Mitochondrial DNA mutations in Japanese patients with optic neuropathy unassociated with a mutation at nucleotide position 11,778.
We examined for mitochondrial DNA (mtDNA) mutations at nucleotide positions(nt) 3460, 14,484, 9438, 9804, and 15,257 in ten Japanese patients with idiopathic optic neuropathy unassociated with a mutation at nt11,778. The mtDNAs were amplified by polymerase chain reaction (PCR), the products were digested with restriction enzymes, and the sizes of the fragments were analyzed on 8% polyacrylamide gel. Of the ten patients, one had an mtDNA mutation at nt3460 and another patient had a mutation at nt14,484. We suggest that mtDNA mutations in Japanese patients with optic neuropathy unassociated with a mutation at nt11,778 should be further investigated.


Effects of race and ethnicity on depression treatment outcomes: the CO-MED trial.
The investigators examined whether outcomes differ by race-ethnicity for patients with major depressive disorder in acute- (12 weeks) and continuation-phase (weeks 12-28) treatment with one of two antidepressant combinations or one selective serotonin reuptake inhibitor. This single-blind, seven-month prospective, randomized trial enrolled 352 non-Hispanic white (59%), 169 black (28%), and 79 white Hispanic (13%) participants from six primary and nine psychiatric care U.S. sites. Patients had nonpsychotic chronic or recurrent major depressive disorder (or both) of at least moderate severity. Escitalopram plus placebo, bupropion sustained-release plus escitalopram, or venlafaxine extended-release plus mirtazapine were delivered according to measurement-based care. The primary outcome was remission (last two consecutive 16-item Quick Inventory of Depressive Symptomatology-Self-Report ratings <8 and <6); secondary outcomes included side effects, adverse events, quality of life, function, and attrition. Black participants had greater baseline psychiatric and medical comorbidity. Baseline depression severity did not significantly differ between groups. In both phases more blacks than those in other groups exited the trial early. There were only minor differences in side effects, no significant differences in remission rates, and no significant differences between groups in other outcomes for each treatment. Despite differences in sociodemographic characteristics and comorbidities, when measurement-based care was used, members of different minority groups had similar outcomes when treated with one antidepressant or a combination of two antidepressants. Black participants had the highest attrition rate, an important issue to address in clinical care.


Functional relevance of nonsynonymous mutations in the HIV-1 tat gene within an epidemiologically-linked transmission cohort.
Here we investigated the nature and functional consequences of mutations in the HIV-1 tat gene within an epidemiologically-linked AIDS transmission cohort consisting of a non-progressing donor (A) and two normal progressing recipients (B and C). Multiple nonsynonymous mutations in the tat first exon were observed across time in all individuals. Some mutations demonstrated striking host specificity despite the cohort being infected with a common virus. Phylogenetic segregation of the tat clones at the time of progression to AIDS was also observed especially in recipient C. Tat clones supporting high levels of transactivation were present at all time points in all individuals, although a number of clones defective for transactivation were observed for recipient C in later time points. Here we show that the tat quasispecies in a linked transmission cohort diversify and evolve independently between hosts following transmission. It supports the belief that quasispecies variation in HIV-1 is a mechanism for selection towards defining a fitter gene variant that is capable of resisting the human immune system.


Physicochemical properties of alkaline serine proteases in alcohol.
The alkaline proteases subtilisin Carlsberg and alcalase possess substantial enzymatic activity even when dissolved in ethanol. The crude enzymes were purified by gel filtration and the main fractions suspended in ethanol to give a translucent suspension. Both the supernatant and the resuspended precipitate after high-speed centrifugation were found to have enzymatic activities. The solubility of subtilisin Carlsberg in anhydrous ethanol was found to be 45.1 micrograms/ml and that of alcalase was 48.1 micrograms/ml by Coomassie blue dye-binding method using bovine serum albumin as a standard. In the presence of water, the solubility of both enzymes increased with water content. The stability of enzymes incubated in ethanol was assayed by their amidase and transesterase activities using Ala-Ala-Pro-Phe-pNA as substrate in phosphate buffer (pH8.2) and Moz-Leu-OBzl as substrate in anhydrous ethanol, respectively. The soluble enzymes have a half-life of about 36 hr and that of suspended enzymes about 50 hr in the amidase activity assay, whereas the same soluble enzymes have a half-life of about several hours and that of suspended enzymes 1 h by the transesterase activity assay. The stability of both enzymes decreased as water concentration increased. The diastereoselectivity of the enzyme-catalyzed hydrolysis of diastereo pairs of tetrapeptide esters, L-Ala-L-Ala-(D- or L-)Pro-L-Phe-OMe and L-Ala-L-Ala-(D- or L-)Ala-L-Phe-OMe, in phosphate is as high as that of the transesterification of these substrates in ethanol. It is concluded that active sites and selectivity of alkaline serine proteases in anhydrous alcohol are probably very similar to those in aqueous solution in spite of the fact that a lower reactivity is usually associated with the enzymes in nonaqueous solvents.


Increased Expression of Aquaporin-1 and Aquaporin-3 in Pterygium.
Recent studies have shown that aquaporins (AQPs) play an important role in proliferating tumor microvessels and angiogenesis. In this study, the authors investigated the expression of aquaporin-1 (AQP1) and aquaporin-3 (AQP3) in pterygial and normal conjunctival tissues. Fifteen patients with pterygium were enrolled in the study. Pterygium was excised, and a conjunctival rotational flap or autograft was inserted. Normal conjunctival tissue was obtained from the flap or graft. Western blot analysis was performed to assess the expression of AQP1 and AQP3 in pterygial and normal conjunctival tissues. Tissue localization of AQP1 and AQP3 was determined by immunohistochemical analysis. AQP1 and AQP3 are localized in the epithelial and subepithelial regions in pterygial and normal conjunctival tissues. Protein expression of both AQP1 and AQP3 was elevated in pterygia when compared with conjunctival tissues. The significant increase in protein expression of AQP1 was 3-fold in pterygium over normal conjunctiva (P = 0.004) and 2-fold increase in AQP3 expression of pterygium was detected (P = 0.02) according to densitometric analysis. Elevated protein expression of AQP1 and AQP3 was observed in pterygial tissues when compared with normal conjunctiva. The data suggest that the increased expression of AQP1 and AQP3 in pterygial tissues may be involved in the pathogenesis of pterygia, and therefore, AQP1 and AQP3 are potential therapeutic targets for preventing or delaying the progression of the disease.


Hollow waveguide quantum cascade laser spectrometer as an online microliter sensor for gas chromatography.
An optical absorption sensor for gas chromatography (GC) is presented. It consists of a quantum cascade laser along with a long piece of Hollow Waveguide for Infrared (HWIR) transmission inserted into the GC line. It measures the infrared absorption in each individual gas peak after separation by the GC column, and maintains the shapes of gas peaks after the HWIR sensor, making the gas samples further available for other sensors. By adding an inline combustion module before the HWIR sensor, the concentrations of many carbon containing compounds can be acquired by measuring CO2 absorption in their peaks. The HWIR sensor detects isotopologues of CO2 separately, and therefore can be used to measure carbon isotope ratios of heavy compounds. Application of the HWIR sensor to the detection of 13CO2 and CDH3 is described.


Gain of androgen receptor gene copies in primary prostate cancer due to X chromosome polysomy.
Prostate cancer is an androgen dependent tumor. In advanced prostate cancers androgen deprivation has proved to be an effective therapy, but 25% show no response. In this study prostatectomy specimens from patients without preoperative therapy were analyzed to determine the possible mechanism of primary antiandrogen resistance. The number of androgen receptor (AR) gene copies and X-centromeres were investigated from 80 prostate cancer specimens by FISH analysis. In 9 out of 80 prostate cancers additional X-chromosomes with the corresponding AR gene could be detected. Polysomy of the X-chromosome correlates with pathological classification and tumor volume. Additional AR genes due to polysomy of the X-chromosome are present in a subgroup of primary prostate cancers prior to antiandrogen therapy. Because the growth of prostate cancers is androgen dependent, these specimens may have an advantage in low concentrations of androgens. This may be a factor for initial antiandrogen resistance.


Property-activity relationship between physicochemical properties of PM2.5 and their activation of NLRP3 inflammasome.
Air pollution is becoming severe environment factor affecting human health. More and more research has indicated that fine particulate matter (PM2.5) plays a critical role in causing pulmonary inflammation or fibrosis, which potentially is ascribed to the activation of nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome. However, the underlying property-activity relationship between the physicochemical properties of PM2.5 and their activation of NLRP3 inflammasome remains unclear. Herein, various ways, such as metal chelation, organic extraction, ROS consumption, charge neutralization and particle dispersion, were applied to interfere with the effects of metal ion, polycyclic aromatic hydrocarbons (PAHs), reactive oxygen species (ROS), charge and size. It was found that aggregated size and PAHs could activate the NLRP3 inflammasome through lysosome rupture and potassium efflux, respectively. Metal ion, PAHs and surface ROS could also activate the NLRP3 inflammasome through mitochondrial ROS production. However, neutralization of PM2.5 with the negative surface charge could not relieve the activation of NLRP3 inflammasome. Furthermore, oropharyngeal aspiration of various modified PM2.5 were adopted to explore their effects on lung fibrosis, which showed the consistent results with those in cellular levels. Removal of metal ion, PAHs and ROS as well as reduction of size of PM2.5 could reduce collagen deposition in the lung tissue of mice, while the charge neutralization of PM2.5 increased this collagen deposition. This study provides great insights to clarify the property-activity relationship of PM2.5.


Gold nanobipyramid colorimetric sensing array for the differentiation of strong aroma-type baijiu with different geographical origins.
It is of great significance to quickly and effectively distinguish strong aroma-type baijiu (SAB) with the largest baijiu market share and the most extensive production regions. Colorimetric sensor arrays based on gold nanobipyramids (AuNBPs) with extraordinary plasmonic properties were constructed for the differentiation of SAB from different geographical origins. The sensing strategy was based on silver deposition on different morphologies of AuNBPs under different reducing conditions containing amino or hydroxyl groups. The deposition process can be effective for distinguishing differences in baijiu due to the chemical interaction between the trace ingredients in baijiu and reductants. The colorimetric sensor arrays were implemented for the response of the main ingredients and further used for the differentiation of SAB from different regions by linear discriminant analysis. The results showed that the sensing strategy had excellent performance in distinguishing SAB from different origins, and provides a promising application strategy for baijiu quality control.


