MA-NOS radical sigmoidectomy: report of a transvaginal resection in the human.
With available laparoscopic and endoscopic instruments/technology a standard radical sigmoid resection is feasible and safe using transvaginal minilaparoscopic-assisted natural orifice surgery (MA-NOS). The intervention was a transvaginal MA-NOS sigmoidectomy in a 78-year-old woman with a sigmoid adenocarcinoma. Maintaining triangulation the surgeon positioned himself at the right side of the patient and used the transvaginal trocar for dissection and stapling of both the inferior mesenteric vessels and the upper rectum. The colonic resection was performed extracorporeally in the conventional fashion and was followed by an intra-abdominal endoscopically assisted stapled anastomosis. Advantages of minimally invasive surgery seemed to be enhanced with this hybrid laparoscopic approach. Postoperative course was uneventful. All oncological principles governing resection and management were accomplished and the pathology examination confirmed a T3N1 lesion. The patient was discharged on the fourth postoperative day. Transvaginal MA-NOS radical sigmoidectomy is a feasible and oncologically safe procedure. MA-NOS is a realistic option for avoiding the need of assisting incisions and related morbidity in the laparoscopic resection of large intra-abdominal lesions. Combined hybrid laparoscopic NOS in humans (MA-NOS) currently provides a safe and reliable way of defining future clinical applications and advantages of NOS and NOTES. Additionally, it stimulates the active development and evaluation of the underpinning technologies and instrumentation.


RKIP does not contribute to MAP kinase pathway silencing in the Merkel Cell Carcinoma cell line UISO.
The Raf kinase inhibitor protein (RKIP) has been shown to block MAP kinase pathway as well as NFkappaB signalling. By means of immunohistochemistry, we previously demonstrated that the MAP kinase pathway is virtually inactive in Merkel cell carcinoma (MCC). Similarly to MCC in situ high RKIP expression accompanies absence of ERK phosphorylation in the MCC cell line UISO suggesting that RKIP might be causative for MAP kinase pathway silencing. Applying an siRNA approach RKIP expression was knocked down in UISO cells and a possible influence on MAP kinase pathway activity was assessed by Western blot analysis using phospho-specific antibodies. Moreover, a possible effect of RKIP knock down in UISO cells on proliferation as well as chemosensitivity to cisplatin were examined applying the MTS assay. Surprisingly the absence of phosphorylation of the MAP kinases ERK1 and ERK 2 even following growth factor stimulation was not affected by the RKIP knock down indicating that RKIP is not essential for blocking the MAP kinase pathway in the MCC cell line UISO. Moreover, proliferation as well as chemosensitivity towards cisplatin were not altered upon knock down of RKIP.


What drives citations of frontier application publications?
A large body of literature exists on analysis of citation and reviews of application of efficiency frontier. However, the reviews that assessed the determinants of citation counts did not focus on frontier applications. We contribute to the literature by identifying the drivers of citations of frontier application publications on Ghana. We employed two-part mixture modelling with inverse hyperbolic sine (IHS) transformation of the second part, which was found to be more appropriate than single equation IHS transformation modelling, for our data. Use of stochastic frontier analysis or data envelopment analysis did not drive citations counts. However, quality of journals in which frontier application studies were published and accessibility of the journals to readers, drive citation counts. Authors, institutions and funders of studies on frontier applications may consider these over collaborations, in seeking growth in citation counts.


TOR on the brain.
Signaling by target of rapamycin (mTOR in mammals) has been shown to modulate lifespan in several model organisms ranging from yeast to mice. In mice, reduced mTOR signaling by chronic rapamycin treatment leads to life span extension, raising the possibility that rapamycin and its analogs may benefit the aging brain and serve as effective treatments of age-related neurodegenerative diseases. Here, we review mTOR signaling and how neurons utilize mTOR to regulate brain function, including regulation of feeding, synaptic plasticity and memory formation. Additionally, we discuss recent findings that evaluate the mechanisms by which reduced mTOR activity might benefit the aging brain in normal and pathological states. We will focus on recent studies investigating mTOR and Alzheimer's disease, Parkinson's disease, and polyglutamine expansion syndromes such as Huntington's disease.


Candida nivariensis: Identification strategy in mycological laboratories.
Candida nivariensis is a cryptic fungal species classified within the Candida glabrata complex. It was described for the first time in 2005 by the means of DNA sequencing. We report a rare case of C. nivariensis deep-seated infection occurring in a 77-year-old man hospitalized for cysto-prostatectomy. Phenotypic testing based on the direct examination and the macroscopic features of the in vitro culture initially suggested C. glabrata species, while MALDI-TOF mass spectrometry enables correct identification. The isolate was found resistant to fluconazole, like in almost 20% of the reported cases. Herein, we present our practical strategy to reliably characterize this rare cryptic species. To date, MALDI-TOF mass spectrometry-based analysis showed very good results for such a purpose.


Recent desiccation of Western Great Basin Saline Lakes: Lessons from Lake Abert, Oregon, U.S.A.
Although extremely important to migrating waterfowl and shorebirds, and highly threatened globally, most saline lakes are poorly monitored. Lake Abert in the western Great Basin, USA, is an example of this neglect. Designated a critical habitat under the Western Hemisphere Shorebird Reserve Network, the lake is at near record historic low levels and ultra-high salinities that have resulted in ecosystem collapse. Determination of the direct human effects and broader climate controls on Lake Abert illustrates the broader problem of saline lake desiccation and suggests future solutions for restoration of key habitat values. A 65-year time series of lake area was constructed from Landsat images and transformed to lake volume and salinity. "Natural" (without upstream withdrawals) conditions were calculated from climate and stream flow data, and compared to measured volume and salinity. Under natural conditions the lake would have higher volume and lower salinities because annual water withdrawals account for one-third of mean lake volume. Without withdrawals, the lake would have maintained annual mean salinities mostly within the optimal range of brine shrimp and alkali fly growth. Even during the last two years of major drought, the lake would have maintained salinities well below measured values. Change in climate alone would not produce the recent low lake volumes and high salinities that have destroyed the brine shrimp and alkali fly populations and depleted shorebird use at Lake Abert. Large scale withdrawal of water for direct human use has drastically increased the imbalance between natural runoff and evaporation during periods of drought in saline lakes worldwide but could be offset by establishing an "environmental water budget" to lay a foundation for the conservation of saline lake habitats under continued threats from development and climate change.


[Influenza in piglets, back again?].
A diagnosis of Mycoplasma hyopneumoniae infection in coughing piglets was verified using an ELISA technique by the Animal Health Service of the province of Limburg, the Netherlands.


Persistent biotic interactions of a Gondwanan conifer from Cretaceous Patagonia to modern Malesia.
Many plant genera in the tropical West Pacific are survivors from the paleo-rainforests of Gondwana. For example, the oldest fossils of the Malesian and Australasian conifer Agathis (Araucariaceae) come from the early Paleocene and possibly latest Cretaceous of Patagonia, Argentina (West Gondwana). However, it is unknown whether dependent ecological guilds or lineages of associated insects and fungi persisted on Gondwanan host plants like Agathis through time and space. We report insect-feeding and fungal damage on Patagonian Agathis fossils from four latest Cretaceous to middle Eocene floras spanning ca. 18 Myr and compare it with damage on extant Agathis. Very similar damage was found on fossil and modern Agathis, including blotch mines representing the first known Cretaceous-Paleogene boundary crossing leaf-mine association, external foliage feeding, galls, possible armored scale insect (Diaspididae) covers, and a rust fungus (Pucciniales). The similar suite of damage, unique to fossil and extant Agathis, suggests persistence of ecological guilds and possibly the component communities associated with Agathis since the late Mesozoic, implying host tracking of the genus across major plate movements that led to survival at great distances. The living associations, mostly made by still-unknown culprits, point to previously unrecognized biodiversity and evolutionary history in threatened rainforest ecosystems.


Reduction of blood pressure by indirect biofeedback.
Forty-five randomly assigned subjects served in either a relaxation control, an EMG plus thermal, or a thermal biofeedback group. All groups received the same relaxation manipulation. Experimental results demonstrated a significant drop in both diastolic and systolic blood pressure for the feedback treatment. Diastolic measures showed a somewhat greater decrease for the EMG plus thermal treatment condition. A learning effect was demonstrated both within and across the three experimental sessions. Given that the sample was normotensive, the 20% reduction in blood pressure was notable. The results support the idea that blood pressure biofeedback is not a necessary condition for reduction of arterial blood pressure.


Ten Key Observations on the Analysis of Resting-state Functional MR Imaging Data Using Independent Component Analysis.
For more than 20 years, the powerful, flexible family of independent component analysis (ICA) techniques has been used to examine spatial, temporal, and subject variation in functional magnetic resonance (fMR) imaging data. This article provides an overview of 10 key principles in the basic and advanced application of ICA to resting-state fMR imaging. ICA's core advantages include robustness to artifact; false-positives and autocorrelation; adaptability to variant study designs; agnosticism to the temporal evolution of fMR imaging signals; and ability to extract, identify, and analyze neural networks. ICA remains in the vanguard of fMRI methods development.


High-field magnetic resonance imaging of Wilson's disease.
A single case of Wilson's hepatolenticular degeneration was imaged by computed tomography and magnetic resonance (1.5 Tesla). Findings included generalized cerebral atrophy seen both on computed tomography and magnetic resonance images. T1-weighted images revealed a slight symmetric hypointensity in the lentiform nuclei and thalamus. T2-weighted images demonstrated marked symmetric hypointensity in the lentiform nuclei. These hypointensities are ascribed to the deposition of intracellular hemosiderin (and perhaps copper), which produce heterogeneous magnetic susceptibility and preferential T2-proton relaxation. Areas of increased signal activity on T2-weighted images were also seen in areas of presumed demyelination known to occur in Wilson's disease.


