3-Hydrogenkwadaphnin targets inosine 5'-monophosphate dehydrogenase and triggers post-G1 arrest apoptosis in human leukemia cell lines.
3-Hydrogenkwadaphnin (3-HK) is a recently characterized daphnane-type compound isolated from Dendrostellera lessertii with high anti-tumor activity in animal models. Herein, we report on time- and dose-dependent effects of this compound on growth, differentiation, IMPDH inhibition, cell cycle and apoptosis of a panel of human leukemia cell lines (HL-60, K562 and Molt4). The drug decreased the growth of leukemia cells in less than 24 h of treatment. However, longer exposure times and/or higher concentrations were required to promote cell apoptosis. Cell cycle analysis revealed the accumulation of cells in their G1 phase as early as 12 h after drug exposure but sub-G1 population was recorded after 24 h. Occurrence of apoptosis was constantly accompanied by morphological (staining with DNA-binding dyes) and biochemical (DNA fragments) variations among drug-treated cells. Despite these observations, non-activated normal human PBL were insensitive to the drug action. In addition, treatment of PHA-activated PBL, K562, Molt4 and HL-60 cells with a single dose of the drug for 24 h led to the inhibition of IMPDH activity by almost 37, 38, 44 and 50%, respectively. In contrast, no difference in IMPDH activities were seen between normal PBL and the drug treated PBL cells. Restoration of the depleted GTP concentration by exogenous addition of guanosine (25-50 microM) reversed the drug effects on cell growth, DNA fragmentation and apoptosis. Furthermore, the drug effects were potentiated by exogenous addition of hypoxanthine to the drug-treated cells. Reduction of the drug potency on the non-proliferative (retinoic acid treated) HL-60 cells by almost 40%, compared to the proliferative cells, clearly shows type II IMPDH as one of the main targets of the drug. These results suggest that 3-HK may be a powerful candidate for treatment of leukemia.


MiRNA-Mediated Subpathway Identification and Network Module Analysis to Reveal Prognostic Markers in Human Pancreatic Cancer.
Pancreatic cancer (PC) remains one of the most lethal cancers. In contrast to the steady increase in survival for most cancers, the 5-year survival remains low for PC patients. We describe a new pipeline that can be used to identify prognostic molecular biomarkers by identifying miRNA-mediated subpathways associated with PC. These modules were then further extracted from a comprehensive miRNA-gene network (CMGN). An exhaustive survival analysis was performed to estimate the prognostic value of these modules. We identified 105 miRNA-mediated subpathways associated with PC. Two subpathways within the MAPK signaling and cell cycle pathways were found to be highly related to PC. Of the miRNA-mRNA modules extracted from CMGN, six modules showed good prognostic performance in both independent validated datasets. Our study provides novel insight into the mechanisms of PC. We inferred that six miRNA-mRNA modules could serve as potential prognostic molecular biomarkers in PC based on the pipeline we proposed.


Secondary central nervous system involvement by follicular lymphoma: case report and review of the literature.
We report a patient with indolent stage IV follicular lymphoma, grade 1, initially successfully treated with chemotherapy, who later developed aggressive diffuse large B-cell lymphoma in the parieto-occipital lobe 8 years after initial presentation. The differing patterns of lymphomatous involvement of the central nervous system (CNS) are briefly reviewed, with a focus on the patterns seen in secondary CNS spread by low-grade lymphomas. A 53-year-old man was diagnosed with stage IV follicular lymphoma, grade 1, in 1996. Although initial chemotherapy was successful, he developed several recurrences of lymphoma over the following years. In May 2004, he presented with a discrete, single, massive parieto-occipital lobe brain lesion. The mass failed to regress with empiric cranial external beam radiotherapy. Because of suspicion of an unusual infection, the lesion was surgically excised in its entirety. The mass proved to be an aggressive diffuse large B-cell lymphoma, transformed from his previous follicular cell lymphoma, with retention of strong Bcl-2 and Bcl-6 immunoreactivity. Parenchymal brain involvement, as opposed to dural or leptomeningeal, is a relatively uncommon pattern of spread to the CNS for systemic lymphomas. More significantly, follicular lymphomas are one of the least frequent types of indolent lymphomas to develop clinically apparent, secondary CNS spread. The presentation of an indolent follicular lymphoma with transformation to an aggressive diffuse large B-cell lymphoma within the brain parenchyma is rare. Its manifestation as a massive, singular lesion is unique and prompted diagnostic confusion.


The use of propranolol and nifedipine in the medical management of angina pectoris.
This study investigates the use of propranolol and nifedipine in the treatment of angina pectoris. The clinical response and the effects on the precordial 16-lead electrocardiogram before and after exercise were studied in 52 patients with frequent angina pectoris. Relief of chest pain and abolition of exercise-induced ST-segment depression was achieved in 16 patients on treatment with propranolol alone (mean dose, 300 mg/d). Of the remaining 36 patients, the precordial area and severity of exercise-induced ST-segment depression were unchanged in 8 patients, of whom 2 reported they were free from chest pain, improved in 10 patients of whom 4 reported they were free of chest pain, and abolished in 14 patients, all of whom were free from chest pain following treatment with both propranolol and nifedipine (mean dose, 50 mg/d). Four patients were unable to tolerate this combination. This study has shown that in patients who do not respond to treatment with propranolol alone the combination of propranolol and nifedipine can be used to control not only anginal pain, but also the precordial electrocardiographic manifestations of ischemia.


Global approaches to identify novel participants that modulate intestinal epithelial cell development.
Combinatorial control of lineage-specific gene expression is commonly mediated by suites of diverse transcriptional regulators. In this issue of Developmental Cell, Verzi et al. (2010) use an unbiased global and computational approach to identify distinct partners and functions of CDX2 in intestinal epithelial cell differentiation.


Rapid detection of glyoxalase I (GLO) on cellulose acetate gel and the distribution of GLO variants in a Dutch population.
A rapid electrophoretic procedure is described for detecting the human red cell glyoxalase I variants (GLO 1, GLO 2-1, and GLO 2) on cellulose acetate gel (cellogel) on which the sites of enzymed activity are visualized as purple bands against white background. The frequency of GLO1 gene in a Dutch population living in and around Leiden was found to be 0.4544.


Rehabilitation program after mesenchymal stromal cell transplantation augmented by vascularized bone grafts for idiopathic osteonecrosis of the femoral head: a preliminary study.
To determine the feasibility and safety of implementing a 12-week rehabilitation program after mesenchymal stromal cell (MSC) transplantation augmented by vascularized bone grafting for idiopathic osteonecrosis (ION) of the femoral head. A prospective case series. University clinical research laboratory. Participants (N=10) with ION who received MSC transplantation augmented by vascularized bone grafting. A 12-week exercise program, which included range-of-motion (ROM) exercises, muscle-strengthening exercises, and aerobic training. Measures of ROM, muscle strength, Timed Up and Go test, and Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) were collected before surgery and again at 6 and 12 months after surgery. All participants completed the 12-week program. External rotation ROM as well as extensor and abductor muscle strength significantly improved 6 months after treatment compared with that before treatment (P<.05). Significant improvements were also seen in physical function, role physical, and bodily pain subgroup scores of the SF-36 (P<.05). No serious adverse events occurred. This study demonstrates the feasibility and safety of a multiplex rehabilitation program after MSC transplantation and provides support for further study on the benefits of rehabilitation programs in regenerative medicine.


Postoperative imaging follow-up at 2 years as a predictor of long-term outcomes after endovascular aneurysm repair.
Lifelong imaging follow-up remains the reference standard after endovascular aneurysm repair (EVAR). Because the number of EVARs has been increasing, an individually optimized follow-up protocol is desirable. The aim of the present study was to investigate the possibility of creating such a protocol by evaluating patients' follow-up images and to compare the findings with their freedom from reintervention and abdominal aortic aneurysm (AAA) rupture. From 2000 to 2010, 282 patients with an AAA had undergone elective EVAR with the Zenith stent-graft. The patients were followed up annually until the end of 2019. The patients were categorized into two groups according to the presence of any endoleak or sac shrinkage at 2 years. Group A included those with no detectable endoleak plus aneurysm sac shrinkage of ≥5 mm (n = 137; 63%), and group B included those with any type of endoleak and/or no significant aneurysm sac shrinkage (<5 mm; n = 82; 37%). The mean follow-up was 83 months (range, 0-229 months), and the overall survival at 2 years was 84% (n = 237). No significant difference was found in overall survival between groups A and B (P = .73). However, a significant difference was found in freedom from AAA rupture at 12 years, favoring group A (group A, 100%; group B, 91%; P = .002). Furthermore, in group A, the freedom from reintervention was 95% at 12 years compared with only 31% in group B (P < .001). The sensitivity of the categorization was 89% and the specificity was 74% for the finding of a complication requiring a reintervention during long-term follow-up. Patients without an endoleak and a reduction of ≥5 mm in aneurysm size at 2 years had significantly fewer late reinterventions and ruptures during long-term follow-up compared with their counterparts using the Zenith stent-graft (Cook Medical, Bloomington, Ind). This finding suggests that, for these patients, the follow-up interval can be personalized and safely extended after 2 years.


A sample-preparation-free, automated, sample-to-answer system for cell counting in human body fluids.
While many clinical laboratory tests are now highly automated, body fluid cell counting, particularly in low-cellularity samples such as cerebral spinal fluid (CSF), is often performed manually. Here, we report a simple, cost-effective method to obtain white and red blood cell counts from human body fluids such as CSF. The method consists of a compact, automated, and low-cost fluorescence microscope system, coupled to a sample chamber containing all of the necessary reagents in dry form to stain and prepare the sample. Sample focus and scanning are handled automatically, and the acquired multimodal images are automatically analyzed to extract cell counts. Comparison with manual counting on over 200 clinical samples shows excellent agreement. As the system counts a substantially larger image region than a standard manual cell count, we find our sensitivity to extremely low cellularity samples to potentially be higher than the manual gold standard, evidenced by our system recording images of cells in samples whose cell count was registered as "0" by a trained user. Thus, our system holds promise for routine, automated, and sensitive analysis of body fluids whose cellularity extends across a wide dynamic range.


