On local anomaly detection and analysis for clinical pathways.
Anomaly detection, as an imperative task for clinical pathway (CP) analysis and improvement, can provide useful and actionable knowledge of interest to clinical experts to be potentially exploited. Existing studies mainly focused on the detection of global anomalous inpatient traces of CPs using the similarity measures in a structured manner, which brings order in the chaos of CPs, may decline the accuracy of similarity measure between inpatient traces, and may distort the efficiency of anomaly detection. In addition, local anomalies that exist in some subsegments of events or behaviors in inpatient traces are easily overlooked by existing approaches since they are designed for detecting global or large anomalies. In this study, we employ a probabilistic topic model to discover underlying treatment patterns, and assume any significant unexplainable deviations from the normal behaviors surmised by the derived patterns are strongly correlated with anomalous behaviours. In this way, we can figure out the detailed local abnormal behaviors and the associations between these anomalies such that diagnostic information on local anomalies can be provided. The proposed approach is evaluated via a clinical data-set, including 2954 unstable angina patient traces and 483,349 clinical events, extracted from a Chinese hospital. Using the proposed method, local anomalies are detected from the log. In addition, the identified associations between the detected local anomalies are derived from the log, which lead to clinical concern on the reason resulting in these anomalies in CPs. The correctness of the proposed approach has been evaluated by three experience cardiologists of the hospital. For four types of local anomalies (i.e., unexpected events, early events, delay events, and absent events), the proposed approach achieves 94%, 71% 77%, and 93.2% in terms of recall. This is quite remarkable as we do not use a prior knowledge. Substantial experimental results show that the proposed approach can effectively detect local anomalies in CPs, and also provide diagnostic information on the detected anomalies in an informative manner.


Cortical GABA turnover during bicuculline seizures in rats.
The rate of cortical gamma-aminobutyric acid (GABA) turnover was estimated by determining the rate of GABA accumulation following inhibition of GABA transaminase by gamma-vinyl-GABA (1.5 g/kg, i.v.) in paralysed, ventilated rats. During 1 h of bicuculline-induced seizures (1.2 mg/kg, i.v.) the rate of accumulation of cortical GABA level is approximately threefold greater than in the control group receiving gamma-vinyl-GABA alone, suggesting that the GABA shunt activity increases in parallel with the increase in overall cortical metabolic rate observed during bicuculline seizures. Pretreatment with gamma-vinyl-GABA did not affect the bicuculline-induced changes in other major cortical amino acids.


Safety of SARS-CoV-2 vaccination in patients with Behcet's syndrome and familial Mediterranean fever: a cross-sectional comparative study on the effects of M-RNA based and inactivated vaccine.
Most of the published data relate to classical forms of rheumatic diseases (RD) and information on rare inflammatory disorders such as Behçet's syndrome (BS) and familial Mediterranean fever (FMF) is limited. We studied the frequency of side effects and disease flares after COVID-19 vaccination with either Pfizer/BioNTech or Sinovac/CoronaVac in 256 patients with BS, 247 with FMF, and 601 with RD. Telephone interviews were conducted using a questionnaire survey in a cross-sectional design in patients with BS, FMF, and RD followed by a single university hospital. Study participants were vaccinated either with CoronaVac (BS:109, FMF: 90, and RD: 343,) or BioNTech (BS: 147, FMF: 157 and RD: 258). The majority have received double dose (BS: 94.9%, FMF 92.3% and RD: 86.2%). BioNTech ensured a significantly better efficacy than CoronaVac against COVID-19 in all patient groups (BS: 1.4% vs 10.1%; FMF: 3.2% vs 12.2%, RD:2.7% vs 6.4%). Those with at least one adverse event (AE) were significantly more frequent among those vaccinated with BioNTech than those with CoronaVac (BS: 86.4% vs 45%; FMF: 83.4% vs 53.3%; and RD: 83.3% vs 45.5%). The majority of AEs were mild to moderate and transient and this was true for either vaccine. There were also AEs that required medical attention in all study groups following CoronaVac (BS: 5.5%, FMF: 3.3%, and RD:2.9%) or BioNTech (BS: 5.4%, FMF: 1.9%, and RD: 4.7%). The main causes for medical assistance were disease flare and cardiovascular events. Patients with BS (16.0%) and FMF (17.4%) were found to flare significantly more frequently when compared to those with RD (6.0%) (p < 0.001). This was true for either vaccine. BS patients reported mainly skin-mucosa lesions; there were however, 11 (4.3%) who developed major organ attack such as uveitis, thrombosis or stroke. Flare in FMF patients were associated mainly with acute serositis with or without fever. Arthralgia/arthritis or inflammatory back pain were observed mainly in the RD group. Our study demonstrates that BS and FMF patients vaccinated with either CoronaVac or BioNTech demonstrated similar AE profile and frequency compared to RD patients. AEs that required physician consultation or hospitalization occurred in all study groups after either CoronaVac or BioNTech. Increased frequency of flares in BS and FMF compared to that seen in RD might reflect defects in innate immunity and deserves further investigation. Caution should be required when monitoring these patients after vaccination.


Spontaneous massive haemorrhage into acoustic neuroma during anticoagulation therapy.
We report the case of a 58-year old man who bled into an undiagnosed acoustic neuroma while on long-term anticoagulation therapy which was commenced following aortic valve replacement. The patient presented with multiple cranial nerve-paralysis of sudden onset. The tumour was subtotally removed but died 5 days postoperatively from recurrent haemorrhage into the tumour bed.


New Marker Genes for Real-Time PCR-based Detection of Circulating Tumour Cells from Blood of Breast Cancer Patients.
The detection of circulating tumour cells (CTCs) from peripheral blood of cancer patients can be carried out by real-time PCR approaches using different gene expression levels of tumour cells and surrounding blood cells. Potential marker genes were first analyzed in a model system and then applied to 20 blood samples of adjuvant breast cancer patients and gene expression levels were correlated to tumour characteristics. The mean of gene expression levels was found elevated for the four genes analyzed in the adjuvant breast cancer patient group in comparison to the samples of the group of healthy donors, but no correlation between gene expression and tumour characteristics could be detected as being statistically significant. The results demonstrated, that the employed methodology is functional, but has to be refined by certain approaches like simultaneously running a state-of-the-art system of CTC-detection comparing the results, and by an enlargement of patient collective and number of marker genes.


No thick carbon dioxide atmosphere on the rocky exoplanet TRAPPIST-1 c.
Seven rocky planets orbit the nearby dwarf star TRAPPIST-1, providing a unique opportunity to search for atmospheres on small planets outside the Solar System1. Thanks to the recent launch of the James Webb Space Telescope (JWST), possible atmospheric constituents such as carbon dioxide (CO2) are now detectable2,3. Recent JWST observations of the innermost planet TRAPPIST-1 b showed that it is most probably a bare rock without any CO2 in its atmosphere4. Here we report the detection of thermal emission from the dayside of TRAPPIST-1 c with the Mid-Infrared Instrument (MIRI) on JWST at 15 µm. We measure a planet-to-star flux ratio of fp/f⁎ = 421 ± 94 parts per million (ppm), which corresponds to an inferred dayside brightness temperature of 380 ± 31 K. This high dayside temperature disfavours a thick, CO2-rich atmosphere on the planet. The data rule out cloud-free O2/CO2 mixtures with surface pressures ranging from 10 bar (with 10 ppm CO2) to 0.1 bar (pure CO2). A Venus-analogue atmosphere with sulfuric acid clouds is also disfavoured at 2.6σ confidence. Thinner atmospheres or bare-rock surfaces are consistent with our measured planet-to-star flux ratio. The absence of a thick, CO2-rich atmosphere on TRAPPIST-1 c suggests a relatively volatile-poor formation history, with less than [Formula: see text] Earth oceans of water. If all planets in the system formed in the same way, this would indicate a limited reservoir of volatiles for the potentially habitable planets in the system.


Enhanced thromboxane synthesis and vacuolization in human polymorphonuclear leucocytes induced by human lymphokine containing supernatants.
PMN's were cultivated in vitro and treated with supernatants obtained from mitogenic-induced lymphocytes of human tonsil. Cytoplasmic vacuolization increased with time and there was a lower number of neutrophilic clumps in the culture treated with a supernatant containing lymphotoxin. In addition, the PMN's released more thromboxane B2 which was inhibited by indomethacin. We conclude that the action of lymphotoxin on the target PMN's is not mediated by the production of thromboxane B2.


Health status and work burden of Alzheimer patients' informal caregivers: comparisons of five different care programs in the European Union.
In 1998, a research study was conducted to compare existing programs in the European Union providing both care to people with senile dementia of the Alzheimer type, and support to their informal caregiver. Five programs were selected in seven centres. Home social services (Denmark), Day centres (Germany), Expert Centres (Belgium, Spain), Group Living/Cantou (Sweden, France), Respite hospitalization (France). In each centre, 50 patients were randomly selected. The questionnaire addressed informal caregivers (or referents). It included the Nottingham Health Profile (NHP), the Zarit Scale, and it collected data on age, sex and position (spouse or child) of the informal caregiver, as well as age, level of mental deterioration and disabilities of the patient. (n=322 subjects) Comparatively with caregivers of Respite hospitalization patients chosen as the reference, caregivers of patients cared by Group living/Cantou and Home social services experienced a significantly lower burden. The benefit from the Expert centre program concerned emotional reactions (depression) (odds ratio=0.32; P=0.02) and work burden (Zarit) (OR=0.32; P=0.04). The main benefit for caregivers who received Day centre help was the important reduction of feelings of social isolation (OR=0.13; P=0.0003). The Group Living/Cantou program appeared as the most efficient way to reduce informal caregiver burden, independently from the country considered.


Increased incidence of live births in implanted day 5 versus day 6 blastocysts following single embryo transfers with PGT-A.
Elective single-embryo transfers of euploid or low-level mosaic blastocysts were analyzed in this retrospective study to determine the correlations of live birth (LB) probability with embryonic developmental features of implanted day 5 (D5, n = 245) or day 6 (D6, n = 73) blastocysts using time-lapse (TL) monitoring. According to the logistic regression analyses (adjusted odds ratio [OR] = 0.341, 95% confidence interval [CI] = 0.169-0.685, P < 0.05), the LB probability was negatively associated with the D6 group. The LB rate of the D5 group was higher than the D6 group (88.2% vs. 75.3%; P < 0.05). Compared with the D5 blastocysts, the D6 blastocysts exhibited comparable dysmorphisms except for the multinucleation at the 4-cell stage (10.9% vs. 2.9%, P < 0.05). Moreover, D6 blastocysts had considerably slower developmental kinetics and poorer blastocyst morphologies. Further analysis confirmed that the LB rate was not associated with developmental kinetics or dysmorphisms but rather with blastocyst morphology (inner cell mass [ICM] grade ≤ C vs. ICM grade A, adjusted OR = 0.155, 95% CI = 0.04-0.596, P < 0.05; trophectoderm [TE] grade ≤ C vs. TE grade A, adjusted OR = 0.157, 95% CI = 0.032-0.760, P < 0.05). In conclusion, D6 implanted blastocysts have a considerably lower LB rate than D5 implanted blastocysts. As determined by TL monitoring, the diminished blastocyst morphology can be one of the primary reasons underlying the decreased likelihood of LB.


