Upfront lower dose lenalidomide is less toxic and does not compromise efficacy for vulnerable patients with relapsed refractory multiple myeloma: final analysis of the phase II RevLite study.
The combination of lenalidomide and dexamethasone is an established treatment for patients with multiple myeloma (MM). Increasingly, treatment attenuation is advocated for frail/elderly patients to minimize toxicity even though there have been no prospective studies to demonstrate whether lenalidomide dose attenuation impacts on response and survival outcome. This prospective multicentre phase II study assessed the efficacy and tolerability of lower dose lenalidomide (15 mg) and dexamethasone (20 mg) in 149 eligible patients with relapsed/refractory MM aged over 59 years and/or with renal impairment. The overall response rate was 71% (complete response 15%). Median (range) progression-free survival (PFS) and overall survival (OS) were 8·9 (6·9-11·5) and 30·5 (20·0-36·2) months, respectively. Upon formal statistical comparison of these endpoints to that of a matched cohort of patients from the pivotal phase III MM009/MM010 studies who received standard-dose lenalidomide (25 mg) and high-dose dexamethasone (40 mg) no difference was seen in PFS (P = 0·34) and OS (P = 0·21). Importantly, grade 3-4 toxicities were reduced with low-dose lenalidomide, mainly lower neutropenia (29% vs. 41%), infections (23% vs. 31%) and venous thromboembolism (3% vs. 13%). This study supports a strategy of lenalidomide dose reduction at the outset for at-risk patients, and prospectively confirms that such an approach reduces adverse events while not compromising patient response or survival outcomes.


Perspectives of Children with Physical Disabilities on Inclusion and Empowerment: Supporting and Limiting Factors.
The purpose was to explore the personal experiences of children with physical disabilities in physical education (PE) and to identify supporting and limiting mechanisms to their inclusion and empowerment. A computerized analysis of individual profiles was performed based on in-depth interviews with 8 females and 2 males, ages 9 to 15, who were included in regular PE classes. Two individual profiles served as examples for situations faced during inclusive settings and typical reaction patterns. A comparative qualitative analysis of interview themes generated five main categories of themes: assistive devices, physical activity, peers, important adults, and self. Experiences during physical activity were identified as supporting or limiting empowerment within each category, based on selected criteria. An almost equal distribution of supporting and limiting factors was observed.


Large Negative Linear Compressibility in InH(BDC)₂ from Framework Hinging.
Materials with negative linear compressibility (NLC) counterintuitively expand along one specific direction coupled to the volume reduction when compressed uniformly. NLC with a large value is desired for compression and materials science. However, NLC is generally smaller than -20 TPa-1. High-pressure X-ray diffraction experiments reveal that the β-quartz-like InH(BDC)2 generates an extreme NLC (-62.4 TPa-1) by framework hinging. InH(BDC)2 is much safer and lower-cost than Au+/Ag+ and CN--containing materials that dominated the fields of large NLC. This work reconfirms that a negative thermal expansion flexible framework could likely exhibit large NLC. Moreover, a large NLC could be anticipated to arise from β-quartz-like or related frameworks composed of rigid linear ligands and flexible framework angles.


High-Performance and Simply-Synthesized Ladder-Like Structured Methacrylate Siloxane Hybrid Material for Flexible Hard Coating.
A high performance ladder-like structured methacrylate siloxane hybrid material (LMSH) was fabricated via simple hydrolytic sol⁻gel reaction, followed by free-radical polymerization. A structurally ordered siloxane backbone, the ladder-like structure, which is an essential factor for high performance, could be achieved by a short period of sol⁻gel reaction in only 4 h. This results in superior optical (Transmittance > 90% at 550 nm), thermal (T5 wt % decomposition > 400 ℃ ), mechanical properties(elastic recovery = 0.86, hardness = 0.6 GPa) compared to the random- and even commercialized cage-structured silsesquioxane, which also has ordered structure. It was investigated that the fabricated ladder-like structured MSH showed the highest overall density of organic/inorganic co-networks that are originated from highly ordered siloxane network, along with high conversion rate of polymerizable methacrylate groups. Our findings suggest a potential of the ladder-like structured MSH as a powerful alternative for the methacrylate polysilsesquioxane, which can be applied to thermally stable and flexible optical coatings, even with an easier and simpler preparation process.


