Diagnostic yield of oesophageal pH monitoring in patients with chronic unexplained cough.
One of the main causes of persistent cough is gastro-oesophageal reflux. In these patients, excessive oesophageal acid exposure and/or a temporal association between gastro-oesophageal reflux and cough can be demonstrated during 24-h pH monitoring. Impedance pH monitoring may have a higher yield than pH monitoring alone, but this technique is not yet widely available. The aim of this study was to assess the diagnostic yield of ambulatory 24-h oesophageal pH monitoring for the evaluation of chronic unexplained cough. Twenty-four-hour pH monitoring studies were analysed in 55 patients with chronic cough. In 14 of these studies concurrent ambulatory pressure monitoring was done. A cough episode was considered to be related to reflux if the cough occurred within two minutes after the onset of the reflux episode ("reflux-cough sequence"). Temporal relationships between cough and reflux were expressed by using the symptom association probability (SAP). Thirty-seven patients actually coughed during the 24-h study. Eleven patients (20%) had a positive SAP for the reflux-cough sequence. In 5 patients, reflux followed coughing. Pathological oesophageal acid exposure was found in 15 subjects. Interestingly, only a minority (39.2%) of the cough bursts detected manometrically were marked by patients who had undergone both combined 24-h pH and pressure recording. This study shows that, in a routine clinical setting, combined 24-h pH and pressure monitoring is useful in the evaluation of patients with chronic unexplained cough, as positive findings are not infrequently found and have diagnostic and therapeutic consequences.


Trial registration and results disclosure: impact of US legislation on sponsors, investigators, and medical journal editors.
Recently enacted federal legislation, the Food and Drug Administration Amendments Act of 2007 (FDAAA), mandates public registration and disclosure of results of "applicable" clinical trials of drugs, biologics and devices on www.clinicaltrials.gov. The law calls for registering more information about more trials than has been the policy of many medical journal editors to date. Beginning December 2007, results disclosure will occur in three stages initially with links to information from the FDA and NIH about FDA-approved products, as well as to Medline citations. A Basic Results Database will appear in September 2008, and an Expanded Results Database two years later. Results for trials of FDA-approved products must be posted within 12 months of trial completion. Such postings will not be peer reviewed or contain explanatory text or discussion. Sponsors who file regulatory submissions (IND, NDA, 510(k), PMA, etc.) to the FDA must certify compliance with FDAAA's registration and disclosure provisions. The FDA's determination of such compliance will be made public, and if non-compliance is not cured within 30 days, sponsors may be fined up to $10,000/day. FDAAA requirements differ in a number of ways from those of the International Committee of Medical Journal Editors (ICMJE) and other journal editors, creating potential conflicts for sponsors and investigators who must comply with the law, and a need for better alignment of editors' policies with the law. The public will have access to massive amounts of clinical trial data as a result of FDAAA but it is unclear this will be useful to patients and prescribing physicians.


[Imaging diagnostics of hyperparathyroidism].
Primary hyperparathyroidism is diagnosed by the presence of hypercalcemia, hypercalciuria and elevated serum levels of parathyroid hormone and is treated surgically by removal of the enlarged gland. Both ultrasound and 99m-Tc-MIBI scintigraphy are used to localize enlarged parathyroid glands. With sonography, enlarged parathyroid glands are hypoechoic and are most frequently found dorsally or caudally to the thyroid and medially to the carotid arteries. Ectopic parathyroid glands in the mediastinum can be detected by scintigraphy only. Computed tomography and magnetic resonance imaging are not primarily indicated. The sensitivity of ultrasound is 90% at best. Causes for false negative ultrasound examinations are ectopic glands in the mediastinum, small glands weighing less than 200 mg and large goiters which make assessment of the retrothyroid space difficult. Ultrasound and scintigraphy in combination can achieve a sensitivity of more than 90%. A combination of both is indicated prior to minimally invasive resection and in cases of recurrence or persistence of hyperparathyroidism after resection.


A straightforward graphical/statistical approach to help substantiate cheating on multiple-choice examinations.
Academic dishonesty is prevalent in universities in the form of cheating on examinations, with the problem being much greater in classes that have a large number of students that require close seating arrangements for in-class exams. The scenario described below was experienced during an in-class exam that included the possibility of an Honor Code violation between two students that was observed independently by three different faculty proctors. Herein we detail an objective, statistical approach taken to maintain exam and academic integrity that is compelling and transparent to students and the University Honor Council. Using the established error-similarity analysis for multiple-choice exams, it was determined that the number of identical incorrect answers found on the exams of the two individuals in question was sufficiently greater than the number expected by chance (probability of P < 0.00001). The number of total identical incorrect answers found on the remaining exams (across 65 students, n = 89 comparisons) was plotted as function of the number of total incorrect answers found on these exams (incorrect answers ranged from 1 to 22) and clearly supported that there was an Honor Code violation between the two students in question. The techniques used herein established, beyond a reasonable doubt, that a form of cheating had occurred between these students. However, caution must be taken as further investigation is requisite to establish whether the Honor Code violation was unidirectional (one student copying off the other) or bidirectional (collusion between the two students) in nature.NEW & NOTEWORTHY Academic dishonesty is prevalent in universities, especially on examinations with a large number of students in close seating arrangements. Cheating on a multiple-choice exam was suspected by observations from proctors of the examination. Application of error-similarity analysis associated with identical incorrect answers demonstrated that the probability of cheating was confirmed (P < 0.00001) between two examinees. Further comparisons with the remaining exams provided graphic evidence that a violation of the University's Honor Code had occurred.


Follicular phase cycle programming using estradiol in oocyte donors-a convenient and effective approach.
To study the efficacy of estradiol for cycle programming in oocyte donors when administered in the follicular phase only. Prospective interventional study. Single fertility center. Ninety-three oocyte donors underwent programmed stimulation using estradiol in the follicular phase. Their previous unprogrammed cycles were used as historical controls. Donors received 8 mg of estradiol hemihydrate from day 2 till 1 day before the start of stimulation. The primary outcome measures studied were the number of oocytes retrieved, duration of stimulation, and total gonadotropin dose. The number of mature oocytes, oocyte maturation rate, fertilization rate, blastulation rate, implantation rate, and pregnancy rate were the secondary outcomes. The average number of oocytes retrieved was higher in the study group (36.4 vs. 32.5). The duration of stimulation (9.22 vs. 9.21 days) and the total gonadotropin dose were similar (3,085.5 vs. 3,026 IU) between both groups. The mean number of mature oocytes retrieved was higher in the study group (30.1 vs. 26.3), but the maturation rate was similar (84.6% vs. 81.2%). The fertilization rate (77.8% vs. 78.7%), number of blastocysts, blastulation rate (32.7% vs. 33.2%), implantation rate (59.3% vs. 66.3%), and pregnancy rate (77.3% vs. 77.1%) showed no statistically significant difference. Estradiol usage in the follicular phase alone is an effective and convenient option for cycle programming in oocyte donors. It can yield similar mature oocytes and does not affect the clinical outcomes. Further larger sample-sized studies may be needed to validate its use which can also be extended to routine in vitro fertilization cycles. CTRI/2020/09/027815.


Team improvement and patient safety conferences: culture change and slowing the revolving door between skilled nursing facility and the hospital.
To improve the safety culture of a skilled nursing facility, we conducted multidisciplinary "Team Improvement for Patient and Safety" (TIPS) case conferences biweekly to identify causes of transfers to acute care hospitals and improvement opportunities. Staff perceptions of organizational patient safety culture were assessed with the Nursing Home Survey on Patient Safety Culture. Over the course of the year, we held 22 TIPS conferences. Mean item scores increased during the study, indicating improved staff perceptions of patient safety culture (P < .005).


Cyclic voiding urosonography in detecting vesicoureteral reflux in children.
Three methods are currently used to identify vesicoureteral reflux (VUR) in children, namely X-ray voiding cystourethrography (VCUG), radionuclide voiding cystography (RVC), and, recently, echo-enhanced voiding urosonography (VUS). It is known that the sensitivity of VCUG and RVC for detecting VUR can be improved by using cyclic procedures, such as repeated bladder filling and voiding. The purpose of our prospective study was to evaluate whether the cyclic procedure is superior to the conventional (one cycle only) procedure in VUS also. VUS was performed in 49 patients, aged 1.4-15.8 years (mean 4.1 years). After the first micturition, the catheter was left in place and the whole procedure was repeated under the same conditions. The results of the first and second cycles and the combined procedure were compared. In the initial cycle, 7 of 35 (20%) refluxing renal units that were detected in the second cycle and 4 of 26 (15%) children with at least unilateral VUR were missed. Cyclic VUS detected 25% more VURs than the conventional (one cycle only) VUS ( P=0.049) and revealed 50% more VUR III than the first cycle. Our results suggest that cyclic VUS is superior to conventional VUS.


An inhalation anaesthesia approach for neonatal mice allowing streamlined stereotactic injection in the brain.
Investigating brain function requires tools and techniques to visualise, modify and manipulate neuronal tissue. One powerful and popular method is intracerebral injection of customised viruses, allowing expression of exogenous transgenes. This technique is a standard procedure for adult mice, and is used by laboratories worldwide. Use of neonatal animals in scientific research allows investigation of developing tissues and enables long-term study of cell populations. However, procedures on neonatal mice are more challenging, due to the lack of reliable methods and apparatus for anaesthesia of these animals. Here, we report an inhalation-based protocol for anaesthesia of neonatal (P0-2) mice and present a custom 3D-printed apparatus for maintenance of anaesthesia during surgical procedures. Our optimised method of anaesthesia enables a rapid method of stereotactic injection in neonatal mice for transduction of brain tissue. This approach significantly enhances animal welfare and facilitates wider and simpler use of neonatal rodents in scientific research. We demonstrate this procedure for targeted labelling of specific brain regions, and in vivo modification of tissue prior to organotypic culture. Our protocol for reliable delivery of inhalational anaesthetics can be readily adopted by any laboratory and will enable safer use of neonatal rodents across a diverse spectrum of scientific disciplines. Application to stereotactic injections allows a rapid and efficient method for modification of brain tissue.


