Analysis of CDS-located miRNA target sites suggests that they can effectively inhibit translation.
Most of what is presently known about how miRNAs regulate gene expression comes from studies that characterized the regulatory effect of miRNA binding sites located in the 3' untranslated regions (UTR) of mRNAs. In recent years, there has been increasing evidence that miRNAs also bind in the coding region (CDS), but the implication of these interactions remains obscure because they have a smaller impact on mRNA stability compared with miRNA-target interactions that involve 3' UTRs. Here we show that miRNA-complementary sites that are located in both CDS and 3'-UTRs are under selection pressure and share the same sequence and structure properties. Analyzing recently published data of ribosome-protected fragment profiles upon miRNA transfection from the perspective of the location of miRNA-complementary sites, we find that sites located in the CDS are most potent in inhibiting translation, while sites located in the 3' UTR are more efficient at triggering mRNA degradation. Our study suggests that miRNAs may combine targeting of CDS and 3' UTR to flexibly tune the time scale and magnitude of their post-transcriptional regulatory effects.


[Comparison of ILM peeling with and without the use of indocyanine green. Functional results for idiopathic macular hole after pars plana vitrectomy].
Pars plana vitrectomy with internal limiting membrane (ILM) peeling is the best known therapy for idiopathic macular holes. Indocyanine green (ICG) is useful for staining the ILM, although there is a dose related toxic effect on the inner retinal layers. We compared outcome results with and without the use of ICG. Data from 61 patients with idiopathic macular holes, who underwent macular hole surgery were analyzed retrospectively. ICG was used on 36 eyes while for 25 eyes it was not used. After calculating logMAR, differences in visual acuity between both groups were analyzed for significance using the Mann-Whitney-U-Test. The logMAR for the entire group was 0.71+/-0.30 (20/100) preoperatively, after 1 month 0.71+/-0.36 (20/100), after 3 months 0.57+/-0.26 (20/80), after 6 months 0.54+/-0.38 (20/66) and after 12 months 0.36+/-0.32 (20/50). There were no significant differences between groups. There seem to be no significant differences in the development of visual acuity and the occlusion rate between patients treated with or without the use of ICG.


Efficacy of Precise Foot Massage Therapy on Pain and Anxiety Following Cardiac Surgery: Pilot Study.
Pain is the most pervasive distressing symptom following cardiac surgery. Forty percent of postoperative cardiac patients report inadequate pain management. Undertreated acute pain results in increased anxiety, delayed wound healing, and increased chance of persistent chronic pain. Foot massage is a safe, visible complementary approach to manage acute pain following surgery. The aim of this study is to evaluate the efficacy of integrating foot massage therapy for managing postcardiac pain. A randomized placebo controlled single blinded trial comparing foot massage to placebo was conducted at a large hospital in Saudi Arabia. Thirty-one patients who had undergone cardiac surgery (16 in experimental and 15 in placebo group) participated in the study. Ten-minute foot massage was delivered to the experimental group by a nurse researcher, twice during one day, within 30 minutes after receiving an opioid pain medication. The findings of this study indicate that foot massage significantly (p < .05) decreases pain intensity and anxiety in patients who have undergone cardiac surgery compared with a placebo control group. Providing non-pharmacologic interventions for pain is the responsibility of the nursing staff. Foot massage is within the scope of nursing practice and is a safe and effective manner of improving patient care. Foot massage in conjunction with pharmacological interventions is effective in improving pain and anxiety. Future studies should consider focusing on frequency, dose, feasibility, acceptability, and participants' satisfaction.


A nanopore interface for higher bandwidth DNA computing.
DNA has emerged as a powerful substrate for programming information processing machines at the nanoscale. Among the DNA computing primitives used today, DNA strand displacement (DSD) is arguably the most popular, with DSD-based circuit applications ranging from disease diagnostics to molecular artificial neural networks. The outputs of DSD circuits are generally read using fluorescence spectroscopy. However, due to the spectral overlap of typical small-molecule fluorescent reporters, the number of unique outputs that can be detected in parallel is limited, requiring complex optical setups or spatial isolation of reactions to make output bandwidths scalable. Here, we present a multiplexable sequencing-free readout method that enables real-time, kinetic measurement of DSD circuit activity through highly parallel, direct detection of barcoded output strands using nanopore sensor array technology (Oxford Nanopore Technologies' MinION device). These results increase DSD output bandwidth by an order of magnitude over what is currently feasible with fluorescence spectroscopy.


Depression literacy among Chinese in Shanghai, China: a comparison with Chinese-speaking Australians in Melbourne and Chinese in Hong Kong.
The study reported in this paper was aimed at developing understanding of depression-related knowledge and preferences surrounding professional help, medication, and treatment methods among Chinese living in Shanghai, China. A multi-stage cluster sampling method in which participants were taken from 6 of the 20 districts in Shanghai was adopted for this study. The 522 Shanghai Chinese participants were presented with a vignette describing an individual with depression before being asked questions designed to assess both their understanding of depression and their preferences surrounding professional help, medication, and treatment methods. A comparative approach was adopted to identify similarities and differences between our findings and those of two previous studies on the mental health literacy of Chinese living in Melbourne, Australia, and Hong Kong, respectively. A similarly low percentage of Chinese people in each of Shanghai, Hong Kong, and Australia recognized depression. Fewer Shanghai Chinese than Chinese living in Hong Kong and Australia ascribed the 'anxiety/stress' label to the depression vignette and endorsed professionals and informal network members as helpful. Although a far lower percentage of Shanghai Chinese endorsed the use of counseling professionals, a much higher percentage of the same group endorsed Chinese medical doctors and herbal medication. A lower percentage of Shanghai Chinese endorsed 'lifestyle changes' as a strategy for combating depression than did Chinese subjects living in Australia and Hong Kong. On the other hand, a higher percentage of Shanghai residents endorsed psychiatric treatment and the traditional Chinese practices of 'eating nutritious food/taking supplements' and 'qigong' than among the other two groups of Chinese. This study underlines the need for campaigns aimed at improving the mental health literacy of Chinese in Shanghai. Such campaigns must take into consideration the socially and culturally driven beliefs to facilitate the development of specific education programs.


Incidence, Predictors, and Outcomes of Endocarditis After Transcatheter Aortic Valve Replacement in the United States.
This study sought to evaluate the incidence and outcomes of endocarditis after transcatheter aortic valve replacement (TAVR). Data about endocarditis after TAVR are limited. The study investigated Medicare patients who underwent TAVR from 2012 to 2017 and identified patients admitted with endocarditis during follow-up using a validated algorithm. The main study outcome was all-cause mortality. Of 134,717 patients who underwent TAVR, 1868 patients developed endocarditis during follow-up (incidence 0.87%/year), with majority of infections (65.0%) occurring within 1 year. Incidence of endocarditis declined in recent years. The most common organisms were Staphylococcus (22.0%), Streptococcus (20.0%), and Enterococcus (15.5%). Important predictors for endocarditis were younger age at TAVR, male sex, prior endocarditis, end-stage renal disease, repeat TAVR procedures, liver and lung disease, and post-TAVR acute kidney injury. Thirty-day and 1-year mortality were 18.5% and 45.6%, respectively. After adjusting for comorbidities and procedural complications, endocarditis after TAVR was associated with 3-fold higher risk of mortality (44.9 vs. 16.2 deaths per 100 person-years; adjusted hazard ratio [aHR]: 2.94; 95% confidence interval [CI]: 2.77 to 3.12; p < 0.0001). End-stage renal disease (aHR: 2.12; 95% CI: 1.72 to 2.60), endocarditis complicated by cardiogenic shock (aHR: 2.50, 95% CI: 1.56 to 4.02), ischemic stroke (aHR: 1.56; 95% CI: 1.07 to 2.28), intracerebral hemorrhage (aHR: 1.67; 95% CI: 1.01 to 2.76), acute kidney injury (aHR: 1.44; 95% CI: 1.27 to 1.63), blood transfusion (aHR: 1.28; 95% CI: 1.09 to 1.50), staphylococcal (aHR: 1.71; 95% CI: 1.49 to 1.97), and fungal endocarditis (aHR: 1.72; 95% CI: 1.23 to 2.39) (p < 0.05 for all) portended higher mortality following endocarditis. The incidence of endocarditis after TAVR is low and declining. However, it is associated with poor prognosis with one-half the patients dying within 1 year.


Brainstem Volumetric Integrity in Preclinical and Prodromal Alzheimer's Disease.
Neuropathological studies have suggested the tau pathology observed in Alzheimer's disease (AD) originates in brainstem nuclei, but no studies to date have quantified brainstem volumes in clinical populations with biomarker-confirmed mild cognitive impairment (MCI) or dementia due to AD or determined the value of brainstem volumetrics in predicting dementia. The present study examined whether MRI-based brainstem volumes differ among cognitively normal older adults and those with MCI or dementia due to AD and whether preclinical brainstem volumes predict future progression to dementia. Alzheimer's Disease Neuroimaging Initiative participants (N = 1,629) underwent baseline MRI scanning with variable clinical follow-up (6-120 months). Region of interest and voxel-based morphometric methods assessed brainstem volume differences among cognitively normal (n = 814), MCI (n = 542), and AD (n = 273) participants, as well as subsets of cerebrospinal fluid biomarker-confirmed MCI (n = 203) and AD (n = 160) participants. MCI and AD cases showed smaller midbrain volumes relative to cognitively normal participants when normalizing to whole brainstem volume, and showed smaller midbrain, locus coeruleus, pons, and whole brainstem volumes when normalizing to total intracranial volume. Cognitively normal individuals who later progressed to AD dementia diagnosis exhibited smaller baseline midbrain volumes than individuals who did not develop dementia, and voxel-wise analyses revealed specific volumetric reduction of the locus coeruleus. Findings are consistent with neuropathological observations of early AD-related pathology in brainstem nuclei and further suggest the clinical relevance of brainstem substructural volumes in preclinical and prodromal AD.


Dysphagia due to cervical osteophytes: a controversial entity revisited.
Although cervical osteophytes have been reported to cause dysphagia, most remain clinically silent. A case of osteophytic dysphagia is reported in which an unusually large osteophytic ridge caused marked deviation and narrowing of the cervical esophagus. The subject of osteophytic dysphagia is reviewed.


Analysis of Interaction Between Porphyromonas gingivalis and Endothelial Cells In Vitro.
Chronic periodontitis is the most common periodontitis observed in adults. Recently, its association with systemic diseases such as ischemic heart-brain disease and diabetes has been pointed out. Porphyromonas gingivalis, a major causative bacterium of chronic periodontitis, has properties of adhering to blood vessels and inducing inflammation, and those properties are involved in the induction of vascular inflammation and promotion of atherosclerosis. Therefore, analysis of the interaction of P. gingivalis with vascular endothelial cells will contribute to an understanding of the link between periodontitis and vascular lesions.