Stratification of the severity of critically ill patients with classification trees.
Development of three classification trees (CT) based on the CART (Classification and Regression Trees), CHAID (Chi-Square Automatic Interaction Detection) and C4.5 methodologies for the calculation of probability of hospital mortality; the comparison of the results with the APACHE II, SAPS II and MPM II-24 scores, and with a model based on multiple logistic regression (LR). Retrospective study of 2864 patients. Random partition (70:30) into a Development Set (DS) n = 1808 and Validation Set (VS) n = 808. Their properties of discrimination are compared with the ROC curve (AUC CI 95%), Percent of correct classification (PCC CI 95%); and the calibration with the Calibration Curve and the Standardized Mortality Ratio (SMR CI 95%). CTs are produced with a different selection of variables and decision rules: CART (5 variables and 8 decision rules), CHAID (7 variables and 15 rules) and C4.5 (6 variables and 10 rules). The common variables were: inotropic therapy, Glasgow, age, (A-a)O2 gradient and antecedent of chronic illness. In VS: all the models achieved acceptable discrimination with AUC above 0.7. CT: CART (0.75(0.71-0.81)), CHAID (0.76(0.72-0.79)) and C4.5 (0.76(0.73-0.80)). PCC: CART (72(69-75)), CHAID (72(69-75)) and C4.5 (76(73-79)). Calibration (SMR) better in the CT: CART (1.04(0.95-1.31)), CHAID (1.06(0.97-1.15) and C4.5 (1.08(0.98-1.16)). With different methodologies of CTs, trees are generated with different selection of variables and decision rules. The CTs are easy to interpret, and they stratify the risk of hospital mortality. The CTs should be taken into account for the classification of the prognosis of critically ill patients.


Use of high-dose cisplatin with aprepitant in an outpatient setting.
Chemotherapy-induced nausea and vomiting (CINV) and nephrotoxicity are adverse events induced by cisplatin administration. These effects can be reduced by treatment regimens with low-dose cisplatin, but high-dose cisplatin is still used. In Japan, high-dose cisplatin is usually administered in an inpatient setting to permit management of CINV. However, with use of new-generation antiemetic agents such as aprepitant, CINV and nephrotoxicity are controllable in an outpatient setting. Here, we discuss issues related to the management of high-dose cisplatin administration in outpatients. Grade 2 or worse CINV induced by high-dose cisplatin occurs in more than 40% of patients without treatment with aprepitant, but is controllable by administration of a 5-HT3 receptor antagonist, steroids and aprepitant. Moreover, prevention of CINV using these drugs is cost-effective, since outpatient settings have advantages with regard to health economics and patient quality of life. These findings suggest that shifting high-dose cisplatin administration to the outpatient setting may be achieved with co-administration of aprepitant. Available facilities and the status of the patient should be considered when selecting whether an outpatient setting is suitable for administration of cisplatin, but the use of aprepitant and adequate oral hydration should allow use of cisplatin in this setting.


[Suicidal stab wounds through clothing].
Most authors of medico-legal textbooks emphasize that suicides bare the chest before self-infliction of stab wounds and vice versa that cuts in the clothing indicate homicide. The paper presents three cases of suicidal stabs to the chest and/or abdomen with concomitant damage to the clothing.


Morphological changes and synaptogenesis of corticothalamic neurons in the somatosensory cortex of rat during perinatal development.
When rat fetuses grew from embryonic day (E) 18 to the day of birth (P0), the corticothalamic (CT) neurons, as identified by back labeling with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine (DiI), in the somatosensory cortex underwent gradual changes in the shape of their cell bodies, in their distribution in the cortical plate and in the complexity of dendritic branching. Fluorescence immunocytochemical studies indicated that in the marginal zone (MZ) the apical dendrites of the CT neurons formed contacts with horizontally oriented axons and contained putative glutamatergic, as clusters exhibiting both synaptophysin and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR1 subunit immunoreactivities, and γ-aminobutyric acid (GABA)-ergic synapses, as clusters exhibiting both synaptophysin and gephyrin immunoreactivities. Quantitative analyses further revealed that during this perinatal period, the proportion of CT neurons containing glutamatergic synapses increased significantly, whereas the proportion of CT neurons containing GABAergic synapses remained virtually unchanged. Our results indicate that glutamatergic and GABAergic synapses between the CT neurons and the axons in the MZ are already formed in rat cortices as early as E18 and further suggest that the activities of the neural networks in the somatosensory cortex could be conveyed to their targets in the thalamus in rat brains at least 3 days before birth.


