Sodium-potassium adenosine triphosphatase activity of human lymphocyte membrane vesicles: kinetic parameters, substrate specificity, and effects of phytohemagglutinin.
We have prepared human blood lymphocyte membrane vesicles of high purity in sufficient quantity for detailed enzyme analysis. This was made possible by the use of plateletpheresis residues, which contain human lymphocytes in amounts equivalent to thousands of milliliters of blood. The substrate specificity and the kinetics of the cofactor and substrate requirements of the human lymphocyte membrane Na+, K+-ATPase activity were characterized. The Na+, K+-ATPase did not hydrolyze ADP, AMP, ITP, UTP, GTP or TTP. The mean ATPase stimulated by optimal concentrations of Na+ and K+ (Na+, K+-ATPase) was 1.5 nmol of P(i) hydrolyzed, microgram protein-1, 30 min-1 (range 0.9-2.1). This activity was completely inhibited by the cardiac glycoside, ouabain. The K(m) for K+ was approximately 1.0 mM and the K(m) for Na+ was approximately 15 mM. Active Na+ and K+ transport and ouabain-sensitive ATP production increase when lymphocytes are stimulated by PHA. Na+, K+-ATPase activity must increase also to transduce energy for the transport of Na+ and K+. Some studies have reported that PHA stimulates the lymphocyte membrane ATPase directly. We did not observe stimulation of the membrane Na+, K+-ATPase when either lymphocytes or lymphocyte membranes were treated with mitogenic concentrations of PHA. Moreover, PHA did not enhance the reaction velocity of the Na+, K+-ATPase when studied at the K(m) for ATP, Na+, K+ OR Mg++, indicating that it does not alter the affinity of the enzyme for its substrate or cofactors. Thus, our data indicate that the increase in ATPase activity does not occur as a direct result of PHA action on the cell membrane.


[Treatment of non iatrogenic injury of retrohepatic inferior vena cava].
To study a repair method for injured retrohepatic inferior vena cava (IVC) associated with liver trauma. Laceration of IVC was sutured bloodlessly after the injured retrohepatic IVC was occluded by compression combined with occlusion of the first hepatic hilus. From April 1996 to January 1999, the injured IVC was successfully repaired in 6 patients. The length of laceration was 2.9 cm (1.5 - 4 cm). The occlusion time was 9.2 min (6 - 15 min) for the IVC and 20.5 min (15 - 29 min) for the first hepatic hilus, respectively. All patients recovered uneventfully, and the IVC was patency without stricture as showed by B-mode ultrasonography and CT. The injured retrohepatic IVC can be repaired by direct compression when the laceration of the IVC is caused by liver trauma.


Voronoi-based spatial analysis reveals selective interneuron changes in the cortex of FALS mice.
The neurodegenerative disease amyotrophic lateral sclerosis affects lower motoneurons and corticospinal cells. Mice expressing human mutant superoxide dismutase (SOD)1 provide widely investigated models of the familial form of disease, but information on cortical changes in these mice is still limited. We here analyzed the spatial organization of interneurons characterized by parvalbumin immunoreactivity in the motor, somatosensory, and visual cortical areas of SOD1(G93A) mice. Cell number and sociological spatial behavior were assessed by digital charts of cell location in cortical samples, cell counts, and generation of two-dimensional Voronoi diagrams. In end-stage SOD1-mutant mice, an increase of parvalbumin-containing cortical interneurons was found in the motor and somatosensory areas (about 35% and 20%, respectively) with respect to wild-type littermates. Changes in cell spatial distribution, as documented by Voronoi-derived coefficients of variation, indicated increased tendency of parvalbumin cells to aggregate into clusters in the same areas of the SOD1-mutant cortex. Counts and coefficients of variation of parvalbumin cells in the visual cortex gave instead similar results in SOD1-mutant and wild-type mice. Analyses of motor and somatosensory areas in presymptomatic SOD1-mutant mice provided findings very similar to those obtained at end-stage, indicating early changes of interneurons in these cortical areas during the pathology. Altogether the data reveal in the SOD1-mutant mouse cortex an altered architectonic pattern of interneurons, which selectively affects areas involved in motor control. The findings, which can be interpreted as pathogenic factors or early disease-related adaptations, point to changes in the cortical regulation and modulation of the motor circuit during motoneuron disease.


11C-2-deoxy-D-glucose: synthesis and preliminary comparison with 11C-D-glucose as a tracer for cerebral energy metabolism in PET studies.
11C-2-Deoxy-D-glucose has been prepared by the reaction of 11C-hydrogen cyanide with a stable precursor, 1-deoxy-2,3:4,5-di-O-isopropylidine-1-iodo-D-arabitol, thereby avoiding the synthesis of starting material immediately prior to labeling. Fast, efficient, and reproducible solvent change from dimethyl sulfoxide to ether by flash chromatography enabled the use of diisobutylaluminium hydride in the reduction of the intermediate nitrile. Hydrolysis of the imine-aluminum complex with sulfuric acid, removal of the isopropylidine protecting groups with formic acid, and HPLC purification with an Aminex HPX-87P column yielded 11C-2-deoxy-D-glucose in an aqueous solution, sterile, pyrogen-free, and ready for use in human studies. The radiochemical yield was approximately 20% after a synthesis time of 50 min. The 11C-2-deoxy-D-glucose thus obtained is presently being compared with photosynthetically prepared 11C-D-glucose in PET studies of cerebral metabolism. A preliminary report of the regional cerebral metabolic rate of glucose obtained with the two tracers in a healthy subject with visual stimulation is presented.


The sleep patterns and their associations with mental health among nursing home residents: a latent profile approach.
Nursing home residents commonly experience poor sleep conditions. However, few studies have explored the potential sleep patterns among nursing home residents. This study aimed to identify the sleep patterns in nursing home residents, compare residents' characteristics across sleep patterns, and examine the relationships between sleep patterns and residents' mental health (i.e., depressive and anxiety symptoms). This cross-sectional study was conducted in 27 nursing homes in Jinan, China, from March to June 2018. In total, 353 participants were recruited via convenience sampling, and of which, 326 completed the survey. A latent profile analysis was performed to identify sleep patterns based on the seven dimensions of the Pittsburgh Sleep Quality Index. Bivariate analyses were conducted to compare residents' characteristics among the sleep patterns. Mixed-effects logistic regression analyses were adopted to investigate the relationships between sleep patterns and residents' mental health. Three sleep patterns were identified, including 'good sleepers', 'poor sleepers without hypnotic use', and 'poor sleepers with hypnotic use'. Residents' gender, education, pain, instrumental activities of daily living, and number of chronic conditions were significantly differentiated across the sleep patterns. Compared with 'good sleepers', 'poor sleepers without hypnotic use' were significantly associated with more depressive symptoms (OR = 3.73, 95% CI = 2.09, 6.65, p < 0.001), but not with anxiety symptoms (OR = 2.04, 95% CI = 0.97, 4.29, p = 0.062); whereas 'poor sleepers with hypnotic use' had significantly more depressive (OR = 5.24, 95% CI = 2.54, 10.79, p < 0.001) and anxiety symptoms (OR = 5.02, 95% CI = 2.13, 11.83, p < 0.001). This study reveals three distinct sleep patterns in nursing home residents and their significant associations with residents' mental health. These findings can inform future research to develop appropriate and tailored intervention strategies for improving sleep and promoting mental health for nursing home residents.


Effect of dentine matrix proteins on human endometrial adult stem-like cells: in vitro regeneration of odontoblasts cells.
Human endometrium has enormous regenerative capacity due to the presence of endometrial stem cells. The present study sought to assess the possibility of differentiation of these cells into odontoblast-like cells by in vitro induction. Endometrial stem-like cells were obtained using enzymatic digestion of the biopsy samples of the endometrium after hysterectomy and cultured in Dulbecco's Modified Eagle's Medium (DMEM) which contained dentine non-collagenous proteins (dNCPs). The results were evaluated using the following assays: analysis of morphology, enzymatic assay for measuring alkaline phosphatase activity, Alizarin Red staining to detect in vitro formation of mineralized nodules, immunofluorescence for detection of dentine sialoprotein (DSP) and dentine-matrix protein (DMP1), and Western blotting for DMP1 expression. Following induction, endometrial stem-like cells demonstrated high alkaline phosphatase activity, and expression of DSP and DMP1 confirmed the odontoblast phenotype. DMP1 level increased in samples treated with dNCPs. Study results indicated that odontoblastic differentiation of endometrial stem cells can be induced by extracellular matrix proteins (e.g. dNCPs). The capacity of endometrial stem-like cells to differentiate into odontoblast-like cells under specific conditions gives new insights into the mechanism of odontogenesis and highlights the potential of such approaches for further research on dental tissue regeneration.


Reply to "Predictors of Recurrence for T3a RCC: A Recurring Conundrum".
We really appreciate Leopold et al's thoughtful comments in response to our manuscript regarding the prognostic value of pT3 renal cell carcinoma (RCC)-related features [...].


Spatial relationships and competition in a Chilean desert cactus.
In the Atacama Desert of northern Chile, cacti of the genus Copiapoa occur in extensive, relatively dense, monospecific stands. The spatial distribution patterns within several stands of Copiapoa cinerea v. columna-alba were analyzed for evidence of competitive interactions among individuals. There was no indication that competition was affecting stand density. Mean annual precipitation is only 25 mm/yr, but estimates of maximum possible water use within a stand were much lower. It was shown that the time between rainstorms is long compared to the water storage capacity of the plant stems, especially in the case of small individuals. We conclude that population densities in Copiapoa are limited by the difficulty of establishment, not by competition.


HIV-1 subtype C Tat exon-1 amino acid residue 24K is a signature for neurocognitive impairment.
Variation and differential selection pressures on Tat genes have been shown to alter the biological function of the protein, resulting in pathological consequences in a number of organs including the brain. We evaluated the impact of genetic variation and selection pressure on 147 HIV-1 subtype C Tat exon 1 sequences from monocyte-depleted peripheral lymphocytes on clinical diagnosis of neurocognitive impairment. Genetic analyses identified two signature amino acid residues, lysine at codon 24 (24K) with a frequency of 43.4% and arginine at codon 29 (29R) with a frequency of 34.0% in individuals with HIV-associated neurocognitive impairment. The analyses also revealed two signature residues, asparagine, 24 N (31.9%), and histidine, 29H (21.3%), in individuals without neurocognitive impairment. Both codons, 24 and 29, were associated with high entropy but only codon 29 was under positive selection. The presence of signature K24 increased by 2.08 times the risk of neurocognitive impairment, 3.15 times higher proviral load, and 69% lower absolute CD4 T-cell count compared to those without the signature. The results support a linkage between HIV-1 C Tat N24K polymorphism, proviral load, immunosuppression, and neurocognitive impairment. The signature may induce more neurotoxic effects, which contributes to establishment and severity of HIV-associated neurocognitive impairment.