Evaluation of the azoospermic patient.
Azoospermia is found in up to 10 to 20 per cent of the men who present to an infertility clinic. The main causes are testicular failure and ductal obstruction. Testicular biopsy remains the definitive test used to differentiate these 2 disorders. A retrospective study of 133 azoospermic men was performed to determine the accuracy and limitations of noninvasive variables in predicting testicular failure in an effort to limit the need for diagnostic testicular biopsy. Of 49 patients (37 per cent) with ductal obstruction a third had bilateral vasal agenesis. The remaining 84 azoospermic patients (63 per cent) had testicular failure. The results of the complete evaluation of these patients are described. Among the 101 patients with a testicular biopsy confirmed diagnosis there was a significant difference in testicular size (p less than 0.001), ejaculate volume (p less than 0.001) and serum follicle-stimulating hormone (p less than 0.001) between patients with testicular failure and those with ductal obstruction. The sensitivity and specificity of various parameters were determined. The best criteria to predict ductal obstruction preoperatively are a serum follicle-stimulating hormone level of less than 2 times greater than normal and the absence of bilateral testicular atrophy (100 per cent sensitivity and 71 per cent specificity). An algorithm for evaluation of the azoospermic patient is described such that all men with ductal obstruction and a minimal number with testicular failure undergo testicular biopsy.


Structure-function studies of bacteriorhodopsin XV. Effects of deletions in loops B-C and E-F on bacteriorhodopsin chromophore and structure.
Bacteriorhodopsin mutants containing deletions in loop B-C, delta Thr67-Glu74 or delta Gly65-Gln75 or a deletion in the loop E-F, delta Glu161-Ala168, were prepared. Following their expression in Escherichia coli, the mutant proteins were purified to homogeneity and refolded with retinal in detergent-phospholipid mixtures. The mutants containing deletions in the loop B-C were normal at 4 degrees C but showed the following changes at 20 degrees C. 1) The lambda max shifted from 540 to below 510 nm; 2) the rates of bleaching by hydroxylamine in the dark increased; and 3) the rate and steady state of proton pumping decreased. Deletion of the eight amino acids in loop E-F did not affect wild-type behavior. However, all the mutant proteins were more prone to thermal and sodium dodecyl sulfate denaturation than the wild-type bacteriorhodopsin. These observations show that the structures of the B-C and E-F loops are not essential for correct folding of bacteriorhodopsin, but they contribute to the stability of the folded protein.


Blindness and glaucoma: a comparison of patients progressing to blindness from glaucoma with patients maintaining vision.
To compare patients becoming legally blind from glaucoma with those who did not go blind. Retrospective, cohort, and case-control study. A retrospective community-based longitudinal study of residents of Olmsted County, Minnesota, who were newly diagnosed with open-angle glaucoma between 1965 and 1980 and followed through 1998. A case-control study was performed comparing patients progressing to legal blindness from glaucoma with aged-matched and visual field-matched patients not progressing to blindness. Fifty-six of 290 patients progressed to legal blindness in at least one eye over the 34-year period of the study. Most who progressed to blindness had moderate to advanced visual field loss at the time of diagnosis of glaucoma. Those becoming legally blind had mean intraocular pressures (IOP) on therapy lower than or similar to patients who did not go blind, although the variability of IOP was higher in the blind group. Different susceptibilities to IOP were apparent, as some eyes with initially normal disks and visual fields became blind at an IOP of 20 mm, while others did not worsen. Changes in medical therapy after progression of visual field damage were less effective in lowering IOP in the group becoming blind than in the nonblind group. Patients at greatest risk of blindness had visual field loss at the time of diagnosis of glaucoma. Different susceptibilities to IOP were apparent, with some patients becoming blind at pressures that others tolerated without significant progression. This suggests that continued monitoring of visual fields and reassessment of target IOP levels when field damage occurs are fundamental in the management of glaucoma.


Contribution of hGH20K variant to blood hGH response in sauna and exercise.
Exercise-induced increases in blood somatotropin (hGH) have always been considered in terms of quantity of the circulating molecules. Knowing that the hypophysis can release several GH species, we investigated the differential release in blood of total hGH (hGHT) and the main hGH variant (hGH20K) molecules in six trained male swimmers exposed to three different conditions known to favor GH release in blood: 45 min--70% maximum oxygen uptake (VO2max) bicycling and swimming, and 20 min of sauna bathing. Based on the binding specificity of hGH antibodies, hGH20K was isolated then assayed using the Nichols immunoradiometric assay system. All three experimental conditions produced significant (P less than 0.001) elevations in blood hGHT and hGH20K. In all three cases, mean blood hGH20K contribution to blood hGHT was relatively constant (11.9, SE 0.7%). Rises in rectal temperature were not statistically related to the changes in blood hGHT. This demonstration of a relatively constant elevation in hGH20K during bicycling, swimming, and sauna bathing can hardly explain the large differences in blood hGHT responses reported in literature under similar conditions.


Pasta products enriched with moringa sprout powder as nutritive dense foods with bioactive potential.
Five fettuccini formulations containing 5% (5MSP), 10% (10MSP), 15% (15MSP), 20% (20MSP), and 30% (30MSP) of moringa sprout powder (MSP) were produced aimed at improving the nutritional and bioactive profile of conventional pasta. A gradual increase of protein, lipids, fiber and mineral content was observed in fettuccine as the MSP amount increased, while carbohydrates were reduced. MSP-addition also increased the levels of thiamine, riboflavin, γ- aminobutyric acid, glucosinolates and the antioxidant activity in pasta. All pasta doughs showed similar rheological parameters. Textural properties decreased after MSP inclusion, but the values obtained were close to those of control. Incorporation of MSP up to 10% did not modify substantially the sensory attributes of fettuccine, but higher amounts had a negative impact. Thus, addition of MSP up to 10% is a promising technological approach to improve the nutritional and functional properties of pasta without compromising consumer acceptance.


Prokaryotic and viral genomes recovered from 787 Japanese gut metagenomes revealed microbial features linked to diets, populations, and diseases.
We reconstructed 19,084 prokaryotic and 31,395 viral genomes from 787 Japanese gut metagenomes as Japanese metagenome-assembled genomes (JMAG) and Japanese Virus Database (JVD), which are large microbial genome datasets for a single population. Population-specific enrichment of the Bacillus subtilis and β-porphyranase among the JMAG could derive from the Japanese traditional food natto (fermented soybeans) and nori (laver), respectively. Dairy-related Enterococcus_B lactis and Streptococcus thermophilus were nominally associated with the East Asian-specific missense variant rs671:G>A in ALDH2, which was associated with dairy consumption. Of the species-level viral genome clusters in the JVD, 62.9% were novel. The β crAss-like phage composition was low among the Japanese but relatively high among African and Oceanian peoples. Evaluations of the association between crAss-like phages and diseases showed significant disease-specific associations. Our large catalog of virus-host pairs identified the positive correlation between the abundance of the viruses and their hosts.


Perspective: researching the transition from non-living to the first microorganisms: methods and experiments are major challenges.
Methods to research the origin of microbial life are limited. However, microorganisms were the first organisms on the Earth capable of cell growth and division, and interactions with their environment, other microbial cells, and eventually with diverse eukaryotic organisms. The origin of microbial life and the supporting scientific evidence are both an enigma and a scientific priority. Numerous hypotheses have been proposed, scenarios imagined, speculations presented in papers, insights shared, and assumptions made without supporting experimentation, which have led to limited progress in understanding the origin of microbial life. The use of the human imagination to envision the origin of life events, without supporting experimentation, observation and independently replicated experiments required for science, is a significant constraint. The challenge remains how to better understand the origin of microbial life using observations and experimental methods as opposed to speculation, assumptions, scenarios, envisioning events and un-testable hypotheses. This is not an easy challenge as experimental design and plausible hypothesis testing are difficult. Since past approaches have been inconclusive in providing evidence for the origin of microbial life mechanisms and the manner in which genetic instructions was encoded into DNA/RNA, it is reasonable and logical to propose that progress will be made when testable, plausible hypotheses and methods are used in the origin of microbial life research, and the experimental observations are, or are not reproduced in independent laboratories. These perspectives will be discussed in this article as well as the possibility that a pre-biotic film preceded a microbial biofilm as a possible micro-location for the origin of microbial cells capable of growth and division.


Autoregulation of the ccd operon in the F plasmid.
Mini-F sequences, including the promoter and portions of the ccd region, were inserted upstream of lacZ in promoterless lacZ vectors, and beta-galactosidase specific activities were measured. The results showed that the H (ccdA), G (ccdB) and D genes, together with a promoter, comprise an operon. Ccd operon expression was shown to be regulated at the level of transcription by the G gene product, probably in concert with the H gene product. Thus expression is autoregulated. Expression of the D gene was largely dependent on the ccd promoter, although low levels of transcription from another promoter within the ccd coding region were detected.


Scoring Single-Response Multiple-Choice Items: Scoping Review and Comparison of Different Scoring Methods.
Single-choice items (eg, best-answer items, alternate-choice items, single true-false items) are 1 type of multiple-choice items and have been used in examinations for over 100 years. At the end of every examination, the examinees' responses have to be analyzed and scored to derive information about examinees' true knowledge. The aim of this paper is to compile scoring methods for individual single-choice items described in the literature. Furthermore, the metric expected chance score and the relation between examinees' true knowledge and expected scoring results (averaged percentage score) are analyzed. Besides, implications for potential pass marks to be used in examinations to test examinees for a predefined level of true knowledge are derived. Scoring methods for individual single-choice items were extracted from various databases (ERIC, PsycInfo, Embase via Ovid, MEDLINE via PubMed) in September 2020. Eligible sources reported on scoring methods for individual single-choice items in written examinations including but not limited to medical education. Separately for items with n=2 answer options (eg, alternate-choice items, single true-false items) and best-answer items with n=5 answer options (eg, Type A items) and for each identified scoring method, the metric expected chance score and the expected scoring results as a function of examinees' true knowledge using fictitious examinations with 100 single-choice items were calculated. A total of 21 different scoring methods were identified from the 258 included sources, with varying consideration of correctly marked, omitted, and incorrectly marked items. Resulting credit varied between -3 and +1 credit points per item. For items with n=2 answer options, expected chance scores from random guessing ranged between -1 and +0.75 credit points. For items with n=5 answer options, expected chance scores ranged between -2.2 and +0.84 credit points. All scoring methods showed a linear relation between examinees' true knowledge and the expected scoring results. Depending on the scoring method used, examination results differed considerably: Expected scoring results from examinees with 50% true knowledge ranged between 0.0% (95% CI 0% to 0%) and 87.5% (95% CI 81.0% to 94.0%) for items with n=2 and between -60.0% (95% CI -60% to -60%) and 92.0% (95% CI 86.7% to 97.3%) for items with n=5. In examinations with single-choice items, the scoring result is not always equivalent to examinees' true knowledge. When interpreting examination scores and setting pass marks, the number of answer options per item must usually be taken into account in addition to the scoring method used.


