Small intestinal absorption of bropirimine in rats and effect of bile salt on the absorption.
The intestinal absorption characteristics of a poorly water-soluble drug, bropirimine, were investigated by the in-situ small intestinal loop method using male Sprague-Dawley rats. Bropirimine in solution was well absorbed in the overall small intestine, following first-order kinetics. The rate determining step for the disappearance of bropirimine from the small intestinal loop after dosing in the suspension was the dissolution process from suspension. Bropirimine was solubilized by sodium glycocholate. The disappearance of bropirimine from the small intestinal loop was suppressed by sodium glycocholate contained in the solution, because of the loss of thermodynamic activity of bropirimine after its involvement in the micellar complex, not by the direct effect of bile salt on the permeability of intestinal mucosa. The disappearance of bropirimine was also suppressed by sodium glycocholate contained in the suspension. The suppression by sodium glycocholate seemed to be caused by the greater influence of sodium glycocholate on the thermodynamic activity of bropirimine than on the dissolution from suspension.


Molecular characterization of Mycobacterium tuberculosis isolates presenting various drug susceptibility from Greece using three DNA typing methods.
The purpose of the present study was the molecular characterization of Mycobacterium tuberculosis clinical isolates using three DNA typing methods. One hundred nineteen independent (77 susceptible to all antituberculous drugs, 17 rifampin-resistant and 25 isoniazid-resistant), and nine related Mycobacterium tuberculosis isolates obtained over a 3-years period (1997-1999) from Greece were typed with restriction fragment length polymorphism (RFLP), using the non-radioactive IS6110 probe (IS6110-RFLP), and two PCR-based molecular methods: random amplification of polymorphic domains (RAPD) using four different primers and double repetitive element-PCR (DRE-PCR). IS6110-RFLP and RAPD-PCR using IRIS primer were proved to be the most discriminatory methods, while DRE-PCR gave satisfactory results and RAPD-PCR methods using the other three primers (A1245, B1245 and Leg2) were not so effective. The related strains, isolated from affected members of four families, gave similar PCR and RFLP patterns, while the independent strains presented a high degree of polymorphism. In terms of cost effectiveness and technical simplicity, the PCR-based methods were found to be superior. So, they may serve as screening methods to classify a large number of isolates into clusters for further subtyping and recognition of well-defined genotype families.


Clinical evaluation of Statstrip® Lactate for use in fetal scalp blood sampling.
Point-of-care testing of fetal scalp blood lactate is used as an alternative to pH analysis in fetal scalp blood sampling (FBS) during labor. Lactate measurements are not standardized and values vary with each device used. The aim of this study was to evaluate StatStrip® Lactate (SSL) in the clinical setting in comparison with lactate (RLL) and pH (RLpH) using RapidLab® . We obtained 323 FBS samples from 139 women. Parallel sampling of SSL and RLL/RLpH was performed in 247 samples. Outcome measures were the agreement and discrepancy rates between SSL, RLL and RLpH and the failure rate of all three methods. We constructed a Bland-Altman graph to assess the variability between the measurements across the range of values. The discrepancy rates between methods were compared using previously established cut-off values for SSL indicating reassurance (<5.7 mmol/L) and immediate delivery (>7.0 mmol/L) with those for RLpH (<7.20 and >7.25). SSL showed excellent agreement with RLL (R2 = 0.742) and poor agreement with RLpH (R2 = 0.204). Failure rates for SSL, RLL and RLpH were 7, 43 and 23%, respectively. Using the cut-off values for reassurance and immediate delivery, the discrepancy rates between SSL and RLpH were 14 and 5%, respectively. SSL is a reliable test to measure lactate in FBS with a low failure rate. As there are discrepancies between SSL and RLpH, and the cut-off values have not yet been evaluated prospectively regarding intervention rates and neonatal outcome, we recommend using SSL in addition to pH in FBS.


Characterization of the p53-rescue drug CP-31398 in vitro and in living cells.
The Pfizer compound CP-31398 has been reported to stabilize the core domain of the tumour suppressor p53 in vitro and be an effective anti-cancer drug by virtue of rescuing destabilized mutants of p53. We did not detect any interaction between the p53 core domain and CP-31398 in vitro by a wide range of quantitative biophysical techniques over a wide range of conditions. CP-31398 did not stabilize p53 in our experiments. However, we found that CP-31398 intercalated with DNA and also altered and destabilized the DNA-p53 core domain complex. We analysed by NMR TROSY the interaction of the domain with a DNA oligomer and identified the changes in the complex on the binding of CP-31398. CP-31398 also decreased sequence-specific DNA binding of wild-type p53 and His-273 mutant p53. CP-31398 had a non-specific toxic effect independent of mutant p53 expression in several cell lines carrying Tet-regulated mutant p53. CP-31398 caused a small increase in MDM-2 expression and a more pronounced p53-independent increase in Bax expression. CP-31398 did, however, induce the PAb1620 epitope (characteristic of native p53) in cells expressing His-175 mutant p53. This was prevented by cycloheximide, suggesting that any stabilizing action of CP-31398 would have to be on newly synthesized p53. One of the unstable mutants that was reported to have been rescued by CP-31398, R249S, does not bind DNA when folded at lower temperatures.


Isocyanines and pseudoisocyanines as a novel class of potent noradrenaline transport inhibitors: synthesis, detection, and biological activity.
Noradrenaline, the neurotransmitter of the sympathetic nervous system, is removed from the extracellular space by both neuronal and extraneuronal transport mechanisms. In the past, further investigation of the extraneuronal type of noradrenaline transporter was severely hampered by the lack of potent inhibitors. Here, we describe the synthesis of various novel noradrenaline transport inhibitors which belong to the chemical class of isocyanine and pseudoisocyanine dyes. The biological activity of these compounds was investigated in a tissue culture system (Caki-1 cells). 1,1'-Diisopropyl-2,4'-cyanine, 1,1'-diethyl-2,2'-cyanine, and 1-ethyl-1'-isopropyl-2,2'-cyanine turned out as the most potent inhibitors of the extraneuronal noradrenaline transport known so far. At 100 nmol/L, these compounds diminished extraneuronal noradrenaline transport by about 95%. Their IC50's were below 20 nmol/L. In addition, a rapid and sensitive method (based on HPLC with fluorometric detection) to measure these compounds in body fluids is reported.


A practical guide for building a highway between atria during transseptal puncture without radiation.
To investigate whether switching the ablation catheter between the right and left atria through transseptal puncture site can be accurately performed without fluoroscopy. Forty patients with persistent atrial fibrillation (mean age, 60.2±7.4 years; 65% males) got "2C3L" approach were randomized in a 1:1 ratio to undergo either crossing interatrial septum guided by fluoroscopy (trackless group) or crossing septum guided by track image that was mapped by Carto3 system (track group). The three-dimensional image of the track could be mapped smoothly and shown clearly. No significant differences were found in the success rates between the two groups (100% vs. 100%, p>0.05). However, the procedure of crossing septum was completed without any fluoroscopy use in track group, which showed a shorter procedure time than trackless group (4±3 s vs. 20±10 s, p<0.01). Visualizing the track passing through the puncture site using Carto3 system can guide the ablation catheter in safely crossing the intra-atrial septum quickly with zero fluoroscopy.


Ab initio and density functional computations of the vibrational spectrum, molecular geometry and some molecular properties of the antidepressant drug sertraline (Zoloft) hydrochloride.
Sertraline hydrochloride is a highly potent and selective inhibitor of serotonin (5HT). It is a basic compound of pharmaceutical application for antidepressant treatment (brand name: Zoloft). Ab initio and density functional computations of the vibrational (IR) spectrum, the molecular geometry, the atomic charges and polarizabilities were carried out. The infrared spectrum of sertraline is recorded in the solid state. The observed IR wave numbers were analysed in light of the computed vibrational spectrum. On the basis of the comparison between calculated and experimental results and the comparison with related molecules, assignments of fundamental vibrational modes are examined. The X-ray geometry and experimental frequencies are compared with the results of our theoretical calculations.


Routine Use of Fluoroscopic-Guided Femoral Arterial Puncture to Minimise Vascular Complication Rates in CTO Intervention: Multi-centre UK Experience.
Chronic total occlusion (CTO) revascularisation has a crucial role in contemporary percutaneous coronary intervention (PCI). Procedural success is influenced by disease complexity, calcific burden and patient characteristics but has substantially improved with the implementation of novel hybrid strategies. However, vascular-access related complications remain a cause of morbidity and mortality. This study aimed to assess the effectiveness of fluoroscopic-guided femoral arterial puncture to minimise this risk during CTO PCI. Standardised data were retrospectively collected from four high-volume UK CTO centres between September 2011 and November 2013. Demographic, clinical and procedural data (vascular access site, sheath size, anticoagulation use) was collated. The anatomical location of the femoral puncture in relation to the femoral bifurcation, femoral head position and inferior epigastric artery were recorded. Adverse events related to vascular access were documented. A total of 528 patients were included (676 femoral punctures) with the majority being male (n=432, 81.8%). Large sheaths (8F) were used in 81.2% of cases. Fluoroscopy-enabled punctures were made in the 'safe zone' in over > 93% of cases. Vascular closure devices (VCD) were used in 88.3% of cases. The adverse event rate per puncture was 0.89%. This study demonstrates an extremely low incidence of vascular-access complications in CTO PCI when fluoroscopic guidance is used to obtain femoral arterial access by default radial operators.


Personality and longevity: findings from the Georgia Centenarian Study.
Centenarians are thought of as unique and exceptional survivors. This study evaluated specific personality traits and configurations of traits among participants of the Georgia Centenarian Study. Two hundred and eighty five centenarians and their nominated proxies participated in this study. Self ratings and proxy informant ratings were obtained for different traits and facets of the Big-5 personality typology. Results suggested that centenarians overall had low levels of Neuroticism, but high levels of Extraversion, Competence, and Trust. When compared to centenarian self ratings, proxies provided significantly higher ratings for Neuroticism, Hostility, and Vulnerability, but lower ratings for Competence and Trust. Among Centenarians, the personality configuration of low Neuroticism, high Competence, and high Extraversion traits is over-represented relative to chance. The results confirm that centenarians show several unique single traits, but that a special combination of traits (i.e., low levels of Neuroticism, high Competence, and high Extraversion) are also notable in this group of exceptional survivors.


Experimental studies of pollen carryover: Hummingbirds and Ipomopsis aggregata.
We present results of experiments designed to identify floral characteristics that influence patterns of pollen carryover by hummingbirds visiting Ipomopsis aggregata flowers. We used fluorescent dye powders as pollen analogues. For all four experimental treatments considered, amounts of dye deposited on recipient stigmas declined linearly as a function of flower position in a visitation sequence. The decline was significantly steeper when recipient flowers had pollen-carrying anthers than when they did not; whereas degree of stigma clogging and presence or absence of empty anthers did not influence carryover. From this we conclude that presence of pollen on recipient flowers significantly reduces the average number of subsequent flowers reached by donor pollen. We discuss mechanisms for this effect and its significance for the evolution of floral structure.


