Hidden branches: developments in root system architecture.
The root system is fundamentally important for plant growth and survival because of its role in water and nutrient uptake. Therefore, plants rely on modulation of root system architecture (RSA) to respond to a changing soil environment. Although RSA is a highly plastic trait and varies both between and among species, the basic root system morphology and its plasticity are controlled by inherent genetic factors. These mediate the modification of RSA, mostly at the level of root branching, in response to a suite of biotic and abiotic factors. Recent progress in the understanding of the molecular basis of these responses suggests that they largely feed through hormone homeostasis and signaling pathways. Novel factors implicated in the regulation of RSA in response to the myriad endogenous and exogenous signals are also increasingly isolated through alternative approaches such as quantitative trait locus analysis.


Resolvin D1, a metabolite of omega-3 polyunsaturated fatty acid, decreases post-myocardial infarct depression.
We hypothesized that inflammation induced by myocardial ischemia plays a central role in depression-like behavior after myocardial infarction (MI). Several experimental approaches that reduce inflammation also result in attenuation of depressive symptoms. We have demonstrated that Resolvin D1 (RvD1), a metabolite of omega-3 polyunsaturated fatty acids (PUFA) derived from docosahexaenoic acid, diminishes infarct size and neutrophil accumulation in the ischemic myocardium. The aim of this study is to determine if a single RvD1 injection could alleviate depressive symptoms in a rat model of MI. MI was induced in rats by occlusion of the left anterior descending coronary artery for 40 min. Five minutes before ischemia or after reperfusion, 0.1 μg of RvD1 or vehicle was injected in the left ventricle cavity. Fourteen days after MI, behavioral tests (forced swim test and socialization) were conducted to evaluate depression-like symptoms. RvD1 reduced infarct size in the treated vs. the vehicle group. Animals receiving RvD1 also showed better performance in the forced swim and social interaction tests vs. vehicle controls. These results indicate that a single RvD1 dose, given 5 min before occlusion or 5 min after the onset of reperfusion, decreases infarct size and attenuates depression-like symptoms.


Analysis of Mortality Rate of Illicit Substance Abuse and its Trend in Five Years in Iran, 2014-2018.
Addiction and drug misuse is an illness that affects every community in every country. Based on the previous research in many parts of the world, illicit drug use is considered as a well-known risk factor for morbidity, disability, and premature mortality. Although this issue is a hot topic for public health, little studies have looked the epidemiology of substance abuse death and its trends among Iranian society. This study aims to calculate the rate of substance misuse mortality and investigate its trend in Iran. This research was a cross-sectional study. For doing this study, the demographic and epidemiological data of people who died from substance misuse from 2014-2018 were extracted from Legal Medicine Organization (LMO). Finally, descriptive statistics were used to analyze the data. 15304 deaths due to drug misuse were recorded in 2014-2018. The substance abuse mortality rate has increased during the study period in men and women. There were significant differences in death rates between men and women. Crude mortality rate was significantly higher among men compared to women. The majority of deaths has occurred in young men aged 30-39 years with high school education and self-employed. The results revealed that death from substance misuse has increased during the study period. This increasing trend was observed in women and men. Further preventive measures, however, should be devised to reduce drug-related deaths. The majority of deaths occurred in young men aged 30-39 years with high school education and self-employed. In our opinion and based on the study results, programs, policies, and preventive measures should be taken to prevent these people from accessing and using the drug.


E-prescription and invisible work in genomics in France.
This article aims to analyze the transformations in medical prescription work and infrastructures brought by digitalization. Our fieldwork takes place in the context of precision medicine development based on genomics High Throughput Sequencing (HTS) in France, through the Plan France Médecine Génomique (PFMG 2025). The Plan aims at industrializing the production of genomic testing in clinical context at a national scale, particularly in oncology. To ensure the intensified flow of information between hospitals and HTS platforms required, a centralized process has been organized around two sequencing platforms and the introduction of a new e-prescription software (E-PRES). We start by analyzing how the e-prescription software changes the practices of health professionals by imposing new technological and professional standards. We show that, more than a mere prescription tool, this software is also a monitoring tool for the platforms and prescribers' work, and a support tool for the logistical and work organization. Secondly, we question the division of labor among the different professionals involved in the organizational or technical tasks required. We show that the feasibility of this new form of digitalized prescription relies on an important datawork performed by "small hands" to select, translate and process a vast amount of heterogeneous data.


Statins inhibit angiotensin II/Smad pathway and related vascular fibrosis, by a TGF-β-independent process.
We have recently described that in an experimental model of atherosclerosis and in vascular smooth muscle cells (VSMCs) statins increased the activation of the Smad pathway by transforming growth factor-β (TGF-β), leading to an increase in TGF-β-dependent matrix accumulation and plaque stabilization. Angiotensin II (AngII) activates the Smad pathway and contributes to vascular fibrosis, although the in vivo contribution of TGF-β has not been completely elucidated. Our aim was to further investigate the mechanisms involved in AngII-induced Smad activation in the vasculature, and to clarify the beneficial effects of statins on AngII-induced vascular fibrosis. Infusion of AngII into rats for 3 days activates the Smad pathway and increases fibrotic-related factors, independently of TGF-β, in rat aorta. Treatment with atorvastatin or simvastatin inhibited AngII-induced Smad activation and related-fibrosis. In cultured rat VSMCs, direct AngII/Smad pathway activation was mediated by p38 MAPK and ROCK activation. Preincubation of VSMCs with statins inhibited AngII-induced Smad activation at all time points studied (from 20 minutes to 24 hours). All these data show that statins inhibited several AngII-activated intracellular signaling systems, including p38-MAPK and ROCK, which regulates the AngII/Smad pathway and related profibrotic factors and matrix proteins, independently of TGF-β responses. The inhibitory effect of statins on the AngII/Smad pathway could explain, at least in part, their beneficial effects on hypertension-induced vascular damage.


Aspirin-Mediated Acetylation Protects Against Multiple Neurodegenerative Pathologies by Impeding Protein Aggregation.
Many progressive neurological disorders, including Alzheimer's disease (AD), Huntington's disease, and Parkinson's disease (PD), are characterized by accumulation of insoluble protein aggregates. In prospective trials, the cyclooxygenase inhibitor aspirin (acetylsalicylic acid) reduced the risk of AD and PD, as well as cardiovascular events and many late-onset cancers. Considering the role played by protein hyperphosphorylation in aggregation and neurodegenerative diseases, and aspirin's known ability to donate acetyl groups, we asked whether aspirin might reduce both phosphorylation and aggregation by acetylating protein targets. Aspirin was substantially more effective than salicylate in reducing or delaying aggregation in human neuroblastoma cells grown in vitro, and in Caenorhabditis elegans models of human neurodegenerative diseases in vivo. Aspirin acetylates many proteins, while reducing phosphorylation, suggesting that acetylation may oppose phosphorylation. Surprisingly, acetylated proteins were largely excluded from compact aggregates. Molecular-dynamic simulations indicate that acetylation of amyloid peptide energetically disfavors its association into dimers and octamers, and oligomers that do form are less compact and stable than those comprising unacetylated peptides. Hyperphosphorylation predisposes certain proteins to aggregate (e.g., tau, α-synuclein, and transactive response DNA-binding protein 43 [TDP-43]), and it is a critical pathogenic marker in both cardiovascular and neurodegenerative diseases. We present novel evidence that acetylated proteins are underrepresented in protein aggregates, and that aggregation varies inversely with acetylation propensity after diverse genetic and pharmacologic interventions. These results are consistent with the hypothesis that aspirin inhibits protein aggregation and the ensuing toxicity of aggregates through its acetyl-donating activity. This mechanism may contribute to the neuro-protective, cardio-protective, and life-prolonging effects of aspirin. Antioxid. Redox Signal. 27, 1383-1396.


Close encounters of the sticky kind: Brownian motion at absorbing boundaries.
Encounter-based models of diffusion provide a probabilistic framework for analyzing the effects of a partially absorbing reactive surface, in which the probability of absorption depends upon the amount of surface-particle contact time. In this paper we develop a class of encounter-based models that deal with absorption at sticky boundaries. Sticky boundaries occur in a diverse range of applications, including cell biology, colloidal physics, finance, and human crowd dynamics. They also naturally arise in active matter, where confined active particles tend to spontaneously accumulate at boundaries even in the absence of any particle-particle interactions. We begin by constructing a one-dimensional encounter-based model of sticky Brownian motion (BM), which is based on the zero-range limit of nonsticky BM with a short-range attractive potential well near the origin. In this limit, the boundary-contact time is given by the amount of time (occupation time) that the particle spends at the origin. We calculate the joint probability density or propagator for the particle position and the occupation time, and then identify an absorption event as the first time that the occupation time crosses a randomly generated threshold. We illustrate the theory by considering diffusion in a finite interval with a partially absorbing sticky boundary at one end. We show how various quantities, such as the mean first passage time (MFPT) for single-particle absorption and the relaxation to steady state at the multiparticle level, depend on moments of the random threshold distribution. Finally, we determine how sticky BM can be obtained by taking a particular diffusion limit of a sticky run-and-tumble particle (RTP).


[Effect of recombinant beta-defensin-2 peptide on apoptosis of pulmonary tissue in rats with sepsis].
To investigate the effect of recombinant beta-defensin 2 (BD-2) on the apoptosis of pulmonary tissue in rats with sepsis. Forty-eight SD rats were randomly divided into defensin group and controls. In control group 24 rats received 10(7)PFU adenovirus via trachea intubation. In defensin group 24 rats received 10(7)PFU recombinant adenovirus carrying all expression cassette of rat BD-2 (Ad-rBD2). All rats received cecal ligation and puncture (CLP) to induce sepsis 48 h following the administration of adenovirus. Rats of both groups were sacrificed at 0, 12, 36 and 72 h after CLP; lungs were removed and fixed for Haematoxylin and Eosin (HE) stain. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) technique. The apoptosis index (AI) of lung cells increased significantly following CLP in control group,while it was significantly lower in defensin group than that of control group (P<0.05). In addition, a significant alveolar damage, interstitial edema, and infiltration of inflammatory cells were observed in control lungs, while it was less severe in defensin group. Recombinant beta-defensin 2 may reduce the apoptosis of lung cells and attenuate lung injury.


Identification of combustion intermediates in low-pressure premixed pyridine/oxygen/argon flames.
Combustion intermediates of two low-pressure premixed pyridine/oxygen flames with respective equivalence ratios of 0.56 (C/O/N = 1:4.83:0.20) and 2.10 (C/O/N = 1:1.29:0.20) have been identified with tunable synchrotron vacuum ultraviolet (VUV) photoionization and molecular-beam mass spectrometry techniques. About 80 intermediates in the rich flame and 60 intermediates in the lean flame, including nitrogenous, oxygenated, and hydrocarbon intermediates, have been identified by measurements of photoionization mass spectra and photoionization efficiency spectra. Some radicals and new nitrogenous intermediates are identified in the present work. The experimental results are useful for studying the conversion of volatile nitrogen compounds and understanding the formation mechanism of NO(x) in flames of nitrogenous fuels.