Small bowel obstruction from barbed suture following laparoscopic myomectomy-A case report.
Myomectomy is commonly performed for symptomatic fibroids in women who wish to conserve fertility. Laparoscopic myomectomy provides advantages as a minimally invasive procedure. To facilitate the closure of the uterine wound after enucleation of the fibroid, barbed sutures have been introduced as they can shorten the operative time and reduce the amount of bleeding. However, the use of barbed suture is not without risk. There were a few reports on the risks of barbed sutures in the literature. We report herein a case of acute abdomen because of small bowel entrapment and obstruction following the use of barbed suture in laparoscopic myomectomy. Surgeons using barbed suture in myomectomy should be vigilant on the possibility of this bowel complication whenever adverse clinical situation arises as the outcome could be serious if the condition was left unchecked.


DLA based compressed sensing for high resolution MR microscopy of neuronal tissue.
In this work we present the implementation of compressed sensing (CS) on a high field preclinical scanner (17.2 T) using an undersampling trajectory based on the diffusion limited aggregation (DLA) random growth model. When applied to a library of images this approach performs better than the traditional undersampling based on the polynomial probability density function. In addition, we show that the method is applicable to imaging live neuronal tissues, allowing significantly shorter acquisition times while maintaining the image quality necessary for identifying the majority of neurons via an automatic cell segmentation algorithm.


Moving beyond the arabidopsis-centric view of G-protein signaling in plants.
Heterotrimeric G-protein-mediated signaling is a key mechanism to transduce a multitude of endogenous and environmental signals in diverse organisms. The scope and expectations of plant G-protein research were set by pioneering work in metazoans. Given the similarity of the core constituents, G-protein-signaling mechanisms were presumed to be universally conserved. However, because of the enormous diversity of survival strategies and endless forms among eukaryotes, the signal, its interpretation, and responses vary even among different plant groups. Earlier G-protein research in arabidopsis (Arabidopsis thaliana) has emphasized its divergence from Metazoa. Here, we compare recent evidence from diverse plant lineages with the available arabidopsis G-protein model and discuss the conserved and novel protein components, signaling mechanisms, and response regulation.


Translating the new International IFOMPT Cervical Framework into a framework flowchart for clinical practice and education.
In 2020, a revised version of the International IFOMPT Cervical Framework was published. This framework provides both physical therapists and educators the necessary information to guide the assessment of the cervical spine region for potential vascular pathologies of the neck in advance of planned Orthopaedic Manual Therapy (OMT) interventions. The objective was to develop a framework flowchart which is useful in clinical practice and education to assist physical therapists to improve the safety of OMT, and apply this in a case report. The framework was developed in co-creation with manual therapy experts, researchers, educators in manual therapy, patients, medical specialists and the Manual Therapy Association in The Netherlands and Belgium. Manual therapists and patients tested the framework for intelligibility and usefulness. A framework flowchart is developed and presented, that is easy to use in both clinical practice and education. It is a visual representation of the sequence of steps and decisions needed during the process. A case description of a patient with neck pain and headache is added to illustrate the clinical usefulness of the framework flowchart. The framework flowchart helps physical therapists in their clinical reasoning to provide safe OMT interventions.


Large-Scale Databases and Portals on Cancer Genome to Analyze Chaperone Genes Correlated to Patient Prognosis.
Molecular chaperones, such as heat shock proteins (HSPs), have attracted attention as molecules involved in malignant events in cancers and are potential therapeutic targets and biomarkers for tumor therapy. Furthermore, mutations in chaperones can significantly impact cancer risk and prognosis. Bioinformatics is a particularly useful method for developing biomarkers as a practical consideration for the immediate clinical application of data. Many large-scale databases and portals on cancer genome are nowadays publicly available, including the International Cancer Genome Consortium (ICGC); The Cancer Genome Atlas (TCGA), renamed as Genomic Data Commons (GDC); Catalogue of Somatic Mutations in Cancer (COSMIC); and Cancer Cell Line Encyclopedia (CCLE). Referring to these databases, advanced web portals are publicized, including cBioPortal, Human Protein Atlas (HPA), Kaplan-Meier (KM) plotter, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), Genomics of Drug Sensitivity in Cancer (GDSC), and Dependency Map (DepMap). Here, we assemble these databases and portals to clarify what is available and useful for current cancer research and provide protocols to utilize the HPA, KM plotter, and GEPIA2 for studies on chaperone genes in cancer patients. Utilizing these portals will reveal the correlation between tumor subtype-specific high expression of chaperone genes and patient prognosis. Our protocols are useful to increase systematic awareness of chaperones and find new biomarkers for diagnosis and prognosis and new targets for anticancer drugs.


Thrombelastographic haemostatic status and antiplatelet therapy after coronary artery bypass surgery (TEG-CABG trial): assessing and monitoring the antithrombotic effect of clopidogrel and aspirin versus aspirin alone in hypercoagulable patients: study protocol for a randomized controlled trial.
Hypercoagulability, assessed by the thrombelastography (TEG) assay, has in several observational studies been associated with an increased risk of post-procedural thromboembolic complications. We hypothesize that intensified antiplatelet therapy with clopidogrel and aspirin, as compared to aspirin alone, will improve saphenous vein graft patency in preoperatively TEG-Hypercoagulable coronary artery bypass surgery (CABG) patients and reduce their risk for thromboembolic complications and death postoperatively. This is a prospective randomized clinical trial, with an open-label design with blinded evaluation of graft patency. TEG-Hypercoagulability is defined as a TEG maximum amplitude above 69 mm. Two hundred and fifty TEG-Hypercoagulable patients will be randomized to either an interventional group receiving clopidogrel 75 mg daily for three months (after initial oral bolus of 300 mg) together with aspirin 75 mg or a control group receiving aspirin 75 mg daily alone. Monitoring of antiplatelet efficacy and on-treatment platelet reactivity to clopidogrel and aspirin will be conducted with Multiplate aggregometry. Graft patency will be assessed with Multislice computed tomography (MSCT) at three months after surgery. The present trial is the first randomized clinical trial to evaluate whether TEG-Hypercoagulable CABG patients will benefit from intensified antiplatelet therapy after surgery. Monitoring of platelet inhibition from instituted antithrombotic therapy will elucidate platelet resistance patterns after CABG surgery. The results could be helpful in redefining how clinicians can evaluate patients preoperatively for their postoperative thromboembolic risk and tailor individualized postoperative antiplatelet therapy. Clinicaltrials.gov Identifier NCT01046942.


Selective termination, fetal reduction and analogical reasoning.
Analogical reasoning is a basic method in bioethics. Its main purpose is to transfer the rule from an existing or known situation to a new and problematic situation. This commentary applies the lifeboat analogy to the context of selective termination and fetal reduction. It turns out that the analogy is only partially helpful as the main principle in the case of selective termination is the procreative beneficence principle. However, the wide person-affecting form of this principle doubly justifies selective termination: i.e. one prevents the harm caused by the birth of an affected child and one increases the life chances of the remaining fetuses. I conclude, however, that all analogies are basically flawed since they assume that fetuses as such have interests. I argue that fetuses only have interests to the extent that they are potential future persons.


Genetic polymorphisms of glutathione S-transferases and the risk of adult brain tumors: a meta-analysis.
Studies investigating the association between genetic polymorphisms of glutathione S-transferases (GST) and risk of adult brain tumors have reported conflicting results. The rationale of this meta-analysis was to determine whether GST variants increase the susceptibility of adult brain tumors by pooling data. Two investigators independently searched the HuGENet database, MEDLINE, EMBASE, conference articles, and manually reviewed bibliographies of retrieved articles. Papers were included if they were observational studies investigating the influence of GSTM1, GSTT1, GSTP1 I105V, or GSTP1 A114V on the development of adult brain cancers. Potential sources of heterogeneity between studies were explored in a meta-regression. We identified eight eligible studies, which included 1,630 cases of glioma, 245 cases of meningioma, and 7,151 controls. Using the random effects model, there was no association between any of the GST variants and the risk of glioma [overall odds ratio (OR), 1.08; 95% confidence interval (95% CI), 0.95-1.22]. Subgroup analyses also showed no relationship between GST variants and histopathologic groups; the overall ORs were 1.13 (95% CI, 0.88-1.43) for high-grade glioma and 1.08 (95% CI, 0.76-1.55) for low-grade glioma. A random effects meta-regression suggested that the use of in-hospital controls produced larger effect estimates in glioma than the use of population controls (overall OR, 1.30; 95% CI, 1.03-1.65). The T1 null genotype was significantly associated with a risk of meningioma (OR, 1.95; 95% CI, 1.02-3.76), but the M1 variant was not. This study did not suggest any relationship between GST variants and risks of glioma; the T1 null genotype may influence the susceptibility of meningioma, but larger studies are needed to substantiate this relationship.


Characterization of regulatory sequences and nuclear factors that function in cooperation with the promoter of the human thymidylate synthase gene.
To identify the essential sequence of the promoter of the human thymidylate synthase (hTS) gene, deletion mutants were constructed and assayed for promoter activity. The essential sequence was located within 65 bp upstream from the major cap site and a sequence that reduces the promoter activity was found in a region upstream from the essential promoter sequence. We previously identified two DNA-binding nuclear factors, NF-TS2 and NF-TS3, that bind to a region around the site of initiation of translation of the hTS gene. In this study, we confirmed the binding site of these factors by gel mobility shift analysis and found that NF-TS2 is the major factor that binds to the hTS gene in HeLa cells, whereas NF-TS3 is the major factor in the TIG-1 line of human fibroblast cells. To clarify the function of these factors, we examined the effects of the binding of these factors on the promoter activity. Our findings suggest that the binding of NF-TS2 enhances the promoter activity of the hTS gene in HeLa cells, whereas the binding of NF-TS3 represses the activity of the same promoter in TIG-1 cells.


Novel imprint cytological classification is correlated with tumor spread through air spaces in lung adenocarcinoma.
Spread through air spaces (STAS) is a risk factor for local recurrence after sublobar resection in lung cancer patients. We recently proposed the novel Nakayama-Higashiyama imprint cytological classification (N-H classification) based on small-sized lung adenocarcinoma surgical specimens, which correlated with histological patterns and nodal involvement. This study aimed to evaluate the correlation between STAS and the N-H classification and to validate the N-H classification as an intraoperative predictor of the presence of STAS. We retrospectively analyzed 164 intraoperative imprint cytologies and their paired histologic specimens from patients undergoing surgical resection for lung adenocarcinoma in our institute in 2017-2019. Using the NH classification, imprint cytological findings were classified into 5 groups (Groups I to V) based on cell cluster shape, cell and nucleus size, and the existence of necrosis. We examined the characteristics of imprint cytology and STAS in the resected tissues and analyzed the relationship between them. Tumor STAS was observed in 29 (17.7 %) cases. The presence of STAS was significantly associated with the NH classification (P < 0.0001). STAS was present in 6 of 57 cases (10.5 %) in NH classification Group II, 11 of 42 cases (26.2 %) in Group III, and 12 of 28 cases (42.9 %) in Group IV/V; STAS was not observed in any case in Group I. Logistic regression analysis revealed that tumors with a ground glass opacity rate of <50 % on computed tomography (P = 0.00867) and Groups III-V of the NH classification (P = 0.00201) were significant independent predictors for STAS. Intraoperative imprint cytology with the N-H classification for lung adenocarcinoma is well correlated with the STAS status of the tumor and might have applications as an intraoperative predictive marker of STAS. This classification may be useful for intraoperative detection of STAS and in the decision-making process for the surgical procedure.