Design Strategies for Anodes and Interfaces Toward Practical Solid-State Li-Metal Batteries.
Solid-state Li-metal batteries (based on solid-state electrolytes) offer excellent safety and exhibit high potential to overcome the energy-density limitations of current Li-ion batteries, making them suitable candidates for the rapidly developing fields of electric vehicles and energy-storage systems. However, establishing close solid-solid contact is challenging, and Li-dendrite formation in solid-state electrolytes at high current densities causes fatal technical problems (due to high interfacial resistance and short-circuit failure). The Li metal/solid electrolyte interfacial properties significantly influence the kinetics of Li-metal batteries and short-circuit formation. This review discusses various strategies for introducing anode interlayers, from the perspective of reducing the interfacial resistance and preventing short-circuit formation. In addition, 3D anode structural-design strategies are discussed to alleviate the stress caused by volume changes during charging and discharging. This review highlights the importance of comprehensive anode/electrolyte interface control and anode design strategies that reduce the interfacial resistance, hinder short-circuit formation, and facilitate stress relief for developing Li-metal batteries with commercial-level performance.


T-lymphocyte subpopulations do not express identical combinations of interleukin-2 receptor chains in the early phase of their activation and proliferation.
Owing to the contrasting observations in the field of interleukin(IL)-2 receptor research, the expression of IL-2 receptor chains was analysed on resting and anti-CD3 antibody (OKT3) activated CD4 and CD8 T cells by flow cytometry. Prior to the stimulation, 49% of CD4+ cells expressed IL-2Ralpha (CD25), whereas the expression of IL-2Rbeta (CD122) was very low (8%). The reverse was true for CD8 cells: 48% of them were positive for CD122, but only a fraction (10%) expressed CD25. Practically all lymphocytes expressed IL-2Rgamma (CD132). Interestingly, the unbalanced expression of IL-2Ralpha and -beta continued throughout the stimulation period of 2 days. In addition, the expression of CD45 isoforms in combination with the IL-2R chains and CD71 was followed during the activation of CD4+ T cells. Although CD45RA+/RO- CD4 cells were effectively activated, they retained their naive phenotype up to 2 days of stimulation. On the other hand, CD45RA+low/RO+low (Ddull) CD4+ cells shifted to the memory phenotype rapidly after being activated. However, by day 6 of stimulation the shift of both naive and Ddull cells to memory ones was obvious. The role of the IL-2 receptor in the activation of CD4 subpopulations is discussed.


Accretionary prism collapse: a new hypothesis on the source of the 1771 giant tsunami in the Ryukyu Arc, SW Japan.
The giant 1771 Yaeyama tsunami occurred in the southwestern part of the Ryukyu Arc, a region on an obliquely subducting plate boundary, which shows no direct evidence of inter-plate coupling. Studies of tsunami boulders and deposits suggest that the recurrence interval of comparably giant tsunamis is roughly 500 to 1000 years. Tsunami source models, which include either slip on a shallow plate boundary or active faulting plus a landslide on the overriding plate, are controversial because of inconsistencies in the geophysical and geological data. We discovered a seafloor depression that is approximately 30 km wide and 80 km long extending in the ESE-WNW direction. This depression is accompanied by a seaward bulge on the accretionary prism along the Ryukyu Trench, which is based on detailed bathymetric data and interpreted to be the result of accretionary prism collapse and seaward displacement by rotational slide. A simple tsunami simulation shows that the slide is a plausible source of the 1771 tsunami. We propose a collapse model, in which the accretionary prism remained over-steepened as strike-slip faulting removed the prism toe. Our model indicates that some oblique subduction zones are capable of generating giant tsunamis regardless of weak or strong coupling.


Factors Associated with Thrombolysis Outcome in Ischemic Stroke Patients with Atrial Fibrillation.
The outcome of early intravenous thrombolysis for ischemic stroke in patients with atrial fibrillation (AF) is worse than that without thrombosis. How to increase the efficacy of intravenous thrombolysis for AF-related ischemic stroke remains largely unknown. In this study, we investigated factors that influence the effect of intravenous thrombolysis in these patients. Our results showed that thrombolysis was independently associated with a favorable outcome (P < 0.001) and did not influence the mortality of AF-related ischemic stroke, although it increased the risk of hemorrhage within 24 h after treatment. Risk factors for a poor outcome at admission were: heart failure (P = 0.045); high systolic pressure (P = 0.039); high blood glucose (P = 0.030); and a high National Institutes of Health Stroke Scale (NIHSS) score (P < 0.001). Moreover, high systolic pressure at admission (P = 0.007), high blood glucose (P = 0.027), and a high NIHSS score (P < 0.001) were independent risk factors for mortality at 3 months. Besides thrombolysis, a high NIHSS score (P = 0.006) and warfarin taken within 48 h before stroke onset (P = 0.032) were also independent risk factors for symptomatic hemorrhage within 24 h after treatment. Ischemic stroke patients with AF benefited from intravenous thrombolysis with recombinant tissue plasminogen activator within 4.5 h after stroke.


Flow injection analysis of picric acid explosive using a copper electrode as electrochemical detector.
A simple and fast electrochemical method for quantitative analysis of picric acid explosive (nitro-explosive) based on its electrochemical reduction at copper surfaces is reported. To achieve a higher sample throughput, the electrochemical sensor was adapted in a flow injection system. Under optimal experimental conditions, the peak current response increases linearly with picric acid concentration over the range of 20-300 μmol L(-1). The repeatability of the electrode response in the flow injection analysis (FIA) configuration was evaluated as 3% (n=10), and the detection limit of the method was estimated to be 6.0 μmol L(-1) (S/N=3). The sample throughput under optimised conditions was estimated to be 550 samples h(-1). Peroxide explosives like triacetone triperoxide (TATP) and hexamethylene triperoxide diamine (HMTD) were tested as potential interfering substances for the proposed method, and no significant interference by these explosives was noticed. The proposed method has interesting analytical parameters, environmental applications, and low cost compared with other electroanalytical methods that have been reported for the quantification of picric acid. Additionally, the possibility to develop an in situ device for the detection of picric acid using a disposable sensor was evaluated.


Nonhepatitis B-associated liver disease in a renal transplant population.
The spectrum of liver disease in a population of 293 patients receiving 353 renal transplants (1971-1984) was reviewed. This study looked retrospectively at the histological features of liver disease in this population, and prospectively at the clinical and biochemical features of liver disease associated with renal transplantation. In all patients, infection with hepatitis B was excluded. Six deaths, primarily attributable to hepatic failure have occurred: one, acute herpes simplex infection; one, subacute massive hepatic necrosis of uncertain etiology; two, pretransplant liver disease; and two, posttransplantation cirrhosis of uncertain etiology. Review of the hepatic histology of 26 patients with known liver disease following transplantation revealed a wide range of pathologies with few specific correlations with their clinical status or biochemical tests of liver function. The prevalence of hepatic dysfunction following transplantation in our patient population was assessed by prospective biochemical screening of 111 transplant recipients over a 6-month interval. During this time period, 27 patients (24%) displayed biochemical evidence of hepatic dysfunction. Liver disease was known to have predated transplantation in only three of 27. Episodes of abnormal liver function occasionally occurred during an identifiable acute illness (six of 27), although the majority (21 of 27) had chronic hepatic dysfunction. Transplant recipients with abnormal liver function could not be differentiated from a cohort with normal liver function on the basis of age, sex, duration of graft function, or alcohol/drug intake. The possible etiologies of nonhepatitis B liver dysfunction following renal transplantation are discussed, and the high prevalence of biochemical evidence of hepatic dysfunction in this population free of hepatitis B infection is emphasized.


Transanal minimally invasive surgery for rectal neuroendocrine tumors.
There is no literature that mainly searched for rectal neuroendocrine tumor (rNET) using transanal minimal invasive surgery (TAMIS). We report our clinical experiences of TAMIS for rectal neuroendocrine tumors to evaluate the feasibility and safety. Between December 2010 and March 2020, the 25 consecutive patients with rectal neoplasma underwent the TAMIS procedure performed by single laparoscopic surgeon at the two hospitals. Of these, ten patients with rectal neuroendocrine tumors were reviewed retrospectively. The full-thickness excision down to the outer fatty tissues was completed using TAMIS technique. Clinicopathological findings, perioperative and postoperative complications were recorded. TAMIS for small rNET was successfully completed in all cases. There were seven cases with a tumor size of less than 10 mm, and three cases with a tumor size between 10 and 15 mm. Six patients underwent the primary tumor excision; the remaining four patients underwent resection for the scar after endoscopic procedure. The median surgical duration was 80.5 (53-124) minutes and the median blood loss was 1 (1-12) ml. All removed tumors in the 6 primary excisions were diagnosed as neuroendocrine tumor G1. The margins of specimens were completely free in all cases. Among the four patients after endoscopic procedure, all had no histological evidence of residual tumor. The median length of hospital stay was 7 days postoperatively. There was no post-operative mortality or severe complication. The median length of observation was 54 months. No recurrence, no local or distant metastasis and no mortality of all patients were observed. TAMIS is safety and feasible procedure for small rNET. Further experience and clinical trials are needed to fully define the advantages, disadvantages, and indications of TAMIS for rNET.


Risk of non-sentinel node metastases in patients with symptomatic cancers compared to screen-detected breast cancers.
Symptomatic breast cancers may be more aggressive as compared to screen-detected breast cancers. This could favor axillary lymph node dissection (ALND) in patients with symptomatic breast cancer and positive sentinel nodes. We identified 955 patients registered in the Danish Breast Cancer Cooperative Group (DBCG) Database in 2008 - 2010 with micrometastases (773) or isolated tumor cells (ITC) (182) in the sentinel node. Patients were cross-checked in the Danish Quality Database of Mammography Screening and 481 patients were identified as screen-detected cancers. The remaining 474 patients were considered as having symptomatic cancers. Multivariate analyses of the risk of non-sentinel node metastases were performed including known risk factors for non-sentinel node metastases as well as method of detection. 18% of the patients had metastases in non-sentinel nodes. This was evenly distributed between patients with symptomatic and screen-detected cancers; 18.5% vs 17.5% (OR 1.07; 95% CI 0.77-1.49; p = 0.69). In patients with micrometastases 21% had non-sentinel node metastases in the group with symptomatic cancers compared to 19% of patients with screen-detected cancers. This difference was not significant (OR 1.16; 95% CI 0.81-1.65, p = 0.43). Neither the multivariate analysis showed an increased risk of non-sentinel node metastases in patients with symptomatic cancers compared to screen-detected cancers (OR 1.12, CI 0.77-1.62, p = 0.55). In patients with ITCs 8% of patients with symptomatic cancers had non-sentinel node metastases compared to 13% of patients with screen-detected cancers. This difference was not significant (OR 0.58; 95% CI 0.22-1.54, p = 0.27). In the multivariate analysis, the risk of non-sentinel node metastases was still not significantly increased in patients with symptomatic cancers compared to screen-detected cancers (OR 0.45; 95% CI 0.16-1.27, p = 0.13). We did not find any clinically relevant difference in the risk of non-sentinel node metastases between patients with symptomatic and screen-detected cancers with micrometastases or ITC in the sentinel node.