Evaluation of adenosine 5'-diphosphate (ADP)- and collagen-induced platelet aggregation in canine leishmaniasis.
Leishmania-infected dogs, which represent an important reservoir of infection in many parts of the world, frequently suffer from haematological disorders, including thrombocytopenia. In this study, the ability of platelets from healthy (control) dogs (n = 11) and from dogs with naturally acquired clinical leishmaniasis (n = 24) to aggregate in the presence of two different agonists (adenosine 5'-diphosphate [ADP] and collagen) was assayed. Haematological parameters examined consisted of the platelet count, prothrombin time, activated partial thromboplastin time (aPTT), fibrinogen concentration and D-dimer concentration. In dogs with leishmaniasis, a significant decrease in ADP- and collagen-induced platelet aggregation was observed. Compared with platelets from the control dogs, those from leishmania-infected dogs showed a higher sensitivity to collagen, as demonstrated by a reduction in platelet aggregation of up to 20.4%, and a significant (P < 0.0001) difference for all the doses tested. With ADP the reduction was up to 10.4%, the difference reaching a significant level of P < 0.0001 only at the maximum dose used. The nature of this response, which was not accompanied by any clinical signs of bleeding other than an increase in aPTT, emphasizes the role of platelets in the parasite-host cell interaction.


Transformation of phenazone-type drugs during chlorination.
Chlorination is one of the most popular disinfection steps for water treatment in Europe. However, chlorine can react with pharmaceuticals and other micropollutants leading to either their elimination or by-products being formed. These by-products are frequently not identified and therefore the consequences of chlorination can be underestimated. In this work, the degradation of two analgesics and antipyretics, phenazone (antipyrine) and propyphenazone, during chlorination was investigated by liquid chromatography-mass spectrometry (LC-MS). A quadrupole-time-of-flight (Q-TOF) system was used to follow the time course of the pharmaceuticals, and also used in the identification of the by-products. The degradation kinetics was investigated at different concentrations of chlorine (1-10 mg/L), bromide (0-100 μg/L) and sample pH (5.7-8.3) by means of a Box-Behnken experimental design. Depending on these factors, half-lives were in the ranges: 0.9-295 s for phenazone and 0.4-173 s for propyphenazone. Also, it was observed that chlorine concentration was a significant factor for propyphenazone, resulting in increased degradation rate as it is increased. The transformation path of these drugs consisted mainly of halogenations, hydroxylations and dealkylations. After several days of reaction two derivatives remained stable for phenazone: chloro-hydroxy-phenazone and N-demethyl-chloro-hydroxy-phenazone and two for propyphenazone: N-demethyl-hydroxy-propyphenazone and N-demethyl-chloro-hydroxy-propyphenazone. Moreover, experiments conducted with real water matrices, tap and surface water, showed that reaction, and formation of by-products, can take place both at the emission source point (household) and during drinking water production.


Cocaine: peak time of action on isolation-induced fighting.
Cocaine (35 mg/kg i.p.) produced a peak increase in fighting duration in isolated male ICR mice at 30 minutes. However, the crest of this peak ranged from 15--45 minutes. During the offset period (45--120 min.), fight duration remained elevated, but at a lower level. At 240 and 360 minutes, fighting had essentially returned to control levels. The results coincide with peak effects reported by others for locomotor activity, stereotypy, and other cocaine-induced behaviors in animals but later than physiological and subjective parameters measured in human volunteers (cocaine addicts) after intravenous and intranasal administration of the drug.


Ligands playing musical chairs with G-quadruplex DNA: a rapid and simple displacement assay for identifying selective G-quadruplex binders.
We report here the details of G4-FID (G-quadruplex fluorescent intercalator displacement), a simple method aiming at evaluating quadruplex-DNA binding affinity and quadruplex- over duplex-DNA selectivity of putative ligands. This assay is based on the loss of fluorescence upon displacement of thiazole orange from quadruplex- and duplex-DNA matrices. The original protocol was tested using various quadruplex- and duplex-DNA targets, and with a wide panel of G-quadruplex ligands belonging to different families (i.e. from quinacridines to metallo-organic ligands) likely to display various binding modes. The reliability of the assay is further supported by comparisons with FRET-melting and ESI-MS assays.


Pseudoaneurysm of Left Ventricle following Staphylococcal Pericarditis in a Child.
Formation of pseudo-aneurysm of the left ventricle is a rare entity particularly in the pediatric age group. We report a case of a pseudo-aneurysm of the left ventricle in a 6-year-old boy who initially presented to us with staphylococcus aureus septicemia. The left ventricular pseudo-aneurysm was surgically resected and the boy was discharged in a healthy condition.


Novel sugar-cholestanols as anticancer agents against peritoneal dissemination of tumor cells.
Chemically synthesized sugar-cholestanols with mono-, di-, and tri-saccharides attached to cholestanol showed strong inhibiting activity against the proliferation of colorectal and gastric cancer cells. In contrast, cholestanol without sugar moieties was totally ineffective. Furthermore, when cancer cells were exposed to GlcNAcRbetacholestanol (R=(-) or beta1-3Gal), the compound was rapidly taken up via the lipid rafts/microdomains on the cell surface. The uptake of sugar-cholestanol in mitochondria increased gradually and was followed by the release of cytochrome c from mitochondria and the activation of apoptotic signals through the mitochondrial pathway and the caspase cascade, leading to apoptotic cell death, characterized by DNA ladder formation and nuclear fragmentation. Additionally, the examination of GlcNAcRbetacholestanol in a mouse model of peritoneal dissemination showed a dramatic reduction of tumor growth (P < 0.003) and prolonged mouse survival time (P<0.0001). Based on these observations, we believe that the sugar-cholestanols described here have clinical potential as novel anticancer agents.


The developmental segregation of posterior crista and saccular vestibular fibers in mice: a carbocyanine tracer study using confocal microscopy.
The developmental segregation of gravistatic input mediated by saccular fibers and of angular acceleration input mediated by posterior crista (PC) fibers was analyzed for the first time in a developing mammal using carbocyanine dye tracing in fixed tissue. The data reveal a more extensive projection of either endorgan in 7-day-old mice (P7) than has previously been reported in adult mammals. While we confirm and extend many previous findings, we also describe a novel segregation of saccular and posterior crista fibers in the anterior half of the medial vestibular nucleus (Mv) not reported before. Our developmental analysis shows a progressive segregation of posterior crista and saccular fibers to their respective discrete projection areas between embryonic day 15 (E15) and birth (P0). Retention of overlap in young adult animals appears to reflect the early embryonic overlap found in most areas. The vestibular projection does not show a topological projection as has been described in many other sensory systems. We propose that the unique projection features of the vestibular endorgans may relate to the transformation of vestibular signals into a motor output in the three neuron reflex arc of the VOR, of which the primary vestibular projection constitutes the first leg.


Challenges in accurate registration of 3-D medical imaging and histopathology in primary prostate cancer.
Due to poor correlation between slice thickness and orientation, verification of medical imaging results by histology is difficult. Often validation of imaging findings of lesions suspicious for prostate cancer is driven by a subjective, visual approach to correlate in vivo images with histopathology. We describe fallacious assumptions in the correlation of imaging findings with pathology and identify the lack of accurate registration as a major obstacle in the validation of PET and PET/CT imaging in primary prostate cancer. Specific registration techniques that facilitate the most difficult part of the registration process--the mapping of pathology onto high-resolution imaging, preferably aided by the ex vivo prostate specimen--are discussed.


Localisation of a group of antigenic sites in complement component C3, and identification of a new fragmentation pattern.
Immunisation of rabbits or goats with denaturated human C3 reproducibly gives rise to an antiserum of restricted specificity which precipitates native C3, C3b and iC3b, but not C3c or C3d isolated from 'aged' serum. The antigenic sites recognised by the antiserum appear to be localised in a small segment of the polypeptide chain located close to the N-terminus of the C3b alpha' chain. Affinity chromatography using antibodies developed by this procedure reveals an unusual pattern of degradation of C3 which occurs on conventional 'ageing' of serum at 37 degrees C.


Per-pathogen virulence of HIV-1 subtypes A, C and D.
HIV-1 subtypes differ in their clinical manifestations and the speed in which they spread. In particular, the frequency of subtype C is increasing relative to subtypes A and D. We investigate whether HIV-1 subtypes A, C and D differ in their per-pathogen virulence and to what extend this explains the difference in spread between these subtypes. We use data from the hormonal contraception and HIV-1 genital shedding and disease progression among women with primary HIV infection study. For each study participant, we determine the set-point viral load value, CD4+ T cell level after primary infection and CD4+ T cell decline. Based on both the CD4+ T cell count after primary infection and CD4+ T cell decline, we estimate the time until AIDS. We then obtain our newly introduced measure of virulence as the inverse of the estimated time until AIDS. After fitting a model to the measured virulence and set-point viral load values, we tested if this relation varies per subtype. We found that subtype C has a significantly higher per-pathogen virulence than subtype A. Based on an evolutionary model, we then hypothesize that differences in the primary length of infection period cause the observed variation in the speed of spread of the subtypes.


Enantiomerically pure bicyclo[3.3.1]nona-2,6-diene as the sole source of enantioselectivity in BIPHEP-Rh asymmetric hydrogenation.
In situ resolution of the rapidly racemising diphosphine BIPHEP and its relatives with the cationic Rh complex of (S,S)-bicyclonona-2,6-diene permits the asymmetric hydrogenation of dehydroamino esters.


A noninvasive method of estimating patient-specific left ventricular pressure waveform.
The left ventricular pressure waveform is indispensable for the construction of the pressure strain loop when investigating coronary artery disease (CAD) patients. In previous studies by others, exclusion of CAD patients has not allowed a reliable estimation of the left ventricular pressure waveform from the pressure strain loop of these patients. To remedy this, we propose a patient-specific noninvasive method for the estimation of left ventricular pressure. A simplified systemic circulation model consisting primarily of a single fiber model and a 1D simulation of the arterial tree was used. Sensitivity analysis based on the Morris method was performed to select a subset of the important parameters. Following this, the important parameter subset and the set of all the parameters were identified in the model using the pressure waveform of a peripheral artery as input, in a two-step process. In addition, the left ventricular pressure waveform was estimated using the set of all parameters. Reducing the size of the parameter subset significantly decreases the computational cost of parameter optimization in the first step and greatly simplifies the identification of the full parameter set in the second step. Comparison with the reference left ventricular pressure waveform from CAD patients, showed that the proposed method provides a good estimate of the reference left ventricular pressure waveform. The correlation coefficients between the estimated and reference were r = 0.907, r = 0.904 and r = 0.780 for systolic blood pressure, pulse pressure and mean blood pressure, respectively. This work may provide a convenient surrogate for the estimation of the left ventricular pressure waveform.