Measurement of Brn-3a levels in Pap smears provides a novel diagnostic marker for the detection of cervical neoplasia.
We have previously demonstrated that Brn-3a cellular transcription factor activates transcription of the human papillomavirus (HPV) E6 and E7 oncogenes in human cervical cancer cells and that Brn-3a levels are dramatically elevated in biopsies from women with high-grade cervical neoplasia. The aim of this study was to establish the relationship between Brn-3a levels in Pap smears and the histological diagnoses. We also analysed whether Brn-3a levels can be used in combination with Pap smear to predict the presence of cervical intraepithelial lesion. Two hundred thirty-eight women who were referred with abnormal Pap smear underwent a diagnostic colposcopy, repeat in-study Pap smear, colposcopically directed biopsy, and assessment of Brn-3a and HPV-16 E6 m-RNA levels. Data were analysed to assess the association between Brn-3a levels and the histological diagnosis. Brn-3a was readily measured in smears and showed a statistically significant correlation with the grade of cervical abnormality. Positive Brn-3a is associated with increased relative risk of higher-grade lesion. Moreover, measurement of Brn-3a levels in smears can be used to detect a significant proportion of cervical lesions that were missed by Pap smear. Measurement of Brn-3a levels in routinely taken Pap smears is a feasible technique that correlates with the severity of the epithelial abnormality and is a useful adjunct to cytology. Brn-3a appears to have great promise since it detects activation of oncogenic HPVs rather than simply detecting their presence, as is currently being done.


In vitro biocompatibility of a polyurethane catheter after deposition of fluorinated film.
The in vitro biocompatibility of an experimental surface-treated polyurethane was compared with an untreated polyurethane already used for intravascular catheters. The experimental surface was coated with a fluorinated film using a glow discharge treatment. Neither of the catheters was cytotoxic for L929 murine fibroblasts, caused platelet adhesion or release reaction, or changed the mean platelet volume. The surface-treated polyurethane, however, caused a higher adhesion of Staphylococcus aureus than did the untreated one. Therefore, using in vitro testing, it has been ascertained that the examined material, though not being cytotoxic and not modifying platelet behaviour, could favour bacterial adherence.


Inhibition of the stem cell factor 248 isoform attenuates the development of pulmonary remodeling disease.
Stem cell factor (SCF) and its receptor c-kit have been implicated in inflammation, tissue remodeling, and fibrosis. Ingenuity Integrated Pathway Analysis of gene expression array data sets showed an upregulation of SCF transcripts in idiopathic pulmonary fibrosis (IPF) lung biopsies compared with tissue from nonfibrotic lungs that are further increased in rapid progressive disease. SCF248, a cleavable isoform of SCF, was abundantly and preferentially expressed in human lung fibroblasts and fibrotic mouse lungs relative to the SCF220 isoform. In fibroblast-mast cell coculture studies, blockade of SCF248 using a novel isoform-specific anti-SCF248 monoclonal antibody (anti-SCF248), attenuated the expression of COL1A1, COL3A1, and FN1 transcripts in cocultured IPF but not normal lung fibroblasts. Administration of anti-SCF248 on days 8 and 12 after bleomycin instillation in mice significantly reduced fibrotic lung remodeling and col1al, fn1, acta2, tgfb, and ccl2 transcript expression. In addition, bleomycin increased numbers of c-kit+ mast cells, eosinophils, and ILC2 in lungs of mice, whereas they were not significantly increased in anti-SCF248-treated animals. Finally, mesenchymal cell-specific deletion of SCF significantly attenuated bleomycin-mediated lung fibrosis and associated fibrotic gene expression. Collectively, these data demonstrate that SCF is upregulated in diseased IPF lungs and blocking SCF248 isoform significantly ameliorates fibrotic lung remodeling in vivo suggesting that it may be a therapeutic target for fibrotic lung diseases.


Dégénérescence systématisée optico-cochléo-dentelée.
During the first year of life a girl, the first child of non-consanguineous parents, developed a progressive neurological disease characterized by blindness, severe hypotonia, impaired motor development, microcephaly and mental retardation. Later she became unresponsive to auditory stimuli. She died at the age of 13 months. Post-mortem examination revealed atrophy of the optic nerves and chiasm, lateral geniculate nuclei and superior colliculi, degeneration of the cochlear nerve roots, dorsal and ventral cochlear nuclei, superior olives, lateral lemnisci, medial geniculate nuclei and inferior colliculi and atrophy of the dentate nuclei, hilus and superior cerebellar peduncles. These were consistent with dégénérescence systématisée optico-cochleéo-dentelée. Additional abnormalities included degeneration of the posterior columns in the spinal cord, gracilis and cuneate nuclei and medial lemnisci, atrophy of the spinocerebellar tracts and Clarke's columns, cerebral cortex, cerebellum, chiefly involving the rostral vermis, inferior olivary nuclei and demyelination of the sural nerves.


Bats initiate vital agroecological interactions in corn.
In agroecosystems worldwide, bats are voracious predators of crop pests and may provide services to farmers worth billions of U.S. dollars. However, such valuations make untested assumptions about the ecological effect of bats in agroecosystems. Specifically, estimates of the value of pest suppression services assume bats consume sufficient numbers of crop pests to affect impact pest reproduction and subsequent damage to crops. Corn is an essential crop for farmers, and is grown on more than 150 million hectares worldwide. Using large exclosures in corn fields, we show that bats exert sufficient pressure on crop pests to suppress larval densities and damage in this cosmopolitan crop. In addition, we show that bats suppress pest-associated fungal growth and mycotoxin in corn. We estimate the suppression of herbivory by insectivorous bats is worth more than 1 billion USD globally on this crop alone, and bats may further benefit farmers by indirectly suppressing pest-associated fungal growth and toxic compounds on corn. Bats face a variety of threats globally, but their relevance as predators of insects in ubiquitous corn-dominated landscapes underlines the economic and ecological importance of conserving biodiversity.


Ultrarapid detection of blaKPC₁/₂-₁₂ from perirectal and nasal swabs by use of real-time PCR.
The novel real-time PCR assay developed as described here was able to detect bla(KPC1/2-12) (bla(KPC-1/2) to bla(KPC-12)) from easily available clinical specimens in less than 2 h. The genotypic assay was highly sensitive (100%) and specific (98%). In some cases, it was able to detect bla(KPC) 48 h before positive detection by standard phenotypic assay on patients who were monitored daily. The high sensitivity and rapidity of the molecular method make it the method of choice for KPC surveillance and, thus, containment purposes.


[Glaucoma].
Glaucoma is a group of afflictions that have loss of eyesight in common. This impairment of vision is caused by damage to the optic nerve as a result of high intraocular pressure. The patient's optical fields narrow and at last only a tiny rest is left. The mechanisms of the disease are well known but it is in most cases unexplained why a person develops glaucoma. This review discusses the several forms of glaucoma, the diagnosis and therapy, and the epidemiology and prevention.


Use of In Vitro Transcription System for Analysis of Corynebacterium glutamicum Promoters Recognized by Two Sigma Factors.
Promoter activities in Corynebacterium glutamicum strains with deletions of genes encoding sigma factors of RNA polymerase suggested that transcription from some promoters is controlled by two sigma factors. To prove that different sigma factors are involved in the recognition of selected Corynebacterium glutamicum promoters, in vitro transcription system was applied. It was found that a typical housekeeping promoter Pper interacts with the alternative sigma factor σ(B) in addition to the primary sigma factor σ(A). On the other way round, the σ(B)-dependent promoter of the pqo gene that is expressed mainly in the stationary growth phase was active also with σ(A). Some promoters of genes involved in stress responses (P1clgR, P2dnaK, and P2dnaJ2) were found to be recognized by two stress-responding sigma factors, σ(H) and σ(E). In vitro transcription system thus proved to be a useful direct technique for demonstrating the overlap of different sigma factors in recognition of individual promoters in C. glutamicum.


alpha-Tocopheryl succinate-induced apoptosis in human gastric cancer cells is modulated by ERK1/2 and c-Jun N-terminal kinase in a biphasic manner.
Gastric neoplastic disease is one of the most frequent causes of cancer-associated deaths with poor prognosis. Here we studied the effect of the redox-silent analogue alpha-tocopheryl succinate (alpha-TOS), a strong apoptogen and anti-cancer agent, on the gastric cancer cell line SGC-7901. alpha-TOS inhibited proliferation of the cells and induced their apoptosis in a concentration- and time-dependent manner, while succinate or alpha-tocopherol showed no effect. The effect of alpha-TOS was modulated by components of the MAPK signaling network, including ERK1/2 and c-Jun N-terminal kinase (JNK), but not p38. Activation of ERK1/2 occurred early and increased until 12h, coinciding with an in crease in apoptosis in the cells, after which it dropped abruptly, while activation of JNK rose steadily, reaching a plateau at 12h of alpha-TOS treatment. The effects of ERK1/2 and JNK on the apoptosis outcome are transmitted via c-Jun, since transfection of the cells with c-Jun antisense oligodeoxynucleotide inhibited alpha-TOS-induced apoptosis. We conclude that ERK1/2 and JNK positively regulate apoptosis induced in gastric cancer cells by alpha-TOS.


Preliminary report of a new method of whole body CT-scanning.
The authors suggest a new approach to CT-body examination derived from their experience in spinal investigations. They introduce a method of gantry tilt in association with inclination of the patient, and call the new mode "longitudino-axial sectioning". This method makes possible the simultaneous display of several vertebral levels, which is not possible with conventional CT-scanning. They suggest that by extrapolation, the method may be applied to thoracic and abdominal investigations, as well as to the study of joints. In addition, this technique could be the method of choice whenever urinary and biliary tracts have to be investigated for diagnostic and/or interventional purposes.