Occurrence and chemotaxonomical analysis of amatoxins in Lepiota spp. (Agaricales).
About 95% of fatal mushroom poisonings worldwide are caused by amatoxins and phallotoxins mostly produced by species of Amanita, Galerina, and Lepiota. The genus Lepiota is supposed to include a high number of species producing amatoxins. In this study, we investigated 16 species of Lepiota based on 48 recently collected specimens for the presence of amatoxins by liquid chromatography coupled to a diode-array detector and mass spectrometry (UHPLC-QTOF-MS/MS). By comparing the retention times, UV absorptions, and diagnostic MS fragment ions with data obtained from the benchmark species Amanita phalloides, we detected α-amanitin and γ-amanitin in Lepiota subincarnata, α-amanitin and amaninamide in Lepiota brunneoincarnata, and β-amanitin and α-amanitin in Lepiota elaiophylla. Phallotoxins have not been detected any of these species. Two possibly undescribed amatoxin derivatives were found in Lepiota boudieri and L. elaiophylla, as well as one further non-amatoxin compound in one specimen of L. cf. boudieri. These compounds might be used to differentiate L. elaiophylla from L. xanthophylla and species within the L. boudieri species complex. No amatoxins were detected in L. aspera, L. castanea, L. clypeolaria, L. cristata, L. erminea, L. felina, L. fuscovinacea, L. lilacea, L. magnispora, L. oreadiformis, L. pseudolilacea, L. sp. (SeSa 5), and L. subalba. By combining the occurrence data of amatoxins with a phylogenetic analysis, a monophyletic group of amatoxin containing species of Lepiota is evident. These chemotaxonomic results highlight the relevance of systematic relationships for the occurrence of amatoxins and expand our knowledge about the toxicity of species of Lepiota.


Effect of electrical stimulation of sciatic nerve on synaptic plasticity of spinal dorsal horn and spinal c-fos expression in neonatal, juvenile and adult rats.
To explore the response to nociceptive stimuli in spinal cord of immature rat and observe the electrical stimulation of the sciatic nerve on synaptic plasticity of the spinal dorsal horn and spinal c-fos expression in rats of different ages, MK-801 was added to the spinal cord of rats, and the resulting changes in field potential as well as c-fos expression were recorded. LTP in neonatal rats was mainly evoked by A-type nerve fibers, whereas LTP in juvenile and adult rats was mainly evoked by C-type nerve fibers. C-fos expression was significantly increased in the superficial and deep layers of the spinal dorsal horn and in the ventral horn in neonatal rats indicating that the pain signal changed with age.


Effects of elevated CO2 on plant C-N-P stoichiometry in terrestrial ecosystems: A meta-analysis.
A substantial number of experiments have so far been carried out to study the response of the C-N-P stoichiometry of terrestrial plants to the rising CO2 level of the earth. However, there is a need of systematic evaluation for assessing the impact of the elevated CO2 on plant C-N-P stoichiometry. In the present investigation, a comprehensive meta-analysis involving 386 published reports and including 4481 observations has been carried out. The goal of the research was to determine the response of plants to their C-N-P stoichiometry due to elevated levels of global atmospheric CO2. The results showed that rising CO2 altered the concentration of C (+2.19%, P < 0.05), N (-9.73%, P < 0.001) and P (-3.23%, P < 0.001) and C:N (+13.29%, P < 0.001) and N:P ratios (-7.32%, P < 0.0001). Overall, a slightly increasing trend in the C:P ratio (P > 0.05) in the plant was observed. However, plant leaf, shoot and herbaceous type of plants showed more sensitivity to rising CO2. CO2 magnitude exhibited a positive effect (P < 0.05) on C:N ratio. Additionally, "CO2 acclimation" hypothesis as proposed by the authors of the current paper was also tested in the study. Results obtained, especially, show changes of C and N concentrations and C:P ratio to an obvious down-regulation for long-term CO2 fumigation. At spatial scales, a reduction of plant N concentration was found to be higher in the southern hemisphere. The CO2 enrichment methods affected the plant C-N-P stoichiometry. Compared to FACE (free-air CO2 enrichment), OTC (open top chamber) showed larger changes of C, N, P, and N:P. The results of the present study should, therefore, become helpful to offer a better understanding towards the response of the terrestrial plant C-N-P stoichiometry to an elevated global atmospheric CO2 in the future.


Subtrochanteric fractures of the femur: update.
Because of the anatomical peculiarities of the subtrochanteric region, treatment of fractures in this region remains challenging. The undeniable evolution of implants has not been accompanied by the expected decrease in the complication rate. The aim of this study was to discuss critical points in detail, such as preoperative planning, reduction tactics and the current scientific evidence concerning treatment of subtrochanteric fractures of the femur.


Persistent embryonic veins in the arteriovenous malformations of the dura.
The basic anatomy of the arteriovenous malformations of the dura is similar to that of the internal carotid (pial) malformations, as the arterial feeders in both these lesions arise from the internal carotid artery in the embryo. The venous drainage occurs through definite channels into the major venous sinuses. Therefore, the dural and the pial malformations should be classified together. The scalp malformations have no features similar to these groups. The prominent occipital artery is not necessarily the primary feeder. Whenever a prominent occipital artery is seen, special efforts must be made to locate the primary dural feeders arising from the internal carotid artery.


A Comparative Analysis of Acyl-Homoserine Lactone Synthase Assays.
Quorum sensing is cell-to-cell communication that allows bacteria to coordinate attacks on their hosts by inducing virulent gene expression, biofilm production, and other cellular functions, including antibiotic resistance. AHL synthase enzymes synthesize N-acyl-l-homoserine lactones, commonly referred to as autoinducers, to facilitate quorum sensing in Gram-negative bacteria. Studying the synthases, however, has proven to be a difficult road. Two assays, including a radiolabeled assay and a colorimetric (DCPIP) assay are well-documented in literature to study AHL synthases. In this paper, we describe additional methods that include an HPLC-based, C-S bond cleavage and coupled assays to investigate this class of enzymes. In addition, we compare and contrast each assay for both acyl-CoA- and acyl-ACP-utilizing synthases. The expanded toolkit described in this study should facilitate mechanistic studies on quorum sensing signal synthases and expedite discovery of antivirulent compounds.


[Value of transesophageal atrial pacing in neonates with tachyarrhythmia].
To study the value of transesophageal atrial pacing (TEAP) in neonates with tachyarrhythmia. The clinical data of 26 neonates with tachyarrhythmia who underwent TEAP electrophysiological examination or cardioversion were collected. Of the 26 neonates, 15(58%) were diagnosed with atrioventricular reentrant tachycardia, 3(12%) were diagnosed with sinus tachycardia, 3(12%) were diagnosed with ventricular tachycardia, 2(8%) were diagnosed with fast/slow atrioventricular nodal reentrant tachycardia, 2(8%) were diagnosed with atrial tachycardia, and 1(4%) was diagnosed with sinus tachycardia with ventricular preexcitation. Overdrive suppression was performed for 22 neonates, among whom 18 achieved successful cardioversion, and 2 with atrial tachycardia and 2 with ventricular tachycardia failed to restore sinus rhythm. TEAP is helpful to the diagnosis of tachyarrhythmia in neonates and can bring about a high rate of cardioversion success.


Immunobiotics and the probiotic evolution.
The term 'probiotic' was coined by the food industry to describe microbes beneficial to health. Scientific criticism based on poorly characterised isolates, soft clinical targets, and an absence of a mechanistic framework limited value of this concept. Current clinical and animal model studies support a role for certain 'probiotics', activating the common mucosal system through the stimulation of gut antigen-presenting cells to both promote protection and to switch regulatory mechanisms. It is concluded that a new term is required to identify bacteria that promote health through driving mucosal immune mechanisms, compared to those with strictly local effects. The term 'immunobiotics' is suggested as appropriate to fulfil this need.


Thermal and non-thermal treatment effects on Staphylococcus aureus biofilms formed at different temperatures and maturation periods.
The objective of this study was to investigate the effect of temperature and maturation period on the resistance of Staphylococcus aureus biofilms to thermal and non-thermal treatments. First, biofilm development was compared at three different temperatures (15, 25, and 37°C) for 5 days. The cell population at 15 and 25°C remained relatively consistent approximately at 6.3 log CFU/cm2, whereas 37°C resulted in the highest cell population on day 1 (7.6 log CFU/cm2) followed by a continual decline. Then, biofilm resistance to steam and sodium hypochlorite (NaOCl) treatments was evaluated. Obtained results highlighted that biofilms had different resistance to both treatments depending on development conditions. Specifically, steam treatment of 10 s eliminated 4.1 log CFU/cm2 of the biofilm formed at 25°C for 5 days. The same treatment inactivated over 5 log population of biofilms developed in other temperature and maturation period conditions. Treatment with NaOCl reduced approximately 1 log CFU/cm2 of biofilm cells developed at 25°C for 5 days. However, inactivation was found to be over 2 log CFU/cm2 under other development conditions. An extracellular polymeric substances (EPS) quantification using 96-well plates and stainless steel coupons was conducted. In the 96-well plate experiment, it was found that the highest amount of polysaccharide was secreted at 25°C (p < 0.05), while total biomass and protein contents were greatest at 37°C (p < 0.05). No significant difference in EPS content was observed for stainless steel, but the results displayed a similar trend to the 96-well plate. In particular, biofilms developed at 25°C tended to secret the highest amount of polysaccharide, which aligned with the current literature. This finding indicated that polysaccharide was the main contribution to the enhanced resistance of S. aureus biofilms. Overall, it was shown that biofilms formed at 25°C for 5 days exhibited the greatest resistance to thermal and nonthermal treatments due to the elevated exopolysaccharide secretion. This study demonstrates that temperature and maturation period significantly affect the resistance of S. aureus biofilms to thermal and non-thermal treatments.


Firibastat: a Novel Treatment for Hypertension.
The purpose of this review is to discuss the unique mechanism of firibastat, a new antihypertension medication. Hypertension continues to be a highly prevalent public health issue. Firibastat is a novel agent developed to treat hypertension. As the first member in the class of centrally acting agents to target the brain renin angiotensin system, firibastat offers new pathways to consider and enhances the regimen of agents currently available to treat hypertension. Recent clinical trials have demonstrated effectiveness and safety in mild hypertension as well as resistant hypertension. This review introduces firibastat as a new therapeutic class of treatment for hypertension focused on the renin angiotensin system in the brain. Early studies have shown a significant reduction in blood pressure with minimal side effects particularly in patients who are difficult to treat.