Circadian learning and memory changes in Aβ1-42 induced Alzheimer's mice.
Alzheimer disease (AD) is a growing health problem globally, which causes a progressive decline in learning and memory and multiple disturbances of circadian rhythms. Six Alzheimer's mice and six wild type (WT) mice were involved in this study. Morris Water Maze (MWM) tasks were conducted hourly to evaluate their circadian learning and memory performance. We used a single cosinor-based method to evaluate the circadian learning and memory of Alzheimer's mice and WT mice, respectively. An area sensor was used to record locomotor activity for 2 weeks continuously, including 7 days of 12 h light/12 h dark (LD) conditions and 7 days of 12 h dark/12 h dark (DD) conditions. All WT mice showed circadian rhythm presence in learning and memory, and the peak of escape latency appeared at circadian time (CT) 12. Only one in six Alzheimer's mice showed a circadian rhythm, but the peak of escape latency was postponed to CT20. Alzheimer's mice showed rhythm absence under LD or DD conditions. Under LD conditions, the WT mice activity was higher than that in the Alzheimer's mice during ZT0-5 (p = 0.007) and ZT18-23 (p = 0.353) but lower during ZT6-11 (p < 0.001) and ZT12-17 (p < 0.001). Learning and memory of wild type mice is proved to have a circadian variation throughout a day. In Alzheimer's mice, rhythmic locomotor activity and circadian learning and memory performance were disrupted. Understanding the role of rhythmic disturbances in the process of AD may assist to identify therapeutic targets.


Changes in production, yield, and chemical composition of corn (Zea mays) after ultrasound treatments of the seeds.
In the spring of each year (1972-1974) air-dry grains of two inbred lines of Z. mays (7275-13-1 and 106) were exposed for 17 h to a low level (25 kHz) of ultrasound and subsequently planted in the field together with untreated controls and grown to maturity. In the fall of each year the ears of each group were harvested and the number of broken stalks, the yield and weight of grains and grain parts and the alcohol-soluble amino acid complement of the grain parts were determined. Broken stalks and yields were unaffected, however the embryos from the treated groups retained more moisture than their respective controls, dry weights were also significantly increased. The alcohol-soluble amino acid composition of the embryos was markedly changed, levels of proline were severely depressed in the embryos of both lines and generally increased in the endosperms. Sonication resulted in an overall decrease of up to 40% in totalled alcohol-soluble amino acids in the grains of 7275-13-1.


Researching Nursing Students' Attitudes toward Mental Health Practice: Cultural Adaptation and Validation of the Greek Version of the Acceptability of Locking the Door Questionnaire in Acute Psychiatric Care.
The present article describes the cultural adaptation and validation of the Greek version of the Acceptability of Locking the Door Questionnaire and aims to determine students' preference regarding mental health nursing as a possible career choice. The linguistic adaptation of the original instrument was performed according to the most recent guidelines and it was then administered to 274 third-year nursing students. Results support the validity and reliability of the instrument, which can be used to assess effectively the attitudes of the intended population. Sixty per cent of students considered mental health nursing as a possible career choice. Research on students' attitudes appeared to be a strategy of creating the space for lively discussions among them and capturing their interest in mental health education and practice. Theoretical preparation and clinical placements of mental health nursing students should incorporate strategies to improve their perceptions of working in mental health settings.


Societal burden and quality of life in patients with Lisfranc Injuries.
The incidence of Lisfranc fractures is rising, along with the incidence of foot fractures in general. These injuries can lead to long-term healthcare use and societal costs. Current economic evaluation studies are scarce in Lisfranc fracture research, and only investigate the healthcare costs. The aim of the present study was to accurately measure the monetary societal burden of disease and quality of life in the first 6 months after the injury in patients with Lisfranc fractures in the Netherlands. This study used a prevalence-based, bottom-up approach. Patients were included through thirteen medical centres in the Netherlands. Both stable and unstable injuries were included. The societal perspective was used. The costs were measured at baseline, 12 weeks and 6 months using the iMTA MCQ and PCQ questionnaires. Reference prices were used for valuation. Quality-of-life was measured using the EQ-5D-5 L and VAS scores. 214 patients were included. The mean age was 45.9 years, and 24.3% of patients had comorbidities. The baseline questionnaires yielded approximately €2023 as the total societal costs in the 3 months prior to injury. The follow-up questionnaires and surgery costs assessment yielded approximately €17,083 as the total costs in the first 6 months after injury. Of these costs, approximately two thirds could be attributed to productivity losses. The EQ-5D-5 L found a mean index value of 0.449 at baseline and an index value of 0.737 at the 6-month follow-up. The total monetary societal costs in the first 6 months after injury are approximately €17,083. Approximately two thirds of these costs can be attributed to productivity losses. These costs appear to be somewhat higher than those found in other studies. However, these studies only included the healthcare costs. Furthermore, the baseline costs indicate relatively low healthcare usage before the injury compared to the average Dutch patient. The mean QoL index was 0.462 at baseline and 0.737 at 6 months, indicating a rise in QoL after treatment as well as a long-lasting impact on QoL. To our knowledge, this is only the first study investigating the societal costs of Lisfranc injuries, so more research is needed.


Pre-cystectomy radiation for carcinoma of the bladder: 17-year experience.
Our experience with pre-cystectomy radiation for carcinoma of the bladder from July 1959 through June 1976 is presented. Pre-cystectomy radiation would appear to be beneficial in the management of patients with invasive bladder cancer. There is an impressive improvement in survival rates in those patients demonstrating reduction in staging after radiation. Our experience correlates well with other comparative series. Based on this 17-year experience guide lines are outlines for the subsequent management of patients with bladder cancer.


A phase II trial of dose-dense (biweekly) paclitaxel plus carboplatin as neoadjuvant chemotherapy for operable breast cancer.
The aim of the present study is to investigate the efficacy and safety of dose-dense (biweekly) carboplatin and paclitaxel as a neoadjuvant treatment for operable breast cancer. Patients with previously untreated breast cancer (stages Ic-III) were treated with four cycles of paclitaxel (175 mg/m(2), intravenous drip, D1) and carboplatin (area under the curve of 5, D1). Patients with HER2+ disease simultaneously received trastuzumab (6 mg/kg initial dose with subsequent doses of 4 mg/kg biweekly). The primary endpoint was a pathologically complete response (pCR). Between January 2012 and February 2014, 110 patients were enrolled. The overall pCR rate was 35.45 % (39 of 110). The pCR rates for the different cancer subtypes were as follows: 10.53 % (2 of 19) among the patients with the luminal A subtype, 12.50 % (5 of 40) among the patients with the luminal B (HER2-) subtype, 58.33 % (14 of 24) among the patients with the luminal B (HER2+) subtype, 57.14 % (8 of 14) among the patients with the triple-negative subtype, and 76.92 % (10 of 13) among the patients with the HER2+ subtype. The patients experienced the following toxicity side effects: grade 3/4 neutropenia (N = 27, 24.55 %), grade 3/4 anemia (N = 6, 5.45 %), grade 3/4 thrombocytopenia (N = 2, 1.82 %), grade 3 alanine aminotransferase (ALT) elevation (N = 1, 0.91 %), grade 3 neuropathy (N = 3, 2.73 %), grade 3 pain (N = 2, 1.82 %), and grade 3 fatigue (N = 1, 0.91 %). In total, 19.09 % of the patients experienced treatment delay or discontinuation due to hematological toxicity, and one patient discontinued treatment due to non-hematological toxicity. Neoadjuvant biweekly paclitaxel plus carboplatin is a feasible therapy that achieved high pCR rates in patients with the HER2+, triple-negative, and luminal B (HER2+) cancer subtypes (NCT0205986).


Hyperuricemia induces endothelial dysfunction via mitochondrial Na+/Ca2+ exchanger-mediated mitochondrial calcium overload.
Uric acid (UA) has proven to be a causal agent in endothelial dysfunction in which ROS production plays an important role. Calcium overload in mitochondria can promote the mitochondrial production of ROS. We hypothesize that calcium transduction in mitochondria contributes to UA-induced endothelial dysfunction. We first demonstrated that high concentrations of UA cause endothelial dysfunction, marked by a reduction in eNOS protein expression and NO release in vitro. We further found that a high concentration of UA increased levels of [Ca2+]mito, total intracellular ROS, H2O2, and mitochondrial O2·-, and Δψmito but not the [Ca2+]cyt level. When the mitochondrial calcium channels NCXmito and MCU were blocked by CGP-37157 and Ru360, respectively, the UA-induced increases in the levels of [Ca2+]mito and total intracellular ROS were significantly reduced. Mitochondrial levels of O2·- and Δψmito were reduced by inhibition of NCXmito but not of MCU. Moreover, inhibition of NCXmito, but not of MCU, blocked the UA-induced reductions in eNOS protein expression and NO release. The increased generation of mitochondrial O2·- induced by a high concentration of UA is triggered by mitochondrial calcium overload and ultimately leads to endothelial dysfunction. In this process, the activation of NCXmito is the major cause of the influx of calcium into mitochondria. Our results provide a new pathophysiological mechanism for UA-induced endothelial dysfunction and may offer a new therapeutic target for clinicians.


Characteristics of hyperthermia and its complications in patients with Prader Willi syndrome.
Thermoregulation problems, resulting in hypo- or hyperthermia, have been infrequently reported in children with Prader Willi syndrome (PWS), yet their clinical details remained unknown. The clinical characteristics of three infants with PWS are reported. Etiologies of high fever could not be identified in three children with PWS. One of these children was also admitted to the intensive care unit with extremely high body temperature in a life-threatening condition, similar to septic shock, without a plausible explanation. Hyperthermia may be a part of the clinical spectrum in young infants with PWS and should be carefully monitored, since it may cause life-threatening complications.


Experimental removal of invasive Africanized honey bees increased breeding population size of the endangered Lear's macaw.
Invasive Africanized honey bees potentially compete with cavity-nesting birds in South America. However, the impacts of this competition and its conservation consequences to threatened species are poorly known. We quantified the presence of these bees and assessed their competition for cliff cavities used by nesting Lear's macaws Anodorhynchus leari, a globally endangered parrot endemic to the Caatinga biome of Brazil. We treated beehives with permethrin by shooting them with a crossbow bolt that distributed the compound upon impact. When feasible, we removed the comb and applied an insecticide (fipronil) to deter bee recolonization. We subsequently surveyed the macaw breeding population to verify whether our treatment allowed for nest recruitment in cavities previously occupied by bees. We recorded > 100 beehives in the nesting cliffs. Hives outnumbered macaw nests tenfold in two areas recently recolonized by macaws. Cavities occupied by bees were significantly higher than those occupied by macaws, suggesting that macaws may be forced to breed in lower cavities. None of the untreated cavities (n = 50) were occupied by nesting macaws, whereas 15% of treated cavities (n = 52) were occupied within 2 years post treatment. Treated cavities occupied by macaws were significantly higher than those not occupied. Hive management increased macaw breeding population by 71% of the macaw breeding population increase. Experimental hive treatments were effective in restoring nesting resources lost due to bee infestation. An intensive and continued eradication program is recommended to enhance macaw habitat restoration, facilitating its expansion into historical areas. © 2020 Society of Chemical Industry.