In vivo activity of the combination of daptomycin and fosfomycin compared with daptomycin alone against a strain of Enterococcus faecalis with high-level gentamicin resistance in the rat endocarditis model.
The in vivo activity of the combination of daptomycin and fosfomycin against a beta-lactamase-producing, highly gentamicin-resistant strain of Enterococcus faecalis in a relapse model of rat endocarditis was studied. Minimum inhibitory concentrations (MICs) (micrograms per milliliter) for these agents against this strain were 4 (daptomycin) and 16 (fosfomycin). Time-kill studies demonstrated synergistic bactericidal activity when daptomycin (0.5 micrograms/ml) and fosfomycin (32 micrograms/ml) were combined. There was no significant difference between the number of valves sterilized by daptomycin alone [six (35%) of 17 valves sterilized] and daptomycin+fosfomycin [ten (59%) of 17 valves sterilized] p = 0.3. These results suggest that the in vitro bactericidal synergism demonstrable between these two agents against strains of enterococci will not necessarily translate into greater therapeutic efficacy in clinical infections.


Characterization of functional surface structures on human natural killer cells.
Recent studies on human NK cells have identified a number of surface antigens that can be utilized to define this population of cells and to identify functionally distinct subsets within this heterogeneous population. In addition, it has been possible to associate specific functional activities with several antigens expressed on NK cells as well as other hematopoietic cells. This information, which is summarized in Table III can be utilized to develop a framework for the classification of cytolytic effector cells. Of primary importance, this classification identifies subsets of cytolytic cells with distinct functional repertoires and distinct cytolytic mechanisms. The majority of NK cells in unstimulated peripheral blood and the majority of NK clones express NKH1 and CD2 antigens but do not express CD3 antigen. These cells morphologically appear as large granular lymphocytes and have broad cytolytic activity against a variety of allogeneic targets without primary sensitization. Consistent with the finding that these cells are CD3 negative, they have not been found to have rearrangement of genes encoding for TCR, or functional mRNA transcripts of either TCR alpha, TCR beta, or TCR gamma genes. In addition, these cells do not express heterodimeric surface proteins similar to those that have now been demonstrated to be MHC-restricted T cell receptors for antigen. Taken together, these findings provide strong evidence that NKH1+CD3- NK clones do not interact with target cells through a T cell receptor-like structure. Nevertheless, these NK cells do share several properties with conventional CTL. These functional T cell characteristics include (1) expression of CD2-T11/E rosette receptor antigen, and (2) utilization of LFA-1 surface antigen to enhance effector cell adhesion to target cells. As previously demonstrated for T cells, NK cells can be activated through the CD2 molecule and this has recently been shown to result in the enhancement of cytolytic function by these effectors. Since CD2 can also function as a cell surface ligand for LFA-3, an antigen expressed on NK targets, the CD2 molecule may be considered as a potential NK receptor structure. The fact that a very small subset of NK cells (approximately equal to 10%) as well as some NK clones (JT11) does not express CD2 argues against a potential role for CD2 as the NK cell receptor. Certainly, further studies will be necessary to clarify the role of CD2 on NK cells and to identify the mechanisms whereby NKH1+CD3- NK cells interact with targets in a non-MHC-restricted fashion.(ABSTRACT TRUNCATED AT 400 WORDS)


Differential expression and properties of phenylalanine ammonia-lyase isoforms in tomato leaves.
In tomato leaves, excision and light treatments increase phenylalanine ammonia-lyase activity, which is contributed by three PAL isoforms. These isoforms possessed similar native and subunit Mr, but were different in their pI, Km for Phe and optimal pH for activity. Also these were differentially induced and affected by metabolites belonging to particular branches of phenylpropanoid pathway.


If it makes you feel bad, don't do it! Egoistic rather than altruistic empathy modulates neural and behavioral responses in moral dilemmas.
According to Greene et al.'s dual-process theory, the differential involvement of emotional processes would explain the different patterns of moral judgments people typically produce when faced with Trolley- and Footbridge-type dilemmas. As a relevant factor, dispositional empathy is known to motivate prosocial behaviors, thus playing a central role in moral judgment and behavior. The present study was aimed at investigating how behavioral and neural correlates of moral decision-making are modulated by the cognitive and affective dimensions of empathy. Thirty-seven participants were presented with 30 Footbridge-type and 30 Trolley-type dilemmas. Participants were required to decide between two options: letting some people die (non-utilitarian) vs. killing one person to save more people (utilitarian). Event-related potentials (ERPs) were recorded stimulus-locked to a "decision slide". Response choices and ratings of valence and arousal were also collected. Trait empathy was measured through the Interpersonal Reactivity Index (IRI), assessing both the cognitive and affective dimensions. Scores on the Empathic Concern affective subscale of the IRI positively predicted unpleasantness experienced during decision-making for all dilemmas. On the other hand, for Footbridge-type dilemmas only, scores on the Personal Distress affective subscale predicted negatively the mean percentages of utilitarian choices and positively the mean amplitudes of the P260, an ERP component reflecting an immediate emotional reaction during decision-making. It is concluded that "self-oriented" feelings of anxiety and unease, rather than "other-oriented" feelings of concern, affect behavioral choices and emotion-related cortical activity in Footbridge-type moral dilemmas.


A formal redefinition of the genera Nosema and Vairimorpha (Microsporidia: Nosematidae) and reassignment of species based on molecular phylogenetics.
The microsporidian genera Nosema and Vairimorpha comprise a clade described from insects. Currently the genus Nosema is defined as having a dimorphic life cycle characterized by diplokaryotic stages and diplosporoblastic sporogony with two functionally and morphologically distinct spore types ("early" or "primary" and "environmental"). The Vairimorpha life cycle, in addition to a Nosema-type diplokaryotic sporogony, includes an octosporoblastic sporogony producing eight uninucleate spores (octospores) within a sporophorous vesicle. Molecular phylogeny, however, has clearly demonstrated that the genera Nosema and Vairimorpha, characterized by the absence or presence of uninucleate octospores, respectively, represent two polyphyletic taxa, and that octosporogony is turned on and off frequently within taxa, depending on environmental factors such as host species and rearing temperature. In addition, recent studies have shown that both branches of the Vairimorpha-Nosema clade contain species that are uninucleate throughout their life cycle. The SSU rRNA gene sequence data reveal two distinct clades, those closely related to Vairimorpha necatrix, the type species for the genus Vairimorpha, and those closely related to Nosema bombycis, the type species for the genus Nosema. Here, we redefine the two genera, giving priority to molecular character states over those observed at the developmental, structural or ultrastructural levels and present a list of revised species designations. Using this approach, a series of species are renamed (combination novum) and members of two genera, Rugispora and Oligosporidium, are reassigned to Vairimorpha because of their phylogenetic position. Moreover, the family Nosematidae is redefined and includes the genera Nosema and Vairimorpha comprising a monophyletic lineage of Microsporidia.


MTHFR polymorphism and the risk of prostate cancer: a meta-analysis of case-control studies.
5,10-Methylenetetrahydrofolate reductase (MTHFR) polymorphisms implicated in the cancer development, but the published studies had yielded inconsistent results. Pubmed was searched for all published case-control studies about MTHFR polymorphisms and prostate cancer risk. In all, 13 studies including 5872 cases and 6255 controls described C677T genotypes, among which 9 articles, containing 2847 cases and 3657 controls described A1298C genotypes, were involved in our meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between MTHFR polymorphisms and prostate cancer risk, heterogeneity, publication bias and sensitivity were also calculated. Overall, meta-analysis indicated that the 677T allele was more likely to exert protective effect on prostate cancer risk (random-effects pooled OR, 0.78 (0.64-0.96); P=0.016 (P=0.033 for heterogeneity studies)) in a recessive genetic model, no associations were found in other genetic models or in comparing a/a versus A/A homozygous. Neither did we find any difference in effects on high or low aggressive prostate cancer. No evidence of an association of MTHFR A1298C polymorphism with prostate cancer was found. C677T of the MTHFR gene may provide protective effects on susceptibility to prostate cancer risk.


Imaging Evaluation of Insertion Point Accuracy in Retrograde Intramedullary Femoral Nailing.
When compared with visual retrograde intramedullary nail placement in the femur, fluoroscopic retrograde intramedullary nail placement in the femur improved the accuracy of insertion. Ninety-six patients treated with retrograde intramedullary nailing of the femur for femoral fracture were included in this retrospective case-control study, including 48 patients treated with nailing under direct vision and 48 patients treated with nailing under fluoroscopy. Influencing factors potentially associated with the deviation of the needle insertion point on the coronal and sagittal planes (including the needle insertion method, use of limited open reduction, side, intramedullary nail diameter, mechanism of injury, and fracture classification) were analyzed univariately; then, the variables with a p value < 0.20 on univariate analysis were included in the linear regression equation to assess the independent factors associated with needle insertion point deviation. On the coronal plane, the insertion point deviation in the visual nail placement group (1.11 ± 4.08 mm) was not significantly different (p = 0.13) from that in the fluoroscopic nail placement group (-0.44 ± 3.48 mm); on the sagittal plane, the insertion point deviation in the visual nail placement group (4.91 ± 4.67 mm) was significantly greater than that in the fluoroscopic nail placement group (2.08 ± 2.97 mm) (p < 0.01). Visual nail placement was a risk factor for insertion point deviation on the sagittal plane compared with fluoroscopic nail placement (β = -0.84, p < 0.01). Compared with visual nail placement, fluoroscopic nail placement improves the accuracy of insertion on the sagittal plane, with no difference between the two methods on the coronal plane. These findings indicate that surgeons should exercise more caution when placing nails under direct vision.


Automated machine learning for differentiation of hepatocellular carcinoma from intrahepatic cholangiocarcinoma on multiphasic MRI.
With modern management of primary liver cancer shifting towards non-invasive diagnostics, accurate tumor classification on medical imaging is increasingly critical for disease surveillance and appropriate targeting of therapy. Recent advancements in machine learning raise the possibility of automated tools that can accelerate workflow, enhance performance, and increase the accessibility of artificial intelligence to clinical researchers. We explore the use of an automated Tree-Based Optimization Tool that leverages a genetic programming algorithm for differentiation of the two common primary liver cancers on multiphasic MRI. Manual and automated analyses were performed to select an optimal machine learning model, with an accuracy of 73-75% (95% CI 0.59-0.85), sensitivity of 70-75% (95% CI 0.48-0.89), and specificity of 71-79% (95% CI 0.52-0.90) on manual optimization, and an accuracy of 73-75% (95% CI 0.59-0.85), sensitivity of 65-75% (95% CI 0.43-0.89) and specificity of 75-79% (95% CI 0.56-0.90) for automated machine learning. We found that automated machine learning performance was similar to that of manual optimization, and it could classify hepatocellular carcinoma and intrahepatic cholangiocarcinoma with an sensitivity and specificity comparable to that of radiologists. However, automated machine learning performance was poor on a subset of scans that met LI-RADS criteria for LR-M. Exploration of additional feature selection and classifier methods with automated machine learning to improve performance on LR-M cases as well as prospective validation in the clinical setting are needed prior to implementation.