Potential of xenon to induce or to protect against neuroapoptosis in the developing mouse brain.
Drugs that suppress neuronal activity, including all general anesthetics that have been tested thus far (ketamine, midazolam, isoflurane, propofol, and a cocktail of midazolam, nitrous oxide and isoflurane), trigger neuroapoptosis in the developing rodent brain. Combinations of nitrous oxide and isoflurane, or ketamine and propofol, cause more severe neuroapoptosis than any single agent by itself, which suggests a positive correlation between increased levels of anesthesia and increased severity of neuroapoptosis. In contrast, there is evidence that the rare gas, xenon, which has anesthetic properties, protects against isoflurane-induced neuroapoptosis in the infant rat brain, while not inducing neuroapoptosis by itself. The present study was undertaken to evaluate the potential of xenon to induce neuroapoptosis or to protect against neuroapoptosis induced by isoflurane in the infant mouse brain. Seven-day-old C57BL/6 mice were exposed to one of four conditions: air (control); 0.75% isoflurane; 70% xenon; or 0.75% isoflurane + 70% xenon for four hours. For histopathological evaluation of the brains, all pups were euthanized two hours later using activated caspase-3 immunohistochemical staining to detect apoptotic neurons. Under each condition, quantitative assessment of the number of apoptotic neurons in the cerebral cortex (CC) and in the caudate/putamen (C/P) was performed by unbiased stereology. The combination of xenon + isoflurane produced a deeper level of anesthesia than either agent alone. Both xenon alone (p < 0.003 in CC; p < 0.02 in C/P) and isoflurane alone (p < 0.001 in both CC and C/P) induced a significant increase in neuroapoptosis compared to controls. The neuroapoptotic response to isoflurane was substantially more robust than the response to xenon. When xenon was administered together with isoflurane, the apoptotic response was reduced to a level lower than that for isoflurane alone (p < 0.01 in CP; marginally non-significant in CC). We conclude that xenon, in the infant mouse brain, has paradoxical properties. It triggers neuroapoptosis, and when combined with isoflurane, it increases the depth of anesthesia, and retains its own apoptogenic activity. However, it suppresses, rather than augments, isoflurane's apoptogenic activity.


Relationship between Candida albicans producing proteinase (CAPP) and its environmental pH--comparison with a case of trichophyton mentagrophytes.
Candida albicans produced a karatinolytic proteinase (KPase) or C. albicans producing proteinase (CAPP), a proposed new term for this enzyme, and Trichophyton mentagrophytes also produced KPase when cultivated in liquid medium containing human stratum corneum (HSC) as the nitrogen source, but were unable to do so when cultivated in sabouraud dextrose broth. Purified KPase from the culture supernatants of C. albicans had a molecular weight of 42,000 and an optimum pH at 4.0. The KPase was found to belong to the carboxyl proteinases group and its activity was strongly inhibited by pepstatin. Both fungi were able to grow by secreting KPase which digested HSC for nutrients. KPase from both fungi had high activity in each optimum pH, such as weakly acidic pH on C. albicans and neutral pH on T. mentagrophytes to adapt their surrounding environment by changing the environmental pH into their own optimum pH.


Enhanced detection of cardiac arrhythmias utilizing 14-day continuous ECG patch monitoring.
To evaluate the performance of a single‑lead, 14-day continuous electrocardiogram (ECG) patch for the detection of arrhythmias compared to conventional 24-h monitoring. This prospective clinical trial enrolled patients suspected of arrhythmias but not diagnosed by 12‑lead ECGs. Each patient underwent a 24-h Holter and 14-day ECG patch simultaneously. Seven types of arrhythmias were classified: supraventricular tachycardia (SVT, repetitive atrial beats >4 beats), irregular SVT without P wave (>4 beats), AF/AFL (irregular SVT without P wave ≥30 s), pause ≥3 s, atrioventricular block (AVB; Mobitz type II, third-degree, two to one or high degree AVB), ventricular tachycardia (VT), and polymorphic VT. A total of 158 patients were recruited (mean wear time:12.3 ± 3.2 days). The overall arrhythmia detection rate was higher with 14-day ECG patches (59.5%) compared to 24-h Holter (19.0%, P < 0.001). Up to 87.2% of arrhythmias recorded with 14-day ECG patches were not associated with symptoms. The 14-day ECG patch was associated with higher detection rates compared to the 24-h Holter in patients with SVT (52.5% versus 15.8%, P < 0.001), irregular SVT without P wave (12.7% versus 4.4%, P = 0.002), AF/AFL (9.5% versus 3.8%, P = 0.042), and critical arrhythmias (pause ≥3 s, AVB, VT, polymorphic VT) (16.5% versus 2.5%, P < 0.001). The 14-day ECG patch detected more than 2 types of arrhythmias in 5.1% of patients. No serious adverse events in patients wearing the 14-day ECG patch were reported. The 14-day ECG patch outperformed 24-h Holter to detect overall, asymptomatic, critical and multiple arrhythmias. It is safe and has the potential to identify individuals with hidden arrhythmias, especially those with critical arrhythmias.


pH-Dependent mitigation of aluminum toxicity in pea (Pisum sativum) roots by boron.
Boron (B) deficiency and aluminum (Al) toxicity are two major constraints on plants grown in acidic soils. B supply mitigates Al toxicity; however, the underlying mechanisms of this process remain elusive. In this work, Pisum sativum plants were used to address this issue. In the absence of pH buffers, B supply had a better mitigation effect on Al-induced root inhibition at pH 4.0 than pH 4.8. However, in MES buffered solution, mitigating effects of B on Al-induced root inhibition were more pronounced at pH 4.8, indicating a strong pH dependency of this process. Quantification of pH-dependent accumulation of Al in various root zones, modification of root pH by an exogenous addition of rapid alkalization factor (RALF), and measuring changes in the rhizosphere pH by fluorescent dyes have revealed operation of two concurrent mechanisms to explain alleviation of the inhibition of root elongation induced by Al toxicity by boron: (1) via enhancing rhizosphere pH under strong acidic stress (pH4.0), and (2) via stabilizing of cell wall by cross-linking with RGII at relatively higher pH (4.8). These findings provide scientific basis and support for the application of B fertilizers in the regions with inherited soil acidity.


Essential role of mouse telomerase in highly proliferative organs.
We have investigated the role of the enzyme telomerase in highly proliferative organs in successive generations of mice lacking telomerase RNA. Late-generation animals exhibited defective spermatogenesis, with increased programmed cell death (apoptosis) and decreased proliferation in the testis. The proliferative capacity of haematopoietic cells in the bone marrow and spleen was also compromised. These progressively adverse effects coincided with substantial erosion of telomeres (the termini of eukaryotic chromosomes) and fusion and loss of chromosomes. These findings indicate an essential role for telomerase, and hence telomeres, in the maintenance of genomic integrity and in the long-term viability of high-renewal organ systems.


Evaluation of the painful total knee arthroplasty.
There are a substantial number of patients who continue to complain of pain following total knee arthroplasty (TKA). There are many potential causes of continued pain, and these are broadly categorized into intrinsic and extrinsic sources. When evaluating a patient with a painful TKA, the physician begins with a thorough history and physical examination, along with the appropriate radiographs. Further workup includes laboratory analysis, specifically evaluating the inflammatory markers erythrocyte sedimentation rate and C-reactive protein, along with a synovial fluid aspirate evaluating the white blood cell count with differential and culture. Advanced imaging modalities are sometimes helpful when the diagnosis remains unclear, including stress radiographs, live fluoroscopic imaging, ultrasound, nuclear imaging, and magnetic resonance imaging. Further surgery is not advisable without a clear diagnosis, as this is associated with very poor results. Instead, serial follow-up or a referral to a specialist for a second opinion may be most appropriate.


Lymphangioleiomyomatosis (LAM).
LAM is characterised by lung cysts (air-filled sacs which gradually destroy the lung), changes to the lymphatic system and tumours in the kidneys.


Adenocarcinoma of the prostate. Stage-by-stage treatment alternatives.
The best treatment for adenocarcinoma of the prostate depends on the patient's age, general medical condition, life expectancy, and willingness to accept such side effects as impotence. Radical prostatectomy or full-dose radiation therapy are usually curative when cancer is confined to the gland. The technique of prostatectomy has been improved and potency often can be preserved. Once the tumor extends beyond the gland, treatment alternatives are radiation or endocrine therapy. If lymph nodes are negative, radiation therapy may result in a long period without progression. If lymph nodes are positive, the expense and morbidity of radiation therapy may not be worthwhile because the likelihood of cure is low. Androgen deprivation, or endocrine manipulation, is preferred for metastatic disease. Response is varied and may depend on the patient's testosterone level when therapy is initiated. Survival is shorter in those with levels below normal.


Regulation of pancreatic beta-cell function by the forkhead protein FoxO1.
Forkhead transcription factors of the FoxO family play a critical role in cellular differentiation, proliferation, apoptosis and stress resistance. FoxO1 regulates glucose and lipid production in liver; food intake in the hypothalamus and cell differentiation in preadipocytes, myoblasts and vascular endothelium. In this review, we summarize recent literature on the role of FoxO1 in pancreatic beta cells. FoxO1 regulates beta-cell proliferation and protects against beta-cell failure induced by oxidative stress through NeuroD and MafA induction. In addition, FoxO1 nuclear exclusion is required for the proliferative effects of glucoincretin glucagon-like peptide-1 in islets. The data begin to outline an overarching role of FoxO1 in beta-cell function.


Reproductive characteristics of Japanese monkeys on Shimokita Peninsula, Japan, the northernmost habitat of wild primates in the world.
The Shimokita Peninsula in Aomori Prefecture, Japan, which is inhabited by Japanese monkeys (Macaca fuscata), is the northernmost habitat for wild primates in the world. This study was the first to determine the conception dates of specific individuals and estimate the pregnancy rate of wild populations in this region. The pregnancy rate of animals aged 5 years or more at delivery was estimated to be 40.9% (27/66). Conception dates of each fetus were also estimated using a regression line of Pig-tail monkeys (Macaca nemestrina), which are taxonomically related to Japanese monkeys and have a similar physique. The conception dates were distributed across 90 days between September 24th and December 23rd, with a mean conception date of November 4th (SD=22.3 days, n=53). Using these findings, the mean birth date was estimated as April 25th, more than two weeks earlier than the mean birth date in previous research determined using direct observations carried out over the past 20 years ago. Global warming due to climate change is thought to be one of the main causes of this difference.


