[alpha-n-benzoylarginine-2-naphthylamide-amidohydrolase activity in chicken liver (author's transl)].
The enzyme activity from chicken liver that hydrolizes alpha-N-benzoil-DL-arginine-2-naphthylamide (BANA) has been separated into three active fractions by chromatography on Sephadex G-100 and DEAE-cellulose. The enzyme in Fraction FEA has a molecular weight greater than or equal to 100,000. The other two enzymes in Fractions FE1B and FE2B have a molecular weight around 23,000 and are separated by DEAE-cellulose chromatography. The BANA-hydrolase of fraction FE2B is unstable at pH alkaline and activates trypsinogen, in contrast with the enzyme of fraction FEB1. Both are thiol enzymes which behave analogously against activators (cysteine, dithiotreitol and 2-mercaptoethanol) and inhibitors (PCMB, IAA, N-ethylmaleimide, Cu2+, Hg2+ and Zn2+).


Audiometric, impedance, and otoscopic findings in children with cleft palates.
We examined the prevalence of hearing loss and/or middle ear disease among 34 children with cleft palates, using pure-tone audiometry, acoustic impedance, and pneumatic otoscopy. The overall incidence of hearing loss and otitic complications varied from 57% to 68%, depending on the procedure used. Of the three clinical procedures used in this study, pure-tone audiometry exhibited the poorest diagnostic efficiency. Close predictive agreement was found between impedance and otoscopy.


[Pathophysiology of secondary testicular dysfunction].
This review summarizes the most important forms of secondary testicular dysfunctions. The gonads are controlled by overlapping regulation systems. Disturbances within these systems possibly lead to gonadal dysfunction. Physicians should be aware of factors that might have a pathogenic effect on gonadal functions, because only then is it possible to prevent infertility.


Antagonism between viral infection and innate immunity at the single-cell level.
When infected with a virus, cells may secrete interferons (IFNs) that prompt nearby cells to prepare for upcoming infection. Reciprocally, viral proteins often interfere with IFN synthesis and IFN-induced signaling. We modeled the crosstalk between the propagating virus and the innate immune response using an agent-based stochastic approach. By analyzing immunofluorescence microscopy images we observed that the mutual antagonism between the respiratory syncytial virus (RSV) and infected A549 cells leads to dichotomous responses at the single-cell level and complex spatial patterns of cell signaling states. Our analysis indicates that RSV blocks innate responses at three levels: by inhibition of IRF3 activation, inhibition of IFN synthesis, and inhibition of STAT1/2 activation. In turn, proteins coded by IFN-stimulated (STAT1/2-activated) genes inhibit the synthesis of viral RNA and viral proteins. The striking consequence of these inhibitions is a lack of coincidence of viral proteins and IFN expression within single cells. The model enables investigation of the impact of immunostimulatory defective viral particles and signaling network perturbations that could potentially facilitate containment or clearance of the viral infection.


Supramolecular Self-Assembly of 3D Conductive Cellulose Nanofiber Aerogels for Flexible Supercapacitors and Ultrasensitive Sensors.
Nature employs supramolecular self-assembly to organize many molecularly complex structures. Based on this, we now report for the first time the supramolecular self-assembly of 3D lightweight nanocellulose aerogels using carboxylated ginger cellulose nanofibers and polyaniline (PANI) in a green aqueous medium. A possible supramolecular self-assembly of the 3D conductive supramolecular aerogel (SA) was provided, which also possessed mechanical flexibility, shape recovery capabilities, and a porous networked microstructure to support the conductive PANI chains. The lightweight conductive SA with hierarchically porous 3D structures (porosity of 96.90%) exhibited a high conductivity of 0.372 mS/cm and a larger area-normalized capacitance (Cs) of 59.26 mF/cm2, which is 20 times higher than other 3D chemically cross-linked nanocellulose aerogels, fast charge-discharge performance, and excellent capacitance retention. Combining the flexible SA solid electrolyte with low-cost nonwoven polypropylene and PVA/H2SO4 yielded a high normalized capacitance (Cm) of 291.01 F/g without the use of adhesive that was typically required for flexible energy storage devices. Furthermore, the supramolecular conductive aerogel could be used as a universal sensitive sensor for toxic gas, field sobriety tests, and health monitoring devices by utilizing the electrode material in lightweight supercapacitor and wearable flexible devices.


High density lipoproteins and endothelial functions: mechanistic insights and alterations in cardiovascular disease.
Prospective population studies in the primary prevention setting have shown that reduced plasma levels of HDL cholesterol are associated with an increased risk of coronary disease and myocardial infarction. Experimental and translational studies have further revealed several potential anti-atherogenic effects of HDL, including protective effects on endothelial cell functions. HDL has been suggested to protect endothelial cell functions by prevention of oxidation of LDL and its adverse endothelial effects. Moreover, HDL from healthy subjects can directly stimulate endothelial cell production of nitric oxide and anti-inflammatory, anti-apoptotic, and anti-thrombotic effects as well as endothelial repair processes. However, several recent clinical trials using HDL cholesterol-raising agents, such as torcetrapib, dalcetrapib, and niacin, did not demonstrate a significant reduction of cardiovascular events in patients with coronary disease. Of note, growing evidence suggests that the vascular effects of HDL can be highly heterogeneous and vasoprotective properties of HDL are altered in patients with coronary disease. Characterization of underlying mechanisms and understanding of the clinical relevance of this "HDL dysfunction" is currently an active field of cardiovascular research. Notably, in some recent studies no clear association of higher HDL cholesterol levels with a reduced risk of cardiovascular events was observed in patients with already established coronary disease. A greater understanding of mechanisms of action of HDL and its altered vascular effects is therefore critical within the context of HDL-targeted therapies. In this review, we will address different effects of HDL on endothelial cell functions potentially relevant to atherosclerotic vascular disease and explore molecular mechanisms leading to "dysfunctional HDL".


Double-hit mantle cell lymphoma with MYC gene rearrangement or amplification: a report of four cases and review of the literature.
Mature B-cell lymphomas with both BCL2 and MYC translocations are known as "double hit" lymphomas. These lymphomas are aggressive and show high proliferation rate due to the growth advantages provided by MYC and BCL2 translocation and overexpression. Mantle cell lymphoma (MCL) is a neoplasm of mature B-lymphocytes with characteristic t(11;14) and subsequent Cyclin D1 overexpression. Secondary cytogenetic changes are frequent in MCL, but MYC translocation has only been rarely reported. In this study, we report four cases of MCL with MYC translocation or MYC gene amplification detected by conventional cytogenetics, fluorescence in situ hybridization and whole genome single nucleotide polymorphism (SNP) array, and determined the clinicopathologic features. Our study provides further evidence supporting the concept of "double hit" MCL with co-involvement of MYC gene rearrangement and/or amplification and CCND1 gene rearrangement.


Role of G proteins in shear stress-mediated nitric oxide production by endothelial cells.
Exposure of cultured endothelial cells to shear stress resulting from well-defined fluid flow stimulates the production of nitric oxide (NO). We have established that an initial burst in production is followed by sustained steady-state NO production. The signal transduction events leading to this stimulation are not well understood. In the present study, we examined the role of regulatory guanine nucleotide binding proteins (G proteins) in shear stress-mediated NO production. In endothelial cells not exposed to shear stress, AIF4-, a general activator of G proteins, markedly elevated the production of guanosine 3',5'-cyclic monophosphate (cGMP). Pretreatment with NO synthase inhibitor N omega-nitro-L-arginine completely blocked this stimulation. Incubation with guanosine 5'-O-(2-thiodiphosphate) (GDP beta S), a general G protein inhibitor, blocked the flow-mediated burst in cGMP production in a dose-dependent manner. Likewise, GDP beta S inhibited NOx (NO2 + NO3) production for the 1st h. However, inhibition was not detectable between 1 and 3 h. Pertussis toxin (PTx) had no effect on the shear response at any time point. The burst in NO production caused by a change in shear stress appears to be dependent on a PTx-refractory G protein. Sustained shear-mediated production is independent of G protein activation.


The titration of death: a new sin.
..."Titration of death" is the phrase I have used, in private musings and discussions, to express the undertaking of causing or permitting death to occur within carefully delimited parameters. It is, I think, a new form of sin. I distinguish it from a similar enterprise, in principle benign, that we might call "titration of dying," which attempts to manage the dying process. The focus of attention of titration of dying is the experience of the patient prior to death, with little or no concern given to the condition of the cadaver following death. Titration of death, on the other hand, is primarily concerned with producing, at the close of the process, a cadaver that is usable in some manner; and titration of death, per se, has only incidental concern with the dying process.


Regional lung function in long-term survivors after chemotherapy for small cell lung cancer.
In order to evaluate the regional lung function in patients with small cell lung cancer with long-term survival, we measured the regional lung function in 17 patients. We studied the patients with 81m-krypton ventilation scans and 99m-technetium perfusion scans, as well as measurements of static lung volumes (VC, RV, TLC), flow volume indices (FEV1, FVC, MEF50), and carbon monoxide diffusing capacity (DLCO). We found both the ventilation and the perfusion of the affected lung to be slightly but significantly lower (P less than 0.05), while no obvious ventilation or perfusion defects could be identified at the former tumor site. The static volumes of the lungs, the FVC and the FEV1 were within predicted normal values, while a significant decrease was seen in the PEF, MEF50, and DLCO. It is concluded that patients with small cell lung cancer who obtain complete remission with normalization of the chest X-ray and long-term survival after 18 months of intensive chemotherapy also have a nearly normal lung function.


Development of novel fast-dissolving tacrolimus solid dispersion-loaded prolonged release tablet.
The goal of this research was to develop a novel prolonged release tablet bioequivalent to the commercial sustained release capsule. A number of tacrolimus-loaded fast-dissolving solid dispersions containing various amounts of DOSS were prepared using the spray drying technique. Their solubility, dissolution and pharmacokinetics in rats were studied. DOSS increased drug solubility and dissolution in the solid dispersions. Compared with the drug powder, the solubility, dissolution and bioavailability of tacrolimus with the fast-dissolving solid dispersion containing tacrolimus/HP-β-CD/DOSS in the weight ratio of 5:40:4 were boosted by approximately 700-, 30- and 2-fold, respectively. Several tablet formulations were accomplished with this solid dispersion in combination with various ratios of HPMC/ethylcellulose. The release behaviour and pharmacokinetic studies in beagle dogs were assessed compared with the commercial prolonged release capsule. A decrease in HPMC/ethylcellulose ratios reduced the dissolution of tacrolimus from the tablets. Particularly, the tacrolimus-loaded prolonged release tablet consisting of fast-dissolving tacrolimus solid dispersion, HPMC, ethylcellulose and talc at the weight ratio of 20:66:112:2 exhibited a dissolution profile similar to that produced by the commercial prolonged release capsule. Furthermore, there were no significant differences in the AUC, Cmax, Tmax and MRT values between them in beagle dogs. Consequently, this tacrolimus-loaded prolonged release tablet might be bioequivalent to the tacrolimus-loaded commercial capsule.