Two cases of ectopic ureter opening into the ejaculatory duct: double vas deferens revisited.
We report 2 rare cases of single ectopic ureter simulating double vas deferens. Clinical, radiographic and macroscopic signs at operation indicated a single ectopic ureter opening into the seminal tract. However, histological examination of the surgical specimen revealed that the lumen of the supposed ureter was lined in part by columnar epithelium, although chiefly by transitional epithelium. The wall of the ureter contained 3 well defined muscular coats in case 1 but only 1 layer was distinguishable in case 2. Histological composition of the structure removed from the cranial site resembled that of the epididymis. A review of the literature revealed a few comparable cases. Analysis of these cases suggests that double vas deferens and a single ectopic ureteral opening into the seminal tract are such that their differentiation may only have semantic significance. We speculate that these 2 diseases are included as 1 entity, only to be distinguished by the difference of ureterization of the ureteral bud.


Chemical stability of thiopental sodium injection in disposable plastic syringes.
The chemical stability of thiopental sodium injection (2.5%) when stored at 25 degrees and 5 degrees in disposable plastic syringes of two manufacturers (Monoject and Becton Dickenson and Co.) has been studied using the USP-NF method. The injection appeared to be stable for five days at 25 degrees and 45 days at 5 degrees with a loss in potency of less than 7%. The thiopental sodium did not adsorb on the syringes. The pH values and the physical appearance did not change. An additional peak was obtained in the chromatogram from both the freshly prepared and the assay solution probably due to an impurity in the powder.


Congenital platelet disorders.
Congenital platelet disorders include thrombocytopathies and thrombocytopenias, which often occur in association. Thrombocytopathies constitute a model for exploring platelet physiology at the molecular level: adhesion, activation, release phenomena, aggregation. Further advances in understanding thrombocytopenias now require studies of medullary physiology. A better knowledge of these disorders is necessary to improve their management.


A cross sectional survey on UK older adult's attitudes to ageing, dementia and positive psychology attributes.
With an increasingly ageing population worldwide, the predominant attitude towards ageing is still negative. Negative stereotypes have detrimental effects on individuals' physical and mental health. Evidence is required about factors that may predict and change these views. This study aimed to investigate if an older person's attitude towards dementia, their belief in a just world and sense of coherence is associated with their attitudes to ageing. A 25-min online survey was completed by 2,675 participants aged 50 or over who were current residents of the United Kingdom (UK). Questions included demographics, overall health, dementia carer, dementia relative status and retirement status. Standardised scales used were the Attitudes to Ageing Questionnaire (AAQ), Dementia Attitudes Scale (DAS), Just World Scale (JWS) and Sense of Coherence Scale-13 (SOC). Data was analysed with descriptive, two-tailed bivariate Pearson's correlations, simple, and hierarchical regression analyses. Attitudes to dementia, just world beliefs, and sense of coherence were all significantly positively correlated with AAQ-Total, with SOC sub-scale "Meaningfulness" showing the strongest correlation. In a hierarchical regression model, higher scores on SOC-Meaningfulness, DAS-Total and belief in a just world for oneself all predicted more positive attitudes to ageing. The more positive an individual's attitude to dementia and the stronger they hold the belief that the world is just and coherent, the more likely they are to display positive attitudes to ageing. This initial evidence helps create a greater understanding of the factors that drive attitudes and stigma and may have implications for public health messaging.


Intercellular variation in levels of adducts of aflatoxin B1 and G1 in DNA from rat tissues: a quantitative immunocytochemical study.
Adducts between aflatoxin B1 and G1 and DNA have been visualised and quantified in various rat tissues by a sensitive immunocytochemical approach. The quantitative validity of this assay has been examined by comparison with experiments using radioactively labelled aflatoxin. Rats were exposed to single and multiple doses of aflatoxin and a marked intercellular variation in adduct levels was observed in kidney and lung, in contrast to the liver, where binding was more homogeneous. No adducts were detected in the oesophagus, forestomach, colon, spleen or testes (detection limit approximately 300 pg aflatoxin/mg DNA). The DNA adduct data are discussed in relation to the carcinogenicity of aflatoxin B1 and G1.


[Thrombo-haemorrhagic disease-related hypoprothrombinemia-lupus anticoagulant syndrome revealing a light chains multiple myeloma].
Thrombosis and hemorrhage are two opposing manifestations of multiple myeloma. These hemostatic disorders are present in less than 12% of patients at diagnosis and involve various pathophysiological mechanisms. We report the case of a 39-year-old patient with multiple myeloma revealed by the association of a hemorrhagic syndrome and deep vein thrombosis related to a hypoprothrombinemia-anticoagulant lupus syndrome.


Pregnancy-associated plasma protein A: purification under mild conditions, peptide mapping and tests for possible interactions with trypsin, plasmin and complement.
Pregnancy-associated plasma protein A (PAPP-A) has been obtained in an enriched state under mild conditions of purification involving cibacron blue dye-ligand chromatography, negative antibody-affinity chromatography and gel filtration. The product was a mixture of PAPP-A and alpha-2-macroglobulin (alpha 2M). The ability of these proteins to bind 125I-trypsin and 125I-plasmin was studied. In contrast to previous studies by others, there was no evidence that PAPP-A could bind either protease. It is pointed out that protease-inhibitory activity in samples of PAPP-A can be due to the presence of very small amounts of contaminating alpha 2M in the preparations of PAPP-A. In further experiments PAPP-A did not inhibit the complement-induced lysis of sensitized red cells. Finally, cyanogen bromide peptide mapping experiments failed to yield evidence of structural homologies between PAPP-A and alpha 2M.


Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids.
Transient receptor potential canonical (TRPC) 4 channels are calcium-permeable, nonselective cation channels and are widely expressed in mammalian tissue, especially in the GI tract and brain. TRPC4 channels are known to be involved in neurogenic contraction of ileal smooth muscle cells via generating cationic current after muscarinic stimulation (muscarinic cationic current (mIcat)). Polyamines exist in numerous tissues and are believed to be involved in cell proliferation, differentiation, scar formation, wound healing, and carcinogenesis. Besides, physiological polyamines are essential to maintain inward rectification of cardiac potassium channels (Kir2.1). At membrane potentials more positive than equilibrium potential, intracellular polyamines plug the cytosolic surface of the Kir2.1 so that potassium ions cannot pass through the pore. Recently, it was reported that polyamines inhibit not only cardiac potassium channels but also nonselective cation channels that mediate the generation of mIcat. Here, we report that TRPC4, a definite mIcat mediator, is inhibited by intracellular spermine with great extent. The inhibition was specific to TRPC4 and TRPC5 channels but was not effective to TRPC1/4, TRPC1/5, and TRPC3 channels. For this inhibition to occur, we found that glutamates at 728th and 729th position of TRPC4 channels are essential whereby we conclude that spermine blocks the TRPC4 channel with electrostatic interaction between negative amino acids at the C-terminus of the channel.


Chronic sparing of delayed alternation performance and choline acetyltransferase activity by CEP-1347/KT-7515 in rats with lesions of nucleus basalis magnocellularis.
Peripheral injection of the indolocarbazole CEP-1347/KT-7515 into rats that have sustained ibotenic acid lesions of the nucleus basalis magnocellularis has been shown to prevent the loss of cortically-projecting neurons in that basal forebrain region. The present study tested whether this neuroprotective activity would lead to chronic sparing of a behaviour known to be impaired by that lesion, as well as to chronic maintenance of cholinergic activity in cortical target regions of the nucleus basalis. CEP-1347/KT-7515 was injected into adult rats that had sustained bilateral ibotenic acid lesions of the nucleus basalis magnocellularis; the first injection occurred 18-24 h after lesioning, with subsequent injections of CEP-1347/KT-7515 occurring every other day over 12 days. One day following the last injection the animals were tested for retention of a previously-learned delayed alternation task. Animals that received CEP-1347/KT-7515 committed significantly fewer errors than lesioned animals receiving vehicle. These same animals were tested again eight to 10 weeks later (which was 10-12 weeks post-dosing), without receiving further drug or behaviour training during the test-retest interval. The animals that had received CEP-1347/KT-7515 continued to commit significantly fewer errors than vehicle animals. Furthermore their performance at this time point was indistinguishable from normal controls. Analysis of errors showed that CEP-1347/KT-7515 prevented a lesion-induced increase in perseverative errors, suggesting the drug improved attention in the lesioned animals. Choline acetyltransferase activity in the frontal cortex of the behaviourally tested animals that received CEP-1347/KT-7515 three months previously showed a significant 40% recovery of the lesion-induced loss seen in the vehicle animals. These results demonstrate that treatment with CEP-1347/KT-7515 over 12 days following excitotoxic damage to the nucleus basalis magnocellularis produces long-term sparing of an attention-demanding behaviour.


The prognostic significance of the lymph node ratio in oral cancer differs for anatomical subsites.
The aim of this study was to validate the prognostic significance of the lymph node ratio (LNR) in patients suffering from oral squamous cell carcinoma in regard to different anatomical subsites. A cohort of 430 patients was investigated to determine the rates of primary metastasis and local and regional disease recurrence. Correlation analysis of the LNR with relevant clinical and pathological parameters was performed. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the prognostic impact for different subsites. Significantly differing rates of primary metastasis and loco-regional disease recurrence were found for cancer of different anatomical subsites of the head and neck. Furthermore, ROC curve analysis suggested that LNR has prognostic relevance in subsets of cancer (tongue, P< 0.001; alveolar process, P= 0.04; maxilla, P= 0.03; buccal mucosa, P= 0.02). The LNR of cancer located in the soft palate (P= 0.6) and floor of the mouth (P= 0.11) showed little or no association with the clinical outcome. There is the need for a more sensitive consideration of the LNR as a factor in the assessment of risk and the treatment decision, as the anatomical subsite plays a crucial role in its impact on the clinical outcome.


Semantic interference during object naming in agrammatic and logopenic primary progressive aphasia (PPA).
This study examined the time course of object naming in 21 individuals with primary progressive aphasia (PPA) (8 agrammatic (PPA-G); 13 logopenic (PPA-L)) and healthy age-matched speakers (n=17) using a semantic interference paradigm with related and unrelated interfering stimuli presented at stimulus onset asynchronies (SOAs) of -1000, -500, -100 and 0 ms. Results showed semantic interference (SI) (i.e. significantly slower RTs in related compared to unrelated conditions) for all groups at -500, -100 and 0 ms, indicating timely spreading activation to semantic competitors. However, both PPA groups showed a greater magnitude of SI than normal across SOAs. The PPA-L group and six PPA-G participants also evinced SI at -1000 ms, suggesting an abnormal time course of semantic interference resolution, and concomitant left hemisphere cortical atrophy in brain regions associated with semantic processing. These subtle semantic mapping impairments in non-semantic variants of PPA may contribute to the anomia of these patients.