Ewing sarcoma/primitive neuroectodermal tumor of the kidney: clinicopathologic analysis of 34 cases.
The present study describes the clinicopathologic analysis of 34 cases of Ewing sarcoma/primitive neuroectodermal tumor occurring in the kidney. The patients were 21 males and 13 females with an age range of 6 to 44 years. Clinically, patients presented with multiple symptoms including hematuria, pain, and/or lump in the abdomen. Nephrectomy was performed in most of the cases. Grossly, whole of the renal parenchyma was involved by a variegated tumor. Histologically, the tumor was composed of monomorphic, small, and round cells arranged in a variety of patterns. Rosettes, geographical areas of necrosis, and arborizing vascular pattern were the prominent histologic features. The nucleus was monomorphic and round. Anisonucleosis was also noted in some cases. The nucleus was mostly hyperchromatic. A mixture of hyperchromatic and powdery chromatin was noted in few cases. Immunohistochemically, MIC2 (CD99) was positive in 32 of 34 cases followed by neuron-specific enolase (9/12 cases), vimentin (8/14 cases), synaptophysin (1/8 cases), and S-100 protein (1/4 cases). Molecular analysis by reverse transcriptase-polymerase chain reaction that was carried out in 26 cases revealed presence of EWS-FLI-1 type 1 translocation in 12 cases, EWS-FLI-1 type 2 translocation in 10 cases, and both type 1 and type 2 EWS-FLI-1 translocation in 2 cases. Two cases did not demonstrate any translocation. Follow-up data were available for 17 of 34 cases. Local recurrence of the tumor was seen in 4 patients, and 10 patients were recorded to have distant metastasis in various organs, such as lung, bone, and lymph node, during the course of the disease.


The performance of screening tests for ovarian cancer: results of a systematic review.
To estimate the performance of currently available tests in detecting ovarian cancer in asymptomatic women. Systematic review of prospective screening studies. Twenty-five studies were identified: sixteen studied women at average risk and nine studied women at higher risk. Most studies evaluated only one screening method, were small, detecting few cancers, and gave few follow up details. Sensitivity estimates are therefore imprecise. In a typical larger study, reported sensitivity of ultrasound screening at one year was around 100% (95% CI 54%-100%), while the sensitivity of CA125 measurement followed by ultrasound (multimodal screening) was about 80% (95% CI 49%-95%). False positive rates ranged between 1.2% and 2.5% for grey scale ultrasound, between 0.3% and 0.7% for ultrasound with colour Doppler and between 0.1% and 0.6% for multimodal screening. This implies that, in annual screening of a population with an incidence of 40 per 100,000, and if no cancers were missed, between 2.5 and 60 women would undergo surgery for every primary ovarian cancer detected. Ultrasound and multimodal screening can detect ovarian cancer in asymptomatic women, but there is currently no evidence on whether screening improves outcome for women in any risk group. On-going randomised controlled trials should establish the magnitude of any benefit of screening. The low prevalence of ovarian cancer in the population, and its rate of progression, may limit the potential cost-effectiveness of screening.


Correction to: Structural basis for a highly (S)-enantioselective reductase towards aliphatic ketones with only one carbon difference between side chain.
The original version of this article contains error for some of the authors corrections were not included during correction stage.


Treatment with percutanous testosterone gel in postmenopausal women with decreased libido--effects on sexuality and psychological general well-being.
To elucidate if percutanous treatment with 10mg testosterone per day could enhance sexuality and psychological well-being in postmenopausal women presenting problems with low libido. Secondary to study the influence on blood lipids, hemoglobin and erythropoietin levels. Fifty-three postmenopausal women participated. As a complement to their already on-going HRT, 10mg of a testosterone gel (Testogel, Besins-Iscovesco) or placebo was administered. Treatment continued for three plus three months in a double blind, randomized, crossover design. The scores concerning "frequency of sexual activity, orgasm and intercourse", "sexual arousal, fantasies and enjoyment", "satisfaction with orgasms", and "interest in sex" were all significally improved for testosterone addition as compared to placebo both before and after crossover. Testosterone levels increased more than 10-fold during treatment while DHT-levels were more than doubled. Estrogen levels were not affected during the addition of testosterone. Liver enzymes, total cholesterol, triglycerides, HDL and LDL revealed no significant differences between any of the periods or groups. Endometrial thickness did not change significantly during treatment. Hemoglobin and erythropoietin remained unchanged. No significant differences in the number of experienced side effects were found. Testosterone gel of 10mg had positive effects on several aspects of sexual life such as frequency of sexual activity, orgasm, arousal, fantasies and sexual interest in postmenopausal women on HRT. Several psychological variables were positively influenced. The given dose resulted in too high serum levels. Even if no negative effects were observed, monitoring of serum levels and a decreased dose should be considered in future studies.


Serum albumin, serum antiproteases and polymorphonuclear leucocyte neutral collagenolytic protease in the tear fluid of patients with corneal ulcers.
Using a micro-electroimmune assay, the concentration of polymorphonuclear leucocyte neutral collagenolytic protease, serum-albumin, alpha-1-antitrypsin and alpha-2-macroglobulin were measured in the tear fluid from 18 eyes of 16 patients with severe, melting corneal ulcers. By this method, PML-c-ase was the first time detected in tear fluid. All proteins normalized during healing of the ulcer. The findings are indicative of an important role for PML-proteases in the degradation of the corneal stroma, and of a regulative effect of the serum antiproteases leaking into the tear fluid from inflamed conjunctival vessels.


The Assessment of Withdrawal Interval for Enrofloxacin in Yellow Catfish (Pelteobagrus fulvidraco) after Multiple Oral Administrations at Disparate Temperatures.
The objective of the present study was to investigate the residue depletion of EF and CF in yellow catfish to estimate its WTs in plasma and tissues after multiple oral doses for 3 days at 20 mg/kg at 15, 20, and 25 °C. Samples were collected at pre-designed time points after oral doses. A validated method was performed to quantify EF and CF in plasma and tissues by high-performance liquid chromatography. Statistical differences were conducted using one-way ANOVA analysis. According to the maximum residue limit of China and Europe considering 95% percentile with 95% confidence, the WTs were estimated to be 44, 72, 66, 99, and 95 days at 15 °C; 32, 66, 65, 86, and 73 days at 20 °C; and 32, 61, 64, 55, and 59 days at 25 °C in the plasma, muscle and skin, gill, liver, and kidney, respectively. We found that increased temperature shortened the WTs in plasma and tissues. Therefore, this study can help the risk assessment of EF in aquatic products for human health at different temperatures to avoid residue violation.


High cell density and latent membrane protein 1 expression induce cleavage of the mixed lineage leukemia gene at 11q23 in nasopharyngeal carcinoma cell line.
Nasopharyngeal carcinoma (NPC) is commonly found in Southern China and South East Asia. Epstein-Barr virus (EBV) infection is well associated with NPC and has been implicated in its pathogenesis. Moreover, various chromosome rearrangements were reported in NPC. However, the underlying mechanism of chromosome rearrangement remains unclear. Furthermore, the relationship between EBV and chromosome rearrangement with respect to the pathogenesis of NPC has not been established. We hypothesize that during virus- or stress-induced apoptosis, chromosomes are initially cleaved at the base of the chromatin loop domain structure. Upon DNA repair, cell may survive with rearranged chromosomes. In this study, cells were seeded at various densities to induce apoptosis. Genomic DNA extracted was processed for Southern hybridization. In order to investigate the role of EBV, especially the latent membrane protein 1 (LMP1), LMP1 gene was overexpressed in NPC cells and chromosome breaks were analyzed by inverse polymerase chain (IPCR) reaction. Southern analysis revealed that high cell density resulted in cleavage of the mixed lineage leukemia (MLL) gene within the breakpoint cluster region (bcr). This high cell density-induced cleavage was significantly reduced by caspase inhibitor, Z-DEVD-FMK. Similarly, IPCR analysis showed that LMP1 expression enhanced cleavage of the MLL bcr. Breakpoint analysis revealed that these breaks occurred within the matrix attachment region/scaffold attachment region (MAR/SAR). Since MLL locates at 11q23, a common deletion site in NPC, our results suggest a possibility of stress- or virus-induced apoptosis in the initiation of chromosome rearrangements at 11q23. The breakpoint analysis results also support the role of chromatin structure in defining the site of chromosome rearrangement.


Subcellular remodeling and heart dysfunction in chronic diabetes.
Heart dysfunction in chronic diabetes has been observed to be associated with depressed myofibrillar adenosine triphosphatase activities as well as abnormalities in the sarcoplasmic reticular and sarcolemmal calcium transport processes. The evidence has been presented to show that alterations in the expression of myosin isozymes and regulatory proteins as well as myosin phosphorylation contribute to the development of myofibrillar remodeling in the diabetic heart. Defects in sarcoplasmic reticular and sarcolemmal calcium transport appear to be due to the accumulation of lipid metabolites in the membrane. Different agents, such as calcium-antagonists, beta-adrenoceptor blockers, angiotensin converting enzyme inhibitors, metabolic interventions and antioxidants, have been reported to exert beneficial effects in preventing subcellular remodeling and cardiac dysfunction in chronic diabetes. Clinical and experimental investigations have suggested that increased sympathetic activity, activated cardiac renin-angiotensin system, myocardial ischemia/functional hypoxia and elevated levels of glucose for a prolonged period, due to insulin deficiency, result in oxidative stress. It is proposed that oxidative stress associated with a deficit in the status of the antioxidant defense system may play a critical role in subcellular remodeling, calcium-handling abnormalities and subsequent diabetic cardiomyopathy.


Persistent impairment of liver function caused by a pendulated accessory liver lobe.
A large pendulated accessory liver lobe and complete absence of the left lobe were discovered by liver scintigraphy and ultrasound scanning in a patient suspected of having an ovarian tumor. The patient had a history of fluctuating impaired liver function tests for many years, probably caused by intermittent torsion of the peduncle. Pedunculated accessory liver lobes are extremely rare and seldom diagnosed in vivo. Our patient seems to be the 11th published case, and the only 1 in which longstanding fluctuating impaired liver function tests have been observed.


