose of BM was gradually increased every 7 days up to 10 mg kg-1 per day, which was maintained for 14 days. The administration of BM significantly increased renal expression of the Nrf2 target antioxidant gene. Tubulointerstitial damage was significantly ameliorated in the Ald-BM group compared to the Ald group. The increase in reactive oxygen species (ROS) and upregulation of angiotensinogen expression in the kidneys of the Ald group was significantly prevented in the Ald-BM group. The upregulation of human L-FABP expression induced in the kidneys and increase in urinary L-FABP in the Ald group were significantly suppressed by BM administration. In conclusion, BM ameliorated tubulointerstitial damage in the Ald- and salt-induced hypertension model through suppression of both ROS production and intrarenal renin-angiotensin system activation. Urinary L-FABP may be a useful marker reflecting the therapeutic efficacy of BM.


Recent progress in translational cystic fibrosis research using precision medicine strategies.
Significant progress has been achieved in developing precision therapies for cystic fibrosis; however, highly effective treatments that target the ion channel, CFTR, are not yet available for many patients. As numerous CFTR therapeutics are currently in the clinical pipeline, reliable screening tools capable of predicting drug efficacy to support individualized treatment plans and translational research are essential. The utilization of bronchial, nasal, and rectal tissues from individual cystic fibrosis patients for drug testing using in vitro assays such as electrophysiological measurements of CFTR activity and evaluation of fluid movement in spheroid cultures, has advanced the prediction of patient-specific responses. However, for precise prediction of drug effects, in vitro models of CFTR rescue should incorporate the inflamed cystic fibrosis airway environment and mimic the complex tissue structures of airway epithelia. Furthermore, novel assays that monitor other aspects of successful CFTR rescue such as restoration of mucus characteristics, which is important for predicting mucociliary clearance, will allow for better prognoses of successful therapies in vivo. Additional cystic fibrosis treatment strategies are being intensively explored, such as development of drugs that target other ion channels, and novel technologies including pluripotent stem cells, gene therapy, and gene editing. The multiple therapeutic approaches available to treat the basic defect in cystic fibrosis combined with relevant precision medicine models provide a framework for identifying optimal and sustained treatments that will benefit all cystic fibrosis patients.


Pediatric Crohn Disease Clinical Outcome Assessments and Biomarkers: Current State and Path Forward for Global Collaboration.
There is a pressing need for drug development in pediatric Crohn disease (CD). Our aim was to provide strategic approaches toward harmonization of current thinking about clinical outcome assessments (COAs) and biomarkers to facilitate drug development in pediatric CD. Scientists from the United States Food and Drug Administration, European Medicines Agency, Health Canada, and the Pharmaceuticals and Medical Devices Agency of Japan had monthly teleconferences from January 2014 through May 2015. A literature review was conducted to assess the measurement properties of all existing COA tools and to evaluate the current landscape of biomarkers used in pediatric CD. Based on the findings of literature review, we reached the consensus on the strategic approaches for evaluating outcomes in pediatric CD trials. The pediatric Crohn's Disease Activity Index, Crohn's Disease Activity Index, and Harvey-Bradshaw's index were used in pediatric CD clinical studies. But they lack adequate measurement properties (validity, reliability, and ability to detect change of the treatment) that are required to support approval of products intended to treat pediatric CD. Biomarkers (ie, fecal lactoferrin, osteoprotegerin, and calprotectin) have shown some promise for their potential as noninvasive surrogate endpoints in CD. Lack of well-defined and reliable COAs presents a hurdle for global drug development in pediatric CD. It is essential to develop well-defined and reliable COAs that can measure meaningful clinical benefit for patients in terms of how they feel, function, and survive. Development of noninvasive biomarkers as reliable surrogate endpoints needs to be further explored.


Disseminated peritoneal leiomyomatosis with endometriosis.
Herein is described the case of a 41-year-old woman with disseminated peritoneal leiomyomatosis with distinct endometriosis. The pathogenesis of both conditions is as yet unclear; however, the 2 main hypotheses are discussed. Metaplastic origin from the secondary müllerian system has been suggested, as well as metastatic development. Inasmuch as spontaneous regression is likely, and the course of the disease can be influenced by hormonal withdrawal, operative measures could be refined to ensure the correct diagnosis and benignity.


Effect of cold adaptation on liver peroxisomes and peroxisomal oxidative activities of rat. A morphometric/stereologic and biochemical study.
The variations in liver peroxisomes and in peroxisomal enzymes were studied in the rat during adaptation to cold (5 degrees C). An increase in the number and in the volume and surface fractions of peroxisomes was detected by day 7. Qualitative ultrastructural changes of the peroxisome compartment were observed. Several peroxisomal enzyme activities were found to exhibit a significant increase with different temporal patterns. These results are discussed with regard to the possible contribution of liver peroxisomes to non-shivering thermogenesis.


Effectiveness of a psycho-oncology training program for oncology nurses: a randomized controlled trial.
Oncology nurses are expected to play an important role in psychosocial care for cancer patients. The aim of this study was to examine whether a novel training program aimed at enhancing oncology nurses' ability to assess and manage common psychological problems in cancer patients would improve participants' self-reported confidence, knowledge, and attitudes regarding care of patients with common psychological problems (trial register: UMIN000008559). Oncology nurses were assigned randomly to either the intervention group (N = 50) or the waiting list control group (N = 46). The intervention group received a 16-h program, the content of which focused on four psychological issues: normal reactions, clinically significant distress, suicidal thoughts, and delirium. Each session included a role-play exercise, group work, and didactic lecture regarding assessment and management of each problem. Primary outcomes were changes in self-reported confidence, knowledge, and attitudes toward the common psychological problems between pre-intervention and 3 months post-intervention. Secondary outcomes were job-related stress and burnout. Intervention acceptability to participants was also assessed. In the intervention group, confidence and knowledge but not attitudes were significantly improved relative to the control group. No significant intervention effects were found for job- related stress and burnout. A high percentage (98%) of participants considered the program useful in clinical practice. This psycho-oncology training program improved oncology nurses' confidence and knowledge regarding care for patients with psychological problems. Copyright © 2015 John Wiley & Sons, Ltd.