Keap1 knockdown in melanocytes induces cell proliferation and survival via HO-1-associated β-catenin signaling.
Nrf2-Keap1 signaling pathway protects cells against photo-oxidative stress. Yet in recent works, its role in melanogenesis together with cell protection functions against oxidative stress has been gaining interest. However, its effect on melanogenesis still has contradictory results from different studies. The aims of our study were to investigate the effect of Keap1 silencing in melanocyte on melanogenesis and its associated mechanism. Primary human epidermal melanocytes and melan-a cell line were used for this experiment. RNA sequencing was done to identify genes involved in melanocyte biology using Keap1 knockdown through siRNA techniques. And melanogenesis and the expression of melanogenesis-associated molecules were evaluated in Keap1 silenced melanocyte to examine the effects of Keap1 on melanogenesis, melanocyte growth, and related pathways. RNA-sequencing data revealed that Keap1 knockdown in primary human epidermal melanocytes (PHEMs) induced cell survival-related gene expression. Additionally, siRNA-mediated inhibition of Keap1 led to upregulation of MITF and melanogenesis-associated molecules along with Nrf2 activation in PHEMs. HO-1, a major gene that is upregulated in RNA-sequencing using Keap1-silenced PHEMs, protected melanocytes against H2O2-induced cell death and upregulated MITF and β-catenin expression. Further, increased expression of melanogenesis-associated molecules after Keap1 silencing was validated to occur through HO-1-associated β-catenin activation in a Keap1 and HO-1 double knockdown experiment. This work suggests that Keap1 silencing in melanocytes induced melanogenesis and the expression of melanogenesis-associated molecules through HO-1-associated β-catenin activation. Keap1 downregulation in melanocytes is important for cell proliferation and survival.


[Adequacy of antifungal agents in a teaching hospital: too many inappropriate prescriptions despite training].
The aim of this study was to assess adequacy and conformity of systemic antifungal drugs prescriptions in comparison with local, French, European and international recent guidelines in the Grenoble Teaching Hospital. Each prescription of itraconazole, liposomal amphotericin B, voriconazole, caspofungin, micafungin, posaconazole and anidulafungin made between February and October 2010 were reviewed by an infectious diseases specialist. Fluconazole prescriptions' were reviewed only for 15 days. Two hundred and eight patients received 295 systemic antifungal prescriptions. Most of them had at least one risk factor and immunodeficiency was one of the most common. Antifungal treatment starting, molecules choice, administrations conformity (dosage, administration way) were appropriate in 126 cases on 208 (60.5 %) at the treatment beginning evaluation and in 171 cases on 295 (58 %) at the treatment ending evaluation. Antifungal combinations (9.4 %) were less frequent than in the study carried out in Grenoble teaching hospital in 2007 (16.3 %). Most common non-conformities encountered were use of caspofungin instead of fluconazole, antifungal combinations prescription, administration modalities misguiding. The economy that could have been generated by appropriate prescriptions represented 18 % of the antifungal budget of 2010 in the Grenoble Teaching Hospital. An improvement was highlighted in the antifungal prescriptions in comparison to the previous study led in 2007 in the Universitary Grenoble Hospital. However, the antifungal use was not optimal and further training is planned.


Anti-inflammatory effect of the monoterpene myrtenol is dependent on the direct modulation of neutrophil migration and oxidative stress.
Myrtenol is a bicyclic monoterpene with anti-inflammatory properties. However, the mechanisms involved are partially unknown. Here, we investigated the effect of myrtenol during experimental chronic arthritis and the possible modulating activity of oxidative stress and neutrophil migration. Complete Freund's Adjuvant (CFA)-sensitized rats were treated with vehicle (1 mL/kg, po), myrtenol (12.5, 25 or 50 mg/kg, po), indomethacin (10 mg/kg, po) or dexamethasone (0.4 mg/kg) followed by intra-articular injection of CFA (0.5 mg/mL, 50 μL per joint). Then, paw edema and articular incapacitation (paw elevation time) were evaluated for 14 days. On the last day, a blood concentration superoxide dismutase (SOD) and nitrite was determined. In another experimental setting, human neutrophils were incubated with vehicle (sterile saline, 1 mL) or myrtenol (10-100 ng/mL) and the in vitro chemotaxis to N-formylmethionine-leucyl-phenylalanine (fMLP) (10-7 M/well) was evaluated. In addition, antiinflammatory effect of myrtenol was investigated in carrageenan-induced peritonitis. We found that CFA induced a prominent paw swelling and incapacitation of the joint, which were significantly prevented by myrtenol (P < 0.05). In addition, blood accumulation nitrite was attenuated by myrtenol when compared with vehicle-treated CFA group (P < 0.05). Furthermore, plasma levels of SOD were significantly increased by myrtenol versus vehicle-treated CFA group (P < 0.05). Moreover, fMLP-triggered neutrophil chemotaxis and carrageenan-induced peritonitis were markedly prevented by myrtenol (P < 0.05). Therefore, myrtenol showed anti-inflammatory and antinociceptive effects on experimental chronic arthritis, which seems to be related to the direct modulation of neutrophil migration and antioxidant activity.


The roles of transcription, chromatin organisation and chromosomal processes in holocentromere establishment and maintenance.
The centromere is a unique functional region on each eukaryotic chromosome where the kinetochore assembles and orchestrates microtubule attachment and chromosome segregation. Unlike monocentromeres that occupy a specific region on the chromosome, holocentromeres are diffused along the length of the chromosome. Despite being less common, holocentromeres have been verified in almost 800 nematode, insect, and plant species. Understanding of the molecular and epigenetic regulation of holocentromeres is lagging that of monocentromeres. Here we review how permissive locations for holocentromeres are determined across the genome, potentially by chromatin organisation, transcription, and non-coding RNAs, specifically in the nematode C. elegans. In addition, we discuss how holocentric CENP-A or CENP-T-containing nucleosomes are recruited and deposited, through the help of histone chaperones, licensing factors, and condensin complexes, both during de novo holocentromere establishment, and in each mitotic cell cycle. The process of resolving sister centromeres after DNA replication in holocentric organisms is also mentioned. Conservation and diversity between holocentric and monocentric organisms are highlighted, and outstanding questions are proposed.


A 19F NMR study of lomefloxacin in human erythrocytes and its interaction with hemoglobin.
19F NMR spectroscopy of a model fluoroquinolone, lomefloxacin, in an erythrocyte suspension showed separate resonances for the intra- and extra-cellular compartments. The intra-cellular peak revealed significant line broadening of the fluorine signals of lomefloxacin. Line broadening also occurred in the presence of oxyhemoglobin (HbO2), hematin, globin and iron. This evidence indicated that lomefloxacin interacted with these compounds; however, ultrafiltration experiments indicated that there was only weak binding (5%) of lomefloxacin to HbO2. 19F and 31P NMR spectroscopy revealed that lomefloxacin may compete with 2,3-diphosphoglycerate for its binding site on HbO2. An apparent partition coefficient of 1.90 +/- 0.15 was observed for lomefloxacin in human erythrocytes, utilizing LC analysis.


Octodon degus. A useful animal model for social-affective neuroscience research: basic description of separation distress, social attachments and play.
A challenge for social-affective neuroscience programs is to identify simple and yet valid animal models for studying the expression of basic social emotions and their role during different developmental windows, from infancy to adulthood. For example, although laboratory rats are useful for studying juvenile social interactions, they are not ideal for studying infant attachment bonds. Here, we evaluate current understanding of the social behavior of Octodon degus, a diurnal precocial rodent, to elucidate the value of this species as a model for social-affective neuroscience research. After a synopsis of species-specific characteristics and brain susceptibility to changes of social environment, our behavioral findings on degu social proclivities are summarized. We then discuss why this pre-clinical model provides a valuable addition to the commonly available animal models for the study of human psychopathology.


Granuloma-forming activity and antitumor activity of newly isolated mycoloyl glycolipid from Rhodococcus terrae 70012 (Rt. GM-2).
A newly isolated mycoloyl glycolipid (Rt. GM-2) from Rhodococcus terrae 70012 was identified and the granulomagenic and antitumor activities were studied as compared with trehalose-6,6'-dimycolate (cord factor) also from R. terrae (Rt. TDM). The alkaline hydrolysis products of Rt. GM-2 contained trehalose, methyl-alpha-mycolate and a less-polar ester than the usual methyl-alpha-mycolate, possibly beta-keto mycolate (1:1:1, by mol. ratios). On the other hand, analysis of alditol acetate obtained after the mild permethylation, NaBH4 reduction, and acetylation showed the occurrence of 2,3,4-tri-O-methyl-6-O-acetylglucitol. Therefore, the original glycolipid (Rt. GM-2) was identified tentatively as 6-O-alpha-mycoloyl 6'-O-beta-ketomycoloyl trehalose. Intravenous injection of Rt. GM-2 in the form of water-in-oil-in-water emulsion caused prominent granulomas in lungs and spleen of ICR and BALB/c mice. The granulomagenic effects were as strong as those caused by Rt. TDM. The lung and spleen weights reached peaks one week after an injection of Rt. GM-2 in mice and then gradually decreased. Multiple intravenous injections of Rt. GM-2 and Rt. TDM showed antitumor activity against subcutaneously implanted Sarcoma-180, and caused prominent granulomatous changes and growth suppression of mice.


Interleukin-targeted therapy for metabolic syndrome and type 2 diabetes.
Interleukin-1β Interleukin-1β (IL-1β) is a key regulator of the body's inflammatory response and is produced after infection, injury, and an antigenic challenge. Cloned in 1984, the single polypeptide IL-1β has been shown to exert numerous biological effects. It plays a role in various diseases, including autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, and Type 1 diabetes, as well as in diseases associated with metabolic syndrome such as atherosclerosis, chronic heart failure, and Type 2 diabetes. The macrophage is the primary source of IL-1β, but epidermal, epithelial, lymphoid, and vascular tissues also synthesize IL-1. Recently, IL-1β production and secretion have also been reported from pancreatic islets. Insulin-producing β-cells β-cells within the pancreatic islets are specifically prone to IL-β-induced destruction and loss of function. Macrophage-derived IL-1β production in insulin-sensitive organs leads to the progression of inflammation inflammation and induction of insulin resistance in obesity. This chapter explains the mechanisms involved in the inflammatory response during diabetes progression with specific attention to the IL-1β signal effects influencing insulin action and insulin secretion insulin secretion . We highlight recent clinical studies, rodent and in vitro experiments with isolated islets using IL-1β as a potential target for the therapy of Type 2 diabetes.