Ion transport in the simplest single file pore.
A kinetic scheme is developed to describe single-file transport through pores containing up to two ions which may be of different species. The solution for the fluxes in terms of rate constants for entry, exit, and transfer is derived without specific assumptions about symmetry or the voltage and activity dependence of the constants. For a symmetrical pore the relation between the slope conductance at zero applied potential and ion activity can have two distinct regions in which the conductance increases linearly. Zero current or reversal potentials depend on the absolute values of the activities as well as their ratios. The use of this theory to describe the cation fluxes through the pores formed by gramicidin A will be considered in a subsequent paper. Here the model is discussed for a number of more specific assumptions, most extensively the following combination: (1) while entry to a pore is less likely when the pore is already occupied at the opposite end, this entry is still rapid; (2) exit is much more rapid when the pore is occupied by two ions; and (3) transfer from one end to the other of a singly occupied pore is rapid. With these assumptions and for a range of concentrations over which the fluxes are proportional to ion activities, the model predicts a flux ratio exponent nearly equal to 2, blocking by impermeant ions, rectification due to blocking particles on one side only, relief of block by increase in the permeant ion concentration on the opposite side, and anomalous variations of the conductance and zero current potential with mole ratio when the total concentration of the two permeants is held constant.


The impact of tracheotomy on levels of procalcitonin in patients without sepsis: a prospective study.
Procalcitonin is a reliable biomarker of infection and sepsis. We aimed to determine whether tracheotomy influences the procalcitonin concentrations in patients without sepsis and assess whether operative duration and procedure affect the peak procalcitonin level. A total of 38 non-septic patients who required a tracheotomy underwent either a percutaneous dilatational tracheotomy (n=19) or a surgical tracheotomy (n=19). Procalcitonin levels were measured at the beginning of the tracheotomy and at 2 h, 4 h, 8 h, 24 h, 48 h and 72 h after the procedure. The baseline procalcitonin concentration before the tracheotomy was 0.24 ± 0.13 ng/mL. The postoperative levels increased rapidly, with a 4-fold elevation after 2 h, reaching a peak 4 h later with a 5-fold increase over baseline. Thereafter, the levels gradually returned to 2-fold greater than the baseline level within 72 h. The peak levels of procalcitonin showed a significant positive correlation with operative durations (r=0.710, p<0.001) and procedures (rho=0.670, p<0.001). In patients without sepsis, tracheotomy induces a rapid release of serum procalcitonin, and the operative duration and procedure have significant impacts on the peak procalcitonin levels. Thus, the nonspecific increase in procalcitonin levels following tracheotomy needs to be considered when this measure is used to evaluate infection.


Study of polycyclic aromatic hydrocarbons accumulation in bioretention facilities and its influence on microbial community structure.
Bioretention facilities are one of the most widely used measures for urban stormwater control and utilization. In this study, the accumulation characteristics of polycyclic aromatic hydrocarbons (PAHs) in bioretention facilities and the effects of PAHs on the structure of microbial communities were explored by combining on-site monitoring and water distribution simulation experiments. The correlation between pollutant accumulation and dominant microorganisms in the bioretention systems was also clarified. The results showed that all 16 priority PAHs were detected in the bioretention facilities in the sponge city pilot area. The PAH concentrations in the soil during the non-rainy season were higher than those in the rainy season and medium- and high-ring PAHs dominated. PAHs in the study area were mainly derived from coal and biomass combustion. The potential carcinogenic risk of PAHs accumulated in the bioretention facilities in the study area was low. The microbial diversity during the non-rainy season was greater than that during the rainy season. Firmicutes, Bacteroidetes, Bacteroides, and Massilia were strongly correlated with naphthalene (NAP), pyrene (PYR), fluoranthene (FLT), and benzo[a]pyrene (BaP). According to the results of the small-scale water distribution test, the addition of PAHs had little effect on the decline in water quantity, and there was no significant regularity in the reduction of water quality including TP, NH4+-N, NO3-N, and TN. The addition of PAHs had a significant effect on the microbial community structure and an inhibitory effect on enzyme activity.


Silencing dopamine D3-receptors in the nucleus accumbens shell in vivo induces changes in cocaine-induced hyperlocomotion.
The dopamine D(3) receptor (D(3)R) is an important pharmacotherapeutic target for its potential role in psychiatric disorders and drug dependence. To further explore its function in rats, a regulatable lentivirus, Lenti-D3, holding the rat D(3)R cDNA, has been constructed as well as three nonregulatable lentiviruses, Lenti-D3-siRNA1, Lenti-D3-siRNA2 and Lenti-D3-siRNA3, expressing small hairpin RNAs, aimed at silencing D(3)R expression and specifically targeted against different regions of the D(3)R mRNA. In vitro, Lenti-D3 expressed D(3)R and could efficiently be blocked with Lenti-D3-Sils. These viruses were stereotaxically injected into the shell part of the nucleus accumbens (NAcc) and effects of passive cocaine delivery on locomotor activity were assessed. Manipulations of D(3)R levels induced changes in the locomotor stimulant effects of cocaine as compared to control treatment. Suppression of dopamine (DA) D(3)R in the NAcc by means of local knockdown (with Lenti-D3-Sils) increased locomotor stimulant effects, whereas its overexpression with Lenti-D3 drastically reduced them. The latter effects could be reversed when animals were fed doxycycline, which prevented lentiviral-mediated DA D(3)R overexpression in the NAcc. Gene expression assessed by quantitative RT-PCR confirmed very efficient gene knockdown in vivo in animals treated with Lenti-D3-Sils (> 93% silencing of D(3)R gene). Thus D(3)R expression significantly contributes to behavioural changes associated with chronic cocaine delivery.


Comparison of two suspension injection tracers of nano activated carbon and methylene blue in mapping and tracing of sentinel lymph nodes of patients with endometrial cancer.
To analyze the application efficiency of two tracers for sentinel lymph node mapping in patients with endometrial cancer. The records of endometrial cancer patients treated in our hospital from July 2019 to July 2021 were selected. Among them, 29 patients received methylene blue suspension injection and 33 patients received nano activated carbon suspension injection. The staining of sentinel lymph nodes was recorded and the application efficiency of two different tracers were analyzed. Total detection rate, average number of sentinel lymph nodes and bilateral detection rate of nano activated carbon suspension injection were significantly higher than those of methylene blue suspension injection (P<0.05). Detection accuracy, positive predictive value and sensitivity of nano activated carbon suspension injection were significantly higher than those of methylene blue suspension injection (P<0.05). Incidence of complications was the same in the two groups (P>0.05). Tracing time of nano activated carbon suspension injection was significantly lower than that of methylene blue suspension injection, and the total duration was significantly higher than that of methylene blue suspension injection (P<0.05). Nano activated carbon can obtain good detection effect in sentinel lymph node recognition in endometrial cancer patients, with shorter tracing time and higher total duration than methylene blue suspension.


Role of extracellular cGMP and of hyperammonemia in the impairment of learning in rats with chronic hepatic failure. Therapeutic implications.
Hepatic encephalopathy is a complex neuropsychiatric syndrome present in patients with chronic or acute liver disease. We review here some recent advances in the study, in animal models, of the mechanisms involved in the impairment in intellectual function in hepatic encephalopathy. These studies show that the function of the glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in rats with chronic hyperammonemia or liver failure and from patients died in hepatic encephalopathy. This impairment leads to a reduced extracellular concentration of cGMP in the cerebellum and is associated with reduced learning ability in these animal models. Moreover, learning ability of hyperammonemic rats was restored by increasing cGMP by: (1) continuous intracerebral administration of zaprinast, an inhibitor of the cGMP-degrading phosphodiesterase, (2) chronic oral administration of sildenafil, an inhibitor of the phosphodiesterase that crosses the blood-brain barrier and (3) continuous intracerebral administration of cGMP. The data summarized indicate that impairment of learning ability in rats with chronic liver failure or hyperammonemia is due to impairment of the glutamate-nitric oxide-cGMP pathway. Moreover, increasing extracellular cGMP by pharmacological means may be a new therapeutic approach to improve cognitive function in patients with hepatic encephalopathy.


Characterization of the 12q13-15 amplicon in soft tissue tumors.
Amplification of the genes MDM2, SAS, and CDK4, all located on the long arm of chromosome 12, has recently been demonstrated in human soft tissue tumors. To determine the extent of the amplification unit, we examined 16 soft tissue tumor samples, including pleomorphic liposarcoma, malignant fibrous histiocytoma (MFH), and atypical lipoma, by Southern blot analysis using 13 chromosome 12 probes. All tumors had previously been shown to have 3- to 20-fold amplification of MDM2. In five samples, all MFH, only MDM2 was amplified, whereas in the remaining 11 samples, two to five additional genes were amplified. The amplicon included markers both proximal and distal to MDM2, but was in all but one atypical lipoma confined to the chromosome region 12q13-15. Discontinuous amplicons were found in two of the tumors. This study indicates that MDM2, or possibly an as-yet-unidentified gene in its proximity, is the target gene of the 12q13-15 amplification in soft tissue tumors.


New spermidines from the florets of Carthamus tinctorius.
Two new spermidine compounds, namely safflospermidine A (1) and safflospermidine B (2), together with two known compounds, N(1),N(5),N(10)-(Z)-tri-p-coumaroylspermidine (3) and N(1),N(5),N(10)-(E)-tri-p-coumaroylspermidine (4), were isolated from the florets of Carthamus tinctorius L. Their structures were elucidated by spectroscopic means.


A comparison of the effects of phenylpropanolamine, d-amphetamine and d-norpseudoephedrine on open-field locomotion and food intake in the rat.
d,l-Norephedrine (PPA) is available as an over-the-counter appetite suppressant and nasal decongestant in the U.S.A. The pseudoisomer d-norpseudoephedrine, is available as an appetite suppressant in Europe, and has been isolated as one of the stimulatory components (cathine) of the Khat plant. Some authors have misidentified cathine as PPA and this confusion in the literature has resulted. PPA and d-norpseudoephedrine possess significantly different pharmacological properties despite having identical structural formulae. Anorectic activity was determined in a food-deprived rat model. PPA and d-norpseudoephedrine were approximately one-tenth as potent as d-amphetamine with all compounds producing a dose-dependent decrease in food intake. Locomotor activity in an open-field apparatus was determined as an index of CNS stimulation. Male Sprague-Dawley rats treated with d-norpseudoephedrine, in doses between 10 and 50 mg/kg, exhibited significantly increased locomotor scores compared to saline (control) treated animals, an increase similar to that caused by 2 mg/kg d-amphetamine. PPA (5-50 mg/kg) failed to increase locomotion significantly. These results indicate that although each compound tested decreased food intake in a dose-dependent fashion, significant differences in open-field locomotion do exist between PPA, d-norpseudoephedrine, and d-amphetamine. Stereoisomeric compounds, although structurally similar, frequently have different pharmacological effects. Thus extreme care must be taken to properly identify these compounds in the literature.


