Combined herbicide and saline stress differentially modulates hormonal regulation and antioxidant defense system in Oryza sativa cultivars.
Plants are simultaneously exposed to a combination of biotic and abiotic stresses in field conditions. Crops respond to the combined stress in a unique way which cannot be understood by extrapolating the results of individual stress. In the present study, effects of individual and combined stress of herbicide (2,4-dichlorophenoxyacetic acid) and salinity (NaCl) on two Oryza sativa cultivars (ZJ 88 and XS 134) were investigated. Both herbicide and saline stress affected the plant growth differentially and produced oxidative stress in rice cultivars. Interestingly, the combination of herbicide and salinity showed a significant protection to both rice cultivars by reducing ROS (H2O2, O2(-)) and lipid peroxidation through modulation of enzymatic (SOD, POD, CAT and APX) and non-enzymatic (TSP, sugars, phenolic and proline) antioxidants. In addition, active regulation of transcript levels of genes encoding Na(+) and K(+) (OsHKT1;5, OsLti6a,b, OsHKT2;1, OsSOS1, OsCNGC1, OsNHX1 and OsAKT1) transporter proteins reduced sodium and enhanced potassium accumulation under combined stress, resulted a better growth and ionic homeostasis in both rice cultivars. The production of ABA and IAA was significantly higher in cultivar XS 134 compared to cultivar ZJ 88 under control conditions. However, combined herbicide and saline stress enhanced the accumulation of phytohormones (IAA and ABA) and transcription of ethylene in cultivar ZJ 88, which might be one of the factors responsible for poor salt tolerance in sensitive cultivar. These findings indicated that herbicide application under saline stress confers tolerance to salinity in rice cultivars, likely by reducing oxidative damage, modulating mineral absorption, upgradation of antioxidant defense and by dynamic regulation of key genes involved in Na(+) and K(+) homeostasis in plants.


The effect of myelin basic protein on the endogenous phosphorylation of platelets.
Bovine myelin basic protein (BP) induced a shape change and endogenous phosphorylation of a 45,000 (45K) molecular weight protein of intact human platelets. This effect occurred rapidly over an effective concentration range of 5-100 microM BP. BP peptides encompassing residues 1-42, 43-88, and 89-169 from the BP molecule of 169 residues, neither induced phosphorylation of platelets nor blocked the effect of intact BP. Subfractionation of disrupted platelets demonstrated the phosphorylated 45K protein in the 100,000 xg supernate. When isolated platelet membranes were used, no BP induced phosphorylation of a 45K protein could be detected. The amino acid composition of the purified, phosphorylated 45K protein differed from those of other known platelet proteins. BP itself was also phosphorylated by an endogenous platelet protein kinase(s) present both in the 100,000 xg supernatant and in the isolated membrane fraction of platelets. These results indicate that the normal or pathological release of BP from myelin may lead to phosphorylation of an internal protein of platelets and possibly other tissue elements with resultant metabolic and functional changes.


Distance between the lead-implanted site and tricuspid valve annulus in patients with left bundle branch pacing: Effects on postoperative tricuspid regurgitation deterioration.
Left bundle branch pacing (LBBP) is an alternative strategy for His-bundle pacing (HBP); however, little is known about tricuspid regurgitation (TR) deterioration after LBBP implantation. The purpose of this study was to characterize the incidence of post-LBBP TR deterioration and identify predicting factors, especially lead position parameters. Patients who received LBBP were continuously enrolled from January 2018 to August 2020. The progression of TR and the anatomic position of LBBP were characterized by echocardiography. A total of 89 patients were enrolled and assigned to 2 subgroups based on the degree of TR before LBBP implantation: 58 (65.2%) with relatively normal tricuspid valve (TV) function (grade 0/1 subgroup: with none/trivial or mild TR) and 31 (34.8%) with more severe TR (grade 2/3 subgroup: with moderate or severe TR). At 19.0 ± 6.5 months of follow-up, 29 patients (32.6%) had TR deterioration, and 23 of them were in the grade 0/1 subgroup. In the grade 0/1 subgroup, patients with TR deterioration had a shorter distance between the lead-implanted site and TV (Lead-TA-dist) than those without TR (19.0 ± 7.6 vs 23.9 ± 5.4; P = .006). The receiver operating characteristic (ROC) curve (area under the curve 0.721; 95% confidence interval [CI] 0.575-0.867; P = .005) indicated the favorable efficacy of Lead-TA-dist for predicting TR deterioration after LBBP. Lead-TA-dist ≤16.1 mm was independently associated with TR deterioration after LBBP (hazard ratio 0.20; 95% CI 0.06-0.76; P = .017). TR was a common complication of LBBP implantation. In patients with none/trivial or mild TR, Lead-TA-dist ≤16.1 mm was an independent predictor of TR deterioration after LBBP implantation.


Long-term results of the retrocapital metatarsal percutaneous osteotomy for hallux valgus.
The current trend in hallux valgus surgery is directed toward percutaneous procedures. However, no evidence that any of these methods of treatment are superior to the others has been described, excepting studies in the long term. The aim of this study was to analyse a series of patients who had undergone a percutaneous distal retrocapital osteotomy of the first metatarsal, and had been followed up for ten years. We carried out a clinical and radiological evaluation of 115 feet ten years after surgery. The AOFAS scale results in the tenth postoperative year remained significantly favourable compared to their corresponding values in the preoperative period, yielding an improvement of 42.2 points overall on average. In relation to radiological findings, the mean hallux angle was maintained below 20 °, with a mean intermetatarsal angle of 8.1 °. Percutaneous retrocapital metatarsal osteotomy for treatment of mild to moderate hallux valgus is effective in the long term, with the advantages of a minimally invasive procedure.


The use of magnetic resonance imaging to predict ACL graft structural properties.
Magnetic resonance imaging (MRI) could potentially be used to non-invasively predict the strength of an ACL graft after ACL reconstruction. We hypothesized that the volume and T2 relaxation parameters of the ACL graft measured with MRI will predict the graft structural properties and anteroposterior (AP) laxity of the reconstructed knee. Nine goats underwent ACL reconstruction using a patellar tendon autograft augmented with a collagen or collagen-platelet composite. After 6 weeks of healing, the animals were euthanized, and the reconstructed knees were retrieved and imaged on a 3T scanner. AP laxity was measured prior to dissecting out the femur-graft-tibia constructs which were then tested to tensile failure to determine the structural properties. Regression analysis indicated a statistically significant relationship between the graft volume and the failure load (r(2)=0.502; p=0.049). When graft volume was normalized to the T2 relaxation time, the relationship was even greater (r(2)=0.687; p=0.011). There was a significant correlation between the graft volume and the linear stiffness (r(2)=0.847; p<0.001), which remained significant with T2 normalization (r(2)=0.764; p=0.002). For AP laxity at 30° flexion, there was not a significant correlation with graft volume, but there was a significant correlation with volume normalized by the T2 relaxation time (r(2)=0.512; p=0.046). These results suggest that MRI volumetric measures combined with graft T2 properties may be useful in predicting the structural properties of ACL grafts.


Sustained vertebral antifracture efficacy of oral anti-osteoporotic therapies in postmenopausal osteoporosis.
Vertebral fractures are common in women with postmenopausal osteoporosis, a chronic condition requiring long-term treatment with anti-osteoporotic treatments. Therefore, it is important to assess sustainability of antifracture efficacy. A review of the literature to determine pivotal vertebral fracture studies for oral bisphosphonates (ibandronate, risedronate and alendronate), strontium ranelate, and raloxifene and to evaluate vertebral antifracture efficacy over time. Data from the BONE trial showed that ibandronate sustained vertebral antifracture efficacy over time (58% vertebral fracture risk reduction in first year p = 0.0561, increased to 62% for years 0-3; p < 0.001). The Vertebral Efficacy with Risedronate Therapy-North America (VERT-NA) and VERT-multi-national (VERT-MN) studies demonstrated that the relative risk reduction (RRR) with risedronate versus placebo decreased over time (VERT-NA: 65% for first year to 41% for years 0-3; VERT-MN: 61% for first year to 49% for years 0-3). Data from the Fracture Intervention Trial (FIT) I trial with alendronate showed that the RRR in the cumulative incidence of new vertebral fractures versus placebo decreased from 62% for years 0-2 to 47% for years 0-3. Similar decreases in RRR over time were reported with strontium ranelate in the Spinal Osteoporosis Therapeutic Intervention study (SOTI; 49% for first year to 33% for years 0-4) and Treatment of Peripheral Osteoporosis Study (TROPOS; 45% for first year to 24% for years 0-5). No clear trend exists for sustained efficacy over time with raloxifene. Vertebral fracture protection could be interpreted to decrease over time with alendronate, risedronate and strontium ranelate, and may be due to multiple factors. Ibandronate sustained vertebral antifracture efficacy over time.


A positive feedback loop involving the LINC00346/β-catenin/MYC axis promotes hepatocellular carcinoma development.
In recent years, long noncoding RNAs (lncRNAs) have received increasing attention as important regulators of cancer development. As yet, however, a large fraction of them has not been characterized in detail, and the functional role of LINC00346 in hepatocellular carcinoma (HCC) has remained unclear. The role of LINC00346 in HCC development was investigated using both in vitro and in vivo assays. Interactions between LINC00346, miR-542-3p and WDR18 were assessed using luciferase reporter, RT-qPCR and Western blotting assays. Loss- and gain-of-function experiments were performed to assess the roles of LINC00346, miR-542-3p and WDR18 in HCC cell viability, proliferation, migration and invasion. We found that LINC00346 was upregulated in primary HCC tissues and HCC-derived cell lines and that LINC00346 may promote HCC cell viability, proliferation, migration and invasion. Furthermore, we found that LINC00346 may regulate WDR18 expression via competitively binding to miR-542-3p. This miRNA was found to be downregulated in primary HCC tissues and to act as a tumor suppressor that can inhibit HCC cell viability, proliferation, migration and invasion. In contrast, WDR18 was found to be upregulated in primary HCC tissues and to act as an oncogene. Additional functional studies indicated that WDR18 can activate the Wnt/β-catenin signaling pathway and its downstream effectors in HCC cells. We also found that LINC00346, through competitive sponging of miR-542-3p, may enhance the expression of WDR18 and activate the Wnt/β-catenin signaling pathway in HCC cells. Finally, a positive feedback loop involving LINC00346, β-catenin and MYC in HCC cells was uncovered. Our results indicate an oncogenic role of LINC00346 in HCC cells via a positive feedback loop involving LINC00346, β-catenin and MYC, and they may be instrumental for the design of novel HCC biomarkers and/or therapeutic strategies.


