Adjuvant radiation followed by chemotherapy is associated with improved overall survival in endometrial cancer.
Although multimodality therapy has been shown to improve outcomes for patients with high-risk endometrial carcinoma, optimal type and timing of adjuvant therapies is unknown. Patients with stage I-IVA endometrial carcinoma diagnosed from 2004 to 2015, and treated with surgery, chemotherapy, and radiation were identified in the National Cancer Database. Adjuvant treatment was categorized as sequential radiation followed by chemotherapy (RT-CT), concurrent chemoradiation (CCRT, RT and CT started within 7 days), or sequential chemotherapy followed by radiation (CT-RT). Analysis for propensity score matched (PSM) cohorts comparing RT-CT to CCRT and CT-RT groups was additionally performed. A total of 17,070 patients were identified, including 12,402 (72.7%) treated with RT-CT, 2,153 (12.6%) with CCRT, and 2,515 (14.7%) with CT-RT. Median follow-up was 44.3 months. Five-year overall-survival (OS) by adjuvant treatment regimen was 77.3% (95% CI 76.4%-78.2%), 74.3% (95% CI 72.0%-76.3%), and 74.4% (95% CI 72.5%-76.3%), respectively (p < .001). When unmatched cohorts were stratified by stage, adjuvant RT-CT was associated with improved OS in stage I and III patients. A similar survival advantage associated with RT-CT was observed in PSM cohorts comparing RT-CT group to CCRT/CT-RT group (5-year OS 77.4% vs 74.2%, p = .001). However, the difference in OS was significant only among stage III patients (RT-CT 73.9% compared to CCRT/CT-RT 69.7%, p =.002). Our findings suggest survival benefit with adjuvant RT-CT compared to CT-RT or CCRT in patients undergoing trimodality therapy for endometrial cancer. This survival benefit may be limited to stage III patients.


Position of Mercenaria regulatory light-chain Cys50 site on the surface of myosin visualized by electron microscopy.
Mercenaria regulatory light-chains, specifically labelled at cysteine 50 with N-iodoacetyl-N'-biotinylhexylenediamine, were rebound to regulatory light-chain denuded scallop myosin, and the hybrid myosin formed was decorated with avidin. These hybrid myosins were visualized by rotary-shadowing electron microscopy. Three distinct images of avidin-decorated hybrid myosin molecules were obtained. These comprise singly decorated molecules, where the avidin is bound symmetrically or asymmetrically with respect to the two heads of myosin, in addition to "figures-of-five", where two myosin molecules associate with a centrally placed avidin molecule. Analysis of these images indicates that the Mercenaria regulatory light-chain Cys50 site is located 15 to 35 A from the head-rod junction when the light-chain is bound in situ to myosin. Implications with respect to head topology and probe studies are discussed.


Eyes wide shut: Exploring practices of negotiated ignorance in water resources modelling and management.
Formalised methods to address uncertainty are becoming the norm in hydrological modelling, yet they remain fragmented and highly academic, thus limiting their utility for practitioners. Using a qualitative, empirical study of the PIREN-Seine program in France, this paper explores the proccesses behind this trend in an effort to elucidate its prevalence despite inherent limitations when applied to a decision-making context. We identify: 1/ displacement of 'uncomfortable knowledge', 2/ fragmented responsibility, 3/ confidence, and 4/ relational framing as interconnected factors, which concurrently support the production of scientific knowledge and the social construction of ignorance, whether it be wilful or intentional. We posit that ignorance is implicitly negotiated among researchers and practitioners in order to reconcile cognitive dissonance and maintain confidence, thereby allowing water managers to take action in the face of uncertainty. Finally, we put forth the notion that having our 'eyes wide shut' can be interpreted in two ways: one facilitates the normalisation of ignorance, leaving us vulnerable to unexpected surprises; the other promotes transparent and explicit communication in support of more adaptive and robust decisions.


Directing the Selectivity of Oxygen Reduction to Water by Confining a Cu Catalyst in a Metal Organic Framework.
Electrocatalysis is to play a key role in the transition towards a sustainable chemical and energy industry and active, stable and selective redox catalysts are much needed. Porous structures such as metal organic frameworks (MOFs) are interesting materials as these may influence selectivity of chemical reactions through confinement effects. In this work, the oxygen reduction catalyst Cu-tmpa was incorporated into the NU1000 MOF. Confinement of the catalyst within NU1000 steers the selectivity of the oxygen reduction reaction (ORR) towards water rather than peroxide. This is attributed to retention of the obligatory H2 O2 intermediate in close proximity to the catalytic center. Moreover, the resulting NU1000|Cu-tmpa MOF shows an excellent activity and stability in prolonged electrochemical studies, illustrating the potential of this approach.


A novel synthetic sealant to treat air leaks at cardiac reoperation.
Pulmonary injury with resultant air leak is common at cardiac reoperation. Sequelae of this complication include prolonged chest tube drainage and time to ambulation, extended hospitalization and increased costs, and mediastinitis. The purpose of this study was to test the efficacy of a new synthetic absorbable sealant at treatment air leaks occurring at cardiac reoperation. Fifteen patients having cardiac reoperation had lung injuries repaired with FocalSeal-L Sealant (Focal, Inc., Lexington, MA). Mean age was 61+/-15 years, and mean interval from the previous to the current operation was 44+/-38 months. In all patients, FocalSeal-L Sealant was successful at sealing intraoperative air leaks. Postoperatively, 73% of patients had no air leak. Four patients (27%) developed a recurrent air leak, three on postoperative day 1 and one on postoperative day 2. In three of these patients, the air leak sealed within 3 days. In the fourth patient, an immunosuppressed heart transplant recipient with mediastinitis, the air leak never sealed; that patient died of sepsis after an omental flap failed to control the air leak. In patients without air leak, chest tubes were removed on postoperative day 1 (9 patients) or 2 (1 patient). This novel synthetic sealant prevents postoperative air leaks in the majority of patients suffering lung injury at cardiac reoperation.


Evaluation of the use of patient-focused simulation for student assessment in a surgery clerkship.
The purpose of this study was to evaluate the use of simulated patients in conjunction with anatomic and tissue task-training models to assess skills. Faculty reviewed the objectives of the clerkship to identify skills to be acquired. Three cases were developed related to rectal examination, suturing, and inserting intravenous lines and nasogastric tubes. Student scores were based on their ability to gather data from simulated patients and perform procedures on simulation models. A total of 670 students were assessed between 2006 and 2009. Alpha reliability coefficients were .97 for Communication/Interpersonal Skills, .71 for Procedures, and .58 for Data Gathering. Students receiving low ratings from faculty in the clerkship had significantly (P < .001) lower simulation scores. There were significant (P < .001) relationships between scores and grades in other clerkships. The combination of simulated patients and simulation models yielded reliable scores for procedural and interpersonal skills, and evidence of validity related to clinical ratings.


Chemical and biological evaluation of some new antipyrine derivatives with particular properties.
Starting from 4-amino-antipyrine, six new compounds were synthesized and characterized. The new compounds contain moieties with particular properties, such are ionophore (benzo-15-crown-5), fluorescent (nitrobenzofurazan), stable free radical (nitroxide), or other types of biological active residues, like nitroderivatives, antipyrine or isoniazid residues. They were fully characterized by appropriate means ((1)H and (13)C NMR, IR, UV-Vis, fluorescence, EPR, elemental analysis) and some of their biological properties were evaluated. Hydrophobicity (R(M0), log P), total antioxidant capacity (TAC), and antimicrobial properties are also presented and discussed.


Relationships between nurses' observations and patients' self-reports of pain.
Pain researchers and clinicians alike are often troubled by a lack of correspondence between non-verbal behavior and patients' self-reports of level of pain. This paper discusses some of the variables which can effect the relationship between these measures. In addition, the paper reports on the reliability of nurses' observations of pain behavior and of their inferences about the intensity of a patient's pain. In general, though these observations and inferences have adequate reliability, the correspondence between such inferences and patients' reports of pain intensity are modest, though significant. Discrepancies between observers' and patients' ratings of pain are greater in a chronic pain sample (N = 37) than in an acute pain sample (N = 34). Theoretical implications of these results are discussed.


Cochlear implantation in superficial siderosis: a viable option?
Superficial siderosis of the central nervous system is characterized by accumulation of haemosiderin in the subpial layers of the brain and spinal cord. The evidence largely suggests a retro-cochlear cause for hearing loss with questionable involvement of cochlea. We present our experience with two patients of superficial siderosis who underwent cochlear implantation, and discuss their outcomes and the underlying pathology. The first patient developed a gradually progressive, profound hearing loss over 25 years, clinical diagnosis being made on MRI scans. The second patient was referred to us with bilateral sensorineural hearing loss, tinnitus, ataxia, dementia, seizures, and visual impairment. Both underwent cochlear implantation for auditory rehabilitation. The first patient gained significant benefit, whereas the second patient has not developed any meaningful auditory stimulation at 9-month post-operative follow-up. Hearing loss due to superficial siderosis even though predominantly retro-cochlear may be successfully rehabilitated with a cochlear implant. However, outcomes are variable and more evidence regarding experience with cochlear implant in such patients with long-term follow-up is desirable.


The measurement of neuropeptide Y in discrete hypothalamic and limbic regions of male rhesus macaques with a human NPY-directed antiserum.
The distribution of neuropeptide Y (NPY) in microdissected brain regions of male macaques was quantified with a specific radioimmunoassay (RIA). The RIA consisted of a specific antiserum (R31) against human NPY that could detect 7 pg/tube with an IC50 of 125 pg/tube at a final dilution of 1:20,000. Varying amounts of rabbit and monkey mediobasal hypothalami yielded parallel [125I]NPY displacement curves in the assay and similar chromatographic elution profiles with those of synthetic human NPY. The NPY activity in acid extracts of discrete brain regions in castrate and castrated-testosterone-treated rhesus males was highest in mediobasal hypothalamus, followed by more rostral hypothalamic regions and amygdaloid nuclei. Testosterone did not alter NPY levels in any of the brain areas that we examined.


Cascade Catalytic Nanoparticles Selectively Alkalize Cancerous Lysosomes to Suppress Cancer Progression and Metastasis.
Lysosomes are critical in modulating the progression and metastasis for various cancers. There is currently an unmet need for lysosomal alkalizers that can selectively and safely alter the pH and inhibit the function of cancer lysosomes. Here an effective, selective, and safe lysosomal alkalizer is reported that can inhibit autophagy and suppress tumors in mice. The lysosomal alkalizer consists of an iron oxide core that generates hydroxyl radicals (•OH) in the presence of excessive H+ and hydrogen peroxide inside cancer lysosomes and cerium oxide satellites that capture and convert •OH into hydroxide ions. Alkalized lysosomes, which display impaired enzyme activity and autophagy, lead to cancer cell apoptosis. It is shown that the alkalizer effectively inhibits both local and systemic tumor growth and metastasis in mice. This work demonstrates that the intrinsic properties of nanoparticles can be harnessed to build effective lysosomal alkalizers that are both selective and safe.


