Association of thyroid function test abnormalities with preeclampsia: a systematic review and meta-analysis.
Preeclampsia is a life-threatening disorder during pregnancy and postpartum periods. Preeclampsia can affect the activity of many organs. It is very important because if this disorder is associated with changes in thyroid function, it can affect the results of maternal and fetal tests. Accordingly, the aim of this meta-analysis study was to assess the abnormalities in thyroid function tests in preeclampsia. Studies were selected through a systematic search of the MEDLINE/PubMed, Scopus, Web of Science Core Collection, and Google Scholar databases in 31st August 2021. Also, reference lists of review articles and relevant studies were manual-searched to identify other potentially eligible studies. English studies that compared TSH, T4 and T3 of normal pregnant with preeclamptic women (Known to be normotensive before pregnancy; gestational age 20 week or more; singleton pregnancy; no previous history of thyroid dysfunction) were screened. Data sets were screened for eligibility by two independent reviewers. Articles were assessed by the Newcastle-Ottawa Scale. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used for quality assessment of evidence on outcome levels. After reviewing 886 published studies, 63 observational studies were selected and used for this meta-analysis. The study population included 21,528 pregnant women. The findings revealed that TSH (SMD = 1.70, 95%CI: 1.39 to 2.02; p < 0.001) was significantly higher in preeclamptic women. TT4 (SMD = -0.82, 95%CI: -1.16, -0.49; p < 0.001), TT3 (SMD = -0.88, 95%CI: -1.36 to -0.41; p < 0.001) and FT3 (SMD = -0.59, 95%CI: -0.91 to -0.27; p < 0.001) were less in preeclamptic women. There was no statistically significant difference in FT4 between two groups (SMD = 0.002, 95%CI: -0.27 to 0.27; p = .990). The results of publication bias and sensitivity analysis confirmed the reliability and stability of this meta-analysis. The quality of evidence was regarded as moderate, low, and very low for these risk factors according to the GRADE approach. Findings of this meta-analysis indicated preeclamptic women were more at risk of changes in thyroid function tests. In order to prevent thyroid disorders, it is recommended that thyroid function tests be performed in women with pre-eclampsia.


Marginal pulmonary function is associated with poor short- and long-term outcomes in lung cancer surgery.
We sought to determine the short- and long-term prognoses among 'marginal-risk' non-small cell lung cancer patients who have a predicted postoperative- (ppo) forced expiratory volume in the first second (FEV1) of 30-60% and/or a ppo-diffusing capacity of the lung for carbon monoxide (DLCO) of 30-60%. The present study included 73 'marginal-risk' and 318 'normal-risk' patients who underwent anatomical resection for clinical stage I lung cancer between 2008 and 2012. The rates of postoperative morbidity, prolonged hospital stay, and overall survival were assessed. Postoperative morbidity occurred in 35 (48%) 'marginal-risk' patients and 66 (21%) 'normal-risk' patients, and 17 (23%) 'marginal-risk' patients and 20 (6%) 'normal-risk' patients required a prolonged hospital stay. The three- and five-year survival rates were 79% and 64% in the 'marginal-risk' patients and 93% and 87% in the 'normal-risk' patients, respectively. A 'marginal-risk' status was a significant factor in the prediction of postoperative morbidity (odds ratio [OR] 2.97, p < 0.001), the rate of prolonged hospital stay (OR 3.83, p < 0.001), and overall survival (hazard ratio 2.07, p = 0.028). In conclusion, 'Marginal-risk' patients, who are assessed based on ppo-values, comprise a subgroup of patients with poorer short- and long-term postoperative outcomes.


PARAPAPILLARY GAMMA AND DELTA ZONES IN HIGH MYOPIA.
To examine parapapillary zones gamma and delta in highly myopic eyes. The retrospective observational study included patients attending the Tokyo high myopia clinics. Fundus photographs were morphometrically examined. The study population included 600 eyes (304 individuals) with a mean age of 62.7 ± 14.3 years (range: 13-90 years) and mean axial length of 29.6 ± 2.2 mm (range: 23.2-35.4 mm). In multivariate analysis (regression coefficient r:0.90), larger horizontal gamma zone diameter was correlated with wider delta zone diameter (P < 0.001; standardized regression coefficient beta: 0.81), higher ratio of vertical-to-horizontal disk diameter (P < 0.001; beta: 0.10), shorter fovea-outer gamma zone border distance (P < 0.001; beta: -0.19), longer disk-fovea distance (P < 0.001; beta: 0.18), and higher count of chorioretinal atrophic lesions (P < 0.001; beta: 0.07). Longer horizontal delta zone width was correlated with longer horizontal gamma zone diameter (P < 0.001; beta: 1.00), longer horizontal disk diameter (P < 0.001; beta: 0.15), shorter disk-fovea distance (P < 0.001; beta: -0.19), longer fovea-outer gamma zone border distance (P < 0.001; beta: 0.19), and smaller diameter of the largest chorioretinal lesion (P = 0.03; beta: -0.04). Longer width of both zones together was associated with longer horizontal disk diameter (P < 0.001; beta: 0.31), higher ratio of vertical-to-horizontal disk diameter (P = 0.001; beta: 0.18), longer disk-fovea distance (P < 0.001; beta: 0.19), shorter fovea-outer gamma zone border distance (P < 0.001; beta: -0.18), higher number of chorioretinal lesions (P < 0.001; beta: 0.30), and longer vertical distance between the superior and inferior temporal arterial arcade (P = 0.001; beta: 0.13). Larger gamma and delta zones were correlated with larger optic disk and more marked vertical optic disk rotation, longer disk-fovea distance, higher number of chorioretinal lesions, and longer temporal vascular arcade diameter. Parapapillary gamma and delta zones may develop before chorioretinal lesions develop and enlarge.


Anesthetic technique and oncological outcomes in urology: A clinical practice review.
There is increasing awareness that different anesthetic and analgesic techniques may impact outcomes after oncological surgery, generally through modifying effects on the immune system but potentially via other mechanisms including mitigating the surgical stress response. This narrative review aims to summarize the mechanisms underlying the effect of perioperative factors on oncological outcomes, with an emphasis on the available urologic literature. Literature on anesthetic technique (i.e., general vs. regional) and oncological outcomes were reviewed with a particular focus on urological studies. In prostate cancer surgery, the risk of mortality has been reported to be reduced with the use of regional (i.e., neuraxial) anesthesia, but there was no association between anesthetic technique and progression-free or biochemical recurrence-free survival. In nonmuscle invasive bladder cancer, regional anesthesia has been associated with lower recurrence rates and longer time to recurrence following transurethral resection of bladder tumor. This review highlights the role of regional anesthesia to improve oncoimmunological responses after surgery, potentially through decreased use of volatile anesthetics and opioids, decreased activation of the surgical stress response, and a direct local anesthetic-mediated anti-inflammatory effect. Available urological literature suggests an association of anesthetic type and outcomes for nonmuscle invasive bladder cancer and prostate cancer surgeries but the evidence is limited. Prospective studies are needed to further investigate the relationship between anesthetic technique and urologic oncological outcomes.


Ambulatory drug changes in the elderly after hospital discharge: A cohort study.
To describe the ambulatory changes in drug prescriptions 3 months after hospital discharge among elderly patients aged 75 and over, and to identify the reasons for these changes. A prospective cohort study was conducted on subjects, discharged between 09/2016 and 01/2017 from the Bordeaux University Hospital. Prescription forms were collected from patients' pharmacists. The main outcome was the occurrence of at least one significant change (SC) defined as an initiation, a discontinuation, a switch or change in drug daily dosage as regards the drugs prescribed upon hospital discharge and those prescribed 3 months after. Whenever drug SC occurred, general practitioners were requested to elicit reasons for such changes. Among the 126 patients included in our study, 73 underwent a 3-month follow-up period, without death or being re-hospitalised. 87.7% of them had at least one SC 3 months after discharge, with an average of 3.1±2.5 SC per patient. Main changes involved: discontinuation or dose decrease of anxiolytics, hypnotics, antalgics, betablockers and calcium channel blockers; start or dose increase of diuretics, ACE inhibitors and angiotensin receptor blockers. In patients with a 3-month follow-up period, 27.4% underwent at least one ADR-induced SC. Most elderly patients experience drug prescription changes after discharge. Some, according to drug iatrogenic, could be avoided through better cooperation between hospital and ambulatory prescribers.


Chemical inhibition of oxygen-sensing prolyl hydroxylases impairs angiogenic competence of human vascular endothelium through metabolic reprogramming.
Endothelial cell (EC) metabolism has emerged as a driver of angiogenesis. While hypoxia inactivates the oxygen sensors prolyl-4 hydroxylase domain-containing proteins 1-3 (PHD1-3) and stimulates angiogenesis, the effects of PHDs on EC functions remain poorly defined. Here, we investigated the impact of chemical PHD inhibition by dimethyloxalylglycine (DMOG) on angiogenic competence and metabolism of human vascular ECs. DMOG reduced EC proliferation, migration, and tube formation capacities, responses that were associated with an unfavorable metabolic reprogramming. While glycolytic genes were induced, multiple genes encoding sub-units of mitochondrial complex I were suppressed with concurrent decline in nicotinamide adenine dinucleotide (NAD+) levels. Importantly, the DMOG-induced defects in EC migration could be partially rescued by augmenting NAD+ levels through nicotinamide riboside or citrate supplementation. In summary, by integrating functional assays, transcriptomics, and metabolomics, we provide insights into the effects of PHD inhibition on angiogenic competence and metabolism of human vascular ECs.


How would Australian hospital staff react to an avian influenza admission, or an influenza pandemic?
To estimate the expected staff absentee rates and work attitudes in an Australian tertiary hospital workforce in two hypothetical scenarios: (i) a single admission of avian influenza; and (ii) multiple admissions of human pandemic influenza. A survey conducted at hospital staff meetings between May and August 2006. Out of 570 questionnaires distributed, 560 were completed. For scenario one, 72 (13%) indicated that they would not attend work, and an additional 136 (25%) would only work provided that immunizations and/or antiviral medications were immediately available, so that up to 208 (38%) would not attend work. For scenario two, 196 (36%) would not attend work, and an additional 95 (17%) would work only if immunizations and/or antiviral medications were immediately available, so that up to 291 (53%) staff would not attend work. Staff whose work required them to be in the ED (odds ratios 2.2 and 1.6 for each scenario respectively) or on acute medical wards (odds ratios 2.2 and 2.0 respectively) were more likely to work. High absenteeism among hospital staff should be anticipated if patients are admitted with either avian or pandemic influenza, particularly if specific antiviral preventative measures are not immediately available. Measures to maximize the safety of staff and their families would be important incentives to attend work. Education on realistic level of risk from avian and pandemic influenza, as well as the effectiveness of basic infection control procedures and personal protective equipment, would be useful in improving willingness to work.