Increase ethyl acetate production in Saccharomyces cerevisiae by genetic engineering of ethyl acetate metabolic pathway.
Ethyl acetate has attracted much attention as an important chemical raw material and a flavor component of alcoholic beverages. In this study, the biosynthetic pathway for the production of ethyl acetate in Chinese liquor yeast was unblocked. In addition to engineering Saccharomyces cerevisiae to increased intracellular CoA and acetyl-CoA levels, we also increased the combining efficiency of acetyl-CoA to ethanol. The genes encoding phosphopantothenate-cysteine ligase, acetyl-CoA synthetase, and alcohol acetyltransferase were overexpressed by inserting the strong promoter PGK1p and the terminator PGK1t, respectively, and then combine them. Our results finally showed that the ethyl acetate levels of all engineering strains were improved. The final engineering strain CLy12a-ATF1-ACS2-CAB2 had a significant increase in ethyl acetate yield, reaching 610.26 (± 14.28) mg/L, and the yield of higher alcohols was significantly decreased. It is proved that the modification of ethyl acetate metabolic pathway is extremely important for the production of ethyl acetate from Saccharomyces cerevisiae.


Cardiac output monitoring in horses.
Cardiac output (CO) is the volume of blood pumped out by the heart in 1 minute. Monitoring of CO can guide therapy and improve clinical outcome in critically ill patients and during anesthesia. Although there is increasing research into clinically useful methods of monitoring CO in equine patients, there are limitations to the available methods. There are 4 basic methods of measuring CO: (1) indicator methods, (2) a derivation of the Fick principle, (3) arterial pulse wave analysis, and (4) imaging diagnostic techniques. This article discusses the importance of CO, available technology, and challenges of monitoring CO in equine medicine.


Significant melting point depression of two-dimensional folded-chain crystals of isotactic poly(methyl methacrylate)s observed by high-resolution in situ atomic force microscopy.
The properties of polymer ultrathin films are a subject of intense study from both practical and academic viewpoints. Previously, we found that upon compression, an isotactic poly(methyl methacrylate) (it-PMMA) Langmuir monolayer crystallized to form a two-dimensional (2D) folded-chain crystal, and the molecular image of the crystal with chain folding and tie chains was clearly visualized by atomic force microscopy (AFM). In the present study, the melting behaviors of the it-PMMA 2D crystals were successfully observed in situ by high-temperature AFM at the molecular lever for the first time. The chain-chain distances (~1.2 nm) of the crystals were clearly resolved even at temperatures close to the melting temperatures (Tm) of the 2D crystals. We found that the Tm of the 2D crystals was at most 90 °C lower than the bulk crystals. The Tm depression strongly depended on the molecular weight, while the molecular weight dependence of the bulk Tm was negligible in the molecular weight regime studied. The Tm depression also depended on the substrates, a slightly larger depression being observed on a sapphire substrate compared to that on a mica. The large Tm depressions of the 2D crystals could not be explained by a simple Thomson-Gibbs argument, theoretical developments are necessary to understand the melting of the 2D crystals.


Protective Role of Peroxisome Proliferator-Activated Receptor-γ in the Development of Intracranial Aneurysm Rupture.
Inflammation is emerging as a key component of the pathophysiology of intracranial aneurysms. Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear hormone receptor of which activation modulates various aspects of inflammation. Using a mouse model of intracranial aneurysm, we examined the potential roles of PPARγ in the development of rupture of intracranial aneurysm. A PPARγ agonist, pioglitazone, significantly reduced the incidence of ruptured aneurysms and the rupture rate without affecting the total incidence aneurysm (unruptured aneurysms and ruptured aneurysms). PPARγ antagonist (GW9662) abolished the protective effect of pioglitazone. The protective effect of pioglitazone was absent in mice lacking macrophage PPARγ. Pioglitazone treatment reduced the mRNA levels of inflammatory cytokines (monocyte chemoattractant factor-1, interleukin-1, and interleukin-6) that are primarily produced by macrophages in the cerebral arteries. Pioglitazone treatment reduced the infiltration of M1 macrophage into the cerebral arteries and the macrophage M1/M2 ratio. Depletion of macrophages significantly reduced the rupture rate. Our data showed that the activation of macrophage PPARγ protects against the development of aneurysmal rupture. PPARγ in inflammatory cells may be a potential therapeutic target for the prevention of aneurysmal rupture.


Absence of CD26 expression on skin-homing CLA+ CD4+ T lymphocytes in peripheral blood is a highly sensitive marker for early diagnosis and therapeutic monitoring of patients with Sézary syndrome.
Patients with Sézary syndrome (SS) show clonal expansion in the peripheral blood of skin-homing CD4+ T-helper cells expressing cutaneous lymphocyte antigen (CLA). However, an increase of CLA+ CD4+ T cells can also be observed in various inflammatory dermatoses. To facilitate early diagnosis and therapeutic monitoring of SS using flow cytometry, we evaluated the expression of CD7 and CD26 on the CLA+ CD4+ lymphocyte subset. Peripheral lymphocytes from 7 patients with SS, 16 patients with mycosis fungoides (MF) and 11 healthy controls were analysed by flow cytometry for the expression of CD4, CD7, CD26, CLA and CCR4. In addition, a longitudinal study was performed over 16 months in two patients with SS. Absence of CD7 and CD26 on CLA+ CD4+ T cells was highly specific for SS. Importantly, the absence of CD26 on CLA+ CD4+ T cells was very sensitive for SS, at 100% in our patient cohort. The number of CD26- CLA+ CD4+ T cells closely correlated with therapeutic interventions in the longitudinal analysis of two patients over more than 1 year. We conclude that the absence of CD26 expression on skin-homing CLA+ CD4+ T-helper cells is a very sensitive and highly specific parameter for early diagnosis and therapeutic monitoring of patients with SS.


Aging of the immune system and impaired muscle regeneration: A failure of immunomodulation of adult myogenesis.
Skeletal muscle regeneration that follows acute injury is strongly influenced by interactions with immune cells that invade and proliferate in the damaged tissue. Discoveries over the past 20 years have identified many of the key mechanisms through which myeloid cells, especially macrophages, regulate muscle regeneration. In addition, lymphoid cells that include CD8+ T-cells and regulatory T-cells also significantly affect the course of muscle regeneration. During aging, the regenerative capacity of skeletal muscle declines, which can contribute to progressive loss of muscle mass and function. Those age-related reductions in muscle regeneration are accompanied by systemic, age-related changes in the immune system, that affect many of the myeloid and lymphoid cell populations that can influence muscle regeneration. In this review, we present recent discoveries that indicate that aging of the immune system contributes to the diminished regenerative capacity of aging muscle. Intrinsic, age-related changes in immune cells modify their expression of factors that affect the function of a population of muscle stem cells, called satellite cells, that are necessary for normal muscle regeneration. For example, age-related reductions in the expression of growth differentiation factor-3 (GDF3) or CXCL10 by macrophages negatively affect adult myogenesis, by disrupting regulatory interactions between macrophages and satellite cells. Those changes contribute to a reduction in the numbers and myogenic capacity of satellite cells in old muscle, which reduces their ability to restore damaged muscle. In addition, aging produces changes in the expression of molecules that regulate the inflammatory response to injured muscle, which also contributes to age-related defects in muscle regeneration. For example, age-related increases in the production of osteopontin by macrophages disrupts the normal inflammatory response to muscle injury, resulting in regenerative defects. These nascent findings represent the beginning of a newly-developing field of investigation into mechanisms through which aging of the immune system affects muscle regeneration.


Automated detection of intercellular signaling in astrocyte networks using the converging squares algorithm.
Intercellular calcium waves in central nervous system astrocyte networks underline the principle mechanism of cell signaling in astrocyte syncsytiums, which putatively contribute to the modulation of neuronal signaling and metabolic regulation. In support of carrying out systems level analyses of astrocyte networks, we have optimized and validated the converging squares image segmentation algorithm to automatically detect the relative spatial locations of all cells in a visible network as a preliminary step towards analyzing the dynamics of astrocyte intracellular calcium transients, which are the signals that mediate intercellular calcium waves. We used the temporal derivatives of pixel intensities as the data source for the algorithm. The method works by converging progressively smaller squares until the signal peak is reached. It is robust to noise and performs comparably to manual cell signal identification, but is much faster and efficient. This is the first reported application of this algorithm to glial networks that we are aware of.


[Cancer care access in Chile's vulnerable populations during the COVID-19 pandemicAcesso a tratamento de câncer em populações vulneráveis no Chile durante a pandemia de COVID-19].
To examine the COVID-19 pandemic's impact on cancer care access in Chile, analyzing differential effects by insurance type, gender, and age. We conducted a quasi-experimental study using interrupted time series analysis. We used multiple data sources for a broad evaluation of cancer-related health care utilization from January 2017 to December 2020. We fit negative binomial models by population groups for a range of services and diagnoses. A sharp drop in oncology health care utilization in March was followed by a slow, incomplete recovery over 2020. Cumulative cancer-related services, diagnostic confirmations, and sick leaves were reduced by one third in 2020; the decrease was more pronounced among women and the publicly insured. Early diagnosis was missed in 5132 persons with 4 common cancers. The pandemic stressed the Chilean health system, decreasing access to essential services, with a profound impact on cancer care. Oncology service reductions preceded large-scale lockdowns and supply-side disruptions. Importantly, not all population groups were equally affected, with patterns suggesting that gender and socioeconomic inequalities were exacerbated.


[Formation of thymine nucleotides in bone marrow of animals of different species].
The activity of enzymes of thymidine and thymidylic acid phosphorylation up to thymidine triphosphate and dCMP-desaminase was studied in bone marrow of rats, rabbits and dogs. A soluble fraction of hyaloplasm obtained after bone marrow homogenates centrifugation at 105000xg for an hour at 0-4 degrees C used as a source of the enzymes. It is found that the rate of thymidine and TMP phosphorylation up to TTP by the rat and dog bone marrow extracts is approximately the same, in rabbits this process is slower. The formation of TTP from TMP in animals of all three species is 1.4-2 times as active as in thymidine phosphorylation. The highest activity of dCMP-desaminase is found in the bone marrow cells of dogs, in rabbits and rats it is 1.6 and 2 times as low, respectively.


Remaining useful lifetime estimation for discrete power electronic devices using physics-informed neural network.
Estimation of Remaining Useful Lifetime (RUL) of discrete power electronics is important to enable predictive maintenance and ensure system safety. Conventional data-driven approaches using neural networks have been applied to address this challenge. However, due to ignoring the physical properties of the target RUL function, neural networks can result in unreasonable RUL estimates such as going upwards and wrong endings. In the paper, we apply the fundamental principle of Physics-Informed Neural Network (PINN) to enhance Recurrent Neural Network (RNN) based RUL estimation methods. Through formulating proper constraints into the loss function of neural networks, we demonstrate in our experiments with the NASA IGBT dataset that PINN can make the neural networks trained more realistically and thus achieve performance improvements in estimation error and coefficient of determination. Compared to the baseline vanilla RNN, our physics-informed RNN can improve Mean Squared Error (MSE) of out-of-sample estimation on average by 24.7% in training and by 51.3% in testing; Compared to the baseline Long Short Term Memory (LSTM, a variant of RNN), our physics-informed LSTM can improve MSE of out-of-sample estimation on average by 15.3% in training and 13.9% in testing.