Identification of a subpopulation of nasopharyngeal carcinoma cells with cancer stem-like cell properties by high aldehyde dehydrogenase activity.
Cancer stem cells have been reported as a new therapeutic target in many cancers, but their existence in nasopharyngeal carcinoma (NPC) is largely unknown. This study was conducted to determine cancer stem-like cells in NPC cell line. Basic science experimental study. Aldehyde dehydrogenase (ALDH) activity, a putative functional marker for cancer stem cells, was assessed in Epstein-Barr virus-associated NPC cell line C666-1 cells. The ability of cells with high and low ALDH activity to proliferate, resist therapy, and initiate tumor formation was compared. Enrichment of cancer stem-like cells (with high ALDH activity) in C666-1 was associated with a significantly greater ability to proliferate, be clonogenic, resist chemotherapy drugs and radiation, reconstitute a heterogeneous population, and express pluripotent markers. Furthermore, subcutaneous injection of these cells into immunodeficient nude mice resulted in a tendency of tumor formation at a higher rate as compared to cells with low ALDH activity. These results provide evidence for the existence of cancer stem-like cells in the NPC cell line C666-1 cells.


Sequential recruitment of the mRNA decay machinery to the iron-regulated protein Cth2 in Saccharomyces cerevisiae.
Post-transcriptional factors importantly contribute to the rapid and coordinated expression of the multiple genes required for the adaptation of living organisms to environmental stresses. In the model eukaryote Saccharomyces cerevisiae, a conserved mRNA-binding protein, known as Cth2, modulates the metabolic response to iron deficiency. Cth2 is a tandem zinc-finger (TZF)-containing protein that co-transcriptionally binds to adenine/uracil-rich elements (ARE) present in the 3'-untranslated region of iron-related mRNAs to promote their turnover. The nuclear binding of Cth2 to mRNAs via its TZFs is indispensable for its export to the cytoplasm. Although Cth2 nucleocytoplasmic transport is essential for its regulatory function, little is known about the recruitment of the mRNA degradation machinery. Here, we investigate the sequential assembly of mRNA decay factors during Cth2 shuttling. By using an enzymatic in vivo proximity assay called M-track, we show that Cth2 associates to the RNA helicase Dhh1 and the deadenylase Pop2/Caf1 before binding to its target mRNAs. The recruitment of Dhh1 to Cth2 requires the integrity of the Ccr4-Pop2 deadenylase complex, whereas the interaction between Cth2 and Pop2 needs Ccr4 but not Dhh1. M-track assays also show that Cth2-binding to ARE-containing mRNAs is necessary for the interaction between Cth2 and the exonuclease Xrn1. The importance of these interactions is highlighted by the specific growth defect in iron-deficient conditions displayed by cells lacking Dhh1, Pop2, Ccr4 or Xrn1. These results exemplify the stepwise process of assembly of different mRNA decay factors onto an mRNA-binding protein during the mechanism of post-transcriptional regulation.


The effect of locally delivered doxycycline as an adjunctive therapy to scaling and root planing in smokers.
Locally delivered doxycycline is found to be effective in managing periodontitis as an adjunct to scaling and root planing. To evaluate the effect of locally delivered doxycycline (10%) with scaling and root planing in the periodontal treatment of smokers and to compare it with scaling and root planing alone. Twelve smokers with chronic periodontitis and a pocket depth (⩾5 mm) on posterior teeth that bleed on probing were selected. Patients were randomly assigned to scaling and root planing (SRP) or scaling and root planing followed by local application of doxycycline (SRP-D). Plaque, bleeding on probing, gingival recession, clinical attachment level (CAL), and probing depth (PD) were recorded at the baseline, 6 and 12 weeks. Both groups showed a significant reduction in Plaque, Bleeding on Probing and pocket depth at 6th and 12th week from the baseline. A statistically significant gain of attachment was observed in both groups after treatment. Even though the doxycycline group showed slightly higher attachment gain it was not statistically significant compared to the control group. The observations of the study reveal that the additional benefit of topical application of doxycycline as an adjunct to scaling and root planing in smokers is not convincing. However, further clinical studies may be necessary to substantiate the present observations.


Scalp topography of human somatosensory evoked potentials: the effect of interfering tactile stimulation applied to the hand.
A detailed topographical analysis of human SEPs in response to median nerve stimulation was performed, with and without concurrent tactile stimulation of the hand. Twenty-eight recording sites on the scalp and neck were referred to earlobe and non-cephalic reference electrodes. The following components were identified in the control wave form: N10, N11, N13, P14, N19, P20, P22, N22, N29, P30 and P44. The interference wave form showed significant attenuation of P14, N19, P20, P22 and N29, while P30 was abolished. N10, N11, N13 and N22 remained unchanged and P44 was enhanced. In the interference wave form there also appeared an N33 component, supplanting P30 over the posterior contralateral quadrant, and a P36 frontally. The pattern of changes was best demonstrated by subtracting the interference from the control response to derive a 'difference' wave form. This consisted of 'P'14, 'N'19, 'P'21, 'P'32 and 'N'36 components. The last 2 were of large amplitude over the posterior contralateral quadrant and frontal cortex, respectively, and overlapped for at least 10 msec of their duration. The results indicate that the interfering effect occurred at the level of the brain-stem or above. The topography of the difference wave form suggests that the 'P'32 and 'N'36 components may be attributable to a generator situated in the posterior bank of the central sulcus (Brodmann's area 3b), concerned with the processing of input from cutaneous mechanoreceptors. It is proposed that the P22 and N22 components of the control and interference wave forms may be due to a generator located at the bottom and in the anterior bank of the central sulcus (area 3a).


Sympathetic skin response: a new test to diagnose ejaculatory dysfunction.
Sympathetic skin responses were elicited from the palm and sole (plantar) with electrical stimulation on the dorsal nerve of the penis in 24 individuals. The palmar and plantar sympathetic skin responses were obtained in 12 subjects with normal ejaculatory function. On the other hand, the plantar sympathetic skin response was absent in 11 of 12 patients who lacked ejaculation. Since the plantar sympathetic skin response is correlated closely to the mechanism of ejaculation, this test is expected to be helpful to diagnose sexual dysfunction and to monitor the effects of treatment.


Maintenance therapy for acute lymphoblastic leukemia: basic science and clinical translations.
Maintenance therapy (MT) with oral methotrexate (MTX) and 6-mercaptopurine (6-MP) is essential for the cure of acute lymphoblastic leukemia (ALL). MTX and 6-MP interfere with nucleotide synthesis and salvage pathways. The primary cytotoxic mechanism involves the incorporation of thioguanine nucleotides (TGNs) into DNA (as DNA-TG), which may be enhanced by the inhibition of de novo purine synthesis by other MTX/6-MP metabolites. Co-medication during MT is common. Although Pneumocystis jirovecii prophylaxis appears safe, the benefit of glucocorticosteroid/vincristine pulses in improving survival and of allopurinol to moderate 6-MP pharmacokinetics remains uncertain. Numerous genetic polymorphisms influence the pharmacology, efficacy, and toxicity (mainly myelosuppression and hepatotoxicity) of MTX and thiopurines. Thiopurine S-methyltransferase (encoded by TPMT) decreases TGNs but increases methylated 6-MP metabolites (MeMPs); similarly, nudix hydrolase 15 (encoded by NUDT15) also decreases TGNs available for DNA incorporation. Loss-of-function variants in both genes are currently used to guide MT, but do not fully explain the inter-patient variability in thiopurine toxicity. Because of the large inter-individual variations in MTX/6-MP bioavailability and metabolism, dose adjustments are traditionally guided by the degree of myelosuppression, but this does not accurately reflect treatment intensity. DNA-TG is a common downstream metabolite of MTX/6-MP combination chemotherapy, and a higher level of DNA-TG has been associated with a lower relapse hazard, leading to the development of the Thiopurine Enhanced ALL Maintenance (TEAM) strategy-the addition of low-dose (2.5-12.5 mg/m2/day) 6-thioguanine to the 6-MP/MTX backbone-that is currently being tested in a randomized ALLTogether1 trial (EudraCT: 2018-001795-38). Mutations in the thiopurine and MTX metabolism pathways, and in the mismatch repair genes have been identified in early ALL relapses, providing valuable insights to assist the development of strategies to detect imminent relapse, to facilitate relapse salvage therapy, and even to bring about changes in frontline ALL therapy to mitigate this relapse risk.


Day-case laparoscopic cholecystectomy: analysis of the factors allowing early discharge.
Despite a number of studies have already demonstrated that majority of patients can be safely discharged early after laparoscopic cholecystectomy, this approach did not gain widespread diffusion yet. The present study was set up to assess safety and feasibility of 24 h or same-day discharge after laparoscopic cholecystectomy and to identify the prognostic factors. Perioperative variables of 229 patients undergoing cholecystectomy have been analyzed. Primary endpoints were: postoperative length of stay, rate of patients discharged within 24 h, and rate of those discharged on the same day. Secondary endpoints were rate of 30-day readmission and rate of 30-day postoperative complications. Two-hundred twenty-three cases have been started by laparoscopy. Conversion rate was 3.1%. Overall mean postoperative stay was 1.8 ± 3.5 days (median 1 day). Seventy-eight percent of patients have been discharged within 24 h, and 22.3% have been discharged on the same day. Postoperative morbidity was 2.2%. Readmission rate was 3.9%. At univariate analysis, factors related to early discharge were age (more or less than 65), diagnosis (simple symptomatic gallstones vs complicated gallstones), ASA score, timing of operation (elective vs emergency), history of CBD stones, laparoscopic operation, and use of drain. No single factor was significantly related to readmission rate, but the use of drains in laparoscopic cases. At multivariate analysis, only elective operation, simple symptomatic gallstones, no history of CBD stones, laparoscopic approach, and no abdominal drain resulted independently associated with discharge within 24 h from the operation. The predictive models are all fit and significant. Early postoperative discharge within 24 h should be considered in all patients with simple symptomatic gallstones who had laparoscopic cholecystectomy. Same-day discharge should be considered if no drain was left at the end of the operation.