Two-dimensional electrophoresis computerized processing.
This paper describes various methods suitable for implementation of two-dimensional processing software. The different steps leading to a complete processing are described, from the digitalization of the image to the processing of the resulting data. The characteristics of a convenient digitalization system are discussed. The different software devoted to spot detection is reviewed with respect to the presence or otherwise of a spot model and its characteristics. The major techniques for gel matching are compared as are designs for database structures suitable for tabulation of measurements. Finally, the need for a sophisticated system of data processing is stressed and its main requirements are described.


The association between health anxiety, physical disease and cardiovascular risk factors in the general population - a cross-sectional analysis from the Tromsø study: Tromsø 7.
Health anxiety (HA) is defined as a worry of disease. An association between HA and mental illness has been reported, but few have looked at the association between HA and physical disease. To examine the association between HA and number of diseases, different disease categories and cardiovascular risk factors in a large sample of the general population. This study used cross-sectional data from 18,432 participants aged 40 years or older in the seventh survey of the Tromsø study. HA was measured using a revised version of the Whiteley Index-6 (WI-6-R). Participants reported previous and current status regarding a variety of different diseases. We performed exponential regression analyses looking at the independent variables 1) number of diseases, 2) disease category (cancer, cardiovascular disease, diabetes or kidney disease, respiratory disease, rheumatism, and migraine), and 3) cardiovascular risk factors (high blood pressure or use of cholesterol- or blood pressure lowering medication). Compared to the healthy reference group, number of diseases, different disease categories, and cardiovascular risk factors were consistently associated with higher HA scores. Most previous diseases were also significantly associated with increased HA score. People with current cancer, cardiovascular disease, and diabetes or kidney disease had the highest HA scores, being 109, 50, and 60% higher than the reference group, respectively. In our general adult population, we found consistent associations between HA, as a continuous measure, and physical disease, all disease categories measured and cardiovascular risk factors.


The Arabidopsis acetylated histone-binding protein BRAT1 forms a complex with BRP1 and prevents transcriptional silencing.
Transposable elements and other repetitive DNA sequences are usually subject to DNA methylation and transcriptional silencing. However, anti-silencing mechanisms that promote transcription in these regions are not well understood. Here, we describe an anti-silencing factor, Bromodomain and ATPase domain-containing protein 1 (BRAT1), which we identified by a genetic screen in Arabidopsis thaliana. BRAT1 interacts with an ATPase domain-containing protein, BRP1 (BRAT1 Partner 1), and both prevent transcriptional silencing at methylated genomic regions. Although BRAT1 mediates DNA demethylation at a small set of loci targeted by the 5-methylcytosine DNA glycosylase ROS1, the involvement of BRAT1 in anti-silencing is largely independent of DNA demethylation. We also demonstrate that the bromodomain of BRAT1 binds to acetylated histone, which may facilitate the prevention of transcriptional silencing. Thus, BRAT1 represents a potential link between histone acetylation and transcriptional anti-silencing at methylated genomic regions, which may be conserved in eukaryotes.


Evaluation of mRNA by Q-RTPCR and protein expression by AQUA of the M2 subunit of ribonucleotide reductase (RRM2) in human tumors.
The purpose of this study was to evaluate baseline RRM2 protein and gene expression in tumors of patients receiving 3-AP. Tumor blocks from patients enrolled in phase I and II clinical studies using 3-AP, were evaluated for RRM2 gene and protein expression by quantitative real time polymerase chain reaction (Q-RTPCR) and automated quantitative analysis (AQUA). Esophageal and gastric cancers overexpressed RRM2 protein when compared to prostate cancer (Z-score, 0.68 +/- 0.94 SD, vs 0.41 +/- 0.84 SD, respectively; p = 0.04). Esophageal and gastric cancers also overexpressed RRM2 mRNA when compared to prostate cancer (relative gene expression 2.56 +/- 1.49 SD, vs 0.29 +/- 0.20 SD, respectively; p = 0.02). Protein and gene expression were moderately associated (Spearman's rank correlation = 0.30; p = 0.12). RRM2 gene and protein expression varies by tumor type.


Optimizing Antibody-Antigen Binding Affinities with the ADAPT Platform.
The ADAPT (Assisted Design of Antibody and Protein Therapeutics) platform guides the selection of mutants that improve/modulate the affinity of antibodies and other biologics. Predicted affinities are based on a consensus z-score from three scoring functions. Computational predictions are interleaved with experimental validation, significantly enhancing the robustness of the design and selection of mutants. A key step is an initial exhaustive virtual single-mutant scan that identifies hot spots and the mutations predicted to improve affinity. A small number of proposed single mutants are then produced and assayed. Only the validated single mutants (i.e., having improved affinity) are used to design double and higher-order mutants in subsequent rounds of design, avoiding the combinatorial explosion that arises from random mutagenesis. Typically, with a total of about 30-50 designed single, double, and triple mutants, affinity improvements of 10- to 100-fold are obtained.


Endomorphins fully activate a cloned human mu opioid receptor.
Endomorphins were recently identified as endogenous ligands with high selectivity for mu opioid receptors. We have characterized the ability of endomorphins to bind to and functionally activate the cloned human mu opioid receptor. Both endomorphin-1 and endomorphin-2 exhibited binding selectivity for the mu opioid receptor over the delta and kappa opioid receptors. Both agonists inhibited forskolin-stimulated increase of cAMP in a dose-dependent fashion. When the mu opioid receptor was coexpressed in Xenopus oocytes with G protein-activated K+ channels, application of either endomorphin activated an inward K+ current. This activation was dose-dependent and blocked by naloxone. Both endomorphins acted as full agonists with efficacy similar to that of [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO). These data indicate that endomorphins act as full agonists at the human mu opioid receptor, capable of stimulating the receptor to inhibit the cAMP/adenylyl cyclase pathway and activate G-protein-activated inwardly rectifying potassium (GIRK) channels.


An Experimental Therapeutics Focus on Novel Mechanistic Targets in Cognitive Behavioral Treatments: Introduction to the Special Section.
This article introduces the special section, "An Experimental Therapeutics Focus on Novel Mechanistic Targets in Cognitive Behavioral Treatments." The purpose of this special section is to highlight research that follows the recommended Science of Behavior Change (SOBC) developmental progression for an experimental medicine approach to identifying and testing mechanisms of behavior change. Emphasis was placed on the earlier stage "pipeline" of investigations of novel mechanisms for behavior change: mechanisms that are undergoing the initial stages of validation. In this series, seven empirical articles are presented and are followed by an article detailing a checklist for reporting mechanistic research studies in order to improve communication of findings in the field. The final article in this series discusses the history, current status, and future directions for the SOBC approach to mechanistic science as viewed by National Institute of Health program officials.


High diversity and novelty of Actinobacteria isolated from the coastal zone of the geographically remote young volcanic Easter Island, Chile.
Easter Island is an isolated volcanic island in the Pacific Ocean. Despite the extended knowledge about its origin, flora, and fauna, little is known about the bacterial diversity inhabiting this territory. Due to its isolation, Easter Island can be considered as a suitable place to evaluate microbial diversity in a geographically isolated context, what could shed light on actinobacterial occurrence, distribution, and potential novelty. In the present study, we performed a comprehensive analysis of marine Actinobacteria diversity of Easter Island by studying a large number of coastal sampling sites, which were inoculated into a broad spectrum of different culture media, where most important variations in composition included carbon and nitrogen substrates, in addition to salinity. The isolates were characterized on the basis of 16S ribosomal RNA gene sequencing and phylogenetic analysis. High actinobacterial diversity was recovered with a total of 163 pure cultures of Actinobacteria representing 72 phylotypes and 20 genera, which were unevenly distributed in different locations of the island and sample sources. The phylogenetic evaluation indicated a high degree of novelty showing that 45% of the isolates might represent new taxa. The most abundant genera in the different samples were Micromonospora, Streptomyces, Salinispora, and Dietzia. Two aspects appear of primary importance in regard to the high degree of novelty and diversity of Actinobacteria found. First, the application of various culture media significantly increased the number of species and genera obtained. Second, the geographical isolation is considered to be of importance regarding the actinobacterial novelty found.


Mesna for treatment of hyperhomocysteinemia in hemodialysis patients: a placebo-controlled, double-blind, randomized trial.
Increased plasma total homocysteine is a graded, independent risk factor for the development of atherosclerosis and thrombosis. More than 90% of patients with end-stage renal disease have hyperhomocysteinemia despite vitamin supplementation. It was shown in previous studies that a single intravenous dose of mesna 5 mg/kg caused a drop in plasma total homocysteine that was significantly lower than predialysis levels 2 d after dosing. It was hypothesized 5 mg/kg intravenous mesna administered thrice weekly, before dialysis, for 8 wk would cause a significant decrease in plasma total homocysteine compared with placebo. Patients with end-stage renal disease were randomly assigned to receive either intravenous mesna 5 mg/kg or placebo thrice weekly before dialysis. Predialysis plasma total homocysteine concentrations at weeks 4 and 8 were compared between groups by paired t test. Mean total homocysteine at 8 wk in the placebo group was 24.9 micromol/L compared with 24.3 micromol/L in the mesna group (n = 22 [11 pairs]; mean difference 0.63). Interim analysis at 4 wk also showed no significant difference between mesna and placebo (n = 32 [16 pairs]; placebo 26.3 micromol/L, mesna 24.5 micromol/L; mean difference 1.88). Multivariable adjustments for baseline characteristics did not alter the analysis. Plasma mesna seemed to reach steady-state concentrations by 4 wk. It is concluded that 5 mg/kg mesna does not lower plasma total homocysteine in hemodialysis patients and that larger dosages may be required.


Stochastic Modeling of Behavioral Response to Anthropogenic Sounds.
The effect of anthropogenic sounds on marine wildlife is typically assessed by convolving the spatial, temporal, and spectral properties of a modeled sound field with a representation of animal distribution within the field. Both components benefit from stochastic modeling techniques based on field observations. Recent studies have also highlighted the effect of context on the probability and severity of the animal behavioral response to sound. This paper extends the stochastic approach to three modeling scenarios, including key contextual variables in aversion from a given level of sound and as a means of evaluating the effectiveness of passive acoustic monitoring.


Cardiovascular magnetic resonance in unsuspected interrupted inferior vena cava.
Interrupted inferior vena cava (IVC) is a rare anomaly. Anomalies of IVC are clinically important for cardiologists and radiologists who plan to intervene in the right heart. We describe three cases of IVC interruption diagnosed by cardiac magnetic resonance imaging study.


Urethral pressure profile and retrograde urethrography in diagnosis of urethral strictures.
In 20 male patients with urethral strictures, urethral pressure profile was compared with retrograde urethrography. There was good accordance between the two methods with only minor discrepancies in multiple or very distal strictures. Urethral profile did not provide more exact information than did urethrography.