Leptin in relation to resumption of menses in women with anorexia nervosa.
Serum levels of leptin are decreased in underweight AN patients and increase with weight restoration. To assess the relationship of decreased leptin levels with other hormonal abnormalities in AN and to evaluate the possible role of increasing leptin levels, alone or in combination with other hormones, in the resumption of menses that accompanies weight gain, we studied cross-sectionally sixty-five consecutively enrolled AN patients. Subjects were divided in three groups: (I) underweight and amenorrheic; (II) weight-recovered but still amenorrheic; and (III) weight-recovered and eumenorrheic women. Patients in group I had decreased BMI, serum leptin, estradiol (E2), insulin-like growth factor 1 (IGF-1) and urinary growth hormone (GH) levels and increased sex hormone-binding globulin (SHBG) levels, compared to AN patients in groups II and III. Moreover, although no differences in leptin levels or BMI were observed between amenorrheic and eumenorrheic weight-recovered patients (groups II and III), free E2 and GH levels were higher (P<0.02) in weight-recovered, eumenorrheic women. Thus, it appears that leptin is a necessary, but not a sufficient, factor for the resumption of menses in AN patients.


Treatment of soft tissue sarcomas by preoperative irradiation and conservative surgical resection.
From 1970-1984, 114 patients with soft-tissue sarcomas received preoperative irradiation at U.T.M.D. Anderson Hospital. Two patients refused surgery and two had progressing disease and therefore did not proceed to surgery; in the remaining 110 patients, conservative surgical resections were performed 3-6 weeks following irradiation. Analysis of survival by histologic type, age, primary size, and histologic grade revealed a significant negative correlation with grade 3 and to a lesser extent to primary size greater than 15 cm. Eleven patients failed within the radiation portal for the primary, four in conjunction with distant metastases. Of the remaining seven, four were salvaged by further surgery for an ultimate primary-only failure rate of three. Distant metastasis occurred in 35 patients and was the major mechanism of treatment failure in this experience. Adjunctive chemotherapy was not used for the majority of patients and it remains to be seen if its routine employment in large, high-grade, lesions will diminish the deaths caused by distant metastases.


Getting boards on board: engaging governing boards in quality and safety.
As hospitals seek to drive rapid quality improvement, boards have an opportunity-and a significant responsibility--to make better quality of care the organization's top priority. "Six things all boards should do to improve quality and reduce harm" are recommended: (1) setting aims--set a specific aim to reduce harm this year; make an explicit, public commitment to measurable quality improvement; (2) getting data and hearing stories--select and review progress toward safer care as the first agenda item at every board meeting, grounded in transparency--and putting a "human face" on harm data; (3) establishing and monitoring system-level measures--identify a small group of organizationwide "roll-up" measures of patient safety that are continually updated and are made transparent to the entire organization and its customers; (4) changing the environment, policies, and culture--commit to establish and maintain an environment that is respectful, fair, and just for all who experience the pain and loss as a result of avoidable harm and adverse outcomes: the patients, their families, and the staff at the sharp end of error; (5) learning, starting with the board--develop the board's capability and learn about how "best-in-the-world" boards work with executive and medical staff leaders to reduce harm; (6) establishing executive accountability--oversee the effective execution of a plan to achieve aims to reduce harm, including executive team accountability for clear quality improvement targets.


The effectiveness of progressively increasing stimulation frequency and intensity to maintain paralyzed muscle force during repetitive activation in persons with spinal cord injury.
To compare the effectiveness of progressively increasing stimulation intensity, progressively increasing frequency, or progressively increasing both frequency and intensity on paralyzed quadriceps femoris muscle force maintenance during repetitive activation. Factorial design with different stimulation protocols as independent variables. A muscle performance laboratory. People (N=8) with spinal cord injury (SCI) (age, 14.63+/-1.77y). Not applicable. Number of contractions when the peak force was 90% or more of a subject's maximal twitch force. The protocol involving progressively increasing stimulation intensity and then frequency generated more successful contractions (189.88+/-53.33) than progressively increasing the frequency followed by intensity (122.75+/-26.56 contractions). Regardless of the order, progressively increasing both intensity and frequency generated more successful contractions than progressively increasing intensity (97 contractions) or frequency (62 contractions) alone. Our findings suggest that during repetitive electric activation, progressively increasing both stimulation frequency and intensity can produce more successful contractions than progressively increasing only frequency or intensity. These findings can help researchers and clinicians design more effective stimulation protocols for persons with SCI during functional electric stimulation applications.


LPS-induced cytokine production and expression of beta2-integrins and CD14 by peripheral blood mononuclear cells of patients with homozygous familial hypercholesterolemia.
It has been suggested that proinflammatory cytokines such as tumor necrosis factor-alpha (TNF) and interleukin-1beta (IL-1), as well as adhesion molecules such as beta2-integrins and CD14, play a role in the pathogenesis of atherosclerosis. Familial hypercholesterolemia (FH) is an autosomal disease in which defective or absent LDL receptors are the cause for extreme LDL concentrations and early development of atherosclerosis. We studied lipopolysaccharide-induced cytokine production and the expression of adhesion molecules by mononuclear cells of three homozygous FH patients and compared them with first-degree relatives and healthy controls. There was a tendency towards increased cytokine production by cells of FH patients, whereas the expression of adhesion molecules was not modified compared to controls. In addition, LDL-apheresis inhibited IL-1 and TNF production and the expression of CD11a, CD11b, CD11c and CD14 by the mononuclear cells of FH patients and this may be an additional beneficial effect of LDL-apheresis apart of decreasing LDL concentrations.


Controlling the molecular weights of polyethylene waxes using the highly active precatalysts of 2-(1-aryliminoethyl)-9-arylimino-5,6,7,8-tetrahydrocycloheptapyridylcobalt chlorides: synthesis, characterization, and catalytic behavior.
A series of 2-(1-aryliminoethyl)-9-arylimino-5,6,7,8-tetrahydrocycloheptapyridylcobalt chlorides were synthesized and characterized using FT-IR and elemental analysis, and the molecular structures of complexes , and were confirmed to present a pseudo-square-pyramidal or trigonal-bipyramidal geometry around the cobalt center using single-crystal X-ray diffraction. Upon activation with either methylaluminoxane (MAO) or modified methylaluminoxane (MMAO), all cobalt precatalysts gave high activities up to the level of 10(7) gPE mol(-1) (Co) h(-1) toward ethylene polymerization, being one of most active cobalt-based precatalysts. In comparison with cobalt analogues, the title precatalysts generally possessed longer lifetime along with good thermo-stability; moreover, the resultant polyethylenes were highly linear and unimodal in most cases.


High-Throughput Microfluidic Device for Rare Cell Isolation.
Enumerating and analyzing circulating tumor cells (CTCs)-cells that have been shed from primary solid tumors-can potentially be used to determine patient prognosis and track the progression of disease. There is a great challenge to create an effective platform that can isolate these cells, as they are extremely rare: only 1-10 CTCs are present in a 7.5mL of a cancer patient's peripheral blood. We have developed a novel microfluidic system that can isolate CTC populations label free. Our system consists of a multistage separator that employs inertial migration to sort cells based on size. We demonstrate the feasibility of our device by sorting colloids that are comparable in size to red blood cells (RBCs) and CTCs.


Formaldehyde-induced and spontaneous alterations in human hprt DNA sequence and mRNA expression.
Human lymphoblast mutants at the X-linked hprt locus have been examined by Southern blot, Northern blot and DNA sequence analysis. A previous study had shown that approximately a third of the spontaneously-arising mutants and half those induced by formaldehyde showed no alteration in restriction fragment pattern and thus were classified as point mutations. In this report, Northern blot analysis was used to show that these point mutants fall into 4 categories: normal size and amount of RNA, normal size but reduced amounts, reduced size of RNA or no RNA. Sequence analyses of cDNAs prepared from hprt mRNAs were performed on 1 spontaneous and 7 formaldehyde-induced mutants with normal Northern blots. The spontaneous mutant was caused by an AT----GC transition. 6 of the formaldehyde-induced mutants were base substitutions, all of which occurred at AT base-pairs. There was an apparent hot spot, in that 4/6 independent mutants were AT----CG transversions at one specific site. The remaining mutant had lost exon 8.


The heterogeneity of the serum activity of gamma-glutamyl transpeptidase in hepatobiliary diseases as studied by agarose gel electrophoresis.
Using electrophoresis on agarose gel, the serum activity of gamma-GT in various hepatobiliary diseases has been separated into several electrophoretic fractions. Predominance of activity was always found in fractions corresponding to either alpha1-, alpha2- or beta-globulins. The predominant activity fractions have been related to the various disease states and to the zymogram patterns of gamma-GT found in bile and tissue homogenates of liver, bile duct and pancreas. Bile disclosed activity in the beta-region, tissue homogenates of liver mostly in the alpha1- and alpha2- areas, bile dict showed very faint activity in the alpha1- position, while extracts of pancreas revealed activity in the regions of alpha2, alpha2-beta and beta-gamma. In serum, dominance of alpha1-activity was found in all cases associated with alcoholism and alcoholic cirrhosis, this activity also appeared as the most frequent dominant one in biliary obstruction. Predominance of alpha2 and/or the beta-fraction in most cases occurred associated with malignant processes involving liver and/or pancreas.