Symptomatic sclerosing cholangitis in patients with a normal alkaline phosphatase: two case reports and a review of the literature.
The diagnosis of sclerosing cholangitis is usually not considered in the absence of an elevation of serum alkaline phosphatase. The purpose of this paper is to report two symptomatic cases of primary sclerosing cholangitis (PSC) which presented with a normal alkaline phosphatase, and to review the literature regarding alkaline phosphatase in PSC. A total of 172 patients with PSC were identified in the literature; six of these patients (3%) presented with a normal alkaline phosphatase. Patients with diseases known to be associated with primary sclerosing cholangitis and having a compatible clinical presentation should be considered for evaluation with endoscopic retrograde cholangiography, even in the presence of a normal level of serum alkaline phosphatase.


On classifying interactions between populations.
The classification of interspecific interactions can have an important impact on ecologists' world views. Previous classifications have often been incomplete, have suffered from ambiguously defined categories, and/or have wrongly equated categories of population level effects with particular mechanisms of interaction. I use several simple mathematical models to argue that effects on short-term population growth rate, long term population size, and short term relative fitness of interactants may differ qualitatively. Equating all (--) effects with competition and all (+-) effects with predation may have caused ecologists to ignore a variety of potentially important interaction mechanisms. Failure to define the type of effect used in classifying interactions has led to confusion about the nature of interactions; several controversies regarding competition have apparently been caused or exaccerbated by problems with definition or clasification. In applying classification schemes, ecologists should realize that the classification of an interaction between two populations may change with the sizes of those populations or of other populations with which they interact.


Retraction: Shape-specific silver nanoparticles prepared by microwave-assisted green synthesis using pomegranate juice for bacterial inactivation and removal.
[This retracts the article DOI: 10.1039/C5RA18575K.].


Gercumin synergizes the action of 5-fluorouracil and oxaliplatin against chemoresistant human cancer colon cells.
Advanced colon cancer is extremely difficult to cure, underscoring the need to develop novel therapeutic agents. Prenylated curcumins that are semisynthetic curcumin derivatives with significant anti-cancer potential have been studied herein to assess their therapeutic potential for colon cancer and tested to this aim in vitro for their growth inhibitory properties against 5-fluorouracil + oxaliplatin resistant human colon cancer CR-HT29 and HCT-116 cells. The resulting most active product, gercumin (mono-O-geranylcurcumin), has been further tested for its synergistic effects with FOLFOX (a combination of 5-fluorouracil and oxaliplatin) on the same cell lines. Activity of this combination on colonosphere formation was also investigated. Gercumin was able to suppress the growth of cancer cells with a potency similar to that of curcumin. A synergistic effect of this compound and FOLFOX was also observed. doses tested for synergy in the colonosphere assays did not show greater suppression of colonosphere formation than independent treatment with either reagent alone. Only one of the combinations was shown to be more effective at suppressing colonosphere formation [gercumin 5 μM + FOLFOX (2x)]. Thus, the growth inhibitory effects of curcumin against human cancer cells can be modulated and enhanced by the introduction of hydrophobic chains, normally found in several natural compounds, like the geranyl one. Such compounds are also able to synergize with known chemotherapeutics.


Somatostatin Receptor SSTR-2a Expression Is a Stronger Predictor for Survival Than Ki-67 in Pancreatic Neuroendocrine Tumors.
Somatostatin receptors (SSTR) are commonly expressed by neuroendocrine tumors. Expression of SSTR-2a and SSTR-5 may impact symptomatic management; however, the impact on survival is unclear. The aim of this study is to correlate SSTR-2a and SSTR-5 expression in pancreatic neuroendocrine tumors (PNETs) with survival. This study is designed to determine the prognostic significance of somatostatin receptors SSTR-2a and SSTR-5 in PNETs. This retrospective cohort study included cases of resected PNETs between 1992 and 2014. Clinical data, histopathology, expression of SSTR and Ki-67 by immunohistochemistry, and long-term survival were analyzed. A total of 99 cases were included in this study. The mean age was 57.8 years (18-87 years) and median tumor size was 25 mm (range 8-160 mm). SSTR-2a and SSTR-5 expression was scored as negative (n = 19, 19.2%; n = 75, 75.8%, respectively) and positive (n = 80, 80.1%; n = 24, 24.2%). The median follow-up was 49 months. SSTR-2a expression was associated with improved overall survival, with cumulative survival rates at 1, 3, and 5 years being 97.5%, 91.5%, and 82.9%, respectively. Univariate analysis demonstrated better survival in SSTR-2a positive patients (log rank P = 0.04). SSTR-5 expression was not associated with survival outcomes (log rank P = 0.94). Multivariate analysis showed that positive SSTR-2a expression is a stronger prognostic indicator for overall survival [Hazard Ratio (HR): 0.2, 95% Confidence interval (CI): 0.1-0.8] compared to high Ki-67 (HR: 0.8, 95% CI: 0.1-5.7). Expression of SSTR-2a is an independent positive prognostic factor for survival in PNETs.


Postnatal development of GABA-mediated synaptic inhibition in rat hippocampus.
Developmental alterations in GABAergic synaptic transmission were examined physiologically and biochemically in hippocampus of rats from 3 days of age to adulthood. Neither antidromic nor orthodromic stimulation could elicit identifiable inhibitory postsynaptic potentials in CA1 neurons in slices from rats 5 or 6 days of age. In contrast, at this age these stimuli result in large inhibitory postsynaptic potentials in CA3 pyramidal cells. In the latter cells orthodromic stimulation produced a brief monosynaptic excitatory postsynaptic potential which was followed by a large prolonged biphasic hyperpolarization. These signals were strikingly similar to those recorded in 1-month-old rats. In addition, large recurrent inhibitory postsynaptic potentials were produced by antidromic stimulation. By postnatal day 9 similar inhibitory postsynaptic potentials could be elicited in a majority of neurons of the CA1 subfield. As in mature pyramidal cells, application of GABA antagonists, such as bicuculline, selectively eliminated the antidromic inhibitory postsynaptic potential and the first component of the biphasic inhibitory postsynaptic potential generated by stimulation of stratum radiatum. In the CA3 subfield, this blockade of GABA receptors resulted in prolonged afterdischarges in slices from immature but not month-old rats. Measurements of the equilibrium potential and the conductance of antidromic inhibitory postsynaptic potentials in CA3 neurons were very similar when made during the first postnatal week and at 1 month of age. While on days 10-11 the equilibrium potential was very similar to measurements made at these other ages, the conductance was 3-4 times greater. The activity of glutamate decarboxylase, the synthetic enzyme for GABA, was very low at 3 days in hippocampus, and increased until 30 days of age at which time adult values were obtained. By comparison, hippocampal GABA levels were high early in postnatal life. Glutamate decarboxylase activities in microdissected CA3 and CA1 subfields were similar in immature hippocampus. These results demonstrate dramatic differences in the ontogenesis of functional GABAergic inhibitory synaptic transmission in the CA1 and CA3 subfields of rat hippocampus. The late development of GABA-mediated synaptic inhibition in the CA1 subfield could play a role in the susceptibility of immature hippocampus to seizures. However, the large GABA-mediated inhibitory postsynaptic potentials present in the CA3 subfield at the same age have a critical role in dampening neuronal excitability.(ABSTRACT TRUNCATED AT 400 WORDS)


Differential increments of basal glucagon-like-1 peptide concentration among SLC47A1 rs2289669 genotypes were associated with inter-individual variability in glycaemic response to metformin in Chinese people with newly diagnosed Type 2 diabetes.
To elucidate the effects of rs2289669, an intron variant of the SLC47A1 gene, on glucose response to metformin in Chinese people with newly diagnosed Type 2 diabetes. Rs2289669 was genotyped, using Sequenom, in 291 participants receiving 48 weeks of metformin monotherapy. The changes in HbA1c were compared among rs2289669 genotypes, and associations with rs2289669 were evaluated using linear regression analysis. We found that, compared with participants with a homozygous G allele, those carrying the minor A allele had significantly greater HbA1c reduction and greater increases in basal glucagon-like peptide-1 concentration. Regression analysis showed that there was a significant association between rs2289669 and the glucose response to metformin after adjusting for confounding factors, except for changes in basal glucagon-like peptide-1, for which an association was not observed. Our findings suggest that rs2289669 might help predict the glycaemic response to metformin in Chinese people newly diagnosed with Type 2 diabetes, and that differential increases in basal glucagon-like peptide-1 concentration among rs2289669 genotypes might be associated with inter-individual response to metformin.


Construction of a 12-Phosphomolybdate-based Coordination Polymer@Crumpled Graphene Balls Composite as Anode for Lithium Batteries.
To address the poor electronic conductivity and easily dissolved in electrolyte of polyoxometalates (POMs), and considering the high electrical conductivity and configuration advantages of crumpled graphene balls (CGBs), herein, a series of POM-based coordination polymers [Cu(pyttz)2 ]PMo12 @CGB (n, n=1, 2, 3) were successfully synthesized, and electrochemical lithium storage performance and lithium ion diffusion kinetics were comprehensively investigated. Galvanostatic intermittent titration technique (GITT) and electrochemical impedance spectroscopy (EIS) study confirm that [Cu(pyttz)2 ]PMo12 @CGB (n, n=1, 2, 3) integrates the advantage of high electronic conductivity of CGB and excellent Li+ migration kinetics of POMs, which greatly ameliorates the electrochemical performances of POMs, among [Cu(pyttz)2 ]PMo12 @CGB (2) exhibits an excellent reversible specific capacity of around 941.4 mA h g-1 at 0.1 A g-1 after 150 cycles and admirable rate performance. This work will promote the development of POMCP anodes, thus fulfilling their potential in high-performance LIBs.


Altered expression of Lewis blood group and related antigens in fetal, normal adult and malignant tissues of the uterine endometrium.
The expression of the Lewis blood group and its related antigens in fetal, normal adult and malignant tissues of the uterine endometrium was examined immunohistochemically using a panel of mouse monoclonal antibodies with specificities for Lewis-a (La), Sialyl Lewis-a (SLa), Lewis-b (Lb), Lewis-X (LX), Sialyl Lewis-X (SLX) and Lewis-Y (LY) antigens. La, SLa and SLX having one fucose residue were detected in a small number of fetal tissues, while Lb and LY having two fucose residues were found in most cases. In the adult endometrium, expression of Lb and LY was considerably lower than those in fetal tissues, although expression of La and SLa was not different between these two tissues. Expression of LX and SLX was pronounced in adult when compared with fetal tissues. Malignant endometrial glands expressed La, SLa, Lb and LY, extensively, while LX and SLX were expressed less than in normal tissues. Lb and LY can thus be considered oncofetal antigens, extensively expressed in fetal and malignant tissues but not in normal adult tissues. Expression of Lb and LY was greater than that of La and SLA in carcinoma; an increase in the activity of fucose transferase might be associated with malignant transformation in the uterine endometrium.