Template synthesis of water-dispersible and magnetically responsive carbon nano test tubes.
Water-dispersible and magneto-responsive carbon nano test tubes with a controlled length (1.3 microm) and diameter (35 nm) were synthesized by using the nanochannels of anodic aluminium oxide as a template.


Roseomonas aeriglobus sp. nov., isolated from an air-conditioning system.
A novel pale pink-coloured, strictly aerobic, Gram-stain negative bacterial strain, designated strain KER25-12T, was isolated from a laboratory air-conditioning system in South Korea. Cells were observed to be non-motile cocci showing positive catalase and oxidase reactions. Strain KER25-12T was found to grow at 10-30 °C (optimum, 25-30 °C), at pH 4.0-9.0 (optimum, pH 6.0-7.0) and in the presence of 0-2% (w/v) NaCl (optimum, 0%). Ubiquinone-10 and spermidine were detected as the sole respiratory quinone and the predominant polyamine, respectively. The major fatty acids were identified as summed feature 8 (comprising C18:1 ω7c and/or C18:1 ω6c), summed feature 3 (comprising C16:1 ω7c and/or C16:1 ω6c), C16:0 and C18:0. The genomic DNA G+C content of strain KER25-12T was determined to be 70.0 mol%. The major polar lipids were identified as diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine and an unidentified aminolipid. Phylogenetic analysis based on 16S rRNA gene sequence comparison revealed that strain KER25-12T belongs to the genus Roseomonas and shows high sequence similarity to Roseomonas aerilata 5420S-30T (98.57%), Roseomonas pecuniae N75T (97.44%) and Roseomonas vinacea CPCC 100056T (97.40%). Based on the morphological, physiological, chemotaxonomic and phylogenetic features, strain KER25-12T is concluded to represent a novel species of the genus Roseomonas, for which the name Roseomonas aeriglobus sp. nov. is proposed. The type strain is KER25-12T (= KACC 19282T = JCM 32049T).


Protecting patients from harm: taking aim at heart failure.
Learn how initiating best practices for managing chronic heart failure can lessen the toll of this dangerous and increasingly prevalent problem.


Mseleni disease serum is not harmful to cultured chondrocytes.
The origins of Mseleni disease, an acquired polyarticular degenerative joint disease, are unknown. We examined sera from 12 patients with the disease, 5 unaffected Mseleni residents, and 5 Durban residents. The effects of sera from the 12 patients with Mseleni disease on DNA or sulfated proteoglycan synthesis by cultured rabbit or human infant articular chondrocytes were no different from those of control sera. Cells derived from 2 children contained no stainable DR antigens; coculture had no impact on either of the above measures of cell function.


New constituents from the rhizomes of Egyptian Iris germanica L.
Chemical investigation of the methanolic extract of the rhizomes of Iris germanica L. (Iridaceae) afforded two new compounds; irigenin S (7) and iriside A (12), together with ten known compounds: stigmasterol (1), a-irone (2), γ-irone (3), 3-hydroxy-5-methoxyacetophenone (4), irilone (5), irisolidone (6), irigenin (8), stigmasterol-3-O-β-D-glucopyranoside (9), irilone 4'-O-β-D-glucopyranoside (10) and iridin (11). Their structures were established by UV, IR, 1D (¹H and ¹³C) and 2D (¹H-¹H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to mass spectroscopic data and comparison with literature data. The methanolic extract was evaluated for its antimicrobial activity. Both the methanolic extract and the isolated flavonoids were tested for their anti-inflammatory activity.


Estimation of lake water - groundwater interactions in meromictic mining lakes by modelling isotope signatures of lake water.
A method is presented to assess lake water-groundwater interactions by modelling isotope signatures of lake water using meteorological parameters and field data. The modelling of delta(18)O and deltaD variations offers information about the groundwater influx into a meromictic Lusatian mining lake. Therefore, a water balance model is combined with an isotope water balance model to estimate analogies between simulated and measured isotope signatures within the lake water body. The model is operated with different evaporation rates to predict delta(18)O and deltaD values in a lake that is only controlled by weather conditions with neither groundwater inflow nor outflow. Comparisons between modelled and measured isotope values show whether the lake is fed by the groundwater or not. Furthermore, our investigations show that an adaptation of the Craig and Gordon model [H. Craig, L.I. Gordon. Deuterium and oxygen-18 variations in the ocean and the marine atmosphere. In Stable Isotopes in Oceanographic Studies and Paleotemperature, Spoleto, E. Tongiorgi (Ed.), pp. 9-130, Consiglio Nazionale delle Ricerche, Laboratorio di Geologia Nucleare, Pisa (1965).] to specific conditions in temperate regions seems necessary.


An epidemic of acute post-streptococcal glomerulonephritis among aboriginal children.
To describe an epidemic of acute post-streptococcal glomerulonephritis (APSGN) that occurred in Aboriginal children in three remote Aboriginal communities in Far North Queensland between July and October, 1993. Children at the communities aged between 2 and 14 years were screened so as to identify all cases of APSGN. Parenteral penicillin was administered to all 583 children who presented for the screening procedure. APSGN was diagnosed in 58 (10%) of the 583 children. A further 142 (24%) children had microscopic haematuria. Children aged 5-8 years had the highest APSGN attack rate, and the highest prevalence of microscopic haematuria. Of all 583 children, 34% had skin sores, and group A streptococci (GAS) were isolated from 71% of the skin swabs. The prevalence of both skin sores and GAS were greater in the children with APSGN, and in those with microscopic haematuria, than in children with normal urine. A marked decline in the number of cases of APSGN occurred after the mass administration of penicillin. The epidemic of APSGN was associated with GAS skin infections. The mass use of penicillin may have had an effect in reducing the transmission of the nephritogenic strain of GAS. Microscopic haematuria was a significant finding in many of the children, and further prospective studies are required to understand the significance of this finding.