In vitro alternative for reactogenicity assessment of outer membrane vesicle based vaccines.
Intrinsic or added immune activating molecules are key for most vaccines to provide desired immunity profiles but may increase systemic reactogenicity. Regulatory agencies require rabbit pyrogen testing (RPT) for demonstration of vaccine reactogenicity. Recently, the monocyte activation test (MAT) gained popularity as in vitro alternative, yet this assay was primarily designed to test pyrogen-free products. The aim was to adjust the MAT to enable testing of pyrogen containing vaccines in an early stage of development where no reference batch is yet available. The MAT and RPT were compared for assessing unknown safety profiles of pertussis outer membrane vesicle (OMV) vaccine candidates to those of Bexsero as surrogate reference vaccine. Pertussis OMVs with wild-type LPS predominantly activated TLR2 and TLR4 and were more reactogenic than Bexsero. However, this reactogenicity profile for pertussis OMVs could be equalized or drastically reduced compared to Bexsero or a whole-cell pertussis vaccine, respectively by dose changing, modifying the LPS, intranasal administration, or a combination of these. Importantly, except for LPS modified products, reactogenicity profiles obtained with the RPT and MAT were comparable. Overall, we demonstrated that this pertussis OMV vaccine candidate has an acceptable safety profile. Furthermore, the MAT proved its applicability to assess reactogenicity levels of pyrogen containing vaccines at multiple stages of vaccine development and could eventually replace rabbit pyrogen testing.


Exploratory study on the potential regulating role of Peroxiredoxin 6 on proteolysis and relationships with desmin early postmortem.
The objective of the present study was to explore the effect of Peroxiredoxin 6 (Prdx 6) on beef tenderization during the early postmortem period. The longissimus lumborum (LL) were obtained at 45 min postmortem from 6 beef carcasses and then incubated with or without the inhibitor of Prdx6 (NSC348884) for different times, followed by incubation with or without the H2O2 (simulation of oxidative stress). The expression of Prdx6, proteolysis indicated by desmin degradation, cell apoptosis rate and expression of caspases were measured. The results indicated that the inhibitor significantly reduced the Prdx6 level, while the cells adaptively increased Prdx6 expression to resist the oxidative stress caused by H2O2. Moreover, the samples in which Prdx6 was inhibited demonstrated more severe desmin degradation accompanied by a higher apoptosis rate which was induced by the increase in caspase degradation as well as the ratio of Bax/Bcl-2. These results demonstrated that inhibiting Prdx6 could promote cell apoptosis and further accelerate beef tenderization.


Depression, medical illness, and interleukin-1beta in older cardiac patients.
A model has been proposed in which atherosclerosis contributes to depression in later life by the effects of cytokines on central monoamine systems. We collected pilot data to test the hypothesis that interleukin-1beta (IL-1beta) is associated with depression in a cardiac patient group. Thirty-seven subjects completed research evaluations that included depression diagnosis (Structured Clinical Interview for DSM-III-R), depressive symptom severity (Hamilton Rating Scale for Depression), medical illness burden (Cumulative Illness Rating Scale), and serum IL-1beta level measured by enzyme linked immunosorbent assay. Serum IL-1beta level was not significantly associated with depressive symptom severity or depression diagnosis, whether or not controlled for medical illness burden, age, and gender. IL-1beta level was significantly correlated with medical illness burden. We did not confirm our study hypothesis. The correlation of IL-1beta level with medical illness burden likely reflects its release as part of the "sickness response" in a wide variety of disease states. Further research using a larger sample size and a non-cardiac comparison group is warranted.


The AIM2 inflammasome: A novel biomarker and target in cardiovascular disease.
Absent in melanoma 2 (AIM2) is a cytoplasmic sensor that recognises the double-strand DNA. AIM2 inflammasome is a protein platform in the cell that initiates innate immune responses by cleaving pro-caspase-1 and converting IL-1β and IL-18 to their mature forms. Additionally, AIM2 inflammasome promotes pyroptosis by converting Gasdermin-D (GSDMD) to GSDMD-N fragments. An increasing number of studies have indicated the important and decisive roles of the AIM2 inflammasome, IL-1β, and pyroptosis in cardiovascular diseases, such as coronary atherosclerosis, myocardial infarction, ischaemia/reperfusion injury, heart failure, aortic aneurysm and ischaemic stroke. Here, we review the molecular mechanism of the activation and effect of the AIM2 inflammasome in cardiovascular disease, revealing new insights into pathogenic factors that may be targeted to treat cardiovascular disease and related dysfunctions.


A 3D-Bioprinted dual growth factor-releasing intervertebral disc scaffold induces nucleus pulposus and annulus fibrosus reconstruction.
Regeneration of Intervertebral disc (IVD) is a scientific challenge because of the complex structure and composition of tissue, as well as the difficulty in achieving bionic function. Here, an anatomically correct IVD scaffold composed of biomaterials, cells, and growth factors were fabricated via three-dimensional (3D) bioprinting technology. Connective tissue growth factor (CTGF) and transforming growth factor-β3 (TGF-β3) were loaded onto polydopamine nanoparticles, which were mixed with bone marrow mesenchymal stem cells (BMSCs) for regenerating and simulating the structure and function of the nucleus pulposus and annular fibrosus. In vitro experiments confirmed that CTGF and TGF-β3 could be released from the IVD scaffold in a spatially controlled manner, and induced the corresponding BMSCs to differentiate into nucleus pulposus like cells and annulus fibrosus like cells. Next, the fabricated IVD scaffold was implanted into the dorsum subcutaneous of nude mice. The reconstructed IVD exhibited a zone-specific matrix that displayed the corresponding histological and immunological phenotypes: primarily type II collagen and glycosaminoglycan in the core zone, and type I collagen in the surrounding zone. The testing results demonstrated that it exhibited good biomechanical function of the reconstructed IVD. The results presented herein reveal the clinical application potential of the dual growth factors-releasing IVD scaffold fabricated via 3D bioprinting. However, the evaluation in large mammal animal models needs to be further studied.


Diabetes Health Literacy Among Somali Patients with Diabetes Mellitus in a US Primary Care Setting.
The purpose of this study was to describe diabetes literacy among Somali immigrants with diabetes and its association with diabetes outcomes. Among Somali immigrants in North America, the prevalence of diabetes exceeds that of the general population, and their measures of diabetes control are suboptimal when compared with non-Somali patients. Diabetes literacy is an important mediator of diabetes outcomes in general populations that has not been previously described among Somali immigrants and refugees. Diabetes literacy was measured using a translated version of the spoken knowledge in low literacy in diabetes (SKILLD) scale among Somali immigrants and refugees with type 2 diabetes. Diabetes outcome measures, including hemoglobin A1C, low-density lipoprotein (LDL) cholesterol, and blood pressure, were obtained for each patient. Multivariate logistic regression was used to assess associations between diabetes literacy and diabetes outcomes. Among 50 Somali patients with diabetes who completed the survey, the mean SKILLD score was low (42.2 %). The diabetes outcome measures showed a mean hemoglobin A1C of 8 %, LDL cholesterol of 99.17 mg/dL (2.57 mmol/L), systolic blood pressure of 130.9 mmHg, and diastolic blood pressure of 70.2 mmHg. There was no association between diabetes literacy scores and diabetes outcome measures. Somali patients with diabetes mellitus had low diabetes literacy and suboptimal measures of diabetes disease control. However, we found no association between diabetes literacy and diabetes outcomes. Future work aimed at reduction of diabetes-related health disparities among Somali immigrants and refugees to high-income countries should go beyond traditional means of patient education for low-literacy populations.


A Single-Dose Bioavailability Study of Pamidronate Disodium after Oral Administration as Encapsulated Enteric-Coated Pellets, Enteric-Coated Tablets, and a Solution to Patients with Postmenopausal Osteoporosis.
This was a pilot, single-center, single-dose, open-label, randomized three-way crossover study comparing the relative bioavailability of pamidronate disodium after oral doses of the drug administered as four capsules, each containing 75 mg enteric-coated pellets, two 150-mg enteric-coated tablets and 300 mg in solution (reference standard) in patients with postmenopausal osteoporosis. Results from seven patients are reported; five subjects completed all three phases of the study---one received solution and pellets, and another one received pellets and tablets. The onset of urinary excretion (an indicator of relative onset of oral absorption) of pamidronate disodium occurred in the first 2 h in all (except one) patients for solution and pellets, whereas the onset of urinary excretion for the tablets was prolonged and more variable. The extent of absorption was estimated in terms of percent of administered dose excreted in urine up to 72 h after dosing. The extend of absorption was highest after the pellets (mean plus minus S.D., 0.37 plus minus 0.27%), followed by the solution (0.20 plus minus 0.16%). The extent of absorption after the tablets (0.09 plus minus 0.10%) was the lowest and most variable. The poorer and more variable bioavailability of the tablets may be explained by the longer and more variable residence time of the tablets in the stomach.


Urinary laminin-γ2 is a novel biomarker of non-muscle invasive urothelial carcinoma.
Lack of appropriate biomarkers has hampered early detection of urothelial cancer (UC), therefore, development of biomarkers for its diagnosis at earlier stages is of importance. Laminin-332 (Ln-332, formerly Ln-5), a component of basement membranes, consists of Ln-α3, Ln-β3, and Ln-γ2 polypeptides. However, monomeric Ln-γ2 alone is frequently expressed in malignant neoplasms. If Ln-γ2 is also expressed in UC and secreted into the urine, its detection could be useful for UC diagnosis. Here, we evaluated Ln-γ2 levels from 60 patients with urinary diseases (including UC) by Western blotting, and detected it in approximately 53% of UC cases. Using immunohistochemistry, we confirmed Ln-γ2 expression in UC tissues that were positive for Ln-γ2, whereas Ln-α3 expression was absent. We next developed a sandwich enzyme-linked immunosorbent assay and applied it for screening 39 patients with non-muscle invasive UC and 61 patients with benign urologic diseases. The Ln-γ2 levels were higher in UC patients than in those with benign urologic diseases. Ln-γ2 was detected even in patients with earlier stages of UC, such as Ta, T1, or carcinoma in situ. The sensitivity of Ln-γ2 testing for UC was 97.4%, and the specificity was 45.9%, using a cut-off of 0.5 μg/g∙crn. Ln-γ2 had greater diagnostic value for detecting non-muscle invasive UC compared to conventional urine cytology and available biomarkers for UC, and may be useful as a urine biomarker for the diagnosis and monitoring of UC.


Intestinal fat digestion plays a significant role in fat-induced suppression of gastric acid secretion and gastrin release in the rat.
We have investigated the role of intestinal fat digestion in fat-induced suppression of gastric acid secretion and gastrin release in the rat. Intraduodenal administration of oleic acid (10%, pH 6.5) and triglyceride (10%, pH 6.5) at a rate of 2 ml/hr resulted in significant suppression of gastric acid secretion and gastrin release stimulated by intragastric perfusion of peptone (0.5%). Diversion of pancreatic juice from the duodenum completely abolished triglyceride-induced inhibition of peptone-stimulated gastric acid secretion and plasma gastrin release, but oleic acid-suppressed gastric acid secretion and gastrin release were unaffected by pancreatic juice diversion. Intraduodenal administration of digested triglyceride, prepared by preincubation with lipase, caused significant suppression of the peptone-induced gastric acid secretion and rise in plasma gastrin levels, even though pancreatic juice was excluded. The results of this study indicate that digestive products of triglyceride by pancreatic juice, especially by lipase, are responsible for the intestinal fat-induced inhibition of gastric acid secretion and gastrin release and that intestinal fat digestion plays a significant role in the mechanism.