Neurophysiological correlates of age-related changes in working memory capacity.
Cognitive abilities such as working memory (WM) capacity decrease with age. To determine the neurophysiological correlates of age-related reduction in working memory capacity, we studied 10 young subjects (<35 years of age; mean age=29) and twelve older subjects (>55 years of age; mean age=59) with whole brain blood oxygenation-level dependent (BOLD) fMRI on a 1.5 T GE MR scanner using a SPIRAL FLASH pulse sequence (TE=24 ms, TR=56 ms, FA=60 degrees , voxel dimensions=3.75 mm(3)). Subjects performed a modified version of the "n" back working memory task at different levels of increasing working memory load (1-Back, 2-Back and 3-Back). Older subjects performed as well as the younger subjects at 1-Back (p=0.4), but performed worse than the younger subjects at 2-Back (p<0.01) and 3-Back (p=0.06). Older subjects had significantly longer reaction time (RT) than younger subjects (p<0.04) at all levels of task difficulty. Image analysis using SPM 99 revealed a similar distribution of cortical activity between younger and older subjects at all task levels. However, an analysis of variance revealed a significant group x task interaction in the prefrontal cortex bilaterally; within working memory capacity, as in 1-Back when the older subjects performed as well as the younger subjects, they showed greater prefrontal cortical (BA 9) activity bilaterally. At higher working memory loads, however, when they performed worse then the younger subjects, the older subjects showed relatively reduced activity in these prefrontal regions. These data suggest that, within capacity, compensatory mechanisms such as additional prefrontal cortical activity are called upon to maintain proficiency in task performance. As cognitive demand increases, however, they are pushed past a threshold beyond which physiological compensation cannot be made and, a decline in performance occurs.


Spontaneous electric fields in solid carbon monoxide.
Reflection-absorption infrared spectroscopy (RAIRS) is shown to provide a means of observing the spontelectric phase of matter, the defining characteristic of which is the occurrence of a spontaneous and powerful static electric field within a film of material. The presence of such a field is demonstrated here through the study of longitudinal-transverse optical splitting in RAIR spectra in films of carbon monoxide, based upon the deposition temperature dependence of this splitting. Analysis of spectral data, in terms of the vibrational Stark effect, allows the measurement of the polarization of spontelectric films, showing for example that solid carbon monoxide at 20 K may maintain a spontelectric field of 3.78 × 10(7) V m(-1), representing a polarization of 3.34 × 10(-4) cm(-2). We comment on the astrophysical implications of polarized carbon monoxide ices, on the surface of cosmic grains in star-forming regions.


Origin and Phylogeny of Microbes Living in Permanent Antarctic Lake Ice.
A BSTRACTThe phylogenetic diversity of bacteria and cyanobacteria colonizing sediment particles in the permanent ice cover of an Antarctic lake was characterized by analyses of 16S rRNA genes amplified from environmental DNA. Samples of mineral particles were collected from a depth of 2.5 m in the 4-m-thick ice cover of Lake Bonney, McMurdo Dry Valleys, Antarctica. A rRNA gene clone library of 198 clones was made and characterized by sequencing and oligonucleotide probe hybridization. The library was dominated by representatives of the cyanobacteria, proteobacteria, and Planctomycetales, but also contained diverse clones representing many other microbial groups, including the Acidobacterium/Holophaga division, the Green Non-Sulfur division, and the Actinobacteria. Six oligonucleotide probes were made for the most abundant clades recovered in the library. To determine whether the ice microbial community might originate from wind dispersal of the algal mats found elsewhere in Taylor Valley, the probes were hybridized to 16S rDNAs amplified from three samples of terrestrial cyanobacterial mats collected at nearby sites, as well as to bacterial 16S rDNAs from the lake ice community. The results demonstrate the presence of a diverse microbial community dominated by cyanobacteria in the lake ice, and also show that the dominant members of the lake ice microbial community are found in terrestrial mats elsewhere in the area. The lake ice microbial community appears to be dominated by organisms that are not uniquely adapted to the lake ice ecosystem, but instead are species that originate elsewhere in the surrounding region and opportunistically colonize the unusual habitat provided by the sediments suspended in lake ice.


Microstructure Characteristics and Hydrogen Storage Kinetics of Mg77+xNi20-xLa3 (x = 0, 5, 10, 15) Alloys.
Mg77+xNi20-xLa3 (x = 0, 5, 10, 15) alloys were successfully prepared by the vacuum induction melting method. The structural characterizations of the alloys were performed by using X-ray diffraction and scanning electron microscope. The effects of nickel content on the microstructure and hydrogen storage kinetic of the as-cast alloys were investigated. The results showed that the alloys are composed of a primary phase of Mg2Ni, lamella eutectic composites of Mg + Mg2Ni, and some amount of LaMg12 and La2Mg17. Nickel addition significantly improved the hydrogen-absorption kinetic performance of the alloy. At 683 K, Mg77Ni20La3 alloy and Mg82Ni15La3 alloy underwent hydrogen absorption and desorption reactions for 2 h, respectively, and their hydrogen absorption and desorption capacities were 4.16 wt.% and 4.1 wt.%, and 4.92 wt.% and 4.69 wt.%, respectively. Using the Kissinger equation, it was calculated that the activation energy values of Mg77Ni20La3, Mg82Ni15La3, Mg87Ni10La3 and Mg92Ni5La3 alloys were in the range of 68.5~75.2 kJ/mol, much lower than 150~160 kJ/mol of MgH2.


Exosomal RNF157 mRNA from prostate cancer cells contributes to M2 macrophage polarization through destabilizing HDAC1.
Exosomes have been identified to mediate the transmission of RNAs among different cells in tumor microenvironment, thus affecting the progression of different diseases. However, exosomal messenger RNAs (mRNAs) have been rarely explored. RNF157 mRNA has been found to be up-regulated in PCa patients' exosomes, but the role of exosomal RNF157 mRNA in PCa development remains unclear. Online databases were utilized for predicting gene expression and binding correlation between different factors. RT-qPCR and western blot assays were respectively done to analyze RNA and protein expressions. Flow cytometry analysis was implemented to analyze M2 polarization. RNF157 expression was high in PCa tissues and cells. M2 polarization of macrophages was enhanced after co-culture with PCa cells or with exosomes released by PCa cells. Upon RNF157 knockdown in PCa cells, the extracted exosomes could not lead to the facilitated M2 polarization. Mechanistically, RNF157 could bind to HDAC1 and contribute to HDAC1 ubiquitination, which led to HDAC1 degradation and resulting in promoting M2 polarization of macrophages. Animal experiments validated that exosomal RNF157 accelerated PCa tumor growth through facilitating macrophage M2 polarization. Exosome-mediated RNF157 mRNA from PCa cells results in M2 macrophage polarization via destabilizing HDAC1, consequently promoting PCa tumor progression.


Histamine H1 receptor occupancy triggers inositol phosphates and intracellular calcium mobilization in human non-pigmented ciliary epithelial cells.
Agonists and antagonists of histamine were used to characterize the stimulation of inositol phosphates formation and elevation of intracellular Ca2+ by histamine in cultured non-pigmented epithelial (NPE) cells from human ciliary body. Agonists specific for the H1 histamine receptor subtype were 20- to 200-fold more potent than the H2-specific agonists tested, and 5-16% as potent as histamine in inositol phosphates stimulation. An H1 antagonist was 10,000-fold more potent than an H2 antagonist in blocking histamine stimulation of inositol phosphates. H1 agonists also mimicked and H1 antagonists inhibited the elevation of intracellular Ca2+ by histamine. The first phase of the Ca2+ response to histamine was largely independent of extracellular Ca2+ while the second phase required extracellular Ca2+. Dose-response curves for histamine elevation of intracellular Ca2+ (EC50 = 10 microM, maximum at 100 microM) and inositol phosphates (EC50 = 2 microM, maximum at 100 microM) were similar. These data support the characterization of the NPE histamine receptor as an H1 receptor linked to elevation of inositol phosphates and intracellular Ca2+.


Dentin-derived BMP-2 and odontoblast differentiation.
It is known that stem cells from exfoliated deciduous teeth (SHED) can be induced to differentiate into odontoblasts. However, the nature of dentin-derived morphogenic signals required for dental pulp stem cell differentiation remains unclear. The hypothesis underlying this work is that dentin-derived Bone Morphogenetic Proteins (BMP) are necessary for the differentiation of SHED into odontoblasts. We observed that SHED express markers of odontoblastic differentiation (DSPP, DMP-1, MEPE) when seeded in human tooth slice/scaffolds and cultured in vitro, or implanted subcutaneously into immunodeficient mice. In contrast, SHED cultured in deproteinized tooth slice/scaffolds, or scaffolds without a tooth slice, do not express these markers. SHED express the BMP receptors BMPR-IA, BMPR-IB, and BMPR-II. Notably, blockade of BMP-2 signaling inhibited the expression of markers of odontoblastic differentiation by SHED cultured in tooth slice/scaffolds. Collectively, this work demonstrates that dentin-derived BMP-2 is required to induce the differentiation of SHED into odontoblasts.


Gamma bang time/reaction history diagnostics for the National Ignition Facility using 90 degrees off-axis parabolic mirrors.
Gas Cherenkov detectors (GCDs) have been used to convert fusion gamma into photons to achieve gamma bang time and reaction history measurements. The GCDs designed for OMEGA used Cassegrain reflector optics in order to fit inside a 10 in. manipulator. A novel design for the National Ignition Facility using 90 degrees off-axis parabolic mirrors will increase light collection efficiency from fusion gammas and achieve minimum time dispersion. The broadband Cherenkov light (from 200 to 800 nm) is relayed into a high-speed detector using three parabolic mirrors. Because light is collected from many source planes throughout the CO(2) gas volume, the detector is positioned at the stop position rather than at an image position. The stop diameter and its position are independent of the light-generation location along the gas cell. The current design collects light from a 100 mm diameter by 500 mm long gas volume. Optical ray tracings demonstrate how light can be collected from different angled trajectories of the Compton electrons as they fly through the CO(2) gas volume. A cluster of four channels will allow for increased dynamic range as well as for different gamma energy threshold sensitivities.