Cloze enough? Hemodynamic effects of predictive processing during natural reading.
Evidence accrues that readers form multiple hypotheses about upcoming words. The present study investigated the hemodynamic effects of predictive processing during natural reading by means of combining fMRI and eye movement recordings. In particular, we investigated the neural and behavioral correlates of precision-weighted prediction errors, which are thought to be indicative of subsequent belief updating. Participants silently read sentences in which we manipulated the cloze probability and the semantic congruency of the final word that served as an index for precision and prediction error respectively. With respect to the neural correlates, our findings indicate an enhanced activation within the left inferior frontal and middle temporal gyrus suggesting an effect of precision on prediction update in higher (lexico-)semantic levels. Despite being evident at the neural level, we did not observe any evidence that this mechanism resulted in disproportionate reading times on participants' eye movements. The results speak against discrete predictions, but favor the notion that multiple words are activated in parallel during reading.


Schisantherin A protects lipopolysaccharide-induced acute respiratory distress syndrome in mice through inhibiting NF-κB and MAPKs signaling pathways.
Acute respiratory distress syndrome (ARDS) is characterized by polymorphonuclear neutrophils (PMNs) adhesion, activation, sequestration and inflammatory damage to alveolar-capillary membrane. Schisantherin A, a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra sphenanthera, has been reported to have anti-inflammatory properties. In the present study, we aimed to investigate the protective effects of schisantherin A on LPS-induced mouse ARDS. The pulmonary injury severity was evaluated 7 h after LPS administration and the protective effects of schisantherin A on LPS-induced mouse ARDS were assayed by enzyme-linked immunosorbent assay and Western blot. The results revealed that the wet/dry weight ratio, myeloperoxidase activity, and the number of total cells, neutrophils and macrophages in the bronchoalveolar lavage fluid (BALF) were significantly reduced by schisantherin A in a dose-dependent manner. Meanwhile, pretreatment with schisantherin A markedly ameliorated LPS-induced histopathologic changes and decreased the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in the BALF. In addition, the phosphorylation of nuclear transcription factor-kappaB (NF-κB) p65, inhibitory kappa B alpha (IκB-α), c-jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 induced by LPS were suppressed by schisantherin A. These findings indicated that schisantherin A exerted potent anti-inflammatory properties in LPS-induced mouse ARDS, possibly through blocking the activation of NF-KB and mitogen activated protein kinases (MAPKs) signaling pathways. Therefore, schisantherin A may be a potential agent for the prophylaxis of ARDS.


[Inhibition of mouse-killing behavior by rats with taurine, GABA, and its analogues].
The injection of Gaba, of taurine or of a structural analog of GABA (n-dipropylacetate) in the olfactive bulb of "killer" Rats was found to inhibit the mouse-killing behaviour of the rat. The same effect was obtained when taurine or n-dipropylacetate (which increases GABA in the central nervous system), was injected intraperitoneally. The experiments reported here are interpreted to explain certain molecular mechanisms of muricidal behaviour.


Acaricidal properties of ylang-ylang oil and star anise oil against nymphs of Ixodes ricinus (Acari: Ixodidae).
Ylang-ylang oil (YYO) from Cananga odorata (Lam.) Hook.f. & Thomson and star anise oil (SAO) from Illicium verum Hook.f. were tested at four concentrations 0.05, 0.1, 0.2, 0.4 µl/cm2. Mortality rates were obtained by counting dead nymphs at 30-min intervals during the first 5 h after the start of exposure and then at 24, 48 and 72 h. Mortality increased with increasing oil concentration and time of exposure. The two highest concentrations of YYO (0.2, 0.4 µl/cm2) gave maximum lethal concentrations (LC) of 50 and 95% mortality after 4.5 h exposure. Mortality of 95% was obtained after 24 h with the next highest dose (0.1 µl/cm2), whereas LC95 required 3 days with the lowest YYO (0.05 µl/cm2). The lethal effect time (LT) was correlated with the duration of exposure, with a significant effect at 0.4 μl YYO/cm2 after 3 h' (LT50 = 3.2 h, LT95 = 4.3 h). In contrast, only the highest concentration of SAO, 0.4 µl SAO/cm2, showed increasing mortality with time of exposure. This reached LT50 after 10 h and LT95 after 24 h. However, with the lower concentration (0.2 µl/cm2) 50% mortality was reached after 24 h and 100% at 72 h. At to the lowest concentration of SAO (0.1 µl/cm2), 67% mortality after 48 h. The study indicates that YYO and SAO exhibit strong acaricidal properties against nymphs of I. ricinus and suggest that both YYO and SAO should be evaluated as potentially useful in the control of ticks.


Retroperitoneal abscess with pylephlebitis caused by lumbar acupuncture: a case report.
Retroperitoneal abscess (RA) is an unusual life-threatening disease that has insidious and occult presentations. Although the incidence of this disease is low, diagnosis and treatment are challenging due to its nonspecific presentation and the complex anatomy of the retroperitoneal space. Recently, we experienced one case of a RA with extensive thrombophlebitis of the portal venous system. An 80-year-old male presented to the emergency room with symptoms and signs of septic shock; however, the decision making for diagnosis and treatment was difficult, as no clinical and radiological evidence supported key findings regarding the origin of sepsis. Although this patient eventually recovered after surgical drainage, we suggested that more straightforward diagnostic and treatment procedures were required in this patient to avoid possible critical complications. Through a retrospective review of operative findings, patient history, and microbiology, we found that the RA in this patient was caused by lumbar acupuncture, which is usually performed for the management of chronic back pain with long needles. Early surgical intervention should be considered for RA whenever the patient does not respond to broad-spectrum antibiotic treatment. Acupuncture is a possible cause of otherwise unexplained soft tissue infections, such as RA, especially in Asian countries.


Computational analyses of intravascular tracer washout reveal altered capillary-level flow distributions in obese Zucker rats.
Intravascular tracer washout data obtained from gastrocnemius muscle of lean Zucker rats (LZRs) and obese Zucker rats (OZRs) were analysed to investigate flow distributions in the OZR, a model of non-atherosclerotic peripheral vascular disease. A computer model used to simulate the network washout curves was developed based on experimentally observed relative dispersions in large vessels and asymmetrical flow distributions at bifurcations in dichotomous microvascular networks. The model results of simulations were compared to experimental washout data of (125)I-labelled albumin, an intravascular tracer, to uncover flow distributions on the arterial-network and capillary levels. The lean and obese Zucker rats demonstrated distinct capillary-level flow distributions, with higher dispersion and significantly more low-flow capillaries in the OZRs than in the LZRs. Targeted pharmacological treatments against identified sites of vascular dysfunction in OZRs (adrenoreceptor blockade with phentolamine, antioxidant treatment with Tempol and thromboxane receptor antagonism with SQ-29548) were shown to improve the capillary-level flow distributions in treated OZRs toward distributions determined in control LZRs. Combination therapy with multiple pharmacological interventions resulted in a greater degree of recovery. This study demonstrates that the enhanced perfusion heterogeneity at arteriole bifurcations is a potential mechanism underlying perfusion-demand mismatching in OZRs, and suggests that amelioration of this dysfunction must involve a multi-faceted interventional approach.


Pharmacological evidence that 5-HT1A/1B/1D, α2-adrenoceptors and D2-like receptors mediate ergotamine-induced inhibition of the vasopressor sympathetic outflow in pithed rats.
The sympathetic nervous system that innervates the peripheral circulation is regulated by several mechanisms/receptors. It has been reported that prejunctional 5-HT1A, 5-HT1B, 5-HT1D, D2-like receptors and α2-adrenoceptors mediate the inhibition of the vasopressor sympathetic outflow in pithed rats. In addition, ergotamine, an antimigraine drug, displays affinity at the above receptors and may explain some of its adverse/therapeutic effects. Thus, the aims of this study were to investigate in pithed rats: (i) whether ergotamine produces inhibition of the vasopressor sympathetic outflow; and (ii) the major receptors involved in this effect. For this purpose, male Wistar pithed rats were pre-treated with gallamine (25 mg/kg; i.v.) and desipramine (50 µg/kg) and prepared to stimulate the vasopressor sympathetic outflow (T7-T9; 0.03-3 Hz) or to receive i.v. bolus of exogenous noradrenaline (0.03-3 µg/kg). I.v. continuous infusions of ergotamine (1 and 1.8 μg/kgmin) dose-dependently inhibited the vasopressor responses to sympathetic stimulation but not those to exogenous noradrenaline. The sympatho-inhibition elicited by 1.8 μg/kg min ergotamine was (i) unaffected by saline (1 ml/kg); (ii) partially antagonised by WAY 100635 (5-HT1A; 30 μg/kg) and rauwolscine (α2-adrenoceptor; 300 μg/kg), and (iii) dose-dependently blocked by GR 127935 (5-HT1B/1D; 100 and 300 μg/kg) or raclopride (D2-like; 300 and 1000 μg/kg), The above doses of antagonists did not modify per se the sympathetically-induced vasopressor responses. The above results suggest that ergotamine induces inhibition of the vasopressor sympathetic outflow by activation of prejunctional 5-HT1A, 5-HT1B/1D, α2-adrenoceptors and D2-like receptors in pithed rats.


Push-pull tests evaluating in situ aerobic cometabolism of ethylene, propylene, and cis-1,2-dichloroethylene.
In situ aerobic cometabolic transformations of ethylene, propylene, and cis-1,2-dichloroethylene (c-DCE), by microorganisms stimulated on propane, were examined in groundwater contaminated with c-DCE and trichloroethylene (TCE). In situ measurements were performed by conducting field push-pull tests, which consisted of injecting site groundwater amended with a bromide tracer and combinations of propane, dissolved oxygen (DO), nitrate, ethylene, propylene, c-DCE, and TCE into existing monitoring wells and sampling the same wells over time. Mass balance and transformation rate calculations were performed after adjusting for dilution losses using measured tracer concentrations. Initial rates of propane utilization were very low; rates increased substantially following sequential additions of propane and DO. Evidence that propane and DO additions had stimulated organisms expressing a propane monoxygenase enzyme system and that had the capability to transform chlorinated aliphatic hydrocarbons (CAHs) included: (1) the transformation of injected ethylene and propylene to the cometabolic byproducts ethylene oxide and propylene oxide, (2) the transformation of c-DCE, and (3) the inhibition of these transformations in the presence of coinjected acetylene, a known monoxygenase mechanism-based inactivator. These results suggest that a series of push-pull tests performed with nontoxic chemical probes can be useful for detecting and monitoring in situ aerobic cometabolism of CAHs.