Latex allergy.
Latex allergy and hypersensitivity are becoming major health concerns and occupational risks for health care workers. An allergic reaction can be immediate or delayed. Manifestations are either localized-cell mediated (type IV)-or systemic-IgE mediated (type I). The primary populations at risk are children with spina bifida, health care workers, people with atopic allergies, and those with a history of multiple surgeries. This new health care problem may be linked to the increased use of latex gloves and to changes in the manufacturing of gloves to meet the demand. The care of hypersensitive patients is a challenge for health care providers, since natural rubber latex is present in more than 40,000 products.


Radical radiotherapy for locally advanced cancer of uterine cervix.
This study was performed to evaluate the treatment results, prognostic factors and complication rates in patients with locally advanced cancer of uterine cervix after radiotherapy with high-dose rate (HDR) brachytherapy. One hundred and twenty patients with a locally advanced (stages IIB approximately IVA according to FIGO classification) carcinoma of the uterine cervix were treated with radiotherapy at the Department of Radiation Oncology, Samsung Medical Center between September 1994 and December 2001. The median age of the patients was 61 years (range 29 to 81). Sixty-one, 56 and 3 patients had FIGO stage IIB, III, and IV diseases, respectively. All patients were given external beam radiotherapy over the whole pelvis (median 50.4 Gy) and HDR intracavitary brachytherapy, with a median of 4 Gy per fraction, to point A. Twenty-one patients received chemotherapy, of which 13 and 21 received neoadjuvant chemotherapy and concurrent chemotherapy, respectively, during the first and fourth weeks of external beam radiotherapy. The chemotherapy was not randomly assigned and the median follow-up time was 28.5 months (range: 6 approximately 100 months). The three- and 5-year overall survival (OS) and disease-free survival (DFS) rates were 64.4 and 57.0%, and 63.7 and 60.2%, respectively. The 5-year OS and DFS rates of the patients at stages IIB, III and IV were 60.2, 57.9 and 33.3%, and 57.4, 65.4 and 33.3%, respectively. Univariate analysis indicated that the FIGO stage, overall treatment time (OTT) and treatment response were significant variables for the OS (p=0.035, p=0.0649 and p=0.0009) and of the DFS (p=0.0009, p=0.0359 and p=0.0363). Multivariate analysis showed that the treatment response was the only significant variable for the OS (p=0.0018) and OTT for the DFS (p=0.0360). The overall incidence of late complications in the rectum and bladder were 11.7 and 6.7%, respectively. In addition, insufficiency fractures were observed in 7 patients (5.8%). The results of this study suggest that radical radiotherapy with HDR brachytherapy was appropriate for the treatment of locally advanced uterine cervix cancer. Also, the response after treatment and OTT are significant prognostic factors.


Immunohistochemical and scanning electron microscopic study of cytokeratin distribution in the collecting tubule of the rat kidney.
Cytokeratin distribution in the collecting tubules (CTs) of the rat kidney was studied by immunohistochemistry and scanning electron microscopy (SEM). After preparation of sections from formalin-fixed, paraffin-embedded tissue for immunohistochemistry, the remaining tissue was prepared for SEM. The cut surfaces of the tissue were examined by SEM and compared with sections stained with anti-cytokeratin antibody. The immunostained sections revealed positive staining along the entire CTs. However, in addition to diffusely stained cells, unstained and partially stained cells were seen. The latter were not distributed in inner medullary CTs, whereas the diffusely stained cells were observed in cortical, outer medullary and inner medullary CTs. This immunohistochemical heterogeneity of cytokeratin reactivity was prominent in the outer medullary and cortical CTs. From this comparative study of immunostained sections and SEM specimens, it was concluded that the heterogeneously stained cells correspond to intercalated cells, whereas the diffusely stained cells represent most principal cells. These results suggest that the difference in cytokeratin density among CT cells may represent different functional states, at least in intercalated cells.


Multi-frequency force-detected electron spin resonance in the millimeter-wave region up to 150 GHz.
In this article, a novel technique is developed for multi-frequency force-detected electron spin resonance (ESR) in the millimeter-wave region. We constructed a compact ESR probehead, in which the cantilever bending is sensitively detected by a fiber-optic Fabry-Perot interferometer. With this setup, ESR absorption of diphenyl-picrylhydrazyl radical (<1 μg) was clearly observed at multiple frequencies of up to 150 GHz. We also observed the hyperfine splitting of low-concentration Mn(2+) impurities(∼0.2%) in MgO.


Neurostimulation Strategy for Stress Urinary Incontinence.
We have developed a percutaneously implantable and wireless microstimulator (NuStim) to exercise the pelvic floor muscles for the treatment of stress urinary incontinence. It produces a wide range of charge-regulated electrical stimulation pulses and trains of pulses using a simple electronic circuit that receives power and timing information from an externally generated RF magnetic field. The complete system was validated in vitro and in vivo in preclinical studies demonstrating that the NuStim can be successfully implanted into an effective, low threshold location, and the implant can be operated chronically to produce effective and well-tolerated contractions of skeletal muscle.


Effects of the SGLT2 inhibitor canagliflozin on plasma biomarkers TNFR-1, TNFR-2 and KIM-1 in the CANVAS trial.
Higher plasma concentrations of tumour necrosis factor receptor (TNFR)-1, TNFR-2 and kidney injury molecule-1 (KIM-1) have been found to be associated with higher risk of kidney failure in individuals with type 2 diabetes in previous studies. Whether drugs can reduce these biomarkers is not well established. We measured these biomarkers in samples of the CANVAS study and examined the effect of the sodium-glucose cotransporter 2 inhibitor canagliflozin on these biomarkers and assessed whether the early change in these biomarkers predict cardiovascular and kidney outcomes in individuals with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS). Biomarkers were measured with immunoassays (proprietary multiplex assay performed by RenalytixAI, New York, NY, USA) at baseline and years 1, 3 and 6. Mixed-effects models for repeated measures assessed the effect of canagliflozin vs placebo on the biomarkers. Associations of baseline levels and the early change (baseline to year 1) for each biomarker with the kidney outcome were assessed using multivariable-adjusted Cox regression. In total, 3523/4330 (81.4%) of the CANVAS participants had available samples at baseline. Each doubling in baseline TNFR-1, TNFR-2 and KIM-1 was associated with a higher risk of kidney outcomes, with corresponding HRs of 3.7 (95% CI 2.3, 6.1; p < 0.01), 2.7 (95% CI 2.0, 3.6; p < 0.01) and 1.5 (95% CI 1.2, 1.8; p < 0.01), respectively. Canagliflozin reduced the level of the plasma biomarkers with differences in TNFR-1, TNFR-2 and KIM-1 between canagliflozin and placebo during follow-up of 2.8% (95% CI 3.4%, 1.3%; p < 0.01), 1.9% (95% CI 3.5%, 0.2%; p = 0.03) and 26.7% (95% CI 30.7%, 22.7%; p < 0.01), respectively. Within the canagliflozin treatment group, each 10% reduction in TNFR-1 and TNFR-2 at year 1 was associated with a lower risk of the kidney outcome (HR 0.8 [95% CI 0.7, 1.0; p = 0.02] and 0.9 [95% CI 0.9, 1.0; p < 0.01] respectively), independent of other patient characteristics. The baseline and 1 year change in biomarkers did not associate with cardiovascular or heart failure outcomes. Canagliflozin decreased KIM-1 and modestly reduced TNFR-1 and TNFR-2 compared with placebo in individuals with type 2 diabetes in CANVAS. Early decreases in TNFR-1 and TNFR-2 during canagliflozin treatment were independently associated with a lower risk of kidney disease progression, suggesting that TNFR-1 and TNFR-2 have the potential to be pharmacodynamic markers of response to canagliflozin.


[Drying effect of Chinese medicinal pills based on new spiral vibration drying technology].
The present study explored the drying effect of new spiral vibration drying technology on Chinese medicinal pills with Liuwei Dihuang Pills, Zhuanggu Guanjie Pills, and Muxiang Shunqi Pills as model drugs. With the drying uniformity, drying time, energy consumption, pill split, dissolution time, and change of index components as evaluation indicators, the drying effect of spiral vibration drying technology on model drugs was evaluated and compared with traditional drying methods, such as hot air drying and vacuum drying in the oven. The dynamic changes of moisture in Liuwei Dihuang Pills with different drying time were investigated. Compared with the traditional drying methods in the oven(hot air drying and vacuum drying) at 80 ℃, the spiral vibration drying only took 80 min, shortened by 80%, with 10%-13% energy consumed. The results showed that the moisture of Liuwei Dihuang Pills was negatively related to the drying time. By virtue of multi-layer countercurrent drying and super resonant fluidization techniques, the new spiral vibration drying technology can significantly improve the drying quality of Chinese medicinal pills, improve the drying efficiency, and enhance the manufacturing capacity of Chinese medicinal pills. This study is expected to provide references for the innovation and development of new drying technology of Chinese medicinal pills.


Detection of Blastomyces dermatitidis and Histoplasma capsulatum from culture isolates and clinical specimens by use of real-time PCR.
Blastomyces dermatitidis and Histoplasma capsulatum are dimorphic fungi that often cause self-limited respiratory infections. However, they may also cause severe disseminated disease, depending on the level of the exposure to the organism and the host immune status. In addition, patients with infections caused by these fungi may have very similar clinical presentations. Although microbiologic culture is a standard method for detecting these pathogens, their recovery may require days to weeks, and the manipulation of cultures presents a significant safety hazard to laboratory personnel. Therefore, the goal of this study was to design a rapid, real-time PCR assay to detect and differentiate B. dermatitidis and H. capsulatum from culture isolates and directly from clinical specimens. Primers and fluorescence resonance energy transfer hybridization probes were designed to target the histidine kinase and glyceraldehyde-3-phosphate dehydrogenase genes of B. dermatitidis and H. capsulatum, respectively. The analytical sensitivity of the assay was determined to be 100 copies/μl for both fungi. From culture isolates, the assay demonstrated 100% specificity and 100% sensitivity for B. dermatitidis and 100% specificity and 94% sensitivity for H. capsulatum. Detection directly from 797 clinical specimens demonstrated specificities and sensitivities of 99% and 86% for B. dermatitidis and 100% and 73% for H. capsulatum compared with the results for culture. This real-time PCR assay provides a rapid method for the detection of B. dermatitidis and H. capsulatum from culture isolates and directly from clinical specimens.