[Constitution and acceleration from the allometric viewpoint exemplified by data from a longitudinal study in Braunschweig].
Anthropometric measurements of constitution and acceleration are only comparable if they are allometrically standardized. Individual results are only applicable to the population from which they come. Further connections are explained on the basis of date from a longitudinal study.


Brain MRI abnormalities in ataxia-telangiectasia.
Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder, initially characterized by normal brain magnetic resonance imaging (MRI). In a 34-year-old woman patient with AT, MRI revealed extensive and diffuse white matter dismyelination, T1 and T2 hypointense lesions, T1 hypointense but T2 hyperintense lesions, and numerous dilated telangiectases upon gadolinium enhancement. In our patient, brain MRI confirmed extensive extracerebellar lesions in AT. Our report broadens the spectrum of brain MRI abnormalities in AT and supports the hypothesis on cerebrovascular abnormalities occurring in later stages of AT.


The rheological behaviour of cortical bone and cartilage of Bos taurus. The importance of maximal damping capacity in collagen.
The relaxation behaviour of bone and cartilage was investigated with a free-oscillating torsional pendulum. Two relaxations (260 K, and 150 K) were found for bone an; two (at 260 K and 210 K) for cartilage at a frequency of 1 Hz. The translations were the same as those known for collagen. The translation at 260 K is consistent with the frequency of the impulses causing the contraction of skeleton muscles when extrapolated to 37 centrigrades and a frequency of 500 Hz.


Automatic Alberta Stroke Program Early Computed Tomographic Scoring in patients with acute ischemic stroke using diffusion-weighted imaging.
Alberta Stroke Program Early Computed Tomographic Scoring (ASPECTS) is a reliable method for assessing early ischemic changes in the blood supply area of the middle cerebral artery in patients with acute ischemic stroke. This study aims to propose a deep learning based automatic evaluation strategy for DWI-ASPECTS to serve as a reference for clinicians in urgent decision making for endovascular thrombectomy. Ten ASPECTS regions are extracted from the DWI series to train the independent classification network for each region, the accurate training labels of which are confirmed by neuroradiologists. Two classical convolutional neural networks (VGG-16 and ResNet-50) are validated. Subsequently, the innovative CBAM-VGG is designed to improve the accurate scoring of four small-volume DWI-ASPECTS regions, including caudate nucleus, lenticular nucleus, internal capsule, and insular lobe. Average F1-score of 0.929 and 0.840 and the average accuracy of 94.75% and 84.99% are obtained when scoring on six cortical regions M1-M6 and four small ASPECTS regions, respectively. In addition, the modified algorithm CBAM-VGG shows a significant improvement in the accuracy of estimating the four ASPECTS regions with smaller volumes. The experimental results demonstrate that the deep learning methods facilitate the efficiency and robustness of automatic DWI-ASPECTS scoring, which can provide a reference for clinical decision-making.


Bioconjugation of nanozyme and natural enzyme to enable a one-step cascade reaction for the detection of metabolites.
Nanozyme, with enzyme-mimicking activity and excellent stability, has attracted extensive attention. However, some inherent disadvantages, including poor dispersion, low selectivity, and insufficient peroxidase-like activity, still limit its further development. Therefore, an innovative bioconjugation of a nanozyme and natural enzyme was conducted. In the presence of graphene oxide (GO), histidine magnetic nanoparticles (H-Fe3O4) were first synthesized by a solvothermal method. The GO-supported H-Fe3O4 (GO@H-Fe3O4) exhibited superior dispersity and biocompatibility because GO was the carrier and possessed outstanding peroxidase-like activity because of the introduction of histidine. Furthermore, the mechanism of the peroxidase-like activity of GO@H-Fe3O4 was the generation of •OH. Uric acid oxidase (UAO) was selected as the model natural enzyme and covalently linked to GO@H-Fe3O4 with hydrophilic poly(ethylene glycol) as a linker. UAO could specifically catalyze the oxidation of uric acid (UA) to generate H2O2, and subsequently, the newly produced H2O2 oxidized the colorless 3,3',5,5'-tetramethylbenzidine (TMB) to blue ox-TMB under the catalysis of GO@H-Fe3O4. Based on the above cascade reaction, the GO@H-Fe3O4-linked UAO (GHFU) and GO@H-Fe3O4-linked ChOx (GHFC) were used for the detection of UA in serum samples and cholesterol (CS) in milk, respectively. The method based on GHFU exhibited a wide detection range (5-800 μM) and a low detection limit (1.5 μM) for UA, and the method based on GHFC exhibited a wide detection range (4-400 μM) and a low detection limit (1.13 μM) for CS. These results demonstrated that the proposed strategy had great potential in the field of clinical detection and food safety.


A review on solar-powered cooling systems coupled with parabolic dish collector and linear Fresnel reflector.
Solar energy is the most sustainable and free source to manage the world energy demand. One aspect of solar-driven energy supply can be observed in cooling systems. Recently, solar energy-based cooling systems have received many attentions. Solar cooling systems utilizing solar collectors, as the renewable and sustainable-based solution, have the good potentials to overcome the challenges associated with consumption of fossil fuels. In this study, the recent advances about the potentials of dish collectors and linear Fresnel reflectors for the usage in the cooling systems are reviewed. In addition, the solar-powered conventional absorption chiller and cryogenic systems are investigated. Hybrid cooling solar systems and solar-based combined cooling, heating, and power systems are also studied. The hydrogen production in cooling integrated systems and cold thermal energy storage are discussed. In each section, in addition to general description of the system, some explanations about the thermodynamic and economic aspects of the systems are provided. Finally, the main results of the review are summarized and based on the available gaps between the literatures, some suggestions are provided for the future studies. It was found that using solar dish collectors in a hybrid system, designed for the freshwater and LNG production, causes carbon dioxide emissions reduction by 40%, and also increases freshwater and LNG production by 95% and 4.7%, respectively. In the hybrid trigeneration solar-biomass power plants, using the linear Fresnel reflector leads to 29% save in biomass and land.


Hyperventilation and photic stimulation are useful additions to a placebo-based suggestive seizure induction protocol in patients with psychogenic nonepileptic seizures.
The early and definitive diagnosis of psychogenic nonepileptic seizures is a common challenge in epileptology practice. Suggestive seizure induction is a valuable tool to aid the differentiation between epileptic and psychogenic nonepileptic seizures, especially when long-term video-EEG monitoring is inconclusive or unavailable. In this retrospective analysis, we compared the diagnostic yield of a classical, placebo-based induction protocol with that of an extended protocol that includes hyperventilation and photic stimulation as means of suggestion while also implementing more open, standardized patient information. We investigated whether the diversification of suggestive seizure induction has an effect on diagnostic yield and whether it preempts the administration of placebo. Data from 52 patients with confirmed psychogenic nonepileptic seizures were analyzed. While suggestive seizure induction using only placebo-based suggestion provoked a typical event in 13 of 20 patients (65%), the extended protocol was positive in 27 of 34 cases (84%); this improvement was not significant (p=0.11). Noninvasive suggestion techniques accounted for 78% of inductions, avoiding placebo administration in a majority of patients. Still, placebo remains an important part of suggestive seizure induction, responsible for 22% (6 out of 27) of successful inductions using our extended protocol. Our study demonstrates that the diversification of suggestive seizure induction is feasible and beneficial for both patients and diagnosticians.


Production of 9,21-dihydroxy-20-methyl-pregna-4-en-3-one from phytosterols in Mycobacterium neoaurum by modifying multiple genes and improving the intracellular environment.
Steroid drugs are essential for disease prevention and clinical treatment. However, due to intricated steroid structure, traditional chemical methods are rarely implemented into the whole synthetic process for generating steroid intermediates. Novel steroid drug precursors and their ideal bacterial strains for industrial production have yet to be developed. Among these, 9,21-dihydroxy-20-methyl-pregna-4-en-3-one (9-OH-4-HP) is a novel steroid drug precursor, suitable for the synthesis of corticosteroids. In this study, a combined strategy of blocking Δ1-dehydrogenation and the C19 pathway as well as improving the intracellular environment was investigated to construct an effective 9-OH-4-HP-producing strain. The Δ1-dehydrogenation-deficient strain of wild-type Mycobacterium neoaurum DSM 44074 produces 9-OH-4-HP with a molar yield of 4.8%. Hsd4A, encoding a β-hydroxyacyl-CoA dehydrogenase, and fadA5, encoding an acyl-CoA thiolase, were separately knocked out to block the C19 pathway in the Δ1-dehydrogenation-deficient strain. The two engineered strains were able to accumulate 0.59 g L-1 and 0.47 g L-1 9-OH-4-HP from 1 g L-1 phytosterols, respectively. Furthermore, hsd4A and fadA5 were knocked out simultaneously in the Δ1-dehydrogenation-deficient strain. The 9-OH-4-HP production from the Hsd4A and FadA5 deficient strain was 11.9% higher than that of the Hsd4A deficient strain and 40.4% higher than that of the strain with FadA5 deficiency strain, respectively. The purity of 9-OH-4-HP obtained from the Hsd4A and FadA5 deficient strain has reached 94.9%. Subsequently, the catalase katE from Mycobacterium neoaurum and an NADH oxidase, nox, from Bacillus subtilis were overexpressed to improve the intracellular environment, leading to a higher 9-OH-4-HP production. Ultimately, 9-OH-4-HP production reached 3.58 g L-1 from 5 g L-1 phytosterols, and the purity of 9-OH-4-HP improved to 97%. The final 9-OH-4-HP production strain showed the best molar yield of 85.5%, compared with the previous reported strain with 30% molar yield of 9-OH-4-HP. KstD, Hsd4A, and FadA5 are key enzymes for phytosterol side-chain degradation in the C19 pathway. Double deletion of hsd4A and fadA5 contributes to the blockage of the C19 pathway. Improving the intracellular environment of Mycobacterium neoaurum during phytosterol bioconversion could accelerate the conversion process and enhance the productivity of target sterol derivatives.