Drinking water, sanitation, and hygiene (WASH) situation in primary schools of Pakistan: the impact of WASH-related interventions and policy on children school performance.
The United Nation's Sustainable Development Goals include the target of ensuring access to water and sanitation and hygiene (WASH) for all; however, very few studies have assessed comprehensive school WASH service in Pakistan. The purpose of this study was to identify WASH services in primary schools of Pakistan, and to assess how recent WASH interventions and policies are associated with the school's academic performance. A representative cross-sectional study was conducted in primary schools in the Sindh province of Pakistan. Structured observations and interviews were done to ascertain the schools' WASH conditions. The primary exposures of interest were the implementation of previous WASH interventions and National WASH policy in the school and the WASH coverage. Outcomes of interest included WASH conditions and school performance. The structural equation modeling (SEM) using a bootstrap resampling procedure was employed to characterize how WASH exposures were associated with WASH conditions and school performance. Data were collected from 425 schools. The Basic WASH facilities coverage in the primary schools of Sindh remains overall low according to WHO WASH service ladder criteria. Also, inconsistency in all three inclusive domains of WASH (availability, accessibility, and functionality) facilities were found. The school performance was significantly associated (P<0.001) with the presence of WASH interventions and/or WASH policy, while WASH policy and/or recent WASH intervention at the school were not associated with overall water quality. Our assessment unveiled several WASH gaps that exist, including high heavy metal and fecal contamination. Adoption of national WASH policy and financing of evidence-based WASH interventions are recommended in primary schools to improve educational outcomes.


FIGNL1 associates with KIF1Bβ and BICD1 to restrict dynein transport velocity during axon navigation.
Neuronal connectivity relies on molecular motor-based axonal transport of diverse cargoes. Yet the precise players and regulatory mechanisms orchestrating such trafficking events remain largely unknown. We here report the ATPase Fignl1 as a novel regulator of bidirectional transport during axon navigation. Using a yeast two-hybrid screen and coimmunoprecipitation assays, we showed that Fignl1 binds the kinesin Kif1bβ and the dynein/dynactin adaptor Bicaudal D-1 (Bicd1) in a molecular complex including the dynactin subunit dynactin 1. Fignl1 colocalized with Kif1bβ and showed bidirectional mobility in zebrafish axons. Notably, Kif1bβ and Fignl1 loss of function similarly altered zebrafish motor axon pathfinding and increased dynein-based transport velocity of Rab3 vesicles in these navigating axons, pinpointing Fignl1/Kif1bβ as a dynein speed limiter complex. Accordingly, disrupting dynein/dynactin activity or Bicd1/Fignl1 interaction induced motor axon pathfinding defects characteristic of Fignl1 gain or loss of function, respectively. Finally, pharmacological inhibition of dynein activity partially rescued the axon pathfinding defects of Fignl1-depleted larvae. Together, our results identify Fignl1 as a key dynein regulator required for motor circuit wiring.


β-Catenin phosphorylation at Y654 and Y142 is crucial for high mobility group box-1 protein-induced pulmonary vascular hyperpermeability.
Endothelial hyperpermeability is a hallmark of acute lung injury in response to sepsis. The imbalance between adherence junction (AJ) mediated cell-cell adherence forces and stress fiber driven contractile forces contributes to increased endothelial permeability. Here, we spotlight the effects of β-catenin Y654 andY142 phosphorylation on HMGB1-mediated endothelial barrier leakage. Our results showed that phospho-deficiencies at both β-catenin Y654and Y142ameliorated pulmonary vascular dysfunction in male C57 mice receiving a cecal ligation and puncture operation. In vitro analysis indicated that high mobility group box-1 protein (HMGB1) triggered β-catenin Y654 and Y142 phosphorylation, causing β-catenin translocation and adherence junction (AJ) disruptions as well as cytoskeleton rearrangement. In addition,β-catenin Y654 dephosphorylation attenuated HMGB1-mediated dissociation of VE-cadherin/β-catenin and, hence, partially prevented endothelial hyperpermeability. β-catenin Y142 dephosphorylation abolished HMGB1-induced uncoupling of β-catenin and α-catenin, suppressed cytoskeletal reassembly and, hence, alleviated endothelial hyperpermeability. Further investigation demonstrated that RAGE and Src were required forβ-catenin Y654 phosphorylation in response to HMGB1, while FAK was responsible for HMGB1-triggered β-catenin Y142 phosphorylation. In sum, this study revealed the role of β-catenin Y654 and Y142 phosphorylation in HMGB1-mediated endothelial hyperpermeability through dysregulation between adherence and contractile forces. This result advances understanding of the mechanisms underlying pulmonary vascular hyperpermeability in sepsis.


Hemodynamic effects of inotropes during hypothermia and rapid rewarming.
The hemodynamic effects of propranolol, lidocaine, and dopamine were studied in anesthetized, mechanically ventilated dogs, cooled to 25 degrees C with a venovenous shunt through a heat exchanger. After 1 h at 25 degrees C, the shunt was converted to an arteriovenous shunt which remained functional until the study was completed. Before rewarming, the authors treated each group of 8 dogs with intravenous doses of the drugs: group 1: 10 ml saline as control; group 2: propranolol 0.3 mg/kg; group 3: 50 mg lidocaine initially, followed with continuous infusion of 40-50 microgram/kg.min; group 4: dopamine infusion at 12 microgram/kg.min; and group 5: lidocaine as in group 3 and dopamine as in group 4. For the dopamine-treated groups, 2 min of infusion was allowed; in all other groups, 5 min elapsed after injection before the hemodynamic data were recorded. The hemodynamic data were collected at esophageal temperatures of 25, 30, and 37 degrees C. The findings were: (1) hypothermia impaired cardiovascular function; (2) lidocaine and propranolol had minimal hemodynamic effects during hypothermia; lidocaine was physiologically more desirable than propranolol; (3) dopamine, alone or combined with lidocaine, reversed the cardiovascular depression from hypothermia; the improvement was equivalent to rewarming by as much as 5 degrees C; and (4) at the completion of rewarming, cardiovascular recovery was more complete with dopamine/lidocaine-treated animals compared to untreated and propranolol-treated animals. Based on these findings, these inotropes appear to be safe adjuncts to resuscitation during hypothermia.


Insulin fast-dissolving film for intranasal delivery via olfactory region, a promising approach for the treatment of anosmia in COVID-19 patients: Design, in-vitro characterization and clinical evaluation.
The present work aimed to formulate intranasal insulin fast-dissolving films for treatment of anosmia in patients post COVID-19 infection. Variant films were prepared employing the casting method and using hydroxypropyl methyl cellulose and polyvinyl alcohol. The formulated films were investigated for insulin content, weight variation, surface pH, thickness, folding endurance and disintegration time. In vitro release study was conducted for the selected formulations (F6, F7, F8). A drug/polymer interaction was investigated in the optimized formulation (F7) employing Fourier transform infrared spectroscopy. Clinical study was accomplished for F7 on 20 patients. Sniffin's and olfactory discrimination tests were used for assessing patients. The formulated films displayed appropriate physical characteristics. F7 showed the shortest disintegration time (50 ± 7 s) and fastest release. It displayed compatibility between the drug and the used polymers. The results of the clinical study revealed a significant increase in the olfactory detection scores and olfactory discrimination values in the intervention group (7.9 ± 1.2, 6.7 ± 0.5 respectively) compared to placebo group (3 ± 0.8, 2.8 ± 1).. Intervention group showed significant differences between these scores before and after treatment while the placebo group did not display any significant differences. Thus, the optimized film can be considered as an auspicious approach for managing post COVID-19 anosmia.


Intracorneal ring segments followed by toric pseudoaccomodating IOL for treatment of patients with corneal ectasia and cataract.
Surgical management of keratoconus aims to improve corneal curvature, prevent progression of corneal ectasia, and manage refractive error. In older individuals with concurrent cataracts, management can be challenging due to topographic irregularity and difficult-to-interpret IOL calculations. We describe a sequential combination of two surgical techniques-intrastromal corneal ring segments (e.g. intacs) insertion and toric pseudoaccomodating lens implantation-to successfully manage concurrent keratoconus and cataracts. In this case series, we present three eyes with corneal ectasia in two cataractous patients successfully managed by (1) Intacs placement to normalize corneal contour/asymmetry and enable more regular keratometry measurements, followed by (2) correction of astigmatism and presbyopia by placement of toric pseudoaccommodating IOL (Trulign) after cataract extraction. This is the first description, to the authors' knowledge, of the use of intraocorneal ring segments + toric pseudoaccommodating intraocular lenses for the management of concurrent keratoconus, cataract, and presbyopia.


Recognition of the atrioventricular node anatomical structure: Connection between the retroaortic node and the compact node.
The complex electrophysiological phenomena related to the atrioventricular node (AVN) are due to its complex anatomical structures. Aside from the inferior nodal extension (INE), other node-like tissues, such as the retroaortic node (RN), have been described less extensively and may also share the mechanism of normal conduction and abnormal conduction in AVN re-entrant tachycardia. High-density sections of the entire AVN were obtained from rats and rabbits. Fibrosis was analyzed by Masson's trichrome staining. Connexin (Cx43, Cx40, and Cx45) and ion channel (Nav 1.5, Cav 3.1, and HCN4) proteins were immunohistochemically labeled for the analysis of tissue features. Three-dimensional (3D) reconstruction of the AV junction was performed to clarify the relationships among different structures. The RN expressed the same connexin isoforms as the compact node (CN) and INE. Nav 1.5 labeling was observed at low levels in the CN, RN, and INE, where Cav 3.1 and HCN4 were expressed. The CN connected with the RN in a narrow strip pattern at the start of the CN. The RN presented as a shuttle shape and was the only tissue directly connected with the atrium in the anterior septum. The RN connects with the AVN anatomically, suggesting that direct electrical conduction occurs between them. The entrance of the atria into the AVN is distal to the RN, which may form the fast AVN pathway.


Clinical evaluation is better: myoglobin estimation used singly as a discriminant for early acute myocardial infarction does not well identify patients who will benefit from thrombolytic therapy.
We have examined the use of serum myoglobin concentration in the management of cases of suspected acute myocardial infarction (AMI). In a series of 51 patients myoglobin, used as a discriminant, correctly identified 97% (28/29) of cases as AMI with one false positive. Initial clinical judgement based on history, examination and the electrocardiogram correctly identified 66% (19/29) of cases with one false positive. These patients were given streptokinase. However, in these further identified AMI patients, 78% (7/9) had small enzyme rises with non-Q wave infarction and/or non-ST elevation and therefore may not have benefited from thrombolytic therapy in contrast to the Q wave/raised ST segment infarcts with large enzyme rises identified by clinical means. Enthusiasm for myoglobin estimation, where used as a discriminant for AMI, as a direct pointer to thrombolysis in the early diagnosis of AMI should be tempered by this finding.