Polypoid lesion of the gallbladder: indications of carcinoma and outcome after surgery for malignant polypoid lesion.
Of 716 consecutive patients who underwent cholecystectomy, forty-four patients had preoperatively defined polypoid lesions of the gallbladder. Of these 44, 32 patients had benign polypoid lesion and the other 12 had carcinoma of the gallbladder. The aim of the present study was to evaluate the precise differentiating factors between the malignant and benign polypoid lesions and to examine the outcome of patients with polypoid carcinoma after radical surgery. The patients' sex, symptoms and the presence of gallstones were not significantly different between patients with carcinoma and those with benign polypoid lesion. However, the size (> 10 mm), number of polypoid lesion (single) and patients' age (> or = 60-yr-old) were the significant indicators of carcinoma. All but one patient with carcinoma underwent surgery and ten of twelve patients are alive at present with a mean of 6 years after surgery. The maximal size of the lesion was closely associated with the depth of invasion and carcinomas confined to the mucosal or proper muscle layer were free from lymph node metastasis. We concluded that carcinoma is highly suspected when the size of the polypoid lesion is over 10 mm, when the polypoid lesion is solitary and patient's age is over 60 years. The detection of the malignant polypoid lesion results in satisfactory outcome after surgery.


Experimental analysis of parallel excitation using dedicated coil setups and simultaneous RF transmission on multiple channels.
An experimental implementation and first performance analysis of parallel spatially selective excitation with an array of transmit coils and simultaneous transmission of individual waveforms on multiple channels is presented. This technique, also known as Transmit SENSE, uses the basic idea of parallel imaging to shorten the k-space trajectories that accompany multidimensional excitation pulses, and hence shorten the duration of such pulses. So far, this concept has only been presented in simulations and semi-experimental studies since no hardware setup had been available for a full experimental realization. In this study, a hardware solution, in combination with a dedicated coil setup, is presented to overcome this limitation, and in several experiments of localized excitation and transmit field inhomogeneity compensation the practical feasibility of Transmit SENSE is demonstrated and a first performance analysis is given.


Osteopenia in Sparc (osteonectin)-deficient mice: characterization of phenotypic determinants of femoral strength and changes in gene expression.
Sparc null mutants have been generated independently via targeted mutations in exons 4 and 6. Previous studies have identified low-turnover osteopenia in the 129Sv/C57BL/6 exon 4 knockout. Since both Sparc null mutations result in complete absence of Sparc protein, similar phenotypic outcomes are likely. However, genetic background (strain) and/or linkage disequilibrium effects can influence phenotype. Different inactivating mutations should be tested in various mouse strains; similar phenotypic outcomes can then confidently be assigned to the mutated gene. We have evaluated the bone phenotype in the 129Sv/EvSparc(tm1cam) exon 6 knockout at 4 and 9 mo, using physical measurement, mechanical strength tests, and DXA scanning. We have also quantified bone marrow adiposity and circulating leptin levels to assess adipose tissue metabolism. 129Sv/EvSparc(tm1cam) null mice show decreased bone mineral density and bone mineral content and increased mechanical fragility of bone, in line with previous studies. Differences were also noted. Increased body weight and levels of bone marrow adiposity but decreased circulating leptin concentrations were identified at 4, but not 9 mo, and 129Sv/EvSparc(tm1cam) null mice also had shorter femurs. Molecular phenotyping was carried out using mouse HGMP NIA microarrays with cortical femur samples at various ages, using semiquantitative RT-PCR validation. We identified 429 genes highly expressed in normal bone. Six genes (Sparc, Zfp162, Bysl, E2F4, two ESTs) are differentially regulated in 129Sv/EvSparc(tm1cam) cortical femur vs. 129Sv/Ev controls. We confirm low-turnover osteopenia as a feature of the Sparc null phenotype, identifying the usefulness of this mouse as a model for human osteoporosis.


Differential expression of miRNAs by macrophages infected with virulent and avirulent Mycobacterium tuberculosis.
MicroRNAs (miRNAs) are small non-coding RNAs which post-transcriptionally regulate a wide range of biological processes that include cellular differentiation, development, immunity and apoptosis. There is a growing body of evidences that bacteria modulate immune responses by altering the expression of host miRNAs. Since macrophages are immune cells associated with innate and adaptive immunity, we investigated whether Mycobacterium tuberculosis infection affects miRNAs of macrophages. THP-1 macrophages infected with virulent (H37Rv) and avirulent (H37Ra) strains of M. tuberculosis were analyzed for changes in miRNAs' expression using microarray. This revealed that nine miRNA genes (miR-30a, miR-30e, miR-155, miR-1275, miR-3665, miR-3178, miR-4484, miR-4668-5p and miR-4497) were differentially expressed between THP-1cells infected with M. tuberculosis H37Rv and M. tuberculosis H37Ra strains. Additional characterization of these genes is likely to provide insights into their role in the pathogenesis of tuberculosis.


A Retrospective Analysis of Er:YAG Laser Treatment in Solar Lentigines: Our Clinical Observations.
To investigate the efficacy of erbium-doped yttrium aluminium garnet (Er:YAG) laser in the treatment of solar lentigines. A retrospective study was conducted on patients treated with the only Er:YAG laser. In this study, 14 patients with multiple solar lentigines before treatment were included. Treatment parameters and all side effects were recorded. One independent, blinded dermatologist evaluated the clinical improvement and the patients also scored their satisfaction degree with the treatment. The mean age of the patients was 41.07±7.16 years. The number of mean treatment session for each patient was 1.79±1.05. At the final visit, excellent improvement (76-100% clearance) was reached in eight (57.1%) patients, while good improvement (51-75% clearance) was achieved in five (35.7%) patients. Ten patients (71.4%) were very satisfied and four (28.5%) patients were satisfied with the results of the treatment. No side effects occurred. Er:YAG laser treatment may be an effective and safe optional modality for solar lentigines.


Comparison of the Inhibitory Activities of 5,6-Dihydroergosterol Glycoside α- and β-Anomers on Skin Inflammation.
Chronic skin inflammatory diseases, such as atopic dermatitis, are associated with a dysfunctional skin barrier due to an increase in various inflammatory stimuli, for instance inflammatory cytokines and chemokines. In particular, CCL17 and CCL22 expression is increased in patients with chronic skin inflammation. In this study, we synthesized several α- and β-anomers of dihydroergosterol (DHE)-glycosides and assessed their effects on CCL17 and CCL22 expression. We confirmed that the β-anomers of DHE-glycosides were superior to α-anomers of DHE-glycosides in inhibiting CCL17 and CCL22 mRNA and protein expression. In addition, we determined that DHE-glycoside β-anomers showed strong inhibitory activity towards pro-inflammatory cytokine mRNA and protein expression, including that of TNF-α, IL-6, and IL-1β- in stimulated HaCaT cells. These results imply that DHE-glycoside α- and β-anomers should be separated during synthesis of drugs for chronic skin inflammation. Our results also suggest that β-anomers of DHE-glycosides may play an important role as new drugs for chronic skin inflammation because of their ability to inhibit the skin inflammatory biomarker proteins CCL17 and CCL22.


Prompting physicians for cost-effective test ordering in the low prevalence conditions of family medicine.
We have developed a computerized prompting system for test ordering which we feel will decrease the cost of investigations and at the same time promote an evidence based learning approach to test ordering. Prompting systems have been shown to be cost-effective but suffer from many disadvantages in the family practice setting. They tend to be difficult to modify by the user and contingent on an inflexible rule based structure. Many suggestions are ignored implying that they are not relevant. In family practice most conditions are of low prevalence. Prompting for test ordering where the pre-test likelihood of disease is small will result in a large number of false positives and many unnecessary repeat or confirmatory investigations and attendant anxiety unless the prompting system is specifically designed to be used in a low prevalence environment. PROMPTOR-FM (PRObabilistic Method of Prompting for Test ORdering in Family Medicine) was developed to overcome these perceived difficulties. It allows the physician to rapidly calculate the positive and negative predictive values of a test being considered based on the clinical index of suspicion. The physician is able to repeat the calculations and compare the results with previous calculations. By using PROMPTOR-FM repetitively, the clinician can learn to balance the risk of "missing" a rare but serious condition against the risk of falsely identifying disease with its downstream hazards and costs of further investigation. Prompting for test ordering is therefore uniquely tailored to each patient's situation.


[Characterization of Hg-binding metallothioneins in tissues of rat after oral intake of mercury chloride by size-exclusion chromatography coupled with inductively coupled plasma-mass spectrometry].
Hg concentrations, total metallothioneins (MTs) and metal-binding MTs in tissues of the rat after oral intake of HgCl2 were determined by the inductively coupled plasma-mass spectrometry (ICP-MS), a modifield mecurry saturarion assay and the size-exclusion chormatography (SEC) coupled with ICP-MS, respectively. The results indicated that Hg accumulation in all of the rat tissues, including kidney, liver, testicle, brain, heart, serum and blood plasma, in HgCl2 group significantly increased compared with that in the control group, especiallyin kidney,liver and testicle. A large amount of MTs was inducted in these exposed rat tissues, especially in their kidneys and livers. The metal species binding with MTs obtained with SECICP-MS showed that the fractions of Hg-MTs in both kidney and liver of exposed rat were significantly higher compared with those of the control. In addition, higher amounts of Cu-MTs observed in exposed rat liver and kidney demomstrated the effect of MTs in the homeostatis of Cu and in the detoxification of Hg.


Genome-wide differential expression profiling of long non-coding RNAs in FOXA2 knockout iPSC-derived pancreatic cells.
Our recent studies have demonstrated the crucial involvement of FOXA2 in the development of human pancreas. Reduction of FOXA2 expression during the differentiation of induced pluripotent stem cells (iPSCs) into pancreatic islets has been found to reduce α-and β-cell masses. However, the extent to which such changes are linked to alterations in the expression profile of long non-coding RNAs (lncRNAs) remains unraveled. Here, we employed our recently established FOXA2-deficient iPSCs (FOXA2-/- iPSCs) to investigate changes in lncRNA profiles and their correlation with dysregulated mRNAs during the pancreatic progenitor (PP) and pancreatic islet stages. Furthermore, we constructed co-expression networks linking significantly downregulated lncRNAs with differentially expressed pancreatic mRNAs. Our results showed that 442 lncRNAs were downregulated, and 114 lncRNAs were upregulated in PPs lacking FOXA2 compared to controls. Similarly, 177 lncRNAs were downregulated, and 59 lncRNAs were upregulated in islet cells lacking FOXA2 compared to controls. At both stages, we observed a strong correlation between lncRNAs and several crucial pancreatic genes and TFs during pancreatic differentiation. Correlation analysis revealed 12 DE-lncRNAs that strongly correlated with key downregulated pancreatic genes in both PPs and islet cell stages. Selected DE-lncRNAs were validated using RT-qPCR. Our data indicate that the observed defects in pancreatic islet development due to the FOXA2 loss is associated with significant alterations in the expression profile of lncRNAs. Therefore, our findings provide novel insights into the role of lncRNA and mRNA networks in regulating pancreatic islet development, which warrants further investigations. Video Abstract.