[Fecundity, fertility, and sterility: assessment and controversy].
The author reviews problems concerning infertility in developed countries. Topics covered include natural fertility, "demographic and social trends in family planning such as increasing maternal age at first childbirth, the increase of age-specific infertility rates through known ([adnexitis]), unknown (the environment) or debatable (induced abortion, certain contraceptive methods) causes, and the availability of highly developed techniques to assist conception. The actual prevalence of infertility is poorly documented and is either derived from demographic surveys or from hospital populations. To record the true prevalence of infertility, population-based surveys including infertility specialist confirmation of the etiology are needed. One survey of this type indicates a lifetime prevalence of 17% of couples." (SUMMARY IN ENG)


Treatment of an amelanotic melanoma using radiation therapy in a lesser Madagascar hedgehog tenrec (Echinops telfairi).
A 15-yr-old, male lesser Madagascar hedgehog tenrec (Echinops telfairi) presented with a mass caudal to the right ear. Cytology suggested a sarcoma. Surgical removal was attempted. Histology was consistent with a soft tissue sarcoma. The mass recurred within 331 days post operation. Radiation therapy was initiated. Computed tomography was used for staging in conjunction with three-dimensional computerized treatment planning software to permit accurate lesion localization and to optimize normal tissue sparing. A total dose of 6,480 cGy was administered in 24 fractions over 46 days. Transient hind limb paresis developed during the course of the radiation therapy, but resolved after 7 days with prednisone treatment. Minimal acute radiation toxicity was observed. The mass responded with at least a 90% reduction in volume following radiation treatment. The animal survived 266 days from the initiation of treatment. On necropsy, a small mass and granulation tissue were found at the site of the initial neoplasm, indicating good regional control of the tumor; however, extensive metastases to the spleen and liver were present. Immunohistochemically, the original, recurrent, and metastatic populations were strongly positive for HMB 45 and weakly positive for S-100, and the final diagnosis was metastatic amelanotic melanoma.


Peptide hormones in plants.
In recent years, numerous biochemical and genetic studies have demonstrated that peptide signaling plays a greater than anticipated role in various aspects of plant growth and development. A substantial proportion of these peptides are secretory and act as local signals mediating cell-to-cell communication. Specific receptors for several peptides were identified as being membrane-localized receptor kinases, the largest family of receptor-like molecules in plants. These findings illustrate the importance of peptide signaling in the regulation of plant growth, functions that were previously ascribed to the combined action of small lipophilic compounds referred to as "traditional plant hormones." Here, we outline recent advances in the current understanding of biologically active peptides in plants, currently regarded as a new class of plant hormones.


Physical Quality Indicators and Mechanical Behavior of Agricultural Soils of Argentina.
Mollisols of Santa Fe have different tilth and load support capacity. Despite the importance of these attributes to achieve a sustainable crop production, few information is available. The objectives of this study are i) to assess soil physical indicators related to plant growth and to soil mechanical behavior; and ii) to establish relationships to estimate the impact of soil loading on the soil quality to plant growth. The study was carried out on Argiudolls and Hapludolls of Santa Fe. Soil samples were collected to determine texture, organic matter content, bulk density, water retention curve, soil resistance to penetration, least limiting water range, critical bulk density for plant growth, compression index, pre-consolidation pressure and soil compressibility. Water retention curve and soil resistance to penetration were linearly and significantly related to clay and organic matter (R2 = 0.91 and R2 = 0.84). The pedotransfer functions of water retention curve and soil resistance to penetration allowed the estimation of the least limiting water range and critical bulk density for plant growth. A significant nonlinear relationship was found between critical bulk density for plant growth and clay content (R2 = 0.98). Compression index was significantly related to bulk density, water content, organic matter and clay plus silt content (R2 = 0.77). Pre-consolidation pressure was significantly related to organic matter, clay and water content (R2 = 0.77). Soil compressibility was significantly related to initial soil bulk density, clay and water content. A nonlinear and significantly pedotransfer function (R2 = 0.88) was developed to predict the maximum acceptable pressure to be applied during tillage operations by introducing critical bulk density for plant growth in the compression model. The developed pedotransfer function provides a useful tool to link the mechanical behavior and tilth of the soils studied.