The Dysfunctional Immune System in Common Variable Immunodeficiency Increases the Susceptibility to Gastric Cancer.
Gastric carcinoma (GC) represents the most common cause of death in patients with common variable immunodeficiency (CVID). However, a limited number of cases have been characterised so far. In this study, we analysed the clinical features, bacterial/viral infections, detailed morphology and immune microenvironment of nine CVID patients with GC. The study of the immune microenvironment included automated digital counts of CD20+, CD4+, CD8+, FOXP3+, GATA3+ and CD138+ immune cells, as well as the evaluation of PD-L1 expression. Twenty-one GCs from non-CVID patients were used as a control group. GC in CVID patients was diagnosed mostly at early-stage (n = 6/9; 66.7%) and at younger age (median-age: 43y), when compared to non-CVID patients (p < 0.001). GC pathogenesis was closely related to Helicobacter pylori infection (n = 8/9; 88.9%), but not to Epstein-Barr virus (0.0%) or cytomegalovirus infection (0.0%). Non-neoplastic mucosa (non-NM) in CVID-patients displayed prominent lymphocytic gastritis (100%) and a dysfunctional immune microenvironment, characterised by higher rates of CD4+/CD8+/Foxp3+/GATA3+/PD-L1+ immune cells and the expected paucity of CD20+ B-lymphocytes and CD138+ plasma cells, when compared to non-CVID patients (p < 0.05). Changes in the immune microenvironment between non-NM and GC were not equivalent in CVID and non-CVID patients, reflecting the relevance of immune dysfunction for gastric carcinogenesis and GC progression in the CVID population.


Electrophysiological evidence for adenosine receptors on astrocytes of cultured rat central nervous system.
The actions of adenosine, R-N6-phenylisopropyladenosine (R-PIA) and N-(ethyl)carboxamidoadenosine (NECA) were tested on the membrane potential of astrocytes of cultured rat spinal cord and cerebellum. All 3 compounds hyperpolarized the majority of astrocytes studied. A considerable number of cells did, however, not respond to adenosine and its analogues, suggesting that only a certain type of astrocyte possesses adenosine receptors. The hyperpolarizations by adenosine, R-PIA and NECA were reversibly blocked by their antagonist 8-phenyltheophylline indicating that these compounds activate specific adenosine receptors. In agreement with biochemical and autoradiographic binding studies, our electrophysiological data strongly suggest the existence of adenosine receptors on astrocytes.


Intramuscular immunization with plasmid coexpressing tumour antigen and Flt-3L results in potent tumour regression.
Dendritic cells (DC) are professional antigen-presenting cells capable of initiating a potent primary immune response, making them an attractive target for cancer immunotherapy. Flt-3 ligand (Flt-3L) is a haematopoietic growth factor that efficiently induces DC expansion in vivo. To achieve a more efficient and effective method of priming tumour-specific, DC-mediated immune response, we generated a DNA vaccine comprising both human Flt-3L and the tumour antigen, MUC-1 (pNGVL-hFLex-MUC-1). We report that pNGVL-hFLex-MUC-1 is able to induce antigen-specific CTL immunity in vivo, resulting in a potent anti-tumour response, and that the Flt-3L component is essential to the efficacy of the DNA vaccine. Moreover, the route of immunization is critical in determining the type of immune response generated; intramuscular (i.m.) immunization with pNGVL-hFLex-MUC-1 conferred tumour protection in contrast to poor response with hydrodynamic-based intravenous delivery. Post-i.m. immunization, we observed a massive infiltration of mononuclear cells to the injection site, comprised predominantly of CD11c(+)/CD8alpha(-) DC. Therefore, we propose that Flt-3L acts as an adjuvant to recruit DC, thereby priming the anti-tumour response. However, systemic expansion of DC prior to immunization did not enhance the specific cellular response, suggesting that it is in situ recruitment or expansion of DC that is critical for pNGVL-hFLex-MUC-1 potency.


[Results of using high porosity aortofemoral bifurcation prostheses].
The authors report on their four-year experience with the use of extremely highly porous vascular polyester prostheses of Czechoslovak proveniencè, whose wall was sealed with fibrin. Aortofemoral bifurcated prostheses with a permeability of 6 100 ml/cm2/min were implanted in 102 patients. The method of fibrination appears to be simple and safe. No hemorrhage through the prosthetic wall was observed. The authors expect the high porosity of the prostheses to result in longer lasting patency of the grafts and thus in improvement of long-term results.


Association between nephrolithiasis and fatty liver detected on non-enhanced CT for clinically suspected renal colic.
To estimate a direct association between nephrolithiasis and hepatosteatosis in patients referred to CT due to clinical suspicion of renal colic. A 508 non-contrast CT scans were examined for calculi in the kidneys or urinary tract, including measurements of liver attenuation, spleen attenuation, thickness of visceral and subcutaneous fat. Logistic regression examined the association of nephrolithiasis and hepatosteatosis findings. Nephrolithiasis was found in 421 (83.9%) and hepatosteatosis in 80 (15.7%) cases. Univariate analysis showed a statistically significant association between nephrolithiasis and hepatosteatosis OR=3.24 (95% CI 1.36-7.68), p=0.008. A significant association was determined between nephrolithiasis and hepatosteatosis.


Congenital megalourethra presenting with large cystic mass in the inguinal area.
Congenital megalourethra is a rare urogenital malformation characterized by severe dilatation and elongation of the penile urethra. It causes functional obstruction of the lower urinary system. Herein, we present a newborn with congenital megalourethra with single umbilical artery.


A four- to sixfold enhancement in sensitivity for detecting trace proteins in dye or silver stained polyacrylamide gels.
A very simple procedure which enhances sensitivity in visualizing proteins stained by all standard procedures in polyacrylamide gels is described. The process, based on the use of concentrated polyethylene glycol 6000 solutions, produces a conspicuous, reversible, and uniform size reduction of gels. The entity of the reduction depends principally on the polyethylene glycol 6000 concentration and on the acrylamide content of gels. Using an appropriate polyethylene glycol 6000 concentration, it is possible to regulate the final size and then the sensitivity as needed. Depending upon the above conditions it is possible to increase the sensitivity by a factor of 4-6 or more. Reduction of the gel volume by such a factor may eliminate the need for the cumbersome and frequently impossible preconcentration of samples. Besides the Coomassie blue stained gels, silver stained gels may also be treated in a similar manner with a consequent further enhancement in sensitivity. In addition, gels containing radiolabeled materials can be autoradiographed in times proportionally shorter, without significant sacrifice of resolution.


Prognostic Impact of Further Treatments on Distant Metastasis in Patients With Minimally Invasive Follicular Thyroid Carcinoma: Verification Using Inverse Probability of Treatment Weighting.
The aim of this study was to evaluate the prognostic impact of further treatments in minimally invasive follicular thyroid carcinoma (MIFTC) patients. The risk factors for distant metastases were analyzed, and the impact of surgical extent on distant metastasis was verified by using weighted logistic regression models with inverse-probability of treatment weighting (IPTW). 166 patients including 31 males (18.7 %) and 135 females (81.3 %), with the mean age of 41.5 ± 13.5 years, were enrolled for this study. The median follow-up period was 103.5 months (range, 13-244 months). Seven patients (4.2 %) had distant metastases during follow-up period. The presence of vascular invasion (Hazard ratio [HR] = 29.06; 95 % Confidence Interval [CI] = 3.06-209.08; p = 0.015) and extensive vascular invasion ≥4 foci (HR = 40.57; 95 % CI = 2.09-789.13; p = 0.014) were the independent risk factors for distant metastasis by multivariate analysis. Surgical extent did not influence distant metastasis. Logistic regression with IPTW also demonstrated that there were no statistically significant differences in the development of distant metastasis based on surgical extent (HR = 1.28; 95 % CI = 0.15-10.87; p = 0.823). The presence of extensive vascular invasion is the most powerful predictor of distant metastasis. However, it is noteworthy that further treatments do not demonstrate an advantageous effect on preventing distant metastasis during the follow-up period.


Transcriptome sequencing of the central nervous system to identify the neuropeptides and neuropeptide receptors of Antheraea pernyi.
Neuropeptides and neuropeptide receptors are crucial regulators for the behavior, lifecycle, and physiology of insects and are mainly produced and released from the neurosecretory cells of the central nervous system (CNS). In this study, RNA-seq was employed to investigate the transcriptome profile of the CNS which is composed of the brain and ventral nerve cord (VNC) of Antheraea pernyi. From the data sets, a total of 18 and 42 genes were identified, which respectively encode the neuropeptides and neuropeptide receptors involved in regulating multiple behaviors including feeding, reproductive behavior, circadian locomotor, sleep, and stress response and physiological processes such as nutrient absorption, immunity, ecdysis, diapause, and excretion. Comparison of the patterns of expression of those genes between the brain and VNC showed that most had higher levels of expression in the brain than VNC. Besides, 2760 differently expressed genes (DEGs) (1362 up-regulated and 1398 down-regulated ones between the B and VNC group) were also screened and further analyzed via gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses. The results of this study could provide comprehensive profiles of the neuropeptides and neuropeptide receptors of A. pernyi CNS and lay the foundation for further research into their functions.


Epigenetic biomarkers in epithelial ovarian cancer.
Ovarian cancer is the most lethal gynecological malignancy and the 5th leading cause of cancer death in women. Women with ovarian cancer are typically diagnosed at late stage, when the cancer has spread into the peritoneal cavity and complete surgical removal is difficult. The 5-year survival time for patients diagnosed at this stage is 30%, in contrast to a 5-year survival of 90% for patients diagnosed at early stage. Cancer screening and early detection have the potential to greatly decrease the mortality and morbidity from cancer. The emerging field of epigenetics offers a valuable opportunity to identify cancer-specific DNA methylation changes that can be used in the clinic to improve early-stage diagnosis and better predict response in treated patients. To date, numerous DNA methylation aberrations have been identified in epithelial ovarian cancer; here we review some candidate genes and pathways with potential clinical utility as biomarkers for diagnosis and/or prognosis. It has become clear that even with the great promise of DNA methylation biomarkers in epithelial ovarian cancer, the identification of highly specific, sensitive and robust panels of markers and the standardization of analysis techniques are still required in order to improve detection, treatment and thus patient outcome.


MRI-guided thermal therapy of transplanted tumors in the canine prostate using a directional transurethral ultrasound applicator.
To evaluate MRI-based techniques for visual guidance, thermal monitoring, and assessment during transurethral ultrasound thermal therapy of implanted tumors in an in vivo canine prostate model. Transmissible venereal tumors (TVT) were grown in the right lobe of the prostate in four dogs. High-temperature thermal therapy was selectively applied to the tumor-bearing lobe using a transurethral ultrasound applicator with a 180 degrees directional heating pattern. Temperature-sensitive MRI (MRTI) using a fast interleaved gradient-echo echo-planar (iGE-EPI) imaging sequence was used for cumulative thermal dose calculations in multiple image planes during the treatment. The results from MRTI-based dose maps and post-treatment MRI were compared to those from histologic analysis. MRTI monitoring in multiple planes across the prostate guided the use and control of a directive ultrasound applicator for the selective ablation of the sections of the prostate that contained implanted tumors. Findings in gadolinium enhanced MRI obtained immediately after thermal therapy slightly underestimated the size of tissue necrosis after treatment, as verified by histopathologic analysis. The use of multiplanar MRTI with a transurethral ultrasound applicator shows significant potential for selective thermal ablation of prostate tumor and tissue.