Celebrating Magnet® Nursing Excellence: Meet the Recipients of the 2020 National Magnet Nurse of the Year® Awards and ANCC Magnet Prize®.
This month's Magnet® Perspectives column spotlights the recipients of the 2020 American Nurses Credentialing Center (ANCC) Magnet Program® National Magnet Nurse of the Year Awards and the ANCC Magnet Prize®, sponsored by Cerner, who were recognized during the ANCC National Awards virtual event on May 14, 2021.


Coronary artery spasm induced by intravenous epinephrine overdose.
A 27-year-old man was accidentally given 2 mg intravenous epinephrine instead of 2 mg naloxone. He immediately developed chest pain, nausea, and diaphoresis. An ECG taken shortly after the epinephrine administration showed widespread ischemia. Forty-five minutes later the tracing still showed an early repolarization pattern, but ST elevation was less marked and the patient was asymptomatic. Serum potassium was 3.2 mEq/L and serum catecholamines, drawn approximately 20 minutes after the epinephrine administration, were 10 times normal (dopamine, 173 ng/L; epinephrine, 1,628 ng/L; norepinephrine, 1,972 ng/L). There are seven other reports of intravenous epinephrine overdose in the English literature. Two of the previously reported cases had 12-lead ECGs within the first hour. In both there was evidence of transient ischemia similar to that observed in this case. Most of the patients had symptoms consistent with angina, and several developed pulmonary edema. These findings suggest that, in humans, large intravenous doses of epinephrine are likely to produce coronary artery spasm and may decrease coronary artery perfusion.


BLCov: A novel collaborative-competitive broad learning system for COVID-19 detection from radiology images.
With the global outbreak of COVID-19, there is an urgent need to develop an effective and automated detection approach as a faster diagnostic alternative to avoid the spread of COVID-19. Recently, broad learning system (BLS) has been viewed as an alternative method of deep learning which has been applied to many areas. Nevertheless, the sparse autoencoder in classical BLS just considers the representations to reconstruct the input data but ignores the relationship among the extracted features. In this paper, inspired by the effectiveness of the collaborative-competitive representation (CCR) mechanism, a novel collaborative-competitive representation-based autoencoder (CCRAE) is first proposed, and then collaborative-competitive broad learning system (CCBLS) is proposed based on CCRAE to effectively address the issues mentioned above. Moreover, an automated CCBLS-based approach is proposed for COVID-19 detection from radiology images such as CT scans and chest X-ray images. In the proposed approach, a feature extraction module is utilized to extract features from CT scans or chest X-ray images, then we use these features for COVID-19 detection with CCBLS. The experimental results demonstrated that our proposed approach can achieve superior or comparable performance in comparison with ten other state-of-the-art methods.


The relevance of alternative RNA splicing to pharmacogenomics.
The importance of alternative RNA splicing in the generation of genetic diversity is now widely accepted. This article highlights how alternative RNA splicing can have an impact on drug efficacy and safety, and demonstrates its potential pharmacogenomic value. The analysis of the repertoire of alternative RNA splicing events could potentially identify markers of pharmacogenomic relevance with high sensitivity and specificity and also provides a route through which genes can be selected for single nucleotide polymorphism (SNP) genotyping. Recent methodological advances, including microarray and splice-dedicated expression profiling, have made it possible to perform high-throughput alternative splicing analyses.


Role of APR3 in cancer: apoptosis, autophagy, oxidative stress, and cancer therapy.
APR3 (Apoptosis-related protein 3) is a gene that has recently been identified to be associated with apoptosis. The gene is located on human chromosome 2p22.3 and contains both transmembrane and EGF (epidermal growth factor)-like domains. Additionally, it has structural sites, including AP1, SP1, and MEF2D, that indicate NFAT (nuclear factor of activated T cells) and NF-κB (nuclear factor kappa-B) may be transcription factors for this gene. Functionally, APR3 participates in apoptosis due to the induction of mitochondrial damage to release mitochondrial cytochrome C. Concurrently, APR3 affects the cell cycle by altering the expression of Cyclin D1, which, in turn, affects the incidence and growth of malignancies and promotes cell differentiation. Previous reports indicate that APR3 is located in lysosomal membranes, where it contributes to lysosomal activity and participates in autophagy. While further research is required to determine the precise role and molecular mechanisms of APR3, earlier studies have laid the groundwork for APR3 research. There is growing evidence supporting the significance of APR3 in oncology. Therefore, this review aims to examine the current state of knowledge on the role of the newly discovered APR3 in tumorigenesis and to generate fresh insights and suggestions for future research.


The ontogeny of flowering and sex expression in divergent populations of Lomatium grayi.
Populations of Lomatium grayi (Umbelliferae), an andromonoecious, perennial herb, differe in growth rates, flowering frequency, and survivorship. Effects of these different life histories on the ontogeny of sex expression were analyzed for plants from two populations grown from seedlings in a common garden and monitored for six years. Plants from Smoot Hill, Washington grew faster, had a higher probability of flowering at each age and size after the first year of growth, and a higher probability of flowering repeatedly among years than did plants from Clarkston, Washington. The proportion of plants producing some hermaphroditic flowers increased with plant size in both populations. Smoot Hill plants, however, were more likely to begin flowering as small, staminate plants than Clarkston plants. Clarkston plants did not begin flowering until they were older and larger, and most of these plants produced some hermaphroditic flowers when they began reproduction. The positive association between production of hermaphroditic flowers and both plant size and age was consistent with the hypothesis that hermaphroditic flowers are more costly to produce than staminate flowers.Although the populations did not differ in the total number of flowers per plant produced at any age or size, Smoot Hill plants consistently produced a lower percentage of hermaphroditic flowers than Clarkston plants at larger sizes and later ages. Consequently, selection for faster growth rates and higher flowering frequency at small sizes and early ages may have favored the more staminate-biased sex ratios in the Smoot Hill population.


Tetraphenylethene-based aggregation-induced emission fluorescent organic nanoparticles: facile preparation and cell imaging application.
Tetraphenylethene-based (TPE) aggregation-induced emission fluorescent organic nanoparticles (FONs) were facilely prepared via Schiff base condensation with ɛ-polylysine (Ply) and subsequent reduction to form stable CN covalent bond. Thus obtained TPE-Ply FONs were characterized by a series of techniques including fluorescent spectroscopy, Fourier transform infrared spectroscopy and transmission electron microscopy. Biocompatibility evaluation and cell uptake behavior of TPE-Ply FONs were further investigated to explore their potential biomedical application. We demonstrated that such FONs showed high water dispersibility, intense fluorescence, uniform morphology (100-200nm) and excellent biocompatibility, making them promising for cell imaging application.


Pharmacokinetics of ofloxacin enantiomers after intravenous administration for antibiotic prophylaxis in biliary surgery.
The pharmacokinetics of S-(-)- and R-(+)-ofloxacin, enantiomers of the fluoroquinolone ofloxacin, were characterized after prophylactic administration in 15 patients undergoing elective biliary surgery. A single dose of ofloxacin 400 mg given intravenously as an infusion was administered 1 hour before surgery. Plasma levels of S-(-)- and R-(+)-ofloxacin showed very small differences between both enantiomers, although the ratio of S-(-)- to R-(+)-enantiomer concentration in plasma showed significant differences (p < 0.05) at 4 and 12 hours. Adequate S-(-)-ofloxacin (levofloxacin, the active enantiomer) plasma levels (> or = minimum inhibitory concentration [MIC90] for Escherichia coli) were found throughout the procedure. For pharmacokinetic parameters, the authors found small but statistically significant differences (p < 0.05) in the area under the concentration-time curve, AUC0-infinity (22.30 +/- 2.72 mg h/L for S-(-)-ofloxacin vs. 20.50 +/- 2.06 mg h/L for R-(+)-ofloxacin), and in the clearance (0.15 +/- 0.04 L/h/Kg for S-(-)-ofloxacin vs. 0.16 +/- 0.04 L/h/Kg for R-(+)-ofloxacin). To test the penetration of ofloxacin enantiomers into tissues, the authors measured levels in subcutaneous cell tissue and gall-bladder cell tissue. They did not observe statistical differences between the two isomers, which means that distribution is not an estereoselective process. Enantiomer levels in these two tissues decreased rapidly, but the highest concentrations were reached during the 4 first hours (i.e., when the surgical procedure was being performed). In conclusion, with the prophylactic treatment used, levofloxacin plasma and tissue levels are high enough to prevent surgical infections.


Effects of levothyroxine therapy on bone mineral density and bone turnover markers in premenopausal women with thyroid cancer after thyroidectomy.
We investigated the impact of long-term levothyroxine (LT4) treatment on bone mineral density (BMD) and bone turnover markers (BTMs) in premenopausal women with differentiated thyroid cancer (DTC) after thyroidectomy. Sixty-five premenopausal women who received LT4 therapy at least one year (range, 1.5-9.0 years) after thyroidectomy for DTC and 50 premenopausal women without thyroid diseases were enrolled in this study. We measured the Z-scores of lumbar and hip BMD, serum free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), intact parathyroid hormone (iPTH), N-terminal propeptide of type 1 N procollagen (P1NP), C terminal telopeptide of type 1 collagen (CTX-1), calcium (Ca), phosphorus (P), vitamin D3, and alkaline phosphatase (ALP) in all participants. In DTC subjects, serum TSH levels were lower, and serum FT4, P1NP, CTX-1, and ALP levels were higher compared with controls. The prevalence of low BMD was higher in DTC subjects than in controls. Multivariate logistic regression analysis showed that serum TSH levels were negatively associated with CTX-1 and ALP. We found a high prevalence of low BMD among premenopausal women who received long-term LT4 therapy for DTC after thyroidectomy. Long-term TSH suppression therapy was a significant risk factor for decreased bone strength, mainly by increasing bone turnover.