Routine hematology parameters in COVID-19: A predictor of disease severity and mortality.
Our understanding of the pathophysiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still evolving and is limited for prognostication. The study was performed to predict severity and mortality based on hematology parameters in coronavirus disease (COVID-19). The study was a single-center retrospective analysis of 240 patients with COVID-19. The hematological parameters were compared between different grades of severity. The receiver operating characteristics (ROC) curve along with the Classification and Regression Trees (CART) methods were used for the analysis. The total leukocyte count, absolute neutrophil count, neutrophil-lymphocyte ratio (NLR), and neutrophil-monocyte ratio (NMR) were increasing along with an increase in severity; while the absolute lymphocyte count and lymphocyte-monocyte ratio (LMR) were decreasing (P < 0.001). For prediction of severity and mortality on admission, the NLR, NMR, and LMR were significant (P < 0.001). The NLR, NMR, and LMR had an area under the receiver operating characteristics curve (AUROC) of 0.86 (95% CI of 0.80-0.91), 0.822 (95% CI of 0.76-0.88), and 0.69 (95% CI of 0.60-0.79), respectively, for severity. While the NLR, NMR, and LMR had an AUROC value of 0.85 (95% CI of 0.79-0.92), 0.83 (95% CI of 0.77-0.89), and 0.67 (95% CI of 0.57-0.78), respectively, for mortality. With the increase in severity there was an increase in the total leukocyte count and absolute neutrophil count while the absolute lymphocyte count decreased. On admission, the cut-off value of NLR >5.2, NMR >12.1, while LMR <2.4 may predict severity and mortality in COVID-19.


Scanning electron microscopic study of prepared cavities involving enamel, dentin, and cementum.
The dental treatment needs of many elderly people involve root surface caries and class V restorations. A scanning electron microscopic examination of extracted teeth with class V cavity preparations showed that well-developed cementum margins could be produced. Most studies regard the dentinocemental junction as behaving as dentin in relation to the restorative sealing process and possible marginal leakage. This study emphasizes the importance of the inclusion of cementum in class V cavity preparation and the possibility of marginal leakage occurring, depending on the restorative material used and whether acid-etch techniques are involved. Further studies on the cementum margin should be undertaken in regard to special treatment requirements related to bonding, marginal preparation, and marginal leakage.


The ecological state of Boyuk Shor lake of Azerbaijan.
The article is devoted to the pollution problems and the identification of the main sources of pollution of Boyuk Shor lake of the Absheron Peninsula under the ever-increasing rate of industrial development and urbanization. The purpose of the research was to determine the current ecological state of Boyuk Shor lake and adjacent territories. For this purpose, in June-August 2018, 36 samples were taken for analysis from water, bottom sediments of the lake, and soils of adjacent territories. The laboratory analysis revealed a high content of total hydrocarbons, toxic metals (Cd, Co, Hg, Cu), suspended solids, and other pollutants in the lake water samples. Quantitative and qualitative indicators of the lake are presented. The number of suspended particles in water samples was found to be more than 27-250 times higher than the maximum permissible concentration, and the amount of Hg is 180-286 times, Cd is 1-3.3 times, Cu is 1.7-4.8 times, and Co is 1.5-2.4 times higher than MPC. The heavy metal pollution of the soil and the taxonomic composition of the mesofauna of the surrounding area of Boyuk Shor lake were also studied. It was found that the composition of the group of soil invertebrates is very scarce, consisting only of insects (Arthropoda) (85.7%) and mollusks (Mollusca) (14.3%). The research results showed that the long-term negative impact has led to a violation of the ecological balance of the lake; it has lost its natural qualities, has become unsuitable for the flora and fauna of the lake and the surrounding area, and needs thorough cleaning and restoration.


Avellis syndrome as presenting manifestation of ulcerative colitis.
We described a 41-year-old woman presenting with subacute onset of left hemihypesthesia, left facial palsy, dysphagia and dysgeusia. A cranial T2-weighted magnetic resonance imaging revealed bilateral inhomogeneous medullary hyperintensities. The clinical manifestations conformed to Avellis syndrome, and were linked to the diagnosis of ulcerative colitis which was proved by serological findings and pathological evidence on rectosigmoid mucosa. She recovered favorably under conservative medical treatment with complete remission over one month of follow-up. Brainstem syndromes are rarely associated with neurological complications of ulcerative colitis and can be the presenting manifestation beyond gastrointestinal symptoms.


Regulated nuclear entry of the C. elegans Pax-6 transcription factor.
It is shown that the C. elegans Pax-6 locus encodes two protein isoforms. One contains a Paired DNA binding domain as well as a homeodomain; the other consists only of the carboxy-terminal portion of the locus encoding the homeodomain. These two isoforms are expressed in a variety of postembryonic cell lineages. In one set of lineages, nuclear localization of a homeodomain-only form (MAB-18 isoform) appears to be under temporal and spatial control. Nuclear localization of MAB-18 is correlated with the genetic requirement for mab-18 and with activation of a reporter gene driven by a mab-18 promoter. Reporter gene expression is dependent on mab-18 gene activity. It is hypothesized that a positive feedback loop is activated by regulated nuclear entry.


Study on comprehensive evaluation of environmental pollution treatment effect in coal mine subsidence area: taking Xinglongzhuang mining area of Yanzhou energy as an example.
In order to explore the effective evaluation method of environmental pollution treatment effect in China's coal mine subsidence areas, based on the literature review and analysis of current situation, combined with the reality of environmental pollution treatment (EPT) in China's coal mine subsidence areas, this paper selected four categories, including a total of 21 evaluation indicators, and drew lessons from the latest research results in relevant fields to construct the spatial niche suitability model of comprehensive evaluation of environmental pollution treatment effect in coal mine subsidence area. Taking the collapse area of Xinglongzhuang coal mine of Yanzhou energy as an example, the comprehensive evaluation and application of environmental pollution treatment effect in coal mine subsidence area were studied. It is found that the environmental pollution treatment effect of the mining area has increased from moderate pollution (level III) in 2012 to mild pollution (level I) in 2020 within 9 years. The environmental pollution treatment effect has a rapid improvement relatively, but its growth rate has decreased year by year since 2016, and the environmental pollution indicator is still at a high level. Therefore, environmental pollution treatment in the subsidence area is still a long-term task of Dongtan coal mine. The research results of this paper provide an effective quantitative analysis method for the evaluation of environmental pollution treatment effect in coal mine subsidence area, which is conducive to the continuous improvement of environmental pollution treatment effect in mining area.


Exposure-Response Characterization of Tofacitinib Efficacy in Moderate to Severe Ulcerative Colitis: Results From Phase II and Phase III Induction and Maintenance Studies.
Tofacitinib is an oral small molecule JAK inhibitor for the treatment of ulcerative colitis. Relationships between plasma tofacitinib concentration and efficacy were characterized using exposure-response (E-R) models, with demographic and disease covariates evaluated as potential predictors of efficacy. Data were from phase II and III (OCTAVE Induction 1 and 2) induction studies, and a phase III maintenance study (OCTAVE Sustain). Induction studies included 1,355 patients (tofacitinib 0.5, 3, 10, or 15 mg b.i.d. or placebo). The maintenance study included 592 patients (tofacitinib 5 or 10 mg b.i.d. or placebo). E-R models, including induction patients predicted placebo-adjusted remission rates of 6.4% and 12.7% at week 8 for tofacitinib 5 and 10 mg b.i.d., respectively; corresponding rates in patients without prior tumor necrosis factor inhibitor (TNFi) failure were 12.8% and 20.4%. Estimates to achieve/maintain remission at week 52 of maintenance were 29% and 18% (tofacitinib 5 mg b.i.d.), and 41% and 26% (tofacitinib 10 mg b.i.d.), for patients in remission or not following induction, respectively. During maintenance, patients with prior TNFi failure had lower probability of remission on 5 mg b.i.d. (24.9%) than 10 mg b.i.d. (35.0%). Results indicated tofacitinib 10 mg b.i.d. was an appropriate induction dose but suggested efficacy with 5 mg b.i.d. in patients without prior TNFi failure. Tofacitinib 5 mg b.i.d. was efficacious for maintenance, although patients with prior TNFi failure might see additional benefit on 10 mg b.i.d. Per product labeling, recommended tofacitinib induction dose is 10 mg b.i.d., then maintenance at 5 mg b.i.d. For patients who lose response during maintenance, 10 mg b.i.d. may be considered, limited to the shortest duration. Clinicaltrials.gov: NCT00787202; NCT01465763; NCT01458951; and NCT01458574.


External stimuli affecting incubation behavior and prolactin secretion in the duck (Anas platyrhynchos).
The importance of general environmental, including visual and tactile, stimuli on behavior and prolactin secretion during the incubation phase of reproduction in the duck (Anas platyrhynchos) was investigated. Nest occupancy rapidly increased at the end of egg laying and marked the initiation of incubation. Two recesses from the nest each day were synchronized to dawn and dusk; the median occurrence was 0.23 hr after dawn and 1.17 hr before dusk. Mean recess length was 36.1 +/- 1.9 min at dawn and 40.5 +/- 2.1 min at dusk. Plasma prolactin concentrations during incubation, 25.8 +/- 2.3 ng/ml, decreased to baseline levels, 10.8 +/- 1.9 ng/ml, within 24 hr after nestbox removal. The withdrawal of tactile, but not visual, stimuli of the clutch during incubation by either anesthesia or denervation of the incubation patch caused significant decreases in prolactin plasma concentrations within 24 hr. Prolactin plasma concentrations decreased rapidly at the end of incubation in ducks which successfully hatched young as well as in unsuccessful incubators. Temperature manipulations of the clutch, either above or below normal, caused decreases in plasma prolactin concentrations in parallel with temperature modification.


Remote effects of cerebrovascular accidents: visual evoked potentials and electrophysiological coupling.
Performance on two electrophysiological tasks, EEG and VEP, of patients who had sustained either a right or left middle cerebral artery CVA was examined. The occurrence of a stroke disrupted electrophysiological functioning of brain regions beyond the ischemic focus of the CVA, and these remote effects persisted beyond the period of transient diaschisis. CVA reduced the electrophysiological concordance between brain regions as reflected in EEG coupling and VEP intercorrelation procedures, and the disruption was more severe if the CVA affected the right as opposed to left middle cerebral artery. Techniques for characterizing the abnormal event-related potentials of CVA subjects are reviewed, and some possible theoretical explanations of the functional communication and remote effects are offered.