Differentiation of stem cell-derived pancreatic progenitors into insulin-secreting islet clusters in a multiwell-based static 3D culture system.
Orbital shaker-based suspension culture systems have been in widespread use for differentiating human pluripotent stem cell (hPSC)-derived pancreatic progenitors toward islet-like clusters during endocrine induction stages. However, reproducibility between experiments is hampered by variable degrees of cell loss in shaking cultures, which contributes to variable differentiation efficiencies. Here, we describe a 96-well-based static suspension culture method for differentiation of pancreatic progenitors into hPSC-islets. Compared with shaking culture, this static 3D culture system induces similar islet gene expression profiles during differentiation processes but significantly reduces cell loss and improves cell viability of endocrine clusters. This static culture method results in more reproducible and efficient generation of glucose-responsive, insulin-secreting hPSC-islets. The successful differentiation and well-to-well consistency in 96-well plates also provides a proof of principle that the static 3D culture system can serve as a platform for small-scale compound screening experiments as well as facilitating further protocol development.


Hydrogen bonding by the sulphydryl group of glutathione.
The occurrence of hydrogen bond in the sulphydryl group of glutathione was investigated by means of Raman Spectroscopy. Evidence is obtained that SH group is free and H-bonding does not occur.


Hemostasis and uterine contraction promoting effect of the extract from drugs in the Zi-Yin-Tiao-Jing granule, a traditional Chinese compound preparation.
Zi-Yin-Tiao-Jing granule (ZG) is a traditional Chinese medicine compound preparation for perimenopausal dysfunctional uterine bleeding. It is made from 9 Chinese crude drugs based on a modified traditional Chinese prescription recorded in Fu Qingzhu Nvke as Guben Zhibeng Tang. This study aimed to investigate the hemostasis and uterine contraction promoting effect of quality controlled ZG extract on animals as a preclinical study. ZG extract was quality controlled by determining the contents of asperosaponin Ⅵ and tetrahydroxystilbene glucoside (TSG) with high-performance liquid chromatography (HPLC) and the contents of total tannins, total saponins and total flavonoids with ultraviolet spectrophotometry (UV). Bleeding time, clotting time, prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen (FIB) content were assayed to test the hemostasis effect of ZG extract on sixty healthy female Kunming mice. In addition, ten healthy female Sprague-Dawley rats were used to test the effect of ZG extract on uterine contractions in vitro with the BL-420 Biological Function Experiment System. The ZG extract contained 0.81mgg-1 asperosaponin Ⅵ, 0.15mgg-1 TSG, 1.98mgg-1 total tannins, 1.83mgg-1 total saponins, and 4.09mgg-1 total flavonoids. Compared with placebo, the ZG extract shortened the bleeding time at a dosage of 1.2gkg-1 and 2.4gkg-1, and shortened the clotting time at 0.6gkg-1, 1.2gkg-1 and 2.4gkg-1 in mice (P < 0.01). It also decurtated the APTT at a dosage of 0.6gkg-1 (P < 0.05) and raised the content of FIB in the plasma at a dosage of 2.4gkg-1 (P < 0.05). However, the PT showed no changes after the administration of ZG extract (P > 0.05). In addition, ZG extract at the doses of 1.8mgmL-1, 3.6mgmL-1, and 5.4mgmL-1 increased the amplitude and motoricity of uterine contractions of rats (P < 0.05 or P < 0.01) but maintained the frequency as unchanged. The ZG extract was quality controllable by assaying for asperosaponin Ⅵ, TSG, total tannins, total saponins and total flavonoids. It could promote the hemostasis of mice in vivo, as well as the uterine contractions of rats in vitro. Therefore, it may be a promising preparation for clinical treatment of perimenopausal dysfunctional uterine bleeding.


Neonatal abstinence syndrome is a potential cause of low TREC copy number.
Severe combined immunodeficiency (SCID) is a rare genetic condition characterized by significant T cell lymphopenia and impaired T cell function. Many jurisdictions use the quantitation of T cell receptor excision circles (TRECs) to screen for SCID in newborns, but false positives may be seen in several conditions. We report 3 newborns with neonatal abstinence syndrome who presented with decreased TREC copy number.


Doxorubicin overproduction in Streptomyces peucetius: cloning and characterization of the dnrU ketoreductase and dnrV genes and the doxA cytochrome P-450 hydroxylase gene.
Doxorubicin-overproducing strains of Streptomyces peucetius ATCC 29050 can be obtained through manipulation of the genes in the region of the doxorubicin (DXR) gene cluster that contains dpsH, the dpsG polyketide synthase gene, the putative dnrU ketoreductase gene, dnrV, and the doxA cytochrome P-450 gene. These five genes were characterized by sequence analysis, and the effects of replacing dnrU, dnrV, doxA, or dpsH with mutant alleles and of doxA overexpression on the production of the principal anthracycline metabolites of S. peucetius were studied. The exact roles of dpsH and dnrV could not be established, although dnrV is implicated in the enzymatic reactions catalyzed by DoxA, but dnrU appears to encode a ketoreductase specific for the C-13 carbonyl of daunorubicin (DNR) and DXR or their biosynthetic precursors. The highest DXR titers were obtained in a dnrX dnrU (N. Lomovskaya, Y. Doi-Katayama, S. Filippini, C. Nastro, L. Fonstein, M. Gallo, A. L. Colombo, and C. R. Hutchinson, J. Bacteriol. 180:2379-2386, 1998) double mutant and a dnrX dnrU dnrH (C. Scotti and C. R. Hutchinson, J. Bacteriol. 178:7316-7321, 1996) triple mutant. Overexpression of doxA in a doxA::aphII mutant resulted in the accumulation of DXR precursors instead of in a notable increase in DXR production. In contrast, overexpression of dnrV and doxA jointly in the dnrX dnrU double mutant or the dnrX dnrU dnrH triple mutant increased the DXR titer 36 to 86%.


Between hype and hope: What is really at stake with personalized medicine?
Over the last decade, personalized medicine has become a buzz word, which covers a broad spectrum of meanings and generates many different opinions. The purpose of this article is to achieve a better understanding of the reasons why personalized medicine gives rise to such conflicting opinions. We show that a major issue of personalized medicine is the gap existing between its claims and its reality. We then present and analyze different possible reasons for this gap. We propose an hypothesis inspired by the Windelband's distinction between nomothetic and idiographic methodology. We argue that the fuzzy situation of personalized medicine results from a mix between idiographic claims and nomothetic methodological procedures. Hence we suggest that the current quandary about personalized medicine cannot be solved without getting involved in a discussion about the complex epistemological and methodological status of medicine. To conclude, we show that the Gadamer's view of medicine as a dialogical process can be fruitfully used and reveals that personalization is not a theoretical task, but a practical one, which takes place within the clinical encounter.


Enhanced nitrate and cadmium removal performance at low carbon to nitrogen ratio through immobilized redox mediator granules and functional strains in a bioreactor.
The coexistence of multiple pollutants and lack of carbon sources are challenges for the biological treatment of wastewater. To achieve simultaneous removal of nitrate (NO3--N) and cadmium (Cd2+) at low carbon to nitrogen (C/N) ratios, 2-hydroxy-1,4-naphthoquinone (HNQ) was selected from three redox mediators as an accelerator for denitrification of heterotrophic strain Pseudomonas stutzeri sp. GF2 and autotrophic strain Zoogloea sp. FY6. Then, halloysite nanotubes immobilized with 2-hydroxy-1,4-naphthoquinone (HNTs-HNQ) were prepared and a bioreactor was constructed with immobilized redox mediator granules (IRMG) as the carrier, which was immobilized with HNTs-HNQ and inoculated with the two strains. The immobilized HNQ and the inoculated strains jointly improved the removal ability of NO3--N and Cd2+ and the removal efficiency of NO3--N (25.0 mg L-1) and Cd2+ (5.0 mg L-1) were 92.81% and 93.94% at C/N = 1.5 and hydraulic retention time (HRT) = 4 h. The Cd2+ was removed by adsorption of iron oxides (FeO(OH) and Fe3O4) and IRMG. The electron transport system activity (ETSA) of bacteria was improved and the composition of dissolved organic matter in the effluent was not affected by HNQ. The HNQ promoted the production of FeO(OH) and up-regulated the proportion of Zoogloea (54.75% in the microbial community), indicating that Zoogloea sp. FY6 was dominant in the microbial community. In addition, HNQ influenced the metabolic pathways and improved the relative abundance of some genes involved in nitrogen metabolism and the iron redox cycle.


Endovascular obliteration of in situ saphenous vein arteriovenous fistulas during tibial bypass.
Current methods of ligating venous branches during in situ vein tibial bypass are associated with significant wound complications, especially in diabetics. Making only proximal and distal wound incisions could avoid these wound problems. We report the use of endovascular techniques with coils and balloons guided by intraoperative arteriography and angioscopy to obliterate arteriovenous (AV) fistulas in three elderly diabetic patients undergoing tibial bypass. In all cases the proximal and distal vessels were first isolated and deemed suitable for bypass. The greater saphenous vein was prepared for the proximal and distal anastomosis, and angioscopically guided valvulotomy was performed. An introducer sheath was placed through a large proximal saphenous side branch for vascular access. With the use of fluoroscopy, AV fistulas were serially identified and cannulated with a guidewire. A guide catheter, passed over the wire into the side branch, served as the conduit through which coils and balloons were placed. Proximal and distal anastomoses were completed and arteriography performed. We were successful in obliterating AV fistulas in all three patients, but completion arteriography revealed additional AV fistulas requiring surgical ligation in two patients. Furthermore, operative time was increased by 1 1/2 to 5 hours. Two of three patients had wound infections, one at the proximal and one at the distal incision. All patients were discharged with a functioning bypass and no AV fistulas were seen on duplex scans. Endovascular obliteration of AV fistulas is feasible but is currently limited by prolonged operative time and incomplete obliteration.


The variability of aggressiveness of grade 1 breast cancer.
Grade 1 breast cancer represents the lowest grade of invasive breast cancer and is associated with a low risk of recurrence and distant metastasis. However, when grade 1 breast cancer is associated with lymph node involvement, the prognosis may be worse than that of grade 1 breast cancer without lymph node involvement. The study population included all patients who were managed in our institution between January 1, 2007 and December 31, 2013 for grade 1 breast cancer . We compared patients who had lymph node involvement to those who had no lymph node involvement. During the study period 291 grade 1 carcinomas were included of which 23% had associated positive lymph node involvement. Overall survival did not differ significantly between patients without lymph node involvement and those with lymph node involvement, nor was there a significant difference in the risk of local recurrence free survival. However, a significant difference was found in survival without distant metastasis with a significant level of a p at 0.029. Our findings confirm that tumor size and LVSI are strong predictors of axillary lymph node involvement, which is a key determinant of distant metastasis-free survival.