Technical Note: Design and implementation of a high-throughput pipeline for reconstruction and quantitative analysis of CT image data.
With recent substantial improvements in modern computing, interest in quantitative imaging with CT has seen a dramatic increase. As a result, the need to both create and analyze large, high-quality datasets of clinical studies has increased as well. At present, no efficient, widely available method exists to accomplish this. The purpose of this technical note is to describe an open-source high-throughput computational pipeline framework for the reconstruction and analysis of diagnostic CT imaging data to conduct large-scale quantitative imaging studies and to accelerate and improve quantitative imaging research. The pipeline consists of two, primary "blocks": reconstruction and analysis. Reconstruction is carried out via a graphics processing unit (GPU) queuing framework developed specifically for the pipeline that allows a dataset to be reconstructed using a variety of different parameter configurations such as slice thickness, reconstruction kernel, and simulated acquisition dose. The analysis portion then automatically analyzes the output of the reconstruction using "modules" that can be combined in various ways to conduct different experiments. Acceleration of analysis is achieved using cluster processing. Efficiency and performance of the pipeline are demonstrated using an example 142 subject lung screening cohort reconstructed 36 different ways and analyzed using quantitative emphysema scoring techniques. The pipeline reconstructed and analyzed the 5112 reconstructed datasets in approximately 10 days, a roughly 72× speedup over previous efforts using the scanner for reconstructions. Tightly coupled pipeline quality assurance software ensured proper performance of analysis modules with regard to segmentation and emphysema scoring. The pipeline greatly reduced the time from experiment conception to quantitative results. The modular design of the pipeline allows the high-throughput framework to be utilized for other future experiments into different quantitative imaging techniques. Future applications of the pipeline being explored are robustness testing of quantitative imaging metrics, data generation for deep learning, and use as a test platform for image-processing techniques to improve clinical quantitative imaging.


Repeat positron emission tomographic studies in transient middle cerebral artery occlusion in cats: residual perfusion and efficacy of postischemic reperfusion.
The wider clinical acceptance of thrombolytic therapy for ischemic stroke has focused more attention on experimental models of reversible focal ischemia. Such models enable the study of the effect of ischemia of various durations and of reperfusion on the development of infarctions. We used high-resolution positron emission tomography (PET) to assess cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), and cerebral metabolic rate of glucose (CMRglc) before, during, and up to 24 h after middle cerebral artery occlusion (MCAO) in cats. After determination of resting values, the MCA was occluded by a transorbital device. The MCA was reopened after 30 min in five, after 60 min in 11, and after 120 min in two cats. Whereas all cats survived 30-min MCAO, six died after 60-min and one after 120-min MCAO during 6-20 h of reperfusion. In those cats surviving the first day, infarct size was determined on serial histologic sections. The arterial occlusion immediately reduced CBF in the MCA territory to < 40% of control, while CMRO2 was less affected, causing an increase in OEF. Whereas in the cats surviving 24 h of reperfusion after 60- and 120-min MCAO, OEF remained elevated throughout the ischemic episode, the initial OEF increase had already disappeared during the later period of ischemia in those cats that died during the reperfusion period. After 30-min MCAO, the reperfusion period was characterized by a transient reactive hyperemia and fast normalization of CBF, CMRO2, and CMRglc, and no or only small infarcts in the deep nuclei were found in histology. After 60- and 120-min MCAO, the extent of hyperperfusion was related to the severity of ischemia, decreased CMRO2 and CMRglc persisted, and cortical/subcortical infarcts of varying sizes developed. A clear difference was found in the flow/metabolic pattern between surviving and dying cats: In cats dying during the observation period, extended postischemic hyperperfusion accompanied large defects in CMRO2 and CMRglc, large infarcts developed, and intracranial pressure increased fatally. In those surviving the day after MCAO, increased OEF persisted over the ischemic episode, postischemic hyperperfusion was less severe and shorter, and the perfusional and metabolic defects as well as the final infarcts were smaller. These results stress the importance of the severity of ischemia for the further course after reperfusion and help to explain the diverging outcome after thrombolysis, where a relation between the residual flow and the effectiveness of reperfusion was also observed.


[Immunomodulative effects of Chinese herbs in mice treated with anti-tumor agent cyclophosphamide].
Extracts of Chinese herbs were administered with antitumor agent, cyclophosphamide (CY), and their effects on macrophages and lymphocytes were studied. Number of peritoneal macrophages significantly decreased and their chemotactic activity was suppressed by treatment with CY. Blastogenic responsiveness to Concanavalin A and NK cell activity of spleen lymphocytes were suppressed significantly in CY-treated mice. Extracts of Lithospermi radix, Astragali radix and Glycyrrhizae radix showed protective effects on immunosuppressive mice. The number of macrophages, chemotactic activity of macrophages and blastogenic response of lymphocytes were recovered to the same or more than that of normal levels. An extract of Ginseng radix showed protective effects on the number and functions of macrophages by treatment with CY but did not show any effects on the lymphocytic blastogenesis. On the contrary it showed a strong inhibitory effect on the NK cell activity. These results suggest that Chinese herbs could modulate cellular immune response, especially in the activation of macrophages and splenic lymphocytes.


TSV, a putative plastidic oxidoreductase, protects rice chloroplasts from cold stress during development by interacting with plastidic thioredoxin Z.
Rice is vulnerable to cold stress. Seedlings are very sensitive to cold stress and this harms global rice production. The effects of cold on chloroplast development are well known, but little is known about the underlying molecular mechanisms. Here, we isolated a temperature-sensitive virescent (tsv) mutant that is extremely sensitive to cold stress. It displayed defective chloroplasts, decreased chlorophyll and zero survivorship under cold stress. We isolated and identified TSV by map-based cloning and rescue experiments, combined with genetic, cytological and molecular biological analyses. We found that TSV, a putative plastidic oxidoreductase, is a new type of virescent protein. A mutation in tsv causes premature termination of the gene product. The activity of plastid-encoded RNA polymerase (PEP) and the expression of genes participating in chlorophyll synthesis were severely reduced in the tsv mutant under cold stress, but not at normal temperatures. TSV expression was induced by low temperatures. Strikingly, TSV interacted with OsTrxZ (a subunit of PEP in chloroplasts) and enhanced OsTrxZ stability under low temperatures. We demonstrated that TSV protects rice chloroplasts from cold stress by interacting with OsTrxZ. These results provide novel insights into ways in which rice chloroplast development and chlorophyll synthesis are protected by TSV under cold stress.


Ploidy pattern and cell cycle in breast cancer as detected by image analysis and flow cytometry.
Both image analysis (IA) and flow cytometry (FCM) may be applied to detect ploidy pattern and cell cycle fractions. However, they have different performance characteristics and may yield different results. The two approaches are applied in this study to 66 breast cancers: IA on imprints and FCM on fresh tissue. The percent coefficient of variation (CV) ranged from 2.0 to 7.0 (mean 5.5; SD 1.1) in IA and from 2.0 to 7.0 (mean 4.4; SD 1.1) in FCM. The values were well correlated. With regard to ploidy pattern, the agreement between the two methods was 92.4%; disagreements were due to four cases being aneuploid by IA but not detected by FCM and one case being aneuploid by IA but tetraploid by FCM. This suggests that IA is capable of detecting aneuploidy with more sensitivity than FCM. In diploid cases, the percent values of cells in G0/G1, S-phase (SPF), and G2M phase were concordant and well correlated. In aneuploid cases, IA was more sensitive than FCM in detecting aneuploid fraction as well as G2M phase, whereas FCM was more sensitive than IA in detecting SPF. A good correlation was found between the DNA indexes (DIs) obtained with the two methods.


Induction of in vitro differentiation of mouse embryonal carcinoma (F9) cells by inhibitors of topoisomerases.
To investigate the possible involvement of topoisomerases in embryonal differentiation, we examined the effect of topoisomerase inhibitors on the in vitro differentiation of mouse embryonal carcinoma F9 cells. We found that camptothecin, teniposide (VM-26), or genistein, specific inhibitors of topoisomerases, induced morphological as well as biochemical changes (production of tissue plasminogen activator, synthesis of laminin, and disappearance of stage-specific embryonic antigen 1) specific to F9 cell differentiation. Since these changes were indistinguishable from those observed in F9 differentiation induced by retinoic acid (plus dibutyryl cyclic AMP), it was suggested that inhibition of cellular topoisomerase activities triggered F9 cell differentiation into parietal endoderm-like cells in the same manner as retinoic acid (plus dibutyryl cyclic AMP). Experiments using differentiation-resistant mutant F9 cell lines, however, indicated that the molecular cascade involved in topoisomerase inhibitor-induced differentiation involves different steps from those functioning in the retinoic acid-induced differentiation cascade.


[Diabetic asymmetric proximal neuropathy].
To study the prevalence, clinical features and treatment of diabetic asymmetric proximal neuropathy (DAPN). Four hundred and forty-five patients with diabetes mellitus (DM), 257 women and 188 men, mean age 47.6±0.5 years, including 163 patients with DM type I and 282 with DM type II, were examined. Distal symmetric sensory motor polyneuropathy was found in 62% of the patients, autonomic neuropathy in 25.6%, somatic mononeuropathy in 28.5%, DAPN in 7.9%. DAPN was more frequent in patients with DM type II (9.6), with poor control of glycemia and DM duration more than 5 years. Pain and paresthesia in a zone of innervation of several roots and nerves, amyotrophy that spread beyond the definite myotome were key symptoms of DAPN. The efficacy of double therapy of neuropathic pain (pregabalin and duloxetine) and vitamin B complex was shown. A role of glucocorticoids and normal human immunoglobulin in treatment of DAPN is discussed.


p38 mitogen-activated protein kinase plays an inhibitory role in hepatic lipogenesis.
Hepatic lipogenesis is the principal route to convert excess carbohydrates into fatty acids and is mainly regulated by two opposing hormones, insulin and glucagon. Although insulin stimulates hepatic lipogenesis, glucagon inhibits it. However, the mechanism by which glucagon suppresses lipogenesis remains poorly understood. In this study, we have observed that p38 mitogen-activated protein kinase plays an inhibitory role in hepatic lipogenesis. Levels of plasma triglyceride and triglyceride accumulation in the liver were both elevated when p38 activation was blocked. Expression levels of central lipogenic genes, including sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase, hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl pyrophosphate synthase, and cytochrome P-450-51, were decreased in liver by fasting and in primary hepatocytes by glucagon but increased by the inhibition of p38. In addition, we have shown that p38 can inhibit insulin-induced expression of key lipogenic genes in isolated hepatocytes. Our results in hepatoma cells demonstrate that p38 plays an inhibitory role in the activation of the SREBP-1c promoter. Finally, we have shown that transcription of the PGC-1beta gene, a key coactivator of SREBP-1c, was reduced in liver by fasting and in isolated hepatocytes by glucagon. This reduction was significantly reversed by the blockade of p38. Insulin-induced expression of the PGC-1beta gene was enhanced by the inhibition of p38 but suppressed by the activation of p38. Together, we have identified an inhibitory role for p38 in the transcription of central lipogenic genes, SREBPs, and PGC-1beta and hepatic lipogenesis.