Hospital mergers: legal and personal implications for emergency physicians.
In east central Illinois over the last three years, three hospitals in which the authors were contracted as emergency physicians have been in various stages of merger with nearby hospitals. In all, six hospitals will be merged into three "medical centers." This is a basis of experience to be shared with other emergency physicians, as consolidation of health care facilities seems to be a wave of the future due to financial constraints of the health care setting. Lessons to be learned from these experiences involve many issues, including work contract, malpractice insurance payment, physician and nurse staffing, and public information problems.


Therapy insight: how the gut talks to the joints--inflammatory bowel disease and the spondyloarthropathies.
Axial and peripheral arthritis can occur in up to 30% of patients with inflammatory bowel disease. Likewise, the presence of gut inflammation in primary spondyloarthropathies is underappreciated, with subclinical gut inflammation documented in up to two-thirds of patients with this group of inflammatory disorders. Common genetic and immunologic mechanisms underlie the coincidence of inflammation in the joints and the intestine. New research highlights the critical role of innate and adaptive immune responses directed against components of the enteric microbial flora in driving gut and articular inflammation. Indeed, elucidation of genetic and serological immune markers will define clinically important subgroups of patients with these heterogeneous diseases. The treatment of inflammatory articular manifestations of inflammatory bowel disease is similar to the treatment of primary spondyloarthropathies. A notable exception is the use of NSAIDs, which can precipitate flares of inflammatory bowel disease and should be used with caution. Agents that target tumor necrosis factor have been a major advance in the treatment of both gut and joint inflammation in inflammatory bowel disease.


Closing of the nurse-midwifery service at Boston City Hospital: another perspective.
This paper is a response to an article previously published in JNM's Issues and Opinions column. It provides another perspective regarding the recent troubles of Boston City Hospital's nurse-midwifery service.


Hepatic Arterial Blood Flow Modulation in Patients with Hepatocellular Carcinoma: A Pilot Study of the Influence of Intraarterial Norepinephrine Assessed with CT Perfusion.
This pilot study aims to evaluate the effect of hepatic intraarterial norepinephrine injection in vasculature modulation for hepatocellular carcinoma (HCC) tumors. This is a single-center prospective study of patients with HCC with proven single-lobe tumors > 3 cm. Eight patients were included, with a mean age of 63 y ± 8. All patients had Barcelona Clinic Liver Cancer stage B HCC and an Eastern Cooperative Oncology Group performance status of 0. Mean tumor size was 6.1 cm ± 1.8; all tumors were hypervascular. Patients underwent CT hepatic perfusion before and after injection of 24 μg of norepinephrine intraarterially (4 μg/mL; total 6 mL injected at a rate of 1 mL/s). Color-coded perfusion maps were used to assess the effects of local therapy on hepatic perfusion values. Tumor-to-liver ratio (TLR) was calculated from the ratio of tumor perfusion to background liver perfusion value. Seven of 8 patents had significant (P = .04) absolute increase in tumor perfusion vs background liver, varying from incremental (-2 mL/min/100 mL) to 290 mL/min/100 mL. There was a nonsignificant increase in TLR from 2.7 ± 1.3 to 2.9 ± 1.4 after norepinephrine injection (P = .8). Mean peak time to maximal increase in tumor perfusion after injection was 6.1 s (range, 4.5-9.1 s). Norepinephrine injection was well tolerated without major adverse events. Norepinephrine causes increased blood flow toward HCC tumors, but with a corresponding smaller increase in blood flow to noncancerous liver tissue, with no observed systemic side effects.


Comparison of aqueous humor ascorbic acid level in smokers and non-smokers.
In this study, we studied effect of smoking on ascorbic acid level in aqueous humor. A cohort of 112 individuals undergoing cataract surgery for senile cataract (mean ± SD age-65 ± 8 years) was sub-grouped as smoker (n = 56) and non-smoker (n = 56) based on smoking habit. The aqueous humor sample was collected in beginning of the surgery and quantitative ascorbic acid estimation was done by colorimetric method (spectrophotometry at λ = 578 nm) using commercially available assay kits using the auto-analyzer assay procedure. The mean (±SD) aqueous humor ascorbic acid level was 1396 ± 629 μmol/L among non-smokers and 774 ± 436 μmol/L among smokers (p < 0.0001). The aqueous humor ascorbic acid concentration is significantly lower in smokers compared to non-smokers. The aqueous humor ascorbic acid concentration is affected by gender but not by age or morphology of cataract.


Effect of disease related biases on the subjective assessment of social functioning in Alzheimer's disease and schizophrenia patients.
Questionnaires are the current hallmark for quantifying social functioning in human clinical research. In this study, we compared self- and proxy-rated (caregiver and researcher) assessments of social functioning in Schizophrenia (SZ) and Alzheimer's disease (AD) patients and evaluated if the discrepancy between the two assessments is mediated by disease-related factors such as symptom severity. We selected five items from the WHO Disability Assessment Schedule 2.0 (WHODAS) to assess social functioning in 53 AD and 61 SZ patients. Caregiver- and researcher-rated assessments of social functioning were used to calculate the discrepancies between self-rated and proxy-rated assessments. Furthermore, we used the number of communication events via smartphones to compare the questionnaire outcomes with an objective measure of social behaviour. WHODAS results revealed that both AD (p < 0.001) and SZ (p < 0.004) patients significantly overestimate their social functioning relative to the assessment of their caregivers and/or researchers. This overestimation is mediated by the severity of cognitive impairments (MMSE; p = 0.019) in AD, and negative symptoms (PANSS; p = 0.028) in SZ. Subsequently, we showed that the proxy scores correlated more strongly with the smartphone communication events of the patient when compared to the patient-rated questionnaire scores (self; p = 0.076, caregiver; p < 0.001, researcher-rated; p = 0.046). Here we show that the observed overestimation of WHODAS social functioning scores in AD and SZ patients is partly driven by disease-related biases such as cognitive impairments and negative symptoms, respectively. Therefore, we postulate the development and implementation of objective measures of social functioning that may be less susceptible to such biases.


Malignant catarrhal fever virus specific secretory IgA in nasal secretions of wildebeest calves.
Wildebeest IgA was isolated from nasal secretions and precolostrum. It was identified by cross-reaction with anti-human and anti-bovine IgA sera. Nasal secretions collected from wildebeest calves over 3 months old had malignant catarrhal fever virus neutralizing antibody activity. They also contained specific IgA to the virus as detected by indirect immunofluorescence. It is suggested that production of malignant catarrhal fever virus specific IgA in the nasal cavity, contributes to the elimination and cessation of the virus shed in the nasal secretions of wildebeest calves over 3 months. old.


Thrombolysis in the Treatment of Acute Ischemic Stroke.
Unfortunately, intravenous alteplase, when administered within 3 hours of symptom onset, remains the only US Food and Drug Administration-approved treatment for acute ischemic stroke; it is now 7 years since its approval. Intra-arterial thrombolysis of middle cerebral and basilar artery occlusions within 6 hours of stroke onset probably is efficacious also, but the clinical trial evidence supporting this claim is less robust. The whole field of acute stroke intervention is in urgent need of more randomized, controlled clinical trials to advance management. There are several promising avenues of investigation, but clinicians must remain cautious and skeptical until convincing proof of the added benefit of new interventions is obtained.


Visualizing Hierarchical Performance Profiles of Parallel Codes Using CallFlow.
Calling context trees (CCTs) couple performance metrics with call paths, helping understand the execution and performance of parallel programs. To identify performance bottlenecks, programmers and performance analysts visually explore CCTs to form and validate hypotheses regarding degraded performance. However, due to the complexity of parallel programs, existing visual representations do not scale to applications running on a large number of processors. We present CallFlow, an interactive visual analysis tool that provides a high-level overview of CCTs together with semantic refinement operations to progressively explore CCTs. Using a flow-based metaphor, we visualize a CCT by treating execution time as a resource spent during the call chain, and demonstrate the effectiveness of our design with case studies on large-scale, production simulation codes.


Cells in the polyaneuploid cancer cell (PACC) state have increased metastatic potential.
Although metastasis is the leading cause of cancer deaths, it is quite rare at the cellular level. Only a rare subset of cancer cells (~ 1 in 1.5 billion) can complete the entire metastatic cascade: invasion, intravasation, survival in the circulation, extravasation, and colonization (i.e. are metastasis competent). We propose that cells engaging a Polyaneuploid Cancer Cell (PACC) phenotype are metastasis competent. Cells in the PACC state are enlarged, endocycling (i.e. non-dividing) cells with increased genomic content that form in response to stress. Single-cell tracking using time lapse microscopy reveals that PACC state cells have increased motility. Additionally, cells in the PACC state exhibit increased capacity for environment-sensing and directional migration in chemotactic environments, predicting successful invasion. Magnetic Twisting Cytometry and Atomic Force Microscopy reveal that cells in the PACC state display hyper-elastic properties like increased peripheral deformability and maintained peri-nuclear cortical integrity that predict successful intravasation and extravasation. Furthermore, four orthogonal methods reveal that cells in the PACC state have increased expression of vimentin, a hyper-elastic biomolecule known to modulate biomechanical properties and induce mesenchymal-like motility. Taken together, these data indicate that cells in the PACC state have increased metastatic potential and are worthy of further in vivo analysis.


Characterization and crystallization of recombinant human neurotrophin-4.
Neurotrophin-4 (NT-4) is the most recently discovered member of the neurotrophin family. We have expressed, refolded, and purified recombinant human NT-4 from Escherichia coli and compared it with recombinant human NT-4 secreted into the culture medium of baculovirus-infected insect cells. Both preparations were characterized and determined to be indistinguishable according to several biochemical criteria. Recombinant NT-4 from E. coli was crystallized in a form suitable for x-ray analysis, and characterization of these crystals indicated that NT-4 was present as a dimer within the asymmetric unit. NT-4 was active in promoting the survival of rat TrkB receptor-expressing fibroblasts, but was inactive on embryonic chicken sensory neurons, unlike the other members of the neurotrophin family and in contrast to the reported activities of partially purified NT-4.