Outcome of ventriculoperitoneal shunt and predictors of shunt revision in infants with posthemorrhagic hydrocephalus.
Ventriculoperitoneal (VP) shunts in infants with posthemorrhagic hydrocephalus (PHH) are prone to failures, with some patients at risk for multiple revisions. The objective of our study is to observe long-term outcomes and identify factors leading to proximal and distal multiple failures. We performed a retrospective review of infants with PHH that required VP shunt placement between 1982 and 2014. These patients were monitored clinically and radiographically after VP shunt placement. A total of 502 surgical procedures (initial shunt insertion and revisions) were performed, with 380 shunt revisions in 102 (84 %) patients. Median shunt survival time was 54 months (0.03-220 months). Shunt survival was significantly affected by the following factors: intraventricular hemorrhage (IVH, grade II-III, 95 months vs. grade IV, 28 months, p = 0.022), birth weight (<1.5 kg, 59 months vs. >1.5 kg, 22 months, p = 0.005), gestational age (>27 weeks, 90 months vs. <27 weeks, 20 months, p < 0.0001), distal vs. proximal revision (133 months vs. 48 months, p = 0.013), obstruction (yes, 78 months vs. no, 28 months, p = 0.007), and infection (no, 75 months vs. yes, 39 months, p = 0.045). Regression analysis revealed that multiple gestation, head circumference (>27 cm), congenital anomalies, infection, and obstruction increased the proximal and distal shunt malfunction. Long-term outcome of VP shunt placement in infants revealed a relatively high rate of complications requiring shunt revision as late as 30 years after initial placement. Infants with VP shunts should be monitored lifelong of these patients by neurosurgeons.


Peroxisome Proliferator-Activated Receptor-gamma in Amyotrophic Lateral Sclerosis and Huntington's Disease.
Amyotrophic lateral sclerosis (ALS) is a debilitating and one of the most common adult-onset neurodegenerative diseases with the prevalence of about 5 per 100 000 individuals. It results in the progressive loss of upper and lower motor neurons and leads to gradual muscle weakening ultimately causing paralysis and death. ALS has an obscure cause and currently no effective treatment exists. In this review, a potentially important pathway is described that can be activated by peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists and has the ability to block the neuropathological damage caused by inflammation in ALS and possibly in other neudegenerative diseases like Huntington's disease (HD). Neuroinflammation is a common pathological feature in neurodegenerative diseases. Therefore, PPAR-gamma agonists are thought to be neuroprotective in ALS and HD. We and others have tested the neuroprotective effect of pioglitazone (Actos), a PPAR-gamma agonist, in G93A SOD1 transgenic mouse model of ALS and found significant increase in survival of G93A SOD1 mice. These findings suggest that PPAR-gamma may be an important regulator of neuroinflammation and possibly a new target for the development of therapeutic strategies for ALS. The involvement of PPAR-gamma in HD is currently under investigation, one study finds that the treatment with rosiglitazone had no protection in R6/2 transgenic mouse model of HD. PPAR-gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator that works together with combination of other transcription factors like PPAR-gamma in the regulation of mitochondrial biogenesis. Therefore, PPAR-gamma is a possible target for ALS and HD as it functions as transcription factor that interacts with PGC-1alpha. In this review, the role of PPAR-gamma in ALS and HD is discussed based on the current literature and hypotheses.


Postoperative bronchopleural fistula repair: Surgical outcomes and adverse factors for its success.
The purpose of this study was to investigate the results of postoperative bronchopleural fistula repair and to identify adverse factors for its success. We retrospectively reviewed the surgical results of 39 patients who underwent surgical repair for postoperative bronchopleural fistula between January 2010 and June 2020. Success of bronchopleural fistula repair was defined as the visual closure of the bronchopleural fistula with the absence of an air leak, a recurrence of bronchopleural fistula and infection in the thoracic cavity. Twenty-five (64.1%) bronchopleural fistulas occurred after pulmonary resection and 14 (35.9%) after lung transplantation. Bronchopleural fistula was diagnosed 19 days (median) and repaired 28 days (median) after the initial operation by primary closure in 27 (69.2%) patients, and by additional resection in 12 (30.8%) patients. The overall success rate was 59% (23/39) and the overall mortality was 56.4% (22/39). Multivariable analysis revealed that the patients who were supported by mechanical ventilation at the time of repair had significantly lower success rates than those without (15.4%, 2/13 vs. 80.8%, 21/26, respectively, p < 0.001). The omental flap group tended to have a better success rate than the muscle flap group (p = 0.07). There was a high overall mortality rate after bronchopleural fistula repair and a low success rate. Mechanical ventilation at the time of bronchopleural fistula repair was significantly related to the failure of bronchopleural fistula repair.


Optimization of a duplex amplification and sequencing strategy for the HVI/HVII regions of human mitochondrial DNA for forensic casework.
A duplex primer set for the amplification of mitochondrial DNA HVI and HVII control regions was evaluated for the optimization of a DNA sequencing protocol suitable for forensic casework. HVI and HVII products, with the absence of non-specific products, could be detected by agarose gel electrophoresis when as little as 0.5 and 0.1pg of DNA were amplified for 34 and 38 cycles, respectively. Because HVI and HVII amplicons are co-synthesized in the duplex PCR, fewer steps are required (lessening the risk of cross contamination events) and more frugal use of precious extracted DNA samples is possible, both desirable features for forensic casework. The ABI Prism BigDyetrade mark version 1.1 chemistry provided high quality sequencing data, with little or no background noise and uniform peak heights, outcomes that favored reliable detection of heteroplasmy, particularly at early sequence reads (<40 bases). Optimal compromise between sensitivity and sequence accuracy in the absence of noise was achieved starting at 150 mitochondrial genome copies. The protocol is effective (no sequence errors) with highly degraded DNA (average detectable template size of 200bp). Dual artificial template mixtures with the minor component at 15% suggests that heteroplasmy should be detected at this level with confidence.


Multiple bradykinin-related peptides from the capture web of the spider Nephila clavipes (Araneae, Tetragnatidae).
Three bradykinin-related peptides (nephilakinins-I to -III) and bradykinin itself were isolated from the aqueous washing extract of the capture web of the spider Nephila clavipes by gel permeation chromatography on a Sephacryl S-100 column, followed by chromatography in a Hi-Trap Sephadex-G25 Superfine column. The novel peptides occurred in low concentrations and were sequenced through ESI-MS/MS analysis: nephilakinin-I (G-P-N-P-G-F-S-P-F-R-NH2), nephilakinin-II (E-A-P-P-G-F-S-P-F-R-NH2) and nephilakinin-III (P-S-P-P-G-F-S-P-F-R-NH2). Synthetic peptides replicated the novel bradykinin-related peptides, which were submitted to biological characterizations. Nephilakinins were shown to cause constriction on isolated rat ileum preparations and relaxation on rat duodenum muscle preparations at amounts higher than bradykinin; apparently these peptides constitute B2-type agonists of ileal and duodenal smooth muscles. All peptides including the bradykinin were moderately lethal to honeybees. These bradykinin peptides may be related to the predation of insects by the webs of N. clavipes.


[Value of autocrine motility factors in the prediction of the disease progression of PBC- associated hepatocellular carcinoma].
Objective: To clarify the value of autocrine motility factor (ATX) in predicting the disease progression of primary biliary cholangitis (PBC)-associated hepatocellular carcinoma (HCC). Methods: A prospective cohort of 179 newly diagnosed autoimmune liver disease (PBC) patients admitted to the Department of Hepatology at the Fifth Medical Center of the People's Liberation Army General Hospital from January 2016 to January 2018 was selected. All PBC patients received ursodeoxycholic acid (UDCA) treatment and were followed up.The endpoint of the follow-up was the occurrence of primary liver cancer. The relationship between ATX and the clinical characteristics of patients and its significance in predicting disease progression and HCC were analyzed. Results: The peripheral blood ATX level was significantly higher in PBC patients than that of alcoholic cirrhosis (t = 3.278, P = 0.001) and healthy controls (t = 6.594, P < 0.001), but there was no significant difference in ATX levels compared with patients with non-PBC- associated HCC (t = -0.240, P = 0.811). The expression of ATX in liver tissue of PBC patients was significantly higher than that of healthy individuals (Z = -3.633, P < 0.001) and patients with alcoholic cirrhosis (Z = -3.283, P < 0.001), while the expression of ATX in the advanced stage was significantly higher than that in early-stage PBC patients (Z = -2.018, P = 0.034). There was a significant difference in baseline ATX levels between PBC patients without HCC and PBC patients with HCC (228.451 ± 124.093 ng/ml vs. 301.583 ± 100.512 ng/ml, t = 2.339, P = 0.021). Multivariate logistic regression analysis showed that ATX was an independent predictor of PBC progression to HCC (OR = 1.245, 95%CI 1.097-1.413). The baseline peripheral blood ATX level in predicting AUROC of PBC-associated HCC was 0.714, 95%CI 0.597-0.857 and the sensitivity and specificity were 84.6%, and 59.0%, respectively. The optimal cutoff value for predicting serum ATX levels in the occurrence of HCC was 235.254 ng/ml. Conclusion: Patients with PBC have significantly higher levels of ATX expression in their peripheral blood and liver tissue, which can be utilized to assess treatment effectiveness and predict disease progression.


The ethical problems encountered in psychiatric nursing practice with dangerous mentally ill persons.
Psychiatric nursing practice in acute inpatient and emergency settings requires that practitioners identify and manage dangerous patients. The analyses reported here are part of a broader study that sought to understand how psychiatric nurses define and manage the dangerous mentally ill. This paper identifies three ethical problems encountered in the day-to-day practices of psychiatric nurses, as they cared for and managed the dangerous mentally ill. The three ethical problems, balancing support for patient autonomy with the need to maintain unit control; balancing the need for distancing with the desire to establish therapeutic relationships; and balancing the desire to "do the right thing" with the need to get along with colleagues, have implications for psychiatric nursing practice and the institutional settings that treat the dangerous mentally ill. Additionally, this study provides direction for further inquiry into the actual ethical problems encountered in practice.


Baseline Cortical Thickness Reductions in Clinical High Risk for Psychosis: Brain Regions Associated with Conversion to Psychosis Versus Non-Conversion as Assessed at One-Year Follow-Up in the Shanghai-At-Risk-for-Psychosis (SHARP) Study.
To assess cortical thickness (CT) and surface area (SA) of frontal, temporal, and parietal brain regions in a large clinical high risk for psychosis (CHR) sample, and to identify cortical brain abnormalities in CHR who convert to psychosis and in the whole CHR sample, compared with the healthy controls (HC). Magnetic resonance imaging, clinical, and cognitive data were acquired at baseline in 92 HC, 130 non-converters, and 22 converters (conversion assessed at 1-year follow-up). CT and SA at baseline were calculated for frontal, temporal, and parietal subregions. Correlations between regions showing group differences and clinical scores and age were also obtained. CT but not SA was significantly reduced in CHR compared with HC. Two patterns of findings emerged: (1) In converters, CT was significantly reduced relative to non-converters and controls in the banks of superior temporal sulcus, Heschl's gyrus, and pars triangularis and (2) CT in the inferior parietal and supramarginal gyrus, and at trend level in the pars opercularis, fusiform, and middle temporal gyri was significantly reduced in all high-risk individuals compared with HC. Additionally, reduced CT correlated significantly with older age in HC and in non-converters but not in converters. These results show for the first time that fronto-temporo-parietal abnormalities characterized all CHR, that is, both converters and non-converters, relative to HC, while CT abnormalities in converters relative to CHR-NC and HC were found in core auditory and language processing regions.