Intratumor immunologic heterogeneity.
Tumor cells express a great variety of antigens including tumor specific transplantation antigens, tumor-associated antigens, differentiation antigens, histocompatibility antigens, lectin-binding sites and receptors for natural killer cells and natural antibodies. These antigens are distributed unevenly on tumor subpopulations and each subpopulation may induce different immune responses to the same determinant. Intratumor immunologic heterogeneity arises early in cancer, possibly during preneoplasia, and exists throughout the course of progression. Metastatic subpopulations are not generally less antigenic than subpopulations within primary tumors. Different arrays of antigenic determinants are displayed by subpopulations but variability in cell surface expression of a single determinant is also a fundamental type of immunologic heterogeneity. Antigenic specificity patterns commonly reveal one-way cross-reactions between tumor subpopulations. One-way cross-reactions might occur due to quantitative differences, cell-cycle variations, modulation, masking, H-2 expression and restriction phenomena, or alteration in the carbohydrate side-chains of glycoproteins. Interactions which occur when subpopulations co-exist may alter immune responses so that the response to the mixture is not the sum of the responses to the individual subpopulations. It is suggested that the exploitation of the mechanisms involved in immunologic heterogeneity may lead to new therapeutic approaches and that the great diversity of determinants expressed by tumor cells could lead to development of multivalent panel of monoclonal antisera which, acting synergistically, could preferentially lyse tumor cells.


Measurement of vitamin B12 in the livers and sera of sheep and cattle and an investigation of factors influencing serum vitamin B12 levels in sheep.
Modifications of a radioassay method for the analysis of vitamin B12 using chicken serum as the binder are described. This obviates the need to use individual serum blanks to correct for non-specific binding in vitamin B12 assays of the sera and livers of sheep and cattle. Samples with high vitamin B12 levels can be diluted prior to assay without loss of linearity. Recoveries of added cyanocobalamin or hydroxocobalamin were better than 95% and results correlated significantly with those obtained using a microbiological assay (Poteriochromonas malhamensis). Sera and liver samples stored for four weeks at temperatures ranging from -20 degrees to 22 degrees showed no change in vitamin B12 levels. Withholding food from sheep for 44 hours led to a marked increase in serum vitamin B12. This effect was also evident in sheep eating a limited amount of cut grass. In sheep at pasture there was no evidence of a diurnal variation in serum vitamin B12 levels. Serum vitamin B12 levels in sheep at pasture were shown to be an unreliable indicator of liver vitamin B12.


Expression of stem cell markers SALL4, LIN28A, and KLF4 in ameloblastoma.
Ameloblastoma (AME) is a benign odontogenic tumour of epithelial origin characterised by slow but aggressive growth, infiltration, and recurrence; it is capable of reaching large dimensions and invading adjacent structures. Stem cell research has proven to be significant in the sphere of tumour biology through these cells' possible involvement in the aetiopathogenesis of this tumour. Immunohistochemistry was performed on AME, dentigerous cyst (DC), and dental follicle (DF) samples, and indirect immunofluorescence was performed on the AME-hTERT cell line to determine the expression of SALL4, LIN28A, and KLF4. Expression of proteins related to cellular pluripotency was higher in AME cells than in DC and DF cells. The analysis revealed that the proteins in question were mainly expressed in the parenchyma of AME tissue samples and were detected in the nuclei of AME-hTERT cells. Stem cells may be related to the origin and progression of AME.


Virosome-based active immunization targets soluble amyloid species rather than plaques in a transgenic mouse model of Alzheimer's disease.
Active vaccination with amyloid peptides shows promise for the treatment and prevention of Alzheimer's disease (AD). Several studies in transgenic mouse models of AD have revealed the potency of vaccination to prevent or even clear amyloid plaques from mouse brain. However, the idea that soluble oligomeric species of beta-amyloid (Abeta), rather than plaques, trigger the disease has gained momentum, and current active vaccination strategies affect the levels of total or soluble brain Abeta little or not at all. We describe an active vaccination method based on Abeta1-16 presented on the surface of virosomes, which triggered a dramatic decrease in both soluble Abeta40 (75% reduction; p=0.01) and soluble Abeta42 (62% reduction; p=0.03) in a double transgenic mouse model of AD. Whereas Abeta40 and Abeta42 levels in the insoluble fraction tended to be reduced (by 30% and 27%, respectively), the number of thioflavine-S-positive amyloid plaques was not affected. The high specific antibody responses, obtained without eliciting T-cell reactivity, demonstrate that immunostimulating reconstituted influenza virosomes are a promising antigen carrier system against the neuropathology of AD.


Tuning of fast-spiking interneuron properties by an activity-dependent transcriptional switch.
The function of neural circuits depends on the generation of specific classes of neurons. Neural identity is typically established near the time when neurons exit the cell cycle to become postmitotic cells, and it is generally accepted that, once the identity of a neuron has been established, its fate is maintained throughout life. Here, we show that network activity dynamically modulates the properties of fast-spiking (FS) interneurons through the postmitotic expression of the transcriptional regulator Er81. In the adult cortex, Er81 protein levels define a spectrum of FS basket cells with different properties, whose relative proportions are, however, continuously adjusted in response to neuronal activity. Our findings therefore suggest that interneuron properties are malleable in the adult cortex, at least to a certain extent.


[Early invasive strategy in diabetic patients with non-ST-segment elevation acute coronary syndromes].
In the management of non-ST-segment elevation acute coronary syndromes (NSTE-ACS), several studies have shown a reduction in mortality with the use of an invasive strategy in high-risk patients, including diabetic patients. Paradoxically, other studies have shown an under-utilization of this invasive strategy in these patients. The aim of this study is to determine the characteristics of patients managed conservatively and identify determinants of the use of invasive or conservative strategy. Retrospective cohort study conducted in diabetic patients with NSTE-ACS included in the ARIAM-SEMICYUC registry (n=531) in 2010 and 2011. We performed crude and adjusted unconditional logistic regression. We analyzed 531 diabetic patients, 264 (49.7%) of which received invasive strategy. Patients managed conservatively were a subgroup characterized by older age and cardiovascular comorbidity, increased risk of bleeding and the absence of high-risk electrocardiogram (ECG). In diabetic patients with NSTE-ACS, independent predictors associated with conservative strategy were low-risk ECG, initial Killip class>1, high risk of bleeding and pretreatment with clopidogrel. The fear of bleeding complications or advanced coronary lesions could be the cause of the underutilization of an invasive strategy in diabetic patients with NSTE-ACS.


The effect of young age on tumor recurrence in the treated breast after conservative surgery and radiotherapy.
Prognostic factors for local recurrence following conservative surgery and radiation therapy for patients with early breast cancer have not been fully established. To evaluate the importance of young age as a prognostic factor for local recurrence, we reviewed the results of treatment of 597 patients with 607 UICC-AJCC Stage I or II breast cancers, 47 of which were diagnosed when the patient was less than 35 years old. All were treated with excisional biopsy and a total dose to the site of the primary tumor of 60 Gy or more. The median follow-up in survivors was 63 months. Patient age and the presence of an extensive intraductal component (EIC) were both highly associated with the likelihood of tumor recurrence in the treated breast. Patients under 35 had an actuarial 5-year recurrence rate of 26%, compared to 10% for older patients (p = 0.002). Patients with an EIC had a breast recurrence rate of 25%, compared to 5% when EIC was absent (p less than 0.0001). Although the incidence of an EIC was higher in the younger subgroup (44% vs. 31%), this alone did not account for the difference in in breast recurrence rates, since younger patients had a higher recurrence rate than older patients even when an EIC was absent (22% vs. 3%, p = 0.0003). We conclude that the age of the patient is an important prognostic factor for local recurrence following conservative surgery and radiation therapy. This finding is in part attributed to the observation that younger women are more likely to have tumors with an EIC than older women, but even when an EIC is absent, they may be at an increased risk of local recurrence. However, caution is required in interpreting these findings with regard to selecting among treatment options until further data are available comparing the results of conservative surgery and radiation therapy to those of mastectomy in younger patients.


The pH dependence of spin-spin coupling constants J (P-O-P) of ADP and ATP has been determined from the phosphorus NMR spectra at 0 degrees. The variation curves have been interpreted as titration curves. These give different pK values. Comparison with the tripolyphosphate shows the existence of triphosphate chain structural deformation in the nucleotides.


Quantification of Integrin Activation and Ligation in Adherent Cells.
Integrin activation is a crucial event for multiple biological functions. Therefore, methods to detect integrin activation are vital. Since the main cellular function of integrins is adhesion, we and others utilize this feature to measure integrin activation. Here, we describe how to detect the activity of the fibronectin-binding integrin α5β1 using a fusion of glutathione S-transferase (GST) to the 9th, 10th, and 11th type III repeats on fibronectin (GST-FNIII9-11). Moreover, we detail how to measure αvβ3 integrin activity using the ligand-mimetic WOW-1 antibody that selectively binds unoccupied αvβ3 integrins. Finally, we describe methods of testing ligation of fibronectin-binding integrins utilizing monoclonal antibodies against ligand-induced binding sites (LIBS).


Comparison of cold spray and shotblocker to reduce intramuscular injection pain: A randomized controlled trial.
It is important to identify effective, easy-to-use and cost-effective non-pharmacological methods in the management of pain caused by medical interventions. The purpose of this study is to compare the effects of cold spray and ShotBlocker on pain in adults in reducing pain caused by intramuscular injection in the adult emergency department. This is a randomized controlled trial with two experimental groups, two placebo groups and a control group. The study was conducted on 195 adults who received diclofenac sodium injections. In the study, the injection procedure was performed by following the same injection protocol in all five groups. In the injection process, cold spray or ShotBlocker was used in the intervention groups based on the group, and cold spray with distilled water or the smooth surface of the ShotBlocker was used in the placebo groups. Following the injection, the pain caused by the injection was evaluated using the Visual Analog Scale. The study was completed with the remaining 195 patients. In the study, the average pain scores due to injection of the individuals in the cold spray group were lower than those of the control group (p < 0.05). There was no statistically significant difference between the pain score averages due to injection of the individuals in the ShotBlocker group and cold spray, control, ShotBlocker placebo and cold spray placebo groups. The routine use of a fast-acting, cost-effective and easy-to-use method, cold spray, to reduce pain in the intramuscular injection will be beneficial in increasing patient satisfaction and quality of care.