Respiratory syncytial virus bronchiolitis: disease severity, interleukin-8, and virus genotype.
In infants with respiratory syncytial virus (RSV) bronchiolitis, we investigated whether disease severity is associated with the genotype of the infecting virus, or with the infant's immunological response to the infection, as determined by measurement of interleukin-8 mRNA in the nasopharyngeal aspirate. This was a cross-sectional observational study, performed in the Accident and Emergency Department, wards, and Intensive Care Unit of a large pediatric hospital. Participants included 276 infants with respiratory syncytial virus infection. Outcome variables included: disease severity (infants requiring oxygen or ventilation were classified as having severe disease); RSV virus genotype (determined according to typing scheme based on the nucleoprotein and G glycoprotein genes); and amount of interleukin-8 mRNA in the nasopharyngeal aspirate, as measured by a semiquantitative polymerase chain reaction assay. This was corrected for the amount of cellular material in the sample by expressing it relative to mRNA for a constitutively expressed gene, HGPRT. We found a highly significant association between the ratio of interleukin-8 mRNA/HGPRT mRNA in the nasopharyngeal aspirate and the occurrence of severe disease. Odds ratio per unit increase of interleukin-8 mRNA/HGPRT mRNA was 1.15 (95% CI, 1.06, 1.24), P = 0.0004. There was no association between virus genotype and either disease severity or amount of interleukin-8 mRNA/HGPRT mRNA. In conclusion, there is a strong, dose-related association between interleukin-8 mRNA produced locally in the airways and disease severity, and a lack of association with virus genotype. This suggests that clinical manifestations of respiratory syncytial virus bronchiolitis are determined by local immunological responses to infection, rather than by characteristics of the infecting virus.


Ethnic Disparities in Ileal Pouch Anal Anastomosis Outcomes: An ACS-NSQIP Study.
Ileal pouch-anal anastomosis (IPAA) has become the gold standard operation performed for patients with ulcerative colitis (UC) who require colectomy for medically refractory disease or colitis-associated neoplasia. This study aims to evaluate whether differences in surgical outcomes following IPAA creation is associated with minority ethnicity using data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) surgical outcomes database. The ACS-NSQIP proctectomy-targeted data files (2016-2019) were reviewed to identify patients who underwent an IPAA creation (Current Procedural Terminology codes: 44157, 44158, 44211, and 45113). Demographic, comorbidity, perioperative characteristics, and postoperative outcomes, particularly total-morbidity, surgical site infection, and anastomotic leak, were compared for White, African-American, Hispanic, and Asian patients. Separate multivariable logistic regressions were calculated for each outcome of interest. Certain postoperative outcomes required collation to be analyzed due to low numbers, such as combining all surgical site infections (SSIs), anastomotic leak, and septic complications as "infection complications". For each regression, a P value of <0.05 was considered to be significant. A total of 1462 patients were identified who underwent an IPAA creation. There were 1290 (88.2%) Caucasian, 66 (4.5%) African-American, 49 (3.4%) Hispanic, and 57 (3.9%) Asian patients. Minority race or ethnicity was not associated with higher odds of total morbidity, readmission, reoperation, the development of any SSI, anastomotic leak, or other septic complications as compared to White patients. African-American ethnicity was associated with higher odds of developing postoperative bleeding complications (odds ratio [OR] 2.45, 95% confidence interval [CI] 1.15-5.21; P = 0.020) and postoperative renal dysfunction (OR 4.32, CI 1.43-13.07; P = 0.010) as compared to White patients. Elevated body mass index (BMI) was associated with higher odds of developing an SSI (OR 1.03, CI 1.00-1.06; P = 0.045), or an "infection" complication (OR 1.04, CI 1.01-1.07; P = 0.012), but was protective against bleeding complications (OR 0.94, CI 0.9-0.98; P = 0.004). Smoking was associated with higher odds of developing an SSI, anastomotic leak, or septic complications in the combined "infection" regression analysis (OR 2.02, CI 1.25-3.26; P = 0.004). In the analysis of total-morbidity, both hypertension (OR 1.64, CI 1.11-2.42; P = 0.013) and an ASA Class score >3 (OR 1.36, CI 1.03-1.79; P = 0.029) were associated with increased odds of complications. This analysis of the ACS-NSQIP national database data suggests that ethnicity is not associated with disparities in surgical outcomes following IPAA surgery. African-American ethnicity was however associated with higher odds of developing postoperative bleeding complications and renal dysfunction as compared to White patients. Elevated BMI and smoking history are associated with an increased risk of SSI, anastomotic leak and septic complications.


Poorly differentiated lymphocytic lymphoma with ectopic parathormone production: visulization of metastatic calcification by bone scan.
Metastatic soft tissue calcification is known to occur in hypercalcemia and is usually present in the kidneys, stomach and lungs. 1--3 This case presents two unusual features: 1) ectopic parathormone production in association with poorly differentiated lymphocytic lymphoma; and and 2) uptake of 99mTc-pyrophosphate in the liver in the absence of demonstrable abnormality at autopsy. The more usual sites of metastatic calcification also showed uptake of the radionuclide. We will discuss metastatic soft tissue calcification, ectopic parathyroid hormone production, hypercalcemia in malignancy and bone scan agent localization in soft tissues.