A database of circadian and diel rhythmic gene expression in the yellow fever mosquito Aedes aegypti.
The mosquito species Aedes aegypti is the primary vector of many arboviral diseases, including dengue and yellow fevers, that are responsible for a large worldwide health burden. The biological rhythms of mosquitoes regulate many of the physiological processes and behaviors that influence the transmission of these diseases. For insight into the molecular basis of biological rhythms, diel and circadian gene expression profiling has been carried out for many species. To bring these resources to Aedes aegypti researchers, we used microarray technology to carry out a genome wide assessment of gene expression during the 24 hour light/dark (LD) cycle and during constant darkness (DD). The purpose of this report is to describe the methods, the validation of the results, and the organization of this database resource. The Aedes aegypti Circadian Database is a publicly accessible database that can be searched via a text-based query to visualize 44 hour temporal expression patterns of a given gene in Ae. aegypti heads under diel (observed under a 12 hour/12 hour LD cycle) and circadian (observed under DD) conditions. Profiles of gene expression under these conditions were assayed by Nimblegen 12-plex microarrays and rhythmicity was objectively assessed by the JTK_CYCLE algorithm. The output of the search is a graphical representation of the expression data along with computed period length, the time-of-day of gene expression peaks, and statistical determination for rhythmicity. Our results show that at least 7.9% of the gene set present in the Aedes aegypti head are rhythmic under LD conditions and 6.7% can be considered circadian, oscillating under constant dark conditions. We present these results in the Aedes aegypti Circadian Database through Bioclock, a public website hosted by the University of Notre Dame at http://www.nd.edu/~bioclock/. This website allows searchable browsing of this quantitative gene expression information. The visualization allows for gene-by-gene comparison of transcript expression under both diel and circadian conditions, and the results are presented graphically in a plot profile of gene expression. The Ae. aegypti Circadian Database provides a community resource for observing diel and circadian fluctuations in gene expression across the Ae. aegypti genome.


Fanconi Syndrome in Irish Wolfhound Siblings.
Three juvenile male Irish wolfhound littermates presented with marked polyuria and polydipsia. The four female siblings were apparently unaffected. Diagnostic testing revealed glucosuria with normoglycemia, generalized aminoaciduria, hypokalemia and metabolic acidosis consistent with Fanconi syndrome. Renal ultrasonographic and histologic findings are presented. Cases were managed with a supplementation regimen based on a treatment protocol for Fanconi syndrome in basenjis. These dogs did not have angular limb deformities as documented previously in juvenile canine siblings with Fanconi syndrome. Fanconi syndrome has not been previously described in Irish wolfhound siblings.


[Treatment of Urinary incontinence by Teflon injection (author's transl)].
A report is made on the treatment of urinary incontinence by endourethral Teflon injections applied to 43 cases of male and female patients over a period of 18 months. The advantage of the urethral pressure profile for diagnosing urinary incontinence is emphasized. With reference to sclerotherapy, suitable instrumentation for the endourethral and perineal injection of Teflon is described. Due to our experience, urinary incontinence as a frequent and socially severe complication following operations in the bladder neck area, can be cured to a high percentage by the injection of Teflon. The method used is safe, well tolerated, technically easy to handle, inconsumptive, and can be reapplied without any risk.


Structure of asymmetric non-precipitating antibody: presence of a carbohydrate residue in only one Fab region of the molecule.
The reactions between purified precipitating and non-precipitating anti-DNP sheep and rabbit antibodies and the antigens DNP-BSA and DNP-GABA-BSA have been studied by immunodiffusion, complement fixation and an inhibition test. Both antigens reacted identically with precipitating antibodies. On the contrary, non-precipitating antibodies did not precipitate and did not fix complement with DNP-BSA but were able to do so with DNP-GABA-BSA. A different behaviour with both antigens was also demonstrated by an inhibition test. The properties of these antibodies were also studied after treatment with endo-beta-N-acetylglucosaminidase H. Non-precipitating antibody was able to give precipitin bands in gel diffusion and to fix complement with DNP-BSA after treatment with the enzyme. The treated antibody was able to agglutinate sensitized erythrocytes. Studies by fluorescence quenching showed that the affinity for the ligand DNP-GABA was significantly increased after hydrolysis of the carbohydrate residue. The properties of precipitating antibody were not modified by the endoglycosidase. Affinity chromatography of the F(ab')2 and Fab fragments obtained from precipitating and non-precipitating antibodies was made with Con A-Sepharose. The Con A retained all the F(ab')2 and 50% of the Fab from non-precipitating antibody, which were subsequently eluted with alpha-methyl-D-mannoside. The fragments from precipitating antibody were not retained at all. It is concluded that the asymmetry of the non-precipitating antibody molecule is due to a carbohydrate moiety which is present in only one of the Fab regions. This carbohydrate affects the reaction between the combining site and the antigen, and renders the molecule functionally univalent.


[Neonatal resuscitation].
At birth approximately 10 % of term or near-term neonates require initial stabilization maneuvers to establish a cry or regular breathing, maintain a heart rate greater than 100 beats per minute (bpm), and good color and muscular tone. About 1 % requires ventilation and very few infants receive chest compressions or medication. However, birth asphyxia is a worldwide problem and can lead to death or serious sequelae. Recently, the European Resuscitation Council (ERC) and the International Liaison Committee on Resuscitation (ILCOR) published new guidelines on resuscitation at birth. These guidelines review specific questions such as the use of air or 100 % oxygen in the delivery room, dose and routes of adrenaline delivery, the peripartum management of meconium-stained amniotic fluid, and temperature control. Assisted ventilation in preterm infants is briefly described. New devices to improve the care of newborn infants, such as the laryngeal mask airway or CO2 detectors to confirm tracheal tube placement, are also discussed. Significant changes have occurred in some practices and are included in this document.


SPRAWL IN THE 1990S Measurement, Distribution, and Trends.
Although sprawl is a growing national debate, there have been few efforts to measure or monitor changes in degree of sprawl over time. By using a methodology that employs census data, this sprawl index allows computation of levels of sprawl and examination of temporal and geographic changes. The results show that sprawl has increased over the past decade in many metropolitan areas. There are important geographic variations in sprawl, implying that it is neither inevitable nor universal.


How Can Synergism of Traditional Medicines Benefit from Network Pharmacology?
Many prescriptions of traditional medicines (TMs), whose efficacy has been tested in clinical practice, have great therapeutic value and represent an excellent resource for drug discovery. Research into single compounds of TMs, such as artemisinin from Artemisia annua L., has achieved great success; however, it has become evident that a TM prescription (which frequently contains various herbs or other components) has a synergistic effect in effecting a cure or reducing toxicity. Network pharmacology targets biological networks and analyzes the links among drugs, targets, and diseases in those networks. Comprehensive, systematic research into network pharmacology is consistent with the perspective of holisticity, which is a main characteristic of many TMs. By means of network pharmacology, research has demonstrated that many a TM show a synergistic effect by acting at different levels on multiple targets and pathways. This approach effectively bridges the gap between modern medicine and TM, and it greatly facilitates studies into the synergistic actions of TMs. There are different kinds of synergistic effects with TMs, such as synergy among herbs, effective parts, and pure compounds; however, for various reasons, new drug discovery should at present focus on synergy among pure compounds.


Associations of smoking, body mass index, dietary lutein, and the LIPC gene variant rs10468017 with advanced age-related macular degeneration.
A novel locus in the hepatic lipase (LIPC) gene was found to be significantly related to advanced age-related macular degeneration (AMD) in our genome-wide association study. We evaluated its association and interaction with previously identified genetic variants and modifiable factors. Participants in the Age-Related Eye Disease Study with advanced AMD (n=545 cases) or no AMD (n=275 controls) were evaluated. AMD status was determined using fundus photography. Covariates included cigarette smoking, body mass index (BMI), and dietary lutein. Individuals were genotyped for the rs10468017 polymorphism in LIPC as well as seven previously identified AMD genetic loci. Unconditional logistic regression analyses were then performed. The TT genotype of the LIPC variant was associated with a reduced risk of AMD, with odds ratios (OR) of 0.50 (95% confidence interval (CI) 0.20-0.90) and p=0.014 for the TT genotype versus the CC genotype, controlling for age, gender, smoking, body mass index (BMI), and nutritional factors. Controlling for seven other AMD genetic variants, the OR was 0.50, 95% (CI 0.20-1.1, p=0.077). The magnitude of the effect was similar for both atrophic and neovascular forms of AMD. Cigarette smoking and higher BMI increased the risk, while higher dietary lutein reduced the risk of advanced AMD, adjusting for genetic variants. There were no significant interactions between LIPC and smoking, BMI, or lutein. There was a possible association between LIPC and complement factor H (CFH) rs1410996, and a possible interaction effect between LIPC and both CFH rs10033900 and the complement factor I (CFI) variants in terms of risk of AMD. LIPC is associated with reduced risk of advanced AMD, independent of demographic and environmental variables. Both genetic susceptibility and behavioral and lifestyle factors modify the risk of developing AMD.


Liposomal clodronate combined with Cisplatin or Sorafenib inhibits hepatocellular carcinoma cell proliferation, migration and invasion by suppressing FOXQ1 expression.
The purpose of this study was to investigate the effect of liposomal clodronate combined with Cisplatin or Sorafenib on the FOXQ1 expression and biological function of hepatocellular carcinoma cell lines. The expression of FOXQ1 was determined in normal hepatic cell line and hepatocellular carcinoma cell lines using quantitative real-time polymerase chain reaction (qRT-PCR). HepG2 and MHCC97H cells were administered low, medium and high concentrations of cisplatin (3, 5 and 7 μg/ml) or Sorafenib (2, 7 and 20 μg/ml) in combination with liposomal clodronate (LC, 20μg/ml), and the expression of FOXQ1 in each group was determined. Cell migration, MTT and transwell assays were used to determine the effects of the treatments on biological functions of HepG2 and MHCC97H cells. qRT-PCR showed that the expression of FOXQ1 mRNA was higher in the four hepatocellular carcinoma cell lines than in normal cells, and the expression of FOXQ1 mRNA in HepG2 and MHCC97H cells were more dominant. All the tested doses of Cisplatin, but only high dose Sorafenib down-regulated the expression of FOXQ1. However, Sorafenib at low and medium concentrations had no significant effect on the expression of FOXQ1. When Cisplatin or Sorafenib was administered in combination with LC, the expression level of FOXQ1 was significantly reduced. Cell migration, MTT and transwell assays showed that proliferation, migration and invasion were inhibited when each drug was administered alone, but was stronger when the drugs were combined with liposomal clodronate.Liposomal clodronate combined with Cisplatin or Sorafenib down-regulates the expression of FOXQ1 in HepG2 and MHCC97H hepatoma cells, and inhibits their proliferation, migration and invasion.