Vascular effects of timolol and pilocarpine in the iris. A simultaneous bilateral fluorescein angiographic study.
Simultaneous bilateral fluorescein angiography of the iris vessels (SIFA) was performed on 2 groups of patients. One group comprised previously untreated patients with elevated intraocular pressure who underwent a SIFA both before and after a 3 days' timolol treatment in one eye and pilocarpine treatment in the other eye. The other group consisted of glaucomatous patients treated with timolol for 4 to 24 (mean 11) months before the angiography. Short- or long-term use of timolol neither caused, increased nor decreased leak of the dye from the iris vessels, either at the pupillary border, or in other areas of the iris. Dynamics of the blood flow also remained unaffected. Short-term use of pilocarpine increased extrapupillary focal leakage in one eye.


Septicaemic low birthweight neonates treated with human antibodies to endotoxin.
In a double blind controlled study antilipopolysaccharide gammaglobulin given intramuscularly did not reduce mortality in low birthweight babies suffering from septicaemia. It did, however, reduce the recovery period of survivors from 310 to 120 hours.


Evidence for Tautomerisation of Glutamine in BLUF Blue Light Receptors by Vibrational Spectroscopy and Computational Chemistry.
BLUF (blue light sensor using flavin) domains regulate the activity of various enzymatic effector domains in bacteria and euglenids. BLUF features a unique photoactivation through restructuring of the hydrogen-bonding network as opposed to a redox reaction or an isomerization of the chromophore. A conserved glutamine residue close to the flavin chromophore plays a central role in the light response, but the underlying modification is still unclear. We labelled this glutamine with (15)N in two representative BLUF domains and performed time-resolved infrared double difference spectroscopy. The assignment of the signals was conducted by extensive quantum chemical calculations on large models with 187 atoms reproducing the UV-vis and infrared signatures of BLUF photoactivation. In the dark state, the comparatively low frequency of 1,667 cm(-1) is assigned to the glutamine C=O accepting a hydrogen bond from tyrosine. In the light state, the signature of a tautomerised glutamine was extracted with the C=N stretch at ~1,691 cm(-1) exhibiting the characteristic strong downshift by (15)N labelling. Moreover, an indirect isotope effect on the flavin C4=O stretch was found. We conclude that photoactivation of the BLUF receptor does not only involve a rearrangement of hydrogen bonds but includes a change in covalent bonds of the protein.


Estrogen status and psychophysical stress modify temporomandibular joint input to medullary dorsal horn neurons in a lamina-specific manner in female rats.
Estrogen status and psychological stress contribute to the expression of several chronic pain conditions including temporomandibular muscle and joint disorders (TMJD). Sensory neurons that supply the temporomandibular joint (TMJ) region terminate in laminae I and V of the spinal trigeminal nucleus (Vc/C1-2 region); however, little is known about lamina-specificity and environmental influences on the encoding properties of TMJ brainstem neurons. To test the hypothesis that Vc/C1-2 neurons integrate both interoceptive and exteroceptive signals relevant for TMJ nociception, we recorded TMJ-evoked activity in superficial and deep laminae of ovariectomized rats under high and low estradiol (E2) and stress conditions. Rats received daily injections of low (LE) or high (HE) dose E2 and were subjected to forced swim (FS) or sham swim conditioning for 3days. The results revealed marked lamina-specificity in that HE rats displayed enhanced TMJ-evoked activity in superficial, but not deep, laminae independent of stress conditioning. By contrast, FS conditioned rats displayed increased background firing and TMJ-evoked activity of neurons in deep, but not superficial, laminae independent of E2 status. FS also enhanced TMJ-evoked masseter muscle activity and suggested the importance of deep dorsal horn neurons in mediating evoked jaw muscle activity. In conclusion, E2 status and psychophysical stress play a significant role in modifying the encoding properties of TMJ-responsive medullary dorsal horn neurons with a marked lamina-specificity.


Analysis of predictors of mortality after surgical and non-surgical management in proximal humerus fractures.
Proximal humerus fractures are one of the main osteoporotic fractures. Choosing between conservative or surgical treatment is a controversial topic in the literature, as is the functional impact. The main aim of our study was to analyse whether patient comorbidities should influence the final therapeutic decision for these fractures. We collected data from 638 patients with proximal humerus fractures. The main variable collected was exitus. We also collected the following data: age, gender, type of fracture, laterality, type of treatment, production mechanism, comorbidities and the Charlson comorbidity index (CCI) for each patient. The therapeutic indication used the criteria established by the Upper Limb Unit in our centre. We performed chi-square tests, Fischer's exact tests and Student's t-tests to compare the variables. We used the Kaplan-Meier method to analyse both the overall and disease-specific survival rates. We employed the Cox regression model to analyse factors associated with mortality. Patients with a CCI greater than 5 showed greater mortality (HR = 3.83; p < 0.001) than those with a CCI lower than 5. Within the patients who underwent surgery, those with a CCI higher than 5 had an increased mortality rate (HR = 22.6; p < 0.001) compared with those with a CCI lower than 5. Within the patients who received conservative treatment, those with a CCI over 5 showed greater mortality (HR = 3.64; p < 0.001) than those with a CCI under 5. Patients with proximal humerus fractures and associated comorbidities (CCI > 5) presented higher mortality than healthier patients. This mortality risk was greater in patients with comorbidities if surgical treatment was indicated rather than conservative treatment. Patient's comorbidities should be a fundamental parameter when planning the therapeutic strategy. Level 3.


Circuit-Based Biomarkers for Mood and Anxiety Disorders.
Mood and anxiety disorders are complex heterogeneous syndromes that manifest in dysfunctions across multiple brain regions, cell types, and circuits. Biomarkers using brain-wide activity patterns in humans have proven useful in distinguishing between disorder subtypes and identifying effective treatments. In order to improve biomarker identification, it is crucial to understand the basic circuitry underpinning brain-wide activity patterns. Leveraging a large repertoire of techniques, animal studies have examined roles of specific cell types and circuits in driving maladaptive behavior. Recent advances in multiregion recording techniques, data-driven analysis approaches, and machine-learning-based behavioral analysis tools can further push the boundary of animal studies and bridge the gap with human studies, to assess how brain-wide activity patterns encode and drive emotional behavior. Together, these efforts will allow identifying more precise biomarkers to enhance diagnosis and treatment.


Cost and Utilization Outcomes in Huntsman at Home, a Novel Oncology Hospital at Home Program.
In a real-world trial, we previously demonstrated that Huntsman at Home, a novel oncology hospital at home program, was associated with reduced health care utilization and costs. In this study, we sought to understand the impact of Huntsman at Home in specific patient subgroups defined by sex, age, area-level median income, Charlson Comorbidity Index, and current use of systemic anticancer therapy. Retrospective case-control study of the Huntsman Cancer Institute. Electronic Data Warehouse of patients enrolled in Huntsman at Home between August 2018 through October 2019 vs usual-care patients. A total of 169 patients admitted to Huntsman at Home compared with 198 usual-care patients. Five dichotomous subgroups evaluated including sex (female vs male), age (≥65 vs <65), income (≥$78,735 vs <$78,735), Charlson Comorbidity Index (≥2 vs <2), and current systemic anticancer therapy use vs no current systemic anticancer therapy. Groups were compared with patients receiving usual care. Primary outcomes included 30-day costs, hospital length of stay, unplanned hospitalizations, and emergency room visits. Admission to Huntsman at Home was associated with an overall reduction across all 4 health care cost and utilization outcomes. Outcomes favoring admission to Huntsman at Home achieved statistical significance (P < .05) in at least 2 of the 4 outcomes for each subgroup studied. Of the subgroups that did not achieve statistically significant benefit from Huntsman at Home admission in some outcome categories, none of these subgroups favored usual care. Admission to Huntsman at Home decreased utilization of unplanned health care and reduced costs across a wide spectrum of patient subgroups, suggesting overall consistent benefit from the service. Hospital at home models should be considered as a means by which the quality and efficiency of care can be maximized for patients with cancer.


Study of hydrosalpinx on endometrial growth and expression of HOXA10mRNA and related factors.
The objective of the study is to extract the patient's endometrium at the time of proliferative stage using hydrosalpinx in order to culture the cells and decidualization induction in vitro. Further, the study is also intended at identifying the expression of HOXA10mRNA and related factors and understand the hydrosalpinx's impact upon the working mechanism of endometrial cells. Once the extraction of the primary cells is over, the cells are cultured and other activities are performed such as the cell identification, CCK8 assay, cell decidua induction and HE staining. The researchers assessed the expression levels of HOXA10, IGFBP1 and avβ3 in either proliferation or secretion of the endometrium. This was accomplished using Western blot assay and real-time fluorescence quantitative PCR. The results confirmed that at the time of endometrial proliferation, there was a decline in the expression of HOXA10 as a result of tubal effusion influence. This affected its expression in the secretory stage i.e., corresponding function. Further, a significant decline was observed in the levels of HOXA10mRNA of endometrial cells that were subjected to continuous tubal effusion, post decidualization. It was found that during decidualization, if thetubal effusion is removed, it is possible to restore the expression of HOXA10mRNA to a certain extent, though it is not possible to reach the general endometrial level. So, in terms of clinical aspects, the expression of HOxa10 mRNA by the endometrial cells decreases significantly when blocking the hydrosalpinx. Among hydrosalpinx patients, one of the major mechanisms that damage the endometrium was found to be the abnormal expression of HOXA10 followed by IGFBP1 and avβ3, its downstream genes. This further results in the implantation of the embryo as well. Though it is possible to gradually repair the damage after the removal of hydrosalpinx, the recovery is a time-consuming process.


Effects of honokiol protects against chronic kidney disease via BNIP3/NIX and FUNDC1-mediated mitophagy and AMPK pathways.
Chronic kidney disease (CKD) is a serious health threat worldwide. Defective mitophagy has been reported to induce mitochondrial dysfunction, which is closely associated with CKD pathogenesis. Honokiol (HKL) is a bioactive component of Magnolia officinalis that has multiple efficacies. Our study aimed to investigate the effect of HKL on a CKD rat model and explore the possible mechanisms of mitophagy mediated by Bcl-2 interacting protein 3 and BNIP3-like (NIX) (also known as the BNIP3/NIX pathway) and FUN14 domain-containing 1 (the FUNDC1 pathway) and the role of the AMP-activated protein kinase (AMPK) pathway. A CKD rat model was established by feeding the animals dietary adenine (0.75% w/w, 3 weeks). Simultaneously, the treatment group was given HKL (5 mg/kg/day, 4 weeks) by gavage. Renal function was assessed by measuring serum creatinine (Scr) and blood urea nitrogen (BUN) levels. Pathological changes were analyzed by periodic acid-Schiff (PAS) and Masson's trichrome staining. Protein expression was evaluated by Western blotting and immunohistochemistry. HKL treatment ameliorated the decline in renal function and reduced tubular lesions and interstitial fibrosis in CKD rats. Accordingly, the renal fibrosis markers Col-IV and α-SMA were decreased by HKL. Moreover, HKL suppressed the upregulation of the proapoptotic proteins Bad and Bax and Cleaved caspase-3 expression in CKD rats. Furthermore, HKL suppressed BNIP3, NIX and FUNDC1 expression, leading to the reduction of excessive mitophagy in CKD rats. Additionally, AMPK was activated by adenine, and HKL reversed this change and significantly decreased the level of activated AMPK (phosphorylated AMPK, P-AMPK). HKL exerted a renoprotective effect on CKD rats, which was possibly associated with BNIP3/NIX and FUNDC1-mediated mitophagy and the AMPK pathway.