Enzymatic basis of metal ion alterations of cellular heme and glutathione metabolism.
It is becoming increasingly apparent that the enzymes of heme and GSH metabolism pathways are extremely sensitive to metal ions. It follows that alterations in the activities of the enzymes of heme metabolism are often reflected in the heme dependent cellular functions, particularly those which depend on cytochrome P-450. Moreover, perturbations in cellular GSH levels may alter the biological inactivation of the intermediates of cytochrome P-450 activity normally inactivated by GSH-conjugation. The effects of transition and heavy metal ions on the heme metabolism pathway are perhaps of particular significance when exerted on the two key enzymes of the pathway: the delta-aminolevulinate synthetase, the initial and the rate-limiting enzyme of the heme biosynthetic pathway, and heme oxygenase, the rate-limiting enzyme of heme degradation pathway. The activities of other enzymes of the heme metabolism pathway are also effected by metal ions; the nature of the effect is generally that of inhibition. Similarly, the inhibition by heavy metal ions of the activities of GSSG-reductase, gamma-glutamylcysteine synthetase, and gamma-glutamyl transpeptidase, which are the key enzymes of GSH metabolism, have toxicological significance. However, it is important to recognize that the presently discussed effects of metal ions do not necessarily have negative biological implications. The rather intricate and interrelated effects of metal ions on heme and GSH metabolism pathway under certain circumstances may have positive ramifications.


Depigmentation Therapies for Vitiligo.
The general goals of medical management of vitiligo are to repigment vitiliginous areas of skin and to stabilize the progression of depigmentation. However, for some patients with vitiligo affecting extensive body surface areas who are unresponsive to repigmentation therapies, depigmentation of the remaining normal skin may be a better choice. Candidates for depigmentation therapy should be carefully screened and patient education is essential. Permanent topical therapies used for depigmentation include monobenzyl ether of hydroquinone, 4-methoxyphenol, and 88% phenol. Physical modalities, such as cryotherapy and lasers, are also being used successfully.


Bilirubin interactions with phospholipid components of lung surfactant.
This work examines the dynamic surface pressure-area behavior of films of unconjugated bilirubin spread from chloroform solution at 22 degrees C on 0.15 M NaCl and buffered phosphate subphases. Film behavior is examined at pH 5.5, 7.4 and 8.0. The interactions of bilirubin in mixed films with dipalmitoyl phosphatidylcholine and with 9:1 dipalmitoyl phosphatidylcholine:dioleolyl phosphatidylcholine are examined at similar temperature and pH values. It is found that unconjugated bilirubin modifies the dynamic surface pressure-area behavior of phospholipid films in both the high and low surface pressure regimes, with bilirubin exerting its greatest effect at low pH where its subphase solubility is low. Because many premature infants suffering from the Respiratory Distress Syndrome (RDS) have accompanying hyperbilirubinemia, with possible bilirubin transport to the alveolar space, the interactions of bilirubin with phospholipid films are discussed in terms of potential effects on pulmonary surfactant in vivo.


Potential effect of heat adaptation on association between number of heatstroke patients transported by ambulance and wet bulb globe temperature in Japan.
This study analyzed the association between heatstroke incidence and daily maximum wet bulb globe temperature (WBGT) for all 47 prefectures in Japan by age group and severity using time-series analysis, controlling for confounders, such as seasonality and long-term trends. With the obtained association, the relative risk between the reference WBGT (defined as the value at which heatstroke starts to increase) and the daily maximum WBGT at 30 °C (RRwbgt30) of each prefecture were calculated. For the heatstroke data, the daily number of heatstroke patients transported by ambulance at the prefecture level, provided by the Fire and Disaster Management Agency, was utilized. The analysis was conducted for age groups of 7-17 y, 18-64 y, and ≥65 y, and for severity of Deceased, Severe, Moderate (combined as DSM), and Mild. The analysis period was set from May 1 to September 30, 2015-2019. Finally, the correlation between RRwbgt30 and the average daily maximum WBGT during the analysis period (aveWBGTms) of each prefecture was analyzed to examine the regionality of heatstroke incidence. The result showed that RRwbgt30 is negatively correlated with aveWBGTms for the age group 18-64 y and ≥65 y (except for the age group 7-17 y) and for severity. The natural logarithm of the RRwbgt30 of all 47 prefectures ranged from 2.0 to 8.2 for the age group 7-17 y, 1.1 to 4.0 for the age group 18-64 y, 1.8 to 6.0 for the age group ≥65 y, and 1.0 to 3.6 for DSM, and 0.9 to 4.0 for Mild. This regionality can be attributed to the effects of heat adaptation, where people in hotter regions are accustomed to implementing measures against hot environments and are more heat acclimatized than people in cooler regions.


Reduction of spontaneous alcohol drinking and physical withdrawal by levemopamil, a novel Ca2+ channel antagonist, in rats.
Neuronal Ca2+ channels have been shown to be involved in both alcohol drinking behavior in rats and nonhuman primates and in the manifestation of alcohol withdrawal symptoms in rodents. Experiments were performed to determine the effect of a single injection of levemopamil, a novel Ca2+ channel antagonist with antiserotonergic [5-hydroxytryptamine2 (5-HT2)] properties, on alcohol preference and alcohol withdrawal symptoms in alcohol-preferring (P) and Wistar rats, respectively. P rats were individually housed and provided free access to food, water, and a solution of 10% (v/v) ethanol. Ethanol, food, and water intakes were measured daily. After establishing a stable baseline, P rats were injected with levemopamil (0, 3.3, 10, 15, and 20 mg/kg) and their food, water, and alcohol intakes measured 24 h later. In a separate experiment, the ability of acute and chronic (12 consecutive days) administrations of levemopamil to suppress alcohol withdrawal symptoms in chronically alcohol-treated rats was studied. In addition, the effects of levemopamil on the level of monoamines in different areas of the brain, as well as its action in alcohol metabolism, were examined. Our findings showed that a single administration of levemopamil (10, 15, and 20 mg/kg) significantly and dose-dependently attenuated alcohol intake and increased water intake in P rats. Both acute and chronic treatment with levemopamil reduced the alcohol withdrawal symptoms, overall seizure scores, and proportion of rats seizing. A single injection of levemopamil produced a clear, but not significant, trend to increase the 5-HT turnover rate in certain brain areas. This drug did not influence the pharmacokinetics of alcohol.(ABSTRACT TRUNCATED AT 250 WORDS)


Synthesis of TiO2, TiO2/PAni, TiO2/PAni/GO nanocomposites and photodegradation of anionic dyes Rose Bengal and thymol blue in visible light.
Nowadays, fast-growing industrialization has resulted in the release of enormous amounts of contaminants such as toxic dyes into water bodies and leading to cause health and environmental risks. In this regard, we prepared inorganic nanocomposites for the treatment of toxic dyes. Hence, we synthesized TiO2/PAni/GO nanocomposites and examined them by using XRD, SEM, TEM, UV-Vis spectroscopy, BET analysis, and a photoluminescence investigation. In addition, band gap energies of the nanocomposites were determined, and Total Organic Carbon (TOC) testing was used to determine dye degradation levels. The photocatalytic degradations of Thymol Blue and Rose Bengal dyes were investigated at different dye concentrations, illumination periods, solution pH values, and photocatalyst dosages. By using TiO2/PAni/GO, TiO2/PAni, and TiO2 at neutral pH, a photocatalyst dose of 1600 mg/L, and exposure to visible light, Thymol Blue and Rose Bengal were photodegraded 85-99%, 60-97%, and 10-20%, respectively, at a concentration of 25 ppm (180 min). Reductions in the TOCs confirmed their photodegradation, and a kinetic study revealed photodegradation followed first-order kinetics. This study shows the coating of polyaniline (PAni) and graphene oxide (GO) on TiO2 improved its ability to photodegrade Thymol Blue and Rose Bengal dye.


Deoxynivalenol (DON) in hartweizen.
Deoxynivalenol (DON) in Durum Wheat High contamination levels of deoxynivalenol (DON) were found during an investigation of noodles in 2001 and initiated an additional survey of Durum wheat used as raw material for these products. Analyses of 53 samples of Durum wheat by HPLC revealed 89% positives and a median concentration of 790 ug/kg, which clearly exceeded the EU action level of 500 μg/kg. Based on these findings, producers increased quality controls on Durum wheat. In 2002 a total of 60 samples were analysed and 85% positives found. The median, however, lay at 215 μg/kg, below a probable maximum level of 500 μg/kg and demonstrated the positive efforts of food producers to decrease the contamination levels of DON in pasta products.


22β-hydroxytingenone induces apoptosis and suppresses invasiveness of melanoma cells by inhibiting MMP-9 activity and MAPK signaling.
22β-hydroxytingenone (22-HTG) is a quinonemethide triterpene isolated from Salacia impressifolia (Miers) A. C. Smith (family Celastraceae), which has been used in traditional medicine to treat a variety of diseases, including dengue, renal infections, rheumatism and cancer. However, the anticancer effects of 22-HTG and the underlying molecular mechanisms in melanoma cells have not yet been elucidated. The present study investigated apoptosis induction and antimetastatic potencial of 22-HTG in SK-MEL-28 human melanoma cells. First, the in vitro cytotoxic activity of 22-HTG in cultured cancer cells was evaluated. Then, cell viability was determined using the trypan blue assay in melanoma cells (SK-MEL-28), which was followed by cell cycle, annexin V-FITC/propidium iodide assays (Annexin/PI), as well as assays to evaluate mitochondrial membrane potential, production of reactive oxygen species (ROS) using flow cytometry. Fluorescence microscopy using acridine orange/ethidium bromide (AO/BE) staining was also performed. RT-qPCR was carried out to evaluate the expression of BRAF, NRAS, and KRAS genes. The anti-invasiveness potential of 22-HTG was evaluated in a three-dimensional (3D) model of reconstructed human skin. 22-HTG reduced viability of SK-MEL-28 cells and caused morphological changes, as cell shrinkage, chromatin condensation, and nuclear fragmentation. Furthermore, 22-HTG caused apoptosis, which was demonstrated by increased staining with AO/BE and Annexin/PI. The apoptosis may have been caused by mitochondrial instability without the involvement of ROS production. The expression of BRAF, NRAS, and KRAS, which are important biomarkers in melanoma development, was reduced by the 22-HTG treatment. In the reconstructed skin model, 22-HTG was able to decrease the invasion capacity of melanoma cells in the dermis. Our data indicate that 22-HTG has anti-tumorigenic properties against melanoma cells through the induction of cell cycle arrest, apoptosis and inhibition of invasiveness potential, as observed in the 3D model. As such, the results provide new insights for future work on the utilization of 22-HTG in malignant melanoma treatment.