Sinonasal analogue HPV related breast multiphenotypic carcinoma, a report of a case with the first description in the breast.
High grade basal-like breast carcinomas are triple negative, express basal cytokeratins, and are known for the overall poor prognosis and aggressive behavior. HPV related multiphenotypic sino-nasal carcinoma has overlapping histology with basal-like breast carcinomas, but carry the defining feature of association with high risk HPV. We present a case of a perimenopausal woman with a non-healing ulcerated lesion involving the nipple and breast following a trauma. Biopsy performed showed an HPV-positive basal-like carcinoma with squamous differentiation involving the breast, analogous to multiphenotypic carcinoma previously described in the sinonasal tract. This is the first report of a case of a high- risk HPV related basal-like carcinoma with squamous differentiation, described in the literature. We highlight the morphology and immunophenotype of this lesion and its recognition when compared to other multiphenotypic lesions of the breast, and suggest that pathologists should consider HPV evaluation when encountering similar basal-like tumors involving the breast.


Divergent mechanisms in generating molecular variations of alphaRYR and betaRYR in turkey skeletal muscle.
(1) Molecular variations in two turkey skeletal muscle ryanodine receptor gene isoforms, alphaRYR and betaRYR, were analyzed by cloning and sequencing the entire cDNAs of the two isoforms. (2) Ten alternative splicing transcript variants (ASTVs) in the alphaRYR isoform were identified. These variants were clustered in three alternative splicing regions (ASRs). Two ASRs overlap with the divergent regions (DRs) of the two isoforms. Only four ASTVs did not contain a frame shift and potentially can be translated into alphaRYR channel proteins. The expression of these three ASTVs was developmentally or environmentally regulated. (3) Ten SNPs and eight haplotypes, divergent in the ten SNP positions, were identified in betaRYR. Although the ten SNPs were synonymous, different mRNA secondary structures of betaRYR and different stability of the structures were predicted for several SNPs. (4) The intriguing finding of this study is that alphaRYR and betaRYR use completely divergent mechanisms to generate molecular variations. Alternative splicing generates ASTVs of alphaRYR, whereas the presence of SNPs may change the secondary mRNA structure of betaRYR. These divergent mechanisms could affect calcium channel activity of either or both RYR isoforms.


Pituitary adenylate cyclase activating polypeptide (PACAP)-like immunoreactivity in ganglioneuroblastoma and neuroblastoma.
Pituitary adenylate cyclase activating polypeptide (PACAP) is a 38 amino acid peptide originally isolated from ovine hypothalamus. It has a potent stimulatory action on adenylate cyclase in the rat pituitary. The presence of PACAP was studied in the tumor tissues of ganglioneuroblastoma and neuroblastoma by radioimmunoassay and immunocytochemistry. Immunocytochemical studies showed positive immunostaining in 4 out of 7 ganglioneuroblastomas and 4 out of 6 neuroblastomas. Immunoreactive PACAP concentrations in tissues of 3 ganglioneuroblastomas ranged from 14.5 to 27.8 pmol/g wet weight (20.0 +/- 5.7 pmol/g wet weight, mean +/- S.D.) and the concentration in one neuroblastoma tissue was 111.0 pmol/g wet weight. Reverse phase high performance liquid chromatography of the tumor tissue extract of ganglioneuroblastoma showed a peak eluting in the position of PACAP1-38 and smaller broad peaks eluting later. These results indicated that high concentrations of immunoreactive PACAP were present in the tumor tissues of ganglioneuroblastoma and neuroblastoma, and suggest the possibility that this peptide plays a pathophysiological role in some ganglioneuroblastomas and neuroblastomas.


Cancer-related Fatigue in Breast Cancer Survivors: A Review.
Fatigue has been the most distressing and frequent symptom in breast cancer (BC) survivors after treatment. Although fatigue can occur in other cancer survivors, women with a history of BC might share some distinctive features. The present study aimed to recapitulate the knowledge about risk factors and correlates of cancer-related fatigue (CRF) in BC survivors after oncologic therapy. An electronic data search was conducted in PubMed using the terms "fatigue," "breast," "cancer," and "survivors." Records were included if they were original articles, available in English, had used a quantitative scale, had > 100 participants, and had excluded women with BC relapse. BC survivors were required to have finished their treatments ≥ 2 months before, except for hormonal therapy. The physiopathology and other interventions were considered beyond the scope of our review. The correlates were subsequently classified into 7 main categories: (1) sociodemographic data, (2) physical variables, (3) tumor- and treatment-related variables, (4) comorbidities, (5) other symptoms, (6) psychological issues, and (7) lifestyle factors. Fatigue was consistently greater in younger, obese, and diabetic women. Women reporting fatigue often communicated symptoms such as pain, depression, insomnia, and cognitive dysfunction. Coping strategies such as catastrophizing could play an important role in the persistence of fatigue. However, tumor characteristics, previous treatments received, and physical activity were not consistently reported. CRF was a strong predictor of the quality of life of BC survivors after treatment. In conclusion, we found CRF was a frequent and serious symptom that severely affects the quality of life of BC survivors after treatment. Health practitioners require more awareness and information about CRF.


Wavelet coherence as a measure of trunk stabilizer muscle activation in wheelchair fencers.
Intermuscular synchronization constitutes one of the key aspects of effective sport performance and activities of daily living. The aim of the study was to assess the synchronization of trunk stabilizer muscles in wheelchair fencers with the use of wavelet analysis. Intermuscular synchronization and antagonistic EMG-EMG coherence were evaluated in the pairs of the right and the left latissimus dorsi/external oblique abdominal (LD/EOA) muscles. The study group consisted of 16 wheelchair fencers, members of the Polish Paralympic Team, divided into two categories of disability (A and B). Data analysis was carried out in three stages: (1) muscle activation recording using sEMG; (2) wavelet coherence analysis; and (3) coherence density analysis. In the Paralympic wheelchair fencers, regardless of their disability category, the muscles were activated at low frequency levels: 8-20 Hz for category A fencers, and 5-15 Hz for category B fencers. The results demonstrated a clear activity of the trunk muscles in the wheelchair fencers, including those with spinal cord injury, which can be explained as an outcome of their intense training. EMG signal processing application have great potential for performance improvement and diagnosis of wheelchair athletes.


Effect of Wenxin Keli and quinidine to suppress arrhythmogenesis in an experimental model of Brugada syndrome.
Wenxin Keli (WK), a Chinese herb extract, is reported to be effective in the treatment of atrial and ventricular cardiac arrhythmias. Recent studies suggest that WK inhibits the transient potassium outward current (I(to)). To examine the effectiveness of WK, alone and in combination with quinidine, to suppress arrhythmogenesis in an experimental model of Brugada syndrome (BrS). Action potential and electrocardiographic recordings were obtained from epicardial and endocardial sites of coronary-perfused canine right ventricular wedge preparations. The Ito agonist NS5806 (10-15 μM) was used to pharmacologically mimic a genetic predisposition to BrS. The Ito agonist induced Phase 2 reentry (P2R) in 13/19 preparations and polymorphic ventricular tachycardia (pVT) in 11/19 wedge preparations. WK (10 g/L) suppressed P2R and pVT in 100% (3/3) of preparations. A lower concentration of WK (5 g/L) suppressed P2R in 60% (3/5) and pVT in 50% (2/4), but in combination with a low concentration of quinidine (5 μM), was 100% effective in suppressing P2R and pVT. Quinidine alone suppressed P2R and pVT in 60% (3/5) and 50% (2/4), respectively, and in combination with WK (5 g/L) suppressed P2R and pVT by 80% (4/5) and 75% (3/4), respectively. WK reduced Ito, the L-type calcium current, and contractility in single cardiomyocytes, but dose-dependently increased contractility in intact wedge preparations, an effect mimicked by tyramine. Our data provide support for the hypothesis that WK, particularly in combination with quinidine, effectively suppresses arrhythmogenesis in an experimental model of BrS via inhibition of Ito and indirect adrenergic sympathomimetic effects.


Using Fyrite to monitor incubator carbon dioxide levels.
The Fyrite analyzer (Bacharach, Incorporated) was evaluated to ascertain whether it would perform within the range specified by the manufacturer (+/- 0.5%). Fyrite analyzer samples were compared to control samples obtained using an infrared CO2 monitor (Ohmeda, Model Number 5200). Ten Fyrite analyzer measurements from each of three incubators were obtained using two different analyzers by three investigators for a total of 60 measurements per investigator. Twenty control measurements for each of the three incubators were obtained using an infrared monitor calibrated at the 5.0% CO2 level. Fyrite analyzer values fell outside of an acceptable range (Control mean CO2 +/- 0.5%) for 7 of 60 (11.7%) observations for Incubator 1 and 4 of 60 (6.7%) observations for Incubator 2. (Incubator 3 had no values outside the range.) The Fyrite analyzers were significantly different from each other (P = 0.002). The three investigators (I) differed significantly from the control (I1 and I3, P < 0.001; I2, P = 0.02) as well as from each other (I1 vs I2, P < 0.001; I1 vs I3, P < 0.001; I2 vs I3, P < 0.016). Use of an infrared monitor for incubator calibration and monthly CO2 checks in concert with daily use of the Fyrite as a monitoring tool only is the better method.


Prepro-tachykinin gene expression in the brain of the honeybee Apis mellifera.
We have recently identified a tachykinin-related peptide (AmTRP) from the mushroom bodies (MBs) of the brain of the honeybee Apis mellifera L. by using direct matrix-assisted laser desorption/ionization with time-of-flight mass spectometry and have isolated its cDNA. Here, we have examined prepro-AmTRP gene expression in the honeybee brain by using in situ hybridization. The prepro-AmTRP gene is expressed predominantly in the MBs and in some neurons located in the optic and antennal lobes. cDNA microarray studies have revealed that AmTRP expression is enriched in the MBs compared with other brain regions. There is no difference in AmTRP-expressing cells among worker, queen, and drone brains, suggesting that the cell types that express the prepro-AmTRP gene do not change according to division of labor, sex, or caste. The unique expression pattern of the prepro-AmTRP gene suggests that AmTRPs function as neuromodulators in the MBs of the honeybee brain.