Minimal important difference of two methods for assessment of quadriceps femoris strength post exercise program in individuals with COPD.
The assessment of quadriceps femoris (QF) strength is recommended by international guidelines as an outcome of exercise training (ET) programs in patients with chronic obstructive pulmonary disease (COPD). To identify the minimal important difference (MID) of two methods for the assessment of improvement of QF strength after a high-intensity ET program in individuals with COPD: 1-repetition maximum (1RM) and maximal voluntary contraction (MVC). Individuals with moderate to very-severe stable COPD were submitted to high-intensity ET (3 days/week, 36 sessions). Lung function (spirometry), exercise capacity (6-minute walk test [6MWT]) and QF strength (1RM test and MVC by using a strain-gauge) were assessed before and after the ET program. Twenty-one individuals were studied (65±8 years, BMI 27±6; FEV1 51±16%predicted). At the end of the ET program, QF strength improved significantly (10±4 Nm for MVC and 8 ± 6 kg for 1RM) (P<0.05 for both). The MID for improvement of the QF strength calculated by distribution-based methods ranged from 9.4 to 16 Nm (between 7.4% and 12.6% increase from baseline) for the MVC and from 2.5 to 3 kg (between 12% and 15% increase from baseline) for the 1RM test. Anchor-based MIDs could not be calculated since there was no correlation between the improvement of QF strength and the improvement of the proposed anchor (6MWT). The MID for improvement of QF strength after a high-intensity ET program in individuals with moderate-to-severe stable COPD ranges between 9.4 and 16 Nm for the MVC assessed with a strain gauge and between 2.5 and 3 kg for the 1RM test.


Synthesis, characterization and evaluation of anti-hyperalgesia, anticonvulsant and antioxidant activity of novel VV-hemorphin-5 analogs.
Two series of new VV-hemorphin-5 analogs with structures Val-Val-Tyr-Xxx-Trp-Thr-Gln-NH2 and Adam-Val-Val-Tyr-Xxx-Trp-Thr-Gln-NH2 , where Xxx is Ac5c (1-aminocyclopentane-1-carboxylic acid), Ac6c (1-aminocyclohexane-1-carboxylic acid), Ac7c (1-aminocycloheptane-1-carboxylic acid), and Adam is the low-molecular-weight lipophilic adamantyl building block, were synthesized, characterized electrochemically and evaluated for antioxidant, anti-hyperalgesia, and anticonvulsant activity. The design of the compounds followed the strategy to improve the propensity for aqueous solubility and/or to increase their affinity for the target receptor or enzyme. The partition coefficient value shows that the peptide scaffold goes from hydrophilic to lipophilic with the increasing size of the cycloalkane ring and even more with the introduction of the adamantane. The peptides C5-V and C7-V were the only analogs that provoked an immediate antinociceptive effect changing the mechanical pain threshold. The six new peptide analogs produced a significant and long-lasting carrageenan model of inflammatory pain in rats. While the adamantane hemorphin analog Ad7-V was the only compound with the potency to suppress psychomotor seizures in the 6-Hz test, the C6-V and Ad6-V exhibited protective activity against the seizure spread in the maximal electroshock seizure test in mice. The active analogs did not show neurotoxicity or sedative effects. Our results revealed a structure-related specific activity of a newly designed hemorphin analog that could be used as a template for future modification and preparation of compounds with potential analgesic and anticonvulsant activity.


First proof of bismuth oxide nanoparticles as efficient radiosensitisers on highly radioresistant cancer cells.
This study provides the first proof of the novel application of bismuth oxide as a radiosensitiser. It was shown that on the highly radioresistant 9L gliosarcoma cell line, bismuth oxide nanoparticles sensitise to both kilovoltage (kVp) or megavoltage (MV) X-rays radiation. 9L cells were exposed to a concentration of 50μg.mL-1 of nanoparticle before irradiation at 125kVp and 10MV. Sensitisation enhancement ratios of 1.48 and 1.25 for 125kVp and 10MV were obtained in vitro, respectively. The radiation enhancement of the nanoparticles is postulated to be a combination of the high Z nature of the bismuth (Z=83), and the surface chemistry. Monte Carlo simulations were performed to elucidate the physical interactions between the incident radiation and the nanoparticle. The results of this work show that Bi2O3 nanoparticles increase the radiosensitivity of 9L gliosarcoma tumour cells for both kVp and MV energies. Monte Carlo simulations demonstrate the advantage of a platelet morphology.


Dimethylthexylsilyl 2-acetamido-3-O-allyl-2-deoxy-6-O-(4-methoxybenzyl)-beta-D-glucopyranoside, dimethylthexylsilyl 3,4,6-tri-O-benzyl-beta-D-mannopyranosyl-(1-->4)-2-acetamido-3-O-allyl-2-deoxy-6-O-(4-methoxybenzyl)-beta-D-glucopyranoside, and dimethylthexylsilyl 2-O-(benzylsulfonyl)-3,4,6-tri-O-benzyl-beta-D-mannopyranosyl-(1-->4)-2-acetamido-3-O-allyl-2-deoxy-6-O-(4-methoxybenzyl)-beta-D-glucopyranoside: synthesis of authentic samples.
Dimethylthexylsilyl 2-acetamido-3-O-allyl-2-deoxy-6-O-(4-methoxybenzyl)-beta-D-glucopyranoside was prepared by reduction of the corresponding 4,6-O-(4-methoxybenzylidene) acetal with sodium cyanoborohydride and trifluoroacetic acid. This alcohol was coupled to 2-O-benzoyl-3,4,6-tri-O-benzyl-alpha-D-glucopyranosyl trichloroacetimidate to give a beta-glucoside that was converted to dimethylthexylsilyl 3,4,6-tri-O-benzyl-beta-D-mannopyranosyl-(1-->4)-2-acetamido-3-O-allyl-2-deoxy-6-O-(4-methoxybenzyl)-beta-D-glucopyranoside by saponification, Dess-Martin oxidation, and sodium borohydride reduction. Sulfonylation then gave dimethylthexylsilyl 2-O-(benzylsulfonyl)-3,4,6-tri-O-benzyl-beta-D-mannopyranosyl-(1-->4)-2-acetamido-3-O-allyl-2-deoxy-6-O-(4-methoxybenzyl)-beta-D-glucopyranoside.


Increased risk of venous thromboembolism in patients with brain tumors: A systematic review and meta-analysis.
Currently published studies investigating the association between brain tumors and venous thromboembolism (VTE) risk have yielded inconsistent findings. To provide a more precise estimate for this association, we firstly performed a meta-analysis by pooling all currently available data. Pooled relative risks (RRs) with 95% confidence intervals (95% CIs) were calculated by use of STATA 12.0 software. All eligible studies were identified by a comprehensive literature search in databases of PubMed, Embase, Web of Science, and Google scholar. According to the inclusion criteria, 9 independent studies were finally included into this study. Individuals with brain tumors were at an increased risk of VTE (RR=1.66, 95% CI 1.31-2.12, P<0.001), particularly those undergoing surgery (RR=1.68, 95% CI 1.44-1.98, P<0.001). Stratified analysis by type of tumor showed that the risk of VTE was significantly associated with glioma (RR=1.68, 95% CI 1.44-1.98, P<0.001), high-grade glioma (RR=1.70, 95% CI 1.29-2.23, P<0.001), and glioblastoma multiforme (RR=1.74, 95% CI 1.43-2.12, P<0.001). The present meta-analysis suggests increased risk of VTE in patients with brain tumors, particularly those undergoing surgery.


Delayed postoperative cardiac tamponade: diagnosis and management.
Symptoms and signs of decreased cardiac output associated with an elevated venous pressure should alert one to the possibility of delayed cardiac tamponade. Enlargement of the cardiothoracic ratio shown by serial roentgenograms and demonstration of significant pericardial effusion by echocardiogram or radionuclide angiocardiography support the diagnosis. Erratic response of the prothrombin time to administration of warfarin and abnormal results of liver function test are additional clues to its diagnosis. Right heart catheterization documents the presence of tamponade and excludes other diagnostic considerations. Operative decompression of the pericardial space can be accomplished by pericardicentesis, subxiphoid pericardiotomy, median sternotomy, or thoracotomy. Hemodynamic observations following the relief of tamponade assure that an adequate therapeutic procedure has been performed.


Prevalence of antibodies to Borrelia burgdorferi sensu stricto in humans from a Cuban village.
Lyme disease has not been officially reported in Cuba. However, clinical cases have been serologically reported. Seroprevalence survey of Borrelia burgdorferi sensu stricto antibodies in humans in the country has not been conducted. To estimate the prevalence of borrelial antibodies in inhabitants of a village with historically high level of tick infestation. Serum specimens from 247 persons randomly selected from the population of the village were examined by IgG Western blot using B31 strain for estimating the prevalence of antibodies profile. A seroprevalence value interval (95% CI) of 0.6%-7.2% was estimated for the studied population. The prevalent borrelial protein bands on immunoblots were 41, 72, 90/93, 34, 47, 60, 58, 56, 65/66 and 31 kDa in a decreasing order of significance. These results support the previous serological findings, suggesting the presence of this borreliosis in Cuba.