Impact of structural similarity on the accuracy of retention time prediction.
Quantitative Structure-Retention Relationships offer a valuable tool for de-risking chromatographic methods in relation to newly formed or hypothetical compounds, arising from synthetic processes or formulation activities. They can also be used to identify optimal separation conditions, or in support of structural elucidation. In this contribution, we provide a systematic study of the relationship between the accuracy of the retention model, the size of the training set and its structural similarity to the predicted compound. We compare structural similarity expressed either on a fingerprint basis (e.g., Tanimoto index), or by Euclidean distance calculated from of subset of molecular descriptors. The results presented indicate that accurate and predictive models can be built from a small dataset containing as few as 25 compounds, provided that the training set is structurally similar to the test compound. When the training set contains compounds selected by minimizing the Euclidean distance calculated from 3 descriptors most correlated with the retention time, root mean square error of 0.48 min and correlation coefficient of 0.9464 were observed for the test sets of 104 compounds. Moreover, these models meet the Tropsha predictivity criteria. These findings potentially bring the prediction of retention times within the practical reach of pharmaceutical analysts involved in chromatographic method development. We also present an optimisation approach to select algorithm settings in order to minimize the prediction error and ensure model predictivity.


Reduced exhaled NO is related to impaired nasal potential difference in patients with cystic fibrosis.
Nitric oxide (NO) plays a central role in many airway physiological functions, and its production appears to be related with progression of lung disease in patients with cystic fibrosis (CF). However, underlying mechanisms which specifically link NO and CF-related lung disease remain unclear. Following in vitro and animal studies suggesting a role for NO in ion transport in various epithelia, this work investigates the relationship between transepithelial baseline potential difference (BPD), an index of airway ion transport, and exhaled NO in the airways of adult patients with CF. Association with other phenotypic traits, lung function tests and CFTR genotype was also assessed. Using simple linear regression, F(E)NO and transepithelial BPD values were significantly inversely correlated (p<0.001, r=-0.53). Polynomial analysis evidenced an asymptotic relationship between F(E)NO and BPD values, yielding a plateau for absolute BPD values above 50 mV. This relation was not altered by adjustment for clinical and genetic characteristics of the patients. The relationship between exhaled NO and transepithelial BPD suggests that low NO concentrations likely worsens airway ion transport impairment resulting from CFTR defect. These results fit with experimental studies that suggest the inhibitory effect of NO on sodium absorption, which is the main determinant of airway basal transepithelial conductance.


Prognostic factors for survival in patients with brain metastases from renal cell carcinoma.
Patients presenting with brain metastases from renal cell carcinoma portend a poor prognosis, with a reported median survival of 4-6 months. Given their short life expectancy, these patients generally have been excluded from clinical trials that assess the efficacy of medical treatments. However, clinical impression suggests that some patients may achieve long term palliation. The clinical features of 68 patients who were treated at the Institut Gustave Roussy for brain metastases from renal cell carcinoma were collected retrospectively. Using univariate and multivariate analyses, a prognostic model based on independent prognostic factors was established. An external data set of 57 patients was used to validate the model. The median survival was 7 months. On univariate analysis survival was related significantly to the following adverse prognostic factors: no initial nephrectomy, left side and temporal location of brain metastases, presence of fever or weight loss, erythrocyte sedimentation rate > 50 mm/h, and time from initial diagnosis to brain metastases < or = 18 months. Multivariate analyses identified the previous variable as well as the presence of other visceral metastases as independent prognostic factors. Forty-four patients (65%) with no or 1 adverse prognostic factor (average risk group) had a median survival of 8 months and a 26% 1-year survival rate. Twenty-four patients (35%) with 2 adverse prognostic factors (poor risk group) had a median survival of 3 months and a 1-year survival rate of 9%. This model proved to be discriminant in an external data set; the median survival of patients assigned to the average risk group was 11 months (46% 1-year survival rate) compared with 4 months (9% 1-year survival rate) for patients assigned to the poor risk group. Patients presenting with brain metastases from renal cell carcinoma and poor risk prognostic factors are highly unlikely to benefit from medical treatments except symptomatic procedures. Conversely, the enrollment of patients with average risk prognostic factors into clinical trials dealing with chemotherapy or immunotherapy may be considered.


Enzyme histochemical properties of kitten osteoclasts in bone imprint preparations.
The enzyme histochemical characteristics of osteoclasts in imprints of the metaphyseal regions of femurs, from male kittens aged approximately 18 weeks, were investigated. A selected number of enzymes representative of a variety of metabolic pathways were studied. The enzyme profile, time for the first appearance of detectable reaction product, intensity of the reactions, and localization of the reaction products were noted. Osteoclasts are rich in enzymes, and metabolic pathways are well developed in respect of the utilization of the reduced coenzymes NADP and NADPH, succinic, malic, lactic, and isocitric acids, beta-hydroxybutyrate and glucose-6-phosphate, the reactions being mediated by the diaphorases and dehydrogenases. The activities of acid and neutral phosphatases, non-specific esterases, and leucine naphthylamidase were high in these cells. However, little or no activity was demonstrated in respect of glutamate and alpha-glycerophosphate dehydrogenases or of aryl sulphatase, glucose-6-phosphatase and alkaline phosphatase.


Functional characterization and expression analysis of two terpene synthases involved in floral scent formation in Lilium 'Siberia'.
Floral scent formation in Lilium 'Siberia' is mainly due to monoterpene presence in the floral profile. LoTPS1 and LoTPS3 are responsible for the formation of (±)-linalool and β-ocimene in Lilium 'Siberia'. Lilium 'Siberia' is a perennial herbaceous plant belonging to Liliaceae family, cultivated both as a cut flower and garden plant. The snowy white flower emits a pleasant aroma which is mainly caused by monoterpenes present in the floral volatile profile. Previously terpene synthase (TPS) genes have been isolated and characterized from various plant species but less have been identified from Liliaceae family. Here, two terpene synthase genes (LoTPS1 and LoTPS3), which are highly expressed in sepals and petals of Lilium 'Siberia' flower were functionally characterized recombinant LoTPS1 specifically catalyzes the formation of (Z)-β-ocimene and (±)-linalool as its main volatile compounds from geranyl pyrophosphate (GPP), whereas LoTPS3 is a promiscuous monoterpene synthase which utilizes both GPP and farnesyl pyrophosphate (FPP) as a substrate to generate (±)-linalool and cis-nerolidol, respectively. Transcript levels of both genes were prominent in flowering parts, especially in sepals and petals which are the main source of floral scent production. The gas chromatography-mass spectrometry (GC-MS) and quantitative real-time PCR analysis revealed that the compounds were emitted throughout the day, prominently during the daytime and lower levels at night following a strong circadian rhythm in their emission pattern. Regarding mechanical wounding, both genes showed considerable involvement in floral defense by inducing the emission of (Z)-β-ocimene and (±)-linalool, elevating the transcript accumulation of LoTPS1 and LoTPS3. Furthermore, the subcellular localization experiment revealed that LoTPS1 was localized in plastids, whilst LoTPS3 in mitochondria. Our findings on these two TPSs characterized from Lilium 'Siberia' provide new insights into molecular mechanisms of terpene biosynthesis in this species and also provide an opportunity for biotechnological modification of floral scent profile of Lilium.


Manual aspiration thrombectomy: adjunctive endovascular recanalization technique in acute stroke interventions.
We evaluated recanalization rates, clinical outcomes, and safety when manual aspiration thrombectomy is used in conjunction with other thrombolytic modalities in a consecutive case series of patients with large vessel intracranial occlusion. We conducted a retrospective review of a prospectively acquired acute endovascular stroke database. Manual aspiration thrombectomy was carried out with Distal Access and Penumbra reperfusion catheters of different sizes placed in the thrombus and aspirated with a syringe. We identified 191 patients: Occlusion locations were as follows: M1% to 50%, M2% to 10%, internal carotid artery terminus 25%, and vertebrobasilar 15%. Median treatment duration was 90 minutes. Recanalization results were Thrombolysis in Myocardial Ischemia 2/3 93%, Thrombolysis in Myocardial Ischemia 3 27%, Thrombolysis In Cerebral Infarction 2a/2b/3 91%, Thrombolysis In Cerebral Infarction 2b/3 71%, and Thrombolysis In Cerebral Infarction 3 25%. Larger catheters were associated with higher recanalization rates. Parenchymal hematoma rate was 13.6%. The favorable outcome (90-day modified Rankin Scale ≤ 2) rate was 54%. Mortality at 90 days was 25%. Manual aspiration thrombectomy is a useful addition to the armamentarium of endovascular treatment modalities for acute stroke.


Effect of ultrasound on the kinetics of anti-solvent crystallization of sucrose.
The effect of ultrasound on the kinetics of anti-solvent crystallization of sucrose was studied. The influence of temperature, stirring rate, supersaturation and ultrasonic power on the anti-solvent crystallization of sucrose was investigated. The relationship between infrared spectral characteristic band of sucrose and supersaturation was determined with an online reaction analyzer. The crystal size distribution of sucrose was detected by a laser particle-size analyzer. Ultrasound accelerated the crystallization process, and had no impact on the crystal shape. Abegg, Stevens and Larson model was fitted to the experimental data, and the results were the following: At 298.15 K, the average size of crystals was 133.8 μm and nucleation rate was 4.87 × 109 m-3·s-1 without ultrasound. In an ultrasonic field, the average size was 80.5 μm, and nucleation rate was 1.18 × 1011 m-3·s-1. Ultrasound significantly reduced the average size of crystals and improved the nucleation rate. It was observed that the crystal size decreased with the increase of stirring rate in silent environment. When the stirring rate increased from 250 to 400 rpm, the average size decreased from 173.0 to 132.9 μm. However, the stirring rate had no significant impact on the crystal size in the ultrasonic field. In addition, the activation energy of anti-solvent crystallization of sucrose was decreased, and the kinetic constant of nucleation rate was increased due to the effect of ultrasound. In the ultrasonic field, the activation energy was reduced from 20422.5 to 790.5 J·mol-1, and the kinetic constant was increased from 9.76 × 102 to 8.38 × 108.