Difficult-to-Control Asthma Management in Adults.
The management of difficult-to-control asthma remains a significant challenge, which frequently requires the input of the wider multidisciplinary team. This review covers the importance of systematic assessment, phenotyping, treatment options at step 4, an overview of biologics and novel therapies for type 2 (T2) inflammation, and nonpharmacological interventions. Once people have been identified as suffering from difficult-to-control asthma, it is important to use the systematic assessment process to allow accurate diagnosis and optimization of adherence as well as identification and treatment of any relevant comorbidities. Before initiating a biologic, it is important to optimize inhaled therapies and sufficiently phenotype individual patients to allow for the logical use of biologic agents targeting T2 inflammation. For patients who either do not have evidence of T2 inflammation or remain symptomatic despite biologics, attention should be paid to the available nonpharmacological interventions. Difficult-to-treat asthma remains an area of significant unmet need, but improvements in models of service delivery and the ongoing pharmacological pipeline are causes for significant optimism that sooner rather than later there will no longer be asthmatic patients who are difficult to treat.


[Psychiatric Archives: Archive for which History? The Writings and Drawings of René L.]
The archives of the psychiatric institutions are often mobilized to investigate the history of the treatment of mental disorders and its modalities in our societies. From a patient's record, interned in the Hôpital du Bon Sauveur in the department of Manche in France in 1963, this article shows how these archives are part of writing a different story that of decolonization and particularly the independence of Algeria and the end of French colonization. In particular, studied the drawings by this patient and the way it reflects the collective history.


Roles for cardiac MyBP-C in maintaining myofilament lattice rigidity and prolonging myosin cross-bridge lifetime.
We investigated the influence of cardiac myosin binding protein-C (cMyBP-C) and its constitutively unphosphorylated status on the radial and longitudinal stiffnesses of the myofilament lattice in chemically skinned myocardial strips of the following mouse models: nontransgenic (NTG), effective null for cMyBP-C (t/t), wild-type cMyBP-C expressed into t/t (WT(t/t)), and constitutively unphosphorylated cMyBP-C (AllP-(t/t)). We found that the absence of cMyBP-C in the t/t and the unphosphorylated cMyBP-C in the AllP-(t/t) resulted in a compressible cardiac myofilament lattice induced by rigor not observed in the NTG and WT(t/t). These results suggest that the presence and phosphorylation of the N-terminus of cMyBP-C provides structural support and radial rigidity to the myofilament lattice. Examination of myofilament longitudinal stiffness under rigor conditions demonstrated a significant reduction in cross-bridge-dependent stiffness in the t/t compared with NTG controls, but not in the AllP-(t/t) compared with WT(t/t) controls. The absence of cMyBP-C in the t/t and the unphosphorylated cMyBP-C in the AllP-(t/t) both resulted in a shorter myosin cross-bridge lifetime when myosin isoform was controlled. These data collectively suggest that cMyBP-C provides radial rigidity to the myofilament lattice through the N-terminus, and that disruption of the phosphorylation of cMyBP-C is sufficient to abolish this structural role of the N-terminus and shorten cross-bridge lifetime. Although the presence of cMyBP-C also provides longitudinal rigidity, phosphorylation of the N-terminus is not necessary to maintain longitudinal rigidity of the lattice, in contrast to radial rigidity.


A new hydrate form of diflunisal precipitated from a microemulsion system.
Three microemulsion systems were applied as solvents for polymorph screening of seven active pharmaceutical ingredients (APIs): carbamazepine, piroxicam, sulfaguanidine, nitrofurantoin, theophylline, quercetin, and diflunisal. All the recrystallized compounds were examined by using powder X-ray diffractometry, differential scanning calorimetry, elemental analysis, Karl Fischer titration and dissolution rate. A new crystal form of diflunisal hydrate was discovered by the cooling method of recrystallization in a water-in-oil microemulsion system, composed of water, alkane and dioctyl sodium sulfosuccinate. The new hydrate form of diflunisal was characterized and confirmed to be a stoichiometry of diflunisal:water of 1:1. The other two microemulsion systems were able to convert the anhydrous diflunisal Form I to Form III. The dissolution rate of diflunisal hydrate is unexpectedly much higher than that of anhydrous ones (Forms I and III). All the other six APIs (carbamazepine, piroxicam, sulfaguanidine, nitrofurantoin, theophylline and quercetin) recrystallized from the microemulsion systems were all converted into hydrate form.


Instability in the latency of P3a/P3b brain potentials and cognitive function in aging.
Instability in performance is a prominent feature of aging. In this study, 133 participants evenly distributed across the adult lifespan underwent a three-stimulus event-related potentials (ERPs) paradigm, and instability in P3a/P3b latency and reaction time (RT) were measured. P3a is related to alertness or reorientation of attention and it was elicited by distractor stimuli. P3b is related to controlled attentional processes and it was triggered by target stimuli. Maximum-likelihood estimation (MLE) was used to quantify the level of variability in latency across the single sweep ERPs. The results revealed increased variability in RT but not in P3a/P3b latency with age. Variability in P3a/P3b latency was related to executive functions, and variability in RT to speed. Generally, the relationships tended to increase with age. It can be concluded that increased variability in RT with age is caused by instability in processes related to response execution and possibly response selection, but not stimulus classification. Further, the results indicate that intraindividual variability is not a uniform concept, but has unique explanatory value at the neurophysiological and behavioral level.


Xanthine oxidase/hydrogen peroxide generates sulfur trioxide anion radical (SO3.-) from sulfite (SO3(2-)).
In the presence of hydrogen peroxide (H2O2), xanthine oxidase has been found to catalyze sulfur trioxide anion radical (SO3.-) formation from sulfite anion (SO3(2-)). The SO3.- radical was identified by ESR (electron spin resonance) spin trapping, utilizing 5,5-dimethyl-l-pyrroline-l-oxide (DMPO) as the spin trap. Inactivated xanthine oxidase does not catalyze SO3.- radical formation, implying a specific role for this enzyme. The initial rate of SO3.- radical formation increases linearly with xanthine oxidase concentration. Together, these observations indicate that the SO3.- generation occurs enzymatically. These results suggest a new property of xanthine oxidase and perhaps also a significant step in the mechanism of sulfite toxicity in cellular systems.


PPARγ Regulation in Hypertension and Metabolic Syndrome.
Dysregulation of peroxisome proliferator-activated receptor gamma (PPARγ) activity leads to significant alterations in cardiovascular and metabolic regulation. This is most keenly observed by the metabolic syndrome-like phenotypes exhibited by patients carrying mutations in PPARγ. We will summarize recent findings regarding mechanisms of PPARγ regulation in the cardiovascular and nervous systems focusing largely on PPARγ in the smooth muscle, endothelium, and brain. Canonically, PPARγ exerts its effects by regulating the expression of target genes in these cells, and we will discuss mechanisms by which PPARγ targets in the vasculature regulate cardiovascular function. We will also discuss emerging evidence that PPARγ in the brain is a mediator of appetite and obesity. Finally, we will briefly review how novel PPARγ activators control posttranslational modifications of PPARγ and their prospects to offer new therapeutic options for treatment of metabolic diseases without the adverse side effects of thiazolidinediones which strongly activate transcriptional activity of PPARγ.


The new robotic platform Hugo™ RAS for lateral transabdominal adrenalectomy: a first world report of a series of five cases.
Robotic assisted surgery is the most rapidly developing field of minimally invasive surgery. Its wide diffusion has led to the development and standardization of robotic-assisted approaches also for adrenalectomy. In this study, we present the first five robotic-assisted lateral transabdominal adrenalectomies performed with the new Hugo RAS™ system (Medtronic, Minneapolis, MN, USA). After an official training course of the surgical team, five consecutive patients scheduled for unilateral adrenalectomy, underwent robotic-assisted operations in our institution. Patients that were candidates for partial adrenalectomy were excluded. A description of the operating theatre, robotic arms and docking setup is provided. Four female and one male patient underwent lateral transabdominal adrenalectomy, three for lesions on the left side and two on the right. Median lesion size was 3.9 cm (range: 30-90) and preoperative diagnosis was Cushing's syndrome in three patients, an adrenal cystic lesion and a pheochromocytoma. The median docking time was 5 min (range: 5-8) and the median console time was 55 min (range: 29-108). Procedures were performed without intraoperative complications and no conversions or additional ports were needed. System's function and docking were uneventful. Based on our initial experience, adrenalectomy with the Hugo™ system is feasible. This study provides technical notes for other centres that wish to perform robotic-assisted adrenalectomies with the Hugo™ RAS as well as general information and our preliminary insights on this new platform.


Evaluation of intervention measures in reducing the driver's exposure to respiratory particles in a taxi with infected passengers.
In the fifth wave of the COVID-19 epidemic in Hong Kong in early 2022, the large number of infected persons caused a shortage of ambulances and transportation vehicles operated by the government. To solve the problem, taxi drivers were recruited to transport infected persons to hospitals in their taxis. However, many of the drivers were infected after they began to participate in the plan. To tackle this issue, the present study numerically evaluated the effectiveness of several intervention measures in reducing the infection risk for taxi drivers. First, experiments were conducted inside a car to validate the large-eddy simulation (LES)-Lagrangian model for simulation of particle transport in a car. The validated model was then applied to calculate the particle dispersion and deposition in a Hong Kong taxi with intervention measures that included opening windows, installing partitions, and using a far-UVC lamp. The results show that opening the windows can significantly reduce the driver's total exposure by 97.4 %. Installing partitions and using a far-UVC lamp can further reduce the infection risk of driver by 55.9 % and 32.1 %, respectively. The results of this study can be used to support the implementation of effective intervention measures to protect taxi drivers from infection.


Expression of NMDA glutamate receptor subunit mRNAs in neurochemically identified projection and interneurons in the striatum of the rat.
NMDA receptors are composed of proteins from two families: NMDAR1 and NMDAR2. We used quantitative double-label in situ hybridization to examine in rat brain the expression of NMDAR1, NMDAR2A, NMDAR2B, and NMDAR2C mRNA in six neurochemically defined populations of striatal neurons: preproenkephalin (ENK) and preprotachykinin (SP) expressing projection neurons, and somatostatin (SOM), glutamic acid decarboxylase 67 (GAD67), parvalbumin (PARV), and choline acetyltransferase (ChAT) expressing interneurons. NMDAR1 was expressed by all striatal neurons: strongly in ENK, SP, PARV and ChAT neurons, and less intensely in SOM and GAD67 positive cells. NMDAR2A mRNA was present at moderate levels in all striatal neurons except those containing ChAT. Labeling for NMDAR2B was strong in projection neurons and ChAT interneurons, and only moderate in SOM, GAD67 and PARV interneurons. NMDAR2C was scarce in striatal neurons, but a low level signal was detected in GAD67 positive cells. NMDAR2C expression was also observed in small cells not labeled by any of the markers, most likely glia. These data suggest that all striatal neurons have NMDA receptors, but different populations have different subunit compositions which may affect function as well as selective vulnerability.