Defining the presymptomatic phase of frontotemporal dementia.
Frontotemporal dementia (FTD) is a clinically, pathologically and genetically heterogeneous disorder. Whilst disease modifying therapy trials are mostly focused on the symptomatic phase, future studies will move earlier in the disease aiming to prevent symptom onset. This review summarizes the recent work to better understand this presymptomatic period. The presymptomatic phase can be split into preclinical and prodromal stages. The onset of the preclinical phase is defined by the first presence of pathological inclusions of tau, TDP-43 or fused in sarcoma in the brain. Definitive biomarkers of these pathologies do not yet exist for FTD. The prodromal phase is defined by the onset of mild symptoms. Recent work has highlighted the wide phenotypic spectrum that occurs, with the concept of mild cognitive ± behavioural ± motor impairment (MCBMI) being put forward, and additions to scales such as the CDR plus NACC FTLD now incorporating neuropsychiatric and motor symptoms. It will be important to better characterize the presymptomatic period moving forward and develop robust biomarkers that can be used both for stratification and outcome measures in prevention trials. The work of the FTD Prevention Initiative aims to facilitate this by bringing together data from natural history studies across the world.


Biodegradable ion-conductive polyvinyl alcohol/okra polysaccharide composite films for fast-response respiratory monitoring sensors.
Polyvinyl alcohol (PVA) and okra polysaccharide (OP) are biodegradable polymers with high hydrophilicity and good biocompatibility with potential for use as flexible humidity-sensitive materials. Herein, biodegradable flexible composite films (named POP films) were prepared from PVA, OP, and phytic acid using a solution-casting method based on. POP films exhibited excellent mechanical strength, flexibility, flame retardancy, water resistance, humidity response, and humidity-sensing characteristics. Notably, the POP humidity sensors exhibited a hysteresis value of 1.88 % relative humidity for the adsorption and desorption processes and good sensitivity over a wide humidity range of 35-95 %. In addition, the humidity sensor distinguished the frequency of nose breathing, and its response and recovery times were 0.9 and 1.98 s, respectively. The excellent performance of POP sensors in monitoring humidity and human respiratory rates demonstrates the sensor's potential for wearable smart devices.


Candidacy of LPS-based glycoconjugates to prevent invasive meningococcal disease: developmental chemistry and investigation of immunological responses following immunization of mice and rabbits.
Glycoconjugates were prepared by covalently linking the immunogenic protein carrier CRM(197) to O-deacylated lipopolysaccharide (LPS) derived from Neisseria meningitidis (strain H44/76), immunotype L3 galE LPS. This mutant strain elaborates a truncated LPS structure that displays immunological epitopes characteristic of 76% of Group B meningococcal (NmB) strains. CRM(197) was covalently linked either to the reducing glucosamine residue of the lipid A region of the O-deacylated LPS or to a 2-keto-3-deoxy-octulosonic acid (Kdo) residue in the inner core region of the O-deacylated LPS. In both rabbits and mice a much stronger IgG response to the immunising antigen was generated in those animals that received conjugates linked via the lipid A region. Sera from mice that were immunized with these conjugates were assayed for their reactivity with LPS, both mutant and wild-type, of several homologous and heterologous NmB strains. Sera obtained from mice immunized with conjugates in which the carrier protein was linked via the Kdo moiety were only able to react with O-deacylated, but not fully acylated (native), LPS from the homologous strain. However, sera obtained from mice that were immunized with conjugates, in which the carrier protein was coupled to the lipid A region, reacted predominately with inner core epitopes that contained phosphoethanolamine at the same 3-position of the distal heptose residue (HepII) of the inner core LPS as was present on the immunising antigen. Additionally it was observed that sera from rabbits immunised with lipid A linked conjugates, unlike the mice responses, were generally not as specific for LPS antigens that contained phosphoethanolamine at the same 3-position as was present on the immunising antigen, but showed a broader inner core recognition, whereas those rabbits that received the Kdo-linked conjugates gave only a very weak non-specific response to all immunotypes. Finally, the sera from two out of six mice that had received lipid A linked conjugates had bactericidal activity against L3 wild-type NmB strain 8047 and one of these was able to passively protect against meningococcal infection in an infant rat model. This study demonstrates evidence towards the proof-in-principle that by using Nm inner core LPS conjugates coupled via the lipid A region with an intact phosphoethanolamine at the O-3 position of the HepII of the inner core LPS, it is possible to elicit functional and protective antibodies against meningococcal infection.


Mucosal glucosamine synthetase activity in inflammatory bowel disease.
Abnormalities in colonic glycoprotein synthesis have been implicated in the pathogenesis of ulcerative colitis and Crohn's disease. Glucosamine synthetase is the rate-limiting step in the biosynthesis of gastrointestinal glycoprotein and has been measured in control subjects (N = 23) and patients with ulcerative colitis (N = 26) or Crohn's disease of the colon (N = 20) classified according to the macroscopic status of the rectum. Glucosamine synthetase activity was relatively constant around the normal colon but lower levels were found in the terminal ileum. In ulcerative colitis, glucosamine synthetase activity was similar to controls (24.0 +/- 1.9) mmol/g wet (wt/hr) irrespective of disease activity (quiescent: N = 13, = 27.3 +/- 1.9; active N = 16, = 26.2 +/- 2.3). Rectal glucosamine synthetase activity was normal in the presence of active Crohn's proctocolitis (29.4 +/- 3.1) but raised in patients with Crohn's colitis and rectal sparing (37.2 +/- 4.9 P < 0.02). Glucosamine synthetase activity was strongly influence by the degree of epithelial preservation.


Impact of depression and/or anxiety on the presentation of cardiovascular events in a cohort with metabolic syndrome. StreX project: Five years of follow-up.
To determine the role of anxiety and depression on the incidence of cardiovascular events (CVE) in a Catalonian population with metabolic syndrome (MetS) over a five-year follow-up according to the number/type of MetS criteria. Prospective study to determine the incidence of CVE according to the presence of anxiety and depression disorders among individuals with different combinations of clinical traits of the MetS. Primary Care, Catalonia (Spain). 35-75 years old fulfilling MetS criteria without CVE at the initiation of follow-up (2009). We studied 16 MetS phenotypes [NCEP-ATPIII criteria] based on the presence of depression/anxiety. The primary endpoint was the incidence of CVE at five years. We analyzed 401,743 people with MetS (17.2% of the population); 8.7% had depression, 16.0% anxiety and 3.8% both. 14.5% consumed antidepressants and 20.8% tranquilizers. At the 5-year follow-up, the incidence of CVE was 5.5%, being 6.4% in men and 4.4% in women. On comparing individuals with and without depression the incidence of CVE was 6.7% vs. 5.3%, respectively (p<0.01), being 5.5% in both groups in relation to anxiety. Depression and anxiety play a role in the poor prognosis of patients with MetS. In Catalonia, the two predominant MetS phenotypes do not include obesity as a criterion.


Development of an interpretable machine learning model associated with heavy metals' exposure to identify coronary heart disease among US adults via SHAP: Findings of the US NHANES from 2003 to 2018.
Limited information is available on the links between heavy metals' exposure and coronary heart disease (CHD). We aim to establish an efficient and explainable machine learning (ML) model that associates heavy metals' exposure with CHD identification. Our datasets for investigating the associations between heavy metals and CHD were sourced from the US National Health and Nutrition Examination Survey (US NHANES, 2003-2018). Five ML models were established to identify CHD by heavy metals' exposure. Further, 11 discrimination characteristics were used to test the strength of the models. The optimally performing model was selected for identification. Finally, the SHapley Additive exPlanations (SHAP) tool was used for interpreting the features to visualize the selected model's decision-making capacity. In total, 12,554 participants were eligible for this study. The best performing random forest classifier (RF) based on 13 heavy metals to identify CHD was chosen (AUC: 0.827; 95%CI: 0.777-0.877; accuracy: 95.9%). SHAP values indicated that cesium (1.62), thallium (1.17), antimony (1.63), dimethylarsonic acid (0.91), barium (0.76), arsenous acid (0.79), total arsenic (0.01) in urine, and lead (3.58) and cadmium (4.66) in blood positively contributed to the model, while cobalt (-0.15), cadmium (-2.93), and uranium (-0.13) in urine negatively contributed to the model. The RF model was efficient, accurate, and robust in identifying an association between heavy metals' exposure and CHD among US NHANES 2003-2018 participants. Cesium, thallium, antimony, dimethylarsonic acid, barium, arsenous acid, and total arsenic in urine, and lead and cadmium in blood show positive relationships with CHD, while cobalt, cadmium, and uranium in urine show negative relationships with CHD.


Management of the rigid arthritic flatfoot in the adults: alternatives to triple arthrodesis.
Every alternative to triple arthrodesis in the rigid acquired flatfoot deformity is predicated on limiting the patient exposure to the complication associated with triple arthrodesis. When possible, avoiding arthrodesis of either the talonavicular and calcaneocuboid joints, with their higher nonunion rates, seems a cogent option. Successful treatment is dependent on thoughtful patient evaluation and examination, meticulous joint preparation, careful positioning with rigid fixation, and judicious use of adjunctive procedures to achieve the goal of a plantigrade foot that functions well and is minimally painful.


Unidirectional effect of lauryl sulfate on the reversible NADH:ubiquinone oxidoreductase (Complex I).
Lauryl sulfate inhibits the Deltamu;(H)(+)-dependent reverse electron transfer reactions catalyzed by NADH:ubiquinone oxidoreductase (Complex I) in coupled bovine heart submitochondrial particles and in vesicles derived from Paracoccus denitrificans. The inhibitor affects neither NADH oxidase (coupled or uncoupled) nor NADH:ferricyanide reductase and succinate oxidase activities at the concentrations that selectively prevent the succinate-supported, rotenone-sensitive NAD(+) or ferricyanide reduction. Possible uncoupling effects of the inhibitor are ruled out: in contrast to oligomycin and gramicidin, which increases and decreases the rate of the reverse electron transfer, respectively, in parallel with their coupling and uncoupling effects, lauryl sulfate does not affect the respiratory control ratio. A mechanistic model for the unidirectional effect of lauryl sulfate on the Complex I catalyzed oxidoreduction is proposed.


What matters to people with memory problems, healthy volunteers and health and social care professionals in the context of developing treatment to prevent Alzheimer's dementia? A qualitative study.
Alzheimer's disease (AD) is recognized as one of the greatest global public health challenges. There is increasing consensus that optimal disease modification using pharmaceuticals may best be achieved earlier in the disease continuum before symptoms occur. However, more needs to be understood about what outcomes are meaningful to potential participants in clinical trials within this preventative paradigm and how people make trade-offs between risks and benefits. The Electronic Person-Specific Outcome Measure (ePSOM) programme is developing an app to capture person-specific outcomes and preferences in clinical trials. As one phase in the ePSOM programme, this study explored what matters when developing new treatments to prevent AD and how trade-offs are made between risks and benefits, from three perspectives. Focus groups were conducted with people living with memory problems (n = 21) and healthy volunteers (n = 10), and telephone interviews with health and social care professionals (n = 10). Differences and overlap between the three groups were explored. Outcomes that matter lie in five key domains in relation to what matters in everyday life: Everyday Functioning; Relationships and Social Connections; Enjoying Life; Sense of Identity; and Alleviating Symptoms. Insights were gained into the significance of reducing the risk of developing dementia with drugs and the processes of weighing up risks versus benefits. The key domains identified are being used to inform the next stage of the ePSOM programme which is to develop a survey to be distributed nationally in the UK to explore these issues further.