The E3 ligase MREL57 modulates microtubule stability and stomatal closure in response to ABA.
Regulation of stomatal movement is critical for plant adaptation to environmental stresses. The microtubule cytoskeleton undergoes disassembly, which is critical for stomatal closure in response to abscisic acid (ABA). However, the mechanism underlying this regulation largely remains unclear. Here we show that a ubiquitin-26S proteasome (UPS)-dependent pathway mediates microtubule disassembly and is required for ABA-induced stomatal closure. Moreover, we identify and characterize the ubiquitin E3 ligase MREL57 (MICROTUBULE-RELATED E3 LIGASE57) and the microtubule-stabilizing protein WDL7 (WAVE-DAMPENED2-LIKE7) in Arabidopsis and show that the MREL57-WDL7 module regulates microtubule disassembly to mediate stomatal closure in response to drought stress and ABA treatment. MREL57 interacts with, ubiquitinates and degrades WDL7, and this effect is clearly enhanced by ABA. ABA-induced stomatal closure and microtubule disassembly are significantly suppressed in mrel57 mutants, and these phenotypes can be restored when WDL7 expression is decreased. Our results unravel UPS-dependent mechanisms and the role of an MREL57-WDL7 module in microtubule disassembly and stomatal closure in response to drought stress and ABA.


Chondroitin sulfate promotes activation of cathepsin K.
Cathepsin K (CatK), a major lysosomal collagenase produced by osteoclasts, plays an important role in bone resorption. Evidence exists that the collagenase activity of CatK is promoted by chondroitin sulfate (CS), a sulfated glycosaminoglycan. This study examines the role of CS in facilitating CatK activation. We have demonstrated that chondroitin 4-sulfate (C4-S) promotes autoprocessing of the pro-domain of CatK at pH ≤ 5, leading to a fully matured enzyme with collagenase and peptidase activities. We present evidence to demonstrate this autoactivation process is a trans-activation event that is efficiently inhibited by both the covalent cysteine protease inhibitor E-64 and the reversible selective CatK inhibitor L-006,235. During bone resorption, CatK and C4-S are co-localized at the ruffled border between osteoclast bone interface, supporting the proposal that CatK activation is accomplished through the combined action of the acidic environment together with the presence of a high concentration of C4-S. Formation of a multimeric complex between C4-S and pro-CatK has been speculated to accelerate CatK autoactivation and promote efficient collagen degradation. Together, these results demonstrate that CS plays an important role in contributing to the enhanced efficiency of CatK collagenase activity in vivo.


Kinetic cooperativity change after H2O2 modification of (Na,K)-ATPase.
The kinetics of hydrolysis of ATP and p-nitrophenylphosphate and the action of the allosteric effectors, Na+ and K+, upon the hydrolysis of these substrates were used to study the H2O2-modified, uncoupled (Na,K)-ATPase isolated from cultured bovine lenses ( Garner , W. H., Garner , M. H., and Spector , A. (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 2044-2048). Pure bovine renal (Na,K)-ATPase was modified by H2O2 in 150 mM KCl and 20 mM MgCl2 to yield an enzyme with kinetic properties similar to the enzyme isolated from the H2O2-treated, cultured bovine lens. H2O2 modification changes the interaction of the ATP hydrolysis site from negative to positive kinetic cooperativity. H2O2 modification dramatically alters Na+ stimulation of ATP hydrolysis and Na+ inhibition of p-nitrophenylphosphate hydrolysis while having little effect upon K+ control of the hydrolysis of these two substrates.


Giant solitary neurofibroma presenting as a neck mass in an infant.
Solitary neurofibroma is a rare tumor of the head and neck region. It is more common in viscera, where it is associated with features of NF1. It occurs most often between the third and fourth decade. These lesions are extremely rare in infants. We report a case of giant, solitary neurofibroma presenting as a progressive mass in parotid region in an infant. This case is unique in its age of presentation (11 months), site, size (about 8 × 15 cm) without any symptoms or neurological deficit.


Circadian periodic response of Phaseolus vulgaris l. to 2,4-dichlorophenoxyacetic acid.
The susceptibility of bean plants, Phaseolus vulgaris L., cv. Executive, to 2,4-dichlorophentoxyacetic acid (2,4-D) appeared to depend upon the time of application. Oscillations in response to 2,4-D were evident in plants subjected to conditions of alternating light and dark spans, continuous illumination or darkness. The fresh and dry weight of plant material was generally less when 2,4-D was applied to plants near the later portions of the light span.


Development and validation of a liquid chromatographic method for Casiopeina IIIi in rat plasma.
A sensitive and specific liquid chromatographic method using extraction with zinc sulfate has been developed for the determination of Casiopeina IIIi and validated over the linear range 5-100 microg/ml in 1 ml of rat plasma. The analysis was performed on a Symmetry C(18) (5 microm) column. The mobile phase was methanol: 0.01 M phosphate buffer pH 6.5 (40:60, v/v). The column effluent was monitored at 262 nm. The results showed that the assay is sensitive at 5 microg/ml. Maximum intra-day coefficient of variation was 10.6%. The recovery obtained in plasma was 87.2%. The method was used to perform protein binding studies by equilibrium dialysis in rat plasma and was found to be satisfactory.


Docking assisted mechanistic elucidation of bio conversion of hexavalent chromium by Serratia marcescens AJRR-22 that is effective yet long term sustainable in bio-geosphere.
Environmental accumulation of hexavalent chromium [Cr(VI)] in the food chain can induce detrimental effects on plants and animals, which calls for effective remediation strategies using biological entities. The bacterium isolated from an iron mine in Odisha, India, is identified asSerratia marcescensAJRR-22. This multi-metal tolerant strain is capable of bio-converting up to 350 mg/L Cr(VI) within 72 h of incubation. Observable electron dense precipitates in transmission electron microscopic images, data patterns in fluorescence microscopy and flow cytometry clearly reveal the chromate reduction ability of the strain. The molecular study is depicted by X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopic analyses. Furthermore, a simulation study to estimate the interactions of chromium bound flavin reductasewith predicted docked complexes suggests significant negative Gibbs free energy and a low inhibition constant (Ki), signifying strong spontaneous binding of Cr(VI) to the enzyme, which makes the strain an efficient candidate for chromium bioremediation.


Computer assisted diagnosis and treatment planning of brachial plexus injuries.
PLEXUS is a computer program which has been developed to provide recommendations for diagnosis and treatment planning of brachial plexus injuries. This computer program is meant for neurologists, neurosurgeons and orthopaedic surgeons who are not experienced in the field of brachial plexus injuries. The system detects the locations and severity of brachial plexus lesions. PLEXUS also indicates whether the patient may be referred to a specialist centre for nerve surgery. In order to determine whether the advice given by the system is of expert quality, a study of its recommendations is being carried out in cooperation with four international brachial plexus experts. To investigate if the system does indeed have the capability to assist physicians in the area of brachial plexus injuries, it is being tested clinically in four hospitals in The Netherlands.


(S)-1-Ferrocenyl-3-hy-droxy-3-phenyl-propan-1-one.
In the title compound, [Fe(C(5)H(5))(C(14)H(13)O(2))], the dihedral angle between the phenyl ring and the unsubstituted cyclo-petadienyl ring is 85.0 (2)°while that between the phenyl ring and the substituted cyclo-petadienyl ring is 83.6 (2)°. The dihedral angle between the two cyclo-penta-1,3-diene rings of the ferrocene unit is 2.2 (2)°. The mol-ecules are stabilized by inter-molecular O-H⋯O hydrogen-bonding inter-action within the crystal lattice.


Oral trypsin inhibitor can improve reflux esophagitis after distal gastrectomy concomitant with decreased trypsin activity.
The pathogenesis of reflux esophagitis is not well understood and remains controversial. Distal gastrectomy serves as a model to assess the role of duodenal reflux with low gastric acidity in the development of reflux esophagitis. We investigated the clinical usefulness and antitrypsin activity after treatment with a trypsin inhibitor, camostat mesilate, against the reflux esophagitis after distal gastrectomy reconstructed with Billroth-I anastomosis. Twenty-eight patients with gastroesophageal reflux disease after distal gastrectomy were prescreened according to esophageal pH level and trypsin activity, and consequently 11 patients were enrolled in the present clinical study. Esophageal and duodenal washings were aspirated for the evaluation of the pretreatment trypsin activity. Then 100 mg of camostat mesilate was administered orally. At 30 and 120 minutes after the administration, duodenal washings were aspirated for the evaluation of posttreatment trypsin activity. Thereafter, 300 mg of camostat mesilate was administered orally 3 times daily for a 4-week period. On the 28th day of administration, the grade of reflux esophagitis (Los Angeles classification) was re-evaluated under endoscopy and the esophageal washings were aspirated for the evaluation of trypsin activity. The trypsin activities in the duodenum both at 30 and 120 minutes after oral ingestion of camostat mesilate were decreased significantly in comparison with those in the pretreatment period in each patient (P<.001). In 6 of 7 patients with detectable trypsin activity in the esophagus, the activities after the 28th day of treatment were lower than those in the pretreatment period, and the symptoms were milder than those before treatment (P<.05). Furthermore, endoscopic evaluation showed that 40% of patients were grade B, C, and D after treatment (28th day), whereas 70% of patients were grade B, C, and D before the treatment. Oral administration of trypsin inhibitor can improve reflux esophagitis after distal gastrectomy concomitant with decreased trypsin activity.


Nuclear genome of Bulinus truncatus, an intermediate host of the carcinogenic human blood fluke Schistosoma haematobium.
Some snails act as intermediate hosts (vectors) for parasitic flatworms (flukes) that cause neglected tropical diseases, such as schistosomiases. Schistosoma haematobium is a blood fluke that causes urogenital schistosomiasis and induces bladder cancer and increased risk of HIV infection. Understanding the molecular biology of the snail and its relationship with the parasite could guide development of an intervention approach that interrupts transmission. Here, we define the genome for a key intermediate host of S. haematobium-called Bulinus truncatus-and explore protein groups inferred to play an integral role in the snail's biology and its relationship with the schistosome parasite. Bu. truncatus shared many orthologous protein groups with Biomphalaria glabrata-the key snail vector for S. mansoni which causes hepatointestinal schistosomiasis in people. Conspicuous were expansions in signalling and membrane trafficking proteins, peptidases and their inhibitors as well as gene families linked to immune response regulation, such as a large repertoire of lectin-like molecules. This work provides a sound basis for further studies of snail-parasite interactions in the search for targets to block schistosomiasis transmission.