Nimotuzumab Site-Specifically Labeled with 89Zr and 225Ac Using SpyTag/SpyCatcher for PET Imaging and Alpha Particle Radioimmunotherapy of Epidermal Growth Factor Receptor Positive Cancers.
To develop imaging and therapeutic agents, antibodies are often conjugated randomly to a chelator/radioisotope or drug using a primary amine (NH2) of lysine or sulfhydryl (SH) of cysteine. Random conjugation to NH2 or SH groups can require extreme conditions and may affect target recognition/binding and must therefore be tested. In the present study, nimotuzumab was site-specifically labeled using ∆N-SpyCatcher/SpyTag with different chelators and radiometals. Nimotuzumab is a well-tolerated anti-EGFR antibody with low skin toxicities. First, ΔN-SpyCatcher was reduced using tris(2-carboxyethyl)phosphine (TCEP), which was followed by desferoxamine-maleimide (DFO-mal) conjugation to yield a reactive ΔN-SpyCatcher-DFO. The ΔN-SpyCatcher-DFO was reacted with nimotuzumab-SpyTag to obtain stable nimotuzumab-SpyTag-∆N-SpyCatcher-DFO. Radiolabeling was performed with 89Zr, and the conjugate was used for the in vivo microPET imaging of EGFR-positive MDA-MB-468 xenografts. Similarly, ∆N-SpyCatcher was conjugated to an eighteen-membered macrocyclic chelator macropa-maleimide and used to radiolabel nimotuzumab-SpyTag with actinium-225 (225Ac) for in vivo radiotherapy studies. All constructs were characterized using biolayer interferometry, flow cytometry, radioligand binding assays, HPLC, and bioanalyzer. MicroPET/CT imaging showed a good tumor uptake of 89Zr-nimotuzumab-SpyTag-∆N-SpyCatcher with 6.0 ± 0.6%IA/cc (n = 3) at 48 h post injection. The EC50 of 225Ac-nimotuzumab-SpyTag-∆N-SpyCatcher and 225Ac-control-IgG-SpyTag-∆N-SpyCatcher against an EGFR-positive cell-line (MDA-MB-468) was 3.7 ± 3.3 Bq/mL (0.04 ± 0.03 nM) and 18.5 ± 4.4 Bq/mL (0.2 ± 0.04 nM), respectively. In mice bearing MDA-MB-468 EGFR-positive xenografts, 225Ac-nimotuzumab-SpyTag-∆N-SpyCatcher significantly (p = 0.0017) prolonged the survival of mice (64 days) compared to 225Ac-control IgG (28.5 days), nimotuzumab (28.5 days), or PBS-treated mice (30 days). The results showed that the conjugation and labeling using SpyTag/∆N-SpyCatcher to nimotuzumab did not significantly (p > 0.05) alter the receptor binding of nimotuzumab compared with a non-specific conjugation approach. 225Ac-nimotuzumab-SpyTag-∆N-SpyCatcher was effective in vitro and in an EGFR-positive triple negative breast cancer xenograft model.


Antigenic variants of rabies virus in isolates from eastern, central and northern Canada.
Street rabies virus isolated from 51 specimens from Ontario, Quebec, Manitoba and the Northwest Territories have been typed by a panel of 36 antinucleocapsid monoclonal antibodies. Three main groups were found. The first group comprised those terrestrial mammals originating in Ontario, Quebec and the Northwest Territories. The second group was found in terrestrial mammals from Manitoba. The third heterogenous group was made up of bats from Ontario.


A house officer in general practice: a different experience.
This paper describes a single house officer's attachment in general practice, organized in a particular way and with specified aims. The attachment required careful planning and case-by-case supervision of the houseman. However, the extra clinical burden on the supervisor was not excessive. The attachment provided experience similar in some ways to hospital posts, but was broader in general clinical content and emphasized the continuity between primary and secondary care. Many of the important experiences could only be obtained in an attachment which involves responsibility inside and outside the hospital at the same time. We believe such attachments are a unique educational opportunity and should be strongly encouraged.


Toward a BT.2020 green emitter through a combined multiple resonance effect and multi-lock strategy.
Color-saturated green-emitting molecules with high Commission Internationale de L'Eclairage (CIE) y values have great potential applications for displays and imaging. Here, we linked the outer phenyl groups in multiple-resonance (MR)-type blue-emitting B (boron)-N (nitrogen) molecules through bonding and spiro-carbon bridges, resulting in rigid green emitters with thermally activated delayed fluorescence. The MR effect and multiple interlocking strategy greatly suppressed the high-frequency vibrations in the molecules, which emit green light with a full-width at half-maximum of 14 nm and a CIE y value of 0.77 in cyclohexane. These were the purest green molecules with quantum efficiency and color purity that were comparable with current best quantum dots. Doping these emitters into a traditional green-emitting phosphorescence organic light-emitting diode (OLED) endowed the device with a Broadcast Service Television 2020 color-gamut, 50% improved external quantum efficiency, and an extremely high luminescence of 5.1 × 105 cd/m2, making it the greenest and brightest OLED ever reported.


Migration and activation of T cells during development of graft-versus-host disease in a mouse model.
We investigated the pathophysiologic events in graft-versus-host disease (GVHD), a major complication of hematopoietic stem cell transplantation (HSCT). The experimental group included BALB/c female mice conditioned with 8.0 GY total body irradiation that were transplanted with allogeneic C57BL/6 male bone marrow cells (BMCs) plus CD4(+) T cells and CD8(+) T cells isolated from green fluorescent protein transgenic (eGFP-Tg) C57BL/6 male mice by the immunomagnetic beads negative sorting method. The control group was transplanted only with C57BL/6 male BMCs. GVHD clinical manifestations were present in the BMCs plus T-cell-transplanted group, but not the BMCs alone group. eGFP(+) T cells were observed in recipient organs, including the liver, spleen, intestine, skin, lungs, tongue, kidneys and even the brain. Donor eGFP(+) T cells were significantly increased in liver and spleen before day +4 (P < .05); but decreased in the spleen while still increased in the liver after day +4 (P < .05). CD25 expression of donor eGFP(+) T cells in the liver and spleen, and interleukin (IL)-2 levels in the peripheral blood was significantly increased before day +4 (P < .05), but decreased after day +4 (P < .05). These data support the donor T-cell migration hypothesis that accompanied by expression of CD25 and IL-2, during the development of GVHD donor T cells migrate to lymphoid organs, such as the spleen, after activation migrating to GVHD target organs to induce GVHD damage.


Pain thresholds and tolerances of competitive rowers and their use of spontaneous self-generated pain-coping strategies.
Experimental ischaemic pain was induced in 20 male competitive rowers in training and a control group of 20 males not in training. Pain tolerances, but not thresholds, were higher for competitive rowers. The rowers also reported using a range of self-generated pain-coping strategies during testing which, they claimed, they also used during training. Pain tolerances were correlated with the number and quality of coping strategics used during testing.


Dapagliflozin in patients with heart failure with mildly reduced and preserved ejection fraction treated with a mineralocorticoid receptor antagonist or sacubitril/valsartan.
The effects of adding a sodium-glucose cotransporter 2 (SGLT2) inhibitor to a mineralocorticoid receptor antagonist (MRA) or an angiotensin receptor-neprilysin inhibitor (ARNI) in patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) are uncertain, even though the use of all three drugs is recommended in recent guidelines. The efficacy and safety of dapagliflozin added to background MRA or ARNI therapy was examined in patients with HFmrEF/HFpEF enrolled in the DELIVER trial. The primary outcome was the composite of worsening HF or cardiovascular death. Of 6263 patients, 2667 (42.6%) were treated with an MRA and 301 (4.8%) with an ARNI at baseline. Patients taking either were younger, more often men and had lower systolic blood pressure and ejection fraction; they were also more likely to have prior HF hospitalization. The benefit of dapagliflozin was similar whether patients were receiving these therapies. The hazard ratio for the effect of dapagliflozin compared to placebo on the primary outcome was 0.86 (95% confidence interval [CI] 0.74-1.01) for MRA non-users versus 0.76 (95% CI 0.64-0.91) for MRA users (pinteraction = 0.30). The corresponding values for ARNI non-users and users were 0.82 (95% CI 0.73-0.92) and 0.74 (95% CI 0.45-1.22), respectively (pinteraction = 0.75). None of the adverse events examined was more common with dapagliflozin compared to placebo overall or in the MRA and ARNI subgroups. The efficacy and safety of dapagliflozin were similar, regardless of background treatment with an MRA or ARNI. SGLT2 inhibitors may be added to other treatments recommended in recent guidelines for HFmrEF/HFpEF.


Maternal overweight and sexual function in pregnancy.
Obesity and overweight are increasing worldwide and may compromise female sexual function. Our aim was to compare the sexual function of normal and overweight women in pregnancy. A cross-sectional study involving 223 pregnant women: 105 overweight [pre-pregnancy body mass index (BMI) ≥ 25.0 kg/m(2) ] and 118 normal weight (BMI 18.5-24.9 kg/m(2) ), in the 2nd and 3rd trimester of pregnancy. These women were managed at an antenatal clinic of a public university hospital in São Paulo, Brazil, between 2011 and 2014. The Female Sexual Function Index (FSFI) was used. The characteristics of normal and overweight women were compared using two-tailed Student's t- or chi-squared tests. Differences in mean FSFI scores were assessed using the Kruskal-Wallis test. Pearson's correlation coefficient was used to assess the correlation between pre-pregnancy BMI and FSFI scores. In the 2nd trimester, mean total FSFI scores were similar in overweight (n = 51) compared to normal weight (n = 67) women (21.9 ± 9.8 vs. 21.7 ± 10.4, p = 1.000). In the 3rd trimester, overweight women (n = 54) had significantly lower total FSFI scores than normal weight women (n = 51; 19.1 ± 10.3 vs. 24.5 ± 9.7, p = 0.0004). In the 3rd trimester, overweight women also had significantly lower mean scores in desire, arousal, lubrication, orgasm and dyspareunia domains. We found an inverse correlation between pre-pregnancy BMI and mean 3rd trimester total FSFI scores (r = -0.212, p = 0.030), desire (r = -0.216, p = 0.027) and orgasm (r = -0.222, p = 0.023). Overweight women in the 3rd trimester of pregnancy had poorer sexual function compared with normal weight women.


Three-dimensional current density distribution under surface stimulation electrodes.
Overflow to non-target tissue during FNS can be reduced by controlling current density distribution under surface stimulating electrodes. A method is introduced for the acquisition of 3-D current density distributions under complex surface stimulating FNS electrode geometries. The method makes use of a phantom model in which a conventional homogeneous model has been improved by adding a layer to simulate skin impedance properties, based on specific FNS parameters. Signal acquisition and processing circuits have been developed to simulate the process by which excitable tissue responds to external stimulation. In addition, a data analysis method has been introduced to allow for the characterisation of stimulation current intensity, electrode geometry and pulse waveform required to achieve target muscle activation, with minimal overflow and to avoid pain or burning. Measurements of integrated differential voltage corresponding to current density distribution acquired under electrodes of various geometries are presented in terms of 3-D attenuation coefficient maps as examples of the applicability of the method.