Endogenous vasoactive intestinal peptide and nitric oxide modulate cholinergic neurotransmission in guinea-pig trachea.
Guinea-pig tracheal smooth muscle possesses an inhibitory non-adrenergic, non-cholinergic (i-NANC) innervation and the neurotransmitters involved in this response may be vasoactive intestinal peptide (VIP) and nitric oxide (NO). Since i-NANC mechanisms may co-exist with cholinergic nerves we have investigated whether endogenous VIP and NO modulate cholinergic neurotransmission. alpha-Chymotrypsin enhanced the cholinergic contractile responses to electrical field stimulation (EFS at 4 Hz by 38.6 +/- 4.8% (P < 0.05, n = 6) but did not produce a shift in the concentration-response curve to acetylcholine (ACh). L-NG-Nitro-arginine methyl ester (L-NAME) and L-NG-monomethyl arginine (L-NMMA) produced a concentration-dependent enhancement of cholinergic responses to EFS (4 Hz) (at 100 microM, 40.9 +/- 6.6 and 30.2 +/- 5.8%, P < 0.01) with no effect on response curves to ACh. This enhancement was reversed by L-arginine but not D-arginine (1 mM). D-NAME and D-NMMA and L-arginine had no effect on cholinergic neurotransmission. alpha-Chymotrypsin and L-NAME had no effect on excitatory NANC (e-NANC) neural responses in guinea-pig bronchi. These results suggest that endogenous NO and VIP may modulate cholinergic neurotransmission by either functional antagonism at the level of the airway smooth muscle or via a pre-junctional inhibition of ACh release from cholinergic nerve terminals or by both mechanisms.


Facile synthesis of chitosan-based acid-resistant composite films for efficient selective adsorption properties towards anionic dyes.
To effectively and selectively remove toxic anionic dyes which are heavily discharged and to promote them recovery, a sustainable cellulose nanofiber/chitosan (CNF/CS) composite film was elaborately designed through a facile procedure. Based on the strong supporting effect of CNF and excellent compatibility between CNF and CS, the composite film presents low swelling and acid-proof properties, which can prevent the adsorption process from the disintegration of adsorbent. Moreover, the positive electrical property of CNF/CS film increases the discrepancy in adsorption capacities for anionic and cationic dyes. The maximum adsorption capacity of anionic methyl orange (MO) on CNF/CS film reaches 655.23 mg/g with a desirable recyclability. The adsorption behavior attributed to a physico-chemical and monolayer adsorption process. This work opens a new route for the development of eco-friendly and highly efficient adsorbents on selective removal and recycling of anionic dyes from wastewater.


Use of the splanchnic/hepatic balance technique in the study of glucose metabolism.
This chapter examined the applicability of the splanchnic/hepatic balance technique to the study of glucose metabolism in humans and in dogs. When combined with radioisotope turnover methodology, the hepatic/portal venous catheterization technique provides a powerful tool to investigate splanchnic/hepatic carbohydrate metabolism. It should be emphasized that the same principles described on the preceding pages can be applied to study amino acids (Gelfand et al, 1986), potassium (DeFronzo et al, 1980) and insulin (Ferrannini et al, 1983), as well as a variety of other metabolites and hormones.


Determination of vessel size: a putative framework to assess clinical outcome.
Unknown is the predictive value of the coronary artery diameter without the administration of vasomotor stimuli. A small reference diameter of the target vessel has been demonstrated to be an adverse prognostic factor in patients undergoing revascularisation. The present study investigated the prognostic value of the proximal non-stenotic left anterior descending coronary artery (LAD) diameter in patients referred for a first diagnostic angiogram without a previous revascularisation. A total of 277 patients (mean age 57 year, 61% male) were eligible for analysis. The proximal non-stenotic diameter of the LAD was measured by quantitative coronary angiography without prior nitrate infusion. We defined a small LAD as a diameter < or =2.5 mm. Cardiovascular events were defined as cardiac death, myocardial infarction, and hospitalizations for unstable angina. During a median follow-up of 47 months, 24 major cardiac events occurred. The cumulative survival for patients with a small LAD was significantly lower, than for patients with a large LAD (hazard ratio 2.51; 95% confidence interval 1.11-5.66, p=0.03). In the multivariate analysis, a LAD diameter < or =2.5 mm remained a significant predictor of cardiovascular events after adjustment for age, gender, and the presence of significant coronary artery disease (hazard ratio 2.32; 95% confidence interval 1.01-5.34, p=0.048). In patients referred for a first diagnostic angiogram without a previous revascularisation, the diameter of the proximal non-stenotic LAD is an independent predictor of cardiovascular events.


Posttraumatic stress disorder in a war-affected area of Northeast Ethiopia: a cross-sectional study.
Post-Traumatic Stress Disorder (PTSD) is a chronic condition that affects a significant proportion of war survivors following war and conflict. If PTSD is not managed, it can lead to decreased quality of life and impairments in daily functioning and lead to death. This study aimed to assess the prevalence of post-traumatic stress disorder and its associated factors among residents in a war-affected area, Dessie Town, Northeast Ethiopia. A community-based cross-sectional study was conducted among adult residents in the war-affected area, Dessie Town. A total of 615 individuals were selected by a systematic random sampling method. PTSD was assessed using the Post-Traumatic Stress Disorder Checklist, Civilian Version. Multivariable logistic regressions were used to measure the associated factors. Associations between variables were described using odds ratios, 95% confidence intervals, and a p-value less than 0.05. The prevalence of PTSD was 34.5% (95% CI: 31-38). Female sex (AOR: 1.82; CI: 1.18-2.82), divorced or widowed (AOR: 2.12, CI: 1.23-3.66), having only primary schooling (AOR: 2.17; CI: 1.25-3.78), depression (AOR: 2.03; CI: 1.34-3.08), experienced ill health without medical care during the wartime (AOR: 2.97; CI: 1.43-6.16), forced separation from family (AOR: 1.90; CI: 1.16-3.12), and experienced stressful life events (AOR: 1.60; CI: 1.06-2.42) were significantly associated with PTSD. A significant rate of PTSD was found among residents of the war-affected area, Dessie Town. One in three people was experiencing PTSD. As a result, post-war mental health early screening and intervention is a priority, particularly for females, those who are separated or divorced, and those who have experienced stressful life events due to the war.


Ozone flux in plant ecosystems: new opportunities for long-term monitoring networks to deliver ozone-risk assessments.
Ozone (O3) is a photochemically formed reactive gas responsible for a decreasing carbon assimilation in plant ecosystems. Present in the atmosphere in trace concentrations (less than 100 ppbv), this molecule is capable of inhibiting carbon assimilation in agricultural and forest ecosystems. Ozone-risk assessments are typically based on manipulative experiments. Present regulations regarding critical ozone levels are mostly based on an estimated accumulated exposure over a given threshold concentration. There is however a scientific consensus over flux estimates being more accurate, because they include plant physiology analyses and different environmental parameters that control the uptake-that is, not just the exposure-of O3. While O3 is a lot more difficult to measure than other non-reactive greenhouse gases, UV-based and chemiluminescence sensors enable precise and fast measurements and are therefore highly desirable for eddy covariance studies. Using micrometeorological techniques in association with latent heat flux measurements in the field allows for the partition of ozone fluxes into the stomatal and non-stomatal sinks along the soil-plant continuum. Long-term eddy covariance measurements represent a key opportunity in estimating carbon assimilation at high-temporal resolutions, in an effort to study the effect of climate change on photosynthetic mechanisms. Our aim in this work is to describe potential of O3 flux measurement at the canopy level for ozone-risk assessment in established long-term monitoring networks.


Promotion effects of acetoaceto-o-toluidide on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder carcinogenesis in rats.
Recent epidemiological studies have indicated that occupational exposure to the aromatic amine acetoaceto-o-toluidide (AAOT) was associated with a marked increase in urinary bladder cancers in Japan. However, little is known about the carcinogenicity of AAOT. To evaluate the urinary bladder carcinogenicity of AAOT, male and female F344 rats were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks followed by dietary administration of 0, 0.167, 0.5, or 1.5% AAOT for 31 weeks. The incidences and multiplicities of bladder tumors were significantly increased in the 0.5 and 1.5% groups of male and female rats in a dose-response manner. AAOT and seven downstream metabolites were detected in the urine of the male and female rats administered AAOT with levels increasing in a dose-dependent manner. The most abundant urinary metabolite of AAOT was the human bladder carcinogen o-toluidine (OTD), which was at least one order of magnitude higher than AAOT and the other AAOT metabolites. In a second experiment, male F344 rats were administered 0, 0.167, or 1.5% AAOT for 4 weeks. Gene expression analyses revealed that the expression of JUN and its downstream target genes was increased in the urothelium of male rats treated with 1.5% AAOT. These results demonstrate that AAOT promotes BBN-induced urinary bladder carcinogenesis in rats and suggest that overexpressed of JUN and its downstream target genes may be involved the bladder carcinogenicity of AAOT. In conclusion, AAOT, like other carcinogenic aromatic amines, is likely to be a carcinogen to the urinary bladder, and OTD metabolized from AAOT is the ultimate carcinogen.


Optimal VLBI baseline geometry for UT1-UTC Intensive observations.
One of the main tasks of Very Long Baseline Interferometry (VLBI) is the rapid determination of the highly variable Earth's rotation expressed through the difference between Universal Time UT1 and Coordinated Universal Time UTC (dUT1). For this reason, dedicated one hour, single baseline sessions, called "Intensives", are observed on a daily basis. Thus far, the optimal geometry of Intensive sessions was understood to include a long east-west extension of the baseline to ensure a dUT1 estimation with highest accuracy. In this publication, we prove that long east-west baselines are the best choice only for certain lengths and orientations. In this respect, optimal orientations may even require significant inclination of the baseline with respect to the equatorial plane. The basis of these findings is a simulation study with subsequent investigations in the partial derivatives of the observed group delays τ with respect to dUT1 ∂ τ / ∂ d U T 1 . Almost 3000 baselines between artificial stations located on a regular 10 × 10 degree grid are investigated to derive a global and generally valid picture about the best length and orientation of Intensive baselines. Our results reveal that especially equatorial baselines or baselines with a center close to the equatorial plane are not suited for Intensives although they provide a good east-west extension. This is explained by the narrow right ascension band of visible sources and the resulting lack of variety in the partial derivatives. Moreover, it is shown that north-south baselines are also capable of determining dUT1 with reasonable accuracy, given that the baseline orientation is significantly different from the Earth rotation axis. However, great care must be taken to provide accurate polar motion a priori information for these baselines. Finally, we provide a better metric to assess the suitability of Intensive baselines based on the effective spread of ∂ τ / ∂ d U T 1 .