Evaluation of plasma sphingolipids as mediators of the relationship between kidney disease and cardiovascular events.
Sphingolipids are a family of circulating lipids with regulatory and signaling roles that are strongly associated with both eGFR and cardiovascular disease. Patients with chronic kidney disease (CKD) are at high risk for cardiovascular events, and have different plasma concentrations of certain plasma sphingolipids compared to patients with normal kidney function. We hypothesize that circulating sphingolipids partially mediate the associations between eGFR and cardiovascular events. We measured the circulating concentrations of 8 sphingolipids, including 4 ceramides and 4 sphingomyelins with the fatty acids 16:0, 20:0, 22:0, and 24:0, in plasma from 3,463 participants in a population-based cohort (Cardiovascular Health Study) without prevalent cardiovascular disease. We tested the adjusted mediation effects by these sphingolipids of the associations between eGFR and incident cardiovascular disease via quasi-Bayesian Monte Carlo method with 2,000 simulations, using a Bonferroni correction for significance. The mean (±SD) eGFR was 70 (±16) mL/min/1.73 m2; 62% of participants were women. Lower eGFR was associated with higher plasma ceramide-16:0 and sphingomyelin-16:0, and lower ceramides and sphingomyelins-20:0 and -22:0. Lower eGFR was associated with risk of incident heart failure and ischemic stroke, but not myocardial infarction. Five of eight sphingolipids partially mediated the association between eGFR and heart failure. The sphingolipids associated with the greatest proportion mediated were ceramide-16:0 (proportion mediated 13%, 95% CI 8-22%) and sphingomyelin-16:0 (proportion mediated 10%, 95% CI 5-17%). No sphingolipids mediated the association between eGFR and ischemic stroke. Plasma sphingolipids partially mediated the association between lower eGFR and incident heart failure. Altered sphingolipids metabolism may be a novel mechanism for heart failure in patients with CKD. This study was supported by T32 DK007467 and a KidneyCure Ben J. Lipps Research Fellowship (Dr. Lidgard). Sphingolipid measurements were supported by R01 HL128575 (Dr. Lemaitre) and R01 HL111375 (Dr. Hoofnagle) from the National Heart, Lung, and Blood Institute (NHLBI).


Serum gonadotrophin levels in prepubertally castrated male sheep treated for long periods with propionated testosterone, dihydrotestosterone, 19-hydroxytestosterone or oestradiol.
At different times of the year, groups of wethers were treated with 20 mg testosterone, dihydrotestosterone or 19-hydroxytestosterone propionates/day or 2 mg oestradiol dipropionate/day, or the oil vehicle, for 6 weeks after a 2-week control period. LH and FSH values were determined by radioimmunoassay of serum samples collected at regular intervals. Oestradiol and dihydrotestosterone reduced LH and FSH concentrations whereas 19-hydroxytestosterone and testosterone had no effect.


Impairment of PD-L2 positive B1a cells enhances susceptibility to sepsis in RasGRP1-deficient mice.
RasGRP1 is a key molecule that mediates antigen-initiated signaling for activation of the RAS-MAPK pathway in lymphocytes. Patients with aberrant RasGRP1 expression experience lymphocyte dysfunction and are afflicted with recurrent microbial infections. Yet, the underlying mechanism that accounts for microbial infection remains unknown. We previously reported that B1a cells are heterogeneous with respect to PD-L2 expression and that RasGRP1 deficiency preferentially impairs PD-L2+ B1a cell development. In the present study, we show that PD-L2+ B1a cells exhibit increased capacity for differentiation to CD138+ plasma cells that secrete natural IgM antibody, as well as IL-10 and GM-CSF, in response to TLR stimulation. In keeping with this, we show here that RasGRP1-deficent mice are much more susceptible to septic infection triggered by cecalligation and puncture than wild type mice, and that reconstitution of RasGRP1-deficient mice with wild type PD-L2+ B1a cells greatly rescues RasGRP1-deficient mice from sepsis. Thus, this study indicates a mechanism for the association of RasGRP1 deficiency with predispostion to infection in the loss of a particular B1a subpopulation.


Selective cell loss in the lateral geniculate nucleus of adult cats following binocular lid suture.
Two weeks of binocular lid suture in adult cats caused selective cell loss in lamina A1 of the lateral geniculate nucleus. The loss was manifested as a shift in the latency distribution of LGN cell responses to optic chiasm shock. Proportionately fewer LGN cells with slowly conducting retinal afferents (X-cell range) were in evidence following binocular suture. This change was observed only in lamina A1 while laminae A and C retained normal latency distributions. These observations confirm and extend recent reports of the susceptibility of adult cat visual system to environmental modification.


HIV-1 Vpu targets cell surface markers CD4 and BST-2 through distinct mechanisms.
Vpu is a small integral membrane protein encoded by HIV-1 and some SIV isolates. The protein is known to induce degradation of the viral receptor molecule CD4 and to enhance the release of newly formed virions from the cell surface. Vpu accomplishes these two functions through two distinct mechanisms. In the case of CD4, Vpu acts as a molecular adaptor to connect CD4 to an E3 ubiquitin ligase complex resulting in CD4 degradation by cellular proteasomes. This requires signals located in Vpu's cytoplasmic domain. Enhancement of virus release on the other hand involves the neutralization of a cellular host factor, BST-2 (also known as CD317, HM1.24, or tetherin) and requires Vpu's TM domain. The current review discusses recent advances on the role of Vpu in controlling degradation of CD4 and in regulating virus release.


Of flies, mice and neural control of food intake: lessons to learn from both models.
In her book, A Room of One's Own, the famous author Virginia Woolf writes "One cannot think well, love well, sleep well if one has not dined well". This is true. All animals need to forage for food and consume specific nutrients to maintain their physiological homeostasis, maximize their fitness and their reproduction. After decades of research in humans and many model organisms, we now know that our brain is one of the key players that control what, when, and how much we eat. In this review, we discuss the recent literature on neural control of food intake behaviors in mice and flies with the view that these two model organisms complement one another in efforts to uncover conserved principles brains use to regulate energy metabolism and food ingestion.


Comparison of Autonomous AS-OCT Deep Learning Algorithm and Clinical Dry Eye Tests in Diagnosis of Dry Eye Disease.
To evaluate a deep learning-based method to autonomously detect dry eye disease (DED) in anterior segment optical coherence tomography (AS-OCT) images compared to common clinical dry eye tests. In this study, 27,180 AS-OCT images were prospectively collected from 151 eyes of 91 patients. Images were used to train and test the deep learning model. Masked cornea specialist ophthalmologist diagnoses were used as the gold standard. Clinical dry eye tests were performed on patients in the DED group to compare the results of the model. The dry eye tests performed were tear break-up time (TBUT), Schirmer's test, corneal staining, conjunctival staining, and Ocular Surface Disease Index (OSDI). Our deep learning model achieved an accuracy of 84.62%, sensitivity of 86.36%, and specificity of 82.35% in the diagnosis of DED. The positive likelihood ratio was 4.89, and the negative likelihood ratio was 0.17. The mean DED probability score was 0.81 ± 0.23 in the DED group and 0.20 ± 0.27 in the healthy group (P < 0.01). The deep learning model accuracy in the diagnosis of DED was significantly better than that of corneal staining, conjunctival staining, and Schirmer's test (P < 0.05). There was no significant difference between the deep learning diagnostic accuracy and that of the OSDI and TBUT. Based on preliminary results, reliable autonomous diagnosis of DED with our deep learning model was achieved, when compared with standard dry eye clinical tests that correlated significantly more or similarly to diagnoses made by cornea specialist ophthalmologists.


Drug-related hypophosphatemia: Descriptive study and case/non-case analysis of the French national pharmacovigilance database.
Phosphorus is an essential element for all living organisms and is involved in various biological pathways. A severe hypophosphatemia can lead to serious complications (acute heart or respiratory failure, rhabdomyolysis, hemolysis…) and increases mortality in patients at risk. Various drugs are known to induce hypophosphatemia through various mechanisms. The aim of this study was to highlight the main drugs associated with hypophosphatemia and to deduce the underlying mechanisms based on a descriptive analysis and a case/non-case analysis using the cases of drug-induced hypophosphatemia reported to the French Pharmacovigilance Network. A total of 368 cases of hypophosphatemia were included in the study. Patients' mean age was 52±18 years. One hundred and ninety-one cases (52%) were serious including 131 (36%) hospitalizations. The median value of serum phosphorus level was 0.54mmol/L [0.40-0.66] (n=309). Those 368 cases corresponded to 185 different suspected substances among which the most frequent drugs were tenofovir disoproxil (n=175; 48%), ferric carboxymaltose (n=29; 8%), denosumab (n=16; 4%), zoledronic acid (n=14; 4%) and hydrochlorothiazide (n=10; 3%). For these five drugs, a significant disproportionality was found. Tenofovir-disoproxil related hypophosphatemia occurred more than one year after its introduction, and a renal tubulopathy (Fanconi's syndrome) was reported in 44 cases (25%). Hypophosphatemia related to iron carboxymaltose occurred within a median of 20 days after injection and was mostly severe. Mechanism included the fibroblast growth factor 23 which can be measured to confirm drug origin. Concerning anti-osteoporosis treatments, hypophosphatemia could be explained by their mechanism of action (abrupt increase of parathormone induced by hypocalcemia) but the patient history (malignancy condition) was a major bias. For hydrochlorothiazide, hyphosphatemia was often moderate, associated with other electrolytic disturbances and occurred during a long-term treatment. Awareness of healthcare professionals is essential to detect as soon as possible hypophosphatemia and its complications related to these drugs.


Diseases of unstable repeat expansion: mechanisms and common principles.
The list of developmental and degenerative diseases that are caused by expansion of unstable repeats continues to grow, and is now approaching 20 disorders. The pathogenic mechanisms that underlie these disorders involve either loss of protein function or gain of function at the protein or RNA level. Common themes have emerged within and between these different classes of disease; for example, among disorders that are caused by gain-of-function mechanisms, altered protein conformations are central to pathogenesis, leading to changes in protein activity or abundance. In all these diseases, the context of the expanded repeat and the abundance, subcellular localization and interactions of the proteins and RNAs that are affected have key roles in disease-specific phenotypes.


An epidemiological model with a delay and a nonlinear incidence rate.
An epidemiological model with both a time delay in the removed class and a nonlinear incidence rate is analysed to determine the equilibria and their stability. This model is for diseases where individuals are first susceptible, then infected, then removed with temporary immunity and then susceptible again when they lose their immunity. There are multiple equilibria for some parameter values, and, for certain of these, periodic solutions arise by Hopf bifurcation from the large nontrivial equilibrium state.


Intron retention by a novel intronic mutation in DKC1 gene caused recurrent still birth and early death in a Chinese family.
DKC1, the dyskerin encoding gene, functions in telomerase activity and telomere maintenance. DKC1 mutations cause a multisystem disease, dyskeratosis congenita (DC), which is associated with immunodeficiency and bone marrow failure. In this research, we reported a novel intronic mutation of DKC1 causing dyskerin functional loss in a Chinese family. Whole exome sequence (WES) of the proband and validation by sanger sequencing help us identify a pathogenic DKC1 mutation. Minigene splicing assays were performed to evaluate functional change of DKC1. A pathogenic DKC1 intronic mutation(c.84 + 7A > G) was identified in the proband, which was inherited from heterozygous mother and not reported before. We detected the novel transcript with a 7 bp intron retention through minigene splicing assay. The newly spliced transcript is so short that would be degraded by nonsense-mediated mRNA decay in vitro and we infer that the novel DKC1 mutation would influences normal physiological function of dyskerin. Our study identified a novel intronic mutation, which expands the spectrum of pathogenic DKC1 gene mutations and can be used in molecular diagnosis. The mutant allele was transmitted to the next generation with high frequency in the family and causes still birth or early death.