Spatiotemporal treadmill gait measurements using a laser range scanner: feasibility study of the healthy young adults.
Spatio-temporal parameters are typically used for gait analysis. Although these parameters are measured by sophisticated systems such as 3D motion capture system or optoelectronic bars, these systems cannot be deployed easily because of their high costs, large space requirements and elaborate set-up. The purpose of this study is to develope a system for measuring spatiotemporal gait parameters using a laser range scanner during treadmill gait. To calculate accurate spatiotemporal parameters, the differences between the laser range scanner measured values and the reference values obtained from a 3D motion capture system were investigated in thirty subjects. From measurements in time and position at foot contact/off, adjustments to compensate for the differences in time and position were derived. Then, to determine the validity of the proposed system, values from the proposed system and the reference system were compared in four additional subjects. The results indicate that the data from the laser range scanner demonstrate certain differences in time and position compared with reference values. However, when compensation values were introduced, each spatiotemporal parameter correlated well with the reference values. This newer system is smaller, is easier to deploy and requires less training than the 3D motion capture system.


Daphnoretin relieves IL-1β-mediated chondrocytes apoptosis via repressing endoplasmic reticulum stress and NLRP3 inflammasome.
Osteoarthritis (OA), mainly caused by severe joint degeneration, is often accompanied by joint pain and dysfunction syndrome. Inflammatory mediators and apoptosis play key roles in the evolution of OA. It is reported that daphnoretin has significant antiviral and anti-tumor values. The present study aims at investigating the role of daphnoretin in OA. The OA mouse model was constructed by performing the destabilization of the medial meniscus through surgery, and the OA cell model was induced in ATDC5 chondrocytes with IL-1β (10 ng/mL) in vitro. Chondrocyte viability and apoptosis were measured by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT), Caspase-3 activity, and flow cytometry. The levels of COX-2, iNOS, TNF-α, IL-6, Bax, Bcl2, cleaved-Caspase3, endoplasmic reticulum stress (ERS) proteins (GRP78, CHOP, ATF6, and Caspase-12), and NLRP3-ASC-Caspase1 inflammasome were determined by quantitative real-time PCR or western blot. The concentrations of TNF-α, IL-6, and PGE2 were tested by enzyme-linked immunosorbent assay. The content of nitrates was detected by the Griess method. In vivo, morphologic differences in knee joint sections and the thickness of the subchondral bone density plate in mice were observed by hematoxylin-eosin (H&E) staining and safranin O-fast green staining. Daphnoretin effectively choked IL-1β-induced chondrocyte apoptosis and facilitated cell viability. Daphnoretin dose-dependently abated ERS, inflammatory mediators, and the activation of NLRP3 inflammasomes in IL-1β-induced chondrocytes. What's more, in vivo experiments confirmed that daphnoretin alleviated OA progression in a murine OA model by mitigating inflammation and ERS. Daphnoretin alleviated IL-1β-induced chondrocyte apoptosis by hindering ERS and NLRP3 inflammasome.


The efficacy of radio-frequency ablation for metastatic lung or liver tumors of male germ cell tumors as an alternative minimally invasive therapy after salvage chemotherapy.
The aim of this study was to assess the efficacy of radio-frequency ablation (RFA) for metastatic lung or liver tumors of germ cell tumors (GCTs) after chemotherapy. RFA with computed tomography guidance and monitoring was performed in 24 patients with 48 metastatic lung or liver tumors of GCTs. Group A consisted of 9 patients with tumor marker normalization after salvage chemotherapy and group B consisted of 15 patients without tumor marker normalization in spite ofintensive treatment. Out of 48 tumors, 41 tumors in 21 patients were evaluated for the efficacy of the RFA treatment. Of the 41 tumors, successful ablation was achieved in 34 (82.9 %). The patients in group A had significantly better survival than the patients in group B (p = 0.0003). In group A, all 9 patients are still alive with no evidence of disease (NED). Patients with a solitary tumor had significantly better survival than those with multiple tumors (p = 0.0247). In group B, 2 patients are alive with NED, 1 patient is alive with disease, and the remaining 12 patients have died a tumor-related death. Three cases of pneumothorax requiring intubation were observed. RFA is less invasive than surgery and is an effective treatment option for curative and palliative therapy as an alternative to invasive salvage surgery for post-chemotherapeutic metastatic lung or liver lesions from GCT.


Chromium allergy: significance of both Cr(III) and Cr(VI).
Most studies investigating chromium allergy have been performed with Cr(VI). However, real exposure to chromium from leather products includes both Cr(III) and Cr(VI). We have determined and compared the minimum elicitation threshold (MET) concentration for Cr(III) and Cr(VI) in Cr(VI)-sensitive patients. In addition, reactions to combinations of Cr(III) and Cr(VI) were compared to reactions elicited by Cr(III) and Cr(VI) alone. Dilution series of Cr(III) and Cr(VI) were applied in Finn Chambers on the back of 18 patients. The patches were left for 2 days and readings were done on days 2, 3 and 7. The MET10% for Cr(III) and Cr(VI) was calculated from the dose-response curves to be 0.18 microg/cm2/48 h (6 p.p.m.) and 0.03 microg/cm2/48 h (1 p.p.m.), respectively. No significant differences in the response to combined Cr(III) and Cr(VI) solutions versus single solutions were found. Cr(III) was concluded to play an important role in chromium allergy, because Cr(III) and Cr(VI) were both capable of eliciting eczema at low concentrations. Rather than regarding chromium dermatitis as a result of Cr(VI) allergy alone, it may be more correct to consider it as a result of a combined Cr(III) and Cr(VI) allergy.


Housing affordability effects on physical and mental health: household survey in a population with the world's greatest housing affordability stress.
We examined the association of housing affordability with physical and mental health in Hong Kong, where there is a lack of related research despite having the worst housing affordability problem in the world, considering potential mediating effect of deprivation. A stratified random sample of 1978 Hong Kong adults were surveyed. Housing affordability was defined using the residual-income (after housing costs) approach. Health-related quality of life was assessed by the Short-Form Health Survey version 2 (SF-12v2), from which the physical component summary (PCS) and mental component summary (MCS) measures were derived. Multivariable linear regressions were performed to assess associations of housing affordability with PCS and MCS scores, adjusting for sociodemographic, socioeconomic and lifestyle factors. Mediation analyses were also conducted to assess the mediating role of deprivation on the effect of housing affordability on PCS or MCS. Dose-response relationships were observed between housing affordability and mean PCS score (β (95% CI) compared with the highest affordable fourth quartile: -2.53 (-4.05 to -1.01), -2.23 (-3.54 to -0.92), -0.64 (-1.80 to 0.51) for the first, second and third quartiles, respectively) and mean MCS score (β (95% CI): -3.87 (-5.30 to -2.45), -2.35 (-3.59 to -1.11), -1.28 (-2.40 to -0.17) for the first, second and third quartiles, respectively). Deprivation mediated 34.3% of the impact of housing unaffordability on PCS and 15.8% of that on MCS. Housing affordability affects physical and mental health, partially through deprivation, suggesting that housing policies targeting deprived individuals may help reduce health inequality in addition to targeting the housing affordability problem.


Capillary-based fluorescence microsensor with polyoxometalates as nanozyme for rapid and ultrasensitive detection of artemisinin.
A novel capillary-based fluorescence microsensor for artemisinin was developed with functional polyoxometalates (POMs) as nanozyme by a layer-by-layer self-assembly strategy. Vanadomolybdophosphoric heteropoly acid (H5PMo10V2O40, PMoV2) and tungstophosphoric heteropoly acid (Na5PW11O39Cu, PW11Cu) with high peroxidase-like activity were synthesized and immobilized on capillary to catalyze artemisinin/thiamine reaction and generate the amplified fluorescence signal. The wide linear range up to 13.0 μM with the low limit of detection of 0.03 μM (S/N = 3) was achieved for the determination of artemisinin by using the proposed POMs-microsensor. The method has been successfully used to detect artemisinin in human plasma and antimalarial drugs with satisfactory accuracy. This work developed a novel capillary fluorescence microsensor with functional POMs as nanozyme, which can serve as a promising candidate in fluorescence microanalysis.


Polymeric nanoparticle vaccines to combat emerging and pandemic threats.
Subunit vaccines are more advantageous than live attenuated vaccines in terms of safety and scale-up manufacture. However, this often comes as a trade-off to their efficacy. Over the years, polymeric nanoparticles have been developed to improve vaccine potency, by engineering their physicochemical properties to incorporate multiple immunological cues to mimic pathogenic microbes and viruses. This review covers recent advances in polymeric nanostructures developed toward particulate vaccines. It focuses on the impact of microbe mimicry (e.g. size, charge, hydrophobicity, and surface chemistry) on modulation of the nanoparticles' delivery, trafficking, and targeting antigen-presenting cells to elicit potent humoral and cellular immune responses. This review also provides up-to-date progresses on rational designs of a wide variety of polymeric nanostructures that are loaded with antigens and immunostimulatory molecules, ranging from particles, micelles, nanogels, and polymersomes to advanced core-shell structures where polymeric particles are coated with lipids, cell membranes, or proteins.


Molecular characterization, phylogeny, and expression of c-type and g-type lysozymes in brill (Scophthalmus rhombus).
Lysozymes are key proteins of the innate immune system against bacterial infections. In this study we report the molecular cloning and characterization of the c-type and g-type lysozymes in brill (Scophthalmus rhombus). Catalytic and other conserved residues required for functionality were identified. Phylogenetic analysis revealed distinct evolutionary histories for each lysozyme type. Expression profiles of both lysozyme genes were studied in juvenile tissues using a real-time PCR approach. c-Type lysozyme was expressed mainly in stomach and liver, whereas the g-type was detected in all tissues with highest mRNA levels observed in the spleen. Induction experiments revealed that g-type transcripts increased significantly in head kidney after lipopolysaccharide (25- and 23-fold at 12 and 24h, respectively) and Photobacterium damselae subsp. piscicida (17-fold at 24h) treatments. In contrast, no induction was observed for c-type lysozyme. All these data suggest that g-type lysozyme is involved in the response against bacterial infections, whereas c-type lysozyme may also play a role in digestion.


In vivo Histology of the Cornea - from the "Rostock Cornea Module" to the "Rostock Electronic Slit Lamp" - a Clinical "Proof of Concept" Study.
Confocal in vivo microscopy is an established method in ophthalmology research. As it requires contact coupling and calibration of the instruments is suboptimal, this method has been only rarely used in clinical routine work. As a result of close collaboration between physicists, information scientists and ophthalmologists, confocal laser scanning microscopy (CLSM) of the eye has been developed in recent years and a prototype can now be used in patients. The present study evaluates possible clinical uses of this method. The essential innovations in CLSM are (1) a newly designed coupling element with superficial adaptation to corneal curvature and (2) the use of a dual computerised piezo drive for rapid and precise focusing. In post-processing and after elastic imaging registration of the individual images parallel to the surface, it is also possible to produce sagittal sections resembling a split lamp and with resolution in the micrometer range. The concept was tested on enucleated pig bulbi and tested on normal volunteers and selected patients with diseases of the cornea. Simultaneous imaging in planes parallel to the surface and in sagittal planes provided additional information that can help us to understand the processes of wound healing in all substructures of the cornea and the role of immune competent cells. Possible clinical uses were demonstrated in a volunteer with healthy eyes and several groups of patients (keratoconus after CXL, recurrent keratitis, status after PRK). These show that this new approach can be used in morphological studies at cellular level in any desired and appropriate test plane. It could be shown that this new concept of CLSM can be used clinically. It can provide valuable and novel information to both preclinical researchers and to ophthalmologists interested in corneal disease, e.g. density of Langerhans cells and epithelial stratification in ocular surface diseases.