Genuine localization transition in a long-range hopping model.
We introduce and study a banded random matrix model describing sparse, long-range quantum hopping in one dimension. Using a series of analytic arguments, numerical simulations, and a mapping to a long-range epidemics model, we establish the phase diagram of the model. A genuine localization transition, with well defined mobility edges, appears as the hopping rate decreases slower than ℓ^{-2}, where ℓ is the distance. Correspondingly, the decay of the localized states evolves from a standard exponential shape to a stretched exponential and finally to a exp(-Cln^{κ}ℓ) behavior, with κ>1.


Detecting and Tracking of Multiple Mice Using Part Proposal Networks.
The study of mouse social behaviors has been increasingly undertaken in neuroscience research. However, automated quantification of mouse behaviors from the videos of interacting mice is still a challenging problem, where object tracking plays a key role in locating mice in their living spaces. Artificial markers are often applied for multiple mice tracking, which are intrusive and consequently interfere with the movements of mice in a dynamic environment. In this article, we propose a novel method to continuously track several mice and individual parts without requiring any specific tagging. First, we propose an efficient and robust deep-learning-based mouse part detection scheme to generate part candidates. Subsequently, we propose a novel Bayesian-inference integer linear programming (BILP) model that jointly assigns the part candidates to individual targets with necessary geometric constraints while establishing pair-wise association between the detected parts. There is no publicly available dataset in the research community that provides a quantitative test bed for part detection and tracking of multiple mice, and we here introduce a new challenging Multi-Mice PartsTrack dataset that is made of complex behaviors. Finally, we evaluate our proposed approach against several baselines on our new datasets, where the results show that our method outperforms the other state-of-the-art approaches in terms of accuracy. We also demonstrate the generalization ability of the proposed approach on tracking zebra and locust.


Linking the behavioral assessment screening tool to the international classification of functioning, disability, and health as a novel indicator of content validity.
Purpose: To use the International Classification of Functioning, Disability, and Health (ICF) to classify and describe the concepts of the Behavioral Assessment Screening Tool (BAST), a measure of behavioral disruptions after traumatic brain injury (TBI).Methods: Meaningful concepts in the BAST were linked to the International Classification of Functioning to (1) further explore the validity of the conceptual model of behavior; (2) demonstrate ICF linking as a novel indicator of the content validity; (3) identify International Classification of Functioning concepts that characterize behavior; (4) determine the comprehensiveness of the BAST.Results: The body functions component and the activities and participation component were most frequently addressed in the BAST. The majority of the TBI Core Set categories were included in the BAST and the manifest and latent coders agreed 85% of the time.Conclusions: Linking BAST concepts to the International Classification of Functioning demonstrated the BAST's content validity and comprehensiveness. This approach provides a model for how ICF coding could be used to assess content validity.Implications for RehabilitationICF coding can be used to assess content validity and refine rehabilitation measures.The Behavioral Assessment Screening Tool can be used for clinical and research purposes to assess behavior as it relates to a wide range of ICF TBI Core Set categories.


William L. McGuire Memorial Lecture. Antiestrogens: mechanisms of action and resistance in breast cancer.
Antiestrogens have proven to be highly effective in the treatment of hormone-responsive breast cancer. However, resistance to antiestrogen therapy often develops. In addition, although tamoxifen-like antiestrogens are largely inhibitory and function as estrogen antagonists in breast cancer cells, they also have some estrogen-like activity in other cells of the body. Thus, recent efforts are being directed toward the development of even more tissue-selective antiestrogens, i.e. compounds that are antiestrogenic on breast and uterus while maintaining the beneficial estrogen-like actions on bone and the cardiovascular system. Efforts are also being directed toward understanding ligand structure-estrogen receptor (ER) activity relationships and characterizing the molecular changes that underlie alterations in parallel signal transduction pathways that impact on the ER. Recent findings show that antiestrogens, which are known to exert most of their effects through the ER of breast cancer cells, contact a different set of amino acids in the hormone binding domain of the ER than those contacted by estrogen, and evoke a different receptor conformation that results in reduced or no transcriptional activity on most genes. Resistance to antiestrogen therapy may develop due to changes at the level of the ER itself, and at pre- and post-receptor points in the estrogen receptor-response pathway. Resistance could arise in at least four ways: (1) ER loss or mutation; (2) Post-receptor alterations including changes in cAMP and phosphorylation pathways, or changes in coregulator and transcription factor interactions that affect the transcriptional activity of the ER; (3) Changes in growth factor production/sensitivity or paracrine cell-cell interactions; or (4) Pharmacological changes in the antiestrogen itself, including altered uptake and retention or metabolism of the antiestrogen. Model cell systems have been developed to study changes that accompany and define the antiestrogen resistant versus sensitive breast cancer phenotype. This information should lead to the development of antiestrogens with optimized tissue selectivity and agents to which resistance may develop more slowly. In addition, antiestrogens which work through somewhat different mechanisms of interaction with the ER should prove useful in treatment of some breast cancers that become resistant to a different category of antiestrogens.


Cerebral Autoregulation Indices Are Not Interchangeable in Patients With Sepsis.
Dynamic cerebral autoregulation (dCA) is frequently altered in patients with sepsis and may be associated with sepsis-associated brain dysfunction. However, the optimal index to quantify dCA in patients with sepsis is currently unknown. To assess the agreement between two validated dCA indices in patients with sepsis. Retrospective analysis of prospectively collected data in patients with sepsis; those with acute or chronic intracranial disease, arrhythmias, mechanical cardiac support, or history of supra-aortic vascular disease were excluded. Transcranial Doppler was performed on the right or left middle cerebral artery (MCA) with a 2-MHz probe, and MCA blood flow velocity (FV) and arterial pressure (BP) signals were simultaneously recorded. We calculated two indices of dCA: the mean flow index (Mxa), which is the Pearson correlation coefficient between BP and FV (MATLAB, MathWorks), and the autoregulation index (ARI), which is the transfer function analysis of spontaneous fluctuations in BP and FV (custom-written FORTRAN code). Impaired dCA was defined as Mxa >0.3 or ARI ≤ 4. The agreement between the two indices was assessed by Cohen's kappa coefficient. We included 95 patients (age 64 ± 13 years old; male 74%); ARI was 4.38 [2.83-6.04] and Mxa was 0.32 [0.14-0.59], respectively. There was no correlation between ARI and Mxa (r = -0.08; p = 0.39). dCA was altered in 40 (42%) patients according to ARI and in 50 (53%) patients according to Mxa. ARI and Mxa were concordant in classifying 23 (24%) patients as having impaired dCA and 28 (29%) patients as having intact dCA. Cohen's kappa coefficient was 0.08, suggesting poor agreement. ARI was altered more frequently in patients on mechanical ventilation than others (27/52, 52% vs. 13/43, 30%, p = 0.04), whereas Mxa did not differ between those two groups. On the contrary, Mxa was altered more frequently in patients receiving sedatives than others (23/34, 68% vs. 27/61, 44%, p = 0.03), whereas ARI did not differ between these two groups. Agreement between ARI and Mxa in assessing dCA in patients with sepsis was poor. The identification of specific factors influencing the dCA analysis might lead to a better selection of the adequate cerebral autoregulation (CAR) index in critically ill patients with sepsis.


Spatiotemporal organization of alpha-motoneuron activity in the human spinal cord during different gaits and gait transitions.
Here we studied the spatiotemporal organization of motoneuron (MN) activity during different human gaits. We recorded the electromyographic (EMG) activity patterns in 32 ipsilateral limb and trunk muscles from normal subjects while running and walking on a treadmill (3-12 km/h). In addition, we recorded backward walking and skipping, a distinct human gait that comprises the features of both walking and running. We mapped the recorded EMG activity patterns onto the spinal cord in approximate rostrocaudal locations of the MN pools. The activation of MNs tends to occur in bursts and be segregated by spinal segment in a gait-specific manner. In particular, sacral and cervical activation timings were clearly gait-dependent. Swing-related activity constituted an appreciable fraction (> 30%) of the total MN activity of leg muscles. Locomoting at non-preferred speeds (running and walking at 5 and 9 km/h, respectively) showed clear differences relative to preferred speeds. Running at low speeds was characterized by wider sacral activation. Walking at high non-preferred speeds was accompanied by an 'atypical' locus of activation in the upper lumbar spinal cord during late stance and by a drastically increased activation of lumbosacral segments. The latter findings suggest that the optimal speed of gait transitions may be related to an optimal intensity of the total MN activity, in addition to other factors previously described. The results overall support the idea of flexibility and adaptability of spatiotemporal activity in the spinal circuitry with constraints on the temporal functional connectivity of hypothetical pulsatile burst generators.


The origin recognition complex links replication, sister chromatid cohesion and transcriptional silencing in Saccharomyces cerevisiae.
Mutations in genes encoding the origin recognition complex (ORC) of Saccharomyces cerevisiae affect initiation of DNA replication and transcriptional repression at the silent mating-type loci. To explore the function of ORC in more detail, a screen for genetic interactions was undertaken using large-scale synthetic lethal analysis. Combination of orc2-1 and orc5-1 alleles with the complete set of haploid deletion mutants revealed synthetic lethal/sick phenotypes with genes involved in DNA replication, chromatin structure, checkpoints, DNA repair and recombination, and other genes that were unexpected on the basis of previous studies of ORC. Many of these genetic interactions are shared with other genes that are involved in initiation of DNA replication. Strong synthetic interactions were demonstrated with null mutations in genes that contribute to sister chromatid cohesion. A genetic interaction between orc5-1 and the cohesin mutant scc1-73 suggested that ORC function contributes to sister chromatid cohesion. Thus, comprehensive screening for genetic interactions with a replication gene revealed a connection between initiation of DNA replication and sister chromatid cohesion. Further experiments linked sister chromatid cohesion genes to silencing at mating-type loci and telomeres.