A web-based quantitative signal detection system on adverse drug reaction in China.
To establish a web-based quantitative signal detection system for adverse drug reactions (ADRs) based on spontaneous reporting to the Guangdong province drug-monitoring database in China. Using Microsoft Visual Basic and Active Server Pages programming languages and SQL Server 2000, a web-based system with three software modules was programmed to perform data preparation and association detection, and to generate reports. Information component (IC), the internationally recognized measure of disproportionality for quantitative signal detection, was integrated into the system, and its capacity for signal detection was tested with ADR reports collected from 1 January 2002 to 30 June 2007 in Guangdong. A total of 2,496 associations including known signals were mined from the test database. Signals (e.g., cefradine-induced hematuria) were found early by using the IC analysis. In addition, 291 drug-ADR associations were alerted for the first time in the second quarter of 2007. The system can be used for the detection of significant associations from the Guangdong drug-monitoring database and could be an extremely useful adjunct to the expert assessment of very large numbers of spontaneously reported ADRs for the first time in China.


Effect of Chloroaluminium phthalocyanine in cationic nanoemulsion on photoinactivation of multispecies biofilm.
Photosensitizers in nanocarriers have been investigated for antimicrobial Photodynamic Therapy (aPDT). However, most studies are focused against microorganisms in planktonic or monospecies biofilm. Thus, this in vitro study evaluated the effect of aPDT using Chloroaluminium phthalocyanine (ClAlPc) in cationic nanoemulsion (NE) against Candida albicans, Candida glabrata and Streptococcus mutans grown as multispecies biofilm. Standard suspensions of each microorganism were added into wells of a microtiter plate for biofilm growth for 48 h in a candle jar. The biofilms were incubated with ClAlPc in cationic NE at 31.8 μM for 30 min and illuminated with red light fluence of 39.3 J/cm2 (P+L+ group). Additional samples were treated only with photosensitizer (P+L-) or red light (P-L+) or neither (P-L-, control group). aPDT efficacy was assessed by colony quantification, biofilm's metabolic activity, total biomass, and confocal microscopy. Data were analyzed by ANOVA/Welch and post-hoc Tukey/Games-Howell tests (α = 0.05). aPDT (P+L+) reduced the colony count in 1.30 to 2.24 lg10 and the metabolic activity in 53.7% compared with the control group (P-L-). The total biomass showed no statistical difference among the groups. The confocal microscopy analyzes showed uptake of the PS in the biofilm, and dead cells were observed in the biofilm treated with aPDT. aPDT mediated by ClAlPc in cationic NE promoted photoinactivation of the multispecies biofilm, which was confirmed by colony quantification, metabolic activity, and confocal microscopy. However, the total biomass of the biofilm was not affected by the treatment.


Geometric super-resolved imaging based upon axial scanning and phase retrieval.
In this paper, we propose a new geometric super-resolving approach that overcomes the geometric resolution reduction caused by the spatially large pixels of the detector array. The improvement process is obtained by applying an axial scanning procedure. In the scanning process, several images are captured corresponding to focus applied at several axial planes. By applying an iterative Gerchberg-Saxton-based algorithm, we managed to retrieve the phase and to reconstruct the original high-resolution image from the captured set of low-resolution images. In addition, the paper also presents a numerically efficient algorithm to compute the free space Fresnel integral.


Bis(pyrrol-2-yl)arylenes from the tandem bidirectional addition of vinyl Grignard reagent to aryl diesters.
[Chemical reaction: See text] A practical three-step synthesis of bis(pyrrol-2-yl)arylenes has been accomplished, featuring a copper-catalyzed tandem bidirectional addition of vinylmagnesium bromide to aryldicarboxylates. Spectroscopic and cyclic voltammetric analyses revealed the influence of the central aromatic core and pyrrole substitution pattern on the electrochemical properties of these comonomers.


Technology for Improving Street Dog Welfare and Capturing Data in Digital Format during Street Dog Sterilisation Programmes.
Street dogs survive on food handouts provided by individuals, or the wider community yet typically receive limited to no veterinary care. They can also carry a variety of zoonotic diseases such as rabies, posing a significant risk to human and dog population health. Dog sterilisation is one of the most humane and effective methods available to control street dog populations. Dog sterilisation programmes, particularly those operating at a large-scale, often face a variety of challenges including limited resources, staffing, and less-than-ideal facilities. Recordkeeping is often a challenge as well, which can complicate the return of a sterilised dog to their location of capture. Street dogs are territorial, and the return of a dog to an incorrect location is fraught with various welfare issues, as well as an increased risk of postoperative complications, including death. Humane Society International developed a mobile phone-based application called 'HSIApps' drawing on years of field experience and data collection in street dog location recording, as well as clinical and postoperative treatment. HSIApps facilitates the return of dogs back to their exact captured location, which ensures dog welfare, and generates reports of a variety of useful data variables to maximise the efficacy and reliability of sterilisation programmes.


The expression level of ligands for natural killer cell receptors predicts response to bacillus Calmette-Guerin therapy: a pilot study.
Up to 90% of patients with high grade superficial bladder tumors experience tumor recurrence and up to 50% have progression despite bacillus Calmette-Guerin treatment. Natural killer cells have a major role in the mechanism of the response to bacillus Calmette-Guerin but the exact mechanisms are still elusive. The recently discovered natural cytotoxicity receptors are linked to the host response to viral infection and to cancer. We tested the hypothesis that tumor expression of natural cytotoxicity receptor ligands can serve as a predictive factor for the response to intravesical bacillus Calmette-Guerin in patients with nonmuscle invasive, high grade bladder cancer. We developed a histochemical staining method for analysis of the ligands of the 3 known natural cytotoxicity receptors NKp30, NKp44 and NKp46 using genetically engineered fusion proteins and an automated image analysis system. We examined formalin fixed, paraffin embedded sections of specimens of transurethral bladder tumor resection from patients with primary, nonmuscle invasive, high grade bladder cancer who were subsequently treated with bacillus Calmette-Guerin. We compared natural cytotoxicity receptor ligand expression to the response to bacillus Calmette-Guerin immunotherapy. Six of 17 patients (35%) had recurrence despite bacillus Calmette-Guerin treatment. Primary tumors from favorably responding patients expressed higher levels of ligands for all 3 fusion proteins (NKp30, NKp44 and NKp46 p = 0.0026, 0.027 and 0.044, respectively). Bacillus Calmette-Guerin resistant, high grade, nonmuscle invasive bladder tumors express significantly lower levels of ligands of all 3 natural cytotoxicity receptors compared with bacillus Calmette-Guerin responsive tumors. This suggests that down-regulation of these ligands facilitates escape from the bacillus Calmette-Guerin effect. Furthermore, analysis of ligand expression, which can be performed on formalin fixed, paraffin embedded sections, may serve as a new predictive assay for the response to bacillus Calmette-Guerin.


SZ168 treats LPS-induced acute lung injury by inhibiting the activation of NF-κB and MAPKs pathways.
This study aimed to elucidate the effect and underlying molecular mechanisms of SZ168 (Podoplanin (PDPN) monoclonal antibody) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice and LPS-induced MH-S cells. The survival rate was calculated by recording the death of mice in each group. Enzyme linked immunosorbent assay (ELISA) was used to detect the levels of interleukin (IL)- 6 and tumor necrosis factor-alpha (TNF-α) in blood and bronchoalveolar lavage fluid (BALF) of mice. Hematoxylin-eosin (H&E) staining were performed to evaluate the pathological changes in pulmonary tissues. Additionally, the phagocytosis of cells was tested by flow cytometry, and the expression levels of caveolin-1 (CAV-1) and Occludin proteins in lung tissue and the expression of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway-related proteins in MH-S cells were determined by western blot. SZ168 significantly improved the survival rate of ALI mice. Briefly speaking, SZ168 protected pulmonary vascular permeability, reduced the level of pro-inflammatory cytokines, improved the pathological changes of lung tissue, reduced the infiltration of inflammatory cells, increased CAV-1 and Occludin protein expression, and then effectively relieved lung injury. In addition, SZ168 could significantly reduce the phagocytic ability of LPS-induced MH-S cells and inhibit the expression of hospho-extracellular regulated protein kinases (p-ERK), Phospho-Jun N-terminal kinase (p-JNK), Phospho-NF-κB p65 (p-p65) and Phospho-IkappaB-alpha (p-IκBα). SZ168 can treat ALI by inhibiting the activation of NF-κB and MAPK signaling pathways and restoring tight junction protein expression.


Demonstration of channel-spacing-tunable demultiplexing of optical orthogonal-frequency-division-multiplexed subcarriers utilizing reconfigurable all-optical discrete Fourier transform.
We experimentally demonstrate a tunable and reconfigurable optical discrete Fourier transform (DFT) to demultiplex orthogonal-frequency-division-multiplexed subcarriers with 2/3/4 subcarriers at 20/40 GHz frequency spacing. An average power penalty of ~5 dB (~3.5) at bit error ratio of 10(-9) is achieved for 4×20 Gbit/s (4×10 Gbit/s) OFDM signal with 20 GHz frequency spacing.


Histopathological changes in WEHI-3B leukemia cells following intoxication by cytotoxin P4 from Naja nigricollis nigricollis venom.
The histopathological changes in WEHI-3B leukemia cells were followed by light and electronmicroscopy at different time intervals following exposure to cytotoxin P4 from Naja nigricollis nigricollis venom. At 1 hr after exposure to the toxin (2.5 x 10(-7) M) deformation was detected, primarily in the mitochondria, followed by vacuolization in the cytoplasm and an increase in lysosome number at 2 hr post-intoxication. Thereafter, the endoplasmic reticulum assumed a microsomal-like appearance, the plasma membrane was disrupted and, finally, the cells released their content to the culture medium. It is postulated that cytotoxin P4 may affect mitochondria either indirectly, by stimulating intracellular processes after binding to the cell membrane, or directly by interaction with the mitochondria after penetrating into the cell.


A UPLC-MS/MS method for the quantitation of Ulipristal acetate in human serum.
The progesterone receptor modulator, Ulipristal acetate (UPA) has proven to be an effective emergency contraceptive. Conflicting data has been reported that suggests different efficacy of the drug in different populations, which may be explained by the systemic exposure to the drug. A UPLC-MS/MS method was developed and validated for the accurate and sensitive measurement of UPA in human serum to address this matter. UPA was extracted from human serum using liquid-liquid extraction with a combination of hexane and dichloromethane. An analytical platform comprising reverse-phase chromatographic separation followed by mass spectrometric detection by positive electrospray ionization in multiple reaction monitoring was used for quantitation of UPA within 7min. The method was linear from 0.1 to 250ng/mL. The matrix effect was minimal and intra- and inter-assay precision and accuracy were all within the acceptable limits. UPA was found to be stable at all processing and storage conditions. The method was used to investigate the pharmacokinetics of UPA in a clinical trial designed to explore the effect of obesity on its bioavailability.