[Immunodeficiency tuberculosis: report on 5 autopsy cases].
To improve the awareness of immunodeficiency tuberculosis. 5 autopsy cases of immunodeficiency tuberculosis from 1972 to 2000 in two hospitals were reviewed. The 5 cases were found to have hypoplasia of or damage in the thymus, among them 3 had massive tuberculous lymphadenitis lesions. Multiorgan lesions were found more in both lungs than in other organs, accompanied by lymphatic spread and blood dissemination. The microscopic feature was atypical tuberculosis with great amounts of Mycobacterium tuberculosis. Hypoplasia of or damage in the thymus and peripheral lymphoid tissue caused deficiency in the immune response, which resulted in the death of the patients with generalised tuberculosis by blood dissemination and lymphatic spread. The underlying mechanism of immunodeficiency tuberculosis is largely unknown, and further research is needed.


Hydration properties and potentials of mean force of nonpolar amino acid residues in water: a pertubation theoretic approach.
We use a perturbation approach to calculate the solute-solvent and solute-solute pair correlations for infinitely dilute solutions of nonpolar amino acid side chains in water. In particular, from the solute-solute correlations we derive potentials of mean force for all the distances between different residues of amino acids. Comparison with molecular dynamics simulations performed using GROMOS package shows that the goodness of the approximation varies with the amino acid considered. We discuss in terms of hydrophobicity the different effect that the inclusion of the attractions causes on the solute-water and solute-solute correlations.


Instrumented platforms for balance and proprioceptive assessment in patients with total knee replacement: A systematic review and meta-analysis.
The functional outcome of total knee replacement (TKR) is usually satisfying. However, patients may show functional limitations for years after surgery, which have been ascribed to impairments in balance and proprioception, mainly during standing tasks. A number of instrumentations and parameters have been used, rising confusion for clinical decisions on the assessment of patients. Which are the most widespread and consistent procedures to assess balance and proprioception following TKR? A literature review was conducted in Pubmed, PEDro, and Cochrane database. From a total sample of 112 articles, 23 original studies published between 2008 and 2019 met inclusion criteria. The primary outcomes selected were variables related to balance and proprioception assessment in static and dynamic tasks performed with instrumented platforms. Data from papers using the same instrumentation, on patients with unilateral TKA and at least 12 months postoperatively were synthesized quantitatively in a random effect meta-analysis. Fourteen articles were appropriate for the review. A large variability was found both in the instrumentation and the parameters used. The Neurocom Balance Master System™ was the most used instrument (four articles). On a total population of 186 patients with unilateral TKR 12 months postoperatively, a low degree of heterogeneity was found adopting the random effect in the four tasks explored (Firm and Foam Surface both with Eyes Open and Eyes Closed). This review found a large variability in the instrumentation used to assess balance and proprioception in patients operated on TKR. The meta-analysis demonstrated that the Neurocom Balance Master System™ for static assessment of balance showed an acceptable consistency and can be considered as a reference for further studies. However, balance and proprioception impairments following TKR have not been widely quantified by means of instrumented platforms. Further research is needed to address this issue, and improve clinical practice.


Significant variation in presentation of pulmonary tuberculosis across a high resolution of CD4 strata.
The human immunodeficiency virus (HIV) alters the presentation of pulmonary tuberculosis (PTB), but it remains unclear whether alterations occur at a CD4 cell threshold or throughout HIV infection. To better understand the relationship between CD4 count and clinical and radiographic presentation of PTB. Initial presentations of culture-confirmed PTB patients evaluated at a Ugandan national TB referral center and an affiliated research unit were compared by HIV status and across 11 CD4 cell count strata: 0-50 to >500 cells/μl. A total of 873 HIV-infected PTB cases were identified. Among HIV-infected PTB cases with CD4 < 50, 21% had a normal chest X-ray (CXR) vs. 2% with CD4 > 500, with a continuous trend across CD4 strata (test for trend, P < 0.001). All radiographic manifestations of PTB displayed significant trends across CD4 strata. HIV-infected vs. non-HIV-infected patients had no significant difference in CXR findings of miliary patterns or pleural effusion at CD4 > 100, normal CXR or fibrosis at CD4 > 150, adenopathy at CD4 > 250, and cavitation or upper lung disease at CD4 > 300. Twenty-three per cent of co-infected cases with CD4 < 50 and 1% with CD4 > 500 had negative acid-fast bacilli (AFB) smears, with a significant trend between (P < 0.001). Variations in CXR appearance and AFB smear correlate with CD4 decline in significant, continuous trends.


Late Relapses of Membranous Nephropathy: A Case Series.
Relapse of the nephrotic syndrome is co mmon among patients with primary membranous nephropathy (MN). Relapses of MN typically occur within a few years of achieving disease remission. There is limited description, to date, regarding patients with MN who have late relapse of MN, i.e., after >5 years of sustained disease remission. The objective of this case series was to report the clinical course of patients with MN who experience late relapse. We analyzed the patient database of the Glomerular Kidney Disease Center at Columbia University to identify patients seen at our center who had relapse of biopsy specimen-proven MN at least 5 years after achieving sustained disease remission. We identified 16 patients with late relapse of MN. The median time in sustained remission before relapse was 10.2 (range, 7-29.0) years. Ten patients (63%) were diagnosed with late relapse on the basis of laboratory monitoring alone, without clinical symptoms of the nephrotic syndrome. Fourteen patients (88%) received immunosuppression during their initial presentation and late relapse. Patients had favorable long-term renal outcomes over a median 21 (range, 12-56) year follow-up period, with 14 patients (88%) in remission at study conclusion and a median decline in eGFR per year of -0.63 (range, -6.3 to 17.5) ml/min per 1.73 m2 per year. This case series highlights a previously underappreciated, and likely rare, outcome of MN, namely, late relapse. Patients who experience late relapse, and who thus have a longer time in sustained remission, may have a more favorable long-term renal outcome.


Activation and differentiation antigen expression in B-cell non-Hodgkin's lymphoma.
In an attempt to establish whether extended immuno-phenotyping allows more accurate definition of subgroups of B-cell non-Hodgkin's lymphoma (NHL) we have stained a series of 145 cases with a large panel of monoclonal antibodies that recognize B-cell differentiation and activation antigens. No antigen was expressed by all cases. The B-cell histogenesis in many cases could be confirmed only by using a panel of immunoglobulin and pan B-cell markers. There was marked phenotypic heterogeneity within and between major groups of B-cell NHL as delineated by the Kiel classification although the differentiation antigens CD5 (lymphocytic and centrocytic NHL) and OKT10 (plasma cell tumours) were more often expressed by certain morphological groups. The activation antigens 4F2 and transferrin receptor were expressed more strongly and more often by high grade NHL but other activation antigens (CD23 and CD25) were not more frequently associated with these tumours. Extended phenotyping may be of value in improving the understanding of biological abnormalities and processes involved in B-cell NHL, but we conclude that a limited panel of markers (CD3, CD5, CD22, CD45, IgM, kappa, and lambda) should be sufficient for routine diagnosis and classification of most cases.


TRIM29 regulates the SETBP1/SET/PP2A axis via transcription factor VEZF1 to promote progression of ovarian cancer.
Ovarian cancer (OC) is a common gynecological malignant tumor that seriously endangers the health of women worldwide. Tripartite motif containing 29 (TRIM29) is a TRIM family member that is frequently overexpressed in OC. However, the specific role of TRIM29 in OC remains obscure. To investigate the underlying molecular mechanism, a global proteomics analysis identified SET binding protein 1 (SETBP1) as a crucial target of TRIM29. Subsequently, the SETBP1/SET/Protein phosphatase 2 (PP2A) axis was confirmed to be required for the recovery of cancer stem cell (CSC)-like phenotype suppressed by TRIM29 knockdown. Mechanistically, TRIM29 facilitated SETBP1 transcriptional activation via the VEZF1 transcription factor. More importantly, TRIM29 promoted VEZF1 mRNA translation by recruiting RNA binding protein BICC1 to its 3'UTR. The clinical significance was established by the association of TRIM29 and SETBP1 expression with clinicopathological features in OC samples. The SETBP1/SET/PP2A axis driven by TRIM29 via transcription factor VEZF1 is at least one of the primary mechanisms underlying TRIM29 maintenance of the CSC-like characteristics in OC.


Endogenous digoxin-like immunoreactivity in blood is increased during prolonged strenuous exercise.
Digoxin-like immunoreactive factors (DLIFs) in serum may represent endogenous cardiotropic agents. We determined if blood levels of these endogenous factors changed during prolonged strenuous exercise. Total and loosely protein-bound (LPB) DLIF were measured by radioimmunoassay in the serum of nine healthy subjects during prolonged exercise to exhaustion. Mean total and LPB serum levels of DLIF increased by 72% (580 to 945 pg/mL) and 63% (53 to 91 pg/mL) over baseline values in digoxin equivalents (p less than 0.01), respectively, after three hours of exercise at 70% of VO2max. The prevalent serum nonesterified fatty acids (arachidonic, linoleic, oleic, palmitic, and stearic acids) as well as hydrocortisone did not account for the observed elevations in DLIF. Percent left ventricular fractional shortening (%FS) and mean velocity of left ventricular circumferential fiber shortening (mVCF) measured echocardiographically were lower (-18.0% and -16.4%, respectively, p less than 0.05) after exercise as compared to prior to exercise. Cardiac left ventricular dysfunction as measured by %FS did correlate with blood levels of DLIF (r = -0.680, p less than 0.02). These observations may suggest a relationship between serum levels of DLIF and cardiac fatigue.


Comparative analysis of amino acid sequences from mesophiles and thermophiles in respective of carbon-nitrogen hydrolase family.
A comparative study of amino acid sequence and physicochemical properties indicates the affiliation of protein from the nitrilase/cyanide hydratase family. This family contains nitrilases that break carbon-nitrogen bonds and appear to be involved in the reduction of organic nitrogen compounds and ammonia production. They all have distinct substrate specificity and include nitrilase, cyanide hydratases, aliphatic amidases, beta-alanine synthase, and a few other proteins with unknown molecular function. These sequences were analyzed for different physical and chemical properties and to relate these observed differences to the thermostability properties, phylogenetic tree construction and the evolutionary relationship among them. In this work, in silico analysis of amino acid sequences of mesophilic (15) and thermophilic (archaea, 15 and bacteria, 15) proteins has been done. The physiochemical properties of these three groups of nitrilase/cyanide hydratase family also differ in number of amino acids, molecular weight, pI values, positively charged ions, i.e. Arg + Lys, aliphatic index and grand average of hydropathacity (GRAVY). The amino acid Ala (1.37-fold) was found to be higher in mesophilic bacteria as compared to thermophilic bacteria but Lys and Phe were found to be significantly high (1.43 and 1.39-fold, respectively) in case of thermophilic bacteria. The amino acids Ala, Cys, Gln, His and Thr were found to be significantly higher (1.41, 1.6, 1.77, 1.44 and 1.29-fold, respectively) in mesophilic bacteria as compared to thermophilic archaea, where Glu, Leu and Val were found significantly high (1.22, 1.19 and 1.26-fold, respectively).