Exploration of Soil Functional Microbiomes-A Concept Proposal for Long-Term Fertilized Grasslands.
Exploring grassland microbiomes is a challenge in the current context of linking soil microorganism activity with the balance of these ecosystems. Microbiologists are constantly attempting to develop faster and lower-cost methods, and propose new and best-fitted indicators that will provide a more complex data analysis. A different concept was proposed for assessing functional microbiomes by splitting the functional ecological niche into complementary segments. The comparison with the upper and lower limits of the ecological niche provides a clearer image of community alterations due to long-term applied treatments. The method allows the extraction of the most sensitive and stable functional guilds, with the extraction of the most critical dominant-codominant functional groups in every segment of the functional niche. The resulting microbial functional-sociological model is ready to use on community-level physiological profile databases and also can be applied backward for vegetation analysis.


Relapse of Aplastic Anemia with Majority Donor Chimerism (Donor-Type Aplasia) Occurring Late after Bone Marrow Transplantation.
There have been sporadic reports of the development of delayed disease recurrence after bone marrow transplantation for severe aplastic anemia despite sustained majority or full donor chimerism. This is termed "donor-type aplasia" (DTA). We describe the management and outcome of 11 pediatric patients from 8 institutions in Europe, the United States, and the Middle East who developed DTA at a mean of 35 months post-transplant. These patients were initially transplanted at a mean age of 10.0 years (range, 5.8 to 16.0 years), 9 from matched sibling donors and 2 from matched unrelated donors. Attempts to treat DTA with varying combinations of additional immunosuppression (including intravenous immunoglobulin, donor lymphocyte infusions, stem cell boosts, and other therapies) failed. Ten patients have received a conditioned second transplant, 9 from the same donor and 1 from a new matched unrelated donor. Aplasia has resolved in the remaining patient in response to ongoing eltrombopag therapy. All patients were alive at a mean of 92 months (range, 26 to 195) after a second transplant; 6 are in complete remission, but 4 suffered from second/recurrent DTA at 16 to 129 months after retransplant and required further transplant therapy.


Acute pancreatitis in pregnancy and its impact on the maternal and foetal outcomes: A systematic review.
The prevalence of AP in pregnancy (APIP) is uncertain with varying reports of its impact on maternal and foetal outcomes. This study was aimed to find the prevalence of APIP and its effect on the maternal and foetal outcomes. Electronic databases were searched upto 31.05.2020 for the appropriate studies. Prospective, retrospective observational studies or case series evaluating APIP in terms of maternal and foetal outcomes were included. Data on the prevalence of APIP, etiology, maternal mortality rates and foetal outcomes were collated. Due to high heterogeneity among the studies, the data has been represented as a systematic review. A total of 16 studies with 8466 pregnant patients were included in the systematic review. The overall prevalence of APIP ranged from 0.225/1000 pregnancies to 2.237/1000 pregnancies. Gallstone disease was the most common cause ranging from 14.29 to 96.3%, with eastern studies reporting more cases of hypertriglyceridemia as etiology. Mild pancreatitis was noted in 33.33-100% of cases with milder disease among western studies. APIP incidence was higher during 3rd trimester (27.27%-95.24%). Maternal mortality ranged from 0 to 12.12/100 pregnancies. Foetal loss ranged from 0 to 23.08%, with adverse foetal outcomes ranging from 0 to 57.41%. Neonatal mortality ranged from 0 to 75.5/1000 neonatal live birth. APIP is usually mild, but its incidence increases with gestational age. Maternal outcome is usually good but adverse foetal outcome is high in APIP (PROSPERO No.: CRD42020194313).


Simultaneous analysis of the photocatalytic degradation of polycyclic aromatic hydrocarbons using three-dimensional excitation-emission matrix fluorescence and parallel factor analysis.
Polycyclic aromatic hydrocarbons (PAHs) may be photochemically degraded. Monitoring of degradation process of PAHs is carried out by traditional methods, which normally imply time-consuming procedures that do not allow the chemical process to be analyzed in real time. In the present study, photodegradation kinetics of dibenz[a,h]anthracene, benz[a]anthracene, benz[a]pyrene and benz[k]fluorantene were investigated in aqueous solutions under different conditions. A 2(3) factorial design was used for optimizing the degradation process. Fluorescence spectroscopy is a fast, cheap and sensitive analytical method, attractive for use in conjunction with chemometric methods; in this case three-way analytical methodology based on fluorescence excitation-emission matrix (EEM) and parallel factor analysis (PARAFAC) was employed. A four-factor PARAFAC model made it possible to resolve the species presents in the degradation mixture and quantify the relative concentration of the analytes throughout the degradation. Several different parameters, such as core consistency, percentage of fit and correlation coefficients between recovered and reference spectra were employed to determine the suitable number of factors for the PARAFAC model. This new methodology allows us to determine satisfactorily the PAHs concentration during the photodegradation in mixtures of arbitrary composition, representing an interesting alternative to the conventional techniques normally used for the monitoring of degradation reactions.


The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features.
Chemotherapy resistance resulting in incomplete pathologic response is associated with high risk of metastasis and early relapse in breast cancer. The aim of this study was to identify and evaluate biomarkers of treatment-resistant tumor cells. We performed a cell surface marker screen in triple-negative breast cancer patient-derived xenograft models treated with standard care genotoxic chemotherapy. Global expression profiling was used to further characterize the identified treatment-resistant subpopulations. High expression of sialyl-glycolipid stage-specific embryonic antigen 4 (SSEA4) was found in residual tumor cells surviving chemotherapy and in samples from metastatic patients who relapsed after neoadjuvant chemotherapy. Gene and microRNA (miRNA) expression profiling linked SSEA4 positivity with a mesenchymal phenotype and a deregulation of drug resistance pathways. Functional assays demonstrated a direct link between epithelial-mesenchymal transition (EMT) and SSEA4 expression. Interestingly, SSEA4 expression, EMT, and drug resistance seemed to be regulated posttranscriptionally. Finally, high expression of CMP-N-acetylneuraminate-β-galactosamide-α-2,3-sialyltransferase 2 (ST3GAL2), the rate-limiting enzyme of SSEA4 synthesis, was found to be associated with poor clinical outcome in breast and ovarian cancer patients treated with chemotherapy. In this study, we identified SSEA4 as highly expressed in a subpopulation of tumor cells resistant to multiple commonly used chemotherapy drugs, as well as ST3GAL2, the rate-limiting enzyme of SSEA4 synthesis, as a predictive marker of poor outcome for breast and ovarian cancer patients undergoing chemotherapy. Both biomarkers and additionally identified regulatory miRNAs may be used to further understand chemoresistance, to stratify patient groups in order to avoid ineffective and painful therapies, and to develop alternative treatment regimens for breast cancer patients.


Stability of ascorbic acid in a standard total parenteral nutrition mixture.
We investigated the stability of ascorbic acid (AA) and the sum of AA plus dehydroascorbic acid (TAA) in a total parenteral nutrition (TPN) mixture that contained 1000 ml Vamin 14, 1000 ml glucose 30%, 500 ml Intralipid 20%, potassium phosphate, a multivitamin preparation (Cernevit) and trace elements. We used a spectrophotometer to measure AA and TAA. AA decreased from 42.2 (+/-0.9) mug/ml to 6.8 (+/-0.2) mug/ml in 7 days. Over the same time the concentration of TAA decreased from 42.2 (+/-0.5) mug/ml to 35.9 (+/-0.6) mug/ml, i.e. 63.3 (+/-1.2)% of the original concentration. When the solution was stored in glass bottles and saturated with nitrogen or when trace elements were omitted, the concentration decreased by only 25.2 (+/-0.2)% and 23.8 (+/-1.6)% respectively over 7 days. The influence of oxygen, lipids, trace elements and underfilling the bag was also investigated. We conclude that it is acceptable to prepare these bags in advance and to store them for 7 days at 2-4 degrees C.


Combined the SMAC mimetic and BCL2 inhibitor sensitizes neoadjuvant chemotherapy by targeting necrosome complexes in tyrosine aminoacyl-tRNA synthase-positive breast cancer.
Chemotherapy is the standard treatment for breast cancer; however, the response to chemotherapy is disappointingly low. Here, we investigated the alternative therapeutic efficacy of novel combination treatment with necroptosis-inducing small molecules to overcome chemotherapeutic resistance in tyrosine aminoacyl-tRNA synthetase (YARS)-positive breast cancer. Pre-chemotherapeutic needle biopsy of 143 invasive ductal carcinomas undergoing the same chemotherapeutic regimen was subjected to proteomic analysis. Four different machine learning algorithms were employed to determine signature protein combinations. Immunoreactive markers were selected using three common candidate proteins from the machine-learning algorithms and verified by immunohistochemistry using 123 cases of independent needle biopsy FFPE samples. The regulation of chemotherapeutic response and necroptotic cell death was assessed using lentiviral YARS overexpression and depletion 3D spheroid formation assay, viability assays, LDH release assay, flow cytometry analysis, and transmission electron microscopy. The ROS-induced metabolic dysregulation and phosphorylation of necrosome complex by YARS were assessed using oxygen consumption rate analysis, flow cytometry analysis, and 3D cell viability assay. The therapeutic roles of SMAC mimetics (LCL161) and a pan-BCL2 inhibitor (ABT-263) were determined by 3D cell viability assay and flow cytometry analysis. Additional biologic process and protein-protein interaction pathway analysis were performed using Gene Ontology annotation and Cytoscape databases. YARS was selected as a potential biomarker by proteomics-based machine-learning algorithms and was exclusively associated with good response to chemotherapy by subsequent immunohistochemical validation. In 3D spheroid models of breast cancer cell lines, YARS overexpression significantly improved chemotherapy response via phosphorylation of the necrosome complex. YARS-induced necroptosis sequentially mediated mitochondrial dysfunction through the overproduction of ROS in breast cancer cell lines. Combination treatment with necroptosis-inducing small molecules, including a SMAC mimetic (LCL161) and a pan-BCL2 inhibitor (ABT-263), showed therapeutic efficacy in YARS-overexpressing breast cancer cells. Our results indicate that, before chemotherapy, an initial screening of YARS protein expression should be performed, and YARS-positive breast cancer patients might consider the combined treatment with LCL161 and ABT-263; this could be a novel stepwise clinical approach to apply new targeted therapy in breast cancer patients in the future.