Spiritual Care Needs of Terminal Ill Cancer Patients.
Terminal ill cancer patients experience spiritual distress and need spiritual care. They are in need of palliative care in the long term to alleviate suffering. The aim of the study was to investigate spiritual needs of terminal ill cancer patients. This study is a cross-sectional study. The participants were Thai terminal ill cancer patients from seven hospitals in northern, northeast, central, and southern regions of Thailand. Three-hundred-and-twenty-two participants were purposively selected. The instrument used in this study was a spiritual needs scale, consisting of 41 items with 4-point rating scale. Statistical analysis was F-test for one-way analysis of variance. The majority of terminal ill cancer patients aged fifty-one years old. Most of them were females with end stage cancer status that did not respond to treatment. The overall spiritual needs of terminal ill cancer patients were at the moderate level (M = 18.21, SD = 2.56). The highest mean was found in the 'prepare for death' dimension, followed by the 'have meaning, values, and life purposes' and the 'have opportunity to pursue most important things in life' dimensions respectively and had different spiritual needs among status (F(3,318) = 3.66, p < 0.05), number of family members (F(8,313) = 5.07, p < 0.05), living with family (F(2,319) = 3.91, p < 0.05), and spiritual anchor (F(2,319) = 4.13, p < 0.05). The study results provide insight into spiritual needs of terminal ill cancer patients which assists in improving the provision of holistic care to let the patients be happy at end-of-life phase.


Theophylline-induced upregulation of A1-adenosine receptors associated with reduced sensitivity to convulsants.
Chronic administration of theophylline (50 mg/kg twice daily for 14 consecutive days) significantly increased the specific binding of [3H]CHA in membranes of the cerebral cortex and cerebellum of the rat, but not in membranes derived from the hippocampus or diencephalon. To characterize further the upregulation of A1 = adenosine receptors induced by theophylline, saturation analysis with [3H]CHA was performed in membranes of the cerebral cortex and cerebellum. In both saline- and theophylline-treated cortical membranes the binding isotherms for [3H]CHA could be resolved into receptor affinity states having respectively high (KH) and low (KL) affinity for [3H]CHA. The high and low affinity dissociation constants obtained from theophylline-exposed membranes of the cerebral cortex were 1.14 nM and 25.2 nM and did not differ significantly from the corresponding values in saline-treated animals. Chronic exposure to theophylline did, however, produce significant increases in the densities of both the high and low affinity forms of A1-adenosine receptors in the cerebral cortex. Qualitatively and quantitatively similar results were observed in cerebellar membranes. These results suggest that chronic exposure to theophylline increases the density of A1-receptor in the cerebral cortex and cerebellum with no concomitant changes in the ability of [3H]CHA to distinguish separate agonist affinity states of the receptor. The physiological significance of theophylline-induced upregulation was assessed by determining seizure thresholds for convulsants in rats treated chronically with saline or theophylline.(ABSTRACT TRUNCATED AT 250 WORDS)


A comparison between revised Manchester Point A and ICRU-89-recommended Point A definition absorbed-dose reporting using CT images in intracavitary brachytherapy for patients with cervical carcinoma.
This study is a comparison between revised Manchester Point A and International Commission on Radiation Units and measurements (ICRU) 89 report-recommended Point A absorbed-dose reporting in intracavitary brachytherapy for patients with cervical carcinoma. The retrospective dosimetric study is based on the data of 32 patients with cervical carcinoma treated with high-dose-rate brachytherapy. Patients received 21 Gy in three fractions (7.0 Gy X three fractions) to Point A (Aflange, revised Manchester definition). All the patients were replanned with a new Point A (Aicru89) defined on CT images as per the American Brachytherapy Society/ICRU-89. The data collected were compared with the data obtained from Point A (Aflange). When using the Aflange plan normalization method, the mean dose of 0.1 cc, 1 cc, and 2 cc bladder volumes was 820.79 ± 207.47 cGy, 654.66 ± 152.69 cGy, and 588.91 ± 136.35 cGy, respectively. Likewise, when using the ICRU-89 Point Aicru89 normalization method, the mean dose of 0.1 cc, 1 cc, and 2 cc bladder volumes was 869.30 ± 224.67 cGy, 693.24 ± 166.20 cGy, and 616.61 ± 150.32 cGy, respectively. For the rectum, Point Aflange normalization plans, the mean dose of 0.1 cc, 1 cc, and 2 cc volumes was 589.37 ± 163.26 cGy, 487.51 ± 126.03 cGy, and 442.70 ± 111.43 cGy, respectively. Likewise, using the Aicru89 plan, the mean 0.1 cc, 1 cc, and 2 cc rectum volume was 625.07 ± 171.31 cGy, 517.50 ± 131.05 cGy, 464.94 ± 121.81 cGy, respectively. The statistical mean difference of Total Reference Air Kerma rate, V100 (cc), bladder, rectum and sigmoid, was found significant. It has been found that the position of revised Manchester (Aflange) and ICRU-89 Point A does not match on CT images/radiograph, which resulted in variation in doses to the tumor, V100 (cc), organ at risk, and Total Reference Air Kerma.


Effects of 5 beta-chol-3-en-24-oic acid, and lithocholic acid and its sulfates on prostaglandin E2 output in perfusion of the rat colon.
The effects of bile salts on the output of prostaglandin E2(PGE2) were studied in rats by colonic perfusion. Bile salts and their concentrations in infusates were as follows; chenodeoxycholic acid sodium salt (CDCNa), sulfolithocholic acid disodium salt (SLCNa) and sulfotaurolithocholic acid disodium salt (STLCNa) were at 1 mmol/l, lithocholic acid sodium salt (LCNa) was at 0.6 mmol/l, 5 beta-chol-3-en-24-oic acid sodium salt (delta 3Na) was at 0.006 mmol/l, and sulfoglycolithocholic acid disodium salt (SGLCNa) was at 0.8 mmol/l. Median values of PGE2 outputs were 40.9, 52.4, 65.5, trace, 7.6, 9.8 and 9.8 pg/10 min/cm in the CDCNa, LCNa, delta 3Na, SLCNa, STLCNa, SGLCNa and control groups, respectively (control vs CDCNa, LCNa, delta 3Na, SLCNa group, p less than 0.01 by median test). There was such a dissociation in PGE2 output and electrolyte concentration in the perfusates that high concentration of Na+ and Cl- ions was observed only in the SGLCNa group (p less than 0.01 by t-test compared with the control group), whereas in the remainder of the groups substantial net movement of electrolytes and water was not observed. Light microscopy showed no evidence of morphological damage in any group. These results indicated that CDCNa, LCNa and delta 3Na increased PGE2 outputs in the colon at low concentration without functional or morphological changes.


Psychometric Evaluation of the Self-Care in Chronic Obstructive Pulmonary Disease Inventory in the United States.
High quality self-care among individuals with chronic obstructive pulmonary disease (COPD) promotes better outcomes, however, there are few validated self-care measures that are psychometrically sound to be used in research. The purpose of this study is to examine the psychometric properties of the Self-Care in Chronic Obstructive Pulmonary Disease Inventory (SC-COPDI) in an English-speaking population in the United States. Factorial validity, construct validity and reliability of the SCCOPDI were examined using components analysis via principal components analysis, hypothesis testing via multivariate linear regression, Cronbach's alpha, and split-half reliability. The SCCOPDI demonstrated strong evidence of validity and reliability on par with the SCCOPDI's original construction. Component analysis produced item loadings consistent with the theoretical underpinnings of the instrument. Reliability metrics yielded good internal consistency across all subscales of the SCCOPDI. The SCCOPDI is a valid and reliable instrument to measure self-care in people with COPD.


Hiding in Plain Sight: Human Gingival Fibroblasts as an Essential, Yet Overlooked, Tool in Regenerative Medicine.
Adult human gingival fibroblasts (HGFs), the most abundant cells in the oral cavity, are essential for maintaining oral homeostasis. Compared with other tissues, adult oral mucosal wounds heal regeneratively, without scarring. Relative to fibroblasts from other locations, HGFs are relatively refractory to myofibroblast differentiation, immunomodulatory, highly regenerative, readily obtained via minimally invasive procedures, easily and rapidly expanded in vitro, and highly responsive to growth factors and cytokines. Consequently, HGFs might be a superior, yet perhaps underappreciated, source of adult mesenchymal progenitor cells to use in tissue engineering and regeneration applications, including the treatment of fibrotic auto-immune connective tissue diseases such as scleroderma. Herein, we highlight in vitro and translational studies that have investigated the regenerative and differentiation potential of HGFs, with the objective of outlining current limitations and inspiring future research that could facilitate translating the regenerative potential of HGFs into the clinic.


Robustness of implantable algorithms to detect epileptiform activity in the presence of broad-spectrum background noise.
Detection of epileptiform activity is of interest for responsive stimulation and diagnostic or monitoring devices in epilepsy; some implantable systems use low-computational-complexity algorithms such as line length trending and half-wave detection. Broadband noise was added to recorded electrocorticographic signals in order to model the potential impact of factors such as electrode-tissue interface properties and distance from the epileptic focus on these detection tools. Simulation demonstrated that half-wave and line length tools can yield consistent results in the presence of moderate amounts of noise.


[Malignant hyperthermia syndrome in the intensive care unit : Differential diagnosis and acute measures].
Malignant hyperthermia is a life-threatening disease caused by derangement of the autonomic nerve system and hypermetabolism of the peripheral musculature. Commonly body core temperatures of more than 40 °C will be found in this disease which is caused mostly by psychopharmacological drugs like antidepressants, neuroleptics but also antibiotics, pain killers, anti-Parkinson drugs, and volatile anesthetics. The inducers of malignant hyperthermia interact with postsynaptic receptors (serotonin, anticholinergics) or muscular intracellular structures responsible for calcium utilization (volatile anesthetics, succinylcholine). Rarely malignant hyperthermia is a consequence of mental stress or vigorous exercise and or heat. Malignant hyperthermic syndromes lead to a severe dysbalance of the autonomic nerve system accompanied by rhabdomyolysis, disseminated intravascular coagulopathy, and finally multi-organ failure. Accordingly, medical management is primarily directed to stabilize vital functions, withdrawal of the causing drug, and if possible antagonizing toxic substances. The leading symptom hyperthermia needs to be treated physically with available cooling systems.