Energetic response of Atlantic surfclam Spisula solidissima to ocean acidification.
In this study, we assessed the Atlantic surfclam (Spisula solidissima) energy budget under different ocean acidification conditions (OA). During 12 weeks, 126 individuals were maintained at three different ρCO2 concentrations. Every two weeks, individuals were sampled for physiological measurements and scope for growth (SFG). In the high ρCO2 treatment, clearance rate decreased and excretion rate increased relative to the low ρCO2 treatment, resulting in reduced SFG. Moreover, oxygen:nitrogen (O:N) excretion ratio dropped, suggesting that a switch in metabolic strategy occurred. The medium ρCO2 treatment had no significant effects upon SFG; however, metabolic loss increased, suggesting a rise in energy expenditure. In addition, a significant increase in food selection efficiency was observed in the medium treatment, which could be a compensatory reaction to the metabolic over-costs. Results showed that surfclams are particularly sensitive to OA; however, the different compensatory mechanisms observed indicate that they are capable of some temporary resilience.


Characterizing monoclonal antibody formulations in arginine glutamate solutions using 1H NMR spectroscopy.
Assessing how excipients affect the self-association of monoclonal antibodies (mAbs) requires informative and direct in situ measurements for highly concentrated solutions, without sample dilution or perturbation. This study explores the application of solution nuclear magnetic resonance (NMR) spectroscopy for characterization of typical mAb behavior in formulations containing arginine glutamate. The data show that the analysis of signal intensities in 1D 1H NMR spectra, when compensated for changes in buffer viscosity, is invaluable for identifying conditions where protein-protein interactions are minimized. NMR-derived molecular translational diffusion rates for concentrated solutions are less useful than transverse relaxation rates as parameters defining optimal formulation. Furthermore, NMR reports on the solution viscosity and mAb aggregation during accelerated stability study assessment, generating data consistent with that acquired by size-exclusion chromatography. The methodology developed here offers NMR spectroscopy as a new tool providing complementary information useful to formulation development of mAbs and other large therapeutic proteins.


Characterization of multifunctional reverse micelles' interfaces using hemicyanines as molecular probes. II: Effect of the surfactant.
In this work, we have investigated the behavior of the cationic hemicyanine trans-4-[4-(dimethylamino)-styryl]-N-methylpyridinium iodide (HC) in benzene/benzyl-n-hexadecyl dimethylammonium chloride (BHDC)/water reverse micelle media using absorption and emission spectroscopy in addition to the steady-state and time-resolved fluorescence emission techniques and compare the results to those obtained in benzene/sodium 1,4-bis-2-ethylhexylsulfosuccinate (AOT)/water reverse micelle media (Moyano, F.; et al. J. Phys. Chem. B 2009, 113, 4284.) in order to gain more insight about reverse micelle interface properties. Our results show that HC spectroscopic behavior is completely different when dissolved in AOT or in BHDC reverse micelle media. While the dye experiences an intramolecular charge-transfer process upon excitation in the former media, in BHDC, this process is inhibited because of the cationic nature of the surfactant. Interestingly, we also show that the water properties are different for water molecules sequestrated inside of an anionic and cationic reverse micelle system. This come out because the water molecules entrapped inside of the BHDC reverse micelle media appear to be non-electron-donating because of its interaction with the cationic surfactant polar head group. On the other hand, the water molecules sequestrated inside of the AOT reverse micelle systems show its electron-donor ability enhanced in comparison with its water bulk structure. These results could also explain the lack of nucleophilicity shown by the water molecules entrapped in BHDC reverse micelle media reported in previous kinetic studies.