Sphingosine inhibits factor Xa-catalyzed prothrombin activation on the surface of cultured calf pulmonary artery endothelium perturbed by hydrogen peroxide.
The effects of hydrogen peroxide on factor Xa-catalyzed prothrombin activation on the surface of vascular endothelial cells, and the inhibitory effect of sphingosine on prothrombin activation were studied in cultured calf pulmonary artery endothelial cells (CPAEC). Hydrogen peroxide enhanced factor Xa-catalyzed prothrombin activation on the cell surface in a time and dose-dependent manner. Sphingosine, a potent inhibitor of protein kinase C and the extrinsic pathway of blood coagulation, showed a partial inhibition of prothrombin activation on the surface of CPAEC. When cells were perturbed by hydrogen peroxide, sphingosine inhibited prothrombin activation and displaced factor Xa bound to the cell surface.


Characterization of muscarinic acetylcholine receptors in human labial salivary glands.
Muscarinic acetylcholine receptors were studied in human labial salivary glands with (-)-[3H]MQNB. The radioligand bound with a Kd value of 150 pM. The density of muscarinic receptors was 220 fmol/mg protein. Most muscarinic antagonists bound to a homogeneous population of muscarinic receptors in this tissue. However, the inhibition curves of pirenzepine had a Hill slope of 0.57 and could be analyzed by a two site model. These results suggest that the muscarinic receptors in human labial salivary glands are a mixture of M1 and M3 types.


BCR-ABL regulates phosphatidylinositol 3-kinase-p110gamma transcription and activation and is required for proliferation and drug resistance.
The BCR-ABL oncogene is the hallmark of chronic myeloid leukemia, a clonal hematopoietic stem cell disorder. BCR-ABL displays constitutive tyrosine kinase activity, required for its transformation ability. Although the molecular mechanisms behind this malignancy are not fully understood, a role for phosphatidylinositol (PI) 3-kinase has been repeatedly described. Here we report the specific up-regulation of the class I(B) catalytic subunit of PI 3-kinase (p110gamma) in response to BCR-ABL expression. We demonstrate that this upregulation is due to increased transcription and is dependent on both PI 3-kinase and MEK activity. We performed in vitro kinase activity assays and show that BCR-ABL also leads to increased p110gamma activity and that this activation requires both G protein-coupled receptor and Ras signaling. In addition, by transfection of cells with dominant negative p110gamma, we determined that this specific PI 3-kinase isoform is involved in both proliferation and the apoptosis resistance associated with chronic myeloid leukemia. The data presented here define for the first time the ability of BCR-ABL to alter the expression levels of PI 3-kinase isoforms and also demonstrate a previously unreported link between BCR-ABL and p110gamma.


High-Resolution Spectroscopy of the Earth's Free Oscillations, Knowing the Earthquake Source Mechanism.
A new method for identification of normal modes of oscillation of the earth yielded unambiguous determinations of many overtones never before identified. This method consists of the superposition of spectra observed at many stations over the earth, after a correction for the phase determined from the known earthquake source mechanism.


Massive ovarian oedema: 3 cases and clinical considerations.
Three cases (2 of which presented with torsion) of massive ovarian oedema occurring in young women, clinically suspected to be a neoplasm, are presented. Microscopic examination of each showed diffuse interstitial oedema and multiple cysts, some surrounded by luteinized cells. As the patients are young, we advocate conservative management with sparing of reproductive capacity, although that is not what happened with any of our 3 patients.


High levels of nitric oxide synthase activity are associated with nasal polyp tissue from aspirin-sensitive asthmatics.
The pathogenesis of aspirin intolerance remains unclear. Inducible nitric oxide synthase (iNOS) expression is upregulated in nasal polyp epithelium, implying a role for nitric oxide (NO) in its formation. We decided to compare iNOS activity in polyp tissue from patients with and without aspirin intolerance. Nasal polyp tissue was collected from 15 patients undergoing routine nasal polypectomy. These patients were classified into three groups: Group A comprised patients with nasal polyps without asthma; Group B contained patients with nasal polyps and asthma; and Group C comprised patients with nasal polyps, asthma and aspirin sensitivity. All subjects in Group C had a history of aspirin-induced reaction and a confirmatory intranasal challenge with lysine-aspirin. NOS activity was measured by the ability of tissue homogenates to convert 3,4-L-arginine to L-citrulline in an L-N(G)-nitro-L-arginine-inhibitable fashion. The iNOS activity (picomoles) in polyp tissue from the 3 groups was: A, 248.72+/-220.79; B, 23.71+/-41.06; and C, 549.71+/-132.11. Thus, nasal polyps from patients with Samter's triad had a significantly higher iNOS activity (p = 0.004; one-way ANOVA). This finding does not correlate simply with disease severity or with the occurrence of asthma and could indicate another important facet of aspirin-induced airways disease.


Adapting fasting plasma glucose threshold for GDM diagnosis according to the population distribution - An approach to the Danish paradox.
To examine third trimester fasting venous plasma glucose (FVPG) according to the distribution of a Danish population of pregnant women and identify potential local FVPG thresholds for GDM diagnosis related to risks of adverse pregnancy outcomes. In the observational Odense Child Cohort (OCC) study, 1516 women had FVPG measured at 27-28 weeks' gestation and were considered normal by Danish criteria and remained untreated. Maternal FVPG from OCC were standardized according to the local FVPG mean and standard deviation calibrated to data from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. Associations between maternal FVPG and clinical and anthropometric outcomes were analysed. Potential FVPG cut points were identified. Unadjusted areas under the ROC curve for FVPG to discriminate for large for gestational age (LGA) and hypertensive disorders of pregnancy were 0.61 (95% CI 0.56, 0.67) and 0.57 (95% CI 0.52, 0.63), respectively. The Youden FVPG cut point for LGA was 5.5 mmol/L and 5.0 mmol/L for hypertensive disorders of pregnancy. This study identified a potential locally appropriate third trimester FVPG cut point between 5.5 and 5.7 mmol/L based on LGA risk in pregnancy. This cut point should be validated prospectively in other Danish cohorts.


Construction of Fzd6Q152E mice through CRISPR/Cas9 technology and their reproduction and identification.
The CRISPR/Cas9 system is widely used for genome editing in human, rat and mouse cells. In this study, we established Fzd6 mutant mice using CRISPR/Cas9 technology, and obtained Fzd6 homozygous mutant (Fzd6Q152E) mice through breeding. Fzd6 plays a role in depression, but there are few related reports. We used this model to investigate the mechanism of Fzd6 involved in depression, and build a solid foundation for subsequent in-depth studies. The target of Fzd6 mutation was obtained by CRISPR/Cas9 technology and hippocampal tissue was collected for Nissl staining and histological analysis. Blood was collected for enzyme linked immunosorbent assay (ELISA); The gene expression of Fzd6 and the related genes expression in wnt pathway was quantified by quantitative real-time PCR (qRT-PCR), and then expression of Fzd6 and proteins in the Wnt pathway were identified by western blotting. ELISA results showed that the expression levels of brain derived neurotrophic factor (BDNF), 5-hydroxytryptamine (5-HT), and Noradrenaline (NE) in serum were significantly decreased in Fzd6Q152E mice, whereas the mRNA expression of Lrp5, Lrp6, and Dkk2 is increased. The western blotting revealed that the expression of Fzd6 and Lrp6 is decreased, although the expression of Dkk2 and Gsk-3β increased. Our study successfully established homozygous Fzd6 mutant mice model. The relationship between Fzd6-Wnt and depression was preliminarily clarified, which provides an ideal animal model for subsequent research on diseases induced by the Fzd6 mutation.


[Pathophysiology and pathogenesis of Salmonella sepsis].
The authors present a review of current knowledge about complex pathogenetic and pathophysiologic mechanisms involved in the development of sepsis in salmonellosis. Mechanisms such as lipopolysacharide-induced NOD-like receptor activation, escaping lysosomal degradation, intracellular replication niche formation, cytoskeleton reorganization, proapoptotic mechanism induction, changes in cytokine levels (IL-1β, TNF-α) and function of omptin proteases are discussed.


Risk factors for carbapenem-resistant Klebsiella pneumoniae infection: A meta-analysis.
Rates of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) have increased. A meta-analysis was conducted to explore risk factors for CRKP infection in order to provide a theoretical basis for reducing the CRKP infection rate and actively preventing CRKP infection. Online databases, including PubMed, EMBASE, OVID, ClinicalKey, CNKI, CBM, Wanfang Database and CHKD, were searched from inception up to 31 October 2018 for articles regarding risk factors for CRKP infection. Relevant articles were retrieved, supplemented by retrospective and manual search literature. RevMan 5.3 software was used for statistical analysis. A total of 30 articles comprising 5075 cases were included in the study, of which 24 were in English and 6 were in Chinese. The results showed that age, sex and diabetes mellitus were not associated with CRKP infection. The odds ratio (95% confidence interval) of risk factors for CRKP infection were as follows: immunosuppression, 1.47 (1.14-1.90); ICU admission, 3.25 (2.36-4.47); antibiotic exposure, 2.53 (1.56-4.11); carbapenem exposure, 3.99 (2.86-5.56); quinolone exposure, 1.75 (1.38-2.22); glycopeptide exposure, 3.08 (1.93-4.91); β‑lactam/β‑lactamase inhibitor (BL/BLI) exposure, 2.28 (1.37-3.80); surgery, 1.59 (1.08-2.34); mechanical ventilation, 2.91 (1.96-4.31); central venous catheterisation, 2.93 (2.00-4.28); indwelling catheter, 2.62 (1.65-4.17); and nasogastric intubation, 2.38 (1.22-4.62). Immunosuppression, ICU admission, antibiotic exposure (including carbapenems, quinolones, glycopeptides and BL/BLIs), surgery, mechanical ventilation, central venous catheterisation, indwelling catheter and nasogastric intubation were identified as risk factors for CRKP infection and should to be considered in clinical practice.