TRIAD: The Translational Research Informatics and Data Management Grid.
Multi-disciplinary and multi-site biomedical research programs frequently require infrastructures capable of enabling the collection, management, analysis, and dissemination of heterogeneous, multi-dimensional, and distributed data and knowledge collections spanning organizational boundaries. We report on the design and initial deployment of an extensible biomedical informatics platform that is intended to address such requirements. A common approach to distributed data, information, and knowledge management needs in the healthcare and life science settings is the deployment and use of a service-oriented architecture (SOA). Such SOA technologies provide for strongly-typed, semantically annotated, and stateful data and analytical services that can be combined into data and knowledge integration and analysis "pipelines." Using this overall design pattern, we have implemented and evaluated an extensible SOA platform for clinical and translational science applications known as the Translational Research Informatics and Data-management grid (TRIAD). TRIAD is a derivative and extension of the caGrid middleware and has an emphasis on supporting agile "working interoperability" between data, information, and knowledge resources. Based upon initial verification and validation studies conducted in the context of a collection of driving clinical and translational research problems, we have been able to demonstrate that TRIAD achieves agile "working interoperability" between distributed data and knowledge sources. Informed by our initial verification and validation studies, we believe TRIAD provides an example instance of a lightweight and readily adoptable approach to the use of SOA technologies in the clinical and translational research setting. Furthermore, our initial use cases illustrate the importance and efficacy of enabling "working interoperability" in heterogeneous biomedical environments.


Isolation measures for prevention of infection with respiratory pathogens in cystic fibrosis: a systematic review.
Respiratory infections are the most important cause of morbidity and mortality in patients with cystic fibrosis (CF). These infections are typically caused by a limited number of respiratory pathogens, particularly Burkholderia cepacia complex (BCC) and Pseudomonas aeruginosa (PA). Since the 1980s, several outbreaks of unique strains of PA and BCC among CF patients attending the same CF care centres have been described, leading to a sharp decline in the patients' health. One of the measures adopted in CF centres to interrupt ongoing outbreaks is the separation of patients with a respiratory tract culture that is positive for PA or BCC from patients who are not infected. This type of measure has been implemented routinely in many CF centres to prevent cross-transmission of PA and BCC. The aim of this review was to determine what evidence is available to support the efficacy of isolation (or segregation) practices in preventing, delaying or reducing the risk for CF patients of acquiring PA and BCC. A systematic review of scientific literature from 1980 to 31 December 2004 was performed. Existing guidelines regarding infection control in CF were also analysed. In total, 398 relevant papers were retrieved. Only 10 well-designed studies were found that evaluated the efficacy of isolation practices in preventing the transmission of respiratory pathogens in CF care centres (one prospective controlled study, one retrospective cohort study, five 'before-after' studies and three cross-sectional studies. No systematic reviews or randomized controlled trials exist on this subject. In the absence of studies with an experimental, controlled design, the efficacy of isolation practices in preventing the transmission of respiratory pathogens in CF remains unproven. However, notwithstanding the considerable limits represented by the study designs, which were mainly retrospective, the observational studies reviewed seem to support the implementation of isolation (or segregation) measures to reduce the risk of transmission of BCC and PA in CF patients.


Preparation and synthetic applications of 2-halotryptamines: synthesis of elacomine and isoelacomine.
The preparation of 2-halotryptamines from tryptamine is described. New stereoselective intramolecular iminium ion spirocyclization methodology for the construction of spiro[pyrrolidine-3,3'-oxindoles] is outlined in synthetic studies of elacomine (1) and isoelacomine (2). [reaction: see text]


The variation in optical coherence tomography-measured macular thickness in diabetic eyes without clinical macular edema.
To determine the variation in optical coherence tomography (OCT)-measured macular thickness in diabetic eyes without clinical edema and to investigate factors that might influence variation in macular thickness. Retrospective, observational case series from a clinical practice. Review of clinical charts and longitudinal OCT measurements of a consecutive series of 56 eyes of 56 patients with diabetes but no clinical macular edema. Measured variables include OCT central subfield mean thickness (CSMT), total macular volume (TMV), and logarithm of the minimum angle of resolution (logMAR) visual acuity. Over a median follow-up of 17 months, interquartile range (IQR) (9, 23), the median variation in CSMT was 18 microns, IQR (11, 31), and the median variation in TMV was 0.09 mm(3), IQR (0.06, 0.16). Variation in CSMT did not change significantly with increasing CSMT. Absolute, but not relative, variation in TMV increased with increasing baseline values (P = .0127 and P = .1538 for absolute variation and relative variation in TMV, respectively). The variation in CSMT and TMV did not vary with follow-up time and did not vary with age, gender, race, hypertension status, glycosylated hemoglobin, or retinopathy level. Variation in CSMT and TMV in diabetic eyes without DME over intervals up to 17 months is no greater than OCT measurement variability in eyes without and with DME. A change in the OCT-measured macular thickness greater than 10% of the baseline thickness is likely to represent a true change in the macular thickness and not OCT measurement variability, diurnal variation, or variability occurring over longer time scales.


Expression and characterization of a recombinant Cry1Ac crystal protein fused with an insect-specific neurotoxin ω-ACTX-Hv1a in Bacillus thuringiensis.
In order to assess possible enhancement of biopesticide activity, the fusion gene of crystal protein gene cry1Ac with the insect-specific neurotoxin ω-ACTX-Hv1a gene and egfp was expressed in Bacillus thuringiensis acrystalliferous strain Cry-B under the control of the native gene expression system. The fusion recombinant Cry-B(1Ac-ACTX-EGFP) generally produced two or three small crystal-like inclusion bodies in each cell and the GFP signal could be clearly observed. A 166 kDa full-length fusion protein was identified by immunoblot analysis. Virulence of the fusion inclusions was at least fivefold higher toward larvae of Spodoptera exigua. These results demonstrated that a foreign protein could be expressed and accumulate as parasporal inclusions in B. thuringiensis by C-terminal fusion with the native endotoxin while retaining partial insecticidal activity.


Real-time segmentation and tracking of excised corneal contour by deep neural networks for DALK surgical navigation.
Corneal disease is one of the main causes of blindness for humans globally nowadays, and deep anterior lamellar keratoplasty (DALK) is a widely applied technique for corneal transplantation. However, the position of stitch points highly influences the success rate of such surgery, which would require accurate control and manipulation of surgical instruments. In this paper, we present a deep learning framework for augmented reality (AR) based surgery navigation to guide the suturing in DALK. It can robustly track the excised corneal contour by semantic segmentation and the reconstruction of occlusion. We propose a novel optical flow inpainting network to recover the missing motion caused by occlusion. The occluded regions are detected by weakly supervised segmentation of surgical instruments and reconstructed by key frame warping along the completed optical flow. Then we introduce two types of loss function to adapt the inpainting network in the optical flow space. Our techniques are tested and evaluated by a number of real surgery videos from Shandong Eye Hospital in China. We compare our approaches with other typical methods in the corneal contour segmentation, optical flow inpainting and occlusion regions reconstruction. The tracking accuracy reachs 99.2% in average and PSNR reaches 25.52 for the reconstruction of the occluded frames. From the experimental evaluations and user study, both the qualitative and quantitative results indicate that our techniques can achieve accurate detection and tracking of corneal contour under complex disturbance in real-time surgical scenes. Our prototype AR navigation system would be highly useful in clinical practice.


ATF4-Induced Metabolic Reprograming Is a Synthetic Vulnerability of the p62-Deficient Tumor Stroma.
Tumors undergo nutrient stress and need to reprogram their metabolism to survive. The stroma may play a critical role in this process by providing nutrients to support the epithelial compartment of the tumor. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation by the direct control of ATF4 stability through its p62-mediated polyubiquitination. ATF4 upregulation by p62 deficiency in the stroma activates glucose carbon flux through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine generation as a source of nitrogen for stroma and tumor epithelial proliferation. Thus, p62 directly targets nuclear transcription factors to control metabolic reprogramming in the microenvironment and repress tumorigenesis, and identifies ATF4 as a synthetic vulnerability in p62-deficient tumor stroma.


A comprehensive review on microbial lipid production from wastes: research updates and tendencies.
Microbial lipids have recently attracted attention as an intriguing alternative for the biodiesel and oleochemical industries to achieve sustainable energy generation. However, large-scale lipid production remains limited due to the high processing costs. As multiple variables affect lipid synthesis, an up-to-date overview that will benefit researchers studying microbial lipids is necessary. In this review, the most studied keywords from bibliometric studies are first reviewed. Based on the results, the hot topics in the field were identified to be associated with microbiology studies that aim to enhance lipid synthesis and reduce production costs, focusing on the biological and metabolic engineering involved. The research updates and tendencies of microbial lipids were then analyzed in depth. In particular, feedstock and associated microbes, as well as feedstock and corresponding products, were analyzed in detail. Strategies for lipid biomass enhancement were also discussed, including feedstock adoption, value-added product synthesis, selection of oleaginous microbes, cultivation mode optimization, and metabolic engineering strategies. Finally, the environmental implications of microbial lipid production and possible research directions were presented.


On rat alpha-fetoprotein as a fatty acid carrier. Influence of the structure of fatty acids.
Fatty acids interfere with rat alpha-fetoprotein-estrogen interaction. We present here a quantitative study of the association constants for the binding to alpha-fetoprotein of different fatty acids. It can be concluded that fatty acids bind more strongly if the number of carbon atoms increases with the number of double bonds. The maximum binding ability occurred with the C20 fatty acids having three or four double bonds. As these fatty acids are the precursors in the synthesis of prostaglandins, we tested some compounds in this series and showed that prostaglandins presented no particular affinity for rat alpha-fetoprotein.


Large granular lymphocytic proliferation-associated cyclic thrombocytopenia.
Cyclic thrombocytopenia is a rare condition characterized by regular fluctuations in the platelet count, resulting in bleeding at the time of platelet count nadir. We evaluated a male patient whose platelet count cycled between <10x10(9)/L and a maximum of >1300x10(9)/L over a median of every 42 days (range, 28-57 days). Antiplatelet antibodies were present at highest titer just prior to platelet nadirs. A pathologic expansion of CD3+CD57+ large granular lymphocytes (LGLs) along with a clonal rearrangement of the T-cell receptor (TCR) gamma gene in circulating T cells was detected. LGLs decreased in response to treatment with cyclosporine-A (CsA), but the cycling of the platelet count continued. This is the first report of cyclic thrombocytopenia associated with a T-LGL lymphoproliferative disorder.


LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions.
LEDGINs are novel allosteric HIV integrase (IN) inhibitors that target the lens epithelium-derived growth factor (LEDGF)/p75 binding pocket of IN. They block HIV-1 integration by abrogating the interaction between LEDGF/p75 and IN as well as by allosterically inhibiting the catalytic activity of IN. Here we demonstrate that LEDGINs reduce the replication capacity of HIV particles produced in their presence. We systematically studied the molecular basis of this late effect of LEDGINs and demonstrate that HIV virions produced in their presence display a severe replication defect. Both the late effect and the previously described, early effect on integration contribute to LEDGIN antiviral activity as shown by time-of-addition, qPCR and infectivity assays. The late effect phenotype requires binding of LEDGINs to integrase without influencing proteolytic cleavage or production of viral particles. LEDGINs augment IN multimerization during virion assembly or in the released viral particles and severely hamper the infectivity of progeny virions. About 70% of the particles produced in LEDGIN-treated cells do not form a core or display aberrant empty cores with a mislocalized electron-dense ribonucleoprotein. The LEDGIN-treated virus displays defective reverse transcription and nuclear import steps in the target cells. The LEDGIN effect is possibly exerted at the level of the Pol precursor polyprotein. Our results suggest that LEDGINs modulate IN multimerization in progeny virions and impair the formation of regular cores during the maturation step, resulting in a decreased infectivity of the viral particles in the target cells. LEDGINs thus profile as unique antivirals with combined early (integration) and late (IN assembly) effects on the HIV replication cycle.


Intraoperative liver ultrasound still affects surgical strategy for patients with colorectal metastases in the modern era.
The present study was designed to evaluate the role of intraoperative ultrasound (IOUS) in intrahepatic staging and the impact on surgical strategy for patients with colorectal liver metastases (CRLM). The study included 515 patients who had undergone liver resection for CRLM at two tertiary care referral centers. Data from a prospectively collected database were retrospectively analysed. Early intrahepatic recurrence was assessed at 3 and 6 months after resection and was considered as residual disease undetected by IOUS. Performance of imaging modalities was compared by analysis of studies on individual patients. A total of 1,370 liver metastases were detected preoperatively with a median of 3 imaging modalities. MRI and PET were performed in 51 and 42 % of the patients, respectively. Median number of days between last imaging and surgery was 18. Contrast-enhanced IOUS was performed in 136 patients (26.4 %). Intraoperatively, 293 new nodules were found in 132 patients: on histology 280 were CRLM (17.6 %). Surgical strategy was changed in 140 patients (27.2 %). On multivariate analysis synchronous and bilobar metastases ≥ 3 in number, BMI ≥ 30, and time between last imaging and surgery longer than 18 days resulted in predictive factors indicating new nodules detected by IOUS. Early intrahepatic recurrences were 3.7 and 7.9 % at 3 and 6 months. Performance of CT, MRI, FDG-PET, and intraoperative staging was compared: sensitivity was 63.6, 68.8, 53.6, and 92 % and specificity was 91, 92.3, 95.8, and 97.8 %, respectively The use of IOUS continues to be mandatory for correct staging of patients with CRLM undergoing liver resection.


Automatic representation of a visual stimulus relative to a background in the right precuneus.
Our brains represent the position of a visual stimulus egocentrically, in either retinal or craniotopic coordinates. In addition, recent behavioral studies have shown that the stimulus position is automatically represented allocentrically relative to a large frame in the background. Here, we investigated neural correlates of the 'background coordinate' using an fMRI adaptation technique. A red dot was presented at different locations on a screen, in combination with a rectangular frame that was also presented at different locations, while the participants looked at a fixation cross. When the red dot was presented repeatedly at the same location relative to the rectangular frame, the fMRI signals significantly decreased in the right precuneus. No adaptation was observed after repeated presentations relative to a small, but salient, landmark. These results suggest that the background coordinate is implemented in the right precuneus.


Apoptosis and its modulation during B lymphopoiesis in mouse bone marrow.
Studies in normal, gene-deleted, transgenic and mutant mice have examined apoptotic cell death and its role in B lymphopoiesis in bone marrow. Apoptotic activity has been quantitated among phenotypically defined populations of precursor B cells using flow cytometry of apoptotic cells and an established model of B-cell development. In normal mice, the frequencies of apoptotic cells (apoptotic index) and accumulation of apoptotic cells during short-term culture (apoptotic rate) are maximal at around the pro/pre-B-cell transition and among immature B lymphocytes. The brief period between onset of apoptosis and clearance by macrophages (apoptotic transit time) is similar for most precursor B-cells. Apoptosis-modulating factors produce substantial changes in apoptotic activity among pro-B and pre-B cells, associated with altered expression of bcl-2 family proteins. Pro-B-cell apoptosis, normally extensive, is markedly suppressed in the absence of p53. Complete pro-B-cell abortion in RAG-2 deletion provides an assay for apoptotic fractions in other experimental systems. Pre-B-cell apoptosis is enhanced by deficiencies of interleukin (IL)-7, Abl protooncogene or colony-stimulating factor (CSF)-1 and overexpression of heat-stable antigen, and is inhibited by IL-7 and p190bcr/abl transgenes. CSF-1 and melatonin administration inhibit pre-B-cell apoptosis, probably via stromal cell stimulation. Such apoptotic modulation has implications for B-cell homeostasis, quality control, immunodeficiency and neoplasia.


A1- and A2-purinoceptors in the guinea-pig uterus.
1. Radioligand binding and functional studies were undertaken to investigate the P1-purinoceptors present in the separated myometrial layers and the endometrium of the guinea-pig uterus. 2. In preparations of endometrium-denuded circular myometrium, the A2-selective agonists (2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido-adeno sin e (CGS 21680, 100 mumol/L) and N-ethylcarboxamido adenosine (NECA, 1-10 mumol/L) inhibited contractile responses to phenylephrine. In preparations of endometrium-intact circular myometrium, NECA (10 mumol/L) enhanced responses to phenylephrine. NECA did not modulate the spontaneous contractions of longitudinal myometrium. 3. Homogenate binding studies with circular myometrium, longitudinal myometrium and endometrium revealed saturable high affinity [3H]-NECA binding sites. The mean maximal densities of binding sites (Bmax) were 2.08, 14.7 and 15.5 fmol/mg protein, and pKD (neg. log dissociation constant) values were 9.82, 9.19 and 7.44, respectively. 4. (R-) and (S-)-N6-(2-phenylisopropyl)adenosine (R- and S-PIA) both competed for two [3H]-NECA binding sites in preparations of circular myometrium. CGS 21680 competed for two [3H]-NECA binding sites in preparations of endometrium and longitudinal myometrium. All other agonist competition was for one site only. The rank orders of potency of high affinity binding were S-PIA > or =R-PIA > or = CGS 21680 (circular myometrium), R-PIA > CGS 21680 > or = S-PIA (longitudinal myometrium) and CGS 21680 > > S-PIA > or = R-PIA (endometrium). 5. In preparations of circular myometrium, longitudinal myometrium and endometrium the selective A1-purinoceptor antagonist, 1,3-dipropyl-8-(2-amino-4-chloro)-phenylxanthine (PACPX), competed for two [3H]-NECA binding sites, the non-selective antagonist 3,7-dimethyl-1-propargylxanthine (DMPX), competed for one site only.(ABSTRACT TRUNCATED AT 250 WORDS)


Metabolomics of head and neck cancer in biofluids: an integrative systematic review.
Head and neck cancer (HNC) is the fifth most common cancer globally. Diagnosis at early stages are critical to reduce mortality and improve functional and esthetic outcomes associated with HNC. Metabolomics is a promising approach for discovery of biomarkers and metabolic pathways for risk assessment and early detection of HNC. To summarize and consolidate the available evidence on metabolomics and HNC in plasma/serum, saliva, and urine. A systematic search of experimental research was executed using PubMed and Web of Science. Available data on areas under the curve was extracted. Metabolic pathway enrichment analysis were performed to identify metabolic pathways altered in HNC. Fifty-four studies were eligible for data extraction (33 performed in plasma/serum, 15 in saliva and 6 in urine). Metabolites with high discriminatory performance for detection of HNC included single metabolites and combination panels of several lysoPCs, pyroglutamate, glutamic acid, glucose, tartronic acid, arachidonic acid, norvaline, linoleic acid, propionate, acetone, acetate, choline, glutamate and others. The glucose-alanine cycle and the urea cycle were the most altered pathways in HNC, among other pathways (i.e. gluconeogenesis, glycine and serine metabolism, alanine metabolism, etc.). Specific metabolites that can potentially serve as complementary less- or non-invasive biomarkers, as well as metabolic pathways integrating the data from the available studies, are presented. The present work highlights utility of metabolite-based biomarkers for risk assessment, early detection, and prognostication of HNC, as well as facilitates incorporation of available metabolomics studies into multi-omics data integration and big data analytics for personalized health.


Surface-enhanced Raman and fluorescence joint analysis of soil humic acids.
Surface-enhanced Raman scattering (SERS) and surface-enhanced fluorescence (SEF) combined emissions were used in this work to the analysis of humic acids (HA). This study examined HA structure at different pH and HA concentrations and assessed the structural differences taking place in HA as a result of various amendment trials. Raman and fluorescence emissions behave in opposite ways due to the effect of the metal surface on the aromatic groups responsible for these emissions. The information afforded by these techniques can be successfully employed in the structural and dynamic analysis of these important macromolecules. The surface-enhanced emission (SEE) spectra, that is the sum of the Raman and the fluorescence emissions, were acquired by using both macro- and micro-experimental configurations in order to apply imaging and confocal Raman and fluorescence spectroscopy techniques on the analysis of HA.


Case studies of the impact of understanding bioavailability: arsenic.
Arsenic is a metalloid that occurs in virtually all environmental matrices. The inorganic forms of arsenic occurring as As(III) and As(V) are toxic and may pose a health risk to human population. Although exposure can occur in various settings, ingestion of contaminated ground water is more widespread. The toxicity of arsenic is dependent to a large extent on its bioavailability or its ability to be liberated from various matrices and be internalized in the target organs of the host. This article reviews the main health impacts of arsenic and the methodologies for measuring bioavailability, and interprets the bioavailability studies conducted so far. It is argued that, because the bioavailability of arsenic varies with environmental matrices, a single default value is not recommended for risk determination and management in all environmental settings. Precise site-specific knowledge of bioavailability of arsenic is critical for both setting the maximum contaminant levels and directing site-specific cleanup operation in a cost-effective manner. Finally, molecular geochemical knowledge is combined with epidemiological observation to propose a model for disease in which the bioavailability of arsenic plays a determinant role together with other host and environmental factors.