Amburoside A, a glucoside from Amburanacearensis, protects mesencephalic cells against 6-hydroxydopamine-induced neurotoxicity.
This study evaluates the potential neuroprotective properties of amburoside A, a glucoside isolated from Amburana cearensis, on rat mesencephalic cell cultures exposure to the neurotoxin 6-hydroxydopamine (6-OHDA). The parameters determined were cell viability by the 3[4,5-dimethylthiazole-2-il]-2,5-diphenyltetrazolium bromide (MTT) method, nitric oxide (NO) and free radical formation by the measurement of nitrite concentration and thiobarbituric acid reacting substance (TBARS) formation as an indication of cellular lipid peroxidation. The results showed that AMB was less effective as a curative agent in the MTT assay, since its addition after 6-OHDA did not reverse the neurotoxin's effect, except at the highest concentration (AMB, 100 microg/ml). Similarly, the higher nitrite levels observed after exposure of the cells to 6-OHDA were only partially reversed by AMB, at this highest concentration. However, when AMB (0.5, 1, 10 and 100 microg/ml) was added before the toxin, it appeared to protect neuronal cells against 6-OHDA toxicity in a concentration-dependent manner, as shown by MTT assay. AMB also prevented free radical formation indicated by the increased nitrite concentration induced by 6-OHDA. Cells exposed to 6-OHDA showed a 3.4 times increase in TBARS concentration as compared to controls, and this effect was inhibited from 24% up to 64% by AMB (0.1-100 microg/ml), indicative of a neuroprotective effect. In conclusion, we show that AMB, acting as an antioxidant compound, presents a significant neuroprotective effect, suggesting that this compound could provide benefits as a therapeutic agent in neurodegenerative disease such as Parkinson's.


[Hypofractionated radiotherapy in prostate cancer].
Radiotherapy plays a central role in the management of localized prostate cancer, but the total duration of treatment of nearly 2 months poses not only problems of fatigue related to repetitive transports, especially for older patients, but also increases the overall cost of treatment including linear accelerators occupancy and patient transportation. To address this problem, various teams have developed hypofractionated radiotherapy protocols seeking to maintain the same efficacy and toxicity while reducing the total duration of treatment. These hypofractionated protocols require recent techniques such as image-guided radiation therapy (IGRT) and intensity-modulated radiation therapy (IMRT). Single centre series have validated the feasibility of "light" hypofractionation schemes at doses per fraction less than 6 Gy Similarly, different teams have shown the possibility of stereotactic irradiation for delivering "severe" hypofractionation schemes at doses greater than 6 Gy per fraction. Whatever the dose per fraction, the current clinical data support the conclusion that hypofractionated radiotherapy does not increase mid-term toxicity and could even improve biochemical control. Studies with the objective of demonstrating non-inferiority are expected to definitively validate the role of hypofractionated irradiation in the treatment of prostate cancer.


Pig islet xenograft rejection in a mouse model with an established human immune system.
Xenotransplantation from pigs provides a potential solution to the severe shortage of human pancreata, but strong immunological rejection prevents its clinical application. A better understanding of the human immune response to pig islets would help develop effective strategies for preventing graft rejection. We assessed pig islet rejection by human immune cells in humanized mice with a functional human immune system. Humanized mice were prepared by transplantation of human fetal thymus/liver tissues and CD34(+) fetal liver cells into immunodeficient mice. Islet xenograft survival/rejection was determined by histological analysis of the grafts and measurement of porcine C-peptide in the sera of the recipients. In untreated humanized mice, adult pig islets were completely rejected by 4 weeks. These mice showed no detectable porcine C-peptide in the sera, and severe intra-graft infiltration by human T cells, macrophages, and B cells, as well as deposition of human antibodies. Pig islet rejection was prevented by human T-cell depletion prior to islet xenotransplantation. Islet xenografts harvested from T-cell-depleted humanized mice were functional, and showed no human cell infiltration or antibody deposition. Pig islet rejection in humanized mice is largely T-cell-dependent, which is consistent with previous observations in non-human primates. These humanized mice provide a useful model for the study of human xenoimmune responses in vivo.


Endogenous ion channels expressed in human embryonic kidney (HEK-293) cells.
Mammalian expression systems, particularly the human embryonic kidney (HEK-293) cells, combined with electrophysiological studies, have greatly benefited our understanding of the function, characteristic, and regulation of various ion channels. It was previously assumed that the existence of endogenous ion channels in native HEK-293 cells could be negligible. Still, more and more ion channels are gradually reported in native HEK-293 cells, which should draw our attention. In this regard, we summarize the different ion channels that are endogenously expressed in HEK-293 cells, including voltage-gated Na+ channels, Ca2+ channels, K+ channels, Cl- channels, nonselective cation channels, TRP channels, acid-sensitive ion channels, and Piezo channels, which may complicate the recording of the heterogeneously expressed ion channels to a certain degree. We noted that the expression patterns and channel profiles varied with different studies, which may be due to the distinct originality of the cells, cell culture conditions, passage numbers, and different recording protocols. Therefore, a better knowledge of endogenous ion channels may help minimize potential problems in characterizing heterologously expressed ion channels. Based on this, it is recommended that HEK-293 cells from unknown sources should be examined before transfection for the characterization of their functional profile, especially when the expression level of exogenous ion channels does not overwhelm the endogenous ion channels largely, or the current amplitude is not significantly higher than the native currents.


A multi-channel responsive AuNP@COF core-shell nanoprobe for simultaneous subcellular profiling of multiple cancer biomarkers.
The abnormal change in the expression profile of multiple cancer biomarkers is closely related to tumor progression and therapeutic effect. Due to their low abundance in living cells and the limitations of existing imaging techniques, simultaneous imaging of multiple cancer biomarkers has remained a significant challenge. Here, we proposed a multi-modal imaging strategy to detect the correlated expression of multiple cancer biomarkers, MUC1, microRNA-21 (miRNA-21) and reactive oxygen (ROS) in living cells, based on a porous covalent organic framework (COF) wrapped gold nanoparticles (AuNPs) core-shell nanoprobe. The nanoprobe is functionalized with Cy5-labeled MUC1 aptamer, a ROS-responsive molecule (2-MHQ), and a miRNA-21-response hairpin DNA tagged by FITC as the reporters for different biomarkers. The target-specific recognition can induce the orthogonal molecular change of these reporters, producing fluorescence and Raman signals for imaging the expression profiles of membrane MUC1 (red fluorescence channel), intracellular miRNA-21 (green fluorescence channel), and intracellular ROS (SERS channel). We further demonstrate the capability of the cooperative expression of these biomarkers, along with the activation of NF-κB pathway. Our research provides a robust platform for imaging multiple cancer biomarkers, with broad potential applications in cancer clinical diagnosis and drug discovery.


Group hunting in a ponerine ant, Leptogenys nitida Smith.
Field observations on the emigration and foraging behaviours of the southern African ponerine ant, Leptogenys nitida, were undertaken at Mtunzini, Natal, South Africa. These colonies have a single ergatoid queen and 200-1000 workers. The nest sites are found in the leaf litter and these nests are moved frequently over distances ranging from 0.5 to 5 m. Leptogenys nitida is a diurnal predator of arthropods dwelling in the leaf litter. Up to 500 workers participate in each foraging trail, and are not led by definite scouts. Ants form clear trunk trails and fan out at various intervals to search for prey. The prey is searched for and retrieved cooperatively. From laboratory tests it was determined that ants will follow pygidial gland extracts, with the poison gland extract eliciting a limited response. The type of army ant behaviour observed in L. nitida seems to be different to that observed in other ponerine ants.


Large-scale identification of functional microRNA targeting reveals cooperative regulation of the hemostatic system.
Essentials MicroRNAs (miRNAs) regulate the molecular networks controlling biological functions such as hemostasis. We utilized novel methods to analyze miRNA-mediated regulation of the hemostatic system. 52 specific miRNA interactions with 11 key hemostatic associated genes were identified. Functionality and drugability of miRNA-19b-3p against antithrombin were demonstrated in vivo. SUMMARY: Background microRNAs (miRNAs) confer robustness to complex molecular networks regulating biological functions. However, despite the involvement of miRNAs in almost all biological processes, and the importance of the hemostatic system for a multitude of actions in and beyond blood coagulation, the role of miRNAs in hemostasis is poorly defined. Objectives Here we comprehensively illuminate miRNA-mediated regulation of the hemostatic system in an unbiased manner. Methods In contrast to widely applied association studies, we used an integrative screening approach that combines functional aspects of miRNA silencing with biophysical miRNA interaction based on RNA pull-downs (miTRAP) coupled to next-generation sequencing. Results Examination of a panel of 27 hemostasis-associated gene 3'UTRs revealed the majority to possess substantial Dicer-dependent silencing capability, suggesting functional miRNA targeting. miTRAP revealed 150 specific miRNA interactions with 14 3'UTRs, of which 52, involving 40 miRNAs, were functionally confirmed. This includes cooperative miRNA regulation of key hemostatic genes comprising procoagulant (F7, F8, F11, FGA, FGG and KLKB1) and anticoagulant (SERPINA10, PROZ, SERPIND1 and SERPINC1) as well as fibrinolytic (PLG) components. Bioinformatic analysis of miRNA functionality reveals established and potential novel links between the hemostatic system and other pathologies, such as cancer, bone metabolism and renal function. Conclusions Our findings provide, along with an in-vivo proof of concept, deep insights into the network of miRNAs regulating the hemostatic system and present a foundation for biomarker discovery and novel targeted therapeutics for correction of de-regulated hemostasis and associated processes in the future. A repository of the miRNA targetome covering 14 hemostatic components is provided.


Nerve transfers for brachial plexus reconstruction.
Brachial plexus injuries result in devastating loss of function for patients and present incredible challenges for peripheral nerve surgeons. Recently, nerve transfers have produced superior results compared with traditional interposition nerve grafts for brachial plexus reconstruction. The authors present a review of current surgical options for treatment of partial and complete adult brachial plexus injuries using nerve transfers.


NDRG2 promoted secreted miR-375 in microvesicles shed from M1 microglia, which induced neuron damage.
Microglia microvesicles (MVs) has shown to have significant biological functions under normal conditions. A diversity of miRNAs is involved in neuronal development, survival, function, and plasticity, but the exact functional role of NDRG2 and secreted miR-375 in MVs in neuron damage is poorly understood. We investigated the effect of NDRG2 and secreted miR-375 in MVs shed from M1 microglia on neuron damage. Expression of Nos2, Arg-1, miR-375, syntaxin-1A, NDRG2 and Pdk 1 were evaluated using RT-PCR or western blotting. Cell viability of N2A neuron was quantified by a MTT assay. Microglia can be polarized into different functional phenotypes. Expression of NDRG2 and Nos2 were significantly increased by LPS treatment on N9 cells, whereas treatment with IL-4 dramatically suppressed the expression of NDRG2 and remarkably elevated expression of Arg-1. Besides, MVs shed from LPS-treated N9 microglia significantly inhibited cell viability of N2A neurons and expression of syntaxin-1A, and NDRG2 interference reversed the up-regulated miR-375 in LPS-treated N9 microglia and MVs shed from LPS-treated N9 cells. Furthermore, NDRG2 could modulate miR-375 expression in N9 microglia and MVs. And miR-375 inhibitor remarkably elevated Pdk1 expression in N2A neurons. Finally, miR-375 inhibitor could reverse suppression effect of NDRG2 overexpression on cell viability of N2A neurons and expression of syntaxin-1A. Our results demonstrated that NDRG2 promoted secreted miR-375 in microvesicles shed from M1 microglia, which induced neuron damage. The suppression of NDRG2 and secreted miR-375 in MVs shed from M1 microglia may be potential targets for alleviation of neuron damage.