Risk taking and tolerance of uncertainty: implications for surgeons.
Adherence to evidence-based adverse outcome prevention techniques is a critical factor in providing high-quality patient care, but many of these interventions are not used by physicians. It is unclear if surgeons' risk attitudes and reactions to uncertainty influence their use of these or other interventions. A systematic review of the literature was conducted to identify studies evaluating the effects of physicians' risk attitudes, reactions to uncertainty or ambiguity, and personality traits on clinical decision making. A variety of instruments to assess risk attitude and reactions to uncertainty have been developed and tested among physicians involved in critical care and emergency medicine. Scoring systems distinguish risk averse and risk seeking practitioners. In many studies, these characteristics were related to clinical decision making in situations of uncertainty. For example, among patients evaluated in the emergency room for chest pain, "risk-seeking" physicians admitted significantly fewer patients who did not have acute myocardial infarction than risk-avoiding physicians (29% and 47% of patients admitted, respectively). In contrast, risk-seeking physicians were no more likely to discharge a patient who eventually was found to have an acute myocardial infarction. There are very limited data on the extent to which surgical decision making is linked to risk taking behavior and "comfort with uncertainty". Understanding the behaviors, attitudes and beliefs that make up surgical "judgment" remains a challenge for those interested in influencing behavior.


Serologic evidence of prior chlamydial infection in patients with tubal ectopic pregnancy and contralateral tubal disease.
Oviductal damage from infectious salpingitis is a principle cause of ectopic pregnancy. To examine the role of Chlamydia trachomatis in patients with ectopic pregnancy, 24 patients undergoing laparotomy for ectopic pregnancy were evaluated by assessment of chlamydial serology and chlamydial cultures of tubal biopsy specimens. The patients were divided into two groups based on the presence or absence of gross abnormalities in the fallopian tube contralateral to the ectopic gestation. Ten patients in group I showed gross evidence of chronic salpingitis in the contralateral tube; 14 patients in group II had normal-appearing contralateral tubes. Chlamydial cultures were negative in both groups. Chlamydial immunoglobulin M antibodies assayed by indirect microimmunofluorescence were negative in both groups (less than or equal to 1:32). Mean geometric immunoglobulin G titers for C. trachomatis were significantly higher in the patients with evidence of contralateral chronic salpingitis (78.9 versus 13.1). These findings suggest that C. trachomatis may be a major cause of oviductal damage, which predisposes to ectopic pregnancy.


Deferred radical prostatectomy in patients who initially elected for active surveillance: a multi-institutional, prospective, observational cohort of the PRIAS-JAPAN study.
This study aimed to evaluate the pathological findings and oncological outcomes of deferred radical prostatectomy in patients who initially elected for active surveillance in a Japanese cohort. We retrospectively analyzed data collected from a multi-institutional prospective observational cohort of the Prostate Cancer Research International: Active Surveillance-JAPAN study between January 2010 and September 2020. Triggers for radical prostatectomy were disease progression based on pathological findings of repeat biopsy and patients' request. The primary end point was evaluation of prostate-specific antigen recurrence-free survival. Secondary end points were overall survival and comparison of pathological and oncological outcomes between patients stratified into immediate or late radical prostatectomy group by time to radical prostatectomy. Overall, 162 patients (15.7%) with prostate cancer underwent initial active surveillance followed by radical prostatectomy. The median time to radical prostatectomy was 18 months (interquartile range 14-43.3), and the median postoperative follow-up was 32 months (interquartile range 14-57.5). Prostate-specific antigen recurrence was observed in eight patients (4.9%). The 3-year prostate-specific antigen recurrence-free survival rate was 96.9%. The 5-year overall survival rate was 100%; however, one patient died of another cause. There were no significant differences in pathological findings between immediate and late radical prostatectomy groups. No significant difference in prostate-specific antigen recurrence-free survival was found between the two groups (log-rank p = 0.34). Radical prostatectomy after active surveillance, as an initial treatment option, does not lead to loss of curative chances in Japanese patients with early-stage prostate cancer in the short follow-up period.


Can we predict unresponsiveness to methotrexate in rheumatoid arthritis? A pharmacogenetic study.
Methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis (RA) and the therapeutic response to MTX has been observed to vary widely among these patients. The aim of this study was to investigate ABCB1 gene (the multidrug resistant 1 gene; MDR1 gene) polymorphism in patients with RA and to evaluate the relation between MTX unresponsiveness and this polymorphism. Forty-five patients with RA administered MTX were included in this pharmacogenetic cross-sectional study. The gender, age, body mass index (BMI), rheumatoid factor (RF) positivity, anti-cyclic citrullinated peptide (anti-CCP) positivity, doses of MTX and glucocorticoids were recorded. In addition, initial and third month disease activity (DAS28, Simplified and Clinical Disease Activity Index; SDAI and CDAI) scores were evaluated. We also examined frequencies of two single-nucleotide polymorphisms (SNPs), G2677T and C3435T, within the gene encoding ABCB1. 22 patient's responsive and 20 patients unresponsive to MTX were enrolled. Initial demographic and disease related factors were similar between patients responsive or nonresponsive to MTX. In the third month evaluation, disease activity scores were significantly higher in patients unresponsive to MTX (p < 0.05). In addition, almost all patients unresponsive to MTX (19 of the 20 patients) presented heterozygosity in C3435T (p < 0.000). We determined heterozygosity in C3435T SNP of ABCB1 gene (multidrug resistant 1 gene) in almost all patients with RA who were non-responders to MTX. This result may contribute to predict unresponsiveness to MTX in RA. Individualized treatment strategies based on the pharmacogenetic characteristics of MTX may lead to optimization of the treatment.


Brain Exosomes: Friend or Foe in Alzheimer's Disease?
Alzheimer's disease (AD) is the most common neurodegenerative disease. It is known to be a multifactorial disease and several causes are associated with its occurrence as well as progression. However, the accumulation of amyloid beta (Aβ) is widely considered its major pathogenic hallmark. Additionally, neurofibrillary tangles (NFT), mitochondrial dysfunction, oxidative stress, and aging (cellular senescence) are considered as additional hits affecting the disease pathology. Several studies are now suggesting important role of inflammation in AD, which shifts our thought towards the brain's resident immune cells, microglia, and astrocytes; how they interact with neurons; and how these interactions are affected by intra and extracellular stressful factors. These interactions can be modulated by different mechanisms and pathways, in which exosomes could play an important role. Exosomes are multivesicular bodies secreted by nearly all types of cells. The exosomes secreted by glial cells or neurons affect the interactions and thus the physiology of these cells by transmitting miRNAs, proteins, and lipids. Exosomes can serve as a friend or foe to the neuron function, depending upon the carried signals. Exosomes, from the healthy microenvironment, may assist neuron function and health, whereas, from the stressed microenvironment, they carry oxidative and inflammatory signals to the neurons and thus prove detrimental to the neuronal function. Furthermore, exosomes can cross the blood-brain barrier (BBB), and from the blood plasma they can enter the brain cells and activate microglia and astrocytes. Exosomes can transport Aβ or Tau, cytokines, miRNAs between the cells, and alter the physiology of recipient cells. They can also assist in Aβ clearance and regulation of synaptic activity. The exosomes derived from different cells play different roles, and this field is still in its infancy stage. This review advocates exosomes' role as a friend or foe in neurodegenerative diseases, especially in the case of Alzheimer's disease.


A case of widespread non-pigmented hair regrowth in diffuse alopecia areata.
A 62-year-old woman presented with diffuse alopecia areata affecting more than 50% of her scalp hairs with sparing of non-pigmented hairs. She was treated with a 2-month course of oral prednisolone and extensive hair regrowth occurred. The new hairs were completely non-pigmented. As a result, the patient's hair colour is now strikingly and completely white, with a normal hair density. This response has been sustained for 6 months after cessation of treatment.


History of diagnostic enzymology: a review of significant investigations.
This review of the history of diagnostic enzymology includes numerous important publications which were published over 70 years ago by outstanding clinical enzymologists throughout the world. The review includes the clinical enzymology of cardiovascular diseases, skeletal muscle diseases, pulmonary diseases, effusions, neurologic diseases, hematologic diseases, pregnancy, pediatric diseases, cancer, pancreatitis, hepatic diseases, bone diseases and cancer of the prostate. The advent of clinical enzymology thus occurred many years ago.


Diversity and Distribution of Microbial Communities Associated with Reef Corals of the Malay Peninsula.
Coral-associated bacteria play critical roles in the regulation of coral health and function. Environmental perturbations that alter the bacterial community structure can render the coral holobiont more susceptible and less resilient to disease. Understanding the natural variation of the coral microbiome across space and host species provides a baseline that can be used to distinguish shifts in community structure. Using a 16S rRNA gene metabarcoding approach, this study examines bacterial community structure across three scleractinian coral hosts. Our results show that corals of three regions-eastern and western Peninsular Malaysia and Singapore-host distinct bacterial communities; despite these differences, we were able to identify a core microbiome shared across all three species. This core microbiome was also present in samples previously collected in Thailand, suggesting that these core microbes play an important role in promoting and maintaining host health. For example, several have been identified as dimethylsulfoniopropionate (DMSP) metabolizers that have roles in sulfur cycling and the suppression of bacterial pathogens. Pachyseris speciosa has the most variable microbiome, followed by Porites lutea, with the composition of the Diploastrea heliopora microbiome the least variable throughout all locations. Microbial taxa associated with each region or site are likely shaped by local environmental conditions. Taken together, host identity is a major driver of differences in microbial community structure, while environmental heterogeneity shapes communities at finer scales.


A significant net sink for CO2 in Tokyo Bay.
Most estuaries and inland waters are significant source for atmospheric CO2 because of input of terrestrial inorganic carbon and mineralization of terrestrially supplied organic carbon. In contrast to most coastal waters, some estuaries with small freshwater discharge are weak source or sometimes sink for CO2. Extensive surveys of pCO2 in Tokyo Bay showed that the overall bay acts as a strong net sink for atmospheric CO2. Although small area was a consistent source for CO2, active photosynthesis driven by nutrient loading from the land overwhelmed the CO2 budget in the bay. Here we show a comprehensive scheme with a border where air-sea CO2 flux was ±0 between nearshore waters emitting CO2 and offshore waters absorbing CO2. The border in Tokyo Bay was extremely shifted toward the land-side. The shift is characteristic of highly urbanized coastal waters with an extensive sewage treatment system in the catchment area. Because highly urbanized coastal areas worldwide are expected to quadruple by 2050, coastal waters such as Tokyo Bay are expected to increase as well. Through extrapolation of Tokyo Bay data, CO2 emission from global estuaries would be expected to decrease roughly from the current 0.074 PgC year-1 to 0.014 PgC year-1 in 2050.