Numerical study of a macroscopic finite pulse model of the diffusion MRI signal.
Diffusion magnetic resonance imaging (dMRI) is an imaging modality that probes the diffusion characteristics of a sample via the application of magnetic field gradient pulses. The dMRI signal from a heterogeneous sample includes the contribution of the water proton magnetization from all spatial positions in a voxel. If the voxel can be spatially divided into different Gaussian diffusion compartments with inter-compartment exchange governed by linear kinetics, then the dMRI signal can be approximated using the macroscopic Karger model, which is a system of coupled ordinary differential equations (ODEs), under the assumption that the duration of the diffusion-encoding gradient pulses is short compared to the diffusion time (the narrow pulse assumption). Recently, a new macroscopic model of the dMRI signal, without the narrow pulse restriction, was derived from the Bloch-Torrey partial differential equation (PDE) using periodic homogenization techniques. When restricted to narrow pulses, this new homogenized model has the same form as the Karger model. We conduct a numerical study of the new homogenized model for voxels that are made up of periodic copies of a representative volume that contains spherical and cylindrical cells of various sizes and orientations and show that the signal predicted by the new model approaches the reference signal obtained by solving the full Bloch-Torrey PDE in O(ε(2)), where ε is the ratio between the size of the representative volume and a measure of the diffusion length. When the narrow gradient pulse assumption is not satisfied, the new homogenized model offers a much better approximation of the full PDE signal than the Karger model. Finally, preliminary results of applying the new model to a voxel that is not made up of periodic copies of a representative volume are shown and discussed.


Mechanisms of mutagenesis by exocyclic DNA adducts. Construction and in vitro template characteristics of an oligonucleotide bearing a single site-specific ethenocytosine.
By using a gene-targeted random DNA adduction approach, we have recently shown that chloroacetaldehyde, a metabolite of vinyl chloride, induces mutations predominantly at cytosines under conditions in which both ethenoadenine (epsilon A) and ethenocytosine (epsilon C) are formed. Although the observed mutational specificity of epsilon C suggested that it was a noninstructional lesion, the high efficiency of mutagenesis and an apparent lack of SOS dependence were reminiscent of mispairing lesions. To obtain more direct evidence showing that epsilon C has properties of a noninstructional mutagenic lesion, we have examined the in vitro template properties of a single epsilon C residue at a unique position in a synthetic oligonucleotide. The oligonucleotide was constructed by use of the following steps: (a) in vitro treatment of the pentameric oligodeoxyribonucleotide TTCTT with chloroacetaldehyde to convert the central cytosine to ethenocytosine; (b) purification and characterization of TT epsilon CTT; and (c) ligation of purified TT epsilon CTT to two decamers to create a 25 nt long oligodeoxyribonucleotide with a centrally located epsilon C residue. The template characteristics of epsilon C were examined by the annealing of end-labeled primers to the purified epsilon C-containing oligonucleotide and primer elongation by Escherichia coli DNA polymerase I in the presence of one or more nucleotide precursors. The elongation products were analyzed by high-resolution gel electrophoresis followed by autoradiography and quantitated by computing densitometry.(ABSTRACT TRUNCATED AT 250 WORDS)


Larsen's syndrome: anaesthetic implications. Six case reports.
Six cases were examined to review the important anaesthetic implications of Larsen's syndrome. Potential problems arising in these patients are highlighted and emphasis placed on cervical spine and airway/respiratory management.


Promising results after endoscopic vacuum treatment of anastomotic leakage following resection of rectal cancer with ileostomy.
In colorectal surgery, the most feared complication is anastomotic leakage (AL), which is associated with a high morbidity and mortality. In this study, we focus on treatment of perianastomotic abscess following AL after low anterior resection (LAR) of rectal cancer. In the literature, conservative irrigation regimes are reported to perdure for months and some even years and to be associated with a poor stoma closure rate. In the present paper, we evaluated endoscopic vacuum treatment of the perianastomotic abscess. Patients who had LAR due to rectal cancer with total mesorectal excision (TME) performed in Slagelse and Næstved Hospitals in the 2008-2012 (1st February) period were identified in the Danish Colorectal Cancer Group database. We included patients who had AL and who did not require emergency reoperation and were treated with endoscopic vacuum in the study period. Patients who initiated treatment more than one month after the leakage were excluded. All patients had primary ileostomy. A total of 13 patients were included. All patients had successful closure of the perianastomotic abscess for a median of 18 (3-40) days in a median of eight (1-18) sessions. The median length of hospital stay was 25 (7-39) days. Mortality was zero, and the stoma closure rate was 12/13 (97%). Our data support the positive findings previously reported by other studies. Endoscopic vacuum treatment seems to be a safe approach for selected patients in the treatment of perianastomotic abscess after LAR with TME of rectal cancer. not relevant. not relevant.