Gender differences in the regulation of 3 alpha-hydroxysteroid dehydrogenase in rat brain and sensitivity to neurosteroid-mediated stress protection.
The enzyme 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) is involved in the generation of neuroactive steroids through ring-A-reduction of hormonal precursors. We examined the developmental regulation of, gender differences in, and effects of hormonal manipulations on the expression of 3 alpha-HSD in the rat hippocampus. High levels of 3 alpha-HSD mRNA were found on postnatal day 7, coinciding with the stress hyporesponsive period in the rat. Gender differences in 3 alpha-HSD expression were documented during puberty, but not in adulthood. Adrenalectomy and gonadectomy, and supplementation with individual steroid hormones influenced 3 alpha-HSD expression in a gender-specific mode. We also demonstrate that the manifestation of behavioral and endocrine consequences of early life stress depends on the individual's gender and gonadal status. Males are liable to aftereffects of neonatal maternal deprivation, regardless of their adult gonadal status. In females, however, anxiogenic aftereffects of neonatal stress become apparent only after gonadectomy. These data suggest that (i) transient increase of neurosteroid biosynthesis may contribute to stress hyporesponsiveness during early infancy; (ii) gonadal steroids regulate 3 alpha-HSD expression in the hippocampus in a sex-specific mode; (iii) physiological sex steroid secretions in females may mask behavioral consequences of adverse early life events, and (iv) concomitant treatment with the neurosteroid THP counteracts behavioral and endocrine dysregulation induced by neonatal stress in both genders.


Facile fabrication of a novel 3D rose like lanthanum doped zirconia decorated reduced graphene oxide nanosheets: An efficient electro-catalyst for electrochemical reduction of futuristic anti-cancer drug salinomycin during pharmacokinetic study.
An innovative electrochemical nanoprobe, for analysis of salinomycin (SAL), was proposed. The nanoprobe based on decoration of glassy carbon electrode (GCE) with 3D rose like La3+@ ZrO2 supported on reduced graphene oxide (RGO) nanosheets. The 3D rose like La3+@ ZrO2 was synthesized via sintering process. The successful decoration of 3D rose like La3+@ ZrO2 on the surface of RGO was characterized using different spectroscopic and analytical techniques. The obtained voltammetric results confirmed the good electrochemical performance of 3D rose like La3+@ ZrO2 in terms of lower peak potential (Epc) and higher cathodic current (Ipc). Moreover, the modified nanoprobe showed wide linearity range (0.34-115 × 10-8 M), lower detection limit (0.11 × 10-8 M) and higher selectivity. Besides, the nanocomposite showed good applicability for analysis of SAL in biological fluids and during pharmacokinetic evaluation in rabbit plasma. The obtained results opens a new venue for the determination of futuristic drug, SAL, during pharmacokinetic and pharmacodynamics studies.


Extra-cardiac endovascular infections in the critically ill.
Vascular infections are associated with high complication rates and mortality. While there is an extensive body of literature surrounding cardiac infections including endocarditis, this is less so the case for other endovascular infections. The objective of this narrative review is to summarize the epidemiology, clinical features, and selected management of severe vascular infections exclusive of those involving the heart. Endovascular infections may involve either the arterial or venous vasculature and may arise in native vessels or secondary to implanted devices. Management is complex and requires multi-disciplinary involvement from the outset. Infective arteritis or device-related arterial infection involves removal of the infected tissue or device. In cases where complete excision is not possible, prolonged courses of antimicrobials are required. Serious infections associated with the venous system include septic thrombophlebitis of the internal jugular and other deep veins, and intracranial/venous sinuses. Source control is of paramount importance in these cases with adjunctive antimicrobial therapy. The role of anticoagulation is controversial although recommended in the absence of contraindications. An improved understanding of the management of these infections, and thus improved patient outcomes, requires multi-center, international collaboration.


Free and antibody-complexed antigen and antibody profile in apparently healthy HIV seropositive individuals and in AIDS patients.
The pattern of free and antibody-complexed HIV antigen and the antibody profile were investigated retrospectively in 305 serum samples taken from 22 AIDS patients before and during the development of AIDS and from 40 apparently healthy seropositive individuals. Most AIDS patients were found positive for both free and complexed antigen and had high gp41 antibody titres but low or undetectable p24 antibody. Four different patterns of HIV antigenaemia were observed: 1) positive for both free and complexed antigen; 2) negative for free HIV antigen at first, but always positive for complexed antigen; 3) positive for free antigen without complexed antigen; and 4) negative for both free and complexed antigen. The development of immune complexes preceded the appearance of free antigen and might reflect the ongoing viral replication with antigen excess and binding of anticore antibodies. No correlation was found between the development of AIDS symptoms and either the duration of free antigen positivity or the level of antigenaemia. A different pattern was observed in apparently healthy seropositive individuals: 90% of whom had high antibody titres to p24 and gp41 and were persistently negative for free and complexed HIV antigen. This study demonstrates that testing HIV markers in sequentially collected serum samples from HIV seropositive individuals is a useful and simple tool for early identification of persons at risk of developing AIDS.


Historical biogeography and speciation in the Creole wrasses (Labridae, Clepticus).
We tested whether vicariance or dispersal was the likely source of speciation in the genus Clepticus by evaluating the evolutionary timing of the effect of the mid-Atlantic barrier, which separates C. brasiliensis and C. africanus, and the Amazon barrier, which separates C. parrae and C brasiliensis. Genetic data from three mitochondrial genes and one nuclear gene were used. Mitochondrial genes separated Clepticus into three well supported clades corresponding to the three recognized allopatric morpho-species. All analyses provided consistent support for an initial separation (~9.68 to 1.86 mya; 4.84% sequence divergence) of the Caribbean and South Atlantic lineages, followed by a much more recent divergence (~ 0.60 to 0.12 mya; 0.3% sequence divergence) of the Brazilian and African sister morpho-species. Both these phylogenetic events occurred well after the formation of the two barriers that currently separate those three allopatric populations. The planktonic larval duration of these species (35-49 days) and coastal pelagic habits may have facilitated dispersal by this genus across those dispersal barriers after they formed.


Measuring (biological) materials mechanics with atomic force microscopy. 5. Traction force microscopy (cell traction forces).
Cells generate traction forces to probe the mechanical properties of the surroundings and maintain a basal equilibrium state of stress. Traction forces are also implicated in cell migration, adhesion and ECM remodeling, and alteration of these forces is often observed in pathologies such as cancer. Thus, analyzing the traction forces is important for studies of cell mechanics in cancer and metastasis. In this primer, the methodology for conducting two-dimensional traction force microscopy (2D-TFM) experiments is reported. As a practical example, we analyzed the traction forces generated by three human breast cancer cell lines of different metastatic potential: MCF10-A, MCF-7 and MDA-MB-231 cells, and studied the effects of actin cytoskeleton disruption on those traction forces. Contrary to what is often reported in literature, lower traction forces were observed in cells with higher metastatic potential (MDA-MB-231). Implications of substrate stiffness and concentration of extracellular matrix proteins in such findings are discussed in the text. RESEARCH HIGHLIGHTS: Traction force microscopy (TFM) is suitable for studying and quantifying cell-substrate and cell-cell forces. TFM is suitable for investigating the relationship between chemical to mechanical signal transduction and vice versa. TFM can be combined with classical indentation studies providing a compact picture of cell mechanics. TFM still needs new physico-chemical (sample preparation) and computational approaches for more accurate data evaluation.


An infected congenital commissural lip fistula. Report of a case.
A case of infected congenital commissural lip fistula is presented. It appeared as a cheek swelling associated with inflammation due to infection. This case was treated with antibiotics and surgical drainage through the fistula. Our experience suggests that the possibility of infection of the fistula should be considered particularly in cases involved with angular stomatitis and/or scratching injury close to the commissure of the lips.


Dinucleotide deletion in -alpha3.7 allele causes a severe form of alpha+ thalassaemia.
We describe a family of Italian origin in which the father and his two children had hypochromia and microcytosis with normal iron status. All individuals underwent an uneventful clinical course and required no treatment. To investigate the molecular basis of this phenotype, which is a prerequisite for further genetic counselling, we revealed that all affected family members are carriers of a common form of alpha+ thalassaemia resulting from the deletion of 3.7 kb of the alpha-globin cluster (alphaalpha/-alpha3.7). However, this genotype alone could not account for the phenotype presenting in this family. Further characterization of the alpha-globin genes demonstrated an additional AC deletion in the vicinity of the initiation codon of the -alpha3.7 allele. This secondary mutation causes an additional impaired translation of the affected allele producing increased globin chain imbalance. This leads to a more severe phenotype, as heterozygotes for such mutation (alphaalpha/-alphaT) have hypochromic microcytosis and abnormal globin chain synthesis that mimic alpha0 thalassaemia trait (--/alphaalpha). Accurate genotyping of alpha globin determinant is absolutely required as there is a possibility that an interaction of this unusual double mutation with other common alpha0 thalassaemias (--/-alphaT) can give rise to a very severe, probably fatal, alpha thalassaemia.


Minimally invasive kidney transplantation.
Minimally invasive kidney transplantation (MIKT) procedures, starting with lymphocele fenestration and continuing with laparoscopic donor nephrectomy, have been performed in recipients since 2006. From November 2011 to May 2012, we performed 86 consecutive renal transplantation with 43 conventional kidney transplantations (COKT) and 43 MIKTs using an apendectomy like, 4 to 5-cm incision. There were no significant differences between the groups according to age, sex, body mass index, donor type, surgical side, donor kidney or artery number. Mean operative time in the MIKT group was 164.2 minutes versus 153.5 minutes in the COKT group. The cold ischemia times in MIKT and COKT groups were 60.8 and 63.3 minutes, respectively. The lengths of hospital stay, blood creatinine levels at postoperative days 7, 30, and 90, and the 90th day creatinine clearances were similar. In conclusion, considering that the complication rate was equal and the graft functions equal, MIKT seemed to be a safe method for renal transplantation.