Cell-Reprogramming-Inspired Dynamically Responsive Hydrogel Boosts the Induction of Pluripotency via Phase-Separated Biomolecular Condensates.
Induced pluripotent stem cells (iPSCs) have wide applications in disease modeling, personalized medicine, and tissue engineering. The generation of iPSCs from somatic cells via transcriptional-factor- or chemical molecule-based approaches are time-consuming and inefficient. Here, a cell-reprogramming-inspired dynamically responsive hydrogel is fabricated via a synthetic-biology-based strategy. Human and mouse somatic cells (including senescent cells) are efficiently reprogrammed into iPSCs that exhibit key features of embryonic stem cells. The cell-reprogramming-responsive hydrogel possesses dynamic bioresponsiveness, and it faithfully senses metabolic remodeling and extracellular acidification during cell reprogramming, responding by changing its mechanical properties accordingly. Mechanistic study demonstrates that the autonomous change of the mechanical properties of the cell-reprogramming-responsive hydrogel elicits the formation of Yes-associated protein (YAP) biomolecular condensates with the appropriate timing during cell reprogramming, ensuring a faster and more efficient generation of iPSCs than conventional cell reprogramming approach. Taken together, this study reveals the robust induction of pluripotency by coordination of cell-reprogramming-inspired dynamically responsive hydrogel and phase-separated biomolecular condensates.


Personality assessment and postoperative analgesia. A study in male patients undergoing elective gastric surgery.
In 40 patients undergoing surgery for duodenal ulcer, personality was assessed by a PEN Inventory. After operation, the respiratory restoration factor (RRF) was used to indicate the pain relief from nitrous oxide (25%) and i.v. methadone (three doses of 2 mg). There was no correlation between the psychological factors and RRF. Twenty-five per cent nitrous oxide appeared to be equivalent to i.v. methadone 4 mg in terms of RRF. The degree of hypoxia after surgery correlated with vital capacity impairment and the improvement of oxygen tension after analgesia correlated with RRF after methadone 6 mg.


Expression of Wilms tumor-1 protein and CD 138 in malignant mesothelioma of the tunica vaginalis.
Malignant mesothelioma (MM) of the tunica vaginalis is a very rare tumor which can be difficult to diagnose histologically. We report an 83-year-old patient with MM of tunica vaginalis of the left testis. To the best of our knowledge, this is the first reported case of MM of the tunica vaginalis expressing Wilms tumor-1 protein, CD138, the expression of which could help in confirming the histopathological diagnosis and in targeting therapy.


Structural model of ligand-G protein-coupled receptor (GPCR) complex based on experimental double mutant cycle data: MT7 snake toxin bound to dimeric hM1 muscarinic receptor.
The snake toxin MT7 is a potent and specific allosteric modulator of the human M1 muscarinic receptor (hM1). We previously characterized by mutagenesis experiments the functional determinants of the MT7-hM1 receptor interaction (Fruchart-Gaillard, C., Mourier, G., Marquer, C., Stura, E., Birdsall, N. J., and Servent, D. (2008) Mol. Pharmacol. 74, 1554-1563) and more recently collected evidence indicating that MT7 may bind to a dimeric form of hM1 (Marquer, C., Fruchart-Gaillard, C., Mourier, G., Grandjean, O., Girard, E., le Maire, M., Brown, S., and Servent, D. (2010) Biol. Cell 102, 409-420). To structurally characterize the MT7-hM1 complex, we adopted a strategy combining double mutant cycle experiments and molecular modeling calculations. First, thirty-three ligand-receptor proximities were identified from the analysis of sixty-one double mutant binding affinities. Several toxin residues that are more than 25 Å apart still contact the same residues on the receptor. As a consequence, attempts to satisfy all the restraints by docking the toxin onto a single receptor failed. The toxin was then positioned onto two receptors during five independent flexible docking simulations. The different possible ligand and receptor extracellular loop conformations were described by performing simulations in explicit solvent. All the docking calculations converged to the same conformation of the MT7-hM1 dimer complex, satisfying the experimental restraints and in which (i) the toxin interacts with the extracellular side of the receptor, (ii) the tips of MT7 loops II and III contact one hM1 protomer, whereas the tip of loop I binds to the other protomer, and (iii) the hM1 dimeric interface involves the transmembrane helices TM6 and TM7. These results structurally support the high affinity and selectivity of the MT7-hM1 interaction and highlight the atypical mode of interaction of this allosteric ligand on its G protein-coupled receptor target.


Tonsil-derived mesenchymal stem cells incorporated in reactive oxygen species-releasing hydrogel promote bone formation by increasing the translocation of cell surface GRP78.
Controlling the senescence of mesenchymal stem cells (MSCs) is essential for improving the efficacy of MSC-based therapies. Here, a model of MSC senescence was established by replicative subculture in tonsil-derived MSCs (TMSCs) using senescence-associated β-galactosidase, telomere-length related genes, stemness, and mitochondrial metabolism. Using transcriptomic and proteomic analyses, we identified glucose-regulated protein 78 (GRP78) as a unique MSC senescence marker. With increasing cell passage number, GRP78 gradually translocated from the cell surface and cytosol to the (peri)nuclear region of TMSCs. A gelatin-based hydrogel releasing a sustained, low level of reactive oxygen species (ROS-hydrogel) was used to improve TMSC quiescence and self-renewal. TMSCs expressing cell surface-specific GRP78 (csGRP78+), collected by magnetic sorting, showed better stem cell function and higher mitochondrial metabolism than unsorted cells. Implantation of csGRP78+ cells embedded in ROS-hydrogel in rats with calvarial defects resulted in increased bone regeneration. Thus, csGRP78 is a promising biomarker of senescent TMSCs, and the combined use of csGRP78+ cells and ROS-hydrogel improved the regenerative capacity of TMSCs by regulating GRP78 translocation.


Epidemiology of pseudorabies in intensive pig farms in Shanghai, China: Herd-level prevalence and risk factors.
Pseudorabies (PR), also known as Aujeszky's disease, is a highly contagious disease affecting pigs and a wide range of animals. Pseudorabies is enzootic in many countries. In China, it is a priority animal disease for control and eradication, however the data on disease frequency in intensive pig farms and the information on associated risk factors is inadequate. A cross-sectional study of intensive pig farms (≥350 sows) in Shanghai was conducted to determine herd-level prevalence of PRV and associated risk factors. Following a two-stage random sampling design, a total of 1349 sow serum samples were tested by gpI-ELISA from a total of 91 intensive pig farms in Shanghai. A herd was classified as positive if at least one PRV test-positive sow was present. Information on putative risk/protective factors was collected using questionnaires to pig farm owners or veterinarians. A logistic regression model was built to identify risk/protective factors for herd positivity. The results indicated that the herd-level true prevalence was 67.6% (95% CI:57.0-77.0). In the multivariable logistic regression model using backward stepwise procedure, two risk factors were found to be significantly associated with herd positivity: 'Breeding with introduced sows in the last 12 months' (OR = 3.5, 95%CI:1.2, 10.3) and 'Presence of stray dogs or cats' (OR = 4.0, 95%CI: 1.2, 12.6). The multivariable logistic model fitted the data well. Hosmer-Lemeshow goodness of fit test showed χ2 = 10.86 (df = 8, p = 0.21 > 0.05) and the predictability (area under the ROC curve) was 0.86. This study suggested that PR was highly endemic in intensive pig farms in Shanghai. The risk and protective factors identified in this study could be useful to improve the prevention policy of PR in Shanghai and other areas of China.


Exportin XPO7 acts as an oncogenic factor in prostate cancer via upregulation of TCF3.
As a nuclear transport protein, XPO7 has been observed to show abnormal expression in various types of human cancers. However, the role of XPO7 in PCa remains elusive. Here, in this study, immunohistochemistry and bioinformatics were used to determine the expression pattern and prognostic significance of XPO7. To investigate the functions of XPO7 in vitro and in vivo, we knocked down XPO7 in PCa cell lines and established xenograft mice models. Then, we used multiple experiments to determine the cell proliferation, migration, invasion, cell cycle and EMT in PCa cells after XPO7 modulation. Mechanistically, we conducted RNA-seq and identified the regulating effect of XPO7 on cell cycle-related and PI3K-AKT pathways. Furthermore, we assessed the regulating correlation between XPO7 and TCF3 and verified by a series of rescue experiments. We found a higher XPO7 expression in prostate cancer tissues and predicted a poorer prognosis of prostate cancer. Then, we further revealed that the ectopic expression of XPO7 in PCa cells facilitated cells proliferation, migration, cell cycle progression and EMT in vitro and promoted tumor growth in vivo. Mechanistically, we conducted RNA-seq and identified the regulating effect of XPO7 on cell cycle-related and PI3K-AKT pathways. Furthermore, a significantly positive correlation was discovered between the expression of XPO7 and TCF3. In addition, XPO7 may regulate PCa through mediating TCF3 expression. TCF3 depletion could alleviate the influence of XPO7 overexpression on malignant phenotypes of PCa cells. These findings indicate that XPO7 promotes PCa initiation and progression and that targeting XPO7 might be therapeutically beneficial to patients with PCa.


DNA damage, DNA repair gene expression, and topoisomerase IIα activity in CD-1 mice following in utero benzene exposure.
Benzene is an environmental toxicant and known human carcinogen. Recent epidemiological studies show a relationship between exposure to benzene in pregnant women and increased incidence of childhood leukemias. Studies in murine models demonstrate a relationship between carcinogenicity and in utero benzene exposure which was sex dependent, thus the cellular mechanisms of benzene toxicity by sex require further studies. A hypothesized mechanism of benzene-induced in utero carcinogenicity is through increased DNA damage and reduced fetal DNA repair capacity. This includes the potential inhibition of topoisomerase IIα (topo IIα), in part, to generate double stranded DNA (dsDNA) breaks and induction of error-prone DNA repair. Using a mouse model of transplacental benzene carcinogenicity, gestational day (GD) 14 fetal livers were harvested 2, 6, and 24 h following maternal exposure to 200 mg/kg benzene and used to assess DNA damage, DNA repair gene expression and topo IIα activity. DNA damage, measured by levels of modified histone H2AX (γH2AX), is significantly increased in benzene exposed pups, with sex-dependent significance seen only in female pups. Comet assay results confirmed that benzene exposure in utero induces dsDNA damage in the GD14 fetal liver. Genes involved in DNA repair were assessed, and DNA repair gene expression changes were observed after 24 h in genes related to nucleotide excision repair, homologous recombination, and non-homologous end-joining. There were no significant differences in topo IIα activity in GD14 fetal livers at any timepoint, or between sexes. Overall, this study shows that 200 mg/kg benzene exposure induces dsDNA damage and alters fetal DNA repair gene expression in utero, without perturbing fetal topo IIα in CD-1 mice.


Diffusion-weighted imaging abnormalities in the splenium after seizures.
Transient increased T2 signal in the splenium of the corpus callosum after seizures has been reported and sometimes attributed to a postulated toxicity of anticonvulsant medications (AEDs). We describe two patients with bitemporal epilepsy. Transiently increased T2 signal (in one) and decreased apparent diffusion coefficient (ADC) (in both) in the splenium appeared to be related directly to acute seizures. These cases illustrate an unusual acute postictal imaging finding, highlight involvement of an important commissural pathway, and suggest that seizures per se, and not their treatment, are the cause of transient white-matter abnormalities in these cases.