The first description of the leaf-mining Nepticulidae (Lepidoptera) feeding on the South American plant genus Liabum, Asteraceae.
First Liabum Adans. (Asteraceae) feeding Nepticulidae are reported. Two new new species from the Andes (Ecuador) are described: Stigmella serpantina Diškus & Stonis, sp. nov. and S. pangorica Diškus & Stonis, sp. nov. The male genitalia of both species and the female genitalia, as well the leaf-mines of S. serpantina sp. nov. are illustrated.


Periviable birth at 20 to 26 weeks of gestation: proximate causes, previous obstetric history and recurrence risk.
Early preterm birth at 20 to 26 weeks of gestation (periviable birth) carries extreme risks of infant death and morbidities. Prevention of periviable birth could improve infant outcomes significantly. We sought to characterize the causes of periviable birth and to determine whether periviable birth can be predicted by previous pregnancy outcome. We evaluated 104,921 pregnancies (1974-2004) and assessed the frequency and causes of periviable birth. Women who were delivered of both their first and second pregnancies at >20 weeks of gestation at our institution were identified. Predictive values of the first pregnancy outcomes for second pregnancy outcomes were determined. Periviable birth complicated 1981 deliveries (1.9%). Seventy-nine percent of the women with periviable births had no history of periviable births; 44% of the women had no previous deliveries, and 35% of the women had previous term deliveries only. Causes of periviable birth were labor (36%), premature rupture of membranes (34%), bleeding (10%), and preeclampsia (4%). Four percent of the gestations were multiple gestations. Among 7970 pregnancies at >20 weeks of gestation, periviable birth in the first pregnancy was associated with preterm birth and periviable birth in the second pregnancy (35.6%, 6.9%; relative risk, 3.3 and 8.6; P < .0001). Periviable birth and preterm birth in the first pregnancy were insensitive for periviable birth in the second pregnancy (8.8%, 36.8%, respectively). Although periviable birth is associated with subsequent periviable birth and preterm birth, preterm birth and periviable birth are insensitive markers for recurrences in the next pregnancy. Early pregnancy or preconceptional markers for prediction of periviable birth are needed.


Characteristics of an environmental strain, Enterococcus faecalis CECT7121, and its effects as additive on craft dry-fermented sausages.
Lactic acid bacteria are the most adequate microorganisms for natural preservation of food. In the present work, the strain of Enterococcus faecalis CECT7121 was employed in the manufacture of craft dry-fermented sausages and its performance as a biopreservative was analysed. This strain is devoid of the genes for haemolysin and gelatinase and does not produce biogenic amines. It is sensitive to almost all the antibiotics tested and opsonophagocytic assays showed that it is devoid of a capsule. This strain had a high LD50 (10(11)CFU ml(-1)) in mice. No statistical differences were found between control and sausages inoculated with E. faecalis CECT7121 regarding the production of lactic acid, pH variation over time, reaching a minimum pH value of 5.1, and sensory analysis in both series. Sausages inoculated with E. faecalis CECT7121 had lower viable counts of Enterobacteriaceae, Staphylococcus aureus and other Gram-positive cocci at the end of fermentation and 7 days and no viable enterobacteria and S. aureus were recovered at the end of drying. E. faecalis CECT7121 did not affect the growth of Lactobacillus spp. but it displaced the autochthonous populations of enterococci. E. faecalis CECT7121 was recovered in each time point as assessed by its inhibitory activity on Listeria monocytogenes and S. aureus. These results would indicate that the addition of E. faecalis CECT7121 during the manufacture of craft dry-fermented sausages offers an interesting alternative for biopreservation.


Absence of Meissner corpuscles in the digital pads of mice lacking functional TrkB.
The TrkB-expressing sensory neurons seem to be involved in touch and other discriminative sensibilities. Thus, several slowly and rapidly adapting cutaneous mechanoreceptors, as well as muscle spindles, are reduced or absent in the territory of the trigeminal nerve in functionally TrkB-deficient mice. Whether this also occurs in the cutaneous or muscular territories of dorsal root ganglia has not been analyzed. Here we used immunohistochemistry and transmission-electron microscopy to analyze the impact of a mutation in the gene coding for TrkB on Meissner and Pacinian corpuscles, and muscle spindles. The animals were studied at the post-natal days 15 and 25, because at this time all the mechanoreceptors examined are fully developed. Typical Meissner's corpuscles, displaying S-100 protein immunoreactivity, were found in the digital pads of wild-type and TrkB+/- mice whereas they were absent in the TrkB-/- animals. Regarding Pacinian corpuscles, the mutation in the trkB gene does not alter either the immunohistochemical or the ultrastructural characteristics. Finally, in muscle spindles the arrangement of the intrafusal muscle fibers and nerve fibers was unchanged in the mutated animals. Nevertheless, about 10% of muscle spindles showed increased number of the intrafusal cells (between 6 and 12) and were supplied by more than one large myelinic nerve fiber. The present results strongly suggest that TrkB-expressing sensory neurons in dorsal root ganglia, like those of the trigeminal ganglion, are responsible for the development and maintenance of several rapidly adapting cutaneous mechanoreceptors, i.e. Meissner's corpuscles.


Non-peptidyl insulin mimetics as a potential antidiabetic agent.
Insulin has an important role in the maintenance of blood sugar. It is the only available therapeutic agent for the treatment of type 1 diabetes mellitus and there is a dire need for an oral substitute. Different categories of compounds including mono and di substituted benzoquinones, vanadium based compounds and natural products have been reported to cause insulin-like effects either by increasing phosphorylation of insulin receptor (IR) or inhibiting the protein tyrosine phosphatases. This review summarizes the development of various insulin mimetics with special emphasis on their structure-activity relationships and various biological actions they produce.


Severe exercise-associated hyponatremia on the Kokoda Trail, Papua New Guinea.
Exercise-associated hyponatremia is the most common medical complication of ultradistance exercise and is usually caused by excessive hypotonic fluid intake. We report a case of severe hyponatremia in a healthy male trekking the Kokoda Trail in the remote Southern Highlands of Papua New Guinea. A 43-year-old male collapsed and had a generalized seizure in the afternoon of the third day of a guided trek. He was evacuated the following morning and was found to have a serum sodium level of 107 mmol/L on arrival to hospital. The case highlights that a high index of suspicion is required to identify patients with exercise-associated hyponatremia. Early diagnosis and appropriate management is critical to avoid the potentially fatal consequences of severe hyponatremia. The diagnosis and treatment of exercise-associated hyponatremia is particularly challenging in the remote Papua New Guinea jungle. Education of trek leaders, medics, and trekkers in appropriate preventative measures and the rapid treatment of exercise-associated hyponatremia is essential to avoid recurrences of this life-threatening condition.


Naringin derivatives as glucosamine-6-phosphate synthase inhibitors based preservatives and their biological evaluation.
Glucosamine-6-Phosphate synthase enzyme has been targeted for development of better and safe preservative due to its role in microbial cell wall synthesis. In recent year's demand of preservatives for the food, cosmetics and pharmaceuticals have increased. Although, the available synthetic preservatives have associated unwanted adverse effects, soa chain of naringin derivatives were schemed synthesized and judged for antioxidant, antimicrobial, preservative efficacy, stability study and topical evaluation. Molecular docking resulted with excellent dock score and binding energy for compound 7, compound 6 and compound 1 as compared to standard drugs. Resultant data of antimicrobial activity revealed compound 7as most potent antimicrobial compound for P. mirabilis, P. aeruginosa, S. aureus, E. coli, C. albicans, and A. niger, respectively, as compared to the standard drugs. The preservative efficacy test of compound 7 in White Lotion USP showed the log cfu/mL value within prescribed limit of USP standard. Compound 7 stabilize the White lotion USP from microbial growth for a period of six months under accelerated storage condition. Compound 7 was further evaluated for toxicity by using the Draize test in rabbits and showed no sign of eye and skin irritation. The outcome demonstrated that synthesized naringin compounds showed glorious antioxidant, antimicrobial, preservative efficacy, stable and safe as compared to standards.


A balance between meaningfulness and risk of harm - frail elderly patients' perceptions of physical activity and exercise - an interview study.
There is growing evidence of the benefits of physical activity and exercise for frail elderly patients with comorbidity. In order to improve participation in physical activity and exercise interventions, there is a need to increase our understanding of the patient's perspective. The aim of this study is to explore the perceptions of physical activity and exercise among frail elderly patients with a severe comorbidity burden. Face-to-face, in-depth interviews were conducted with eighteen frail elderly patients with a severe comorbidity burden, median age 85.5 years (min-max 75-94). The interviews were transcribed verbatim and analyzed according to content analysis inspired by Krippendorf. An overall theme, defined as "Meaningfulness and risk of harm in an aging body" was identified, followed by three main categories, labeled physical activity in daily life, goals of physical activity and exercise and prerequisites for physical activity and exercise, and eight sub-categories. This study suggests that, in frail elderly patients with severe multimorbidity, physical activity and exercise is a balance between what is perceived as meaningful and the risk of harm. Patients perceived aging as an inevitable process that they needed to accept and gradually adapt their physical activities in daily life to match. As patients said they were unclear about the benefits and risks of exercise and referred to their previous life and experiences when describing physical activity and exercise, it is likely that the communication relating to this within the healthcare system needs to be further developed To promote physical activity and exercise to maintain or improve physical fitness in this frail population, healthcare providers need to use extended, personalized information to tailor the type of physical activities, goals and prerequisites for each patient.


Dihydrotestosterone stimulates cerebrovascular inflammation through NFkappaB, modulating contractile function.
Our previous studies show that long-term testosterone treatment augments vascular tone under physiological conditions and exacerbates endotoxin-induced inflammation in the cerebral circulation. However, testosterone can be metabolized by aromatase to estrogen, evoking a balance between androgenic and estrogenic effects. Therefore, we investigated the effect of the nonaromatizable androgen receptor agonist, dihydrotestosterone (DHT), on the inflammatory nuclear factor-kappaB (NFkappaB) pathway in cerebral blood vessels. Cerebral arteries were isolated from orchiectomized male rats treated chronically with DHT in vivo. Alternatively, pial arteries were isolated from orchiectomized males and were exposed ex vivo to DHT or vehicle in culture medium. DHT treatment, in vivo or ex vivo, increased nuclear NFkappaB activation in cerebral arteries and increased levels of the proinflammatory products of NFkappaB activation, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Effects of DHT on COX-2 and iNOS were attenuated by flutamide. In isolated pressurized middle cerebral arteries from DHT-treated rats, constrictions to the selective COX-2 inhibitor NS398 or the selective iNOS inhibitor L-nil, [L-N6-(Iminoethyl)lysine], were increased, confirming a functional consequence of DHT exposure. In conclusion, activation of the NFkappaB-mediated COX-2/iNOS pathway by the selective androgen receptor agonist, DHT, results in a state of vascular inflammation. This effect may contribute to sex-related differences in cerebrovascular pathophysiology.