Treating methicillin-resistant Staphylococcus aureus infections with compounded vancomycin preparations.
Methicillin-Resistant Staphylococcus aureus infections have been an ongoing problem with institutions. Unfortunately, the problem has crossed over into the community setting. Drug resistance develops so rapidly that it is difficult for drug manufacturers to develop new treatment options in a timely manner. Compounding pharmacists can help physicians treat their Methicillin-Resistant Staphylococcus aureus patients by assisting them in developing new dosage forms or therapies to treat these difficult infections and providing patient counseling to prevent infection.


Examining the dispensing patterns of antipsychotics in Australia from 2006 to 2018 - A pharmacoepidemiology study.
Antipsychotic medications can be prescribed in Australia by medical and nurse practitioners under the Pharmaceutical Benefits Scheme (PBS). The current pharmacoepidemiology study aims to determine the dispensing rates of antipsychotic medicines in Australia, and to produce and examine a time-trend of the dispensing patterns of these medicines. Dispensing counts of antipsychotic medication from 2006 to 2018 were accessed from the PBS dataset. All of the antipsychotic medicines dispensed were included for time trend analysis. Cumulative dispensing counts and defined daily dose (DDD) per 1000 concessional population days (DPD) were analysed for the purpose of time trend analysis. Sixteen antipsychotic medications were assessed and had a total cumulative dispensing count of 33, 732, 404. Olanzapine had the highest cumulative prescription count and Quetiapine experienced the highest average dispensing count and rate as determined by DPD. Twelve out of the sixteen medications were second-generation antipsychotics (SGAs). Overall, eleven out of the sixteen medications (aripiprazole, asenapine, brexpiprazole, clozapine, flupentixol, lurasidone, olanzapine, paliperidone, quetiapine, ziprasidone, zuclopenthixol) had an increase in both dispensing count and rate, as expressed per DPD. The current study highlights the increasing prescription rates of SGAs and the stagnation of FGA prescription among Australian health practitioners. This is observed through particularly large increase in the dispensing rates of Olanzapine and Quetiapine. Further interdisciplinary investigation is required to ensure that these medications are being prescribed under the appropriate medical rationale, particularly to groups that are vulnerable to the adverse effects of the medications.


Screening for breast cancer in Ghent, Belgium: first results of a programme involving the existing health services.
In 1992, a population-based breast cancer screening programme was initiated in the municipality of Ghent: all women aged 40-69 years were personally invited to attend a local radiology unit for a mammogram, after being examined by a general practitioner or gynaecologist of their choice. The results of history taking, clinical breast examination, first and second reading, further investigation and primary treatment were registered. In total, 24.3% of the eligible population was screened in the period 1992-1994. The recall and biopsy rates were 2.9% and 1.4%, respectively. The cancer detection rate was 8.1 per 1000 women screened. Of all cancers detected, 88.0% (66/75) were invasive. Of these, 35.9% (23/64) measured 10 mm or less in diameter. The benign to malignant biopsy ratio was 0.7. Apart from the low participation, these results suggest that the programme is effective, compared with reference standards and the results of other studies.


Dominance of pressure natriuresis in acute depressor responses to increased renal artery pressure in rabbits and rats.
Increasing renal artery pressure (RAP) activates pressure diuresis/natriuresis and inhibits renal renin release. There is also evidence that increasing RAP stimulates release of a putative depressor hormone from the renal medulla, although this hypothesis remains controversial. We examined the relative roles of these antihypertensive mechanisms in the acute depressor responses to increased RAP in anaesthetized rabbits and rats. In rabbits, an extracorporeal circuit was established which allows RAP to be set and controlled without direct effects on systemic haemodynamics. When RAP was maintained at approximately 65 mmHg, cardiac output (CO) and mean arterial pressure (MAP) did not change significantly. In contrast, when RAP was increased to approximately 160 mmHg, CO and MAP fell 20 +/- 5 % and 36 +/- 5 %, respectively, over 30 min. Urine flow also increased more than 28-fold when RAP was increased. When compound sodium lactate was infused intravenously at a rate equal to urine flow, neither CO nor MAP fell significantly in response to increased RAP. In 1 kidney-1 clip hypertensive rats, MAP fell by 54 +/- 10 mmHg over a 2 h period after unclipping. In rats in which isotonic NaCl was administered intravenously at a rate equal to urine flow, MAP did not change significantly after unclipping (-14 +/- 9 mmHg). Our results suggest that the depressor responses to increasing RAP in these experimental models are chiefly attributable to hypovolaemia secondary to pressure diuresis/natruresis. These models therefore appear not to be bioassays for release of a putative renal medullary depressor hormone.


Changes in physical activity during the COVID-19 lockdown based on the sociodemographic profile of 5569 students and academic staff of Austrian universities.
The COVID-19 pandemic and the associated restrictions/lockdowns have influenced the health and lifestyle behaviour of university students and staff, particularly their physical activity (PA) habits. However, the association between the direction of PA changes and sociodemographic characteristics has not been studied. This nationwide study was conducted in Austrian colleges/universities and aimed to identify the magnitude and direction of changes in PA levels during the COVID-19 restrictions and compare participants who had unchanged vs decreased vs increased PA based on sociodemographic characteristics (sex, age, body mass index, study level, living area, nationality and Austrian regions). This was a cross-sectional study to measure the association between the explanatory variable and outcome measures. A total number of 4528 students (mean age 24.9 years) and 1041 academic staff (mean age 46.4 years) participated in an online survey and provided self-reported data on sociodemographic characteristics and PA change during the pandemic. A total of 41.3% of students and 37.5% of academic staff reported a decrease in PA level, whereas PA levels increased in 36.3% and 27.9%, respectively. In students, all sociodemographic variables (including sex, age, body mass index, study level, living area, nationality and Austrian regions) were significantly associated with the direction of PA changes (P < 0.05). Living area and Austrian region were found to be significant indicators of direction of PA changes in academic staff (P < 0.05). These findings suggest that the inconsistency of previous studies in PA change during the pandemic may at least partly be explained by differences in the sociodemographic characteristics of the participants.


Interneuronal transfer of axonally transported proteins: studies with HRP and HRP conjugates of wheat germ agglutinin, cholera toxin and the B subunit of cholera toxin.
Experiments in the visual system and the tongue-hypoglossal nucleus pathway of the rat with HRP and HRP conjugates of wheat germ agglutinin (WGHRP), cholera toxin (CTHRP) and the B subunit of cholera toxin (BHRP) were conducted to study the interneuronal transfer of proteins. Native HRP did not undergo such transfer. Intravitreal injections of WGHRP, CTHRP or BHRP all resulted in interneuronal transfer in the visual system, but there was no evidence for this in the tongue-hypoglossal nucleus pathway. Interneuronal transfer may: (1) require a ligand-cell surface interaction; and (2) occur only after the endocytosis and/or exocytosis of these conjugates at specific sites along the neuronal plasma membrane.


The structure of the NuA4-Tip60 complex reveals the mechanism and importance of long-range chromatin modification.
Histone acetylation regulates most DNA transactions and is dynamically controlled by highly conserved enzymes. The only essential histone acetyltransferase (HAT) in yeast, Esa1, is part of the 1-MDa NuA4 complex, which plays pivotal roles in both transcription and DNA-damage repair. NuA4 has the unique capacity to acetylate histone targets located several nucleosomes away from its recruitment site. Neither the molecular mechanism of this activity nor its physiological importance are known. Here we report the structure of the Pichia pastoris NuA4 complex, with its core resolved at 3.4-Å resolution. Three subunits, Epl1, Eaf1 and Swc4, intertwine to form a stable platform that coordinates all other modules. The HAT module is firmly anchored into the core while retaining the ability to stretch out over a long distance. We provide structural, biochemical and genetic evidence that an unfolded linker region of the Epl1 subunit is critical for this long-range activity. Specifically, shortening the Epl1 linker causes severe growth defects and reduced H4 acetylation levels over broad chromatin regions in fission yeast. Our work lays the foundations for a mechanistic understanding of NuA4's regulatory role and elucidates how its essential long-range activity is attained.


The necessary role of the autopsy in cardiovascular epidemiology.
The autopsy rate in the United States today is remarkably low, with proportionally fewer autopsies for natural causes of death. Consequently, most cardiovascular epidemiology studies do not use autopsy data and rely on death certificates, medical records, questionnaires, and family interviews as sources of mortality information. These practices introduce a high degree of variability and uncertainty regarding cause of death. This review illustrates the necessity for increased use of autopsies in cardiovascular epidemiology by critically evaluating other measures of cardiovascular disease (CVD) incidence. We evaluated the literature regarding CVD as cause of death and conducted discussions with cardiologists, pathologists, and epidemiologists. No attempt was made for meta-analysis. This review shows the limited reliability of death certificates, medical records, and interviews as sources of mortality statistics. In addition, the autopsy's role in clearly indicating the presence of CVD is illustrated. The autopsy used in conjunction with medical records is the only reliable means for establishing cause of death from CVD. There is an urgent need to reassess the current dependence of statistical mortality data on death certificates and other inadequate sources of CVD incidence. Death certificates, in general, are inadequately monitored for quality control and appropriate administrative oversight. With an increase in the number of hospitals performing no autopsies to investigate cause of death, a uniform national autopsy database is needed.


Analysis of an anaesthetic gas scavenging system hazard.
The collapse of the reservoir bag in a circle circuit was observed during anaesthesia. This resulted from the incomplete closure of the pressure relief valve on the absorber whie it was connected to the scavenging system. Although the scavenging system was operating and installed according to the manufacturer's recommendations and to the CSA standard on Anaesthetic Gas Scavenging Systems (Z168.8), the patient was not protected from this hazard. Introducing an air break into the scavenging interface device will protect the patient. However, such a system would not meet the CSA standard and would make the relief valves on the scavenging interface device unnecessary.