Effect of Luffa echinata on lipid peroxidation and free radical scavenging activity.
The dried alcoholic (50%) extract of the plant Luffa echinata was investigated for inhibition of lipid peroxidation, for hydroxyl radical scavenging activity and interaction with 1,1-diphenyl-2-picrylhydrazyl stable free radical (DPPH). It was found that the test extract exhibited a considerable inhibition of lipid peroxidation and possessed hydroxyl radical scavenging activity. Evaluation of antiradical scavenging activity showed significant interaction with DPPH. These properties could be considered as a useful and exploitable combination for justifying the reported activity.


Serum levels of cathepsin D, sirtuin1, and endothelial nitric oxide synthase are correlatively reduced in elderly healthy people.
Nowadays, cathepsins have been reported to be related to aging. The aim of this study is to evaluate the association between serum levels of cathepsin D (CTSD) and human aging. In the present study, we analyzed the serum levels of CTSD and its relation with levels of sirtuin1 (SIRT1) and endothelial nitric oxide synthase (eNOS) activity, which were known having an important role in aging. This study recruited 90 healthy subjects (62 men and 28 women), which were subdivided into three groups with respect to age: young (about 19 years old, n = 30), middle-age (about 40 years old, n = 30), and aged (above 65 years old, n = 30). Altered serum levels of CTSD and SIRT1 were measured by enzyme-linked immunosorbent assay, and eNOS activity was assessed by the conversion of 14(C)-L-arginine to 14(C)-L-citrulline. Elderly subjects had significantly lower CTSD, SIRT1, and eNOS than younger ones. Serum levels of CTSD were negatively correlated with age. There was a statistically significant positive correlation between serum levels of CTSD, eNOS, and SIRT1. This study shows lower serum CTSD values in elderly subjects than in younger subjects. This is the first to demonstrate age-related changes in cathepsin D levels in humans and the association between SIRT1 and eNOS.


Ab Initio Study of Low-Lying Excited States of Carotenoid-Derived Polyenes.
Knowledge about excited states of carotenoids is essential for understanding photophysical processes underlying photosynthesis. However, due to the presence of a large number of optically dark states, experimental study of the excited-state manifold is limited to a significant extent. In this paper, we apply high-level ab initio quantum chemical methods to study the low-lying excited states of polyenes containing from 8 to 13 conjugated double bonds, which serve as a model for natural carotenoids. Vertical and adiabatic excitation energies from the ground 1Ag- state to the excited 2Ag-, 1Bu+, and 1Bu- states were evaluated by means of density matrix renormalization group (DMRG) with NEVPT2 perturbative correction. The energies of all excited states are highly sensitive to nuclear geometry, especially the 2Ag- state. Thus, the 2Ag- and 1Bu+ states interchange their relative positions upon geometry relaxation, while the vertical excitation energy to the 2Ag- state is rather high. At the same time, the 1Bu- state energy is shown to be higher than other studied excited states at any geometry. With relaxed geometries of the excited states, absorption and transient absorption spectra were calculated within the Franck-Condon approximation bridging the gap between experimental spectroscopic data and computational results.


A specific enzyme for glucose 1,6-bisphosphate synthesis.
The reaction: glycerate-1,3-P2 PLUS GLUCOSE-1-P YIELDS TO GLUCOSE-1,6-P2 plus glycerate-P is catalyzed by a distinct enzyme of mouse brain. A divalent metal requirement was shown when the enzyme was treated with imidazole and EDTA. Mg2+, Mn2+, Ca2+, Zn2+, Ni2+, Co2+, and Cd2+ were quite effective cofactors. The enzyme, in better than 50 percent yield, has been purified away from 99 percent of the phosphoglucomutase, phosphoglycrate mutase, and phosphofructokinase. Acetyl-P, ATP, enolpyruvate-P, creatine-P, and fructose-1,6-P2 are not phosphoryl donors. Glucose-6-P and mannose-1-P are good alternate acceptors. Mannose-6-P, galactose-Ps, and fructose-Ps have little or no acceptor activity. Strong inhibition was found with fructose-1,6-P2, glycerate-2,3-P2, enolpyruvate-P, and acetyl CoA. From the amount of activity and the kinetic constants of the purified enzyme it seems likely that this enzyme is responsible for the glucose-1,6-P2 synthesis of brain.


Evaluation of Outcomes Following Pulmonary Artery Stenting in Fibrosing Mediastinitis.
Fibrosing mediastinitis is a rare disease characterized by fibrosis of mediastinal structures with subsequent constriction of the bronchi and pulmonary vessels leading to potential respiratory compromise and death. Presently, there is no effective curative treatment with available treatments focused on reducing symptomology, including placement of pulmonary artery stents. Limited studies examine the use of stents in fibrosing mediastinitis. Given this knowledge gap, we assessed stent patency, hemodynamics, complications, and secondary outcomes of clinical improvement of pulmonary artery stenting for fibrosing mediastinitis. Nine patients with fibrosing mediastinitis and pulmonary artery stents were retrospectively identified for inclusion (six females, three males; mean age 44.17 years, range 13-68; total 13 primary stents) from 2005 to 2018. Eight patients had history of PH. All patients had dyspnea on presentation. Seven patients had ventilation/perfusion studies demonstrating impairment. Results from computed tomography and echocardiography studies were collected to assess patency and physiologic response. All patients received initial angioplasty and stenting of the right pulmonary artery (10 stents). Two patients underwent additional left-sided intervention (3 stents). Stenting significantly increased lesion luminal patency (54-79%; P < 0.005) and reduced systolic pressure gradients across stenoses (mean -9.38 mmHg; P < 0.005). Primary patency at one year was 90%. Two stents received reintervention at 276 and 497 days. 89% reported improvement in dyspnea in the initial post-stenting period. There were no mortalities or major complications. Pulmonary artery stenting improves vascular patency and provides symptomatic relief in patients with fibrosing mediastinitis.


Evidence for transfer of cellular and humoral immunity to cytomegalovirus from donor to recipient in allogeneic bone marrow transplantation.
In order to study the importance of the immune status of the donor in the development of immunity after allogeneic bone marrow transplantation (BMT), we monitored 23 cytomegalovirus (CMV) antibody-positive BMT recipients for humoral and cellular immunity to CMV, of whom 12 had a CMV antibody-positive and 11 a CMV antibody-negative marrow donor. Lymphocyte proliferation to CMV recovered significantly earlier after BMT in recipients of marrow from a CMV+ donor (10.4 weeks after BMT) compared with the recipients of marrow from CMV- donors (16.7 weeks after BMT, P less than 0.05). This seemed to be specific, as lymphocyte proliferation to phytohaemagglutinin and Candida were not different between the to groups. IgM responses after active infection were seen in both groups, but initial IgG rises without IgM were seen only in recipients of marrow from CMV+ donors (P less than 0.05). Lymphocyte proliferative or humoral immune responses to CMV were not detected in any of the patients in a control group consisting of nine CMV- recipients. These results indicate that T cell memory to CMV is transferred with donor marrow from CMV+ donors, leading in most patients to direct IgG anti-CMV responses and to quicker recovery of cellular immunity to CMV.


Regulation of mTOR signaling by long non-coding RNA.
The mechanistic target of rapamycin (mTOR) is a major signaling hub that coordinates cellular and organismal responses, such as cell growth, proliferation, apoptosis, and metabolism. Dysregulation of mTOR signaling occurs in many human diseases, and there are significant ongoing efforts to pharmacologically target this pathway. Long noncoding RNAs (lncRNA), defined by a length > 200 nucleotides and absence of a long open-reading-frame, are a class of non-protein-coding RNAs. Mutations and dysregulations of lncRNAs are directly linked to the development and progression of many diseases, including cancer, diabetes, and neurologic disorders. Recent findings reveal diverse functions for lncRNA that include transcriptional regulation, organization of nuclear domains, and regulation of proteins or RNA molecules. Despite considerable development in our understanding of lncRNA over the past decade, only a fraction of annotated lncRNAs has been examined for biological function. In addition, lncRNAs have emerged as therapeutic targets due to their ability to modulate multiple pathways, including mTOR signaling. This review will provide an up-to-date summary of lncRNAs that are involved in regulating mTOR pathway.


Expression and clinical significance of annexin A2 and human epididymis protein 4 in endometrial carcinoma.
It is well-known that the treatment and monitoring methods are limited for advanced stage of endometrial carcinoma. Biological molecules with expression changes during tumor progression become potential therapeutic targets for advanced stage endometrial carcinoma. Annexin A2 (ANXA2) has been reported to be overexpressed in recurrent endometrial carcinoma, and the expression of human epididymis protein 4 (HE4) is upregulated in endometrial carcinoma. What's more, ANXA2 and HE4 interacted in ovarian cancer and promoted the malignant biological behavior. We speculated that their interaction may exist in endometrial carcinoma as well. We evaluated the expression and the correlation relationship of ANXA2 and HE4 in endometrial carcinoma. The expression of ANXA2 and HE4 protein in 84 endometrial carcinoma, 30 endometrial atypical hyperplasia, and 18 normal endometrial tissue samples were then measured using an immunohistochemical assay in paraffin embedded endometrial tissues. The structural relationship between ANXA2 and HE4 was explored by immunoprecipitation and double immunofluorescent staining. ANXA2 and HE4 co-localized in both endometrial tissues and endometrial carcinoma cells. ANXA2 and HE4 were expressed in 95.2 % and 85.7 % of the the endometrial carcinoma, respectively, which were significantly higher than normal endometrium (55.6 % and 16.7 %, both p < 0.05). The expression of ANXA2 and HE4 was significantly correlated with FIGO stage, degree of differentiation, myometrial invasion, and lymph node metastasis. ANXA2 was an independent risk factor for the prognosis of endometrial carcinoma (p < 0.05, hazard ratio [HR] = 8.004). The expression of ANXA2 and HE4 was positively correlated (Spearman correlation coefficient = 0.228, p < 0.05). HE4 was an independent factor for ANXA2 in multivariate linear regression model (p < 0.05). We revealed the co-localization of ANXA2 and HE4 in endometrial carcinoma. Expression levels of ANXA2 and HE4 were closely related to the malignant biological behavior of endometrial carcinoma, and ANXA2 was an independent risk factor for poor prognosis. The expression of ANXA2 and HE4 can affect each other.