Sources, distribution, and risk assessment of organochlorine pesticides in Nairobi City, Kenya.
The distribution and sources of organochlorine pesticides (OCPs) in air and surface waters were monitored in Nairobi City using triolein-filled semipermeable membrane devices (SPMDs). The SPMDs were extracted by dialysis using n-hexane, followed by cleanup by adsorption chromatography on silica gel cartridges. Sample analysis was done by GC-ECD and confirmed by GC-MS. Separation of means was achieved by analysis of variance, followed by pair-wise comparison using the t-test (p≤ 0.05). The total OCPs ranged between 0.018 - 1.277 ng/m3 in the air and <LOD - 1391.000 ng/m3 in surface waters. Based on the results, the means of Industrial Area, Dandora and Kibera were not significantly different (p≤ 0.05), but were higher (p≤ 0.05) than those of City square and Ngong' Forest. The results revealed non-significant (p≤ 0.05) contribution of long-range transport to OCP pollution in Nairobi City. This indicated possible presence of point sources of environmental OCPs in the city. The water-air fugacity ratios indicated that volatilization and deposition played an important role in the spatial distribution of OCPs in Nairobi City. This indicated that contaminated surface waters could be major sources of human exposure to OCPs, through volatilization. The incremental lifetime cancer risks (ILCR) determined from inhalation of atmospheric OCPs were 2.3745 × 10-13 - 1.6845 × 10-11 (adult) and 5.5404 × 10-13 - 3.9306 × 10-11 (child) in the order: Dandora > Kibera > Industrial Area > City Square > Ngong' Forest. However, these were lower than the USEPA acceptable risks, 10-6 - 10-4. This study concluded that atmospheric OCPs did not pose significant cancer risks to the residents.


Endocytosis and aspects of autophagy in the foot epithelium of the slug Agriolimax reticulatus (Müller).
The foot epithelium of the slug Agriolimax reticulatus (M) can function as a digestive epithelium and possesses a vacuolar system in which heterophagic and autophagic material is hydrolysed. Using ferritin and peroxidase as markers, the process of endocytosis has been demonstrated at the level of the electron microscopy. The mechanisms involved with the uptake of each marker differed in that ferritin was confined to fairly large vacuoles, while peroxidase was present in smaller pinocytotic vesicles which ultimately fused to form larger vacuoles or multivesicular bodies. Cytochemical tests for acid phosphatase revealed that the latter bodies acquired hydrolytic enzyme to become secondary lysosomes. Acid phosphatase was also localized in the Golgi apparatus of the epithelial cells. In addition to the endocytotic activity, evidence of autophagy was found in the epithelial cells and this process was apparently enhanced during starvation.


Cardiac wall rupture in systemic lupus erythematosus: a case report and review of the literature.
Cardiac wall rupture (CWR) is a serious and often fatal complication of myocardial infarction (MI). Despite an increase in the incidence of MI in patients with systemic lupus erythematosus (SLE), cases of CWR in these patients have been reported rarely. This study reports an SLE patient with CWR and pseudoaneurysm formation and reviews previously reported cases of CWR in SLE patients. An English language literature review of from the PubMed, EMBASE, and Scopus databases on published cases of CWR in SLE, up until January 2023, was performed and analyzed. The search identified 4 patients, including the present one, 5 cases altogether. All of them were female aged 27-40 years, and 3 of them had had SLE for 10 years or more. Chest pain and dyspnea were the common presentations. All had left ventricular (LV) wall rupture. Three patients had LV wall rupture with pseudoaneurysm formation (one had MI with normal coronary artery, one myocardial necrosis secondary from small coronary artery vasculitis and one MI from uncertain cause). The other 2 patients had LV free wall rupture (one had MI with extensive coronary atherosclerosis with coronary arteritis, and the other septic myocarditis with septic coronary arteritis) and these 2 patients died before the diagnosis was made. Three patients with pseudoaneurysm received surgical correction with good clinical outcomes in all. Cardiac wall rupture is a serious and often fatal cardiac complication. Emergency diagnosis and appropriate management with an experienced cardiology team is crucial. Surgical correction is the treatment of choice. Key Points • Cardiac wall rupture, a serious and often fatal cardiac complication, has rarely been described in SLE patients. • Emergency diagnosis and appropriate management with an experienced cardiology team is crucial. Surgical correction is the treatment of choice.


Ocular microbiota promotes pathological angiogenesis and inflammation in sterile injury-driven corneal neovascularization.
Microbiota promotes or inhibits the pathogenesis of a range of immune-mediated disorders. Although recent studies have elucidated the role of gut microbiota in ocular disease, the effect of ocular microbiota remains unclear. Herein, we explored the role of ocular commensal bacteria in non-infectious corneal inflammation and angiogenesis in a mouse model of suture-induced corneal neovascularization. Results revealed that the ocular surface harbored a microbial community consisting mainly of Actinobacteria, Firmicutes and Proteobacteria. Elimination of the ocular commensal bacteria by oral broad-spectrum antibiotics or topical fluoroquinolone significantly suppressed corneal inflammation and neovascularization. Disease amelioration was associated with reduced numbers of CD11b+Ly6C+ and CD11b+Ly6G+ myeloid cells, not Foxp3+ regulatory T cells, in the spleen, blood, and draining lymph nodes. Therapeutic concentrations of fluoroquinolone, however, did not directly affect immune cells or vascular endothelial cells. In addition, data from a clinical study showed that antibiotic treatment in combination with corticosteroids, as compared with corticosteroid monotherapy, induced faster remission of corneal inflammation and new vessels in pediatric patients with non-infectious marginal keratitis. Altogether, our findings demonstrate a pathogenic role of ocular microbiota in non-infectious inflammatory disorders leading to sight-threatening corneal neovascularization, and suggest a therapeutic potential of targeting commensal microbes in treating ocular inflammation.


[Malignant melanoma in the area of the head and neck].
Malignant melanoma is one of the most frequent malignancies of the skin. This is particularly true of malignant melanoma in juveniles. Its incidence has more than doubled from the 1970s to the mid-1990s. Presently, 15 new cases are recorded per 100,000 inhabitants a year in Germany. At Fachklinik Hornheide, a tumor center specializing in skin neoplasm with patients being referred from all over Germany, the number of melanoma patients treated per year has been approximately 500-550 for the past 10 years. In the present study, the state-of-the-art therapy for primary melanoma and treatment of the regional lymph node system is discussed. The radical treatment formerly advocated with wide tumor resection plus radical neck dissection is no longer justified for this immunogenic malignant tumor caused by endogenic as well as exogenic factors. "Sentinel lymph node" imaging by means of radioactive substances for diagnosing possible melanoma metastases in adjacent lymph nodes has changed the therapeutical concept. Tumor staging by means of ultrasound, CT, MRT, or PET allows the differentiation of tumors without distant metastases and a favorable prognosis, from melanomas which have to be considered as generalized disease. In addition to surgical resection of the tumor and neck dissection for removal of lymph nodes, adjuvant immunotherapy with interferon-alpha is capable of prolonging survival without a recurrence. Palliative chemotherapy or immunotherapy are valuable options for cases with generalized melanoma. Vaccination with a melanoma-associated antigen or dendritic cells is at an experimental stage and may become part of future treatment strategies.


Lab-scale thermal analysis of electronic waste plastics.
In this work, we experimentally revealed the thermochemical decomposition pathway of Decabromodiphenyl ethane (DBDPE) and tetrabromobisphenol A (TBBPA) containing electronic waste plastics using an online thermogravimetric-fourier transform infrared-mass spectroscopy (TG-FTIR-MS) system, a high resolution gas chromatography/high resolution mass (HRGC-MS) spectroscopy, and a fixed-bed reactor. We found the distribution and species of produced bromides can be easily controlled by adjusting pyrolytic temperature, which is particularly crucial to their recycle. From the analysis of the liquid and solid phase obtained from the fixed-bed reactor, we proposed that the Br radicals formed during the pyrolysis process may be captured by organic species derived from the depolymerization of plastics to form brominated compounds or by the inorganic species in the plastics, and that these species remained in the char residue after pyrolysis. Our work for the first time demonstrates intramolecular oxygen atoms play a pivotal role in the formation of PBDD/Fs that pyrolysis of oxygen-free BFRs is PBDD/Fs-free, whereas pyrolysis of oxygen-containing BFRs is PBDD/Fs-reduced.


Cocaine-induced hepatotoxicity in humans.
A patient with hepatonecrosis associated with cocaine use is presented. Postmortem examination of the liver showed marked periportal inflammation and necrosis, and mild diffuse fatty infiltration. These pathologic findings are identical to those previously reported in a mouse model of cocaine hepatotoxicity.


Whole blood donor deferral analysis at a center in Western India.
Deferrals lead to loss of precious whole blood donors (WBD) and blood units available for transfusion purposes. Knowledge of rate and causes of donor deferral can guide the recruitment strategy for WBD. To find the incidence and causes of deferral in Indian WBD and apply relevant findings to modify recruitment strategy for blood donors. Data for WBD presenting for donation in a blood center and outdoor camps over one and half year were analyzed retrospectively. National guidelines were used for selection and deferral of WBD. 736 (11.6%) WBD were deferred out of 6357 presenting for donation during the study period. Most (69.8%) of the donors were deferred on physical examination and hemoglobin (Hb) testing. Most common reasons for deferral were low Hb (55.8%), abnormal blood pressure (11.1%), medication (6.9%) and underweight donors (2.9%). Significantly more volunteers were deferred than relative donors (13.97% vs 5.80%; P<0.000). Females were found to have higher deferral rate than males (53.5% vs 6.9%; P=0.000) and higher odds ratio for deferral (15.4). Donors older than 40 years of age had significantly higher chance of being deferred (P<0.05). It is important to determine the rate and causes of WBD deferral to guide the recruitment and retention efforts at local, regional, and national level.