Millimetre-resolution mapping of citrate exuded from soil-grown roots using a novel, low-invasive sampling technique.
The reliable sampling of root exudates in soil-grown plants is experimentally challenging. This study aimed at developing a citrate sampling and mapping technique with millimetre-resolution using DGT (diffusive gradients in thin films) ZrOH-binding gels. Citrate adsorption kinetics, DGT capacity, and stability of ZrOH gels were evaluated. ZrOH gels were applied to generate 2D maps of citrate exuded by white lupin roots grown in a rhizotron in a phosphorus-deficient soil. Citrate was adsorbed quantitatively and rapidly by the ZrOH gels; these gels can be stored after sampling for several weeks prior to analysis. The DGT capacity of the ZrOH gel for citrate depends on the ionic strength and the pH of the soil solution, but was suitable for citrate sampling. We generated for the first time 2D citrate maps of rhizotron-grown plants at a millimetre resolution to measure an illustrated plant response to phosphorus fertilization, demonstrating that DGT-based citrate sampling is suitable for studying root exudation in soil environments, at high spatial resolution. The change of binding material would also allow sampling of other exudate classes and exudation profiles of entire root systems. These aspects are crucial in cultivar breeding and selection.


Synthesizing Missing PET from MRI with Cycle-consistent Generative Adversarial Networks for Alzheimer's Disease Diagnosis.
Multi-modal neuroimages (e.g., MRI and PET) have been widely used for diagnosis of brain diseases such as Alzheimer's disease (AD) by providing complementary information. However, in practice, it is unavoidable to have missing data, i.e., missing PET data for many subjects in the ADNI dataset. A straightforward strategy to tackle this challenge is to simply discard subjects with missing PET, but this will significantly reduce the number of training subjects for learning reliable diagnostic models. On the other hand, since different modalities (i.e., MRI and PET) were acquired from the same subject, there often exist underlying relevance between different modalities. Accordingly, we propose a two-stage deep learning framework for AD diagnosis using both MRI and PET data. Specifically, in the first stage, we impute missing PET data based on their corresponding MRI data by using 3D Cycle-consistent Generative Adversarial Networks (3D-cGAN) to capture their underlying relationship. In the second stage, with the complete MRI and PET (i.e., after imputation for the case of missing PET), we develop a deep multi-instance neural network for AD diagnosis and also mild cognitive impairment (MCI) conversion prediction. Experimental results on subjects from ADNI demonstrate that our synthesized PET images with 3D-cGAN are reasonable, and also our two-stage deep learning method outperforms the state-of-the-art methods in AD diagnosis.


Flexor tendon and synovial gliding during simultaneous and single digit flexion in idiopathic carpal tunnel syndrome.
The characteristic pathological finding in carpal tunnel syndrome (CTS) is non-inflammatory fibrosis of the subsynovial connective tissue (SSCT), which lies between the flexor tendons and the visceral synovium (VS). How this fibrosis might affect tendon function is unknown. To better understand the normal function of the SSCT, the relative motion of the middle finger flexor digitorum superficialis (FDS III) tendon and VS was observed during finger flexion in patients with CTS and cadavers with a history of CTS and compared to normal cadavers. A digital camcorder was used to monitor the gliding motion of the FDS III tendon and SSCT in eight patients with idiopathic CTS undergoing carpal tunnel release surgery (CTR), in eight cadavers with an antemortem history of CTS and compared these with eight cadaver controls. There were no significant differences noted in the total movement of the SSCT relative to the FDS III. However, the pattern of SSCT movement relative to the FDS III in the CTS patients and cadavers with an antemortem history of CTS differed from the controls in one of two patterns, reflecting either increased SSCT adherence to FDS III or increased SSCT dissociation from FDS III. In CTS, the gliding characteristics of the SSCT are qualitatively altered. These changes may be the result of increased fibrosis within the SSCT, which in some cases has ruptured, resulting in SSCT-tendon dissociation. Similar changes are also identified postmortem in the CTS patient.


Evaluation of Host Defense Peptide (CaD23)-Antibiotic Interaction and Mechanism of Action: Insights From Experimental and Molecular Dynamics Simulations Studies.
Background/Aim: Host defense peptides (HDPs) have the potential to provide a novel solution to antimicrobial resistance (AMR) in view of their unique and broad-spectrum antimicrobial activities. We had recently developed a novel hybrid HDP based on LL-37 and human beta-defensin-2, named CaD23, which was shown to exhibit good in vivo antimicrobial efficacy against Staphylococcus aureus in a bacterial keratitis murine model. This study aimed to examine the potential CaD23-antibiotic synergism and the secondary structure and underlying mechanism of action of CaD23. Methods: Peptide-antibiotic interaction was evaluated against S. aureus, methicillin-resistant S. aureus (MRSA), and Pseudomonas aeruginosa using established checkerboard and time-kill assays. Fractional inhibitory concentration index (FICI) was calculated and interpreted as synergistic (FIC<0.5), additive (FIC between 0.5-1.0), indifferent (FIC between >1.0 and ≤4), or antagonistic (FIC>4). SYTOX green uptake assay was performed to determine the membrane-permeabilising action of CaD23. Molecular dynamics (MD) simulations were performed to evaluate the interaction of CaD23 with bacterial and mammalian mimetic membranes. Circular dichroism (CD) spectroscopy was also performed to examine the secondary structures of CaD23. Results: CaD23-amikacin and CaD23-levofloxacin combination treatment exhibited a strong additive effect against S. aureus SH1000 (FICI = 0.60-0.69) and MRSA43300 (FICI = 0.56-0.60) but an indifferent effect against P. aeruginosa (FIC = 1.03-1.15). CaD23 (at 25 μg/ml; 2xMIC) completely killed S. aureus within 30 min. When used at sub-MIC concentration (3.1 μg/ml; 0.25xMIC), it was able to expedite the antimicrobial action of amikacin against S. aureus by 50%. The rapid antimicrobial action of CaD23 was attributed to the underlying membrane-permeabilising mechanism of action, evidenced by the SYTOX green uptake assay and MD simulations studies. MD simulations revealed that cationicity, alpha-helicity, amphiphilicity and hydrophobicity (related to the Trp residue at C-terminal) play important roles in the antimicrobial action of CaD23. The secondary structures of CaD23 observed in MD simulations were validated by CD spectroscopy. Conclusion: CaD23 is a novel alpha-helical, membrane-active synthetic HDP that can enhance and expedite the antimicrobial action of antibiotics against Gram-positive bacteria when used in combination. MD simulations serves as a powerful tool in revealing the peptide secondary structure, dissecting the mechanism of action, and guiding the design and optimisation of HDPs.


Neurogranin as an important regulator in swimming training to improve the spatial memory dysfunction of mice with chronic cerebral hypoperfusion.
Vascular cognitive impairment caused by chronic cerebral hypoperfusion (CCH) has become a hot issue worldwide. Aerobic exercise positively contributes to the preservation or restoration of cognitive abilities; however, the specific mechanism has remained inconclusive. And recent studies found that neurogranin (Ng) is a potential biomarker for cognitive impairment. This study aims to investigate the underlying role of Ng in swimming training to improve cognitive impairment. To test this hypothesis, the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) system was utilized to construct a strain of Ng conditional knockout (Ng cKO) mice, and bilateral common carotid artery stenosis (BCAS) surgery was performed to prepare the model. In Experiment 1, 2-month-old male and female transgenic mice were divided into a control group (wild-type littermate, n = 9) and a Ng cKO group (n = 9). Then, 2-month-old male and female C57BL/6 mice were divided into a sham group (C57BL/6, n = 12) and a BCAS group (n = 12). In Experiment 2, 2-month-old male and female mice were divided into a sham group (wild-type littermate, n = 12), BCAS group (n = 12), swim group (n = 12), BCAS + Ng cKO group (n = 12), and swim + Ng cKO group (n = 12). Then, 7 days after BCAS, mice were given swimming training for 5 weeks (1 week for adaptation and 4 weeks for training, 5 days a week, 60 min a day). After intervention, laser speckle was used to detect cerebral blood perfusion in the mice, and the T maze and Morris water maze were adopted to test their spatial memory. Furthermore, electrophysiology and Western blotting were conducted to record long-term potential and observe the expressions of Ca2+ pathway-related proteins, respectively. Immunohistochemistry was applied to analyze the expression of relevant markers in neuronal damage, inflammation, and white matter injury. The figures showed that spatial memory impairment was detected in Ng cKO mice, and a sharp decline of cerebral blood flow and an impairment of progressive spatial memory were observed in BCAS mice. Regular swimming training improved the spatial memory impairment of BCAS mice. This was achieved by preventing long-term potential damage and reversing the decline of Ca2+ signal transduction pathway-related proteins. At the same time, the results suggested that swimming also led to improvements in neuronal death, inflammation, and white matter injury induced by CCH. Further study adopted the use of Ng cKO transgenic mice, and the results indicated that the positive effects of swimming training on cognitive impairments, synaptic plasticity, and related pathological changes caused by CCH could be abolished by the knockout of Ng. Swimming training can mediate the expression of Ng to enhance hippocampal synaptic plasticity and improve related pathological changes induced by CCH, thereby ameliorating the spatial memory impairment of vascular cognitive impairment.


Extracellular calcium does not contribute to cryopreservation-induced cytotoxicity.
The possible role of extracellular calcium ([Ca+2]e) in cryopreservation-induced cytotoxicity was tested using Madin-Darby canine kidney (MDCK) cells and a fluorescent multiple endpoint assay. MDCK cells maintained in 2 mM [Ca+2]e and treated with the calcium ionophore, ionomycin, increased their intracellular calcium ([Ca+2]i) as revealed by the calcium indicator dye, Fluo3 and the bottom-reading spectrofluorometer, CytoFluor 2300. The addition of 10 mM [ethylene bis (oxyethylenenitrilo)]-tetraacetic acid (EGTA) to the extracellular medium before treatment with ionomycin blocked this ionomycin-dependent increase in [Ca+2]i. A number of site and activity-specific fluorescent probes were surveyed to determine which indicator dye might best reveal the ionomycin-induced cytotoxic events during this increase in [Ca+2]i. Although most dyes changed their emission profiles in response to calcium, neutral red was found to best reflect the loss of [Ca+2]i homeostasis. The NR50 for a 15-min exposure to ionomycin in the presence of 2 mM [Ca+2]e was approximately 2 microM ionomycin, but ionomycin had little apparent effect on neutral red retention when 10 mM EGTA was added to the extracellular medium. Thus it was clear that an increase in [Ca+2]i could be cytotoxic to MDCK cells and that neutral red could monitor this cytotoxic episode. To test if [Ca+2]e was similarly cytotoxic during cryopreservation, MDCK cells were subjected to cryopreservation in the presence of dimethylsulfoxide (DMSO). In contrast to previous studies, plasma membrane integrity, not lysosomal function, seemed to best correlate with cell survival subsequent to cryopreservation. In addition, decreasing [Ca+2]e had no discernable effect on the retention of plasma membrane indicator dyes, neutral red, or cell survival. It is concluded that a) plasma membrane indicator dyes, not neutral red, might be better indicators of cytotoxicity occurring during cryopreservation; b) DMSO might be toxic to lysosomes during cryopreservation of cultured cells; and c) although [Ca+2]e can contribute to cytotoxicity, the presence of [Ca+2]e might not influence cryopreservation-induced cytotoxicity.