Ternary solvents to investigate proteins at zub-zero temperatures.
Mixtures of water, ethylene glycol and methanol in different volume ratios have been selected to carry out kinetics of enzyme reactions at sub-zero temperatures with the intention to reduce maximally the viscosity. Density, viscosity and dielectric constant values of these mixtures as a function of temperature are reported, as well as values of the protonic activity of several buffers under such conditions. A procedure to avoid or delay the eventual damaging effect of methanol on proteins is described.


Comparison of propeller perforator flap and venous supercharged propeller perforator flap in reconstruction of lower limb soft tissue defect: A prospective study.
In lower limbs, reliability of propeller perforator flaps (PPF) remains uncertain. The main complication is venous congestion, which can lead to distal necrosis. We aim to highlight if venous supercharging of PPF could substantially limit complications in lower limb coverage. Between 2011 and 2016, we developed a standardized procedure of venous supercharging in the lower limb reconstruction with PPF using saphenous veins anastomosis. Then, we prospectively compared a consecutive series of 30 PPF to cover lower limbs defect, with a consecutive series of 30 venous-supercharged PPF (vsPPF). Etiologies of trauma, flap harvesting, complications, and outcomes were compared. The etiologies of the defect were acute trauma in 67.6% of reconstruction with PPFs and 60% of reconstruction with vsPPFs (P = 0.826). The average size of the skin paddle was 48.1 ±18.2 cm2 for PPF and 58.9 ±19.5 cm2 for vsPPF, and the average arc of rotation was 126.7° ±33.1 for PPF and 121.3° ±31.9 for vsPPF. The average sizes and rotation arcs between the two flaps were not significantly different (P = 0.031, P = 0.527). The operative time was significantly increased for vsPPF when compared to PPF procedure (128.8 ±8.5 minutes vs. 81.3 ±10.1 minutes, P < 0.001). Venous congestion was significantly higher in PPF with 11 cases than in vsPPF with two cases (36.7% versus 6.7%, P = 0.010). Distal necrosis were significantly higher in PPF with nine cases than in vsPPF with 1 cases (30% versus 3.3%, P = 0.012). Following poor flap evolution, stitches removal was significantly more frequent in PPF with 11 cases than in vsPPF with one case (36.7% vs 3.3%, P = 0.002). Leeches application was significantly more frequent for PPF procedures with nine cases, than for vsPPF with one case (30% vs 3.3%, P = 0.012). The average length of hospital stay for PPF was significantly longer than for vsPPF (8.78 versus 7.11 days, P = 0.026). The vsPPF is a reliable alternative to PPF to cover small- and medium-size defect in lower limbs, reducing venous congestion and overall complications.


Voltammetric and electrochemical gravimetric selective detection of interactions between Tl(I) and guanine and the influence on activity of DNA drug-intercalators.
The interactions of Tl(I), a well known toxic species, with selected oligonucleotides were examined. The oligonucleotide sequences selected for the investigation were taken from gene hOGG1 responsible for repairing of DNA damage. Cyclic voltammetry was particularly useful, since nitrogen N-7 in guanine can be electrooxidized while its binding with Tl(I) leads to the loss of electroactivity. So, this selected interaction could be quantitatively used in drawing Scatchard's plot and calculating the binding constants and the number of active sites in guanine molecules occupied by one metal ion. Further, we have shown that the presence of Tl(I) leads to a decrease in activity of doxorubicin (DOX), a popular anticancer drug, vs. DNA. The obtained circular dichroism (CD) spectra and the measurements with an electrochemical quartz crystal microbalance (EQCM) led to a conclusion that in the presence of monovalent thallium cations the DNA double helix was neither damaged/oxidized nor its conformation changed substantially.


Phase transformation and intense 2.7 μm emission from Er3+ doped YF3/YOF submicron-crystals.
Yttrium fluoride YF3:Er(3+) and yttrium oxyfluoride YOF:Er(3+) submicron-crystals with mid-infrared fluorescent emissions were synthesized for the first time. The rhombohedral phase YOF submicron-crystals were synthesized by the crystalline phase transformation from pure orthorhombic YF3 submicron-crystals, which were prepared by co-precipitation method. The composition and morphology were characterized by X-ray diffraction (XRD), scanning electron microscope (SEM) and transmission electron microscopy (TEM), which showed that submicron-crystals were quasi-spherical with the particle size of ~400 nm. A novel formation mechanism of YOF submicron-crystals was proposed. Photoluminescence (PL) spectra indicated the 2.7 μm emission of Er(3+) has remarkably enhanced with the increase of Er(3+) doping concentration, and a novel dynamic circulatory energy transfer mechanism was proposed. Fourier transform infrared spectra (FTIR) were used to demonstrate the change of hydroxyl content. These oxyfluoride submicron-crystals provide a new material for nano/submicron-crystals-glass composites, and open a brand new field for the realization of mid-infrared micro/nano-lasers.


[A rare infectious etiology of COPD exacerbation].
Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder. Its exacerbation is infectious in more than half of the cases: with viral priority, while parasitic causes remain exceptional. In this work, we report a case of a COPD exacerbation caused by a visceral leishmaniasis (VL) complicated by a macrophage activation syndrome in an adult living in a Moroccan non-endemic region for this of leismaniasis form. In such atypical clinical feature, the diagnosis of VL was based on the myelogram after presence of peripheral cytopenia. Despite the seriousness of these pathologies, the early and specific treatment of VL allows a quickly improvement in the disorders caused by these diseases.