Epizootic congenital arthrogryposis-hydranencephaly syndrome in cattle: isolation of Akabane virus from affected fetuses.
Previous serolgoical studies strongly suggested Akabane virus to be the etiologic agent of epizootic abortion and congenital arthrogryposis-hydranencephaly in cattle, and this view was further corroborated in this study by the isolation of the virus from an aborted fetus in an epizootic of the disease and from a fetus extracted froma cow which was suggested by serologic tests to have a recent infection with the virus. The latter fetus had histological changes of encephalomyelitis and polymyositis, and specific antigens of Akabane virus was shown by the immunofluorescent technique in brain tissues as well as skeletal muscular tissues. The virus was recovered from various fetal tissues and fluids, and in relatively large amounts from brain, spinal cord, cerebral fluid, skeletal muscles and fetal placenta. The intracranial inoculation of suckling mice, 1-2 days of age, was the most sensitive system for Akabane virus isolation and HmLu-1, a continuous cell line from hamster lung, seemed almost as sensitive as suckling mice.


Behavioural effects and regulation of PKCalpha and MAPK by huprine X in middle aged mice.
The behavioural effects of huprine X, a new anticholinesterasic inhibitor, as well as its effects on the regulation of protein kinase C (PKC), mitogen activated protein kinase (MAPK) and alpha-secretase (ADAM10 and TACE/ADAM17) related to amyloid precursor protein (APP) processing remain to be established. In the present work, 12 month old 126/SvxC57b/6 male mice which received chronic i.p. treatment with either saline, huprine X (0.04 micromol kg(-1) or huprine X (0.12 micromol kg(-1), were submitted to a battery of behavioural tests and thereafter the brains were dissected to study the neurochemical effects induced by huprine X. The results show that, in a dose dependent manner, huprine X facilitates learning and memory in the Morris water maze and improves some indicators of emotionality without inducing adverse effects, affecting motor activity nor anxiety-like behaviours, as measured in the open-field and corner tests. Moreover activation of downstream PKC/MAPK signaling pathways may underly these behavioural effects as well as the stimulation of the non-amyloidogenic processing of APP. Results obtained herein using a sample of aged animals strongly suggest that huprine X constitutes a promising therapeutic agent for the treatment of cholinergic dysfunction underlying aging and/or dementias.


3D nanoscale imaging of the yeast, Schizosaccharomyces pombe, by full-field transmission X-ray microscopy at 5.4 keV.
Three-dimensional (3D) nanoscale structures of the fission yeast, Schizosaccharomyces pombe, can be obtained by full-field transmission hard X-ray microscopy with 30 nm resolution using synchrotron radiation sources. Sample preparation is relatively simple and the samples are portable across various imaging environments, allowing for high-throughput sample screening. The yeast cells were fixed and double-stained with Reynold's lead citrate and uranyl acetate. We performed both absorption contrast and Zernike phase contrast imaging on these cells in order to test this method. The membranes, nucleus, and subcellular organelles of the cells were clearly visualized using absorption contrast mode. The X-ray images of the cells could be used to study the spatial distributions of the organelles in the cells. These results show unique structural information, demonstrating that hard X-ray microscopy is a complementary method for imaging and analyzing biological samples.


Inositol deficiency resulting in death: an explanation of its occurrence in Neurospora crassa.
The incorporation of radio-active inositol and choline into the cytoplasmzic membranes of inositol-and choline-auxotrophic mnutants of Neuros-pora crassa revealed that the membrane of particles which contain proteases is relatively poor in lecithin and rich in inositol-phospholipid. In mycelia of the mutant requiring inositol, grown in a suboptimum amount of exogenous inositol, the strlctural initegrity of the protease particles is lost, and the bulk of intracellular protease activity is recovered in the soluble fraction of the cell. Death from this kind of inositol deficiency is interpreted as autolysis of the cytoplasm cautsed by free proteases.


[Identification and prenatal diagnosis of a novel NIPBL mutation underlying Cornelia De Lange syndrome].
To explore the genetic basis for an infant featuring developmental delay, hand deformity and hypertonia of extremities. Clinical data and peripheral blood samples of the proband and her parents were collected. Following DNA extraction, potential mutations were screened on an Ion PGM platform using a gene panel. Suspected mutation was verified by PCR and Sanger sequencing. A novel heterozygous nonsense mutation, c.2521C>T(p.R841X), was identified in the NIPBL gene. The mutation may cause premature termination of translation of the adhesion protein loading factor at 841st amino acids. The same mutation was not found in her parents and 931 healthy controls, and was absent from public databases including ExAC and 1000G. Bioinformatic analysis suggested the mutation to be disease causing. The c.2521C>T (p.R841X) mutation of the NIPBL gene probably underlies the Cornelia De Lange syndrome in the infant. Prenatal diagnosis may be provided to this family upon their subsequent pregnancy.


Serological relationships involving potyviral nonstructural proteins.
This report represents a compilation of many of the publications on antigenic properties of potyviral-specified nonstructural proteins. Polyclonal antisera have been prepared for use in characterization of six nonstructural proteins. These include antisera to the cylindrical inclusion proteins of at least 28 potyviruses, to small nuclear inclusion protein (protease) of four potyviruses, to large nuclear inclusion protein (putative replicase) of three viruses, helper component-protease or amorphous inclusion protein of at least four viruses, to the P1 protein (located at the N-terminus of the polyprotein) of one virus, and to the P3 protein (located between helper component protease and cylindrical inclusion protein) of one virus. Monoclonal antibodies also have been prepared to several of these nonstructural proteins. The evidence thus far indicates that cylindrical inclusions of different potyviruses have both conserved and unique epitopes. Nuclear inclusion proteins and amorphous inclusion proteins also may have conserved and unique epitopes. Antigenic relationships of potyviral nonstructural proteins have potential for the identification and classification of potyviruses.


Castleman's disease of the abdomen and pelvis: report of three cases and a review of the literature.
Three cases of Castleman's disease (CD) of the abdomen and pelvis are reported. Tumoral lesions were located in the lymph nodes of the head of the pancreas, the gastropancreatic fold, and around the left iliac artery. Histologically, all the tumoral lesions demonstrated the hyalinevascular type of CD. This unusual presentation made CD difficult to diagnose preoperatively, since these lesions more closely resembled malignant tumors on computed tomography and angiography. We discuss the problems of diagnosing and classifying CD, together with a review of the literature.


StpA represses CRISPR-Cas immunity in H-NS deficient Escherichia coli.
Functional CRISPR-Cas systems provide many bacteria and most archaea with adaptive immunity against invading DNA elements. CRISPR arrays store DNA fragments of previous infections while products of cas genes provide immunity by integrating new DNA fragments and using this information to recognize and destroy invading DNA. Escherichia coli contains the CRISPR-Cas type I-E system in which foreign DNA targets are recognized by Cascade, a crRNA-guided complex comprising five proteins (CasA, CasB, CasC, CasD, CasE), and degraded by Cas3. In E. coli the CRISPR-Cas type I-E system is repressed by the histone-like nucleoid-structuring protein H-NS. H-NS repression can be relieved either by inactivation of the hns gene or by elevated levels of the H-NS antagonist LeuO, which induces higher transcript levels of cas genes than was observed for Δhns cells. This suggests that derepression in Δhns cells is incomplete and that an additional repressor could be involved in the silencing. One such candidate is the H-NS paralog protein StpA, which has DNA binding preferences similar to those of H-NS. Here we show that overexpression of StpA in Δhns cells containing anti-lambda spacers abolishes resistance to λvir infection and reduces transcription of the casA gene. In cells lacking hns and stpA genes, the transcript levels of the casA gene are higher than Δhns and similar to wt cells overexpressing LeuO. Taken together, these results suggest that Cascade genes in E. coli are repressed by the StpA protein when H-NS is absent.


Quality control in cochlear implant therapy: clinical practice guidelines and registries in European countries.
The treatment with a cochlear implant (CI) is the gold standard in therapy of patients with profound hearing loss or deafness. Successful hearing rehabilitation with a CI is a complex, multi-stage process. In medicine, "Clinical Practice Guidelines" (CPG) are widely accepted for the standardization of such processes. These are supplemented by medical registries in which data regarding the treatment can be collected and evaluated. The aim of this paper is to identify currently existing CI-related CPGs and registries in Europe. Between 01/2021 and 06/2021, 42 countries on the European continent, including the United Kingdom, Russia and Turkey, were screened using an internet search (search engine: Google) and a key word search in the Pubmed database. Search terms were the respective country name combined with the following terms: "Cochlear Implant", "CI", "Cochlear implant clinical practice guideline", "CI Guideline", "Cochlear Implant Registry", "CI Registry", "Ear nose throat society". The internet search was conducted in English as well as in the corresponding national language. The objective was to identify a CI-related CPG or registry. A CPG was found in 16 of 42 (38%) countries. In terms of population, this accounts for 645 million out of 838 million people (77%). A registry existed in 4 of the 42 (10%) countries assessed. This corresponds to 102 million out of 838 million (12%) people. In total, 4 out of 42 countries (10%) had both a CPG and a registry. Our work shows numerous efforts in Europe to standardize CI care at the national level. While most people in Europe already live in countries with a CPG, this is not the case for CI registries. European-wide consensus on CPGs or registries does not yet exist. The present study thus provides a first assessment of the distribution of CI-related CPGs and registries.


Experimental reactivation of ocular herpes simplex in rabbits.
Latent herpes simplex virus (HSV) is known to reside in the trigeminal ganglia. Our studies show that the temporary retrobulbar disruption of trigeminal nerve function in chronically infected animals caused a striking decrease in the number of positive HSV cultures obtained during the 20 weeks immediately following surgery. We found that the stereotaxic interruption of intracranial trigeminal nerve function prior to initial HSV infection dramatically reduced the incidence of peripheral recurrence of HSV. Stereotaxic stimulation of the trigeminal ganglion in chronically infected animals produced a significant increase in positive cultures within two days. But, direct neurosurgical stimulation of the trigeminal ganglion proved strikingly effective, producing 83% positive cultures at the eye within 48 hours of operation. These studies further substantiate the premise that the trigeminal ganglion serves as a reservoir for latent HSV from the trigeminal ganglion to its infectious form in the peripheral ocular tissues somehow involves the trigeminal nerve.