Overexpression of CEACAM6 in borderline and invasive mucinous ovarian neoplasms.
Identifying markers specific for mucinous ovarian neoplasms (MON) is important for cancer diagnosis and surveillance, and will help improve our general understanding of the pathobiology of these tumors. CEACAM6 overexpression appears to be an early molecular event with prognostic significance in gastrointestinal carcinomas. Microarray analysis previously demonstrated high CEACAM6 overexpression in MON's and this study sought to validate this finding. Western blot compared CEACAM6 expression in normal human ovarian surface epithelium (HOSE) and ovarian cancer cell lines. Quantitative RT-PCR (qRT-PCR) was performed on 75 laser-microdissected HOSE and ovarian cancer tissue samples. Immunohistochemistry (IHC) was performed and slides were analyzed in a semi-quantitative manner. CEACAM6 was expressed in 2 of 3 mucinous cancer cell lines. Expression was absent in all 2 HOSE, 7 serous cancer, and 2 clear cell cancer cell lines. 100-fold CEACAM6 overexpression (qRT-PCR) was demonstrated in 13/16 (81%) borderline, low-grade, and high-grade invasive MON's, compared to 5/50 (10%) serous and 1/5 (20%) benign mucinous samples. CEACAM6 expression was not different between borderline and invasive MON's (p=0.55) or across tumor stage (p=0.76). CEACAM6 staining was present in 24/28 (86%) borderline, low-grade, and high-grade invasive MON's; 13/28 (46%) exhibited moderate-strong staining. Neither CEACAM6 expression (p=0.36) nor staining intensity (p=0.51) was different between borderline and invasive MON's. None of the serous or benign mucinous tumors exhibited CEACAM6 staining. CEACAM6 is overexpressed in borderline and invasive MON's.


Anorectal function and defecation dynamics in patients with rectal prolapse.
Seven female patients with clinical rectal prolapse and nine healthy female control subjects were studied with anorectal manometry, external sphincter electromyography, and a saline continence test. Resting anal tone, maximum voluntary squeeze, and rectal functional capacity were significantly decreased in the rectal prolapse patients (p less than 0.02). During defecation attempts, external sphincter or pelvic floor electromyographic activity decreased in all of the control subjects, whereas six prolapse patients showed increased electromyographic activity and one had no change in activity (p less than 0.01). Continence to saline solution was also significantly impaired in prolapse patients (p less than 0.001). Postoperative studies in three patients who underwent repair revealed persistence of abnormal anorectal function and defecation dynamics. Patients with rectal prolapse have impaired resting and voluntary sphincter activity, decreased functional rectal capacity, and impaired continence. The failure of normal relaxation of the external sphincter or pelvic floor during defecation attempts, as demonstrated in the patients described herein, may contribute to the development of prolapse and denervation sphincter injury seen in such patients.


A prospective evaluation of the prevalence of thromboemboli and associated hemostatic dysfunction in dogs with carcinoma or sarcoma.
Knowledge of the prevalence of thromboemboli and the associated hemostatic status in dogs with carcinoma or sarcoma is unknown and might allow earlier intervention. Estimate prevalence of thromboemboli and their association with hemostatic changes in dogs with carcinomas or sarcomas; estimate predictive values of hemostatic variables for thromboembolic disease in tumor-bearing dogs. Thirty-two dogs with sarcoma, 30 with carcinoma, 20 healthy age-controlled dogs. Prospective cross-sectional study. A hemostasis panel (platelet concentration, thromboelastography, fibrinogen and D-dimer concentration, factor X, VII and antithrombin activity) was performed in all dogs. Tumor-bearing dogs underwent complete post mortem and histopathological evaluation. Comparisons between healthy dogs and tumor-bearing dogs with and without intracavitary hemorrhage; and tumor-bearing dogs with and without microthrombi were analyzed. Thromboembolic disease was identified in 32/62 (52%, 95% CI: 39%-65%) tumor-bearing dogs. Microthrombi were identified in 31/62 (50%, 95% CI: 37%-63%) dogs, 21/31 (68%, 95% CI: 49%-83%) had exclusively intra-tumoral microthrombi, 10/31 (32%, 95% CI: 17%-51%) had distant microthrombi. Macrothrombi were identified in 3 tumor-bearing dogs. Hemostatic changes potentially consistent with overt and non-overt disseminated intravascular coagulation were identified in some tumor-bearing dogs. D-dimer concentrations were significantly higher (P = .02) and platelet concentration significantly lower (P = .03) in tumor-bearing dogs with microthrombi compared to tumor-bearing dogs without microthrombi. D-dimer concentration above 500 ng/mL was 80% sensitive and 41% specific for the prediction of microthrombi presence. The high microthrombi prevalence and concomitant hemostatic dysfunction in dogs with carcinomas or sarcomas has not previously been reported, though the clinical importance is unknown. Increased D-dimer concentration might increase suspicion of microthrombi.


A hypoglycemia early alarm method for patients with type 1 diabetes based on multi-dimensional sequential pattern mining.
Hypoglycemia is a limiting factor for blood glucose management. Serious symptoms such as seizures, and coma may occur during severe hypoglycemia, and nocturnal hypoglycemia is particularly dangerous for patients with type 1 diabetes (T1D). An effective early alarm method is essential for hypoglycemia prevention but challenging, as blood glucose is affected by many factors and the hypoglycemia sequence patterns vary from person to person. In this paper, we proposed a hypoglycemia early alarm method for mining the hidden information in blood glucose based on multi-dimensional sequential pattern mining. The blood glucose, meal, and insulin time series information were used to construct a multi-dimensional database, then the UniSeq algorithm was used to extract multi-dimensional hypoglycemia sequence patterns. Hypoglycemia early alarm was realized through pattern matching with real-time blood glucose. The public OhioT1DM dataset was used for performance evaluation. The experiment results were: 75.76% Sensitivity, 75% Precision, 75.38% F1 score, and 25.17 minutes early alarm time. The result verified that multi-dimensional sequential pattern mining can extract more hidden information and demonstrate more potential significance in providing comprehensive diagnosis support for personalized treatment. Furthermore, early alarms for potential hypoglycemia can also reserve sufficient time for blood glucose management.


Stereocontrol in the EtAlCl(2)-induced cyclization of chiral gamma,delta-unsaturated methyl ketones to form cyclopentanones.
EtAlCl(2)-induced cyclization of chiral gamma,delta-unsaturated ketones 11c and 17b takes place mainly from the expected face. The selectivity is modest for 11c (60:40) in which the large substituent is a primary alkyl group and the medium substituent is a methyl group and excellent for 17b (93:7) in which the large substituent is a cyclohexyl group and the medium substituent is a methyl group. The cyclization of 17a is anomalous, suggesting that the phenyl group has more than a simple steric effect.


Learning-induced neural plasticity of speech processing before birth.
Learning, the foundation of adaptive and intelligent behavior, is based on plastic changes in neural assemblies, reflected by the modulation of electric brain responses. In infancy, auditory learning implicates the formation and strengthening of neural long-term memory traces, improving discrimination skills, in particular those forming the prerequisites for speech perception and understanding. Although previous behavioral observations show that newborns react differentially to unfamiliar sounds vs. familiar sound material that they were exposed to as fetuses, the neural basis of fetal learning has not thus far been investigated. Here we demonstrate direct neural correlates of human fetal learning of speech-like auditory stimuli. We presented variants of words to fetuses; unlike infants with no exposure to these stimuli, the exposed fetuses showed enhanced brain activity (mismatch responses) in response to pitch changes for the trained variants after birth. Furthermore, a significant correlation existed between the amount of prenatal exposure and brain activity, with greater activity being associated with a higher amount of prenatal speech exposure. Moreover, the learning effect was generalized to other types of similar speech sounds not included in the training material. Consequently, our results indicate neural commitment specifically tuned to the speech features heard before birth and their memory representations.


A rare case of aortic endograft infection by Francisella tularensis: A case report.
INTRODUCTION AND IMPORTANCE: endovascular repair is an alternative to open repair for abdominal aortic aneurysms (AAA), which lowers morbidity and mortality but may presents infectious complications. Endograft infection is a rare but serious life-threatening condition with a mortality rate up to 50 %. We reported a case of aortic endograft infection by Francisella tularensis, rare and highly virulent gram-negative coccobacillus known for use in bioterrorism. CASE PRESENTATION: A 79-year-old man presented with asthenia, weight loss, night sweats and one episode of fever. In 2007, he underwent aorto-bi-iliac endograft repair for AAA without any complication. The diagnostic workup showed some signs of inflammation, but negative blood cultures and no sign of infection on CT scan. The combination of positron emission tomography (PET) and white blood cell (WBC) scintigraphy led to the diagnosis of aortic endograft infection. The management was antimicrobial therapy and surgery. Perioperative analysis shows the presence of Francisella Tularensis. DISCUSSION AND CONCLUSIONS: Aortic endograft infection is a serious complication with a high mortality rate. Its diagnosis may be difficult, but the combination of WBC scintigraphy and PET scan may improve identification of the infection, even if blood cultures and CT scan are negative. The gold standard treatment is removal of the endograft, debridement, and in situ reconstruction along with antibacterial therapy.


Suppression of phosphoinositide 3-kinase signaling and alteration of multiple ion currents in drug-induced long QT syndrome.
Many drugs, including some commonly used medications, can cause abnormal heart rhythms and sudden death, as manifest by a prolonged QT interval in the electrocardiogram. Cardiac arrhythmias caused by drug-induced long QT syndrome are thought to result mainly from reductions in the delayed rectifier potassium ion (K(+)) current I(Kr). Here, we report a mechanism for drug-induced QT prolongation that involves changes in multiple ion currents caused by a decrease in phosphoinositide 3-kinase (PI3K) signaling. Treatment of canine cardiac myocytes with inhibitors of tyrosine kinases or PI3Ks caused an increase in action potential duration that was reversed by intracellular infusion of phosphatidylinositol 3,4,5-trisphosphate. The inhibitors decreased the delayed rectifier K(+) currents I(Kr) and I(Ks), the L-type calcium ion (Ca(2+)) current I(Ca,L), and the peak sodium ion (Na(+)) current I(Na) and increased the persistent Na(+) current I(NaP). Computer modeling of the canine ventricular action potential showed that the drug-induced change in any one current accounted for less than 50% of the increase in action potential duration. Mouse hearts lacking the PI3K p110α catalytic subunit exhibited a prolonged action potential and QT interval that were at least partly a result of an increase in I(NaP). These results indicate that down-regulation of PI3K signaling directly or indirectly via tyrosine kinase inhibition prolongs the QT interval by affecting multiple ion channels. This mechanism may explain why some tyrosine kinase inhibitors in clinical use are associated with increased risk of life-threatening arrhythmias.