Eye movements and the perceptual span in silent and oral reading.
Previous research has examined parafoveal processing during silent reading, but little is known about the role of these processes in oral reading. Given that masking parafoveal information slows down silent reading, we asked whether a similar effect also occurs in oral reading. To investigate the role of parafoveal processing in silent and oral reading, we manipulated the parafoveal information available to readers by changing the size of a gaze-contingent moving window. Participants read silently and orally in a one-word window and a three-word window condition as we monitored their eye movements. The lack of parafoveal information slowed reading speed in both oral and silent reading. However, the effects of parafoveal information were larger in silent reading than in oral reading, because of different effects of preview information on both when the eyes move and how often. Parafoveal information benefitted silent reading for faster readers more than for slower readers.


Peripheral sterile corneal infiltrate in two brothers after photorefractive keratectomy.
This is a report of two brothers who underwent bilateral photorefractive keratectomy and developed bilateral peripheral corneal infiltrate on the third day following surgery. The patients were treated with antibiotics and low concentration steroid until negative culture was reported 48 h later, when intensive topical steroid was started. The infiltrate resolved by day 10 with residual subepithelial haze that was apparent 8 months after surgery. Sterile infiltrate has been reported as complication of photorefractive keratectomy and can be managed successfully with excellent outcome. The fact that it happened in two brothers may raise the possibility of genetic predisposition.


Comparing short-term patient outcomes after fundoplication performed over a traditional bougie versus a functional lumen imaging probe.
The functional lumen imaging probe is a balloon-based catheter that can be used as a bougie during fundoplication. Our goal was to compare the short-term, quality-of-life outcomes and esophageal-injury rate after fundoplication over a functional lumen imaging probe compared to a traditional bougie. This is a retrospective review of a quality database at a single center. Three-week and 6-month Reflux Symptom Index, Gastroesophageal Reflux Disease-health Related Quality of Life, and dysphagia scores were compared. The need for endoscopy and dilation between the groups was also compared. Between 2008 and 2020, 423 fundoplications were performed over a bougie and 62 over the functional lumen imaging probe. Six months after surgery, the functional lumen imaging probe group reported significantly worse dysphagia scores (1.5 ± 1.0 vs 1.1 ± 0.3, P = .007), but rates of endoscopy (4.8% vs 5.0%, P = .966) and dilation (4.8% vs 3.8%, P = .723) were similar. There were no differences between Reflux Symptom Index and Gastroesophageal Reflux Disease-health Related Quality of Life scores. The rate of bougie-related injuries was 2.1% vs 0% for the functional lumen imaging probe group. Patients undergoing fundoplication over the functional lumen imaging probe had comparable short-term outcomes compared with those over a traditional bougie. The rate of esophageal injury while using the functional lumen imaging probe is lower than a bougie and may be preferable for fundoplication creation.


Role of the vestibular nuclear complex in facilitating the jaw-opening reflex following stimulation of the red nucleus.
According to our previous studies, stimulation of the red nucleus (RN) facilitates the low-threshold afferent-evoked jaw-opening reflex (L-JOR). It has been reported that the RN projects to the superior (SVN), lateral (LVN) and inferior vestibular (IVN) nuclei. The SVN and the LVN have reciprocal intrinsic connections with the medial vestibular nucleus (MVN). Our previous study demonstrated that stimulation of the vestibular nuclear complex (VN) modulates the L-JOR. These facts suggest that RN-induced facilitation of the L-JOR is mediated via the VN. In the present work we investigated whether electrically induced lesions of the VN, or microinjection of muscimol into the VN, affects RN-induced facilitation of the L-JOR. The L-JOR was evoked by electrical stimulation of the inferior alveolar nerve. The stimulus intensity was 1.2 times the evocation threshold. Lesions of the MVN or the LVN or the SVN, and the muscimol injection into the MVN or the LVN or the SVN, reduced the RN-induced facilitation of the L-JOR. Conversely, lesions of the IVN, and the muscimol injection into the IVN, increased the RN-induced facilitation of the L-JOR. These results suggest that the RN-induced facilitation of the L-JOR is mediated by a relay in the VN.


Phase II trial of gemcitabine in patients with advanced gastric cancer.
Approximately 22,000 new cases of gastric cancer are diagnosed each year in the United States, most of which are advanced disease and thus are not curable by surgery. Chemotherapy has had little impact on patient survival. Consequently, the evaluation of new agents is needed. Gemcitabine, a cytosine arabinoside analogue, was evaluated in a Phase II trial to assess its efficacy in previously untreated patients with advanced gastric cancer. Patients were treated with weekly gemcitabine, 800 mg/m2, for 3 consecutive weeks, followed by a 1-week rest period. Eighteen patients were enrolled. Fifteen patients were evaluable for response; 2 patients refused therapy before the completion of one cycle of treatment, and one patient was found to have nonmeasurable disease. No major objective responses were seen. Two minor responses occurred. One patient with a minor response was removed from the study at his request after ten cycles of treatment. The other patient remains on the study with stable disease at more than 17 months. Toxicities on this study were mild. Median leukocyte count and platelet nadirs were 5.0 (range, 2.2-51.0) and 234,000/microliters (range, 59,000-554,000/microliters), respectively. Gemcitabine at this dose and schedule has no significant antitumor activity in gastric cancer.


Pulmonary Vascular Capacitance is Associated with Vasoreactivity and Long-Term Response to Calcium Channel Blockers in Idiopathic Pulmonary Arterial Hypertension.
This study aimed to identify the relationship between pulmonary vascular capacitance (PVC) and vasoreactivity in patients with idiopathic pulmonary arterial hypertension (IPAH), and the value of PVC in predicting long-term response to CCB treatment. Pulmonary vasodilator testing with inhaling iloprost was performed in 308 newly diagnosed IPAH patients. Acute vasodilator-responsive patients accepted CCBs treatment. Patients who benefit from long-term CCB were defined as those being in World Health Organization (WHO) functional class II or I after at least 1 year on CCB monotherapy. PVC had significant correlations with WHO function class, 6-min walk distance, mean pulmonary arterial pressure, and pulmonary vascular resistance (r = -0.363, p < 0.001; r = 0.333, p < 0.001; r = -0.514, p < 0.001; r = -0.739, p < 0.001). Thirty-five acute vasodilator-responsive IPAH patients (11.4 %) displayed less severe disease and a higher baseline PVC (1.5 ± 0.6 vs. 1.1 ± 0.7 ml/mmHg, p = 0.003). During acute vasodilator testing, PVC increased significantly by mean of 79 ± 48 % and reached to a higher absolute value of 2.6 ± 1.5 ml/mmHg compared with non-responsive patients (1.4 ± 1.5 ml/mmHg, p < 0.001). Furthermore, PVC increased more during acute vasodilator testing in the 24 patients who benefit from long-term CCB treatment (1.4 ± 1.3 vs. 0.5 ± 0.4 ml/mmHg, p = 0.004). The OR of increased PVC during vasodilator testing for predicting patients with long-term response to CCB was 1.24 (95 % CI 1.02-1.50, p = 0.031) as assessed by multivariable logistic regression analysis. PVC was higher in acute vasodilator-responsive IPAH patients and may be a predictor of long-term response to CCBs therapy.


Effect of coexisting manganese ion on the formation of haloacetic acids during chlorination.
Haloacetic acids (HAAs) are a group of disinfection by-products formed by the reaction of dissolved organic matter (DOM) in source water and disinfectants in the drinking water treatment process. The formation of HAAs is known to be affected by several factors (e.g., pH, temperature, concentration, and DOM components in source water). However, the effects of coexisting substances, such as metal ions, on HAA formation are not well understood. In this study, HAA formation potentials (FPs) of model compounds of DOM and environmental waters in the presence or absence of manganese ion upon chlorination were compared. The results of experiments with model compounds of DOM showed that manganese ion promoted the formation of HAA from citric acid, trans-aconitic acid, and cis-aconitic acid. Even for a manganese concentration of less than 50 μg/L, which is the standard value of manganese in drinking water in the USA, EU, and Japan, manganese had great influence on the dichloroacetic acid FPs of these compounds. However, the manganese ion did not enhance the HAAFPs of the environmental waters tested. Nevertheless, manganese may have an effect on HAAFPs of environmental waters collected at the occurrence of an unusual growth of microorganisms, such as algal bloom.


Rhomboencephalosynapsis: Review of the Literature.
Rhombencephalosynapsis is a rare congenital anomaly, characterized by partial or total agenesis of the cerebellar vermis with midline fusion of the cerebellar hemispheres, dentate nuclei, and the superior cerebellar peduncles, creating the distinctive keyhole appearance of the fourth ventricle. Rhombencephalosynapsis can be isolated or can occur in association with other congenital anomalies and syndromes such as Gómez-López-Hernández syndrome (GLHS) or VACTERL: vertebral anomalies (V), anal atresia (A), cardiovascular defects (C), esophageal atresia and/or tracheoesophageal fistula (TE), and renal (R) and limb/radial (L) anomalies. Recent advances in prenatal imaging have resulted in an increasing rate of prenatal diagnosis of abnormalities of the posterior fossa including rhombencephalosynapsis. Patients with rhombencephalosynapsis may present with motor developmental delay, ataxia, swallowing difficulties, muscular hypotonia, spastic quadriparesis, abnormal eye movements, and a characteristic "figure-of-eight" head shaking. Cognitive outcome varies from severe intellectual disability to normal intellectual function. Rhombencephalosynapsis with VACTERL is often associated with severe cognitive disabilities, whereas patients with GLHS may have better cognitive function. The most common associated findings with rhombencephalosynapsis include hydrocephalus, mesencephalosynapsis, holoprosencephaly, pontocerebellar hypoplasia, corpus callosum dysgenesis, and absence of septum pellucidum. Patients can be categorized into 4 groups: 1) rhombencephalosynapsis associated with GLHS; 2) rhombencephalosynapsis with VACTERL; 3) rhombencephalosynapsis with atypical holoprosencephaly, and 4) isolated rhomboencephalosynapsis. The etiology of rhombencephalosynapsis is unknown. Here, we discuss several hypotheses about its etiology.


High K+-mediated survival of spinal sensory neurons depends on developmental stage.
Elevated concentrations of K+ (35 mM) have previously been shown to support the survival of most embryonic chick sympathetic neurons in vitro (Wakade et al., Exp cell res 144 (1983) 377, [23]) and to be interchangeable with nerve growth factor (NGF) as a survival-promoting agent for these cells (Wakade & Thoenen, Neurosci lett 45 (1984) 71 [21]). In the present study, we show that dorsal root ganglion (DRG) neurons from embryonic day 6 do not survive in the presence of high K+, although both NGF and brain-derived neurotrophic factor (BDNF) each support the survival of more than 50% of the cells at this developmental stage. At E6, high K+ appears to have a cytotoxic effect on BDNF-dependent neurons, and there is also considerable inhibition of neurite outgrowth. At a later developmental stage (E12), high K+ supports the survival of about 40% of DRG cells. This subpopulation of neurons is distinct from that supported by NGF (as evidenced by the additivity of these two agents), but partially overlaps with that supported by BDNF (i.e., the two agents are less than additive). At E12, only approx. 20% of the cells can be supported by either NGF or BDNF, with the rest depending exclusively on one or the other of these factors. This is in contrast to the situation at E6, where there is considerable overlap between NGF- and BDNF-dependent populations.