Lobetyol activate MAPK pathways associated with G1/S cell cycle arrest and apoptosis in MKN45 cells in vitro and in vivo.
The agent lobetyol, which is isolated from Lobelia chinensis, was previously shown to be cytotoxicity againts several cancer cell lines in published report. Today, we perform a study in vitro and in vivo to analyze its anti-carcinoma effect in MKN45 cells and to explore the molecular mechanism. The growth inhibition of lobetyol on MKN45 cells was analyzed with MTT and flow cytometry. Hoechst 33342 staining and TUNEL cover glass staining were used to provide the visual evidence of apoptosis. Western blotting assay was performed to study the activation or blocking of related signaling pathways. Lobetyol induce apoptosis and cell cycle arrest in a time- and dose-dependent manner in MKN45 cells in our study. This process is mediated by the MAPK signaling pathways. This study confirmed the cytotoxicity of lobetyol in MKN45 cells and provided an insight into the molecular mechanism, which demonstrates the potential of lobetyol as an anti-tumor agent.


Exploring In Vitro Biological Cellular Responses of Pegylated β-Cyclodextrins.
βCDPEG5 and βCDPEG2 are two derivatives comprising seven PEG linear chains of 5 and 2 kDa, respectively, conjugated to βCD. As βCDPEGs display different physicochemical properties than their precursors, they could also trigger distinct cellular responses. To investigate the biological behavior of βCDPEGs in comparison to their parent compounds, we performed broad toxicological assays on RAW 264.7 macrophages, MC3T3-E1 osteoblasts, and MDCK cells. By analyzing ROS and NO2- overproduction in macrophages, we found that βCDPEGs induced a moderate stress response without affecting cell viability. Although MC3T3-E1 osteoblasts were more sensitive than MDCK cells to βCDPEGs and the parent compounds, a similar pattern was observed: the effect of βCDPEG5 on cell viability and cell cycle progression was larger than that of βCDPEG2; PEG2 affected cell viability and cell cycle more than βCDPEG2; cell post-treatment recovery was favorable in all cases, and the compounds had similar behaviors regarding ROS generation. The effect on MDCK cell migration followed a similar pattern. In contrast, for osteoblasts, the interference of βCDPEG5 with cell migration was smaller than that of βCDPEG2; likewise, the effect of PEG2 was shorter than its conjugate. Overall, the covalent conjugation of βCD and PEGs, particularly to yield βCDPEG2, improved the biocompatibility profile, evidencing that a favorable biological response can be tuned through a thoughtful combination of materials. Moreover, this is the first time that an in vitro evaluation of βCD and PEG has been presented for MC3T3-E1 and MDCK cells, thus providing valuable knowledge for designing biocompatible nanomaterials constructed from βCD and PEGs.


A review on biomass production from C4 grasses: yield and quality for end-use.
With a dry biomass production exceeding 40Mgha(-1) in many environments, Miscanthus spp. is the most productive perennial C4 grass species thanks to five advantages over North American prairie tallgrasses. However, miscanthus has a slower nutrient remobilization system, resulting in higher nutrient concentrations at harvest. Perennial C4 grasses benefit from soil microbial associations, reducing their nutrient needs. For combustion purposes, grasses with low moisture content, high lignin and low nutrients are desired. For ethanol, preferred feedstock will have lower lignin, higher sugars, starch, or cellulose/hemicellulose depending on the conversion method. Species with high stem-to-leaf ratio provide better biofuel conversion efficiency and quality. Recently-developed transgenic switchgrass lines have much higher ethanol yields and lower transformation costs. Further selection and breeding are needed to optimize biomass quality and nutrient cycling.


An overview on Sardinia's soft ticks (Ixodida: Argasidae).
Knowledge about soft ticks (Ixodida: Argasidae) in Sardinia is incomplete and distribution data need to be updated. This work studies soft ticks on the island focusing on two species, Argas reflexus and Ornithodoros maritimus, both recently recorded. A total number of 12 specimens of these species of interest were collected between 2004 and 2015. This study reports for the first time the presence of O. maritimus in a coastal area in Italy, and more generally in a coastal area rather than small islands near the coastline, confirming the presence of this species on the island 20 years after its last recording. Moreover we confirm the presence of A. reflexus on the island, in the town of Cagliari and, for the first time, in the town of Quartu Sant'Elena. At the present state of knowledge, in Sardinia, Ornithodoros erraticus, which was actively looked for within the surveillance for African swine fever, an endemic disease since 1978 on the island, is not present. The presence of another species reported only once in Sardinia, Argas vespertilionis, needs further confirmation.


Gastric partitioning gastrojejunostomy in unresectable distal gastric cancer patients.
The main purpose of bypass surgery in patients with unresectable distal gastric cancer is to improve their quality of life (QoL). However, the result of conventional gastroenterostomy is dismal including continuous bleeding due to the contact of food material on the tumor surface and early obstruction of the stoma by tumor growth. Developing more effective surgery is warranted to improve the QoL of these patients. Among the 1158 patients with gastric cancer who underwent surgery from March 1993 to July 2002 at Hanyang University Medical Center, 54 (4.7%) had unresectable cancers. Various types of gastrojejunostomy (G-Jstomy), including conventional G-Jstomy (CGJ) (n = 18), antral exclusion G-Jstomy (n = 7), and gastric partitioning G-Jstomy (GPGJ) (n = 17), as well as exploratory laparotomy only (n = 12) were performed in these unresectable cases. In this study, survival and postoperative QoL were compared for the CGJ and GPGJ groups. The median survivals were 120 and 209 days for the CGJ and GPGJ groups, respectively (p = 0.046). The rates of postoperative body weight loss compared to the preoperative weight were 9.3% and 3.1% in the CGJ and GPGJ groups, respectively; the difference showed borderline significance (p = 0.067). The volume of blood transfusion was much less during the postoperative period than during the preoperative period in the GPGJ group but not in the CGJ group. The GPGJ procedure minimized food contact on the tumor surface, which was confirmed by an upper gastrointestinal barium meal series. GPGJ can be recommended as the procedure of choice for bypass surgery in patients with unresectable distal gastric cancer considering their improved survival and postoperative QoL compared to those who underwent CGJ.