Outpatient pacemaker procedures.
Over a 46-month period 181 pacemaker procedures were performed from an outpatient practice. Patients were admitted, operated on and discharged all within a 24-hour period. There were no pacemaker emergencies, major complications or emergency readmissions. The outpatient approach to permanent pacemaker procedures was not limited by the type of pacemaker procedure, pacemaker dependence, patient age or sex. The feasibility and safety of outpatient procedures is demonstrated.


Effects of disopyramide on SA nodal pacemaker activity and contractility in the isolated blood-perfused atrium of the dog.
The isolated blood-perfused preparations of canine atrium were suspended in a bath and perfused with arterial blood led from the carotid artery of the heparinized donor dog. Disopyramide caused dose-related negative chronotropic and inotropic effects in a dose range of 30-1000 microgram when injected directly into the cannulated sinus node artery of the isolated atrium. The order of potencies for inducing the negative chronotropic effect in isolated atrium preparations was verapamil greater than propranolol greater than lidocaine = quinidine greater than phenytoin greater than or equal to disopyramide greater than procainamide. On the other hand, the order of potencies for inducing the negative inotropic effect was verapamil = propranolol greater than lidocaine greater than or equal to phenytoin greater than disopyramide greater than procainamide greater than or equal to quinidine. When disopyramide (1 mg/kg or 3 mg/kg) was administered i.v. into the jugular vein of the donor dog, the systemic blood pressure of the donor dog was markedly decreased. However, the tension developed and sinus rate of the isolated atrium were only slightly decreased. Disopyramide produced greater suppression at higher frequencies and slightly depressed the calcium chloride-induced positive inotropic effects.


Salt-dependent binding of Escherichia coli initiation factor 3 to nucleic acids determined by sedimentation partition chromatography.
The binding of 14CH3- initiation factor 3 (IF3) to polynucleotides is strongly dependent upon the concentration of added salt. The observed association constant, Kobs, increases by ca. a factor of 10(2) when the NaCl concentration is lowered from 200 to 100 mM for the binding of 14CH3-IF3 to all nucleic acids examined. This salt-dependent binding suggests that at physiological salt concentrations the formation of an IF3-polynucleotide complex is primarily driven by the release of cations from the nucleic acid, although anion effects are involved also. For single-stranded nucleic acids, nonelectrostatic interactions may contribute a factor of 10(2) to the value of Kobs, although accurate assessment of these interactions is complicated by anion effects. The binding of 14CH3-IF3 to the double helix, poly(A).poly(U), appears to be exclusively electrostatic. 14CH3-IF3 forms a maximum of 8 +/- 2 ion pairs with most single-stranded polynucleotides. The value of Kobs increases from ca. 10(3) to 10(5) M-1 when the NaCl concentration is lowered from 200 to 100 mM for the binding of 14CH3-IF3 to poly(A), poly(C), poly(U), and poly(A).poly(U). At physiological salt concentrations, IF3 shows no preference for any of these bases or for single or double-stranded structures. However, 14CH3-IF3 binds ca. 60 times greater to poly(A,G), at al NaCl concentrations examined, than to the other nucleic acids, indicating that IF3 has some preference for guanine-containing polynucleotides. The presence of 10 mM Mg2+ tends to reduce the value of Kobs at any given NaCl concentration, but to a smaller degree than predicted by simply a competition between Mg2+ and IF3 for the nucleic acid lattice.


A brefeldin A-like phenotype is induced by the overexpression of a human ERD-2-like protein, ELP-1.
Brefeldin A (BFA) is a unique drug affecting the molecular mechanisms that regulate membrane traffic and organelle structure. BFA's ability to alter retrograde traffic from the Golgi to the endoplasmic reticulum (ER) led us to ask whether the ERD-2 retrieval receptor, proposed to return escaped ER resident proteins from the Golgi, might either interfere with or mimic the effects of the drug. When either human ERD-2 or a novel human homolog (referred to as ELP-1) is overexpressed in a variety of cell types, the effects are phenotypically indistinguishable from the addition of BFA. These include the redistribution of the Golgi coat protein, beta-COP, to the cytosol, the loss of the Golgi apparatus as a distinct organelle, the mixing of this organelle with the ER, the addition of complex oligosaccharides to resident ER glycoproteins, and the block of anterograde traffic. Thus, these receptors may provide signals that regulate retrograde traffic between the Golgi and the ER.


Behavioral and electrophysiological effects of the adenosine A2A receptor antagonist SCH 58261 in R6/2 Huntington's disease mice.
The effect of chronic treatment with the selective adenosine A2A receptor antagonist SCH 58261 on the behavioral and electrophysiological alterations typical of R6/2 mice (a transgenic mouse model of Huntington's disease, HD), has been studied. Starting from 5 weeks of age, R6/2 and wild type (WT) mice were treated daily with SCH 58261 (0.01 mg/kg i.p.) for 7 days. In the following weeks, the ability of mice to perform in the rotarod, plus maze and open field tests were evaluated. In addition, with electrophysiological experiments in corticostriatal slices we tested whether the well-known increased NMDA vulnerability of R6/2 mice was prevented by SCH 58261 treatment. We found that chronic treatment with SCH 58262: i) fully prevented the alterations in emotional/anxious responses displayed by R6/2 mice; ii) did not prevent the impairment in motor coordination; iii) abolished the increase in NMDA-induced toxicity observed in the striatum of HD mice. On balance, targeting A2A receptors seems to have some beneficial effects in HD even though, given the complexity of A2A receptor pharmacology and HD pathogenesis, further studies are necessary to clarify whether A2A receptor antagonists have therapeutic potential in HD.


Arterial hypoxia in acute pancreatitis.
Severe arterial hypoxia while breathing ambient air (Pao2 less than 60 mm Hg) was recorded in 38 (45 per cent) of a group of 84 patients with acute pancreatitis when arterial blood gas monitoring was performed during the first week of illness. This contrasted with an incidence of 19 per cent severe hypoxia in a heterogeneous group of 68 patients with acute abdominal pain admitted as surgical emergencies. Clinical evidence of respiratory embarrassment was rarely present in either the patients with acute pancreatitis or the other patients. Arterial hypoxia was related to the prognosis in both groups. It is recommended that all patients with acute pancreatitis have routine arterial blood gas monitoring performed during the first 5 days of illness. Furthermore, all older patients (over 60 years) and younger patients with moderate hypoxia (Pao2 less than 70 mm Hg) should be given supplementary humidified oxygen. An awareness of occult respiratory insufficiency in surgical emergency admissions, and especially in acute pancreatitis, is of importance.


Social cognition in schizophrenia: Factor structure of emotion processing and theory of mind.
Factor analytic studies examining social cognition in schizophrenia have yielded inconsistent results most likely due to the varying number and quality of measures. With the recent conclusion of Phase 3 of the Social Cognition Psychometric Evaluation (SCOPE) Study, the most psychometrically sound measures of social cognition have been identified. Therefore, the aims of the present study were to: 1) examine the factor structure of social cognition in schizophrenia through the utilization of psychometrically sound measures, 2) examine the stability of the factor structure across two study visits, 3) compare the factor structure of social cognition in schizophrenia to that in healthy controls, and 4) examine the relationship between the factors and relevant outcome measures including social functioning and symptoms. Results supported a one-factor model for the patient and healthy control samples at both visits. This single factor was significantly associated with negative symptoms in the schizophrenia sample and with social functioning in both groups at both study visits.


NH2-terminal acetylation of Dictyostelium discoideum actin in a cell-free protein-synthesizing system.
We present here a new method for inhibiting protein acetylation in a rabbit reticulocyte cell-free protein-synthesizing system. This procedure utilizes S-acetonyl coenzyme A, a nonreactive acetyl-CoA analogue, as an inhibitor of the NH2-terminal protein acetyltransferase in this lysate. With this procedure, we can make, in vitro, Dictyostelium discoideum actin which is 85% nonacetylated but fully translated. With the fully translated but nonacetylated actin as a substrate, the actin can be almost completely acetylated post-translationally in an acetyl-CoA-dependent system after the actin has left the ribosome. Using formylated and nonformylated [35S]Met-tRNAfMet as a source of label and in conjunction with detailed peptide mapping experiments with trypsin and thermolysin, the in vitro acetylation is shown to occur at the NH2 terminus of the newly synthesized actin. Furthermore, the initiator methionine residue, contrary to expectation, is not cleaved off but remains stable for at lest 50 min. thus, in the acetylating reticulocyte lysate system, the primary complete translation product in actin synthesis is Ac-Met-Asp and not Ac-Asp.


MSC-Derived Exosomes Protect Vertebral Endplate Chondrocytes against Apoptosis and Calcification via the miR-31-5p/ATF6 Axis.
Apoptosis and calcification of endplate chondrocytes (EPCs) can exacerbate intervertebral disc degeneration (IVDD). Mesenchymal stem cell-derived exosomes (MSC-exosomes) are reported to have the therapeutic potential in IVDD. However, the effects and related mechanisms of MSC-exosomes on EPCs are still unclear. We aimed to investigate the role of MSC-exosomes on EPCs with a tert-butyl hydroperoxide (TBHP)-induced oxidative stress cell model and IVDD rat model. First, our study revealed that TBHP could result in apoptosis and calcification of EPCs, and MSC-exosomes could inhibit the detrimental effects. We also found that these protective effects were inhibited after miroRNA (miR)-31-5p levels were downregulated in MSC-exosomes. The target relationship between miR-31-5p and ATF6 was tested. miR-31-5p negatively regulated ATF6-related endoplasmic reticulum (ER) stress and inhibited apoptosis and calcification in EPCs. Our in vivo experiments indicated that sub-endplate injection of MSC-exosomes can ameliorate IVDD; however, after miR-31-5p levels were downregulated in MSC-exosomes, these protective effects were inhibited. In conclusion, MSC-exosomes reduced apoptosis and calcification in EPCs, and the underlying mechanism may be related to miR-31-5p/ATF6/ER stress pathway regulation.