Retrobiosynthetic analysis of carbon fixation in the phototrophic eubacterium Chloroflexus aurantiacus.
The phototrophic bacterium Chloroflexus aurantiacus does not use any of the known autotrophic CO2 fixation pathways. There is evidence for a new cyclic autotrophic pathway in which acetyl-CoA is converted to 3-hydroxypropionate and further to succinate and malate. This hypothesis was tested by feeding growing cultures during several generations with 3-hydroxy[1-13C]propionate, [1-13C]acetate, or [2-13C]acetate, in addition to unlabeled CO2. The relative 13C content of individual carbon atoms in biosynthetic amino acids and nucleosides was determined by 1H- and 13C-NMR spectroscopy. 13C coupling patterns were analyzed by two-dimensional 13C-TOCSY experiments which were optimized for the analysis of multiply 13C-labeled biosynthetic samples. From the 13C enrichments of amino acids and nucleosides, the labeling patterns of central metabolic intermediates were evaluated by a retrobiosynthetic approach. Both 3-hydroxypropionate and acetate were incorporated into all central metabolic pools. The 13C labeling and coupling patterns suggest a novel carbon fixation pathway via 3-hydroxypropionate. Specifically, we propose that acetyl-CoA is carboxylated to malonyl-CoA which is reduced under formation of 3-hydroxypropionyl-CoA. Dehydration and reduction yield propionyl-CoA which is converted to succinate by a second carboxylation reaction. The net product of autotrophic carbon fixation appears to be glyoxylate. However, it is not yet known how glyoxylate is channeled into anabolic metabolism. Assimilation of acetate can proceed via the CO2 fixation pathway, but also via the glyoxylate pathway.


Predictors of microvascular invasion in patients with hepatocellular carcinoma who are candidates for orthotopic liver transplantation.
Microvascular invasion affects survival after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). We sought to identify preoperative predictors of microvascular invasion in patients with HCC who were candidates for OLT. A cohort of 245 patients who underwent resection for HCC and fulfilled the criteria for OLT (i.e., single tumors < or =5 cm or no more than three tumors < or =3 cm) were identified from a multi-institutional database. Thirty-three percent of the patients had pathologic evidence of microvascular invasion. Thirty percent of patients with single tumors and 47% with multiple tumors had microvascular invasion (P = 0.04). Only 25% of patients with tumors smaller than < or =2 cm had microvascular invasion, compared to 31% and 50% with tumors greater than 2 to 4 cm or larger than 4 cm, respectively (P = 0.01). Tumor grade was highly correlated with microvascular invasion: 12% of patients with well-differentiated tumors had microvascular invasion, compared to 29% and 50% with moderately or poorly differentiated tumors, respectively (P < 0.001). The independent predictors of microvascular invasion were tumor size greater than 4 cm (odds ratio [OR], 3.0, 95% confidence interval [CI ], 1.2 to 7.1), and high tumor grade (OR, 6.3; 95% CI, 2.0 to 19.9). Tumor size and grade are strong predictors of microvascular invasion. A tumor biopsy with pathologic grading at the time of pretransplantation ablative therapy could improve selection of patients with HCC for OLT.


Effect of various loads on the force-time characteristics of the hang high pull.
The purpose of this study was to investigate the effect of various loads on the force-time characteristics associated with peak power during the hang high pull (HHP). Fourteen athletic men (age: 21.6 ± 1.3 years; height: 179.3 ± 5.6 cm; body mass: 81.5 ± 8.7 kg; 1 repetition maximum [1RM] hang power clean [HPC]: 104.9 ± 15.1 kg) performed sets of the HHP at 30, 45, 65, and 80% of their 1RM HPC. Peak force, peak velocity, peak power, force at peak power, and velocity at peak power were compared between loads. Statistical differences in peak force (p = 0.001), peak velocity (p < 0.001), peak power (p = 0.015), force at peak power (p < 0.001), and velocity at peak power (p < 0.001) existed, with the greatest values for each variable occurring at 80, 30, 45, 80, and 30% 1RM HPC, respectively. Effect sizes between loads indicated that larger differences in velocity at peak power existed as compared with those displayed by force at peak power. It seems that differences in velocity may contribute to a greater extent to differences in peak power production as compared with force during the HHP. Further investigation of both force and velocity at peak power during weightlifting variations is necessary to provide insight on the contributing factors of power production. Specific load ranges should be prescribed to optimally train the variables associated with power development during the HHP.


The essential tremor syndromes.
Essential tremor has not been defined or used consistently in clinical diagnosis and research. Other monosymptomatic disorders are often referred to as essential tremor variants. There is now solid evidence that essential tremor, however defined, is a syndrome with multiple causes. A new tremor classification scheme is being developed by the International Parkinson and Movement Disorder Society Task Force on Tremor. In this scheme, tremor in the absence of other neurological signs is called isolated tremor, and tremor in combination with other signs is called combined tremor. Many isolated and combined tremor syndromes can be defined on the basis of commonly recurring or unique clinical symptoms and signs, including historical features (age at onset, family history, and temporal evolution) and tremor characteristics (body distribution, activation condition, associated features). Essential tremor, however defined, is simply a syndrome and not a specific disease. Essential tremor should be defined and used consistently, or this term should be abandoned. As essential tremor is an arbitrarily defined syndrome, it makes no sense to refer to other tremors as variants of essential tremor or essential tremor syndromes.


Statistical Analysis of Organ Morphometric Parameters and Weights in South Iranian Adult Autopsies.
Organ weight is one important indicator to discern normal from abnormal condition in forensic pathology as well as in clinical medicine. The present study aimed to investigate morphometric parameters and organ weights of southern Iranian adults, which can be fundamental sources to be compared to abnormal cases.Morphometric parameters and weights of 6 organs (heart, liver, kidney, spleen, appendix, and brain), which were harvested from 501 southern Iranian adults (385 males and 116 females) during ordinary postmortem examination, were measured.All the organs were heavier in males than in females. Heart, brain, spleen, and right kidney were significantly heavier in males compared to females, but no significant difference was observed between the 2 sexes regarding the weights of the rest of the organs. Moreover, brain and heart became heavier as one got older and most organs were heavier in middle-aged individuals compared to other age groups. Furthermore, various types of correlations were observed between different organs' weights and body parameters.These results can be useful anatomical data for autopsy investigations, clinical practices, and research in southern Iran.


Diphenyl diselenide reduces inflammation in the mouse model of pleurisy induced by carrageenan: reduction of pro-inflammatory markers and reactive species levels.
We reported the anti-inflammatory action of diphenyl diselenide [(PhSe)(2)] in an acute inflammation model induced by carrageenan. Male adult Swiss mice. Mice were treated with (PhSe)(2) (50 mg/kg) or vehicle (10 ml/kg) per oral route. After 30 min, animals received saline (0.1 ml) or saline containing 1 % carrageenan (0.1 ml) into the pleural cavity. Total and differential leukocyte counts, myeloperoxidase (MPO) activity, pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and interferon (INF)-γ] and reactive species (RS) were determined in pleural fluids. Pleural exudate accumulation was determined by Evans blue assay. Statistical analysis was performed by using a two-way ANOVA followed by the Duncan's test. (PhSe)(2) treatment was effective against the increase in total and differential leukocyte counts, MPO activity, RS levels and pleural exudate caused by carrageenan. (PhSe)(2) partially protected against the increase in TNF-α, IL-1β, IL-6 and INF-γ levels induced by carrageenan. (PhSe)(2) had a similar anti-inflammatory profile to that of dexamethasone. The anti-inflammatory property of (PhSe)(2) was demonstrated in the mouse model of pleurisy induced by carrageenan. The antioxidant property of (PhSe)(2) is related, at least in part, to the anti-inflammatory action of this compound.


[The effect of esmolol on corrected-QT interval, corrected-QT interval dispersion changes seen during anesthesia induction in hypertensive patients taking an angiotensin-converting enzyme inhibitor].
The importance of minimizing the exaggerated sympatho-adrenergic responses and QT interval and QT interval dispersion changes that may develop due to laryngoscopy and tracheal intubation during anesthesia induction in the hypertensive patients is clear. Esmolol decreases the hemodynamic response to laryngoscopy and intubation. However, the effect of esmolol in decreasing the prolonged QT interval and QT interval dispersion as induced by laryngoscopy and intubation is controversial. We investigated the effect of esmolol on the hemodynamic, and corrected-QT interval and corrected-QT interval dispersion changes seen during anesthesia induction in hypertensive patients using angiotensin converting enzyme inhibitors. 60 ASA I-II patients, with essential hypertension using angiotensin converting enzyme inhibitors were included in the study. The esmolol group received esmolol at a bolus dose of 500mcg/kg followed by a 100mcg/kg/min infusion which continued until the 4th min after intubation. The control group received 0.9% saline similar to the esmolol group. The mean blood pressure, heart rate values and the electrocardiogram records were obtained as baseline values before the anesthesia, 5min after esmolol and saline administration, 3min after the induction and 30s, 2min and 4min after intubation. The corrected-QT interval was shorter in the esmolol group (p=0.012), the corrected-QT interval dispersion interval was longer in the control group (p=0.034) and the mean heart rate was higher in the control group (p=0.022) 30s after intubation. The risk of arrhythmia frequency was higher in the control group in the 4-min period following intubation (p=0.038). Endotracheal intubation was found to prolong corrected-QT interval and corrected-QT interval dispersion, and increase the heart rate during anesthesia induction with propofol in hypertensive patients using angiotensin converting enzyme inhibitors. These effects were prevented with esmolol (500mcg/kg bolus, followed by 100mcg/kg/min infusion). During induction, the blood pressure tends to decrease with esmolol where care is needed.


Production of an inducible sucrase activity by Serpulina hyodysenteriae.
Strains of Serpulina hyodysenteriae and Serpulina innocens produced a cell-associated sucrase activity when grown in a medium containing sucrose. S. hyodysenteriae B204 sucrase activity cleaved sucrose and, to a lesser extent, raffinose and had a pH optimum of 5.7 to 6.2. This is the first report of an inducible enzyme produced by either S. hyodysenteriae or S. innocens.