'We should be vaccinating domestic and wild animal species against Covid-19'.
Giovanni Di Guardo argues that there is evidence of zoonotic spread of SARS-CoV-2 from wild and domestic animal species to people, and that to limit the development of new variants, vaccines should be developed for, and vaccination programmes include, species capable of becoming infected with and transmitting the virus.


Integrative Therapies for Women with a High Risk Pregnancy During Antepartum Hospitalization.
High-risk pregnancies that require lengthy hospitalization can cause anxiety and stress for pregnant women. Integrative medicine therapies may be beneficial for this population, but have not been widely studied. The purpose of this study was to evaluate potential effects of acupuncture, guided imagery, Healing Touch, massage therapy, and reflexology on pain and anxiety of hospitalized pregnant women. A retrospective analysis of the effects of integrative medicine therapies was conducted; N = 554 individual therapies were provided to hospitalized women with high-risk pregnancies. They included acupuncture (n = 83), guided imagery (n = 71), Healing Touch (n = 119), massage therapy (n = 196), and reflexology (n = 85) over an 18-month period. Pain and anxiety were measured pre- and posttherapy using a scale of 0 to 10, where 0 means no pain or no anxiety and 10 means high pain or high anxiety. Analysis of mean scores of pre- and posttherapies for pain and anxiety found a decrease of pain and anxiety after all of the therapies, ranging from an 84.5% to 61.4% decrease for pain (p < .0001) and a 91% to 70. 9% decrease for anxiety (p < .0001). Overall, patients rated their anxiety higher than pain prior to each therapy. Hospitalized pregnant women responded favorably to the therapies. There were no adverse reactions reported. Results suggest potential benefits of integrative medicine therapies for this group of inpatients. Anxiety was more prevalent than pain among hospitalized pregnant women who received integrative medicine therapy.


Exercise increases hyper-acetylation of histones on the Cis-element of NRF-1 binding to the Mef2a promoter: Implications on type 2 diabetes.
Exercise brings changes on the chromatin ensuing the upregulation of many genes that confer protection from type 2 diabetes. In type-2 diabetes, critical genes are down-regulated such as those involved in glucose transport (GLUT4, MEF2A) and also oxidative phosphorylation (NRF-1 and its target genes). Recent reports have shown that NRF-1 not only regulate mitochondrial oxidative genes but also controls MEF2A, the main transcription factor for glucose transporter, GLUT4. Such dual control of the two pathways by NRF-1 place it as critical gene in the design of therapeutic modalities much needed to cure or better manage type 2 diabetes. Although it is known that NRF-1 controls these dual pathways (glucose transport and oxidative phosphorylation), the actual molecular mechanisms involved surrounding this regulation remains elusive. NRF-1 itself is regulated through posttranslational modifications (acetylation, methylation and phosphorylation) resulting in enhanced binding to its target genes. This study is therefore aimed at assessing whether CaMKII, a kinase activated by exercise brings about hyper-acetylation of histones in the vicinity of NRF-1 target gene, Mef2a. Five to six weeks old male Wistar rats were used in this study. Chromatin immunoprecipitation (ChIP) assay was used to investigate the extent through which NRF-1 is bound to the Mef2a gene and if this was associated with hyper-acetylation of histones in the region of NRF-1 binding site of the Mef2a gene. Quantitative real time PCR (qPCR) was used to determine the gene expression of MEF2A and NRF-1. Results from this study indicated that exercise-induced CaMKII activation increased hyper-acetylation of histones in the region of NRF-1 binding site on vicinity of Mef2a gene and this was associated with the increased binding of NRF-1 to Mef2a gene. Exercise also increased the expression of NRF-1 and MEF2A genes. Administration of CaMKII inhibitor (KN93) prior to exercise attenuated the observed exercise-induced increase of NRF-1 and MEF2A expressions. In conclusion, this study demonstrated for the first time in our knowledge one mechanism through which NRF-1 regulates MEF2A, pathway critical in glucose transport.


[The focus in neonatology].
During the last years, neonatology has greatly improved. In the last decade, mortality and morbidity have decreased: mortality from respiratory failure of prematurity has decreased from 22% to 12%, mortality of the very low birthweight infants under 1000 g fell from 56% to 35% and mortalities related to asphyxia have diminished from 21% to 12% and to malformations from 33% to 28%. Prematurity is now the first cause of neonatal mortality. During this period, the number of babies under 1000 g has increased 4-fold and the number of multiple births increased more than 2-fold from 3% to 7% of the live births of our hospital. Attitudes towards the premature infant have changed, especially towards the extremely small (called the micropremies). The number of disabled children has increased in parallel with the better survival of the very immature newborns who till recently were not resuscitated.


QT prolongation and development of torsades de pointes with the concomitant administration of oral erythromycin base and quinidine.
Torsades de pointes is a polymorphic ventricular tachycardia characterized by marked QT prolongation on the electrocardiogram. It can be induced by both antiarrhythmic and nonantiarrhythmic drugs, such as quinidine and erythromycin. No extensive literature documents an interaction between quinidine and erythromycin when the agents are administered orally. A 95-year-old man received oral quinidine and erythromycin for the treatment of atrial fibrillation and community-acquired pneumonia. He developed torsades de pointes and subsequently cardiac arrest. Since erythromycin and quinidine are known to cause arrhythmias individually, caution and close monitoring are necessary when the drugs are administered concomitantly.


Use of Aspirin and P2Y12 Response Assays in Detecting Reversal of Platelet Inhibition With Platelet Transfusion in Patients With Traumatic Brain Injury on Antiplatelet Therapy.
At present, guidelines are lacking on platelet transfusion in patients with a traumatic intracranial bleed and history of antiplatelet therapy. The aspirin and P2Y 12 response unit (ARU and PRU, respectively) assays detect the effect of aspirin and P2Y 12 inhibitors in the cardiac population. To describe the reversal of platelet inhibition after platelet transfusion using the ARU and PRU assays in patients with traumatic brain injury. Between 2010 and 2015, we conducted a prospective comparative cohort study of patients presenting with a positive head computed tomography and a history of antiplatelet therapy. ARU and PRU assays were performed on admission and 6 hours after transfusion, with a primary end point of detection of disinhibition after platelet transfusion. One hundred seven patients were available for analysis. Seven percent of patients taking aspirin and 27% of patients taking clopidogrel were not therapeutic on admission per the ARU and PRU, respectively. After platelet transfusion, 51% of patients on any aspirin and 67% of patients on any clopidogrel failed to be reversed. ARU increased by 71 ± 76 per unit of apheresis platelets for patients taking any aspirin, and PRU increased by 48 ± 46 per unit of apheresis platelets for patients taking any clopidogrel. A significant percentage of patients taking aspirin or clopidogrel were not therapeutic and thus would be unlikely to benefit from a platelet transfusion. In patients with measured platelet inhibition, a single platelet transfusion was not sufficient to reverse platelet inhibition in almost half.


Fresh osteochondral allografting for osteochondral lesions of the talus.
Osteochondral lesions of the talus (OLT) are relatively common sequelae of traumatic injuries involving the talus. We report on clinical outcomes of osteochondral allografting (OCA) of the talus for refractory, symptomatic OLT. OCA was performed in 12 ankles in 11 patients with OLT. All involved partial, unipolar grafts of the talar dome, implanted through an anterior approach without osteotomy, under temporary distraction. Clinical evaluation was performed utilizing the Olerud-Molander Ankle Score (OMAS). Subjective outcome measures included patient questionnaires evaluating pain, function, and satisfaction. Eleven patients (seven males, four females) had a mean age of 35.5 (range, 26 to 57) years. One patient had bilateral involvement. Six OLT affected the medial, six the lateral talar dome. Patients had an average of 1.8 previous surgeries (range, 1 to 5). Mean followup was 38 (range, 24 to 107) months. Mean OMAS improved from 28 to 71 points (p < 0.05). Three had further surgery; overall graft survival rate was 10/12. Of surviving grafts, 30% recorded excellent (OMAS: 100 to 91 points), 20% good (OMAS: 90 to 61 points), 30% fair (OMAS: 60 to 31 points), and 20% poor (OMAS: 30 to 0 points) outcomes. All non-failing patients completed questionnaires; 90% were satisfied, 80% reported reduced pain, and 60% improved function. OCA achieved good to excellent results in five of 12 patients, resulting in significant improvement in function and pain with good patient satisfaction. All but one patient avoided arthrodesis. Partial talus OCA is a reasonable treatment option for appropriately selected patients with unipolar OLT.


Reducing visible aerosol generation during phacoemulsification in the era of Covid-19.
To assess potential methods of reducing visible aerosol generation during clear corneal phacoemulsification surgery in the era of Covid-19. Aerosol generation during phacoemulsification was assessed using a model comprising a human cadaveric corneoscleral rim mounted on an artificial anterior chamber. Typical phacoemulsification settings were used and visible aerosol production was recorded using high-speed 4K camera. Aerosolisation was evaluated under various experimental settings: Two different phacoemulsification tip sizes (2.2, 2.75 mm), varying levels of corneal moisture, the use of suction and blowing air in the surgical field, the use of hydroxypropyl methylcellulose (HPMC) coating of the cornea with a static and moving tip. This model demonstrates visible aerosol generation during phacoemulsification with a 2.75-mm phacoemulsification tip. No visible aerosol was noted with a 2.2-mm tip. The presence of visible aerosol was unrelated to corneal wetting. Suction in close proximity to the aerosol plume did not impact on its dispersion. Blowing air redirected the aerosol plume toward the ocular surface. Visible aerosol production was abolished when HPMC was used to coat the cornea. This effect lasted for an average of 67 ± 8 s in the static model. Visible aerosol generation was discerned during movement of the 2.2-mm tip toward the corneal wound. We demonstrate visible aerosol production in the setting of a model of clear corneal phacoemulsification. Visible aerosol can be reduced using a 2.2-mm phacoemulsification tip and reapplying HPMC every minute during phacoemulsification.