2-(1H-1,2,3-Benzotriazol-1-yl)-N'-(2-chloro-benzyl-idene)acetohydrazide.
In the title compound, C(15)H(12)ClN(5)O, the mean planes of the benzotriazole and chloro-phenyl fragments form a dihedral angle of 70.8 (1)°. In the crystal, mol-ecules are linked into infinite chains along the a axis by N-H⋯O hydrogen bonds. Weak inter-molecular C-H⋯N hydrogen bonds further link these chains into layers parallel to the ab plane. The crystal studied was a racemic twin.


Surgical treatment of male genital lymphedema.
The etiologic classification and history of the surgical treatment of male genital lymphedema are presented. Two case reports and their results illustrate the surgical technique of skin flaps and split thickness skin grafting.


Aberrant DNA methylation impacts HOX genes expression in bone marrow mesenchymal stromal cells of myelodysplastic syndromes and de novo acute myeloid leukemia.
DNA methylation, a major biological process regulating the transcription, contributes to the pathophysiology of hematologic malignancies, and hypomethylating agents are commonly used to treat myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). In these diseases, bone marrow mesenchymal stromal cells (MSCs) play a key supportive role through the production of various signals and interactions. The DNA methylation status of MSCs, likely to reflect their functionality, might be relevant to understand their contribution to the pathophysiology of these diseases. Consequently, the aim of our study was to analyze the modifications of DNA methylation profiles of MSCs induced by MDS or AML. MSCs from MDS/AML patients were characterized via 5-methylcytosine quantification, gene expression profiles of key regulators of DNA methylation, identification of differentially methylated regions (DMRs) by methylome array, and quantification of DMR-coupled genes expression. MDS and AML-MSCs displayed global hypomethylation and under-expression of DNMT1 and UHRF1. Methylome analysis revealed aberrant methylation profiles in all MDS and in a subgroup of AML-MSCs. This aberrant methylation was preferentially found in the sequence of homeobox genes, especially from the HOX family (HOXA1, HOXA4, HOXA5, HOXA9, HOXA10, HOXA11, HOXB5, HOXC4, and HOXC6), and impacted on their expression. These results highlight modifications of DNA methylation in MDS/AML-MSCs, both at global and focal levels dysregulating the expression of HOX genes well known for their involvement in leukemogenesis. Such DNA methylation in MSCs could be the consequence of the malignant disease or could participate in its development through defective functionality or exosomal transfer of HOX transcription factors from MSCs to hematopoietic cells.


Clinical clearance of the cervical spine in patients with distracting injuries: It is time to dispel the myth.
The purpose of this study was to prospectively assess the sensitivity and efficacy of clinical examination for screening of cervical spine (c-spine) injury in awake and alert blunt trauma patients with concomitant "distracting injuries." During the 24-month period from December 2009 to December 2011, all blunt trauma patients older than 13 years were prospectively evaluated with a standard cervical spine examination protocol by the trauma surgery team at a Level 1 trauma center. Awake and alert patients with a Glasgow Coma Score (GCS) ≥14 underwent clinical examination of the cervical spine. Clinical examination was performed regardless of "distracting injuries." Patients without complaints of pain or tenderness on physical exam had their cervical collar removed, and the c-spine was considered clinically cleared of injury. All awake and alert patients with "distracting injuries," including those clinically cleared and those with complaints of c-spine pain or tenderness underwent computerized tomographic (CT) scanning of the entire c-spine. "Distracting injuries" were categorized into three anatomic regions: head injuries, torso injuries and long bone fractures. Patients with minor distracting injuries were not considered to have a "distracting injury." During the 24-month study period, 761 blunt trauma patients with GCS ≥14 and at least one "distracting injury" had been entered into the study protocol. Two-hundred ninety-six (39%) of the patients with "distracting injuries" had a positive c-spine clinical examination, 85 (29%) of whom were diagnosed with c-spine injury. Four hundred sixty-four (61%) of the patients with "distracting injuries"' were initially clinically cleared, with one patient (0.2%) diagnosed with a c-spine injury. This yielded an overall sensitivity of 99% (85/86) and negative predictive value greater than 99% (463/464) for cervical spine clinical examination in awake and alert blunt trauma patients with "distracting injuries." In the awake and alert blunt trauma patient with "distracting injuries," clinical examination is a sensitive screening method for cervical spine injury. Radiological assessment is unnecessary for safe clearance of the asymptomatic cervical spine in awake and alert blunt trauma patients with "distracting injuries." These findings suggest the concept of "distracting injury" in the context of cervical spine clinical examination is invalid. Expanding the utility of cervical spine clinical examination to patients with "distracting injuries" allows for significant reduction of both healthcare cost and radiation exposure.


Genome-wide identification of the NAC transcription factors family and regulation of metabolites under salt stress in Isatis indigotica.
NAC (NAM, ATAF1/2 and CUC2) transcription factors (TFs) are a class of TFs families unique to plants, which not only play an important role in the growth and developmental stages of plants but also function in response to stress and regulation of secondary metabolite biosynthesis. However, there are few studies on NAC genes in the medicinal plant Isatis indigotica. In this study, 96 IiNAC genes were identified based on the whole-genome data of I. indigotica, distributed in seven chromosomes and three contigs. IiNAC genes were structurally conserved and divided into 15 subgroups. Cis-elements were identified in the promoter region of the IiNAC gene in response to plant growth and development, abiotic stresses and hormones. In addition, transcriptome and metabolome data of I. indigotica leaves under salt stress were analyzed to construct a network of IiNAC gene co-expression and metabolite association. Ten differentially expressed IiNAC genes were co-expressed with 109 TFs, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that most of these genes were associated with plant growth and development and abiotic stress responses. Eleven IiNAC genes were positively associated with 72 metabolites. Eleven IiNAC genes were positively or negatively associated with 47 metabolites through 37 TFs. Commonly associated secondary metabolites include two terpenoids, abscisic acid and bilobalide, two flavonoids, dihydrokaempferol and syringaldehyde, a coumarin, 7-methoxycoumarin, an alkaloid, lupinine, and quinone dihydrotanshinone I. This study provides important data to support the identification of the NAC gene family in I. indigotica and the regulatory functions of IiNAC genes in metabolites under salt stress.


ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome.
Walker-Warburg syndrome (WWS) is clinically defined as congenital muscular dystrophy that is accompanied by a variety of brain and eye malformations. It represents the most severe clinical phenotype in a spectrum of diseases associated with abnormal post-translational processing of a-dystroglycan that share a defect in laminin-binding glycan synthesis1. Although mutations in six genes have been identified as causes of WWS, only half of all individuals with the disease can currently be diagnosed on this basis2. A cell fusion complementation assay in fibroblasts from undiagnosed individuals with WWS was used to identify five new complementation groups. Further evaluation of one group by linkage analysis and targeted sequencing identified recessive mutations in the ISPD gene (encoding isoprenoid synthase domain containing). The pathogenicity of the identified ISPD mutations was shown by complementation of fibroblasts with wild-type ISPD. Finally, we show that recessive mutations in ISPD abolish the initial step in laminin-binding glycan synthesis by disrupting dystroglycan O-mannosylation. This establishes a new mechanism for WWS pathophysiology.


Multivariate optimization of a dispersive liquid-liquid microextraction method for the determination of six antiparasite drugs in kennel effluent waters by using second-order chromatographic data.
Six veterinary active ingredients (imidacloprid, albendazole, fenbendazole, praziquantel, fipronil and permethrin) were extracted and quantified by liquid chromatography with diode array detection in water samples from a wetland system used for the treatment of waste from a dog breeding plant. Response surface methodology, based on least-squares and artificial neural networks modelling, was applied for the optimization of a dispersive liquid-liquid microextraction (DLLME) procedure. Firstly, two experimental designs were built for screening and optimization, respectively. Then, the desirability function was implemented for the simultaneous optimization of the six recoveries (chromatographic areas of the six compounds). The optimum conditions were: 600 μL of acetone (dispersive solvent), 670 μL of dichloromethane (extractant solvent) and 0.6 min of vortex mixing. The preconcentration factor was 37.5. Then, in order to identify and quantify the six drugs, second-order calibration with MCR-ALS modeling of HPLC-DAD data was implemented attaining successful results. The limits of quantification were 4 ng mL-1 for imidaclopril, albendazole and fenbendazole; 8 ng mL-1 for praziquantel and fipronil; and 26 ng mL-1 for permethrin. The developed method allowed the quantitation of the target analytes, even in the presence of unexpected compounds from dirty water samples. The following maximum levels of veterinary drugs were found (in ng mL-1): imidaclopril, 7; albendazole, 46; fenbendazole, 21; praziquantel, 29; fipronil, 29 and permethrin, 217.


Serum testosterone kinetics after brachytherapy for clinically localized prostate cancer.
To evaluate temporal changes in testosterone after prostate brachytherapy and investigate the potential impact of these changes on response to treatment. Between January 2008 and March 2009, 221 consecutive patients underwent Pd-103 brachytherapy without androgen deprivation for clinically localized prostate cancer. Prebrachytherapy prostate-specific antigen (PSA) and serum testosterone were obtained for each patient. Repeat levels were obtained 3 months after brachytherapy and at least every 6 months thereafter. Multiple clinical, treatment, and dosimetric parameters were evaluated to determine an association with temporal testosterone changes. In addition, analysis was conducted to determine if there was an association between testosterone changes and treatment outcomes or the occurrence of a PSA spike. There was no significant difference in serum testosterone over time after implant (p = 0.57). 29% of men experienced an increase ≥ 25%, 23% of men experienced a decrease ≥ 25%, and the remaining 48% of men had no notable change in testosterone over time. There was no difference in testosterone trends between men who received external beam radiotherapy and those who did not (p = 0.12). On multivariate analysis, preimplant testosterone was the only variable that consistently predicted for changes in testosterone over time. Men with higher than average testosterone tended to experience drop in testosterone (p < 0.001), whereas men with average or below average baseline testosterone had no significant change. There was no association between men who experienced PSA spike and testosterone temporal trends (p = 0.50) nor between initial PSA response and testosterone trends (p = 0.21). Prostate brachytherapy does not appear to impact serum testosterone over time. Changes in serum testosterone do not appear to be associated with PSA spike phenomena nor with initial PSA response to treatment; therefore, PSA response does not seem related to temporal testosterone changes.