Effect of saliva from cystic fibrosis patients and from normal subjects on red blood cell sodium transport.
Saliva, whether taken from patients with cystic fibrosis or from normal subjects, caused an increase in red blood cell Na+ efflux (in the presence or absence of ouabain) of 19-29% as compared with non-saliva controls. However, there was no significant difference between the effects of cystic fibrosis saliva and normal saliva.


Predictors of Surgery and Cost of Care Associated with Patellar Instability in the Pediatric and Young Adult Population.
To determine how patient demographics, socioeconomic status, history of recurrence, and initial point of presentation for health care influenced the decision for surgical treatment following a patellar instability episode. The New York SPARCS database from 2016 to 2018 was queried for patients aged 21 and younger who were diagnosed with a patellar instability episode. These were linked to later surgeries with Current Procedural Terminology (CPT) codes 27405 (MPFL repair), 27418 (tibial tubercle osteotomy), 27420 (dislocating patella reconstruction), 27422 (Campbell/Roux-Goldthwait procedure), and 27427 (extra-articular knee ligamentous reconstruction). χ2-analysis and binary logistic regression were used to assess demographic and injury-specific variables for association with operative management. A generalized linear model was used to estimate charges associated with patellar instability. There were 2,557 patients with patellar instability, 134 (5.2%) of whom underwent surgery. Patients with recurrent instability had 1.875 times higher odds of undergoing surgery (P = .017). Compared to white patients, black patients had 0.428 times the odds of surgery (P = .004). None of the patients without insurance had surgery. In the cost model, an initial visit to an outpatient office was associated with $1,994 lower charges compared to an emergency department (ED) visit (P < .001). Black patients had $566 more in charges than White patients (P = .009). Compared with nonoperative treatment, surgeries with CPT 27405 added $13,124, CPT 27418 added $10,749, CPT 27422 added $18,981, CPT 27420 added $23,700, and CPT 27427 added $25,032 (all P < .001). Patients with recurrent instability had higher odds of surgery, while Black and uninsured patients had lower odds of surgery. ED visits were associated with significantly higher charges compared to office visits, and Black patients had higher charges than white patients. Minority and uninsured patients may face barriers in access to orthopedic care. Level III, retrospective cohort study.


Interhemispheric organization of corticocaudate projections in the cat: a retrograde double-labelling study.
The organization of interhemispheric corticocaudate projections in the cat was assessed by the retrograde axonal transport of different marker substances. These double-labelling methods indicated the existence of three types of neocortical efferents terminating in the caudate nucleus (Cd): (1) uncrossed axons projecting only to the ipsilateral Cd; (2) crossed axons projecting strictly to the contralateral Cd; and, (3) divergent axons projecting to both Cds. In all cases, the corticocaudate projections originated from small-to-medium sized pyramidal neurons situated in layers III, IV and V of the rostral neocortex. Interhemispheric inputs to the Cd may account, to some extent, for the functional coupling of the right and left basal ganglia.


Pertussis toxin treatment attenuates some effects of insulin in BC3H-1 murine myocytes.
The effects of pertussis toxin (PT) treatment on insulin-stimulated myristoyl-diacylglycerol (DAG) generation, hexose transport, and thymidine incorporation were studied in differentiated BC3H-1 myocytes. Insulin treatment caused a biphasic increase in myristoyl-DAG production which was abolished in myocytes treated with PT. There was no effect of PT treatment on basal (nonstimulated) myristoyl-DAG production. Insulin-stimulated hydrolysis of a membrane phosphatidylinositol glycan was blocked by PT treatment. ADP-ribosylation of BC3H-1 plasma membranes with [32P]NAD revealed a 40-kDa protein as the major PT substrate in vivo and in vitro. The time course and dose dependence of the effects of PT on diacylglycerol generation correlated with the in vivo ADP-ribosylation of the 40-kDa substrate. Pertussis toxin treatment resulted in a 71% attenuation of insulin-stimulated hexose uptake without effect on either basal or phorbol ester-stimulated uptake. The stimulatory effects of insulin and fetal calf serum on [3H]thymidine incorporation into quiescent myocytes were attenuated by 61 and 59%, respectively, when PT was added coincidently with the growth factors. Nonstimulated and EGF-stimulated [3H]thymidine incorporation was unaffected by PT treatment. These data suggest that a PT-sensitive G protein is involved in the cellular signaling mechanisms of insulin.


Development of adipose tissues.
Studies on the development of brown and white adipose tissues and their relationship to ordinary connective tissue are the subject of the present review, which is updated to the fall of 1985. Primordial entities described as "primitive organs" have been noted at sites of adipose tissue development by numerous investigators. These "primitive organs" are clearly delineated from surrounding connective tissue and possess a well-defined vascular network in the interstices of which cellular organization takes place. The precursor cells of brown and white adipocytes appear to acquire their distinctive cytogenetic properties at a very early stage in the embryo. These progenitor cells temporarily exhibit structural similarities to fibroblasts and endothelial cells. This resemblance has led to speculation that fibroblasts and/or endothelial cells may be ancestral to adipocytes. However, recent in vivo and in vitro observations suggest that the brown adipose precursor cell is morphogenetically distinct from the white adipose precursor cell on one hand, and from fibroblasts and endothelial cells on the other. In vitro studies have also shown that the pericytic elements present in both brown and white adipose tissue depots in the adult are quiescent precursor cells that may be recruited under certain circumstances. Areas for further inquiry by means of recently developed techniques are indicated.