Inflammation-induced phenoconversion of polymorphic drug metabolizing enzymes: hypothesis with implications for personalized medicine.
Phenoconversion transiently converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, potentially with corresponding changes in clinical response. This phenomenon, typically resulting from coadministration of medications that inhibit certain drug metabolizing enzymes (DMEs), is especially well documented for enzymes of the cytochrome P450 family. Nonclinical evidence gathered over the last two decades also strongly implicates elevated levels of some proinflammatory cytokines, released during inflammation, in down-regulation of drug metabolism, especially by certain DMEs of the P450 family, thereby potentially causing transient phenoconversion. Clinically, phenoconversion of NAT2, CYP2C19, and CYP2D6 has been documented in inflammatory conditions associated with elevated cytokines, such as human immunodeficiency virus infection, cancer, and liver disease. The potential of other inflammatory conditions to cause phenoconversion has not been studied but experimental and anecdotal clinical evidence supports infection-induced down-regulation of CYP1A2, CYP3A4, and CYP2C9 as well. Collectively, the evidence supports a hypothesis that certain inflammatory conditions associated with elevated proinflammatory cytokines may cause phenoconversion of certain DMEs. Since inflammatory conditions associated with elevated levels of proinflammatory cytokines are highly prevalent, phenoconversion of genotypic EM patients into transient phenotypic PMs may be more frequent than appreciated. Since drug pharmacokinetics, and therefore the clinical response, is influenced by DME phenotype rather than genotype per se, phenoconversion (whatever its cause) can have a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies. There is a risk that focusing on genotype alone may miss important associations between clinical outcomes and DME phenotypes, thus compromising future prospects of personalized medicine.


Anaplastic carcinoma occurring in association with a mucinous cystic neoplasm of the pancreas.
Anaplastic carcinomas of the pancreas are considered variants of ductal adenocarcinoma. They typically occur in elderly men. They have rarely been reported to occur in association with mucinous cystic neoplasms of the pancreas. We report a case of anaplastic carcinoma occurring in association with a pancreatic mucinous cystic neoplasm, borderline-type, in a 25-year-old woman who presented with lymph node and hepatic metastases.


The colour degradation of anthocyanin-rich extract from butterfly pea (Clitoria ternatea L.) petal in various solvents at pH 7.
A spectroscopic study was conducted to evaluate the colour degradation mechanism of anthocyanin-rich extract from butterfly pea petal. The extract was diluted in four different solvent systems, which were buffer solution pH 7 (AQ7) and the mixture of organic solvent with buffer solution pH 7 (4:1 v/v). The organic cosolvent involved were methanol (ME7), ethanol (ET7) and acetone (AC7). The samples were stored in containers with 0% and 50% headspace, and their colour intensity, total anthocyanin and hypsochromic shift were evaluated periodically. The rank of colour and anthocyanin degradation from the biggest was AQ7 > ME7 > ET7 > AC7. The longest hypsochromic shift was AQ7 > ME7 > ET7, while in AC7 the shift was absent. There was evidence that the volume of package headspace provoked colour stability. The colour degradation in AC7 was proposed to occur through hydrophobic interaction unfolding, and in AQ7 was through the deacylation, while in ME7 and ET7 was due to both mechanisms.


Urinary N-acetyl-beta-D-glucosaminidase and malondialdehyde as a markers of renal damage in burned patients.
This study was aimed to evaluate renal dysfunction during three weeks after the burn injuries in 12 patients admitted to the Hallym University Hankang Medical Center with flame burn injuries (total body surface area, 20-40%). Parameters assessed included 24-hr urine volume, blood urea nitrogen, serum creatinine, creatinine clearance, total urinary protein, urinary microalbumin, 24-hr urinary N-acetyl-beta-D-glucosaminidase (NAG) activity, and urinary malondialdehyde (MDA). Statistical analysis was performed using repeated measures ANOVA test. The 24-hr urine volume, creatinine clearance, and urinary protein significantly increased on day 3 post-burn and fell thereafter. The urine microalbumin excretion showed two peak levels on day 0 post-burn and day 3. The 24-hr urinary NAG activity significantly increased to its maximal level on day 7 post-burn and gradually fell thereafter. The urinary MDA progressively increased during 3 weeks after the burn injury. Despite recovery of general renal function through an intensive care of burn injury, renal tubular damage and lipid peroxidation of the renal tissue suggested to persist during three weeks after the burn. Therefore, a close monitoring and intensive management of renal dysfunction is necessary to prevent burn-induced acute renal failure as well as to lower mortality in patients with major burns.


Pretreatment with Group II Metabotropic Glutamate Receptor Agonist LY379268 Protects Neonatal Rat Brains from Oxidative Stress in an Experimental Model of Birth Asphyxia.
Hypoxia-ischemia (H-I) at the time of birth may cause neonatal death or lead to persistent brain damage. The search for an effective treatment of asphyxiated infants has not resulted in an effective therapy, and hypothermia remains the only available therapeutic strategy. Among possible experimental therapies, the induction of ischemic tolerance is promising. Recent investigations have shown that activation of group II metabotropic glutamate receptors (mGluR2/3) can provide neuroprotection against H-I, but the mechanism of this effect is not clear. The aim of this study was to investigate whether an mGluR2/3 agonist applied before H-I reduces brain damage in an experimental model of birth asphyxia and whether a decrease in oxidative stress plays a role in neuroprotection. Neonatal H-I on seven-day-old rats was used as an experimental model of birth asphyxia. Rats were injected intraperitoneally with the mGluR2/3 agonist LY379268 24 or 1 h before H-I (5 mg/kg). LY379268 reduced the infarct area in the ischemic hemisphere. Application of the agonist at both times also reduced the elevated levels of reactive oxygen species (ROS) in the ipsilateral hemisphere observed after H-I and prevented the increase in antioxidant enzyme activity in the injured hemisphere. The decrease in glutathione (GSH) level was also restored after agonist application. The results suggest that the neuroprotective mechanisms triggered by the activation of mGluR2/3 before H-I act through the decrease of glutamate release and its extracellular concentration resulting in the inhibition of ROS production and reduction of oxidative stress. This, rather than induction of ischemic tolerance, is probably the main mechanism involved in the observed neuroprotection.


Dual-Path Residual "Shrinkage" Network for Side-Scan Sonar Image Classification.
The underwater environment is complicated and changeable and contains many noises, making it difficult to detect a particular object in the underwater environment. At present, the main seabed detection technology explores the seabed environment with sonar equipment. However, the characteristics of underwater sonar imaging (e.g., low contrast, blurred edges, poor texture, and unsatisfactory quality) have serious negative influences on such image classification. Therefore, in this study, we propose a dual-path deep residual "shrinkage" network (DP-DRSN) module, which is a simple and effective neural network attention module that can classify side-scan sonar images. Specifically, the module can extract background and feature texture information of the input feature mapping through different scales (e.g., global average pooling and global max pooling), whereas scale information passes through a two-layer 1 × 1 convolution to increase nonlinearity. This helps realize cross-channel information interaction and information integration simultaneously before outputting threshold parameters in a sigmoid layer. The parameters are then multiplied by the average value of the input feature mapping to obtain a threshold, which is used to denoise the image features using the soft threshold function. The proposed DP-DRSN study provided higher classification accuracy and efficiency than other models. In this way, the feasibility and effectiveness of DP-DRSN in image classification of side-scan sonar are proven.


Effects of naloxone on prolactin-secreting pituitary adenomas.
The investigators assessed the effects of the opioid antagonist naloxone on anterior pituitary hormone release in hyperprolactinemic females with pituitary microadenoma (n = 6) and macroadenoma (n = 7). In those with microadenoma, intravenous bolus injection of naloxone significantly increased serum luteinizing hormone (LH) concentrations but had no significant effect on serum prolactin (PRL), follicle-stimulating hormone, and thyroid-stimulating hormone concentrations. In patients with macroadenoma, naloxone significantly decreased serum LH and serum PRL concentrations. The response of LH to naloxone differed considerably between the two groups of patients. The results suggest that LH and PRL secretion is influenced by changes in endogenous opiates and in gonadotropin-releasing hormone and PRL inhibitory factor due to hypothalamic dysfunction.


Wavefront sensing and the dynamics of tear film.
To summarize our previous studies regarding the influence of tear-film dynamics on optical quality after blinking. Sequential higher-order aberration (HOA) measurements were performed by using a wavefront sensor. During the measurements, subjects were asked to blink every 10 seconds. The obtained aberration data were analyzed in the central 4-mm diameter for coma-like, spherical-like, and total HOAs up to the sixth-order Zernike polynomials. Serial measurements of HOAs in healthy eyes showed variations even in clinically normal subjects and were classified into 4 groups by pattern: stable, small-fluctuation, sawtooth, and others. The sequential postblink change in HOAs after punctal plug insertion was quantitatively evaluated in a patient with dry eye who complained of paradoxical visual impairment with epiphora despite improvement of dry eye. Wavefront sensing is a useful objective method to evaluate sequential changes of visual performance related to tear-film dynamics. Serial measurement of HOAs might show a relationship between tear dynamics and quality of vision clinically.


Bromocriptine holiday: effects on dopamine receptors and turning behavior in rats.
In experimental Parkinson's disease, we studied the effects of chronic administration (30 days), withdrawal, and reinstitution of bromocriptine. Dopamine (DA) receptor supersensitivity was produced by 6-hydroxydopamine and reversed by chronic bromocriptine administration. Drug holiday reestablished sensitivity of DA receptors, but reinstitution of bromocriptine again downregulated receptors. The effects of a drug holiday on DA receptors are short-lived, and long-term clinical improvement cannot be expected. Apomorphine-induced contralateral turning produced by the lesion was unaffected by any drug regimen.


WMC-79, a potent agent against colon cancers, induces apoptosis through a p53-dependent pathway.
WMC-79 is a synthetic agent with potent activity against colon and hematopoietic tumors. In vitro, the agent is most potent against colon cancer cells that carry the wild-type p53 tumor suppressor gene (HCT-116 and RKO cells: GI50<1 nmol/L, LC50 approximately 40 nmol/L). Growth arrest of HCT-116 and RKO cells occurs at the G1 and G2-M check points at sublethal concentrations (10 nmol/L) but the entire cell population was killed at 100 nmol/L. WMC-79 is localized to the nucleus where it binds to DNA. We hypothesized that WMC-79 binding to DNA is recognized as an unrepairable damage in the tumor cells, which results in p53 activation. This triggers transcriptional up-regulation of p53-dependent genes involved in replication, cell cycle progression, growth arrest, and apoptosis as evidenced by DNA microarrays. The change in the transcriptional profile of HCT-116 cells is followed by a change in the levels of cell cycle regulatory proteins and apoptosis. The recruitment of the p53-dependent apoptosis pathway was suggested by the up-regulation of p53, p21, Bax, DR-4, DR-5, and p53 phosphorylated on Ser15; down-regulation of Bcl-2; and activation of caspase-8, -9, -7, and -3 in cells treated with 100 nmol/L WMC-79. Apoptosis was also evident from the flow cytometric studies of drug-treated HCT-116 cells as well as from the appearance of nuclear fragmentation. However, whereas this pathway is important in wild-type p53 colon tumors, other pathways are also in operation because colon cancer cell lines in which the p53 gene is mutated are also affected by higher concentrations of WMC-79.