Sintilimab plus nab-paclitaxel as second-line treatment for advanced biliary tract cancer: study protocol for an investigator-initiated phase 2 trial (NapaSinti trial).
Biliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. However, there is currently no satisfactory second-line regimen for patients without specific genetic mutations. Nanoparticle albumin-bound paclitaxel, also known as nab-paclitaxel (Abraxane, Bristol Myers Squibb), has shown activity in patients with BTC. Studies investigating the immunogenic features of BTC suggested that checkpoint inhibition may lead to antitumor immune responses. In recent years, improved survival has been observed in patients treated with chemotherapy combined with immunotherapy across multiple cancer types, including BTC. This clinical trial aims to evaluate the efficacy and safety of second-line sintilimab in combination with nab-paclitaxel in advanced BTC patients. The NapaSinti trial is a prospective, nonrandomized, open-label, phase 2 study conducted at a tertiary hospital in Chengdu, China. Eligible patients are those with histologically or cytologically confirmed locally advanced non-resectable or metastatic adenocarcinoma in the biliary tract (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), aged between 18 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who have experienced disease progression after prior gemcitabine- or fluorouracil-based chemotherapy and have not received taxane or immune checkpoint inhibitor treatment. Enrolled patients will receive intravenous administration of sintilimab 200 mg on day 1 and nab-paclitaxel 125 mg/m2 on days 1 and 8, every three weeks. The primary endpoint is the objective response rate (ORR), while the secondary endpoints include overall survival (OS), progression-free survival (PFS), and safety. Exploratory objectives aim to identify biomarkers and molecular signatures for predicting response or prognosis. Using Simon's two-stage design, a total of 63 participants will be enrolled in the study. This trial was initiated in March 2022 in China. The NapaSinti trial evaluates the efficacy and safety of second-line sintilimab plus nab-paclitaxel for advanced biliary tract cancer. Additionally, the trial provides an opportunity for translational research. Chinese Clinical Trial Registry ChiCTR2100052118. Registered October 19, 2021.


Outbreaks of human coronavirus in a pediatric and neonatal intensive care unit.
Human coronavirus 229E (HCoV) has been recently recognized as a potential agent of nosocomial viral respiratory infections (NRVI) in high-risk infants. We have confirmed this as fact through the study of a 1-year period of HCoV outbreaks occurring during a prospective survey of NRVI in a paediatric and neonatal intensive care unit (PNICU) using new molecular techniques for HCoV detection. Nasal samples obtained at admission and weekly thereafter for all hospitalised children, as well as monthly nasal samples from staff, were analysed using immunofluorescence for respiratory syncytial virus (RSV), influenza viruses A and B, paramyxoviruses 1, 2, 3 and adenoviruses. RT-PCR was used for HCoV detection. During the year 1998, 43 HCoV-related NRVI were detected in 152 neonates (incidence 28.3%), and 7 HCoV-related NRVI were found in 92 children (incidence 7.6%). Three HCoV-related outbreaks were observed (February, August and December), associated with a high prevalence of HCoV infection in the staff. During the August outbreak, 50% to 78% of hospitalised neonates and children were infected. Seventy-five percent of hospitalised preterm neonates with a gestational age less than 32 weeks and 52.4% of staff members were infected. Risk factors for NRVI in neonates were birth weight, gestational age, ventilation, oxygenation and hospitalisation length. Ninety-two percent of infected preterm neonates were symptomatic, mainly with bradycardia and respiratory worsening. These data provide additional evidence for a possibly significant role of HCoV in NRVI in a PNICU. The role of staff or hospitalised children in spreading HCoV is hypothesised.


Effect of ultraviolet radiation on photosynthesis, biomass, and fatty acid content and profile of a Scenedesmus rubescens-like microalga.
The effects of ultraviolet radiation (UVR) and nitrogen (NaNO(3)) concentration on photosynthesis, biomass, and fatty acid content and profile of a Scenedesmus rubescens-like microalga were measured in an outdoor 8-day culture study. UV-induced photoinhibition decreased from 42.6% to 3.5%, in the presence of 75 mg/L NaNO(3) (HN) and from 52.9% to 22.6% in the presence of 7.5mg/L NaNO(3) (LN) nitrogen concentration, respectively. The concentrations of UV-absorbing compounds increased 4.3 and 4.9 times under HN and LN, respectively. Biomass accumulation was suppressed (10.7%) by UVR under HN, but not under LN conditions. Carotenoid content decreased from 1.05 ± 0.06 to 0.96 ± 0.15 (with UV radiation) and to 0.91 ± 0.07 (without UV radiation), respectively, under HN, while it decreased to 0.05 ± 0.04 (with UV radiation) and to 0.11 ± 0.08 (without UV radiation), respectively, under LN. The content of C18:1n9 fatty acids increased by about 430%, whereas that of C18:3n3 decreased by about 65% in both radiation treatments during nitrogen starvation. The results showed that the absence of UVR screening does not change the fatty acid content and profile of S. rubescens-like algae cultivated outdoors under HN and LN conditions.


Tumors of the Testis: Morphologic Features and Molecular Alterations.
This article reviews the most frequently encountered tumor of the testis; pure and mixed malignant testicular germ cell tumors (TGCT), with emphasis on adult (postpubertal) TGCTs and their differential diagnoses. We additionally review TGCT in the postchemotherapy setting, and findings to be integrated into the surgical pathology report, including staging of testicular tumors and other problematic issues. The clinical features, gross pathologic findings, key histologic features, common differential diagnoses, the use of immunohistochemistry, and molecular alterations in TGCTs are discussed.


Amino acids in eight species of Monogenea.
The ethanol-extractable amino acids of several species of Monogenea were analysed. In the Monopisthocotylea levels were high ( greater than 1,200 micronmoles/g/ethanol extracted dry wt); in the Polyopisthocotylea lower amounts were present (196-562 micronmoles). High proline levels were present in parasites of hosts from a marine environment but low in freshwater forms. No correlation between diet and proline content was observed.


[Influence of intraoral douches over the parodontium state and leucocytes activity in patients treated in the sanatorium of Swieradow Zdroj].
Using the following indices: gingival--GI, of gingivorrhoea--GBI, of parodontium--PI and of dental deposit--DI and the measure of the gingival pockets' depth and pocket fluid clinical estimation has been performed in 33 men with parodontium inflammation before and after the set 15 balneological procedures. Leucocytes and other morphotic elements in the pockets have been estimated on Styrophlex straps. Examinations of the peripheral blood have comprised NBT spontaneous test and stimulated by concanavalin, phagocytosis and chemotaxis. After treatment considerable clinical improvement, decrease in pocket fluid excretion reduction in the number of granulocytes and increase in epithelial cells' percentage in the gingival pockets as well as existence of disturbances in granulocytes function of the peripheral blood expressed by reduced chemotaxis and phagocytosis have been found.


The histopathology of de Quervain's disease.
The histopathological appearances of the tendon sheath and synovium from 23 patients treated surgically for de Quervain's disease are described and compared with 24 controls. The condition was not characterized by inflammation, but by thickening of the tendon sheath and most notably by the accumulation of mucopolysaccharide, an indicator of myxoid degeneration. These changes are pathognomonic of the condition and are not seen in control tendon sheaths. The term 'stenosing tenovaginitis' is a misnomer and we believe that de Quervain's disease is a result of intrinsic, degenerative mechanisms rather than extrinsic, inflammatory ones.


Long-Term Outcome of Mini-Open Surgical Decompression for Chronic Exertional Compartment Syndrome of the Forearm in Professional Motorcycling Riders.
To evaluate results of mini-open fasciotomy (MOF) in high-level motorcycling or motocross riders with chronic exertional compartment syndrome (CECS) at long-term follow-up (minimum 5 years). Case series. IV. University Hospital/Private Practice. Fifty-four professional motorcycling riders treated with MOF for a CECS of the forearm from January 2006 to June 2011. Inclusion criteria comprised: high-level motorcycling or motocross riders, clinical symptoms of CECS for at least 6 months, diagnosis confirmed using preoperative compartment hydrostatic pressure measurement and/or magnetic resonance imaging of the forearm, minimum follow-up of 5 years. A MOF to obtain decompression of all compartments was performed in all patients. Visual analog scale; a subjective scale to measure strength; QuickDash functional scores. Time to resume full riding capacities as short-term evaluation. A total of 54 patients who underwent 77 MOF procedures overall (23 bilateral) were included. The mean age was 23.6 ± 5.2 years. Mean Visual Analog Scale decreased from a preoperative value of 68.2 to a 3-month postoperative value of 26 (P < 0.001). Mean QuickDash scale was 84 at preoperative registration, falling to 20, 3 months after surgery (P < 0.001) and down to 12 at 1-year follow-up (P = 0.017). The average time to return to full riding capacities was 3.5 ± 1 week. Mini-open fasciotomy resulted safe and effective for the treatment of chronic exertional compartment syndrome in high-level motorcycling or motocross riders. The good outcome at follow-up resulted stable at 5 years and the incidence of complications remained low. Our data demonstrate that the resolution of symptoms is reliable and durable. Pain recovery was immediate after surgery, instead functional scores showed a more gradual recovery throughout the 12 months after surgery. Mini-open fasciotomy is a reliable treatment for CECS of the forearm in professional motorcycling riders. This treatment should also be considered in young riders due to the absence of tardive relapse reported in this study.


Comparison of extracorporeal shock wave therapy with botulinum toxin type A in the treatment of plantar fasciitis.
To compare the efficacy of extracorporeal shock wave therapy (ESWT) with botulinum toxin type A (BoNT-A) in the treatment of plantar fasciitis (PF). Open label, prospective, randomized study. A total of 72 patients were included. In all participants the median (and interquartile range) of the visual analog scale (VAS) of pain result, when taking the first steps, was 8 (6-9) points before treatment and 6 (4-8) points after treatment (p < 0.001). In the group of patients that received ESWT, the median (and interquartile range) of improvement in the VAS of pain result, when taking the first steps, was 2 (1-4) points, and in the group of patients that received BoNT-A the same result was 1 (0-2) points (p = 0.009). In the group of patients that received ESWT, the median (and interquartile range) of improvement in the Roles and Maudsley scale of pain result was 1 (0-1) points, and in the group of patients that received BoNT-A the same result was 0 (0-1) points (p = 0.006). In a multivariate analysis use of ESWT and lower weight were associated with improvement of pain with treatment in at least one of the three VAS of pain scales used in the study. ESWT was superior to BoNT-A in the control of pain in patients with PF. Implications for Rehabilitation Plantar fasciitis is characterized by pain at the calcaneal origin of the plantar fascia, exacerbated by weight bearing after prolonged periods of rest. Although studies comparing extracorporeal shock wave therapy or botulinum toxin type A to placebo suggest a superiority of the first one, no reliable data exist about it. Extracorporeal shock wave therapy was superior to botulinum toxin type A in the control of pain in patients with PF.


Effect of endotoxin on the rat colon glutathione level.
The effect of endotoxin on the colon glutathione level was studied in male rats. Endotoxin (Escherichia coli) from 25 ug to 100 ug/100g body weight was administered intravenously. The Glutathione level was measured 16 hours after endotoxin was given. Results showed that endotoxin significantly enhanced the colon glutathione concentration as measured by 5,5'-dithiobis (2-nitrobenzoic acid). The increase which ranged from 11% to 50% was dose dependent. At an endotoxin dose of 1000 ug/100g body weight, colon glutathione level was found to be enhanced from 2 hours up to 48 hours. In contrast, the duodenum and jejunum glutathione levels were found to be significantly reduced. The increase in the colon glutathione level may have a protective effect against oxidative damage to the colon.