An efficient string matching algorithm with K substitutions for nucleotide and amino acid sequences.
Given a text of length n, a pattern of length m and an integer k, we present an algorithm for finding all occurrences of the pattern in the text, each with at most k substitutions. The algorithm runs in O(k(m log m + n)) time, and requires O(nk) space. This algorithm has direct implications for nucleotide and amino acid sequence comparisons.


Metagenomic Next-Generation Sequencing for Infectious Disease Diagnosis: A Review of the Literature With a Focus on Pediatrics.
Metagenomic next-generation sequencing (mNGS) is a novel tool for identifying microbial DNA and/or RNA in blood and other clinical specimens. In the face of increasingly complex patients and an ever-growing list of known potential pathogens, mNGS has been proposed as a breakthrough tool for unbiased pathogen identification. Studies have begun to explore the clinical applicability of mNGS in a variety of settings, including endocarditis, pneumonia, febrile neutropenia, osteoarticular infections, and returning travelers. The real-world impact of mNGS has also been assessed through retrospective studies, documenting varying degrees of success and limitations. In this review, we will explore current highlights of the clinical mNGS literature, with a focus on pediatric data where available. We aim to provide the reader with a deeper understanding of the strengths and weaknesses of mNGS and to provide direction toward areas requiring further research.


Altering the substrate specificity of glutamate dehydrogenase from Bacillus subtilis by site-directed mutagenesis.
The Lys80, Gly82 and Met101 residues of glutamate dehydrogenase from Bacillus subtilis were mutated into a series of single mutants. The wild-type enzyme was highly specific for 2-oxoglutarate, whereas G82K and M101S dramatically switched to increased specificity for oxaloacetate with kcat values 3.45 and 5.68 s-1, which were 265-fold and 473-fold higher respectively than those for 2-oxoglutarate.


Anomic alexia of kanji in a patient with anomic aphasia.
The ability to read aloud kanji (logogram) words and to comprehend their meaning was systematically examined to clarify the underlying mechanism of kanji alexia in a patient with anomic aphasia. Confrontation naming, reading aloud and reading comprehension tasks were performed using 110 words from 11 semantic categories written in kanji or kana. Performance in oral reading of kanji words was significantly worse than oral reading of the same words transcribed into kana words. In addition, for kanji words reading aloud was much worse than reading comprehension. Oral reading of kanji words had a significant correlation with naming pictures corresponding to the words, but no correlation with comprehension of kanji words. Qualitative analyses demonstrated that errors in oral reading and naming tasks had many features in common. Our results indicated that some common mechanisms underlie both naming and oral reading of kanji words. We propose calling this type of alexia "anomic alexia of kanji", which should be distinguished from kanji alexia with difficulty in both reading aloud and comprehension. Lesions in our patient were located in the middle part of the left middle temporal gyrus and its subcortical area, which could be important for access to the phonological lexicon from semantics.


Pseudorabies virus (PRV) early protein 0 activates PRV gene transcription in combination with the immediate-early protein IE180 and enhances the infectivity of PRV genomic DNA.
Pseudorabies virus (PRV) early protein 0 (EP0) functions as a transactivator of the viral gene promoters. In transient expression assays employing chloramphenicol acetyl transferase (CAT) reporter constructs, EP0 and the immediate-early protein IE180 act in an additive manner to activate transcription from the thymidine kinase (TK) and glycoprotein G (gG) gene promoters. EP0 enhanced the synthesis of infectious virus in cotransfection experiments with the EP0-expression plasmid and PRV genomic DNA. EP0 was detected by Western blot analysis in the purified virions. These results may indicate that EP0 in the virions acts as an important transactivator to express the immediate-early gene efficiently in the first stage of infection, and IE180 and EP0 expressed after the infection cooperatively activate the early and late gene expression in the later stage of infection.


Successful surgical internal drainage of postoperative pancreatic pseudocyst through pancreaticojejunostomy with distal pancreatectomy: a case report.
Pancreatic pseudocyst is usually treated by percutaneous external drainage, endoscopic internal or external drainage, or surgical internal drainage such as cystogastrostomy. Surgical external drainage is an option if these procedures fail. We describe a case of a 70-year-old man with a pancreatic body pseudocyst that developed postoperatively. It was improved by endoscopic external drainage, and the stent was changed to an internal stent. However, surgery was required as the pseudocyst grew again. A direct approach to the pseudocyst was not possible because of severe adhesion. A distal pancreatectomy with pancreaticojejunostomy was performed, and an external pancreatic stent tube was inserted from the cut end into the duodenum to drain the pseudocyst. One month later, the pseudocyst disappeared, and the stent was removed.


The erm(T) gene is flanked by IS1216V in inducible erythromycin-resistant Streptococcus gallolyticus subsp. pasteurianus.
We investigated the sequence and the genetic context of the erm(T) gene in six inducible erythromycin-resistant Streptococcus gallolyticus subsp. pasteurianus (formerly S. bovis biotype II.2) isolates. In all isolates, the erm(T) genes were flanked by two IS1216V-like elements with the same polarity and were found to be inserted in the chromosome.


Epidemiological studies on Japanese encephalitis in Kyoto City area, Japan. III. Seasonal prevalence of virus infections in several pig populations shown by virus recovery from engorged Culex tritaeniorhynchus summorosus.
When vector mosquitoes engorged by feeding on pigs are tested for virus recovery after incubation for 7 to 10 days, the results may show mosquito infection itself. Therefore, seasonal prevalence of infection in each pig population can be estimated from course of the infection rate among mosquitoes. Many mosquitoes of the main vector of Japanese encephalitis virus, Culex tritaeniorhynchus summorosus, collected by light traps everyday or every other day in some pig sheds from 1967 to 1970 were tested for virus recovery after incubation. The tests were positive during about a month period each summer, and the peak infection rate was high being over 10%. The course of the mosquito infection showed a certain pattern with one or two peaks between the initial recovery and the highest peak. From the interval of 12 to 13 days after the first recovery to the peak, cyclic infection between the pig and the mosquito may occur at the same interval.


Diffusion Magnetic Resonance Imaging Detects Progression in Parkinson's Disease: A Placebo-Controlled Trial of Rasagiline.
Rasagiline has received attention as a potential disease-modifying therapy for Parkinson's disease (PD). Whether rasagiline is disease modifying remains in question. The main objective of this study was to determine whether rasagiline has disease-modifying effects in PD over 1 year. Secondarily we evaluated two diffusion magnetic resonance imaging pulse sequences to determine the best sequence to measure disease progression. This prospective, randomized, double-blind, placebo-controlled trial assessed the effects of rasagiline administered at 1 mg/day over 12 months in early-stage PD. The primary outcome was 1-year change in free-water accumulation in posterior substantia nigra (pSN) measured using two diffusion magnetic resonance imaging pulse sequences, one with a repetition time (TR) of 2500 ms (short TR; n = 90) and one with a TR of 6400 ms (long TR; n = 75). Secondary clinical outcomes also were assessed. Absolute change in pSN free-water accumulation was not significantly different between groups (short TR: P = 0.346; long TR: P = 0.228). No significant differences were found in any secondary clinical outcomes between groups. Long TR, but not short TR, data show pSN free-water increased significantly over 1 year (P = 0.025). Movement Disorder Society Unified Parkinson's Disease Rating Scale testing of motor function, Part III increased significantly over 1 year (P = 0.009), and baseline free-water in the pSN correlated with the 1-year change in Movement Disorder Society Unified Parkinson's Disease Rating Scale testing of motor function, Part III (P = 0.004) and 1-year change in bradykinesia score (P = 0.044). We found no evidence that 1 mg/day rasagiline has a disease-modifying effect in PD over 1 year. We found pSN free-water increased over 1 year, and baseline free-water relates to clinical motor progression, demonstrating the importance of diffusion imaging parameters for detecting and predicting PD progression. © 2021 International Parkinson and Movement Disorder Society.


Regulation of finP transcription by DNA adenine methylation in the virulence plasmid of Salmonella enterica.
DNA adenine methylase (Dam(-)) mutants of Salmonella enterica serovar Typhimurium contain reduced levels of FinP RNA encoded on the virulence plasmid. Dam methylation appears to regulate finP transcription, rather than FinP RNA stability or turnover. The finP promoter includes canonical -10 and -35 modules and depends on the sigma(70) factor. Regulation of finP transcription by Dam methylation does not require DNA sequences upstream from the -35 module, indicating that Dam acts at the promoter itself or downstream. Unexpectedly, a GATC site overlapping with the -10 module is likewise dispensable for Dam-mediated regulation. These observations indicate that Dam methylation regulates finP transcription indirectly and suggest the involvement of a host factor(s) responsive to the Dam methylation state of the cell. We provide evidence that one such factor is the nucleoid protein H-NS, which acts as a repressor of finP transcription in a Dam(-) background. H-NS also restrains transcription of the overlapping traJ gene, albeit in a Dam-independent fashion. Hence, the decreased FinP RNA content found in Dam(-) hosts of S. enterica appears to result from H-NS-mediated repression of finP transcription.


Ultrastructure of synovial changes in rheumatoid disease and in seronegative inflammatory arthropathies.
Synovial tissue has been examined by electron microscopy from patients suffering from either sero-positive or sero-negative inflammatory arthropathies to allow direct comparison of the ultrastructural changes found in these groups and to confirm and extend observations previously made in a smaller group of sero-negative arthropathies. Both groups have been compared with material from healthy controls. The sero-positive group comprised 13 cases of 'definite' or 'classical' rheumatoid arthritis. The sero-negative group consisted of 9 cases of arthritis secondary to Crohn's disease (3); Reiter's syndrome (2); Whipple's disease (1); Behcet's disease (1); Wegener's granulomatosis (1) and ankylosing spondylitis (1). The control tissue was obtained from 6 non-arthritic subjects undergoing surgery for non-inflammatory conditions. Confirmation was obtained of changes previously reported in subcellular organelles, especially in synovial B cells, in all forms of inflammatory arthritis as compared with controls. Attention is now drawn to other intracellular changes in B cells and intermediate cells which included: a marked increase of intermediate filaments and microfilaments: and proliferation of pinocytotic vesicles and rough endoplasmic reticulum. These changes were often accompanied by the presence, in the immediate environment of these cells, of extracellular microfibrillary masses but little or no accumulation of intermediate filaments. It was confirmed that synovial A cells were reduced in number but showed changes suggestive of increased phagocytic activity and also exhibited proliferation of cytoskeletal elements. Differences in these structural changes between sero-positive and sero-negative arthritis were of degree rather than of kind and no 'specific' or diagnostic differences were observed between the various forms of seronegative athropathies. The possible significance of the structural changes observed is discussed.