Spectral CT imaging of intranodular hemorrhage in cases with challenging benign thyroid nodules.
While conventional ultrasound and laboratory testing can differentiate most thyroid conditions and malignancies, spectral dual-energy computed tomography (DECT) provides molecular data potentially useful in differential diagnosis of small, complex, and partially obscured hemorrhaged nodules with recent bleeding. To demonstrate that Gemstone Spectral Imaging (GSI) analysis of DECT data differentiates challenging benign thyroid nodule conditions in patients with intranodular hemorrhages. A retrospective study was conducted of 30 intranodular hemorrhage patients from 2010 to 2013, including 18 that underwent surgery and provided thyroid tissues for prospective histological analysis. Iodine and water content were determined in patient CT scans and ex vivo tissue specimen scans by reconstruction of raw CT data at 65 keV (optimal contrast). Slope of spectral curve (λ HU), effective atomic number (Z eff), and final pathological diagnosis were recorded. Iodine content, water content, Z eff, and λ HU significantly varied by region (intranodular hemorrhage, solid thyroid nodule, and adjacent margins) in patients and tissue specimens (P < 0.05). Intranodular hemorrhage exhibited elevated water concentrations (~1100 mg/mL), suggesting a practical threshold of 1075 mg/mL for differentiating intra-plaque hemorrhage and solid nodular regions. Spectral CT provided diagnostic information in 14 thyroid adenomas and four goiters (histologically confirmed in donor specimens), and eight thyroid adenomas and four nodular goiters based on clinical diagnosis. Diagnostically useful regional characteristic of intranodular hemorrhage in the thyroid was visualized via spectral CT employing material decomposition, potentially yielding additional molecular data about complex lesion characteristics no apparent in conventional imaging or laboratory methods.


CYP2C8-mediated interaction between repaglinide and steviol acyl glucuronide: In vitro investigations using rat and human matrices and in vivo pharmacokinetic evaluation in rats.
CYP2C8 is involved in the metabolic clearance of several important drugs and recent reports have shown that acyl glucuronides of gemfibrozil and clopidogrel are potent time-dependent inhibitors of CYP2C8 activity. In the present study, the inhibitory effect of steviol acyl glucuronide (SVAG), a circulating metabolite formed after the ingestion of rebaudioside A, was investigated using in vitro and in vivo systems. Results indicated that SVAG was a reversible but not a time-dependent inhibitor of CYP2C8-mediated paclitaxel 6α-hydroxylation. SVAG was also capable of inhibiting CYP2C8-mediated repaglinide 3'-hydroxylation in human liver microsomes and recombinant human CYP2C8, with Ki values of 15.8 μM and 11.6 μM, respectively. In contrast, SVAG did not exhibit inhibitory effect on CYP2C8 activity in rat liver microsomes. In addition, co-administration of rebaudioside A with repaglinide in rats did not lead to AUC and Cmax changes of repaglinide. Although mathematic prediction using a simplified mechanistic model revealed a moderate interaction potential between repaglinide and SVAG, cautions should be given to patients with hypoglycemia if repaglinide and rebaudioside A are used in combination for the blood sugar control.


Neurotoxicity of MPTP and MPP+ in vitro: characterization using specific cell lines.
The effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its putative toxic metabolite 1-methyl-4-phenylpyridinium ion MPP+ were studied with specific neuronal and glial cell lines in vitro. MPTP had no morphological effect on actively growing neuroblastoma N2AB-1 cells or C6 glioma cells nor did it affect cell numbers. However, a low dose of MPP+ (33.7 microM) was cytotoxic to mitotic N2AB-1 cells inducing vacuole formation, cell lysis, and inhibiting cell growth over a 3-day period. Protein synthesis was inhibited in a dose-dependent fashion in MPP+ treated N2AB-1 cells after 24 h exposure while 33.7 microM of this toxin induced a 50% decrease in protein synthesis as early as 5 h after treatment of these cells. Differentiated, neurite-bearing N2AB-1 cells exhibited a loss of neurites and a change in cell size and shape following exposure to 0.33, 3.37 and 33.7 microM MPP+ after 24 h and some cells appeared to be mitogenically stimulated indicating MPP+ may act as a teratogen. C6 glioma cells, however, were resistant to MPP+. While mitotic N2AB-1 cells incubated with MPTP produced only traces of MPP+, C6 glioma cells generated significant amounts of this metabolite (3.6 microM). Moreover, although the morphology and cell number of cocultures did not change in the presence of MPTP, glioma-neuroblastoma cocultures produced 2.90 microM MPP+ which decreased protein synthesis by 18%.(ABSTRACT TRUNCATED AT 250 WORDS)


Natural history of asymptomatic ulcerative plaques of the carotid bifurcation.
In 79 patients with 91 asymptomatic ulcerating lesions of the carotid bifurcation who were followed an average of 54 months, there were two strokes, one of which was preceded by a warning transient ischemic attack. These data suggest that asymptomatic type A and type B carotid ulcerating lesions do not carry a significant early risk of stroke and do not warrant prophylactic carotid endarterectomy. However, the effect of antiplatelet drugs and anticoagulation in enhancing the development of subintimal hemorrhagic lesions remains uncertain. Further data with serial follow-up, preferably by noninvasive means, will be necessary to define the evolution of asymptomatic ulcerating carotid plaques and eventually permit identification of those lesions that have significant stroke potential.


Childhood lymphoma treatment impacts educational outcomes: a registry study from Sweden.
This study aimed to explore educational outcomes in individuals diagnosed with lymphoma in childhood concerning school grade year 9 and attendance in high school and post-compulsory education. Whether sex or age at diagnosis affected the assessed variables was also explored. Data from 174 children born 1988-1996 and diagnosed with lymphoma before age 15 were matched with approximately five controls per patient. The mean time since diagnosis to receiving school year 9 grades was 4.88 years for Hodgkin lymphoma (HL) cases (mean age at diagnosis 10.62, 11.76, and 10.05 years for all, girls, and boys, respectively) and 7.79 years for non-Hodgkin lymphoma (NHL) cases (mean age at diagnosis 7.85, 7.87, and 7.84 years for all, girls, and boys, respectively). We observed statistically significant differences between cases and controls in physical education, both for failing (p = 0.041) and the highest grade (p = 0.015). Compared with controls, HL cases were three times more likely to fail mathematics, and significantly fewer individuals in the whole lymphoma (p = 0.011) and NHL (p = 0.035) groups attended the third year of high school. Educational outcomes are impacted for children treated for lymphoma, especially in physical education. Since patients with HL are treated without central nervous system-directed therapy, other factors, such as absence from school, may affect school results. Physical late complications in lymphoma survivors warrant special attention. The problems childhood lymphoma survivors face should be known by schools and parents, to enable their management. Children treated for lymphoma should be closely monitored and included in follow-up programs when needed, for example, to support physical activity.


Whole genomic analysis reveals the co-evolutionary phylodynamics of Korean G9P[8] human rotavirus strains.
Three human rotavirus G9P[8] strains, RVA/Human-tc/KOR/CAU05-202/2005/G9P[8], RVA/Human-tc/KOR/CAU09-371/2009/G9P[8], and RVA/Human-tc/KOR/CAU09-376/2009/G9P[8], were isolated from female pediatric patients with diarrhea from 2005 to 2009 using a cell culture system, and their complete genomic sequences were analyzed. The 11 gene segments of the three Korean strains possessed the G9-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1 genotype, which is closely related to the Wa-like genotype 1 constellation. Interestingly, the NSP2 and the NSP3 genes of strain RVA/Human-tc/KOR/CAU09-376/2009/G9P[8] were related to the G9 porcine or human-porcine reassortant strains, providing evidence for porcine-to-human interspecies transmission.


Plasticity of acid phosphatase (FRAP) afferent terminal fields and of dorsal horn cell growth in the neonatal rat.
Peripheral nerve section results in depletion of fluoride-resistant acid phosphatase (FRAP) from the nerve terminals in the dorsal horn of the spinal cord (Schoenen et al., '68) and this has been used in the past to map the termination field of individual nerves (Rustioni et al., '71; Devor and Claman, '80). In the present study we show that a similar central depletion occurs following sciatic nerve section or crush in neonatal rats. Unlike adults, however, the area of depletion is rapidly filled by sprouting of FRAP-containing afferent terminals from nearby intact peripheral nerves. The sprouting is extensive but never completely fills the depleted area. After nerve crush there is some recovery of FRAP from the sciatic nerve terminals themselves as well as from nearby nerve terminals. The source of recovered FRAP is demonstrated by resectioning or recrushing the nerves. The sprouting occurred when the sciatic was injured on day 1 but failed to take place when the injury was applied on or after day 10. Sciatic nerve section on day 1 also produces marked growth retardation of the ipsilateral dorsal horn gray matter that becomes more apparent as the rat matures. Nerve crush produces a less marked shrinkage that is slower in onset. If the nerve is crushed repeatedly, however, so that regeneration is prevented, the shrinkage is analogous to that following nerve section. No shrinkage occurs if the nerve is cut or crushed on day 10. The results show that separation of the spinal cord from its peripheral input at a critical stage in development results in disruption of the somatotopic organization of the C fibre afferent input to the dorsal horn and in slowing of growth of the dorsal horn gray matter.


Description of same-direction car-to-bicycle crash scenarios using real-world data from Sweden, Germany, and a global crash database.
The overall number of traffic crashes is decreasing, but the number of crashes incurring cyclist injuries is not decreasing at the same pace. Of all car-to-bicycle crashes, same-direction crashes are among the ones with the highest risk of a serious-to-fatal injury. In this study, car-to-bicycle crashes occurring when a passenger car and a bicycle are both traveling in the same direction and on the same road (without a physically separated lane) from four different real-world crash databases were investigated. The focus was on analyzing pre-crash factors such as speed and light conditions, as well as other factors such as impact configurations and cyclist injuries. Three main crash scenarios were identified among the crashes that were studied. The most common one (comprising 65%) was CS1: "continued same-direction" with no intention of turning by either road user. The other two scenarios were CS2: "the bicycle crosses the vehicle's path by turning" (16%) and CS3: "the car crosses the bicycle's path by turning" (19%). The CS1 crashes were divided into three overtaking phases: approaching and steering, passing, and returning, representing 42-44%, 41-44%, and 12-17%, respectively, of the CS1 scenario. The three crash scenarios varied in car and bicycle speeds, road type, and weather and light conditions, as well as in impact points and cyclist injuries. The analysis of different same-direction crash scenarios and overtaking phases in this study offers a novel view of same-direction crashes, providing relevant information for the design of methods for the evaluation of crash avoidance and injury mitigation measures for these scenarios.