Spatial Metabolomics Reveals the Multifaceted Nature of Lamprey Buccal Gland and Its Diverse Mechanisms for Blood-Feeding.
Lampreys are blood-sucking vampires in marine environments. From a survival perspective, it is expected that the lamprey buccal gland exhibits a repository of pharmacologically active components to modulate the host's homeostasis, inflammatory and immune responses. By analyzing the metabolic profiles of 14 different lamprey tissues, we show that two groups of metabolites in the buccal gland of lampreys, prostaglandins and the kynurenine pathway metabolites, can be injected into the host fish to assist lamprey blood feeding. Prostaglandins are well-known blood-sucking-associated metabolites that act as vasodilators and anticoagulants to maintain vascular homeostasis and are involved in inflammatory responses. The vasomotor reactivity test on catfish aortic ring showed that kynurenine can also relax the blood vessels of the host fish, thus improving the blood flow of the host fish at the bite site. Finally, a lamprey spatial metabolomics database ( https://www.lampreydb.com ) was constructed to assist studies using lampreys as animal model.


[Late urological complications of reconstructive surgery of the aortic bifurcation (author's transl)].
Ureteral obstruction following aorto-iliac or aorto-femoral dacron prosthesis has rarely been described. It seems, however, as shown in our three cases, that this complication is more common than was previously believed. In all three cases, ureteral obstruction was attributed to retroperitoneal fibrosis enclosing the graft. The threat of such a complication should lead the surgeon to carry out intravenous urography in all patients with a vascular prosthesis.


Germ line transcripts are processed by a Dicer-like protein that is essential for developmentally programmed genome rearrangements of Tetrahymena thermophila.
Abundant approximately 28-nucleotide RNAs that are thought to direct histone H3 lysine 9 (H3K9) methylation and promote the elimination of nearly 15 Mbp of DNA from the developing somatic genome are generated during Tetrahymena thermophila conjugation. To identify the protein(s) that generates these small RNAs, we studied three Dicer-related genes encoded within the Tetrahymena genome, two that contain both RNase III and RNA helicase motifs, Dicer 1 (DCR1) and DCR2, and a third that lacks the helicase domain, Dicer-like 1 (DCL1). DCL1 is expressed upon the initiation of conjugation, and the protein localizes to meiotic micronuclei when bidirectional germ line transcription occurs and small RNAs begin to accumulate. Cells in which we disrupted the DCL1 gene (DeltaDCL1) grew normally and initiated conjugation as wild-type cells but arrested near the end of development and eventually died, unable to resume vegetative growth. These DeltaDCL1 cells failed to generate the abundant small RNAs but instead accumulated germ line-limited transcripts. Together, our findings demonstrate that these transcripts are the precursors of the small RNAs and that DCL1 performs RNA processing within the micronucleus. Postconjugation DeltaDCL1 cells die without eliminating the germ line-limited DNA sequences from their newly formed somatic macronuclei, a result that shows that this Dicer-related gene is required for programmed DNA rearrangements. Surprisingly, DeltaDCL1 cells were not deficient in overall H3K9 methylation, but this modification was not enriched on germ line-limited sequences as it is in wild-type cells, which clearly demonstrates that these small RNAs are essential for its targeting to specific loci.


Cutaneous adverse events in 155 patients with metastatic melanoma consecutively treated with anti-CTLA4 and anti-PD1 combination immunotherapy: Incidence, management, and clinical benefit.
In response to the increased use of combination checkpoint inhibitors (CPIs) and the resulting increased cutaneous adverse events (CAEs), this study reviewed patients with melanoma treated with combination CPIs to characterize CAE features and their clinical impact, correlation to adverse events in other organs, and correlation to tumor response. Patients from the authors' institutional database who received at least 1 dose of ipilimumab in combination with either nivolumab or pembrolizumab between January 1, 2012, and December 31, 2017, for stage IV or unresectable stage III melanoma were identified. The time to next treatment (TTNT) was calculated from the start of CPI therapy to the start of the next treatment or death, and the development of CAEs was tested in a time-dependent Cox regression to identify associations with TTNT. Eighty-one patients (52.3%) experienced a total of 92 CAEs, including eczematous dermatitis (25.0%), morbilliform eruption (22.8%), vitiligo (12.0%), and pruritus without rash (8.7%). The median times to the onset and resolution of CAEs were 21 days (range, 0-341 days) and 50 days (range, 1-352 days), respectively. Most CAEs resolved after patients entered the CPI maintenance phase and treatment with oral antihistamines with or without topical steroids. CPI discontinuation occurred in 4 patients (2.6%) because of CAEs, in 49 (31.6%) because of other immune-related adverse events, and in 20 (12.9%) because of melanoma progression or death. For patients definitively treated with CPIs (n = 134; 86.5%), TTNT was significantly longer with CAEs than without CAEs (hazard ratio, 0.567; 95% CI, 0.331-0.972; P = .039). CAEs were mostly reversible and rarely required therapy discontinuation. The development of CAEs was associated with a longer TTNT, and this suggested a possible clinical benefit.


Long-term prognostic study of carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA 15-3) in breast cancer.
Tumor markers are frequently used for screening and monitoring in oncology. We investigated the use of preoperative tumor marker (carcinoembryonic antigen [CEA] and carbohydrate antigen [CA] 15-3) levels in estimating the prognosis of breast cancer patients. We conducted a retrospective study in patients who underwent breast cancer surgery at National Cancer Center Hospital between 1975 and 1994 and whose serum CEA (n=1663) and CA 15-3 (n=1500) levels were measured prior to operation. When we excluded patients with stage IV disease from the study, the CEA level was within the normal range in 1470 patients, while 150 patients had an elevated CEA level. For CA 15-3, 1395 patients were within the normal range, while 70 patients exhibited an elevated level. The 5-year and 10-year survival rates for patients with normal CEA levels were 87% and 76%, respectively. However, the 5-year and 10-year survival rates for patients with elevated CEA levels were 76% and 65%, respectively. At both time points, patients with normal CEA levels had higher survival rates (P<0.05). The 5-year and 10-year survival rates for the patients with normal CA 15-3 levels were 86% and 76%, respectively, while only 71% and 52% patients with elevated CA 15-3 levels survived at 5 and 10 years, respectively. These differences were also significant (P<0.05). However, there were no significant differences in disease-free survival (DFS) according to CEA or CA 15-3 levels. There was a positive correlation between CEA levels and CA 15-3 levels and patient prognosis. Thus, the levels of these tumor markers may help to determine prognosis in breast cancer patients.