The role of ultrasonography and MRI in patients with non-traumatic nerve fascicle torsion of the upper extremity.
To evaluate the role of ultrasonography and magnetic resonance imaging (MRI) in the diagnosis of non-traumatic nerve fascicle torsion of the upper extremity. Eleven patients (unilateral upper extremity) who underwent surgical treatment for nerve fascicle torsion were included in the study. Ultrasonography and MRI showed the detailed anatomy of the region well enough to reveal nerve fascicle torsion. The characterization and classification (single-segmental or multi-segmental) based on ultrasonography and diffusion-weighted (DW) MRI findings were recorded. The hourglass-shaped appearance was a characteristic feature of nerve fascicle torsion, Characterization and classification based on ultrasonography and MRI findings were consistent with intraoperative findings. Ultrasonography and MRI may be valuable in the diagnosis of non-traumatic nerve fascicle torsion of the upper extremity.


The Hand-sewn Anastomosis with an Absorbable Bidirectional Monofilament Barbed Suture Stratafix® During Laparoscopic One Anastomosis Loop Gastric Bypass. Retrospective Study in 50 Patients.
Laparoscopic One Anastomosis Gastric Bypass (LOAGB) is one of the main bariatric procedures that require a safe and reproducible gastrojejunal anastomosis. Barbed suture has been widely used for surgery in recent years; however, few studies have reported their use for gastro-intestinal anastomosis. We proposed their use for totally hand-sewn anastomosis during LOAGB. The objective of this study is to evaluate the risk of leaks and stenosis after a hand-sewn anastomosis using an absorbable bidirectional monofilament barbed suture: Stratafix®. The study was done in a private practice setting. Between April and November 2014, 50 consecutive patients undergoing a hand-sewn antecolic, antegastric gastrojejunal anastomosis (GJA) using Stratafix®. Pre, intra, and postoperative parameters were assessed for these patients. No fistulas or anastomotic stenosis had occurred up to 6 months after surgery. All procedures were completed laparoscopically, and no intraoperative complications occurred. The mean length of hospital stay was 3 days. The use of an absorbable bidirectional monofilament barbed suture for the GJA was safe. Further prospective studies with a higher number of patients are needed to address the safety and efficacy of the absorbable bidirectional monofilament barbed suture in bariatric surgery.


The interpretation of laterality.
It is suggested that many analyses of laterality are fundamentally confused in that they fail to distinguish between differences in degree of laterality and differences in direction of laterality, and that direction and degree of laterality have different biological and psychological interpretations. Conventional statistical tests, such as analysis of variance or non-parametric procedures, are unable to differentiate the two measures, and necessarily produce uninterpretable results. A maximum likelihood method is described which can discriminate between direction and degree, and its applications to factorial, test-retest, and repeated measure designs is explained. Two worked examples are also given, one based on hypothetical data, the other on actual data.


Surgical correction of scoliosis in pediatric patients with cerebral palsy using the unit rod instrumentation.
Retrospective clinical and radiographic consecutive case series of 2 surgeons. The purpose of this study was to present a large consecutive series of patients with cerebral palsy who were treated with the Unit rod instrumentation at a single institution. The goal was to report the incidence of surgical complications, degree of deformity correction, reoperation rate, prevalence of pseudarthrosis, and the caretakers' perceived outcome. Children with cerebral palsy frequently develop scoliosis that requires surgical correction. Segmental instrumentation has been the primary mode of treatment. There are no reported large series with long-term follow up. This study was a retrospective review of 287 children treated with the Unit rod instrumentation. This instrumentation with fusion included the whole spine (between C7 and T3 into the pelvis) with 242 posterior-only and 45 anterior-posterior procedures. Of this group, 241 patients were observed for more than 2 years. This review focused on the rate of complications and radiographic outcome of the treatment. Parent and caretaker interviews were conducted to define perceived functional outcome after surgery. Scoliosis was corrected from a mean of 76 degrees to 25 degrees (68%). Pelvic obliquity was corrected from a mean of 17 degrees to 5 degrees (71%). In posterior-only procedures the average blood loss was 2.8 L, ICU stay was 4.9 days, and the hospital stay was 19.6 days. In combined procedures, the average blood loss was 3.4 L, ICU stay was 6.7 days, and the hospital stay was 24.5 days. Major complications included 3 perioperative deaths, 18 deep wound infections [12 early deep infections in a total of 287 patients (4.2%); 6 late deep infections in a total of 236 patients (2.5%)], and 2 patients with septicemia who recovered after prolonged antibiotic management. Caretakers' survey reported a 96% satisfaction rate. The Unit rod instrumentation is a common standard technique and the primary instrumentation system for the treatment of pediatric patients with cerebral palsy and neuromuscular scoliosis because it is simple to use, it is considerably less expensive than most other systems, and can achieve good deformity correction with a low loss of correction, as well as a low prevalence of associated complications and a low reoperation rate.


Automatic limb identification and sleeping parameters assessment for pressure ulcer prevention.
Pressure ulcers (PUs) are common among vulnerable patients such as elderly, bedridden and diabetic. PUs are very painful for patients and costly for hospitals and nursing homes. Assessment of sleeping parameters on at-risk limbs is critical for ulcer prevention. An effective assessment depends on automatic identification and tracking of at-risk limbs. An accurate limb identification can be used to analyze the pressure distribution and assess risk for each limb. In this paper, we propose a graph-based clustering approach to extract the body limbs from the pressure data collected by a commercial pressure map system. A robust signature-based technique is employed to automatically label each limb. Finally, an assessment technique is applied to evaluate the experienced stress by each limb over time. The experimental results indicate high performance and more than 94% average accuracy of the proposed approach.


Multimodal drugs and their future for Alzheimer's and Parkinson's disease.
This chapter discusses the rationale for developing multimodal or multifunctional drugs (also called designed multiple ligands or DMLs) aimed at disease-modifying treatment strategies for the most common neurodegenerative diseases Alzheimer's and Parkinson's disease (AD and PD). Both the prevalence and incidence of AD and PD have seen consistent and dramatic increases, a disconcerting phenomenon which, ironically, has been attributed to extended life expectancy brought about by better health care globally. In spite of these statistics, the development and introduction to the clinic of new therapies proven to prevent or delay the onset of AD and PD have been disappointing. Evidence has accumulated to suggest that the etiopathology of these diseases is extremely complex, with an array of potential drug targets located within a number of deleterious biochemical pathways. Therefore, in these diseases, it is unlikely that the complex pathoetiological cascade leading to disease initiation or progression will be mitigated by any one drug acting on a single pathway or target. The pursuit of novel DMLs may offer far better outcomes. Although certainly not the only, and perhaps not even the best, approach but farthest along the drug development pipeline in the DML paradigm are drugs that combine inhibition of monoamine oxidase with associated etiological targets unique to either AD or PD. These compounds will constitute the major focus of this chapter, which will also explore radically new paradigms that seek to combine cognitive enhancers with proneurogenesis compounds.


Diminishing diagnosis of follicular thyroid carcinoma.
Follicular carcinomas have been reported as 10% to 15% of thyroid malignancies. Refinements in the histologic criteria applied in the classification of follicular lesions have occurred. We aim to document the true incidence of follicular cancers in a cohort from a high-volume endocrine practice. Patient charts were reviewed and cancers were classified into major subtypes; papillary cancers were further classified by common variants. Proportions were compared to historic Surveillance, Epidemiology, and End Results (SEER) database proportions. Only 2.7% of patients had follicular carcinoma. The proportion of patients with follicular cancer was less than the reported rates of 10% to 15%, and less than the 6.7% extrapolated from SEER. The proportion of follicular cancers is less than traditionally reported. This change is due to an increased incidence of papillary cancers, and modifications of the histologic criteria used for classification of encapsulated follicular lesions. There are potential prognostic consequences, as follicular cancers have been perceived as more aggressive.


Methods for analyzing and interpreting cooperativity in dose-response curves--II. Partial agonists acting on muscarinic receptors in smooth muscle.
1. Dose-response curves for eight muscarinic agonists contracting guinea pig ileum were transformed into Hanes-Woolf plots and Hill plots respectively. 2. Hill plots for three full agonists were linear with slopes of 1.6, illustrating positive homotropic cooperativity involving two or more agonist binding sites. 3. Five partial agonists gave curved Hill plots with Hill coefficients of 1.2-1.7 at low agonist concentration and Hill coefficients of 0.3-0.5 at high agonist concentrations. 4. Hanes-Woolf transformations were used to delineate the transition from positive to negative cooperativity and to assist in the interpolation of Hill plots. 5. The results show that all of the agonists studied induce positive cooperativity, and that the difference between full agonists and partial agonists results from the ability of the latter to induce pronounced negative cooperativity at higher concentrations.


[Obesity and heart failure].
Obesity doubles the risk of heart failure independent of comorbidities like hypertension or coronary artery disease potentially mediated by altered hemodynamics to compensate increased mass and metabolic activity. Symptoms of obesity cardiomyopathy do not differ from other forms of cardiomyopathy, but may be easily mixed up with obesity associated symptoms. The diagnosis can be made with imaging techniques like echocardiography or magnetic resonance imaging. Therapeutic approaches include weight control by dietary intervention and exercise, as well as bariatric surgery for the morbidly obese. Heart failure treatment should otherwise follow the general heart failure guidelines.


A Putative Plasma Membrane Na+/H+ Antiporter GmSOS1 Is Critical for Salt Stress Tolerance in Glycine max.
Soybean (Glycine max) is a staple crop and a major source of vegetable protein and vegetable oil. The growth of soybean is dramatically inhibited by salt stress, especially by the excessive toxic Na+. Salt Overly Sensitive 1 (SOS1) is the only extensively characterized Na+ efflux transporter in multiple plant species so far. However, the role of GmSOS1 in soybean salt stress responses remains unclear. Herein, we created three gmsos1 mutants using the CRISPR-Cas9 system in soybean. We found a significant accumulation of Na+ in the roots of the gmsos1 mutants, resulting in the imbalance of Na+ and K+, which links to impaired Na+ efflux and increased K+ efflux in the roots of the gmsos1 mutants under salt stress. Compared to the wild type, our RNA-seq analysis revealed that the roots of the gmsos1-1 showed preferential up and downregulation of ion transporters under salt stress, supporting impaired stress detection or an inability to develop a comprehensive response to salinity in the gmsos1 mutants. Our findings indicate that the plasma membrane Na+/H+ exchanger GmSOS1 plays a critical role in soybean salt tolerance by maintaining Na+ homeostasis and provides evidence for molecular breeding to improve salt tolerance in soybean and other crops.