Paper-assisted ratiometric fluorescent sensors for on-site sensing of sulfide based on the target-induced inner filter effect.
Dissolved sulfide tends to species transformation and loss upon leaving the matrix, thus the development of a practical on-site determination of sulfide is crucial for environmental monitoring and human health. In this work, a novel paper-based ratiometric fluorescence sensor was developed for the field analysis of sulfide, which system was constructed by the inner filter effect (IFE) of CdS quantum dots (QDs) toward carbon dots (C-dots). Instead of an aqueous phase system, the conversion of sulfide to its hydride would induce the in-situ formation of CdS QDs on the paper, which acted as an energy acceptor to quench the emission of C-dots, leading to a variation of ratiometric fluorescence from blue to yellow with the increasing concentration of sulfide. Moreover, we proposed a smartphone-based fluorescence capture device integrated with a programmed Python program, accomplishing both color recognition and accurate detection of sulfide. Under the optimal condition, this ratiometric fluorescence sensor allowed for the on-site analysis of sulfide with a limit of detection of 0.05 μM. The accuracy of the sensor was validated via the successful field analysis of environmental water samples with satisfactory recoveries. Compared to other fluorescence methods used for sulfide analysis, this developed system retains the advantages of label-free, low-cost, ease of operation, and miniaturization, showing great potential for the measurement of sulfide on-site, as well as environmental monitoring.


Anaesthesia of small rodents during magnetic resonance imaging.
The use of experimental animals for magnetic resonance studies requires anaesthesia to provide immobility and acquire signals with minimal stress and maximal reproducibility. However, the conduct of anaesthesia within a magnetic resonance imaging (MRI) suite implicates many problems, because most of the anaesthetic and monitoring equipment contains ferromagnetic substances. To decrease disturbances during anaesthesia and make data interpretation more accurate, it is mandatory that investigators become familiar with methods and physiologic effects of anaesthesia under these special conditions. This article is intended to give an overview of anaesthetic medication, administration routes and practical instructions for anaesthesia in small rodents during MRI.


Innate immune memory in plants.
The plant innate immune system comprises local and systemic immune responses. Systemic plant immunity develops after foliar infection by microbial pathogens, upon root colonization by certain microbes, or in response to physical injury. The systemic plant immune response to localized foliar infection is associated with elevated levels of pattern-recognition receptors, accumulation of dormant signaling enzymes, and alterations in chromatin state. Together, these systemic responses provide a memory to the initial infection by priming the remote leaves for enhanced defense and immunity to reinfection. The plant innate immune system thus builds immunological memory by utilizing mechanisms and components that are similar to those employed in the trained innate immune response of jawed vertebrates. Therefore, there seems to be conservation, or convergence, in the evolution of innate immune memory in plants and vertebrates.


An audit of antiemetic use with CMF chemotherapy.
A two-stage retrospective audit of the efficacy of antiemetics used with intravenous cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 (CMF) chemotherapy for breast cancer has been performed in a single centre. The first audit stage examined emesis rates for 21 patients using a policy of metoclopramide and dexamethasone initially and reserving 5-HT3 antagonists for failure of this combination. Because of high failure rates, the policy was changed so that granisetron and dexamethasone were used in all patients. The second audit stage examined the effectiveness of this new policy in 28 patients. Nine of 21 patients (43%) in the first audit group changed from metoclopramide and dexamethasone because of nausea or vomiting. Emesis occurred in 15 out of 66 (23%) cycles of CMF when metoclopramide and dexmethasone were used. Only eight of 43 patients had emesis episodes with granisetron and dexamethasone (19%). Emesis occurred with only 16 of 206 CMF cycles with granisetron and dexamethasone (8%). The granisetron and dexamethasone combination is superior to metoclopramide and dexamethasone in the prophylaxis of CMF-induced nausea and vomiting, although it is more expensive. A reduced dose of granisetron, 1 mg rather than 3 mg, may allow similar control of emesis at reduced cost.


Alzheimer's team care approach-akin to diabetes-in the development, validation, and population assessment of retinal biomarkers for disease.
There exists a public health imperative to discover and to develop disease-modifying Alzheimer's disease (AD) therapeutics to protect the health of millions of individuals facing AD. Achievement of this goal will be dependent on developing the clinical tools to detect high risk, in the earliest phases of the disease, and at the population level. This article describes the study of retinal biomarkers for the identification of, and tracking of change over time for, individuals in the preclinical stage of AD and substantiates the need for a major cross-disciplinary effort for comparison across labs and clinical sites using diabetes risk monitoring as a perfect analogy. Proposed framework would: (1) support AD working groups across disciplines; (2) establish common imaging platforms to develop and test basic standards, and minimum datasets to embrace and test novel innovations as they emerge; and (3) accelerate AD prevention and quality improvement in real-world care.


Persistent megalocystic ovaries after ovarian hyperstimulation syndrome in a postpartum patient with polycystic ovarian syndrome: a case report.
Ovary enlargement is common in controlled ovarian stimulation, which could continue several months during a successful pregnancy. However, persistent megalocystic ovaries 3 years after ovarian hyperstimulation syndrome (OHSS) were rare. Here we will present you the case and treatment as well as discuss the probable etiology. A 34-year-old woman with polycystic ovarian syndrome (PCOS) and a history of infertility presented to the Department of Obstetrics and Gynecology at Peking Union Medical College Hospital with abdominal pain and persistently enlarged ovaries 36 months after OHSS. Enlarged ovaries were evaluated with ultrasonography and serum tests. Diagnostic laparoscopic surgery with detorsion and drainage followed by GnRHa treatment was performed. Symptoms and ovarian size evaluated by vaginal ultrasound were the main outcome measures. The patient was discharged from the hospital 5 days after surgery without any remarkable complications. Both ovaries recovered to almost normal after a monthly injection of GnRHa for 3 months. Ovarian enlargement may persist for a long time in patients with severe OHSS even after sex hormone levels and ovarian functions return to normal. Long term follow-up is necessary and ovarian torsion should be suspected when accompanied by abdominal pain. Acupuncture plus GnRHa treatment may be an effective way for these cases.


Effect of human mesenchymal stem cell secretome administration on morphine self-administration and relapse in two animal models of opioid dependence.
The present study investigates the possible therapeutic effects of human mesenchymal stem cell-derived secretome on morphine dependence and relapse. This was studied in a new model of chronic voluntary morphine intake in Wistar rats which shows classic signs of morphine intoxication and a severe naloxone-induced withdrawal syndrome. A single intranasal-systemic administration of MSCs secretome fully inhibited (>95%; p < 0.001) voluntary morphine intake and reduced the post-deprivation relapse intake by 50% (p < 0.02). Since several studies suggest a significant genetic contribution to the chronic use of many addictive drugs, the effect of MSCs secretome on morphine self-administration was further studied in rats bred as high alcohol consumers (UChB rats). Sub-chronic intraperitoneal administration of morphine before access to increasing concentrations of morphine solutions and water were available to the animals, led UChB rats to prefer ingesting morphine solutions over water, attaining levels of oral morphine intake in the range of those in the Wistar model. Intranasally administered MSCs secretome to UChB rats dose-dependently inhibited morphine self-administration by 72% (p < 0.001); while a single intranasal dose of MSC-secretome administered during a morphine deprivation period imposed on chronic morphine consumer UChB rats inhibited re-access morphine relapse intake by 80 to 85% (p < 0.0001). Both in the Wistar and the UChB rat models, MSCs-secretome administration reversed the morphine-induced increases in brain oxidative stress and neuroinflammation, considered as key engines perpetuating drug relapse. Overall, present preclinical studies suggest that products secreted by human mesenchymal stem cells may be of value in the treatment of opioid addiction.


What is the correct value for the brain--blood partition coefficient for water?
A knowledge of the brain-blood partition coefficient (lambda) for water is usually required for the measurement of CBF with [15O]water. The currently accepted value for whole-brain lambda, 0.95-0.96 ml/g, calculated from brain and blood water content data, is incorrect because in the calculation, the blood water content was not adjusted for the density of blood. The correct value is 0.90 ml/g. Variations in brain or blood water content affect lambda. Thus, lambda changes during development of the brain and varies regionally in it, even among different gray matter structures, owing to variation in brain water content. In addition, lambda would be expected to vary with the hematocrit, owing to changes in blood water content. The impact of using an incorrect value for lambda will depend on the sensitivity of the CBF measurement technique used to errors in lambda.


Validation of a fecal glucocorticoid assay for Steller sea lions (Eumetopias jubatus).
The Steller sea lion (Eumetopias jubatus) is listed as endangered in parts of its range and is suspected of suffering from ecological stressors that may be reflected by fecal glucocorticoid hormones. We validated a fecal glucocorticoid assay for this species with an adrenocorticotropic hormone (ACTH) challenge. Feces were collected from captive Steller sea lions (two males and two females) for 2 days before injection with ACTH, and for 4 or more days postinjection. Feces were freeze-dried, extracted with a methanol vortex method, and assayed for glucocorticoids. The assay demonstrated good parallelism and accuracy. All animals showed the expected peak of fecal glucocorticoid excretion after ACTH injection. However, the two males had higher baselines, higher peaks, and more delayed peaks than the females. Peak glucocorticoid excretion occurred at 5 and 28 h postinjection for the two females, and at 71 and 98 h for the two males. Correction for recoveries by the addition of tritiated hormones produced ACTH profiles that were virtually identical in pattern to uncorrected data, but with higher within-sample coefficients of variation. Based on these results, we conclude that this fecal glucocorticoid assay accurately reflects endogenous adrenal activity of Steller sea lions, and that recovery corrections are not necessary for this species when using the methanol vortex extraction method. More research is needed to address possible sex differences and other possible influences on fecal glucocorticoid concentrations.


Fresh Osteochondral Allograft Transplantation for Treatment of Articular Cartilage Defects of the Knee.
Articular cartilage damage of the knee can cause severe morbidity. Owing to its avascular nature, articular cartilage has limited potential for self-healing and increased propensity to progress to osteoarthritis. Treatment of large, full-thickness cartilage defects is still a challenge for orthopaedic surgeons but has recently achieved high success rates with the use of osteochondral allografts. This article details our technique of osteochondral allograft transplantation for the treatment of articular cartilage defects of the knee.


Non-invasive cell-tracking methods for adoptive T cell therapies.
Adoptive T cell therapies (ACT) have demonstrated groundbreaking results in blood cancers and melanoma. Nevertheless, their significant cost, the occurrence of severe adverse events, and their poor performance in solid tumors are important hurdles hampering more widespread applicability. In vivo cell-tracking allows instantaneous and non-invasive monitoring of the distribution, tumor homing, persistence, and redistribution to other organs of infused T cells in patients. Furthermore, cell-tracking could aid in the clinical management of patients, allowing the detection of non-responders or severe adverse events at an early stage. This review provides a concise overview of the main principles and potential of cell-tracking, followed by a discussion of the clinically relevant labeling strategies and their application in ACT.