First principles of magnetic resonance angiography.
For several years, magnetic resonance imaging (MRI) has shown promise as a noninvasive tool for the study of the vascular system. One interesting format, so-called MR angiography, produces results resembling conventional x-ray angiographic images. This article lays a solid, rigorous foundation for an intuitive understanding of these effects without the use of advanced mathematical concepts. The current state of the art in data acquisition and postprocessing is illustrated. Finally, relevant hemodynamic concepts are introduced, in order to characterize the physiology of complex blood flow at bifurcations. MR angiography is particularly sensitive to artifacts associated with complex flow. The article ends with a call to investigate these phenomena, because they will directly affect the success of MR angiography as a technique.


Estramustine depolymerizes microtubules by binding to tubulin.
To investigate the mechanism of action of the antineoplastic drug estramustine, we compared its effects on human prostate cancer cells with those of vinblastine. At their respective concentrations that result in 50% inhibition of clonogenic growth, both drugs caused an accumulation of cells blocked at mitosis and similar dose- and time-dependent depolymerization of interphase microtubules. Also, colcemid-resistant and colcemid-hypersensitive Chinese hamster ovary cells with tubulin mutations were collaterally cross-resistant or -sensitive to estramustine. Thus, the cytotoxicity of estramustine is due to its microtubule depolymerization properties. This could be caused by interaction with tubulin and/or with microtubule-associated proteins (MAPs). Previous investigations have shown that high concentrations of estramustine phosphate can inhibit microtubule polymerization in vitro by binding to MAPs. However, estramustine phosphate is the clinical prodrug to estramustine, the intracellular active compound. In this study, we investigated the effects of estramustine on the binding of MAPs to taxol-stabilized microtubules in vivo. In contrast to previous reports, no effect of estramustine on the binding of MAPs to microtubules was found. Furthermore, we found that polymerization of purified tubulin could be inhibited by estramustine in vitro. Taken together, these results demonstrate that estramustine causes depolymerization of microtubules by direct interaction with tubulin.


Clinical use of cyclooxygenase inhibitors impairs vitamin B-6 metabolism.
A low circulating vitamin B-6 concentration, which is an independent risk factor for cardiovascular disease, is commonly seen in human inflammation. We investigated whether cyclooxygenase inhibitors alter vitamin B-6 metabolism. To investigate whether subjects taking a cyclooxygenase inhibitor had an altered vitamin B-6 profile, we conducted a cross-sectional study that involved 150 rheumatoid arthritis patients, with and without cyclooxygenase inhibitor treatments. C57BL/6J mice and hyperlipidemic Syrian hamsters received drug regimens that reflected clinical nonsteroidal antiinflammatory drug (NSAID) uses in treating human inflammation. The impact of long-term physiologic use of selective and nonselective cyclooxygenase inhibitors on vitamin B-6 metabolism was systematically investigated in these independent in vivo models. Patients who were taking cyclooxygenase inhibitors had lower circulating pyridoxal-5'-phosphate, especially those taking NSAIDs >6 mo. Long-term celecoxib and naproxen use reduced hepatic pyridoxal-5'-phosphate in mice. Nonselective cyclooxygenase inhibitor naproxen significantly decreased vitamin B-6 vitamers in the kidney. To our knowledge, we show novel findings that long-term physiologic doses of cyclooxygenase inhibitor may impede the synthesis of the coenzymatically active form of vitamin B-6. Because the cause of vitamin B-6 depletion in inflammation remains unknown, this study provides a potential mechanism that could account for the poor vitamin B-6 status in human inflammation. Moreover, this study further raises concerns about the long-term clinical use of antiinflammatory NSAIDs in humans. Vitamin B-6 status should be carefully monitored in long-term NSAID users. Future randomized placebo-controlled studies are needed to determine the impacts of antiinflammatory cyclooxygenase inhibitor use on vitamin B-6 metabolism in humans.