Accurate quantification of T-cells expressing PD-1 in patients on anti-PD-1 immunotherapy.
Increasing numbers of trials employing anti-PD-1 immunotherapy emphasize the requirement for predictive biomarkers of clinical response. Many studies examine the cell surface expression of PD-1 and other key regulators of T-cell activation and inhibition. Here, we compared common commercially available anti-PD-1 diagnostic antibodies and tested whether they can bind the PD-1 receptor in the presence of the therapeutic antagonists pembrolizumab and nivolumab. We observed that currently no antibodies are available that can reliably stain all PD-1 receptors on T-cells from patients treated with anti-PD-1 antibodies. Furthermore, none of the diagnostic antibodies detected the entire population of PD-1+ T-cells relative to indirect staining using the therapeutic antibodies themselves. To overcome this problem, here we present a reliable method for quantifying PD-1 expression on immune cells from treated patients which can be included in any conventional flow or mass cytometry antibody panel used for patient monitoring.


Nurse practitioner students as an essential workforce: The lessons of coronavirus disease 2019.
The coronavirus disease 2019 (COVID-19) disrupted the education and clinical training of nursing students. Clinical sites shut out students over low equipment supplies, physical distancing requirements, and redeployment of staff. The purpose of this paper is to highlight a progressive solution to engage nurse practitioner students as part of the COVID-19 response given the disruption of their traditional clinical training environments so that student could continue to matriculate and graduate in a timely manner. Nurse practitioner students swiftly responded and were deemed an essential part of the nursing workforce. Policy implications for advanced nursing practice and education for telehealth and simulation research moving forward is also provided.


Review of behaviour of oil in freezing environments.
The current knowledge of the physical fate and behaviour of crude oil and petroleum products spilled in Arctic situations is reviewed. The fate and final deposition of oil in marine conditions is presented as based on the extant literature. Spreading models were evaluated for oil on ice, under ice, in snow, in brash ice, and between blocks of ice. Models of oil transport under sheet and broken ice were considered, both for sea and river conditions. The ability of ice sheets to trap oil is discussed in relation to oil storage capacity. The effects of oil on a growing ice sheet were examined, both in terms of ice formation and the thermal effects of oil inclusions in ice. The migration of oil through ice was reviewed, focussing primarily on the movement through brine channels. The effects of oil on the surface of ice were considered, with emphasis on the effects of surface pools on ice melt. Similar consideration was given to the effects of oil on snow on the surface of ice. The few quantitative studies of oil in open and dynamic ice conditions are reviewed. Observations of intentional small-scale spills in leads and ice fields are reviewed and compared with observations from real spills. The conditions under which "oil pumping" from leads occurs were quantified. The most common ultimate fate of oil in an ice field is to be released onto the water surface.


[Glutathione-related enzymes activity during vitrectomy. Effect of BSS Plus(R) in retinal tissue].
To determine changes in the retinal activity of two enzymes related to the glutathione metabolism (Glutathione synthetase -GSHS- and glutathione reductase -GSSGR-) after vitrectomy using BSS Plus(R). Forty-five pigmented rabbits were distributed in 6 groups: group I (GSHS control in retinal tissue); Group II (analysis of GSHS at 3 hours post-vitrectomy); Group III (determination of GSHS at 48 hours after vitrectomy); Group IV (GSSGR control in retinal tissue); Group V (measurement of GSSGR at 3 hours post-surgery) and Group VI (study of GSSGR at 48 hours post-vitrectomy). Statistical analysis was done by a parametric test (ANOVA of single factor) (p<0.05). The activity of these enzymes was: Group I (n=5, basal GSHS). 2785,63 D.S. 419,51 U/g; Group II (n=4, GSHS at 3 hours). 6053,50 D.S. 2788,84 U/g; Group III (n=4, GSHS at 48 hours). 7424,30 D.S. 997,47 U/g; Group IV (n=10, basal GSSGR). 150,86 D.S. 24,40 mU/mL; Group V (n=7, GSSGR at 3 hours). 212,03 D.S. 53,30 mU/mL; Group VI (n=8, GSSGR at 48 hours). 210,84 D.S. 46,03 mU/mL. At retinal tissue, BSS Plus(R) intraocular irrigating solution increases GSHS activity without modifications of GSSGR levels. It seems to be related to the <<novo>> synthesis of glutathione.


Fibroblasts create compartments in the extracellular space where collagen polymerizes into fibrils and fibrils associate into bundles.
Morphogenesis in the animal kingdom is closely coupled with the intracellular synthesis and the extracellular deposition of collagen. These morphogenetically important events involve multiple steps which begin in compartments inside the cell and continue in compartments outside the cell. The movement of matrix components from the intracellular compartments to the extracellular compartments is a functional continuum. Studies of embryonic chick tendon and cornea fibroblasts with the high-voltage (1000 kV) transmission electron microscope have provided the beginnings of an understanding of how this functional continuum is related to the structural compartments which the cells create. This series of compartments, both inside and outside the cell, is involved in collagen fibrillogenesis, collagen fibril bundle formation, and tissue morphogenesis.


Placental ultrasonographic biochemical and histochemical studies in human fetuses affected with Niemann-Pick disease type A.
Placental ultrasonographic, bio- and histochemical studies were performed on four unrelated fetuses affected with Niemann-Pick disease Type A, following prostaglandin-induced abortion at about the 19th week of gestation. An accumulation of sphingomyelin in the placentae of affected fetuses indicates the essential role of the enzyme sphingomyelinase, even during the early stages of gestation. A fair correlation between histochemical localization of sphingomyelin in the placentae and ultrasonographic findings was found, indicating the value of ultrasonic echo wave information in the diagnosis of metabolic disorders.


Differential effects of CpG-DNA in Toll-like receptor-2/-4/-9 tolerance and cross-tolerance.
Lipopolysaccharide (LPS) tolerance is a state of refractoriness towards a second stimulation by LPS after a preceding stimulation. LPS is recognized by Toll-like receptor-4 (TLR-4), which belongs to a group of pattern recognition receptors mediating activation of innate immunity by microbial components. To date, it is not known in detail to what extent other TLR-dependent stimuli also induce tolerance and whether preceding and challenging stimuli are interchangeable. We have examined tolerance induction in detail for lipoteichoic acid (LTA), LPS and CpG-DNA, which are recognized by TLR-2, -4 and -9, respectively. In RAW264.7 macrophages, all three stimuli induced tolerance towards a subsequent challenge with the same stimulus used for priming, as well as cross-tolerance towards subsequent challenge with other stimuli signalling via different TLRs. However, whereas LPS/LTA cross-tolerance was also functional in an in vivo model of galactosamine (GalN)-primed liver damage, pretreatment with CpG only protected against GalN/CpG challenge and failed to induce cross-tolerance for LPS and LTA. CpG-DNA pretreatment even enhanced tumour necrosis factor (TNF)-alpha production and liver damage upon subsequent challenge with LPS or LTA. Stimulation with CpG-DNA resulted in a peculiar sensitization for interferon (IFN)-gamma secretion. The data indicate that, in contrast to in vitro macrophage desensitization, the in vivo consequences of repeated TLR stimulation greatly differ amongst different TLR ligands.


Metabolite-disease interaction prediction based on logistic matrix factorization and local neighborhood constraints.
Increasing evidence indicates that metabolites are closely related to human diseases. Identifying disease-related metabolites is especially important for the diagnosis and treatment of disease. Previous works have mainly focused on the global topological information of metabolite and disease similarity networks. However, the local tiny structure of metabolites and diseases may have been ignored, leading to insufficiency and inaccuracy in the latent metabolite-disease interaction mining. To solve the aforementioned problem, we propose a novel metabolite-disease interaction prediction method with logical matrix factorization and local nearest neighbor constraints (LMFLNC). First, the algorithm constructs metabolite-metabolite and disease-disease similarity networks by integrating multi-source heterogeneous microbiome data. Then, the local spectral matrices based on these two networks are established and used as the input of the model, together with the known metabolite-disease interaction network. Finally, the probability of metabolite-disease interaction is calculated according to the learned latent representations of metabolites and diseases. Extensive experiments on the metabolite-disease interaction data were conducted. The results show that the proposed LMFLNC method outperformed the second-best algorithm by 5.28 and 5.61% in the AUPR and F1, respectively. The LMFLNC method also exhibited several potential metabolite-disease interactions, such as "Cortisol" (HMDB0000063), relating to "21-Hydroxylase deficiency," and "3-Hydroxybutyric acid" (HMDB0000011) and "Acetoacetic acid" (HMDB0000060), both relating to "3-Hydroxy-3-methylglutaryl-CoA lyase deficiency." The proposed LMFLNC method can well preserve the geometrical structure of original data and can thus effectively predict the underlying associations between metabolites and diseases. The experimental results show its effectiveness in metabolite-disease interaction prediction.


Coloenteric fistulas.
A ten-year experience with 12 cases of spontaneously occurring, preoperatively diagnosed coloenteric fistulas is described. Accurate diagnosis can be achieved most often by barium-enema examination. One-stage resection with primary anastomosis, to restore gastronintestinal continuity, is highly successful, and should be the procedure of choice.


Primary cell cultures for the personalized therapy in aggressive thyroid cancer of follicular origin.
Thyroid cancer (TC) is the most prevalent endocrine malignancy. More than 90 % of TC is represented by differentiated TC (DTC) arising from the follicular thyroid cells. DTC includes papillary TC (PTC), follicular TC (FTC), and Hürthle cell TC. Anaplastic TC (ATC) accounts for 1% of TC, and it represents 15-40 % of TC death. Current treatment strategies are not completely effective against aggressive DTC or ATC, and mortality is one of the most important challenges. Recently, progresses have been obtained in the understanding of the molecular/genetic basis of TC progression, and new drugs have been introduced [i.e. tyrosine kinase inhibitors (TKIs)], able to block the oncogenic or signaling kinases, associated with cellular growth. Thyroid cell lines, obtained from tumoral cells and chosen for high proliferation in vitro, have been used as preclinical models. Actually, these cells lose the characteristic features of the primary tumor, because they adapt to in vitro growth conditions. For these reasons, the use of these cell lines has important limitations, and more recently human primary cell cultures have been established as monolayer cultures, and investigated for their biological behavior. Moreover, in the past, primary TC cells could be collected only through surgical biopsies, while recently human primary cell cultures can be established also from samples of fine-needle aspiration citology from aggressive dedifferentiated DTC or ATC. Testing in vitro different TKIs in each patient can help to develop new personalized treatments, without using ineffective drugs. In conclusion, personalized medicine and precise oncology, which consider both patients and their disease features, represent the future of the treatment approach, and further progress is needed in this direction.