[Clinical diagnosis of Colles fracture combined with dorsal subluxation of radial carpal joints].
To study the criteria for evaluating Colles fracture combined with dorsal radiocarpal subluxation (DRS). Fifty cases of Colles fracture combined with DRS, 100 cases of simple Colles fracture without DRS, and 100 normal wrist joint controls were included. We analysed central point displacement and perpendicular line ratio on the lateral view X-ray. For comminuted and severely displaced fracture, central point displacement (CPD) was not adopted because of difficulties in identifying the central point of the articular surface. Perpendicular line ratio (PLR) was suggested. Prominent difference was seen in the CPDs and the PLRs between the Colles fracture combined with DRS group and the simple Colles fracture and the normal control group (P < 0.01). Prominent relevance between the CPD and the PLR was also found (P < 0.05). Central point displacement and perpendicular line ratio can be regarded as the diagnostic criteria for Colles fracture combined with DRS. PLR is especially valuable when the central point is hard to be identified in very comminuted and severely displaced fractures. DRS is suggested when CPD is more than 2.5 mm and PLR is less than 0.76.


Evidence for an altered structure of actin-S1 complexes when Mg-adenylylimidodiphosphate binds.
Simultaneous measurements of actin-S1 binding and light scatter (or turbidity) were made in the presence and absence of saturating Mg-adenylylimidodiphosphate (Mg.AMP.PNP). It was found that if the actin was covalently labelled on cysteine 363 by dansyl aziridine (DAZ) the ternary complex DAZactin-S1-Mg.AMP.PNP scattered 36% less light than the binary complex DAZactin-S1. If the actin was not labelled there was no difference in scatter. The decrease in scatter of DAZactin-S1 was dependent on Mg.AMP.PNP concentration in a hyperbolic manner with half maximal decrease at 40 micrometers. No change in light scatter by DAZactin-S1 was found when H.AMP.PNP or Mg.ADP bound. The change in light scatter is evidence that the structure of DAZactin-S1 is altered when Mg.AMP.PNP binds. The possible nature of the structural change and its role in chemo-mechanical transduction is discussed.


Cerpegin-derived furo[3,4-c]pyridine-3,4(1H,5H)-diones enhance cellular response to interferons by de novo pyrimidine biosynthesis inhibition.
There is an increasing interest in the field of cancer therapy for small compounds targeting pyrimidine biosynthesis, and in particular dihydroorotate dehydrogenase (DHODH), the fourth enzyme of this metabolic pathway. Three available DHODH structures, featuring three different known inhibitors, were used as templates to screen in silico an original chemical library from Erevan University. This process led to the identification of P1788, a compound chemically related to the alkaloid cerpegin, as a new class of pyrimidine biosynthesis inhibitors. In line with previous reports, we investigated the effect of P1788 on the cellular innate immune response. Here we show that pyrimidine depletion by P1788 amplifies cellular response to both type-I and type II interferons, but also induces DNA damage as assessed by γH2AX staining. Moreover, the addition of inhibitors of the DNA damage response led to the suppression of the P1788 stimulatory effects on the interferon pathway. This demonstrates that components of the DNA damage response are bridging the inhibition of pyrimidine biosynthesis by P1788 to the interferon signaling pathway. Altogether, these results provide new insights on the mode of action of novel pyrimidine biosynthesis inhibitors and their development for cancer therapies.


The Antennal sensilla of Oxelytrum erythrurum (Blanchard) and Oxelytrum apicale (Brullé) (Coleoptera: Silphidae).
The typology and placement of antennal sensilla of the carrion beetles Oxelytrum erythrurum (Blanchard) and Oxelytrum apicalis (Brullé) (Coleoptera: Silphidae) were studied using scanning electron microscopy. Two types of sensilla chaetica, two types of sensilla trichodea, four types of sensilla basiconica, one type of sensilla coeloconica, and an unidentified type of sensillum were found in both species. Sensilla chaetica type 1 are found on the antennomeres proximal to antennal club (A1-A8); chaetica type 2 are found on the club (A9-A11). Sensilla trichodea are found on A9-A11; one type (T1) is found on the proximal portion of the club, the other type (T2) on the apical portion. Basiconica type 1 are found on the dorsal surface of A9-A11; they are much denser on the apical portion of the antennal club than on the proximal. In O. erythrurum, a nocturnal species of the Chaco-Pampean plain, T2 two are found on A10 and A11. In Oxelytrum apicale, a mountain species, probably diurnal, only A11 bears T2, but they are denser than in the other species. It is suggested that O. apicale depends more on contact chemoreception than O. erythrurum. The ventral surface of the antennal clubs shows no remarkable difference between species.


The ins and outs of population relationships in west-Mediterranean islands: data from autosomal Alu polymorphisms and Alu/STR compound systems.
The islands of the West Mediterranean have played a central role in numerous archaeological, historical and anthropological studies due to their active participation in the history of main Mediterranean civilisations. However, genetic data failed to fit in both their degree of internal differentiation and relationships. A set of 18 Alu markers and three short tandem repeats (STRs) closely linked to the CD4, F13B and DM Alu have been analysed in seven samples from Majorca, Corsica, Sardinia and Sicily to explore some of these issues. Our samples show a high genetic heterogeneity inside and among islands for the Alu data. Global differentiation among islands (F(ST) 2.2%) is slightly higher than that described for Europeans and North Africans. Both the estimated divergence times among samples and the high population heterogeneity revealed by Alu data are compatible with population differences since the first islands' settlement in the Paleolithic period. However, the high within-population diversities and the remarkable homogeneity observed in both STR and Alu/STR haplotype variation indicated that, at least since Neolithic times, gene flow has been acting in west Mediterranean. Genetic drift in west-coast Sardinia and gene flow in west Sicily have contributed to their general differentiation, whereas Corsica, Majorca and east Sicily seem to reflect more recent historical relationships from continental south Europe.


Impact of retinal fluid in patients with diabetic macular edema treated with anti-VEGF in routine clinical practice.
This study aims to determine the effect of intraretinal (IRF) and subretinal (SRF) fluid on visual outcomes for diabetic macular edema (DME) patients treated with anti-vascular endothelial growth factor (anti-VEGF) in routine clinical practice. Optical coherence tomography scans were analyzed with a deep-learning artificial intelligence software to quantify IRF, SRF, and total retinal fluid (TRF) at baseline and at 3, 6, and 12 months. Predictive variables for best-corrected visual acuity (BCVA) were evaluated with linear mixed-effects regression models. A total of 220 DME eyes of 220 patients from the Cole Eye Institute at Cleveland Clinic. Retrospective, nonrandomized cohort study. BCVA improved from baseline to 12 months (63.36 ± 14.72 to 68.49 ± 13.14 Early Treatment Diabetic Retinopathy Study letters, p < 0.001, respectively). Central subfield thickness improved from baseline to 12 months (411.74 ± 129.7 to 335.94 ± 116.91 mm, p < 0.001, respectively). Injection frequency per patient was 8.25 ± 2.5 injections over 12 months. The linear mixed-effects regression model in the foveal region for TRF, IRF, and SRF volume at the fourth quartile showed BCVA losses of -8.29 letters (range, -10.96 to -5.62 letters, p < 0.001), -7.52 letters (range, -10.3 to -4.74 letters, p < .001), and -6.93 letters (range, -10.54 to -3.41 letters, p < .001), respectively. The highest quartile of TRF, IRF, and SRF volumes led to worse visual outcomes after 12 months of anti-VEGF treatment in patients with DME. Further studies designed to investigate the effect of anti-VEGF treatment on retinal fluid morphology could provide greater insight into individualized DME treatment.


The pivotal role of glycogen synthase kinase 3 (GSK-3) in vomiting evoked by specific emetogens in the least shrew (Cryptotis parva).
Glycogen synthase kinase 3 (GSK-3) is a constitutively active multifunctional serine-threonine kinase which is involved in diverse physiological processes. GSK-3 has been implicated in a wide range of diseases including neurodegeneration, inflammation, diabetes and cancer. GSK-3 is a downstream target for protein kinase B (Akt) which phosphorylates GSK-3 and suppresses its activity. Based upon our preliminary findings, we postulated Akt's involvement in emesis. The aim of this study was to investigate the participation of GSK-3 and the antiemetic potential of two GSK-3 inhibitors (AR-A014418 and SB216763) in the least shrew model of vomiting against fully-effective emetic doses of diverse emetogens, including the nonselective and/or selective agonists of serotonin type 3 (e.g. 5-HT or 2-Methyl-5-HT)-, neurokinin type 1 receptor (e.g. GR73632), dopamine D2 (e.g. apomorphine or quinpirole)-, and muscarinic 1 (e.g. pilocarpine or McN-A-343) receptors, as well as the L-type Ca2+ channel agonist (FPL64176), the sarco/endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin, and the chemotherapeutic agent, cisplatin. We first determined if these emetogens could regulate the phosphorylation level of GSK-3 in the brainstem emetic loci of least shrews and then investigated whether AR-A014418 and SB216763 could protect against the evoked emesis. Phospho-GSK-3α/β Ser21/9 levels in the brainstem and the enteric nerves of jejunum in the small intestine were upregulated following intraperitoneal (i.p.) administration of all the tested emetogens. Furthermore, administration of AR-A014418 (2.5-20 mg/kg, i.p.) dose-dependently attenuated both the frequency and percentage of shrews vomiting in response to i.p. administration of 5-HT (5 mg/kg), 2-Methyl-5-HT (5 mg/kg), GR73632 (5 mg/kg), apomorphine (2 mg/kg), quinpirole (2 mg/kg), pilocarpine (2 mg/kg), McN-A-343 (2 mg/kg), FPL64176 (10 mg/kg), or thapsigargin (0.5 mg/kg). Relatively lower doses of SB216763 exerted antiemetic efficacy, but both inhibitors barely affected cisplatin (10 mg/kg)-induced vomiting. Collectively, these results support the notion that vomiting is accompanied by a downregulation of GSK-3 activity and pharmacological inhibition of GSK-3 protects against pharmacologically evoked vomiting.