The effects of a transitional care program on discharge readiness, transitional care quality, health services utilization and satisfaction among Chinese kidney transplant recipients: A randomized controlled trial.
Kidney transplantation is the major treatment for end-stage renal disease (ESRD). However, kidney transplant recipients (KTRs) face severe challenges during the transition period from hospital discharge to home, increasing the risk of early hospital readmission (EHR) and affecting patient safety. Nevertheless, knowledge of effective transitional care for KTRs is limited in China. To evaluate the effectiveness of an innovative transitional care program in improving discharge readiness, transitional care quality, health services utilization and patient satisfaction among KTRs in China. A prospective randomized controlled trial. Patients admitted to undergo kidney transplantation were recruited in a general tertiary hospital in Chengdu, China. A total of 220 eligible patients were recruited and randomly assigned to the intervention and control groups. Participants in the intervention group received a transitional care intervention developed by the research team, including a risk assessment for early readmission, health education from admission to predischarge, individualized discharge planning, and a telephone follow-up once per week for one month and WeChat follow-up postdischarge. The control group received routine care of comparable length and follow-up contact. A trained research assistant collected all patients' baseline data on admission (T0), evaluated the discharge readiness (by the Readiness for Hospital Discharge Scale) on the day of discharge (T1), collected data on transitional care quality (by the Care Transition Measure-15) and patients' satisfaction with transitional care services (by a self-developed patient satisfaction scale) on the 30th day postdischarge (T2), and collected data on hospital readmission, unscheduled outpatient department visits, and emergency room visits on the 30th and 90th days (by a self-developed health services utilization record table) (T3) postdischarge. Intervention effects were analyzed using independent samples t-tests, Wilcoxon-Mann-Whitney U tests, Chi-square tests or Fisher's exact test. Compared with the control group, the intervention group showed significantly better discharge readiness (personal status, P<0.001; knowledge, P = 0.010; coping ability, P<0.001; expected support, P = 0.007; total score, P<0.001), better transitional care quality (importance of preferences, P<0.001; management preparation, P<0.001; critical understanding, P = 0.003; written and understandable care plan, P = 0.012; total score, P<0.001), lower readmission rate at T2 (P = 0.033) and at T3 (P = 0.013), lower emergency room visit rate at T3 (P = 0.014), and better satisfaction with transitional care services (P<0.001). This study provides evidence that an innovative transitional care program is effective in promoting KTRs' discharge readiness, transitional care quality, reducing hospital readmission and emergency room visits, and improving their satisfaction with transitional care services. Clinical Trials ChiCTR1800014971.


Favorable therapeutic efficacy of low-density lipoprotein apheresis for nephrotic syndrome with impaired renal function.
Many reports have shown the therapeutic efficacy of LDL apheresis (LDL-A) in drug-resistant nephrotic syndrome (NS) for improvement of heavy proteinuria and severely impaired renal function. To obtain comprehensive results in a large number of cases, a post hoc analysis of the Prospective Observational survey on the Long-Term Effects of the LDL-Apheresis on the Drug Resistant Nephrotic Syndrome (POLARIS) study was performed by stratifying enrolled cases according to the pretreatment estimated glomerular filtration rate (eGFR) levels indicating normal (N) (≥60 ml/min/1.73 m2 ), moderately impaired (M) (≥30 to <60 ml/min/1.73 m2 ), and severely impaired (S) (<30 ml/min/1.73 m2 ) renal function. Significant improvements of proteinuria and renal function were found in Group N and, most interestingly, in Group M. A tendency for improvement in proteinuria was found in Group S. Most cases in all groups had not entered end-stage renal disease at 2 years after LDL-A treatment. These results suggest that LDL-A has therapeutic efficacy even in cases in which renal function has declined to 30 ml/min/1.73 m2 .


Identification of an Immune-Related Gene Signature to Improve Prognosis Prediction in Colorectal Cancer Patients.
Despite recent advance in immune therapy, great heterogeneity exists in the outcomes of colorectal cancer (CRC) patients. In this study, we aimed to analyze the immune-related gene (IRG) expression profiles from three independent public databases and develop an effective signature to forecast patient's prognosis. IRGs were collected from the ImmPort database. The CRC dataset from The Cancer Genome Atlas (TCGA) database was used to identify a prognostic gene signature, which was verified in another two CRC datasets from the Gene Expression Omnibus (GEO). Gene function enrichment analysis was conducted. A prognostic nomogram was built incorporating the IRG signature with clinical risk factors. The three datasets had 487, 579, and 224 patients, respectively. A prognostic six-gene-signature (CCL22, LIMK1, MAPKAPK3, FLOT1, GPRC5B, and IL20RB) was developed through feature selection that showed good differentiation between the low- and high-risk groups in the training set (p < 0.001), which was later confirmed in the two validation groups (log-rank p < 0.05). The signature outperformed tumor TNM staging for survival prediction. GO and KEGG functional annotation analysis suggested that the signature was significantly enriched in metabolic processes and regulation of immunity (p < 0.05). When combined with clinical risk factors, the model showed robust prediction capability. The immune-related six-gene signature is a reliable prognostic indicator for CRC patients and could provide insight for personalized cancer management.


S1QELs suppress mitochondrial superoxide/hydrogen peroxide production from site IQ without inhibiting reverse electron flow through Complex I.
Mitochondria are important sources of superoxide and hydrogen peroxide in cell signaling and disease. In particular, superoxide/hydrogen peroxide production during reverse electron transport from ubiquinol to NAD+ though Complex I is implicated in several physiological and pathological processes. S1QELs are small molecules that suppress superoxide/hydrogen peroxide production at Complex I without affecting forward electron transport. Their mechanism of action is disputed. To test different mechanistic models, we compared the effects of two inhibitors of Complex I electron transport (piericidin A and rotenone) and two S1QELs from different chemical families on superoxide/hydrogen peroxide production and electron transport by Complex I in isolated mitochondria. Piericidin A and rotenone (and S1QEL1.1 at higher concentrations) prevented superoxide/hydrogen peroxide production from sites IQ and IF in Complex I by inhibiting reverse electron transport into the complex. S1QELs decreased the potency of electron transport inhibition by piericidin A and rotenone, suggesting that S1QELs bind directly to Complex I. S1QEL2.1 (and S1QEL1.1 at lower concentrations) suppressed site IQ without affecting reverse electron transport or site IF, showing that sites IQ and IF are distinct, and that S1QELs do not work simply by decreasing reverse electron transport to site IF (or site IQ). S1QELs did not affect the reduction of NAD+ or the rate of site IF driven by reverse electron transport, therefore they do not alter the driving forces for reverse electron transport and that is not how they suppress site IQ. We conclude that S1QELs bind to Complex I to influence the conformation of the piericidin A and rotenone binding sites and directly suppress superoxide/hydrogen peroxide production at site IQ, which is a separate site from site IF.


Type of tea consumption and depressive symptoms in Chinese older adults.
Existing research indicates that tea drinking may exert beneficiary effects on mental health. However, associations between different types of tea intake and mental health such as depression have not been fully examined. The purpose of this study was to examine the associations of green tea, fermented tea, and floral tea consumption with depressive symptoms. We used data from the 2018 wave of the Chinese Longitudinal Healthy Longevity Survey, a nationwide survey on older adults in mainland China. A total of 13,115 participants (mean age 83.7 years, 54.2% were women) with valid responses were included in the analysis. The type (green, fermented [black, Oolong, white, yellow, dark, and compressed teas], and floral) and the frequency of tea consumption were recorded, and depressive symptoms were assessed using 10-item of the Center for Epidemiologic Studies Depression Scale (CES-D-10). We examined the associations between the type and the frequency of tea intake and depression, controlling for a set of demographic, socioeconomic, psychosocial, behavioral, and health-related variables. Overall, intakes of green tea, fermented tea, and floral tea were all significantly associated with lower prevalence of depressive symptoms, independent of other risk factors. Compared with the group of no tea intake, the adjusted ORs of depressive symptoms for daily green tea, fermented tea, and floral tea intake were 0.85 (95% CI: 0.76-0.95), 0.87 (95% CI: 0.76-0.99), and 0.70 (95% CI: 0.59-0.82), respectively. Linear associations were observed between the frequencies of all three types of tea intake and depressive symptoms (P < 0.05 for trends for all three types). The associations of the type and the frequency of tea intake and depressive symptoms were robust in several sensitivity analyses. Among Chinese older adults, regularly consumed any type of tea (green, fermented, or floral) were less likely to show depressive symptoms, the associations seemed more pronounced among floral tea and green tea drinkers.


Aging and the alteration of enzymes: a review.
The present status of research on age-related alterations of enzymes is reviewed. Evidence which makes it clear that "altered" enzymes do, in fact, exist in old animals is presented. The alteration may result from either a sequence change or a post-synthetic modification. The "error hypothesis" would support the former mechanism; a proposal based upon increasing half-lives of proteins with age could explain the latter. Evidence supporting or contradicting these alternatives is discussed.


Direct observation of diffuse cone behavior in de Vries smectic-A and -C phases of organosiloxane mesogens.
Simultaneous and direct x-ray measurements of the smectic layer spacing, molecular tilt, and orientational order in the de Vries smectic A (SmA) and C (SmC) phases of two organosiloxane mesogens reveal that (i) the SmC (tilt) order parameter exponent β=0.26±0.01 for 2nd order SmA-SmC transition--in excellent agreement with the tricritical behavior, (ii) the siloxane and hydrocarbon parts of the molecules are segregated and oriented parallel to the director with very different degree of orientational order, and (iii) thermal evolution of the effective molecular length is different in the two phases.


Reconstruction of the cheek and palate using a three-paddle tensor fasciae latae free flap.
A triple-paddle flap may be required to reconstruct the defects of palate, intraoral lining and overlying skin. This report presents a successful case of a triple-paddle flap using the tensor fasciae latae free flap.