Development and Characterization of a Wee1 Kinase Degrader.
The G1/S cell cycle checkpoint is frequently dysregulated in cancer, leaving cancer cells reliant on a functional G2/M checkpoint to prevent excessive DNA damage. Wee1 regulates the G2/M checkpoint by phosphorylating CDK1 at Tyr15 to prevent mitotic entry. Previous drug development efforts targeting Wee1 resulted in the clinical-grade inhibitor, AZD1775. However, AZD1775 is burdened by dose-limiting adverse events, and has off-target PLK1 activity. In an attempt to overcome these limitations, we developed Wee1 degraders by conjugating AZD1775 to the cereblon (CRBN)-binding ligand, pomalidomide. The resulting lead compound, ZNL-02-096, degrades Wee1 while sparing PLK1, induces G2/M accumulation at 10-fold lower doses than AZD1775, and synergizes with Olaparib in ovarian cancer cells. We demonstrate that ZNL-02-096 has CRBN-dependent pharmacology that is distinct from AZD1775, which justifies further evaluation of selective Wee1 degraders.


Exploring motivations for participating in research among Australian women with advanced gynaecological cancer: a qualitative study.
With global moves to increase research among those living with advanced cancer and legitimise consumers as part of cancer research, this article aims to build an understanding of women's motivations and reasons for participating in gynaecological cancer research. As a secondary aim, we considered the role of qualitative methods in enabling active involvement of consumers in research. We applied thematic discursive analysis to 18 in-depth interviews with women diagnosed with advanced (stage III-IV) gynaecological cancer living in Australia. We found that women viewed research as a vehicle for change in two directions: improving the lives of future generations and improving education and awareness. Underpinning these two framings of research, women spoke about their own role and reasons for participating in this interview study. Women's stories were painted against a backdrop of social and medical silences around gynaecological cancer. It was from such silence that women chose to speak up and position themselves as participating in service for knowledge production. We learned that trust, reciprocity and relationships are central to women's decisions to participate in cancer research. Legitimising consumers in cancer research requires methods, methodologies and practices that pay careful attention to power, control and representation.


Functional comparison of bovine, murine, and human beta2-microglobulin: interactions with murine MHC I molecules.
Fetal calf serum is a well known source of bovine beta2-microglobulin (beta2m) which can exchange with endogenous beta2m from, as well as promote peptide binding to, class I major histocompatibility (MHC I) molecules on cells cultured in vitro. Recombinant bovine beta2m was expressed and purified for direct functional comparison to human and murine beta2m for interactions with murine MHC I molecules H-2Kb, Db, Kd, Ld, and Dd. Bovine and human beta2m were equivalent in stabilizing MHC I heavy chains and facilitating peptide loading, suggesting similar affinities for murine MHC I heavy chains. The activity of murine beta2m was significantly weaker, consistent with previous work that demonstrated the lower affinity of murine human beta2m for murine heavy chains compared to human beta2m. Analysis of bovine beta2m in fetal calf serum revealed ten-fold higher concentrations than in adult bovine serum, levels shown to significantly affect MHC I stability and peptide loading. The ramifications for the study of MHC I molecules from cells in culture and the evolutionary implications of the higher affinity interactions of human and bovine beta2m are discussed.


Hydroxyl radicals generated in vivo kill neurons in the rat spinal cord: electrophysiological, histological, and neurochemical results.
We have used microdialysis to establish an experimental model to characterize mechanisms whereby released substances cause secondary damage in spinal cord injury. We use this model here to characterize damaging effects of the hydroxyl radical (OH.) in vivo in the spinal cord. OH. was generated in vivo by pumping H2O2 and FeCl2/EDTA through parallel microdialysis fibers inserted into the spinal cord. These agents mixed in the tissue to produce OH. by Fenton's reaction. Two types of control experiments were also conducted, one administering only 5 mM H2O2 and the other only 0.5 mM FeCl2/0.82 mM EDTA. During administration of these chemicals, electrical conduction was recorded as one test for deterioration. OH. blocked conduction completely in 2.5-5 h and Fe2+/EDTA partly blocked conduction, but H2O2 alone did not cause detectable blockage. Histological examination supported the hypothesis that neurons were killed by OH., as Fe2+/EDTA and H2O2 alone did not destroy significant numbers of neurons. OH., H2O2, and Fe2+ all caused gradual increases in extracellular amino acid levels. These results are consistent with Fe(2+)-catalyzed free radical generation playing a role in tissue damage upon spinal cord injury.


CD28-CD57+ T cells predominate in CD8 responses to glatiramer acetate.
Human T cells adopt a CD28-CD57+ phenotype in chronic viral infections and this has been hypothesized to result from continuous stimulation, however this phenotype may be due to direct viral effects on T cells. Employing MS patients before and after chronic in vivo administration of the antigen glatiramer acetate (GA) we examine this hypothesis. Pre-treatment glatiramer acetate-specific CD8 T cells were CD57-Perforin-. This changed to a predominantly CD28-CD57+Perforin+ response after administration of this drug. This phenotype was only observed after chronic stimulation and not in a recall response to mumps. The relevance to GA's mechanism of action is discussed.