Image analysis of rat satellite cell proliferation in vitro.
Myogenic cells were isolated from adult rat skeletal muscles and cultured in vitro. Cell proliferation was analyzed between days 1 and 14. The cell cycle phases were determined by examining Feulgen-stained cultures with a cell image processor. The nuclei were automatically analyzed by calculating 18 parameters relating to the texture and densitometry of chromatin and the shape of each nucleus. Cell cycle phases were characterized (Moustafa and Brugal, 1984). The recognition methods made it possible to analyse the nuclei of the myogenic cell populations which were either involved in each phase of the mitotic cycle, or left out of the cycle after fusion into myotubes.After 3 hr of culture 10% of the cell population was involved in the cell cycle. In the presence of foetal calf serum, this percentage increased until day 3 after plating. At that time, the DNA content of 28.2% of the cell population was higher than 3C, whereas it is 2C in G1 or G0 nuclei; image analysis showed that 42% of these cells were in S or G2 phase. From day 4, the proliferation rate gradually slowed down until day 8. After day 8, when numerous myotubes differentiated, the percentage of S and G2 phase cells had diminished to between 3 and 8%. The percentage of nuclei in G0 increased when the first myotubes differentiated around day 5. Myotube nuclei were largely in G0. When horse serum was added to the culture medium on day 4 to enhance myotube differentiation, significant cell proliferation was observed before cell fusion.These methods of analysis give the first daily pattern of myogenic cell proliferation and fusion in a cell population isolated from adult muscles.


Effect of chronic administration of chlorpromazine on electrical parameters of command neurons in edible snail.
Electrophysiological experiments showed that chronic administration of neuroleptic chlorpromazine depolarized plasma membrane and decreased the threshold of action potential generation in command neuron of defense behavior of edible snail and motoneurons of pneumostome closure reflex. The effects of chlorpromazine on electrical parameters of the identified neurons can be explained by its serotonin-depleting action.


Analgesia from rostral brain stem stimulation in the rat.
Rats implanted with bipolar stimulating electrodes in the rostral medial brain stem were tested for brain stimulation-produced analgesia using tail-flick, pinch and hot-plate tests. Potent analgesia across all three tests was obtained from stimulation of sites in the gray matter surrounding the aqueduct and the caudal portion of the third ventricle, the posterior hypothalamus, the midline area of the caudal thalamus and the pretectal region of the meso-diencephalic junction. The analgesia obtained from these sites was comparable to that produced by stimulation of the previously studied caudal periaqueductal gray matter: it outlasted the period of brain stimulation, was not due to a generalized motor debilitation of the animal, and was not correlated with changes in electrographic activity. Stimulation of sites in the caudal thalamus and pretectal area yielded analgesia without stimulation-induced aversive reactions, confirming the potential of these sites for use in the relief of clinical pain in man.


Effects of fibrin on the secretion of plasminogen activator inhibitor-1 from endothelial cells and on protein kinase C.
We previously demonstrated that cultured human umbilical vein endothelial cells (HUVECs) overlaid with a fibrin clot induced a slight increase in tissue-type plasminogen activator (t-PA) secretion and marked reduction in plasminogen activator inhibitor-1 (PAI-1) secretion. In this study, the intracellular signal transduction after fibrin stimulation was further investigated by analyzing cyclic AMP (cAMP) and protein kinase C (PK-C). When HUVECs were stimulated by fibrin clots, t-PA mRNA increased to 130% but PAI-1 mRNA decreased to 42%. These changes concurred with the data on the protein levels of t-PA and PAI-1 as previously reported. The effect of fibrin on t-PA production in HUVECs was not significantly altered after the elevation of cAMP by either forskolin or dibutyryl cAMP. Furthermore, an effect of fibrin on t-PA production did not appear when the cells were treated by phorbol 12-myristate 13-acetate (PMA) or 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7). The suppressive effect of fibrin on PAI-1 secretion from HUVECs was not altered by elevation of cAMP. Regarding the activation of PK-C by PMA, PAI-1 secretion was enhanced, but was suppressed by fibrin stimulation. H-7 suppressed PAI-1 secretion and further stimulation by fibrin almost completely abolished PAI-1 secretion. These changes were well associated with mRNA levels of t-PA and PAI-1. These results suggested that fibrin on HUVECs preferably down-regulates PK-C resulting in a decrease of PAI-1 in both the protein and mRNA levels and that effect of fibrin on t-PA secretion is neither involved in PK-C nor cAMP pathway.


Ultrastaging of 'negative' pelvic lymph nodes in patients with low- and intermediate-risk endometrioid endometrial cancer who developed non-vaginal recurrences.
Evidence on micrometastases and isolated tumor cells as factors associated with non-vaginal recurrence in low- and intermediate-risk endometrial cancer is limited. The goal of our study was to investigate risk factors for non-vaginal recurrence in low- and intermediate-risk endometrial cancer. Records of all patients with endometrial cancer surgically managed at the Mayo Clinic before sentinel lymph node implementation (1999-2008) were reviewed. We identified all patients with endometrioid low-risk (International Federation of Gynecology and Obstetrics (FIGO) stage I, grade 1 or 2 with myometrial invasion <50% and negative peritoneal cytology) or intermediate-risk (FIGO stage I, grade 1 or 2 with myometrial invasion ≥50% or grade 3 with myometrial invasion <50% and negative peritoneal cytology) endometrial cancer at definitive pathology after pelvic and para-aortic lymph node assessment. All pelvic lymph nodes of patients with non-vaginal recurrence (any recurrence excluding isolated vaginal cuff recurrences) underwent ultrastaging. Among 1303 women, we identified 321 patients with low-risk (n=236) or intermediate-risk (n=85) endometrial cancer (median age 65.4 years; 266 (82.9%) stage IA; 55 (17.1%) stage IB). Of the total of 321, 13 patients developed non-vaginal recurrence (Kaplan-Meier rate 4.7% by 60 months; 95% CI 2.1% to 7.2%): 11 hematogenous/peritoneal and two para-aortic and distant lymphatic. Myometrial invasion and lymphovascular space invasion were univariately associated with non-vaginal recurrence. In these patients, the original hematoxylin/eosin slides review confirmed all 646 pelvic and para-aortic removed lymph nodes as negative. The ultrastaging of 463 pelvic lymph nodes did not identify any occult metastases (prevalence 0%; 95% CI 0% to 22.8% considering 13 patients; 95% CI 0% to 0.8% considering 463 pelvic lymph nodes). There were no occult metastases in pelvic lymph nodes of patients with low- or intermediate-risk endometrial cancer with non-vaginal recurrence. Myometrial invasion and lymphovascular space invasion appear to be associated with non-vaginal recurrence.


Digital pharmacists: the new wave in pharmacy practice and education.
Pharmacists now face the biggest challenges in the history of the profession: the use of digital technologies in pharmacy practice and education and the outbreak of coronavirus disease 2019. Worldwide, pharmaceutical care and pharmacy education via digital technologies have significantly increased and will be incorporated into patient care and the teaching-learning process, respectively. Thus, in this new era of pharmacy practice and education, curricula should promote the development of specific competencies for the cognitive, conscious, and effective use of digital tools. This requires the training of "disruptive" educators, who are capable of using teaching-learning methods adapted to the digital environment and educational processes suitable for stimulating the use of effective disruptive technologies. This commentary argues that the pharmacy profession can no longer wait for the slow integration of digital technologies into pharmacy practice and education.


NAloxone CARdiac Arrest Decision Instruments (NACARDI) for targeted antidotal therapy in occult opioid overdose precipitated cardiac arrest.
We have recently demonstrated that a significant proportion of fatal out-of-hospital cardiac arrests (OHCAs) are precipitated by occult overdose, which could benefit from antidote therapy administered adjunctively with other cardiac resuscitation measures. We sought to develop simple decision instruments that EMS providers and other first responders can use to rapidly identify occult opioid overdose-associated OHCAs. We examined data from February 2011 through December 2017 in the Postmortem Systematic Investigation of Sudden Cardiac Death study, in which San Francisco (California) County EMS-attended OHCA deaths received autopsy and expert panel adjudication of cause of death. Using classification tree analyses, we derived highly sensitive and specific decision instruments that predicted our primary outcome of occult opioid OD-associated OHCA. We then calculated screening performance characteristics of these instruments. Of 767 OHCA deaths, 80 (10.4%) were associated with occult opioid overdose. Of the eight models with 100% sensitivity for opioid overdose-associated cardiac arrest, the highest specificity model (23.4%, 95% confidence interval [CI] 20.3-26.7%) was age < 60 years OR race = black or non-Latinx white OR arrest in public place. The highest specificity instrument (96.3%, 95% CI 94.6-97.5%) consisting of age < 60 years AND race = black or non-Latinx white AND unwitnessed arrest AND female sex had 25% (95% CI 16-35.9%) sensitivity. We have derived simple decision instruments that can identify patients whose OHCA precipitant was occult opioid overdose. These instruments may be used to guide selective administration of the antidote naloxone in OHCA resuscitations.


Transport of osmoprotective compounds in hybridoma cells exposed to hyperosmotic stress.
Addition of osmoprotective compounds has a positive effect on growth and monoclonal antibody production in hyperosmotic hybridoma cell cultures. In order to better understand the processes involved in the osmoprotective response, uptake of the osmoprotective compounds glycine betaine, proline, sarcosine and glycine in mouse hybridoma cell line 6H11 during exposure to hyperosmotic stress was studied. Hyperosmotic stress (510 mOsmol/kg) was introduced through the addition of NaCl (100 mM) to the growth medium, and amino acid transport activity was measured immediately after transfer of the cells to the hyperosmotic medium. The osmoprotective capability of the four osmoprotectants tested was negatively affected if methylaminosobutyric acid (MeAiB), a specific substrate for amino acid transport system A, was simultaneously included in the hyperosmotic medium in equimolar amounts with one of the osmoprotective compounds. This was due to accumulation of MeAiB in the stressed cells, giving a significant reduction in the concentration of the osmoprotective compound inside the cells. Furthermore, addition of excess meAiB gave approx. 905 reduction in the initial rate of uptake of glycine betaine, while 40-50% reduction in the initial rate of uptake of proline, glycine and sarcosine. Similarly, addition of proline, glycine or sarcosine also gave a significant reduction in the initial rate of glycine betaine uptake. These results suggest that the four osmoprotective compounds share, at least in part, a common, MeAiB inhibitable carrier for transport into osmotically stressed hybridoma cells. This carrier is probably equal to amino acid transport system A.


Adult health practices in the United States and Canada.
The prevalence levels of 12 health practices in the United States and Canada are compared in this study: smoking; drinking status; average daily alcohol consumption; physical activity; eating breakfast; use of seatbelts and child safety restraints; ownership of smoke detectors; recency of blood pressure checks, breast examinations, and Pap tests; and practice of breast self-examination. Data for two additional variables--drinking and driving and blood pressure awareness--are shown for the two countries, but the statistics cannot be strictly compared. Data are presented for four age groups by sex and for three levels of education. Trends in smoking and seatbelt use between 1979 and 1985 are also discussed.