Global transcriptome analysis for identification of interactions between coding and noncoding RNAs during human erythroid differentiation.
Studies on coding genes, miRNAs, and lncRNAs during erythroid development have been performed in recent years. However, analysis focusing on the integration of the three RNA types has yet to be done. In the present study, we compared the dynamics of coding genes, miRNA, and lncRNA expression profiles. To explore dynamic changes in erythropoiesis and potential mechanisms that control these changes in the transcriptome level, we took advantage of high throughput sequencing technologies to obtain transcriptome data from cord blood hematopoietic stem cells and the following four erythroid differentiation stages, as well as from mature red blood cells. Results indicated that lncRNAs were promising cell marker candidates for erythroid differentiation. Clustering analysis classified the differentially expressed genes into four subtypes that corresponded to dynamic changes during stemness maintenance, mid-differentiation, and maturation. Integrated analysis revealed that noncoding RNAs potentially participated in controlling blood cell maturation, and especially associated with heme metabolism and responses to oxygen species and DNA damage. These regulatory interactions were displayed in a comprehensive network, thereby inferring correlations between RNAs and their associated functions. These data provided a substantial resource for the study of normal erythropoiesis, which will permit further investigation and understanding of erythroid development and acquired erythroid disorders.


miR-23a/b promote tumor growth and suppress apoptosis by targeting PDCD4 in gastric cancer.
MicroRNAs (miRNAs) are short non-coding RNAs of 21-23 nucleotides that play important roles in virtually all biological pathways in mammals and in other multicellular organisms. miR-23a and miR-23b (miR-23a/b) are critical oncomiRs (miRNAs that are associated with human cancers) of gastric cancer, but their detailed roles in the initiation and progression of gastric cancer remain to be elucidated. In this study, we found that miR-23a/b were consistently upregulated in gastric cancer tissues. We then investigated the molecular mechanisms through which miR-23a/b contribute to gastric cancer and identified programmed cell death 4 (PDCD4) as a direct target gene of miR-23a/b. In contrast to the upregulated expression levels of miR-23a/b, PDCD4 protein levels were dramatically downregulated and inversely correlated with miR-23a/b in gastric cancer tissues. Moreover, we observed that cell apoptosis was increased by miR-23a/b inhibitors and decreased by miR-23a/b mimics in gastric cancer cells and that the restoration of PDCD4 expression attenuated the anti-apoptotic effects of miR-23a/b in gastric cancer cells, indicating that PDCD4 is a direct mediator of miR-23a/b functions. Finally, we showed that miR-23a/b significantly suppressed PDCD4 expression and enhanced tumor growth in a gastric cancer xenograft mouse model. Taken together, this study highlights an important role for miR-23a/b as oncomiRs in gastric cancer through the inhibition of PDCD4 translation. These findings may shed new light on the molecular mechanism of gastric carcinogenesis and provide a new avenue for gastric cancer treatment.


Research progress on the role of biofilm in heavy metals adsorption-desorption characteristics of microplastics: A review.
Microplastics (MPs) have been found to be widely distributed in aquatic environments, where they will interact with toxic heavy metals and result in more serious adverse effects on the aquatic environments and organisms. However, after entering the aquatic environments, MPs are quickly covered by biofilms, which significantly modify MPs properties and relevant heavy metals adsorption-desorption characteristics In order to better understand the adsorption behavior of heavy metals on biofilm developed MPs (BMPs), we comprehensively reviewed representative studies in this area. First, we summarized the formation process of biofilms on MPs. Subsequently, we reviewed the current understanding on the influence of biofilm formation on the properties of MPs and discussed the metal adsorption-desorption characteristics of MPs affected by these changes. Finally, based on the systematic literature review, some future research needs and strategies were proposed to further understand the interactions between MPs and heavy metals.


Physiological evidence of mitochondrial permeability transition pore opening caused by lipid deposition leading to hepatic steatosis in db/db mice.
Mitochondrial permeability transition pore (mPTP) is an important regulator in cell apoptosis and necrosis. However, its role in hepatic steatosis, especially its electrophysiological properties transformation remains elusive. Herein, using diabetes mice, we investigated the role of mPTP in hepatic steatosis triggered by diabetes and the mechanisms involved. We found that hepatic steatosis altered mitochondrial morphology, generating mega mitochondria, mitochondria swelling, calcein fluorescence quenching and mitochondrial membrane potential depolarization. At the same time, we confirmed an augmented mPTP opening with patch clamping in liver mitoplasts in db/db mice and a similar transformation with arachidonic acid (AA) simulating liquid deposition. We also found mPTP opening was significantly attenuated in wt mice after removing mitochondrial matrix, while that in db/db mice remained active. In addition, we observed that AA could directly activate mPTP in inside-out mode, independent of matrix calcium. In conclusion, we for the first time provided a physiological evidence of mPTP opening in lipid deposition, which could be directly induced by AA without Ca2+ and can be inhibited by cyclosporine A. As a result, it led to mitochondria morphology and function transformation. This might provide insights into potential therapeutic target for future treatment of mitochondrial liver disease.


Drosophila development: the secrets of delayed induction.
Dorsoventral axis formation in Drosophila relies on extracellular signals which are generated only at the ventral side of the egg. This asymmetry, in turn, depends on the expression specifically in ventral follicle cells of pipe, the product of which seems likely to be a glycosaminoglycan-modifying enzyme.


Clinical relevance of CD95 (Fas/Apo-1) on T cells of patients with B-cell chronic lymphocytic leukemia.
Apoptosis mediated via CD95 (Fas/Apo-1) is a key regulator for the biology of normal and malignant lymphocytes. Although the function of CD95 on B-cell chronic lymphocytic leukemia cells (B-CLL cells) has been studied intensively, the clinical importance of CD95 expression on normal T cells in B-CLL has not been clarified. This study aimed to investigate whether expression of CD95 on peripheral blood T cells correlates with clinically relevant parameters of B-CLL disease. Expression of CD95 (Fas/Apo-1) on peripheral blood T lymphocytes of patients with B-CLL was determined using flow cytometry and was correlated with expression of activation markers, sensitivity to apoptosis by anti-CD95, and clinical data, such as blood count, Binet stage, therapy, progression-free probability, and survival probability. Differential CD95 expression did not correlate with activation markers or with levels of apoptosis through anti-CD95. However, high levels of CD95 on T cells from B-CLL patients correlated significantly with low lymphocyte doubling time, increased Binet stages, and requirement for chemotherapeutic treatment. Furthermore, increased cell-surface CD95 on T cells was associated with reduced progression-free probability and poorer survival. CD95 levels on T cells correlate with the clinical course of B-CLL. Prospective studies appear warranted to investigate whether CD95 on T cells has a direct influence on B-CLL disease progression.


Efficacy and safety of fecal microbiota transplantation by washed preparation in patients with moderate to severely active ulcerative colitis.
We aimed to evaluate the short-term efficacy and safety of fecal microbiota transplantation (FMT) by washed preparation for moderate to severely active UC. An open-label prospective trial was conducted in an inflammatory bowel disease (IBD) tertiary referral center from April 2016 to March 2018. Patients with moderate to severely active UC were randomly assigned to undergo FMT thrice on day 1, 3 and 5 by nasojejunal tube (NJT) or transendoscopic enteral tubing (TET). The primary end-point was a clinical response at week 2 post-FMT. The secondary end-points were clinical and endoscopic remission at week 12 post-FMT, safety and disease progression. Of the nine patients included, 77.8% (7/9) achieved a clinical response at week 2. And 55.6% (5/9) and 33.3% (3/9), respectively, achieved clinical remission and endoscopic remission at week 12. In two patients who had no response to FMT, one switched to anti-tumor necrosis factor-α therapy, and the other underwent a colectomy. FMT was delivered through NJT in 44.4% (4/9) of the patients, while TET was used in 55.6% (5/9). The clinical outcomes did not differ significantly based on the delivery route (P > 0.05). Adverse events, all mild and self-limiting, were observed in 33.3% (3/9) of the patients. FMT by washed preparation appears to be a safe and effective adjunct therapy for moderate to severely active UC during a short-term follow-up. The efficacy did not differ significantly between the NJT or TET delivery routes. Further randomized controlled studies are needed to confirm these findings.


Maintenance of androgen deprivation therapy or testosterone supplementation in the management of castration-resistant prostate cancer: that is the question.
Whether or not androgen receptor (AR) axis could still be targetable in castration resistant prostate cancer (CRPC) patients with disease progression to next generation hormonal agents (NGHAs) is a controversial issue. Serum testosterone in CRPC patients has a positive prognostic role and increasing testosterone levels after androgen deprivation therapy (ADT) withdrawal or testosterone supplementation, as part of a bipolar androgen therapy (BAT) strategy, has been shown to potentially restore sensitivity to previous lines of NGHAs. These data suggest that maintenance of ADT in CRPC patients receiving further lines of treatment, as recommended by current international guidelines, could be questionable. Conversely, testosterone supplementation aimed to re-sensitize CRPC to further hormonal manipulation is a strategy worth to be explored in future clinical trials.


Change in cholesterol level during pregnancy and risk of postpartum depressive symptoms: the Japan Environment and Children's Study (JECS).
Women with postpartum depressive symptoms (PDS) are at higher risk of postpartum depression (PPD) and require further assessment. Emerging evidence indicates a relationship between the total cholesterol (TC) level of blood and PPD but the results are inconsistent. In this study, we investigated the possible association of change in serum TC levels during pregnancy with the risk of PDS in a Japanese population. We analyzed complete data on questionnaire responses and serum lipid profiles of pregnant women from 12 datasets obtained from the Japan Environment and Children's Study (n = 61,585 to n = 72,406; 103,063 pregnancies in total). TC was measured at 3 time points-during early pregnancy, during mid-late pregnancy, and after delivery-and we calculated changes in TC in 3 ways: by subtracting early pregnancy from mid-late pregnancy, subtracting mid-late pregnancy from delivery, and subtracting early pregnancy from delivery. These 6 factors were used as predictors to estimate the risk of PDS at 1 and 6 months after delivery. In multivariable logistic regression analysis, point serum cholesterol level did not predict PDS at any time point except for during mid-late pregnancy in the second quintile, indicating an increased risk at 6 months. As for change in TC levels, subtracting mid-late pregnancy from delivery and early pregnancy from delivery showed significant risk reduction for PDS at 1 month. A significant risk reduction was also found for subtracting early pregnancy from mid-late pregnancy and early pregnancy from delivery at 6 months. Increased cholesterol level during pregnancy is associated with reduced risk of PDS.