Time Trends of the Outcomes and Treatment Options for Disseminated Intravascular Coagulation: A Nationwide Observational Study in Japan.
Existing evidence on the mortality time trends of patients with disseminated intravascular coagulation (DIC) is limited, and whether the mortality trend or quality of care of DIC patients has improved remains unknown. This study aimed to investigate the temporal trend in mortality, patient outcomes, and treatment preferences of several anticoagulants in Japan. This retrospective observational study used the Japanese Diagnosis Procedure Combination inpatient database, which contains data from more than 1200 acute-care hospitals in Japan. We identified all adult patients that were diagnosed with DIC from July 2010 to March 2018 and sorted them into one of five predefined underlying conditions: sepsis, solid cancer, leukemia, trauma, or obstetric. The data collected as general outcomes were the 28-day mortality and major bleeding events. We also evaluated anticoagulant use for DIC treatment. A total of 325,327 DIC patients were included in this study. Regarding the baseline characteristics, an increase in median age, worsened comorbid conditions, and higher illness severity were observed over time. The underlying conditions for DIC were largely unchanged. Over the study period, the 28-day mortality for overall DIC patients decreased from 41.8% (95% CI 41.2%-42.3%) to 36.1% (95% CI 35.6%-36.6%), which is a 14% decrease over the 8-year period (P trend < 0.001). The downward trend in mortality was more evident in patients with sepsis and leukemia (15% and 14% decreases, respectively), whereas no clinically meaningful change in mortality occurred in trauma and obstetrics patients. Over time, major bleeding events modestly increased, and the length of hospital stay decreased. The temporal trend in the treatment preferences of anticoagulants for DIC patients clearly changed over time. The overall 28-day mortality for DIC patients clearly decreased from 2010 to 2017. The downward trend in mortality might have resulted from the advances made in the fundamental treatment of underlying diseases and from the changes in anti-DIC strategies.


Cichoń's diagram and localisation cardinals.
We reimplement the creature forcing construction used by Fischer et al. (Arch Math Log 56(7-8):1045-1103, 2017. 10.1007/S00153-017-0553-8. arXiv:1402.0367 [math.LO]) to separate Cichoń's diagram into five cardinals as a countable support product. Using the fact that it is of countable support, we augment our construction by adding uncountably many additional cardinal characteristics, sometimes referred to as localisation cardinals.


Gadolinium-modulated 19F signals from perfluorocarbon nanoparticles as a new strategy for molecular imaging.
Recent advances in the design of fluorinated nanoparticles for molecular magnetic resonance imaging (MRI) have enabled specific detection of (19)F nuclei, providing unique and quantifiable spectral signatures. However, a pressing need for signal enhancement exists because the total (19)F in imaging voxels is often limited. By directly incorporating a relaxation agent, gadolinium (Gd), into the lipid monolayer that surrounds the perfluorocarbon (PFC), a marked augmentation of the (19)F signal from 200-nm nanoparticles was achieved. This design increases the magnetic relaxation rate of the (19)F nuclei fourfold at 1.5 T and effects a 125% increase in signal--an effect that is maintained when they are targeted to human plasma clots. By varying the surface concentration of Gd, the relaxation effect can be quantitatively modulated to tailor particle properties. This novel strategy dramatically improves the sensitivity and range of (19)F MRI/MRS and forms the basis for designing contrast agents capable of sensing their surface chemistry.


The effects of photoperiod on androgen-induced reproductive behavior in male ring doves, Streptopelia risoria.
The effect of photoperiod on reproductive behavior in male ring doves (Streptopelia risoria) was studied in androgen-injected castrates maintained under long (16L:8D) or short (86:16D) photoperiods. Behavioral recordings were made over a 2-week period during which each male was paired with a female for 6.5 hr/day. There was some indication that males held on long days display higher levels of courtship activity during the initial period following pairing, but the evidence was not conclusive. Day length had no effect upon copulatory behavior. Long-day males exhibited consistently higher levels of nest building than short-day males, indicating that photoperiod affects building through some mechanism other than changes in endogenous androgen levels.


Oxidation of adrenaline and noradrenaline by solved molecular oxygen in a FIA assembly.
A simple and effective procedure is proposed for the study and simultaneous determination of adrenaline and noradrenaline. The fluorimetric determination of both substances is performed in a flow injection assembly and by oxidation of both drugs with the solved molecular oxygen. The influence of different parameters is empirically studied and the interpretation of the reaction mechanism is also added. The determination of adrenaline is monitored at 450 nm and the outputs at 520 nm correspond to the adrenaline and noradrenaline global amount; for both lectures lambda(exc) 329 nm. The influence of temperature is relevant and analytical determination occurred at 55 degrees C by immersing the sample loop in a water bath. The linear range for adrenaline is over 0.5-20 microg ml(-1), limit of detection for both compounds is 0.2 microg ml(-1): the influence of foreign compounds as potential interferents is also tested; and, finally the procedure is applied to determination of both chatecolamines in synthetic samples.


Outcomes of drug-resistant urinary retention in patients in the early stage of stroke.
To investigate the prognosis of patients with stroke and urinary retention resistant to alpha blockers and cholinergic agents. Post-void residual urine volume (PVR) was measured in 33 patients with stroke (14 men and 19 women) who were admitted to the department of rehabilitation medicine of our hospital within 30 days after stroke onset. An alpha-blocker and cholinergic agent were administered to patients with PVR >100 mL. If urinary retention had not improved despite the maximum drug doses, the patient was diagnosed with drug-resistant urinary retention. We retrospectively reviewed patient's charts, including PVR at discharge and prognostic factors for PVR. Ten patients (30.3%) could not void or their PVR was >400 mL at discharge (45.7±15.4 days after onset) after rehabilitation. Twelve patients (36.4%) could void, and their PVR was 100-400 mL. PVR was consistently <100 mL in 11 patients (33.3%). These measurements correlated with the Korean version of the Modified Barthel Index score, Functional Ambulation Category, and the presence of a communication disorder. The results show that 22 patients (66.7%) had incomplete bladder emptying or required catheterization at discharge. Outcomes correlated with functional status, walking ability, and the presence of a communication disorder. Patients with urinary retention and poor general condition require close observation to prevent complications of urinary retention.


Evaluation of breast sentinel lymph node coverage by standard radiation therapy fields.
Biopsy of the breast sentinel lymph node (SLN) is now a standard staging procedure for early-stage invasive breast cancer. The anatomic location of the breast SLN and its relationship to standard radiation fields has not been described. A retrospective review of radiotherapy treatment planning data sets was performed in patients with breast cancer who had undergone SLN biopsy, and those with a surgical clip at the SLN biopsy site were identified. The location of the clip was evaluated relative to vertebral body level on an anterior-posterior digitally reconstructed radiograph, treated whole-breast tangential radiation fields, and standard axillary fields in 106 data sets meeting these criteria. The breast SLN varied in vertebral body level position, ranging from T2 to T7 but most commonly opposite T4. The SLN clip was located below the base of the clavicle in 90%, and hence would be excluded from standard axillary radiotherapy fields where the inferior border is placed at this level. The clip was within the irradiated whole-breast tangent fields in 78%, beneath the superior-posterior corner multileaf collimators in 12%, and outside the tangent field borders in 10%. Standard axillary fields do not encompass the lymph nodes at highest risk of containing tumor in breast cancer patients. Elimination of the superior-posterior corner MLCs from the tangent field design would result in inclusion of the breast SLN in 90% of patients treated with standard whole-breast irradiation.


Robot-assisted esophageal surgery using the da Vinci® Xi system: operative technique and initial experiences.
In this review, we would like to illustrate our experience with the da Vinci® Xi system in case of esophageal surgery. Since the da Vinci® Xi system was installed in our department, it has resulted in a great improvement in cases of minimally invasive surgery. After the successful establishment in the field of colorectal surgery, the next step was surgery of the upper gastrointestinal tract. Due to the features of the robotic system, we can definitely observe the advantages and a positive effect in case of minimal invasive esophagectomy (MIE). We have also tried to develop an adequate surgical standard of the robotic-assisted minimal invasive esophagectomy with the da Vinci® Xi.


N-methyl-D-aspartate depresses GABAA receptor-mediated currents in neurons of bullfrog dorsal root ganglia.
The effect of N-methyl-D-aspartate (NMDA) on the function of GABAA receptors was examined in acutely dissociated neurons of bullfrog dorsal root ganglia (DRG) by using whole-cell patch clamp methods. The application of NMDA (100 microM) to DRG neurons suppressed the inward currents produced by GABA (100 microM) and muscimol (100 microM). DL-2-Amino-5-phosphonovaleric acid (APV; 100 microM) antagonized the NMDA-induced depression of the GABA current in a competitive manner. Kainic acid (100 microM) did not depress the GABA current. NMDA induced no depression of the GABA current in a nominally Ca(2+)-free solution containing 5 mM Mg2+. These data indicate that the activation of the NMDA receptor inhibits the GABAA receptor-mediated current via a Ca(2+)-dependent process.


An antigen for the diagnosis of M. pneumoniae infections by passive hemagglutination.
The authors establish the optimal conditions (protein concentration, temperature) for the coupling of purified mycoplasma antigen to sheep red blood cells, in order to obtain an antigenic complex stable for at least 1 year. This comples allows specific determination by passive hemagglutination--a simple and rapid technique--of anti-mycoplasma antibodies in the sera of men or animals suspected of mycoplasma infections. Under the stated experimental conditions, antibody titers equal to or higher than 1/128 indicate an infection with M. pneumoniae.


Resurgence of sexually transmitted diseases in Russia and eastern Europe.
The reasons for the outbreak of syphilis and other STDs in the former USSR are investigated in this article. The most important of those are of socioeconomic, biomedical, and organizational origin. The dramatic changes in society has led to changes in the strategy of the dermatovenereologic service. The role of departments of anonymous testing and treatment in controlling the STDs epidemic is discussed. This article also contains statistical data concerning the STDs morbidity in Russia and Eastern Europe during the last years.