Predicting factors associated with prolonged intensive care unit stay of patients with COVID-19.
Predicting the length of stay (LOS) for coronavirus disease 2019 (COVID-19) patients in the intensive care unit (ICU) is essential for efficient use of ICU resources. We analyzed the clinical characteristics of patients with severe COVID-19 based on their clinical care and determined the predictive factors associated with prolonged LOS. We included 96 COVID-19 patients who received oxygen therapy at a high-flow nasal cannula level or above after ICU admission during March 2021 to February 2022. The demographic characteristics at the time of ICU admission and results of severity analysis (Sequential Organ Failure Assessment [SOFA], Acute Physiology and Chronic Health Evaluation [APACHE] II), blood tests, and ICU treatments were analyzed using a logistic regression model. Additionally, blood tests (C-reactive protein, D-dimer, and the PaO2 to FiO2 ratio [P/F ratio]) were performed on days 3 and 5 of ICU admission to identify factors associated with prolonged LOS. Univariable analyses showed statistically significant results for SOFA score at the time of ICU admission, C-reactive protein level, high-dose steroids, mechanical ventilation (MV) care, continuous renal replacement therapy, extracorporeal membrane oxygenation, and prone position. Multivariable analysis showed that MV care and P/F ratio on hospital day 5 were independent factors for prolonged ICU LOS. For D-dimer, no significant variation was observed at admission; however, after days 3 and 5 days of admission, significant between-group variation was detected. MV care and P/F ratio on hospital day 5 are independent factors that can predict prolonged LOS for COVID-19 patients.


Polarity, protrusion-retraction dynamics and their interplay during keratinocyte cell migration.
Keratinocyte migration on a two-dimensional substrate can be split into four distinct phases: cell extension, attachment, contraction, and detachment. It is preceded by polarization of the cell which leads to a functional asymmetry observable by the formation of a leading lamella. In this work variation of fibronectin coating concentrations and competitive inhibition with RGD peptides are used to investigate the dependency of polarization, migration, lamella dynamics, and ruffling on substrate adhesiveness. Looking at migrating human epidermal keratinocytes with a well-defined polarity we find that a fibronectin-coating concentration of 10 microg/cm(2) stimulates migration and ruffling speed twofold, whereas protrusion speed increases only by 20% (compared to 2.5 microg/cm(2) fibronectin). Nonpolar cells show a constant migration and ruffling speed independent of the amount of fibronectin. In contrast protrusion speeds of polar and nonpolar cells are equal. Treatment of cells on 10 microg/cm(2) fibronectin with 1 mg/ml GRGDS reduces the characteristic migration, protrusion, and ruffling speed of polar cells which corresponds to lowering the effective coating concentration to under 5 microg/cm(2). The probability of being polarized (quantified by a polarity index) increases with increasing fibronectin concentration. However, addition of soluble RGD on 10 microg/cm(2) fibronectin does not simply reduce the polarity index like one would expect from the corresponding changes in the other motility parameters, but it remains unchanged.


Psychiatric morbidity in psoriasis: a review.
Psoriasis is a common condition, affecting 1.5-2% of the population of industrialized countries. It is important for clinicians to be aware that psoriasis can have a substantial emotional impact on an individual, which is not necessarily related to the extent of skin disease. This review examines current literature addressing the psychological and emotional aspects of psoriasis. A literature search of the MEDLINE (1966-2002) and PsycINFO (1984-2002) computer databases and bibliographies was carried out. Papers selected for the review included English language reviews and all original research relevant to the topic, in the form of randomized controlled trials, cohort studies, case-control studies, cross-over and uncontrolled clinical trials, patient surveys, quality-of-life studies, case series and case reports. Despite significant shortcomings, the available prevalence studies showed uniformly high rates of psychopathology among psoriasis sufferers. The few intervention studies available are summarized and critically discussed. Psoriasis is associated with a variety of psychological problems, including poor self esteem, sexual dysfunction, anxiety, depression and suicidal ideation. The clinical severity of the psoriasis may not reflect the degree of emotional impact of the disease. A number of psychological interventions have shown promise in recent trials. It is important that clinicians consider the psychosocial aspects of this illness.


African horse sickness and the overwintering of Culicoides spp. in the Iberian peninsula.
The presence at different latitudes and the seasonal distribution of two known or potential vectors of African horse sickness (AHS) virus--Culicoides imicola and C. obsoletus--were investigated in the Iberian peninsula using light trap collections. Culicoides imicola was present as far north as 41 degrees N but not at 43 degrees N (Asturias, Spain), whereas C. obsoletus was found at all latitudes. In the northern part of the distribution of C. imicola, adults of this species were present for only a few months of the year, but adults were continually present further south. Culicoides obsoletus could be found in all months of the year in the peninsula (as in southern Britain), despite cold winter conditions. These results were compared to data from the AHS outbreak in 1987-1990 in the Iberian peninsula, to indicate the potential for the disease to persist from year to year and expand more fully in the palaearctic regions of Europe.


[How do we reduce the under-reporting of occupational primary lung cancer].
The under-reporting of occupational lung cancer is due to insufficient recognition of occupational exposure and inadequate medico-legal action. All cases of primary bronchial carcinoma seen at the University Hospital of Grenoble between October 1996 and December 1998 completed a standardised questionnaire set by a physician in occupational medicine. When evidence of exposure to occupational carcinogens was established a claim for occupational disease was made and the outcomes of these claims were obtained from the Department of Social Security at the end of 2000. Asbestos was the most common carcinogenic agent found, followed by crystalline silica, diesel fumes, metals, paints and ionising radiation. Among the 305 patients in the study with primary bronchial carcinoma 20% were able to make a claim for occupational disease whereas only 2% would have claimed otherwise. The Department of Social Security accepted 77% of the 39 claims for occupational disease submitted, thus giving a 12% incidence of occupational bronchial carcinoma in this group. It is important to inform and instruct doctors of the environmental risks that are additional to those of tobacco smoking and of the need of inquire into any exposure to carcinogenic agents in order to ensure that the victims receive the appropriate medico-legal benefits. Improved primary prevention alone might eventually avoid the development of up to 3 500 cases of occupation bronchial carcinoma per year in France.


Optimization of Extraction Condition for Alisol B and Alisol B Acetate in Alismatis Rhizoma using Response Surface Methodology.
Alismatis Rhizoma is a perennial herb originating from the rhizomes of Alisma orientalis (Sam) Juzep and the same species which have been used to treat seborrheic dermatitis, eczema, polydipsia, and pedal edema. We aimed to determine the concentrations of the compounds alisol B and alisol B acetate present in a sample of the herb using high-performance liquid chromatography coupled with a photodiode array detector. We selected methanol as the optimal solvent considering the structures of alisol B and alisol B acetate. We estimated the proportion of alisol B and alisol B acetate in a standard extract to be 0.0434% and 0.2365% in methanol, respectively. To optimize extraction, we employed response surface methodology to determine the yields of alisol B and alisol B acetate, which mapped out a central composite design consisting of 15 experimental points. The extraction parameters were time, concentration, and sample weight. The predicted concentration of alisol B derivatives was estimated to be 0.2388% under the following conditions: 81 min of extraction time, 76% of methanol concentration, and 1.52g of sample weight.


Bilateral simultaneous Bell's palsy. Two cases following herpes simplex gingivostomatitis.
Bilateral simultaneous Bell's palsy (BSBP) is an infrequent clinical presentation. Two patients with BSBP following a recent herpes simplex gingivostomatitis are described. From a clinical point of view, these cases support the concept that Bell's palsy may be a partial manifestation of a generalized polyneuropathy, and most probably caused by a reactivated latent herpes simplex virus.


Detection of lymphokines and lymphokine receptors in pulmonary sarcoidosis. Immunohistologic evidence that inflammatory macrophages express IL-2 receptors.
In an investigation of the immunopathogenesis of sarcoidosis, the authors undertook the tissue localization of those lymphokines and lymphokine receptors which are known to play a central role in T-cell and macrophage activation. Using monoclonal antibodies and an ABC immunoperoxidase technique. They determined the distribution of gamma interferon (IFN-g), interleukin-2 (IL-2), and corresponding IL-2 receptors (IL-2R), plus T cells and T cell subsets, B cells, and macrophages within thoracic lymph nodes and lung specimens of 9 patients with active pulmonary sarcoidosis. Epithelioid and multinucleate giant cells within sarcoid granulomas of all specimens showed membrane labeling for IL-2R and IFN-g, in addition to IL-2, suggesting that these cells indeed express functional IL-2 receptors. Infiltrating T cells, largely T4+, were also IL-2R+, and many showed IL-2 and IFN-g labeling. By comparison, macrophages within sections of normal lung or lymph node failed to stain for IL-2, IL-2R, or IFN-g. These immunohistologic studies extend recent in vitro observations by these authors and others that normal human blood monocytes and alveolar macrophages are induced by IFN-g or IL-2 to express functional membrane-bound IL-2 receptors. The in vivo expression of IL-2R by mononuclear phagocytes in pulmonary sarcoidosis is demonstrated, and a new role is suggested for T-cell-derived lymphokines in macrophage activation.


Performance report cards increase adenoma detection rate.
Adenoma detection rate (ADR) is an important measure of colonoscopy quality, as are polyp, advanced ADR, and adenocarcinoma detection rates. We investigated whether performance report cards improved these outcome measures. Endoscopists were given report cards comparing their detection rates to the institutional mean on an annual basis. Detection rates were evaluated at baseline, 1 year after report cards (Year 1), and 2 years after report cards (Year 2). Endoscopists were unaware of the study and received no other interventions. The primary outcome was ADR and secondary outcomes were polyp detection rate (PDR), advanced ADR, and adenocarcinoma detection rate. Multivariate regression was performed to adjust for temporal trends in patient, endoscopists, and procedural factors. Seventeen physicians performed 3,118 screening colonoscopies in patients with positive FOBT or family history of colon cancer. The ADR increased from 34.5 % (baseline) to 39.4 % (Year 1) and 41.2 % (Year 2) ( P = 0.0037). The PDR increased from 45 % (baseline) to 48.8 % (Year 1) and 51.8 % (Year 2) ( P = 0.011). There was no significant improvement in advanced ADR or adenocarcinoma detection rates. On multivariate analysis, the ADR increased by 22 % in Year 1 ( P = 0.03) and 30 % in Year 2 ( P = 0.008). Among physicians with a baseline ADR < 25 %, improvement in ADR was even greater, increasing 2.2 times by the end of the study ( P = 0.004). Improvements in ADR were not correlated with specialty although gastroenterologists were 52 % more likely to find an adenoma than general surgeons. Annual performance report cards increased adenoma detection rates, especially among physicians with low ADR < 25 %.


Enhanced sampling of nonequilibrium steady states.
We review recent progress in methods for accelerating the convergence of simulations of nonequilibrium systems, specifically nonequilibrium umbrella sampling (NEUS) and forward flux sampling (FFS). These methods account for statistics of dynamical paths between interfaces to enforce sampling of low probability regions of phase space for computing steady-state averages, including transition rates, for systems driven arbitrarily far from equilibrium. Recent advances in NEUS allow for efficient sampling of complex systems by focusing sampling in the vicinity of a one-dimensional manifold (string) that connects regions of interest in phase space; this procedure can be extended to the case of two strings that describe the forward and backward transition ensembles separately, which is useful, as they do not, in general, coincide. We recast FFS in the framework of NEUS to facilitate comparison of the two methods. We conclude by discussing selected applications of interest.