Neointimal expression of rapamycin receptor FK506-binding protein FKBP12: postinjury animal and human in-stent restenosis tissue characteristics.
Despite excellent clinical results for sirolimus (rapamycin)-eluting stents, the exact mechanisms of antirestenotic activity and affected cellular targets are incompletely understood. Therefore, we determined the presence and tem- porospatial expression pattern of FKBP12, the primary intracellular receptor of rapamycin, in rat carotid arteries after balloon injury, as well as in human in-stent restenosis and primary stable coronary atheroma. FKBP12 expression was assessed by immunohistochemistry. Rat carotid arteries revealed maximal expression in 57.7 +/- 4.0% of neointimal cells at day 7. A large proportion of these FKBP12+ cells showed luminally confined co-expression with dendritic cell markers. Despite a considerably thicker neointima at day 28, presence of FKBP12 decreased (8.5 +/- 1.9%, p = 0.02) with a scattered pattern in luminal and deep neointima. Likewise, human in-stent restenosis atherectomy specimens (time after stent implantation 2-12 months) revealed a comparable extent of cellular rapamycin receptor expression (9.3 +/- 1.0%) that significantly differed from that found in primary stable atheroma (1.3 +/- 0.4%, p < 0.001). In conclusion, the rapamycin receptor is predominantly present during early neointima formation, while mature neointimal atheromas show a relatively low expression without confinement to luminal areas. Co-expression of FKBP12 and dendritic cell markers suggests that dendritic cells may be another important target for early and long-term rapamycin effects.


The use of diphenylene iodonium, an inhibitor of NADPH oxidase, to investigate the antimicrobial action of human monocyte derived macrophages.
Diphenylene iodonium is an inhibitor of the respiratory burst-generating NADPH oxidase of phagocytes. The effect of this compound on human monocyte-derived macrophages and its usefulness in exploring the antimicrobial mechanisms of phagocytes was examined. 1 microM diphenylene iodonium inhibited hydrogen peroxide production by human macrophages and the activity of these cells against Toxoplasma gondii. At this concentration macrophage degranulation was unaffected.


Antigenic cross-reactivities between mammalian hexokinases.
Immunoelectrophoresis and gel diffusion techniques have demonstrated that, contrary to previous reports, antigenic cross-reactivity does exist between the three major rat hexokinase isoenzymes. Immune inhibition and immune precipitation assays performed in parallel generally failed to detect this cross-reactivity and possible reasons for this failure are discussed. The inability of the latter assay systems to detect cross-reactivity would seem to account for the discrepancies between the present results and those obtained in earlier studies.


PCD-GED: Protein complex detection considering PPI dynamics based on time series gene expression data.
Detection of protein complexes from protein-protein interaction (PPI) networks is essential to understand the function of cell machinery. However, available PPIs are static, and cannot reflect the dynamics inherent in real networks. Our method uses time series gene expression data in addition to PPI networks to detect protein complexes. The proposed method generates a series of time-sequenced subnetworks (TSN) according to the time that the interactions are activated. It finds, from each TSN, the protein complexes by employing the weighted clustering coefficient and maximal weighted density concepts. The final set of detected protein complexes are obtained from union of all complexes from different subnetworks. Our findings suggest that by employing these considerations can produce far better results in protein complex detection problem.


Dinoflagellate Alexandrium tamarense as the source of paralytic shellfish poison (PSP) contained in bivalves from Hiroshima Bay, Hiroshima Prefecture, Japan.
In April 1993, a phytoplankton dinoflagellate was isolated from Hiroshima Bay, Hiroshima Prefecture, Japan, and unambiguously identified as Alexandrium tamarense on the basis of the morphological characteristics. The dinoflagellates, cultures in modified SW-2 medium at 15 degrees C for 15 days, showed a specific toxicity of 30.7 x 10-6 MU/cell. HPLC analysis demonstrated that the toxin was composed mainly of gonyautoxin-4 (GTX4) and protogonyautoxin-2 (PX2 or GTX8)(27.6 and 37.0 mole%, respectively). Total toxin concentration of this strain was 39.5 fmole/cell. Short-necked clams, mussels, and oysters contaminated by the dinoflagellate showed a more complicated composition, with GTX1 as the major component (61.8 mole% for short-necked clams, 60.5 mole% for mussels, 42.5 mole% for oysters), and PX2 was only present in trace amounts.


Effect of mytilotoxin-contaminated mussels on small intestine disaccharidase activities in rat.
An extract of mussels contaminated with Gonyaulax monilata was administered intragastrically to rats (1.5 or 2.0 ml extract/150 g body wt) 3 or 7 h before experiments. Intestinal disaccharidases were determined. Sucrase activity was changed in both mucosa and brush border after treatment. Maltase and lactase activities were affected only by the higher dosage.


Flexure dose: the low-dose limit of effective fractionation.
Total radiation dose often can be increased without subsequent increases in the severity of tissue injury by using reduced doses per fraction. The flexure dose, df, is defined as the largest fractional dose for which further fractionation produces no significant change in the total dose required to reach a specified effect level. Thus, df is clinically relevant in that it represents the limit of effective dose fractionation. For those tissues in which injury reflects depletion of a critical proportion of target cells, the flexure dose is a measure of the extent of the initial, nearly linear portion of the dose-survival curve. More generally, the flexure dose is a measure of the extent of the initial, nearly linear portion of a dose-response curve in organized tissue, whatever its relationship to clonogenic target cells might be. Several quantitative expressions for df are derived. The characteristic common to these is that each defines the flexure dose as a multiple of the ratio alpha/beta of the parameters of the linear-quadratic model of cell survival or dose response, where the multiple is a measure of experimental or statistical resolution. These multiples tend to fall within a limited range, thereby defining the "region of flexure" via the inequality 0.05 (alpha/beta) less than or equal to df less than or equal to 0.15 (alpha/beta). Estimates of the region of flexure are presented for a variety of normal and neoplastic tissues.


Selective Neck Dissection Technique in the Treatment of Recurrent Pyriform Sinus Fistula.
The 3rd and 4th branchial arch fistulas are rare conditions which are due to embryological persistence or incomplete developmental anomalies. They have a typical course as described by the embryological development but the presentation of cases with true course as per embryology is rare. These patients usually present with repeated infections, inadequate surgical interventions and recurrences. We present two index cases of 3rd and 4th pyriform sinus fistulas with their varied anatomical course and clinical presentation who were treated by selective neck dissection technique.


Control of urinary bladder function with devices: successes and failures.
The management of urinary tract dysfunction is crucial for the health and well-being of people with spinal cord injury. Devices, specifically catheters, play an important role in the daily regime of bladder management for most people with spinal cord injury. However, the high incidence of complications associated with the use of catheters, and the fact that the spinal segments involved in lower urinary tract control remain intact in most cord-injured people, continue to motivate research into devices that could harness the nervous system to provide greater control over lower urinary tract function. Mechanical devices discussed in this review include catheters, artificial urethral sphincters, urethral stents and intraurethral pumps. Additionally, many attempts to restore control of the lower urinary tract with electrical stimulation have been made. Stimulation sites have included: inside the bladder, bladder wall, thigh, pelvic floor, dorsal penile nerve, pelvic nerve, tibial nerve, sacral roots, sacral nerves and spinal cord. Catheters and sacral root stimulators are two techniques whose efficacy is well established. Some approaches have proven less successful and others are still in the development stage. Modifications to sacral root stimulation including posterior root stimulation, anodal blockade and high-frequency blockade as well as new techniques including intraspinal microstimulation, urethral afferent stimulation and injectable microstimulators are also discussed. No single device has yet restored the control and function of the lower urinary tract to the pre-injury state, but new techniques are bringing this possibility closer to reality.


Patients with a relapsing course of steroid-responsive encephalopathy associated with autoimmune thyroiditis exhibit persistent intrathecal CD4+ T-cell activation.
Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is a rare condition defined by encephalopathy with acute or subacute onset, the presence of serum anti-thyroid antibodies, and reasonable exclusion of alternative causes. Despite having strong response towards corticosteroid treatment, some patients exhibit a chronic-relapsing course and require long-term immunosuppression. Markers for early identification of those patients are still absent. Thus, we aimed to characterise clinical as well as laboratory parameters of our local SREAT cohort. We retrospectively evaluated a cohort of 22 SREAT patients treated in our hospital from January 2014. A total of 14 patients with a monophasic disease course and eight patients with multiple relapses were identified. Neither baseline characteristics nor routine cerebrospinal fluid (CSF) parameters were able to distinguish between those patient groups. Flow cytometry following initial relapse therapy showed treatment-resistant sequestration of activated CD4+ T cells in patients with a relapsing disease course, whereas other lymphocyte subsets showed uniform changes. Such changes were also present in long-term follow-up CSF examination. Our findings indicate a potential biomarker for risk stratification in patients with SREAT. Currently, it remains unclear whether the observed two phenotypes are different spectra of SREAT or represent separate diseases in terms of pathophysiology.


Biomimetic synthesis of chondroitin sulfate-analogue hydrogels for regulating osteogenic and chondrogenic differentiation of bone marrow mesenchymal stem cells.
As a typical representative of crucial glycosaminoglycans (GAGs), chondroitin sulfate (CS) with sulfonated polysaccharide in structures extensively exists in the extracellular matrix (ECM) and exhibits peculiar bioactivity on the regulation of cells behaviors and fates (e.g. proliferation and differentiation) in organisms. Nevertheless, some intrinsic disadvantages of natural CS mainly ascribe to the intricate structure and inhomogeneous composition (especially the uncontrollable sulfonate degrees), resulting in overt restrictions on its physiological functions and applications. Although recent bionic synthesis of artificial GAGs analogues at the molecular level have already provides an efficient strategy to reconstruct GAG for regulating the cellular behaviors and fates, it still remains great challenges to rationally design and synthesize GAGs analogues with special composition and structure for precisely mimicking ECM. Simultaneously, the relevant regulation process of GAG analogues on cell fate needs to be further studied as well. Herein, chondroitin sulfate-analogue (CS-analogue) hydrogels with diverse contents of saccharide and sulfonate units in the networks were fabricated through photo-polymerization and then characterized by Fourier transform infrared (FT-IR) spectroscopy, zeta potential and scanning electron microscope (SEM). Additionally, CS-analogue hydrogels with proper mechanical properties exhibited favorable swelling, degradation performance and prominent cytocompatibility. According to cell cultivation results, CS-analogue hydrogel with a certain proportion of saccharide and sulfonate units presented preferable promotion on the adhesion, spreading, proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs), shedding light on the significance of saccharide and sulfonate units in regulating cell behaviors. Furthermore, BMSCs cultivated with CS-analogue hydrogels under different culture conditions were also systematically investigated, revealing that with the help of cultivation environment CS-analogue hydrogels owned the remarkable capacity of directing either chondrogenic or osteogenic differentiation of BMSCs. Therefore, it is envisioned that versatile CS-analogue hydrogels would have promising application prospects in the biomedical and clinical fields.