Structural diversification of natural substrates modified by the O-methyltransferase AurJ from Fusarium Graminearum.
Aromatic polyketide and phenylpropanoid derivatives are a large class of natural products produced by bacteria, fungi, and plants. The O-methylation is a unique decoration that can increase structural diversity of aromatic compounds and improve their pharmacological properties, but the substrate specificity of O-methyltransferase hinders the discovery of more natural products with O-methylation through biosynthesis. Here, we reported that the O-methyltransferase AurJ from plant pathogenic fungus Fusarium graminearum could methylate a broad range of natural substrates of monocyclic, bicyclic, and tricyclic aromatic precursors, exhibiting excellent substrate tolerance. This finding will partly change our stereotype about the specificity of traditional methyltransferases, and urge us to mine more O-methyltransferases with good substrate tolerance and discover more methylated natural products for drug discovery and development through directed evolution and combinatorial biosynthesis.


Ovariectomy increases the age-induced hyperphosphorylation of Tau at hippocampal CA1.
One of the main hallmarks of Alzheimer's disease includes the neurofibrillary tangles formation produced by hyperphosphorylation of the Tau protein, whose expression is putatively regulated by the ovarian hormones estradiol and progesterone. Hippocampus is a brain region that participates in many functions related to learning and memory; in addition, it is abundant in both estradiol and progesterone receptors. In this study, we explore the expression of Tau hyperphosphorylation at hippocampus and the performance of rats in an autoshaping learning task at 5, 10 and 15 months after the ovaries removal. In these animals, ovariectomy was performed at 3 months of age. These data were compared with those derived from intact rats at 8, 13 and 18 months old. A clear decrease in the number of conditioned responses of both intact and ovariectomized rats in the autoshaping learning task was observed. The interaction of both factors confirms that, in this test, learning varies depending on aging and the presence or absence of ovaries. A progressive increase in hippocampal Tau phosphorylation at Ser-396 was observed in either intact or ovariectomized rats. Interestingly, an interaction between the analyzed factors shows that such hyperphosphorylation was potentiated by the absence of ovaries. These results emphasize the importance of aging and the lack of ovarian hormones for an associative learning test and for the expression of one of the most important hallmarks of Alzheimer's disease.


Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial.
Oophorectomy reduces serum testosterone levels. We studied the efficacy and safety of transdermal testosterone in treating hypoactive sexual desire disorder in surgically menopausal women. A 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial was conducted in women (aged 24-70 years) who developed distressful low sexual desire after bilateral salpingo-oophorectomy and hysterectomy and who were receiving oral estrogen therapy. Women were randomized to receive placebo (n = 119) or testosterone patches in dosages of 150 microg/d (n = 107), 300 microg/d (n = 110), or 450 microg/d (n = 111) twice weekly for 24 weeks. Sexual desire and frequency of satisfying sexual activity were primary efficacy outcome measures. Of the 447 women randomized, 318 (71%) completed the trial. Compared with placebo, women receiving the 300-microg/d testosterone patch had significantly greater increases from baseline in sexual desire (67% vs 48%; P = .05) and in frequency of satisfying sexual activity (79% vs 43%; P = .049). The 150-microg/d group showed no evidence of a treatment effect. The 450-microg/d group also was not statistically different from the 300-microg/d or placebo groups. Marginally significant linear dose-response trends were observed for total satisfying sexual activity and sexual desire at 24 weeks (P = .06 and .06, respectively). Adverse events occurred with similar frequency in both groups; no serious safety concerns were observed. The 300-microg/d testosterone patch increased sexual desire and frequency of satisfying sexual activity and was well tolerated in women who developed hypoactive sexual desire disorder after surgical menopause.


The protein structure of recombinant human lactoferrin produced in the milk of transgenic cows closely matches the structure of human milk-derived lactoferrin.
Human lactoferrin (hLF) is an iron-binding glycoprotein involved in the host defence against infection and excessive inflammation. As the availability of (human milk-derived) natural hLF is limited, alternative means of production of this biopharmaceutical are extensively researched. Here we report the crystal structure of recombinant hLF (rhLF) expressed in the milk of transgenic cows at a resolution of 2.4 A. To our knowledge, the first reported structure of a recombinant protein produced in milk of transgenic livestock. Even though rhLF contains oligomannose- and hybrid-type N-linked glycans next to complex-type glycans, which are the only glycans found on natural hLF, the structures are identical within the experimental error (r.m.s. deviation of only 0.28 A for the main-chain atoms). Of the differences in polymorphic amino acids between the natural and rhLF variant used, only the side-chain of Asp561 could be modeled into the rhLF electron density map. Taken together, the results confirm the structural integrity of the rhLF variant used in this study. It also confirms the validity of the transgenic cow mammary gland as a vehicle to produce recombinant human proteins.


Quantification of regional volume and systolic function of the left ventricle by real-time three-dimensional echocardiography.
Real-time three-dimensional (3D) echocardiography (RT-3DE) provides a unique technique to evaluate left ventricular regional function in a 3D format. We aimed to explore whether the left ventricular segmental volume and systolic function is uniform and to establish normal values of volume and systolic function parameters of 16 regions in healthy subjects. RT-3DE was performed in 41 normal subjects and four-dimensional (4D)-left ventricle (LV) analysis software and a TomTec workstation were used to analyze data for regional end-diastolic volume (EDV(R)), regional end-systolic volume (ESV(R)), regional stroke volume (SV(R)), regional ejection fraction (EF(R)), ratio of SV(R) to global SV (SV(R/G)) and ratio of SV(R) to global EDV (EF(R/G)). All regional volume and systolic function parameters were not uniform among the left ventricular walls. They all increased in the order of inferior, posterior, lateral, septal, anterior and antero-septal walls with an increasing trend from the apical, middle to basal segments. The systolic function (EF(R), SV(R/G) and EF(R/G)) of the anterior and antero-septal walls was significantly higher than that of the lateral, inferior and posterior walls. And the intra- and interobserver variability for EDV(R), ESV(R), SV(R/G) and EF(R/G) ranged from 2.9% to 5.8%. In conclusion, the regional volume and systolic function of the left ventricle is not uniform and, therefore, a normal left ventricle cannot be regarded as a symmetric model for assessing the regional systolic function. This information may improve the accuracy of RT-3DE techniques in the assessment of the left ventricular regional function. (E-mail: email@example.com and firstname.lastname@example.com).


Climate and landscape changes as driving forces for future range shift in southern populations of the European badger.
Human-Induced Rapid Environmental Change (HIREC), particularly climate change and habitat conversion, affects species distributions worldwide. Here, we aimed to (i) assess the factors that determine range patterns of European badger (Meles meles) at the southwestern edge of their distribution and (ii) forecast the possible impacts of future climate and landcover changes on those patterns. We surveyed 272 cells of 5 × 5 km, to assess badger presence and confirmed its occurrence in 95 cells (35%). Our models estimate that badger's presence is promoted by the occurrence of herbaceous fields and shrublands (5%-10%), and low proportions of Eucalyptus plantations (<~15%). Regions with >50% of podzols and eruptive rocks, higher sheep/goat density (>4 ind/km2), an absence of cattle, intermediate precipitation regimes (800-1000 mm/year) and mild mean temperatures (15-16 °C) are also more likely to host badgers. We predict a decrease in favourability of southern areas for hosting badgers under forecasted climate and landcover change scenarios, which may lead to a northwards retraction of the species southern distribution limit, but the overall landscape favourability is predicted to slightly increase. The forecasted retraction may affect community functional integrity, as its role in southern ecological networks will be vacant.


[When is surgical treatment indicated in metastatic urothelial carcinoma and what is the scientific rationale?]
Patients with metastatic urothelial carcinoma have a poor prognosis. Standard of care is a systemic chemotherapy but surgical excision of metastasis can be performed in individual approaches. To evaluate treatment options and study results and to identify and discuss advantages and disadvantages of metastasectomy in urothelial carcinoma. Database analysis and discussion of clinical trials concerning metastasectomy in urothelial carcinoma. In individual cases, metastasectomy can be a reasonable additional therapeutic approach to systemic chemotherapy. Especially patients suffering from symptomatic metastatic disease benefit from extended surgical effort but further effects on survival cannot be expected. Patients undergoing metastasetomy should be well selected concerning general physical condition. Metastasectomy in urothelial carcinoma remains an individual therapeutic approach and should be performed in combination with systemic chemotherapy.


Dynamic protein changes in the perihaemorrhagic zone of Surgically Treated Intracerebral Haemorrhage Patients.
The secondary injury cascades exacerbating the initial brain injury following intracerebral haemorrhage (ICH) are incompletely understood. We used dual microdialysis (MD) catheters placed in the perihaemorrhagic zone (PHZ) and in seemingly normal cortex (SNX) at time of surgical ICH evacuation in ten patients (range 26-70 years). Routine interstitial MD markers (including glucose and the lactate/pyruvate ratio) were analysed and remaining microdialysate was analysed by two-dimensional gel electrophoresis (2-DE) and nano-liquid chromatography tandem mass spectrometry (nLC-MS/MS). Two time intervals were analysed; median 2-10 hours post-surgery (time A) and median 68-76 hours post-ICH onset (time B). Using 2-DE, we quantified 232 ± 31 different protein spots. Two proteins differed between the MD catheters at time A, and 12 proteins at time B (p < 0.05). Thirteen proteins were significantly altered between time A and time B in the SNX and seven proteins in the PHZ, respectively. Using nLC-MS/MS ca 800 proteins were identified out of which 76 were present in all samples. At time A one protein was upregulated and two downregulated, and at time B, seven proteins were upregulated, and four downregulated in the PHZ compared to the SNX. Microdialysis-based proteomics is feasible for study of secondary injury mechanisms and discovery of biomarkers after ICH.


[Peri-operative management of disease modifying anti-rheumatic drugs: recommendations based on a meta-analysis].
The objective of this paper is make recommendations for the perioperative management of antirheumatic treatment based on the best available evidence. A systematic review was performed including studies in which patients with rheumatic diseases treated with biological and non-biological disease-modifying antirheumatic drugs (DMARDs) had undergone surgery. A total of 5,285 studies were recorded, of which 27 were finally included. These contained information on 5,268 patients and 7,933 surgeries. The majority were women (mean age 55 years) were diagnosed with rheumatoid arthritis, and the most studied drug was methotrexate (MTX). The final recommendations include: maintaining treatment with MTX or leflunomide in the perioperative period in the absence of other risk factors for postoperative complications (Level of Evidence 1c, Grade D recommendation). Biological DMARDs should be temporarily suspended, or the surgery scheduled as far as possible from the last dose, and, if there were other risk factors a space at least two doses (Level of Evidence 2c; Grade D recommendation).