Sex specific impact of perinatal bisphenol A (BPA) exposure over a range of orally administered doses on rat hypothalamic sexual differentiation.
Bisphenol A (BPA) is a high volume production chemical used in polycarbonate plastics, epoxy resins, thermal paper receipts, and other household products. The neural effects of early life BPA exposure, particularly to low doses administered orally, remain unclear. Thus, to better characterize the dose range over which BPA alters sex specific neuroanatomy, we examined the impact of perinatal BPA exposure on two sexually dimorphic regions in the anterior hypothalamus, the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the anterioventral periventricular (AVPV) nucleus. Both are sexually differentiated by estradiol and play a role in sex specific reproductive physiology and behavior. Long Evans rats were prenatally exposed to 10, 100, 1000, 10,000μg/kg bw/day BPA through daily, non-invasive oral administration of dosed-cookies to the dams. Offspring were reared to adulthood. Their brains were collected and immunolabeled for tyrosine hydroxylase (TH) in the AVPV and calbindin (CALB) in the SDN-POA. We observed decreased TH-ir cell numbers in the female AVPV across all exposure groups, an effect indicative of masculinization. In males, AVPV TH-ir cell numbers were significantly reduced in only the BPA 10 and BPA 10,000 groups. SDN-POA endpoints were unaltered in females but in males SDN-POA volume was significantly lower in all BPA exposure groups. CALB-ir was significantly lower in all but the BPA 1000 group. These effects are consistent with demasculinization. Collectively these data demonstrate that early life oral exposure to BPA at levels well below the current No Observed Adverse Effect Level (NOAEL) of 50mg/kg/day can alter sex specific hypothalamic morphology in the rat.


Expression of Fas and Fas ligand in human gastric adenomas and intestinal-type carcinomas: correlation with proliferation and apoptosis.
Fas (APO-1/CD95), a member of the tumor necrosis factor/nerve growth factor receptor superfamily, mediates apoptosis in response to agonistic antibodies or Fas ligand (FasL) binding. Previous reports indicated an up-regulation of FasL in gastric carcinomas to evade host immune attack. Fas/FasL expression, however, has not been analyzed in terms of apoptosis and proliferation in gastric adenoma and carcinoma. This study was conducted on seven human gastric carcinoma cell lines, 47 gastric adenomas, and 75 intestinal-type adenocarcinomas (48 early and 27 advanced carcinomas). Fas/FasL expression was examined by immunohistochemistry, apoptosis by the terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) method, and Fas gene mutation by a reverse transcriptase (RT) polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and sequencing method. Fas and FasL expressions were noted in 18 (38.3%) and 17 (36.2%) adenomas, in 21 (43.8%) and 33 (68.8%) early carcinomas, and in 10 (37.0%) and 19 (70.4%) advanced carcinomas, respectively. The frequency of FasL expression was significantly higher in advanced carcinomas than in the early carcinomas and adenomas; in contrast, there was no significant difference in Fas expression among the three groups. The mean apoptotic index (AI) was 4.96+/-0.51 in the adenomas, 2.96+/-0.23 in the early carcinomas, and 1.67+/-0.17 in the advanced carcinomas. A significantly higher Al was noted in the lesions with Fas expression than in those without Fas expression in all three groups. No missense mutations of the Fas gene were detected in any of the gastric carcinoma cell lines, or in the gastric adenomas or carcinomas. Upregulation of FasL may correlate with the progression of gastric carcinoma. Apoptosis in gastric adenoma and carcinoma cells may occur via Fas-dependent and -independent pathways, but further clarification is needed.


Structure and magnetic properties of a new ferrimagnet containing a paramagnetic [Cr(CN)5(NO)]3- building block.
A new Prussian-blue type molecular magnet containing a paramagnetic [Cr(CN)5(NO)]3- building block has been synthesized and characterized; the observed magnetic behavior displays the nature of a ferrimagnet.


Isolation of human complex-forming glycoprotein, heterogeneous in charge (protein HC), and its IgA complex from plasma. Physiochemical and immunochemical properties, normal plasma concentration.
Human complex-forming glycoprotein, heterogeneous in charge (protein HC) has previously been isolated from urine and immunochemically shown to be present in low and high molecular weight forms in blood plasma (Tejler, L., and Grubb, A. O. (1976) Biochim. Biophys. Acta 439, 82-94). In the present work, the major low and high molecular weight forms of the protein were isolated from plasma by immunosorption followed by gel chromatography. The plasma low molecular weight protein HC and the urinary protein had similar, if not identical, molecular weight, amino acid composition, NH2-terminal and carboxyl-terminal amino acid sequences and electrophoretic mobility. The low molecular weight plasma protein HC carried a yellow chromophore like the urinary protein, but its molar extinction coefficient at 280 nm was lower and its charge heterogeneity less pronounced than that of urinary protein HC. The plasma high molecular weight protein HC had a hydrodynamic volume which was greater than that of monomeric IgA but smaller than that of dimeric IgA. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the isolated high molecular weight protein followed by electrophoretic blotting and immunochemical analysis demonstrated that the protein contained four polypeptide chains: two light immunoglobulin chains (Mr = 23,000), one IgA alpha-chain (Mr = 54,000), and one chain with Mr approximately 90,000 which carried both alpha-chain and protein HC antigenic determinants. Whether the protein HC X IgA complex is a functionally significant part of the humoral immune system cannot be decided without further experimentation, but the complex was found to be completely absent from the blood plasma of patients with a selective deficiency of IgA-secreting immunocytes. The isolated low and high molecular weight plasma protein HC components were used as standard proteins in the construction of a quantitative crossed immunoelectrophoretic assay for the simultaneous quantitation of the two major protein HC components in blood plasma. The plasma concentrations of the low and high molecular weight protein HC components were measured by this method in 13 healthy Caucasians. The results for the low molecular weight protein HC were: mean, 20.3 mg/liter, S.D., 3.2 mg/liter, range, 13.6-26.0 mg/liter; and for the protein HC X IgA complex: mean, 293 mg/liter, S.D., 176 mg/liter, range, 36-620 mg/liter.


Kinetics and mechanism of the degradation of the pesticide metsulfuron methyl induced by excitation of iron(III) aqua complexes in aqueous solutions: steady state and transient absorption spectroscopy studies.
The degradation of the pesticide metsulfuron methyl induced by excitation of iron(III) aqua complexes was studied at 365 nm. The process involved the formation of hydroxyl radicals and was shown to depend on Fe(OH)(2+) concentration. The second order rate constant of the reaction of metsulfuron methyl and hydroxyl radical was evaluated by laser flash photolysis experiments to k = 3.5 x 10(9) mol(-1) L s(-1). Various products were formed. Among them 2-amino-4-methoxy-6-methyl-1,3,5-triazine, 2-(carbomethoxy) benzenesulfonamide and hydroxylated derivatives represent the major photoproducts. Compounds arising from the cleavage of the triazine moiety were also found. After prolonged irradiation, a total disappearance of metsulfuron methyl and a complete mineralization of the solution were obtained.


Poly(methacrylic acid-ethylene glycol dimethacrylate) monolith in-tube solid-phase microextraction applied to simultaneous analysis of some amphetamine derivatives in urine by capillary zone electrophoresis.
A method based on in-tube solid-phase microextraction and capillary zone electrophoresis (CZE) was proposed for simultaneously determining four amphetamines (amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, and 3,4-methylenedioxymethamphetamine) in urine. A poly(methacrylic acid-ethylene glycol dimethacrylate) monolithic capillary column, which can provide sufficient extraction efficiency, was introduced for the extraction of amphetamines from urine samples. The hydrophobic main chains and acidic pendant groups of the monolithic column make it a superior material for extraction of basic analytes from aqueous matrix. After extraction, the samples were analyzed by CZE. The best separation was achieved using a buffer composed of 0.1 M disodium hydrogen phosphate (adjusted to pH 4.5 with 1 M hydrochloric acid) and 20% methanol v/v, with a temperature and voltage of 25 degrees C and 20 kV, respectively. By applying electrokinetic injection with field-amplified sample stacking, detection limits of 25-34 microg/L were achieved. Excellent method of reproducibility was found over a linear range of 0.1-5 mg/L. Determination of these analytes from abusers' urine sample was also demonstrated.


Kinetic studies of cytoplasmic antigen processing and production of MHC class I ligands.
MHC class I molecules present peptides that are derived from intracellular proteins degraded by proteasomes. These peptides often require additional trimming by peptidases to fit into the peptide-binding grove of MHC class I. However, most peptides are rapidly recycled by the large heterogeneous pool of peptidases. Here, we describe a technique to quantify peptide degradation both in living cells and in cell lysates, using quenched peptides that contain a quencher and fluorophore. As degradation results in separation of the quencher and fluorophore, fluorescence will increase. This technique enables the examination of changes in peptide length and amino acid sequence on its half-life, and hence its chances to become presented by MHC class I.


Finite-element simulation of in-plane tear propagation in the dissected aorta: Implications for the propagation mechanism.
Computer modeling and numerical simulation are essential for understanding the progression of aortic dissection. However, tear propagation has not been properly modeled and simulated. The in-plane dissection propagation between concentrically distributed elastic lamellae is modeled using the cohesive zone method with a bilinear traction-separation law. The parameters of cohesive elements are calibrated for the three modes of interfacial damage in the media, enabling quantitative predictions of in-plane tear propagation. An idealized cylindrical tube-shaped bilayer thick-wall model of the aorta is employed to elucidate the influence of geometrical parameters, loading conditions and residual stress on the tear propagation. While the model is capable of replicating that deeper, larger tears are associated with lower critical pressure, new findings include: (i) Larger axial stretch leads to lower critical pressure; (ii) Increased magnitude of residual stress is associated with higher critical pressure; (iii) Pressure difference between true and false lumen alters the critical pressure; (iv) The interfacial damage is mostly opening mode in the axial direction, but shear-dominated in the circumferential direction; (v) Damage due to the opening mode is associated with smaller fracture energy, which makes it easier to propagate than the shear and the mixed modes. (vi) The deformed shape of the tear, which is related to its geometrical features and loading conditions, modulates the critical pressure via two pathways: (a) deformed shapes are associated with specific modes of damage, which influences the critical pressure, and (b) deformed shapes modulate the critical pressure directly via geometrical constraints.


In Nigeria. A study to identify the knowledge and misconceptions of primary school pupils about tropical diseases.
"Since health knowledge is a prerequisite of any health action, health education is seen as an essential component of any disease control programme. However for health education to be effective and relevant the prior knowledge held by the learners must be assessed and information so obtained used in the planning and implementation of the health education programme."