R-matrix theory of driven electromagnetic cavities.
The resonances of cylindrical symmetric microwave cavities are analyzed in R-matrix theory, which transforms the input channel conditions to the output channels. Single and interfering double resonances are studied and compared with experimental results obtained with superconducting microwave cavities. Because of the equivalence of the two-dimensional Helmholtz and the stationary Schrödinger equations, the results give insight into the resonance structure of regular and chaotic quantum billiards.


Along for the ride or missing it altogether: exploring the host specificity and diversity of haemogregarines in the Canary Islands.
Host-parasite relationships are expected to be strongly shaped by host specificity, a crucial factor in parasite adaptability and diversification. Because whole host communities have to be considered to assess host specificity, oceanic islands are ideal study systems given their simplified biotic assemblages. Previous studies on insular parasites suggest host range broadening during colonization. Here, we investigate the association between one parasite group (haemogregarines) and multiple sympatric hosts (of three lizard genera: Gallotia, Chalcides and Tarentola) in the Canary Islands. Given haemogregarine characteristics and insular conditions, we hypothesized low host specificity and/or occurrence of host-switching events. A total of 825 samples were collected from the three host taxa inhabiting the seven main islands of the Canarian Archipelago, including locations where the different lizards occurred in sympatry. Blood slides were screened to assess prevalence and parasitaemia, while parasite genetic diversity and phylogenetic relationships were inferred from 18S rRNA gene sequences. Infection levels and diversity of haplotypes varied geographically and across host groups. Infections were found in all species of Gallotia across the seven islands, in Tarentola from Tenerife, La Gomera and La Palma, and in Chalcides from Tenerife, La Gomera and El Hierro. Gallotia lizards presented the highest parasite prevalence, parasitaemia and diversity (seven haplotypes), while the other two host groups (Chalcides and Tarentola) harbored one haplotype each, with low prevalence and parasitaemia levels, and very restricted geographical ranges. Host-sharing of the same haemogregarine haplotype was only detected twice, but these rare instances likely represent occasional cross-infections. Our results suggest that: (i) Canarian haemogregarine haplotypes are highly host-specific, which might have restricted parasite host expansion; (ii) haemogregarines most probably reached the Canary Islands in three colonization events with each host genus; and (iii) the high number of parasite haplotypes infecting Gallotia hosts and their restricted geographical distribution suggest co-diversification. These findings contrast with our expectations derived from results on other insular parasites, highlighting how host specificity depends on parasite characteristics and evolutionary history.


Digital Image Disintegration Analysis: a Novel Quality Control Method for Fast Disintegrating Tablets.
Measuring tablet disintegration is essential for quality control purposes; however, no established method adequately accounts for the timeframe or small volumes of the medium associated with the dissipation process for fast disintegrating tablets (FDTs) in the mouth. We hypothesised that digital imaging to measure disintegration in a low volume of the medium might discriminate between different types of FTD formulation. A digital image disintegration analysis (DIDA) was designed to measure tablet disintegration in 0.05-0.7 mL of medium. A temperature-controlled black vessel was 3D-printed to match the dimensions of each tablet under investigation. An overhead camera recorded the mean grey value of the tablet as a measure of the percentage of the formulation which remained intact as a function of time. Imodium Instants, Nurofen Meltlets and a developmental freeze-dried pilocarpine formulation were investigated. The imaging approach proved effective in discriminating the disintegration of different tablets (p < 0.05). For example, 10 s after 0.7 mL of a saliva simulant was applied, 2.0 ± 0.3% of the new pilocarpine tablet remained, whereas at the same time point, 22 ± 9% of the Imodium Instants had not undergone disintegration (temperature within the vessel was 37 ± 0.5°C). Nurofen Meltlets were observed to swell and showed a percentage recovery of 120.7 ± 2.4% and 135.0 ± 6.1% when 0.05 mL and 0.7 mL volumes were used, respectively. Thus, the new digital image disintegration analysis, DIDA, reported here effectively evaluated fast disintegrating tablets and has the potential as a quality control method for such formulations.


Diminished ability to integrate target stimuli with context during emotional recognition in individuals with broad autism phenotype.
Individuals with broad autism phenotype (BAP) have a tendency not to integrate emotional stimuli with the surrounding context. They have also shown different patterns and abilities in processing positive and negative emotions. This study aimed to examine whether the effect of context on target stimuli could vary depending on the type of target emotion in individuals with BAP. Based on the Broad Autism Phenotype Questionnaire (BAPQ) and Autism-Spectrum Quotient (AQ), 36 individuals with BAP and 33 healthy controls were selected. All the participants performed an overlap-emotional task consisting of six conditions: 2 (congruence: congruent and incongruent) × 3 (emotion: fearful, sad, and happy). Reaction time and accuracy were measured as dependent variables. The results revealed that the individuals with BAP showed no difference in reaction time between the condition of congruence and incongruence, but that the control group was faster to categorize facial expression on the condition of congruence than that of incongruence regardless of the type of target emotion. There were no differences between the two groups in any of the conditions with regard to accuracy. These findings indicate that individuals with BAP tend not to integrate target emotions with contextual information, a feature that could worsen the speed of emotional recognition in individuals with BAP. This study confirmed that the individuals with BAP have different cognition patterns in emotional recognition than the control group.


[Generation of monoclonal anti-dermatan sulfate antibodies cross-reacting to calf thymus DNA. Analysis of "anti-DNA antibody" directly binding to dermatan sulfate].
Monoclonal anti-dermatan sulfate antibodies were produced by immunizing BALB/c mouse with dermatan sulfate (DS) derived from porcine skin. These antibodies were tested for cross-reactivity to double stranded calf thymus DNA(ds.DNA) and heat-denatured DNA (ss.DNA). Five clones (including 2H8 and 3C4 clones) had binding activities to DS, ds.DNA and ss.DNA in solid phase enzyme linked immunosorbent assay, but no clones binding to DS alone were produced. 2H8 and 3C4 clones could activate mouse complement when they bound to the DS and ss.DNA. The abilities of DS, ds.DNA and ss.DNA to inhibit binding of 2H8 and 3C4 clones to solid phased DS, ds.DNA and ss.DNA were examined. Their binding activities were inhibited by any of DS, ds.DNA and ss.DNA. DNase I treatment abolished the binding activities of 2H8 and 3C4 clones to ds.DNA and ss.DNA completely, but had no effect on the binding activities to Ds. On the other hand, chondroitinase ABC treatment of DS augmented the binding activities of 2H8 and 3C4 to DS. DS digested completely with chondroitinase ABC inhibited the binding activities to DS of 2H8 and 3C4 clones, but not any of delta Di-4S and delta Di-diSB produced from DS digested with this enzyme inhibited the binding activities. Therefore, it was suggested that the epitope recognized by 2H8 and 3C4 clones could not be in delta Di-4S or delta Di-diSB but in the linkage regions of DS.


Comparative evaluation of a commercial enzyme-linked immunoassay and solid-phase immune electron microscopy for rotavirus detection in stool specimens.
Using solid-phase immune electron microscopy (SPIEM) as a reference test, we examined 151 stool specimens from infants and young children with acute gastroenteritis for rotavirus detection by a one-step commercial enzyme-linked immunosorbent assay (ELISA) with labeled monoclonal antibody. Of the 83 samples determined to be positive for rotavirus by SPIEM, 82 were detected as positive by the monoclonal antibody ELISA (sensitivity, 98.7%), while 67 of the 68 specimens determined to be negative by SPIEM were correctly detected as negative by the ELISA (specificity, 98.5%). The diagnostic accuracy of the ELISA kit was 98.6%. Thus, the one-step monoclonal antibody ELISA, which can be completed in less than 90 min, appears to be highly suitable for the rapid and reliable detection of rotavirus in stools.


Photodissociation dynamics of ionic argon pentamer.
Photodissociation of the ionized argon pentamer, Ar(5)(+), is studied using an extended diatomics-in-molecules interaction model with the inclusion of the spin-orbit coupling and various dynamical approaches. A thorough comparison with the experimental data available in the literature is presented, including photofragment abundances and their kinetic and internal energy distributions. New predictions are reported for ultraviolet photoexcitation energies, a range that has not been studied before either experimentally or theoretically.


Thalidomide maintenance following high-dose therapy in multiple myeloma: a UK myeloma forum phase 2 study.
Thalidomide maintenance has unresolved issues regarding dosage and toxicity. We evaluated this in five dose cohorts in 100 patients. At a median follow-up of 32.3 months, 23 patients had stopped thalidomide for disease progression, 54 for side effects. 3-year overall and progression-free survival was 76% and 41% respectively. Dosage did not influence disease outcome but greatly affected toxicity. Fifteen patients converted from partial remission to complete remission on thalidomide at a median of 13.5 months. Maintenance doses >200 mg were largely unachievable and peripheral neuropathy was the main toxicity. Lower doses enabled more patients to stay on the drug for a useful period of time.


Managing and treating chronic kidney disease.
Chronic kidney disease is a long-term condition that commonly exists with other conditions such as diabetes, hypertension and heart failure. The majority of people with CKD are managed in the community by a GP and community nursing team rather than a nephrologist. This article provides an overview of its stages, management and treatment.


Pulmonary vascular response to acetylcholine in isolated rat lungs treated with intratracheal bleomycin.
We tested the hypothesis that during alveolar hypoxia the vasodilator response to acetylcholine (ACh) is impaired in lungs injured by intratracheal bleomycin. Isolated rat lungs were ventilated with normoxic (21% O2) or hypoxic (2% O2) gas and perfused with homologous blood. The effect of ACh on pulmonary vascular resistance was estimated during ongoing hypoxic pulmonary vasoconstriction (HPVC) after the temporal pattern of HPVC was established. The magnitude of the decrease in pulmonary vascular resistance was significantly smaller in the bleomycin-treated group (group B, n = 7) than in the saline-treated group (group S, n = 7) (p less than 0.05). The magnitude of HPVC itself did not differ between groups. The pulmonary vascular reactivities to angiotensin II and KCl were similar in the two groups (group S, n = 4, group B, n = 5). At any given transpulmonary pressure the lung volumes of group B (n = 5) were significantly smaller than those of group S (n = 4) (p less than 0.01). We conclude that vascular dilation in response to ACh during ongoing HPVC was impaired in bleomycin-injured rat lungs.