A chromatin-based mechanism for limiting divergent noncoding transcription.
In addition to their annotated transcript, many eukaryotic mRNA promoters produce divergent noncoding transcripts. To define determinants of divergent promoter directionality, we used genomic replacement experiments. Sequences within noncoding transcripts specified their degradation pathways, and functional protein-coding transcripts could be produced in the divergent direction. To screen for mutants affecting the ratio of transcription in each direction, a bidirectional fluorescent protein reporter construct was introduced into the yeast nonessential gene deletion collection. We identified chromatin assembly as an important regulator of divergent transcription. Mutations in the CAF-I complex caused genome-wide derepression of nascent divergent noncoding transcription. In opposition to the CAF-I chromatin assembly pathway, H3K56 hyperacetylation, together with the nucleosome remodeler SWI/SNF, facilitated divergent transcription by promoting rapid nucleosome turnover. We propose that these chromatin-mediated effects control divergent transcription initiation, complementing downstream pathways linked to early termination and degradation of the noncoding RNAs.


Balancing the effects of solar radiation pressure on the orbital elements of a spacecraft using Lorentz force.
In this work, orbits of Lorentz spacecrafts and satellites are investigated under the perturbation of solar radiation pressure. An attempt is made to control the perturbation of the solar radiation pressure using the effect of Lorentz force that affects an electrically charged spacecraft. The charge per unit mass is the controlling parameter in this process. The redial, transverse and normal components of the mentioned forces are constructed. The Lagrange planetary equations for perturbations in the Keplerian orbital elements are formulated. The formula describing the charge per unit mass, as function of the physical parameter of the problem as well as the orbital elements, were derived. The effects of the combined forces are analytically and numerically studied.


Impact of climate change and population growth on a risk assessment for endocrine disruption in fish due to steroid estrogens in England and Wales.
In England and Wales, steroid estrogens: estrone, estradiol and ethinylestradiol have previously been identified as the main chemicals causing endocrine disruption in male fish. A national risk assessment is already available for intersex in fish arising from estrogens under current flow conditions. This study presents, to our knowledge, the first set of national catchment-based risk assessments for steroid estrogen under future scenarios. The river flows and temperatures were perturbed using three climate change scenarios (ranging from relatively dry to wet). The effects of demographic changes on estrogen consumption and human population served by sewage treatment works were also included. Compared to the current situation, the results indicated increased future risk:the percentage of high risk category sites, where endocrine disruption is more likely to occur, increased. These increases were mainly caused by changes in human population. This study provides regulators with valuable information to prepare for this potential increased risk.


The Impact of Diet on Bone and Fracture Risk in Diabetes.
The purpose of this review is to summarize the recently published scientific evidence on the effects of diet on diabetes and skeletal health. The impact of diet on overall health has been a growing topic of interest among researchers. An inappropriate eating habit is a relatively modified risk factor for diabetes in adults. Parallel with the significant increase in the incidence of diabetes mellitus worldwide, many studies have shown the benefits of lifestyle modifications, including diet and exercise for people with, or at risk of developing, diabetes. In the last years, accumulating evidence suggests that diabetes is a risk factor for bone fragility. As lifestyle intervention represents an effective option for diabetes management and treatment, there is potential for an effect on bone health. Healthy lifestyle is critical to prevent bone fragility. However, more studies are needed to fully understand the impact of diet and weight loss on fracture risk in diabetics.


Feasibility of shortening intravenous antibiotic therapy for bronchiectasis based on bacterial load: a proof-of-concept randomised controlled trial.
There is a lack of evidence to guide the duration of intravenous antibiotics for bronchiectasis exacerbations. The aim of this study was to assess whether it is feasible, based on bacterial load, to shorten intravenous antibiotics during exacerbations and whether 14 days of treatment is superior. We recruited participants requiring intravenous antibiotics for exacerbations. Participants were randomised into two groups: to receive antibiotics for 14 days (14-day group) or to have a shorter duration of treatment based on bacterial load (bacterial load-guided group (BLGG)). Bacterial load was checked on days 0, 7, 10, 14 and 21. If the bacterial load was <106 CFU·mL-1 on day 7 or day 10 in the BLGG, antibiotics were stopped the following day. A total of 47 participants were in the 14-day group and 43 were in the BLGG. 88% of participants in the BLGG were able to stop antibiotics by day 8 and potentially 81% of participants in the 14-day group could have stopped antibiotics at day 8. There was a nonsignificant trend for increased clinical improvement by day 21 in the 14-day group compared to the BLGG. However, overall group data showed the median (interquartile range) time to next exacerbation was 27.5 days (12.5-60 days) in the 14-day group and 60 days (18-110 days) in the in BLGG (p=0.0034). In a Cox proportional hazard model, participants in the 14-day group were more likely to experience exacerbations (HR 1.80, 95% CI 1.16-2.80, p=0.009) than those in the BLGG, and those with mild bronchiectasis were less likely to experience exacerbations than patients with more severe bronchiectasis (HR 0.359, 95% CI 0.13-0.99, p=0.048). Bacterial load-guided therapy is feasible in most exacerbations requiring intravenous antibiotics. There was a nonsignificant trend for increased clinical improvement by day 21 with 14 days of antibiotics compared with bacterial load-guided therapy but paradoxically there was a prolonged time to next exacerbation in the BLGG.


Clinical Practice Guideline: The Diagnosis and Treatment of Unipolar Depression—National Disease Management Guideline
Depression is one of the most common mental disorders worldwide. The German National Disease Management Guideline on Unipolar Depression (NDGM), (Nationale Versorgungsleitlinie, NVL), updated in 2022, contains recommendations on the diagnosis and treatment of acute and chronic depressive disorders. The update was based on the findings of a systematic review of the evidence (2013-2022) and was issued by a multidisciplinary panel after a formalized consensus process. The structure of the guideline was fundamentally revised and is now based on the phases of depression and/or its treatment, as well as on the severity of the disease. There is newly added material with recommendations on Internet- and mobile-device based treatments, esketamine, repetitive magnetic stimulation, psychosocial therapies, rehabilitation, social participation, and complex forms of care. The guideline also emphasizes better coordination of all services in the care of patients with depression. This article covers the most important changes and additions among the 156 recommendations in the guideline. More information and accompanying materials are available at www.leitlinien.de/depression. There are effective treatments for depression and a variety of supportive measures that can be applied with great benefit by primary care physicians, psychiatrists, psychotherapists, and complementary care providers. The updated guideline aims to further improve the early detection, definitive diagnosis, treatment, and interdisciplinary care of people with depression.


Complex traits, complex answers.
There are no simple answers when it comes to the genetic study of complex traits, and schizophrenia is no exception. Debate will continue over the interaction between genes and environment. But now there are new clues.


The effects of HMG-CoA reductase inhibitors on disease activity in multiple sclerosis: A systematic review and meta-analysis.
To assess whether statins (3‑hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) exert disease-modifying effects in multiple sclerosis (MS). A systematic review and meta-analysis was performed including randomized-controlled clinical trials (RCTs) on statin use in MS. A random-effects model was applied to calculate pooled estimates and odds ratios (ORs) with corresponding 95% confidence intervals (CIs), when comparing patients treated with statins alone or adjunct to disease modifying treatment (DMT) to non-statin-treated patients. We identified 7 RCTs including 789 patients with relapsing-remitting MS (RRMS), all of whom received additional DMT with IFN-β. Single identified RCTs in secondary-progressive MS (SPMS), clinically isolated syndrome (CIS) and optic neuritis (ON) were not meta-analyzed. In RRMS, add-on statin use was not associated with the risk of clinical relapse (OR=1.30, 95%CI: 0.901.87) or EDSS-progression from baseline, neither appeared related to the risk of new contrast-enhancing or T2 lesions (OR=1.28, 95%CI: 0.364.58), and the risk of whole-brain volume reduction on MRI. Add-on statins to IFN-β were safe and well-tolerated. In SPMS, stand-alone simvastatin led to significantly reduced annualized rate of whole-brain volume reduction. In CIS and ON, statins were associated with reduced risk for new T2 lesions and improved visual recovery, respectively. We detected no benefit from statin treatment as add-on to IFN-β in RRMS. However, a potential beneficial effect in SPMS, CIS and ON deserves independent confirmation and further evaluation within adequately powered RCTs.


Approximation operators via TD-matroids on two sets.
Rough set theory is an extension of set theory with two additional unary set-theoretic operators known as approximation in order to extract information and knowledge. It needs the basic, or say definable, knowledge to approximate the undefinable knowledge in a knowledge space using the pair of approximation operators. Many existed approximation operators are expressed with unary form. How to mine the knowledge which is asked by binary form with rough set has received less research attention, though there are strong needs to reveal the answer for this challenging problem. There exist many information with matroid constraints since matroid provides a platform for combinatorial algorithms especially greedy algorithm. Hence, it is necessary to consider a matroidal structure on two sets no matter the two sets are the same or not. In this paper, we investigate the construction of approximation operators expressed by binary form with matroid theory, and the constructions of matroidal structure aided by a pair of approximation operators expressed by binary form.First, we provide a kind of matroidal structure-TD-matroid defined on two sets as a generalization of Whitney classical matroid.Second, we introduce this new matroidal construction to rough set and construct a pair of approximation operators expressed with binary form.Third, using the existed pair of approximation operators expressed with binary form, we build up two concrete TD-matroids.Fourth, for TD-matroid and the approximation operators expressed by binary form on two sets, we seek out their properties with aspect of posets, respectively.Through the paper, we use some biological examples to explain and test the correct of obtained results. In summary, this paper provides a new approach to research rough set theory and matroid theory on two sets, and to study on their applications each other.


Automatic determination of phylloquinone in vegetables and fruits using on-line photochemical reduction and fluorescence detection via solid phase extraction and flow injection.
A very simple, rapid and highly sensitive flow injection fluorimetric method was developed for the determination of phylloquinone. The assay was based on the on-line reduction of phylloquinone in dodecylsulfate micelles after irradiation with UV light. The micellar medium enhanced the fluorescence and stability of the reduced phylloquinone. Under optimum experimental conditions, the range of application of the technique was between 0.09 and 45.0 microg mL(-1) and the detection limit was 0.05 microg mL(-1). The sample throughput was 90 injections per hour. The reliability of the method for the routine analysis of phylloquinone in vegetables and fruits is demonstrated. Extractions were made with hexane, and an automated solid phase extraction system was used to purify the sample extracts prior to injection into the flow injection manifold.