Ocular Trauma in Children: An Epidemiological Study.
This study aimed to determine the epidemiology of eye injuries in children and the influential factors involved. Eighty cases of confirmed ocular trauma were included in this cross-sectional study. Data were obtained via a checklist containing demographic information, site of the insult, the interval between the injury and physician visit, trauma mechanism, and medical history, including previous history of ocular trauma. Among 80 children with ocular trauma, 72.5% (n = 58) were boys. A marked preponderance (46.2%) of injuries was seen in the age group younger than 6 years. The youngest patient was a 1-year-old, and the oldest was aged 17. Most (76.25%) of the incidents occurred indoors. A total of 67.5% of accidents were induced by sharp objects (knife and glass). Most accidents occurred in spring, whereas the least number of accidents occurred in winter. The corneoscleral laceration was the most common manifestation, followed by the laceration of the iris, uveal prolapse, hyphema, and cataracts. Furthermore, rare cases of retinal detachment, hypopyon, and corneal epithelial defects were seen. The highest incidents of ocular trauma occurred in boys, especially those younger than 6 years. The high number of sharp object injuries is also concerning. These findings provide us with evidence that further educational interventions and supervision are required in these groups to minimize the possible devastating injuries before the opportunity even arises.


Intestinal metaplasia with dysplasia in pelvis of a horse-shoe kidney.
Intestinal metaplasia of renal pelvis occurs uncommonly and is usually secondary to persistent chronic irritation or inflammation. It is considered to be precursor of adenocarcinoma. A case of horse-shoe kidney which showed extensive intestinal metaplasia and focal severe dysplasia in the renal pelvis is being presented. The metaplastic change in this case is being attributed to persistent inflammation due to more chances of stasis in horse-shoe kidney coupled with renal calculi.


Aelius Aristides and Asklepius: the joy of being ill.
Aelius Aristides, a writer of the 2nd century A.D., belongs to an important group of literary figures who wanted to relaunch Greek culture and civilization against the political power of the Romans. But among those works of his which have been preserved there is also an incomplete diary in which he talks of a terrible illness which had afflicted him as a youth and for which he had sought the help of the god of medicine, Asklepius. His pains and sufferings are described in hyperbolic manner. Aristides also informs the reader about the wonderful cures he received at the temple of Asklepius in Pergamon and about his healing talks with the god of medicine.


Aldosterone-Induced Sarco/Endoplasmic Reticulum Ca2+ Pump Upregulation Counterbalances Cav1.2-Mediated Ca2+ Influx in Mesenteric Arteries.
In mesenteric arteries (MAs), aldosterone (ALDO) binds to the endogenous mineralocorticoid receptor (MR) and increases the expression of the voltage-gated L-type Cav1.2 channel, an essential ion channel for vascular contraction, sarcoplasmic reticulum (SR) Ca2+ store refilling, and Ca2+ spark generation. In mesenteric artery smooth muscle cells (MASMCs), Ca2+ influx through Cav1.2 is the indirect mechanism for triggering Ca2+ sparks. This process is facilitated by plasma membrane-sarcoplasmic reticulum (PM-SR) nanojunctions that drive Ca2+ from the extracellular space into the SR via Sarco/Endoplasmic Reticulum Ca2+ (SERCA) pump. Ca2+ sparks produced by clusters of Ryanodine receptors (RyRs) at PM-SR nanodomains, decrease contractility by activating large-conductance Ca2+-activated K+ channels (BKCa channels), which generate spontaneous transient outward currents (STOCs). Altogether, Cav1.2, SERCA pump, RyRs, and BKCa channels work as a functional unit at the PM-SR nanodomain, regulating intracellular Ca2+ and vascular function. However, the effect of the ALDO/MR signaling pathway on this functional unit has not been completely explored. Our results show that short-term exposure to ALDO (10 nM, 24 h) increased the expression of Cav1.2 in rat MAs. The depolarization-induced Ca2+ entry increased SR Ca2+ load, and the frequencies of both Ca2+ sparks and STOCs, while [Ca2+]cyt and vasoconstriction remained unaltered in Aldo-treated MAs. ALDO treatment significantly increased the mRNA and protein expression levels of the SERCA pump, which counterbalanced the augmented Cav1.2-mediated Ca2+ influx at the PM-SR nanodomain, increasing SR Ca2+ content, Ca2+ spark and STOC frequencies, and opposing to hyperpolarization-induced vasoconstriction while enhancing Acetylcholine-mediated vasorelaxation. This work provides novel evidence for short-term ALDO-induced upregulation of the functional unit comprising Cav1.2, SERCA2 pump, RyRs, and BKCa channels; in which the SERCA pump buffers ALDO-induced upregulation of Ca2+ entry at the superficial SR-PM nanodomain of MASMCs, preventing ALDO-triggered depolarization-induced vasoconstriction and enhancing vasodilation. Pathological conditions that lead to SERCA pump downregulation, for instance, chronic exposure to ALDO, might favor the development of ALDO/MR-mediated augmented vasoconstriction of mesenteric arteries.


Identification of epigenetic methylation-driven signature and risk loci associated with survival for colon cancer.
Abnormal methylation is associated with the survival of colon cancer. This study intended to discover a significant model based on methylation-driven genes (MDGs) and screen relative risk loci to assist with determining the prognoses of colon cancer patients. We downloaded transcriptome expression profiles and 450K methylation data from the TCGA database. We then collected the two normalized profiles and utilized the MethylMix package to identify a significant signature showing the aberrantly methylated events highly correlated with expression levels. Also, functional enriched pathway analysis based on the ConsensusPathDB database was conducted to further explore the underlying cancer-related crosstalk among the identified MDGs. To find the significant MDGs for prognosis, we applied a univariate Cox regression model, and the hub signature was identified based on the stepwise regression method. A risk model based on MDGs was constructed from the multivariate Cox analysis, and a receiver operating characteristic (ROC) curve was drawn to assess the predictive value of the MDG signature. Additionally, the Kruskal-Wallis (K-W) test was conducted to compare differential distributions of risk scores across groups of clinical variables. Furthermore, the methylation sites relating to the hub genes were screened out and the prognostic genes were searched using the Cox regression method. Last, we carried out gene set enrichment analysis (GSEA) with the risk score levels serving as the phenotype base on the JAVA platform. A total of 514 colon cancer samples with transcriptome profiles, including 473 tumor samples and 41 matched normal samples, were downloaded. We also obtained 351 methylation profiles comprising 314 tumor samples and 37 normal samples. The 320 MDGs identified by MethylMix were enriched in the generic transcription pathway, RNA polymerase II transcription, activation of SMO, or glutathione metabolism. Furthermore, a 10-MDGs signature was selected as the hub prognostic marker, and the risk model was constructed from the multivariate Cox regression results. We also discovered multiple specific methylated sites that were highly associated with survival. Finally, the GSEA results suggested that several enriched pathways were associated with the identified risk drivers, including extracellular matrix (ECM) receptor interaction, chemokine receptor interaction, and pathways in cancer, as well as calcium signaling pathways. We conducted a comprehensive investigation of the molecular mechanisms in colon cancer by discovering the risk methylation-driven signature combined with relative methylated sites and constructing a risk model to predict prognosis.


Bilateral carotid body tumor resection in a female patient.
Carotid body tumors also called carotid paragangliomas are rare neuroendocrine neoplasms derived from neural crest cells, approximately 3% of all paragangliomas occur in the head and neck area (Xiao and She, 2015); although they represent 65% of the head and neck paragangliomas (Georgiadis et al., 2008). We present the therapeutic management of a 65-year-old woman with bilateral carotid body tumors. The patient presented to medical clinic for unrelated signs and symptoms of weight loss, dyspepsia, and epigastric pain. Physical examination showed bilateral non-tender neck masses for which imaging studies were ordered resulting in the diagnosis of bilateral carotid tumor. Surgical resection was staged with one week of distance between each tumor resection. Carotid Body Tumors can arise from the paraganglia located within the adventitia of the medial aspect of the carotid bifurcation.Resection is the only curative treatment. Carotid body tumors resection represents a special challenge due to potential neurovascular complications. Surgical resection of carotid body tumors represents a special challenge to the surgeon because of the complex anatomical location of the tumor, including close relationship with the cranial nerves, involvement of the carotid vessels and large vascularization of the tumor. With the advance of diagnosis and improvement in surgical techniques as well as the understanding of biological behavior of tumors, surgical treatment has become a safer alternative for treating these tumors.


Site-Resolved and Quantitative Characterization of Very Weak Protein-Ligand Interactions.
Very weak interactions between small organic molecules and proteins have long been predicted and are expected to have dissociation constants of hundreds of millimolar and above. Unfortunately, quantitative evaluation of binding in a high-resolution structural context for this affinity regime is particularly difficult and often impossible using existing experimental approaches. Here, we show that nanoscale encapsulation of single protein molecules within the water core of reverse micelles enables the detection and evaluation of weak binding interactions at atomic resolution using solution NMR spectroscopy. This strategy is used to survey the interactions of a set of small molecules with the cytokine interleukin-1β (IL-1β). The interaction of IL-1β with these molecules is found to vary from more diffuse and weak binding modes to more specific and with a relatively higher affinity. The interactions detected here cover a large portion of the protein surface and have dissociation constants mostly in the low molar range. These results illustrate the ability of a protein to interact productively with a variety of small molecule functional groups and point to a broader potential to target even relatively featureless protein surfaces for applications in chemical biology and drug discovery.


DNA barcoding in Atlantic Forest plants: What is the best marker for Sapotaceae species identification?
The Atlantic Forest is a phytogeographic domain with a high rate of endemism and large species diversity. The Sapotaceae is a botanical family for which species identification in the Atlantic Forest is difficult. An approach that facilitates species identification in the Sapotaceae is urgently needed because this family includes threatened species and valuable timber species. In this context, DNA barcoding could provide an important tool for identifying species in the Atlantic Forest. In this work, we evaluated four plant barcode markers (matK, rbcL, trnH-psbA and the nuclear ribosomal internal transcribed spacer region - ITS) in 80 samples from 26 species of Sapotaceae that occur in the Atlantic Forest. ITS yielded the highest average interspecific distance (0.122), followed by trnH-psbA (0.019), matK (0.008) and rbcL (0.002). For species discrimination, ITS provided the best results, followed by matK, trnH-psbA and rbcL. Furthermore, the combined analysis of two, three or four markers did not result in higher rates of discrimination than obtained with ITS alone. These results indicate that the ITS region is the best option for molecular identification of Sapotaceae species from the Atlantic Forest.