Neuroanatomical Tracing Techniques in the Ear: History, State of the Art, and Future Developments.
The inner ear has long been at the cutting edge of tract tracing techniques that have shaped and reshaped our understanding of the ear's innervation patterns. This review provides a historical framework to understand the importance of these techniques for ear innervation and for development of tracing techniques in general; it is hoped that lessons learned will help to quickly adopt transformative novel techniques and their information and correct past beliefs based on technical limitations. The technical part of the review presents details of our protocol as developed over the last 30 years. We also include arguments as to why these recommendations work best to generate the desired outcome of distinct fiber and cell labeling, and generate reliable data for any investigation. We specifically focus on two tracing techniques, in part developed and/or championed for ear innervation analysis: the low molecular multicolor dextran amine tract tracing technique and the multicolor tract tracing technique with lipophilic dyes.


Poor sensitization of 50-kHz vocalization response to amphetamine predicts rat susceptibility to self-administration of the drug.
Our previous studies showed promise for using sensitization of the frequency-modulated 50-kHz vocalization response to amphetamine (AMPH) as an index of rat vulnerability to AMPH addiction. This study aimed to test the utility of sensitizing frequency-modulated (FM) 50-kHz vocalization in the AMPH self-administration paradigm as well as the ability of N-acetylcysteine to prevent self-administration relapse. Rats were subjected to the so-called two-injection protocol of sensitization (TIPS) using AMPH and were categorized as low-sensitized callers (LCTIPS) or high-sensitized callers (HCTIPS) based on the individual outcomes. Then, they were given 44 sessions of AMPH self-administration followed by a 17-session N-acetylcysteine-aided extinction course and a single session of AMPH-primed self-administration reinstatement. LCTIPS compared to HCTIPS rats showed no considerable difference in the FM 50-kHz vocalization rate during the self-administration training or extinction course, but they were considerably more likely to acquire AMPH self-administration and experience drug-induced reinstatement of this trait. Moreover, the LCTIPS rats were more likely than HCTIPS rats to have a markedly higher FM 50-kHz vocalization rate after AMPH reinstatement. N-acetylcysteine did not affect the course of self-administration extinction or the instrumental or FM 50-kHz vocalization responses to AMPH reinstatement. There is no link between the FM 50-kHz vocalization and key characteristics of AMPH self-administration. Additionally, N-acetylcysteine does not help prevent AMPH self-administration relapse. However, there is a high predictive value for poor sensitization of the FM 50-kHz vocalization response to AMPH with respect to the acquisition and maintenance of self-administration of this psychostimulant.


Cytochrome P450 isoforms contribution, plasma protein binding, toxicokinetics of enniatin A in rats and in vivo clearance prediction in humans.
Emerging mycotoxins, such as enniatin A (ENNA), are becoming a worldwide concern owing to their presence in different types of food and feed. However, comprehensive toxicokinetic data that links intake, exposure and toxicological effects of ENNA has not been elucidated yet. Therefore, the present study investigated the in vitro (rat and human) and in vivo (rat) toxicokinetic properties of ENNA. Towards this, an easily applicable and sensitive bioanalytical method was developed and validated for the estimation of ENNA in rat plasma. ENNA exhibited high plasma protein binding (99%), high hepatic clearance and mainly underwent metabolism via CYP3A4 (74%). The in-house predicted hepatic clearance (54 mL/min/kg) and observed in vivo rat clearance (55 mL/min/kg) were comparable. The predicted in vivo human hepatic clearance was 18 mL/min/kg. ENNA underwent slow absorption (Tmax = 4 h) and rapid elimination following oral administration to rats. The absolute oral bioavailability was 47%. The toxicokinetic findings for ENNA from this study will help in designing and interpreting toxicological studies in rats. Besides, these findings could be used in physiologically based toxicokinetic (PBTK) model development for exposure predictions and risk assessment for ENNA in humans.


Association of peripheral vertical meniscal tears with anterior cruciate ligament tears.
The purpose of this article is to describe a type of meniscal tear seen on magnetic resonance (MR) imaging, the peripheral vertical tear, and to determine the prevalence of anterior cruciate ligament (ACL) tears in knees with this type of meniscal tear compared to knees with other types of meniscal tears. Following Institutional Review Board approval, a retrospective review of 200 knee MR examinations with imaging diagnoses of 'meniscal tear' was performed to assess the location and morphology of the meniscal tear, and to assess the status of the ACL. Nineteen peripheral vertical meniscal tears were identified in 17 patients, 14 of whom had acute ACL tears, prior ACL reconstruction, or chronic ACL deficiency. Three peripheral vertical tears were seen in the setting of a normal ACL. Of the 183 examinations with other types of meniscal tears, there were 17 cases with acute ACL tears, prior ACL reconstruction, or chronic ACL deficiency. The difference in the prevalence of ACL tear, reconstruction, or deficiency in knees with meniscal tears of the peripheral vertical type (82.4%) compared with the prevalence of ACL tear, reconstruction, or deficiency in knees with other types of meniscal tears (9.3%) was statistically significant (P < 0.001). The calculated specificity of the presence of peripheral vertical tear morphology in detecting an ACL injury in patients with meniscal tears was 98.2%. Peripheral vertical meniscal tears, particularly when involving the posterior horn, are highly associated with ACL tear, deficiency, or reconstruction. The finding of this type of tear on knee MR imaging should prompt close inspection of the ACL for evidence of acute or chronic injury, and its presence may help make the diagnosis of ACL tear in equivocal cases.


Saccharin aversion in the rat following adrenalectomy.
Changes in saccharin preference as a function of concentration were studied in rats after either adrenalectomy of sham surgery. A 48 hr two-bottle preference test was used. Under two different sets of testing conditions, adrenalectomized animals rejected saccharin solutions at concentrations that were highly acceptible to controls and did not show an appetitive behavior towards andy of the concentrations tested. This aversion pattern persisted even when preference tests were conducted for as long as 10 days. However, it was abolished when the adrenalectomized rats wre exposed to saccharin for 6 days prior to surgery, or when they were administered the glucocorticoid dexamethasone. Results are discussed with respect to the effects of adrenal hormones on sensory systems and to taste-aversion learning.


The role of carbon-donor hydrogen bonds in stabilizing tryptophan conformations.
Although most side-chain torsion angles correspond to low-energy rotameric positions, deviations occur with significant frequency. One striking example arises in Trp residues, which have an important role in stabilizing protein structures because of their size and mixed hydrophobic/hydrophilic character. Ten percent of Trp side-chains have unexplained conformations with chi(2) near 0 degrees instead of the expected 90 degrees. The current work is a structural and energetic analysis of these conformations. It is shown that many Trp residues with these orientations are stabilized by three-center carbon-donor hydrogen bonds of the form C-H...X...H-C, where X is a polar hydrogen-bond acceptor in the environment of the side-chain. The bridging hydrogen bonds occur both within the Trp side-chain and between the side-chain and the local protein backbone. Free energy maps of an isolated Trp residue in an explicit water environment show a minimum corresponding to the off-rotamer peak observed in the crystallographic data. Bridging carbon-donor hydrogen bonds are also shown to stabilize on-rotamer Trp conformations, and similar bridging hydrogen bonds also stabilize some off-rotamer Asp conformations. The present results suggest a previously unrecognized role for three-center carbon-donor hydrogen bonds in protein structures and support the view that the off-rotamer Trp side-chain orientations are real rather than artifacts of crystallographic refinements. Certain of the off-rotamer Trp conformations appear to have a functional role.


Weekly large fraction radiotherapy and 5 fluorouracil as a palliative treatment for large bowel carcinoma: a pilot study.
Palliative radiotherapy for large bowel cancer is generally given in fraction sizes of 2-3 Gy. Theoretical considerations led us to believe that a larger fraction size would not lead to a decreased response rate and practical considerations led us to treat patients once a week. The results of a pilot study of 32 patients with large bowel cancer are presented. Patients were treated with a fraction size of 6 Gy given weekly and combined with 5 FU. The response rate of 58% and the median survival of 9 months seems comparable with other regimens, as does the rate of acute side effects. The late high dose effect of subcutaneous fibrosis was seen in 30% of the long term survivors; the implications of this are discussed. We draw the conclusion that this treatment is convenient and effective in terms of tumor response, but that the late high dose effects were more severe than expected and that these effects may be potentiated by 5 FU.


The new era of hypospadias surgery.
The authors review four current techniques in hypospadias surgery that yield superior functional and aesthetic results to those obtained in the older, multi-stage repairs. If the repair is performed before the age of memory recall, there will be less psychological trauma to both the patient and his parents.


Integrated single-base resolution maps of transcriptome, sRNAome and methylome of Tomato yellow leaf curl virus (TYLCV) in tomato.
Geminiviruses are plant ssDNA viruses that replicate through dsDNA intermediates and form minichromosomes which carry the same epigenetic marks as the host chromatin. During the infection, geminiviruses are targets of the post-transcriptional and transcriptional gene silencing machinery. To obtain insights into the connection between virus-derived small RNAs (vsRNAs), viral genome methylation and gene expression, we obtained the transcriptome, sRNAome and methylome from the geminivirus Tomato yellow leaf curl virus-infected tomato plants. The results showed accumulation of transcripts just at the viral ORFs, while vsRNAs spanned the entire genome, showing a prevalent accumulation at regions where the viral ORFs overlapped. The viral genome was not homogenously methylated showing two highly methylated regions located in the C1 ORF and around the intergenic region (IR). The compilation of those results showed a partial correlation between vsRNA accumulation, gene expression and DNA methylation. We could distinguish different epigenetic scenarios along the viral genome, suggesting that in addition to its function as a plant defence mechanism, DNA methylation could have a role in viral gene regulation. To our knowledge, this is the first report that shows integrative single-nucleotide maps of DNA methylation, vsRNA accumulation and gene expression from a plant virus.


Diagnostic and therapeutic problems associated with hereditary deficiency of the C1 esterase inhibitor.
Six patients in a family with a history of hereditary angioedema reported swelling of the extremities and recurrent abdominal pain occurring spontaneously or after trauma. Attacks of oedema involving the airways, the greatest danger with this disorder, were present only in one case. This autosomal dominant disease is due to deficient activity of the inhibitor of the first component of complement. Low levels of C4, and absence of C1 esterase inhibitor confirm the diagnosis. Two asymptomatic cases with the appropriate biochemical abnormality are reported in this study. For short term prophylaxis of attacks (before surgery expecially), fresh frozen plasma is used, or better still, C1 esterase inhibitor. For long term prophylaxis of attacks antifibrinolytic and hormonal drugs are used: in two cases, the authors obtained good results with methyltestosterone after failure of tranexamic acid.