[Efficacy of gefitinib (Iressa) in the treatment of an inoperable bronchioloalveolar cell carcinoma].
Bronchioloalveolar cell carcinoma (BAC) is a rare bronchial tumour. At present the only curative treatment is surgery and inoperable cases are often resistant to radio and chemotherapy. A 76 year old woman was treated surgically for a BAC, stage T2N0M0. Three months later she presented with cough and dyspnoea. Investigation revealed recurrence of the disease with bilateral pulmonarymetastases. She then received two courses of chemotherapy leading, at best, to stabilisation of the disease. At that time the treatment decision was simple observation. Six months later when there was progression of the bilateral lesions treatment was initiated with gefitinib 250 mg daily. This lead to rapid improvement in the clinical symptoms and the chest x-ray and CT scan showed evidence of a partial response that persisted one year after the beginning of treatment. This observation describes the effect of gefitinib in the treatment of inoperable BAC for which there is, at present, no effective therapy.


Birth defects: prevention of neural tube defects by periconceptional use of folic acid and screening.
Folate deficiency is one of today's most common vitamin deficiencies in women. Women who consume a low level of folate during pregnancy are at risk for poor pregnancy outcomes including birth defects. Birth defects are the leading cause of fetal and infant deaths throughout the world. Neural tube defects comprise a major portion of the birth tube defects. Neural tube defects are common and serious malformations that originate early in pregnancy. Each year in the US, about 4000 babies are born with these two most common neural tube defects, spina bifida and anencephaly. Spina bifida is the leading cause of childhood paralysis. Several studies showed that about 70% of the neural tube defects could be prevented if all women capable of becoming pregnant consumed 0.4 mg of folic acid daily before and during early pregnancy. This paper reports results from various human and animal studies.


Opening-assisted coherent transport in the semiclassical regime.
We study quantum enhancement of transport in open systems in the presence of disorder and dephasing. Quantum coherence effects may significantly enhance transport in open systems even in the semiclassical regime (where the decoherence rate is greater than the intersite hopping amplitude), as long as the disorder is sufficiently strong. When the strengths of disorder and dephasing are fixed, there is an optimal opening strength at which the coherent transport enhancement is optimized. Analytic results are obtained in two simple paradigmatic tight-binding models of large systems: the linear chain and the fully connected network. The physical behavior is also reflected in the Fenna-Matthews-Olson (FMO) photosynthetic complex, which may be viewed as intermediate between these paradigmatic models.


The beneficial effects of lymphocytapheresis for treatment of nephrotic syndrome.
A considerable permeability factor (or factors) derived from circulating T cells has a crucial role in proteinuria of nephrotic syndrome (NS). We attempted to remove pathogenic T cells through lymphocytapheresis (LCAP) in 6 patients with primary NS, 2 patients with minimal change nephrotic syndrome (MCNS), 2 patients with focal segmental glomerulosclerosis (FSGS), 1 patient with membranous nephropathy (MN), and 1 patient with MN and FSGS using Cellsorba (Asahi Medical Co., Osaka, Japan). LCAP was performed 2 times in 2 consecutive weeks and was followed with corticosteroid therapy with or without cyclosporine A in 5 patients. Two patients with MCNS, 1 with FSGS, and 1 with MN and FSGS showed a dramatic decrease of proteinuria (-30% and -94%) in their urine protein/creatinine ratio. Three out of 4 patients had a complete or partial remission (proteinuria <1g/day) within 8 weeks following immunosuppressive therapy. During the LCAP, T cells, especially activated T cells, decreased significantly in the response group. The other 2 patients, 1 with FSGS and 1 with MN, however, had no response to LCAP and following immunosuppressive therapy or low-density lipoprotein apheresis and suffered from end-stage renal failure or death by pneumonia. These results suggested that LCAP might have a beneficial effect on the treatment of NS, especially MCNS and in some patients with FSGS, despite varying responses to LCAP and concomitant immunosuppressive therapy.


Influence of caffeine on 3,4-methylenedioxymethamphetamine-induced dopaminergic neuron degeneration and neuroinflammation is age-dependent.
Previous studies have demonstrated that caffeine administration to adult mice potentiates glial activation induced by 3,4-methylenedioxymethamphetamine (MDMA). As neuroinflammatory response seems to correlate with neurodegeneration, and the young brain is particularly vulnerable to neurotoxicity, we evaluated dopamine neuron degeneration and glial activation in the caudate-putamen (CPu) and substantia nigra pars compacta (SNc) of adolescent and adult mice. Mice were treated with MDMA (4 × 20 mg/kg), alone or with caffeine (10 mg/kg). Interleukin (IL)-1β, tumor necrosis factor (TNF)-α, neuronal nitric oxide synthase (nNOS) were evaluated in CPu, whereas tyrosine hydroxylase (TH), glial fibrillary acidic protein, and CD11b were evaluated in CPu and SNc by immunohistochemistry. MDMA decreased TH in SNc of both adolescent and adult mice, whereas TH-positive fibers in CPu were only decreased in adults. In CPu of adolescent mice, caffeine potentiated MDMA-induced glial fibrillary acidic protein without altering CD11b, whereas in SNc caffeine did not influence MDMA-induced glial activation. nNOS, IL-1β, and TNF-α were increased by MDMA in CPu of adults, whereas in adolescents, levels were only elevated after combined MDMA plus caffeine. Caffeine alone modified only nNOS. Results suggest that the use of MDMA in association with caffeine during adolescence may exacerbate the neurotoxicity and neuroinflammation elicited by MDMA. Previous studies have demonstrated that caffeine potentiated glial activation induced by 3,4-methylenedioxymethamphetamine (MDMA) in adult mice. In this study, caffeine was shown to potentiate MDMA-induced dopamine neuron degeneration in substantia nigra pars compacta, astrogliosis, and TNF-α levels in caudate-putamen of adolescent mice. Results suggest that combined use of MDMA plus caffeine during adolescence may worsen the neurotoxicity and neuroinflammation elicited by MDMA.


Copper and gene regulation in yeast.
The essential trace element copper is also highly toxic when accumulated at high intracellular levels. Copper detoxification in the yeasts S.cerevisiae and C.glabrata is carried out, in large part, by small, cysteine-rich metal binding proteins known as metallothioneins (MTs). The biosynthesis of yeast metallothioneins, the S.cerevisiae copper, zinc superoxide dismutase, and presumably other important copper homeostatic proteins, is transcriptionally induced by elevated environmental copper concentrations through the action of copper metalloregulatory transcription factors (MRTFs). Copper coordination drives the formation of a structure distinct from the apo-protein, whereupon the DNA binding function of MRTFs is activated. The copper MRTFs, ACE1 from S.cerevisiae and AMT1 from C.glabrata, directly interact with specific copper-responsive cis-acting elements in the promotor regions of their respective target genes. The binding of copper, as a polynuclear cluster, to MRTFs provides a sensitive and rapid means of transducing the extracellular metal signal to activate gene transcription.


Review article: renal function assessment in cirrhosis - difficulties and alternative measurements.
Renal function in patients with cirrhosis is important prognostically, both before and following liver transplantation. Its prognostic impact is reflected by the inclusion of serum creatinine in the model for end-stage liver disease score, which is now used for recipient prioritization on liver transplantation waiting lists in the USA. To review the accuracy of the surrogate markers for the assessment of renal function, i.e. glomerular filtration rate, particularly in patients with cirrhosis. We reviewed the available literature in PubMed regarding the markers for GFR evaluation and the factors which affect their accuracy in cirrhosis. Although creatinine is widely available, it is an unreliable marker of glomerular filtration rate, particularly in patients with cirrhosis. Clearance of exogenous markers is considered the 'gold standard', but this methodology has many drawbacks, particularly poor applicability. Several mathematical formulae for estimated glomerular filtration rate are used to overcome some of these limitations: Cockcroft-Gault and Modification of Diet in Renal Disease formulae are the most frequently applied, but they are based on serum creatinine. Due to the inaccuracy of serum creatinine and its derived formulae in estimating glomerular filtration rate, alternative serum markers, such as cystatin C, and new formulae are desirable. These need formal evaluation in patients with cirrhosis so as to have a reliable surrogate of glomerular filtration rate, and to obviate many problems that are associated with using creatinine and estimated glomerular filtration rate.


Bone mass in young adulthood following gonadotropin-releasing hormone analog treatment and cross-sex hormone treatment in adolescents with gender dysphoria.
Sex steroids are important for bone mass accrual. Adolescents with gender dysphoria (GD) treated with gonadotropin-releasing hormone analog (GnRHa) therapy are temporarily sex-steroid deprived until the addition of cross-sex hormones (CSH). The effect of this treatment on bone mineral density (BMD) in later life is not known. This study aimed to assess BMD development during GnRHa therapy and at age 22 years in young adults with GD who started sex reassignment (SR) during adolescence. This was a longitudinal observational study at a tertiary referral center. Young adults diagnosed with gender identity disorder of adolescence (DSM IV-TR) who started SR in puberty and had undergone gonadectomy between June 1998 and August 2012 were included. In 34 subjects BMD development until the age of 22 years was analyzed. GnRHa monotherapy (median duration in natal boys with GD [transwomen] and natal girls with GD [transmen] 1.3 and 1.5 y, respectively) followed by CSH (median duration in transwomen and transmen, 5.8 and 5.4 y, respectively) with discontinuation of GnRHa after gonadectomy. How BMD develops during SR until the age of 22 years. Between the start of GnRHa and age 22 years the lumbar areal BMD z score (for natal sex) in transwomen decreased significantly from -0.8 to -1.4 and in transmen there was a trend for decrease from 0.2 to -0.3. This suggests that the BMD was below their pretreatment potential and either attainment of peak bone mass has been delayed or peak bone mass itself is attenuated.


Survival of frozen bone allograft.
One case of transplantation of a large osteochondral allograft, with long (8 years) time follow up is reported. Following excision of a benign giant cell tumour the distal part of the left femur, including the joint surfaces, was replaced by a frozen osteochondral allograft. The patient regained function with pain-free weight bearing, and good walking ability. However, the development of a pseudarthrosis between the graft and the host bone necessitated internal fixation and bone grafting two years after the initial surgery. Due to a progressive instability of the knee joint, the graft was replaced by a prosthetic implant eight years after tumor resection. Preoperative scintigraphy showed a high uptake over the grafted area, which corroborated the finding of good vascularization of the graft at surgery. In contrast, histology and fluorochrome uptake of the allograft showed sparse areas of new bone formation. It is concluded that a frozen bone allograft may prove a useful alternative, with good long term results, in the replacement of bone after large resections, in spite of slow and incomplete incorporation.