High levels of thyrotropin-releasing hormone precursor peptide immunoreactivity and binding substance occur in human cerebrospinal fluid.
A thyrotropin-releasing hormone (TRH) precursor peptide, pGlu-His-Pro-Gly (TRH-Gly) and related peptides were measured in human cerebrospinal fluid (CSF) with a TRH-Gly radiommunoassay and the levels of immunoreactivity (IR) were found to be 136- to 352-fold higher than the corresponding levels of TRH-IR. TRH-IR levels in CSF are elevated during the active phase of multiple sclerosis (MS). We have used this TRH-Gly RIA to determine whether this TRH precursor peptide is also elevated in CSF from MS and Alzheimer's (ALZ) disease patients in comparison with the corresponding levels in non-central nervous system disease (control) patients. A highly significant increase in TRH-Gly-IR was observed in MS and ALZ CSF samples compared to control CSF. Cation exchange and exclusion chromatography of extracts of mixtures of CSF and synthetic TRH-Gly revealed two peaks of TRH-Gly-IR. One cochromatographed with synthetic TRH-Gly and the other was attributable to the formation of a complex between TRH-Gly and a binding substance originating in CSF. Corresponding studies with extracts of mixtures of CSF and synthetic TRH revealed no evidence for TRH binding with any component of CSF. Reverse-phase high-pressure liquid chromatography of pooled extracts of normal CSF revealed that about a third of the total TRH-Gly-IR coeluted with synthetic TRH-Gly. The half-time for in vitro metabolism of synthetic TRH-Gly in fresh CSF was 5 times longer than for synthetic TRH at 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)


Failure of disopyramide to improve right ventricular outflow tract obstruction after living-donor lobar lung transplantation.
Right ventricular (RV) outflow tract obstruction (RVOTO) is an uncommon complication of lung transplantation in patients with pulmonary hypertension (PH) and both medical management and surgical intervention are required. A 28-year-old female with primary PH was referred and because she did not respond to medical treatment, living-donor lobar lung transplantation was performed. The operation was successful, but dyspnea and exercise intolerance developed during rehabilitation and transthoracic echocardiography revealed RVOTO. Intravenous disopyramide during cardiac catheterization reduced the pressure gradient from 35 mmHg to 16 mmHg without decreasing RV systolic pressure. However, electrical and hemodynamic parameters were adversely affected by disopyramide and thus, after cardiac catheterization, administration of fluid and a low dose of atenolol was started, and her symptoms improved. Transthoracic echocardiography showed improvement in the RVOTO. This case suggests that disopyramide should be avoided for patients with RVOTO following lung transplantation and that other negative inotropic agents, such as beta-blockers, are more effective for relief of RVOTO.


Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneration.
Ischemia of the heart, brain, and limbs is a leading cause of morbidity and mortality worldwide. Treatment with tissue type plasminogen activator (tPA) can dissolve blood clots and can ameliorate the clinical outcome in ischemic diseases. But the underlying mechanism by which tPA improves ischemic tissue regeneration is not well understood. Bone marrow (BM)-derived myeloid cells facilitate angiogenesis during tissue regeneration. Here, we report that a serpin-resistant form of tPA by activating the extracellular proteases matrix metalloproteinase-9 and plasmin expands the myeloid cell pool and mobilizes CD45(+)CD11b(+) proangiogenic, myeloid cells, a process dependent on vascular endothelial growth factor-A (VEGF-A) and Kit ligand signaling. tPA improves the incorporation of CD11b(+) cells into ischemic tissues and increases expression of neoangiogenesis-related genes, including VEGF-A. Remarkably, transplantation of BM-derived tPA-mobilized CD11b(+) cells and VEGFR-1(+) cells, but not carrier-mobilized cells or CD11b(-) cells, accelerates neovascularization and ischemic tissue regeneration. Inhibition of VEGF signaling suppresses tPA-induced neovascularization in a model of hind limb ischemia. Thus, tPA mobilizes CD11b(+) cells from the BM and increases systemic and local (cellular) VEGF-A, which can locally promote angiogenesis during ischemic recovery. tPA might be useful to induce therapeutic revascularization in the growing field of regenerative medicine.


[Value of a structured report for the interpretation of parathyroid scintigraphy in primary essential hyperthyroidism].
The aim of the study was to evaluate whether a four-stage report scheme increases the diagnostic accuracy of dual phase Tc-99 m sestamibi scintigraphy (MIBI-scintigraphy) in patients with primary hyperparathyroidism (pHPT). We analysed the scans of 35 patients with primary hyperparathyroidism referred for Tc-99 m sestamibi scintigraphy and compared them with the sonographic and surgical findings. All scans were interpreted following a four-stage report scheme: Group A--typical scintigraphic findings of a single gland disease, group B--scan consistent with single gland disease, group C--multiple gland disease, group D--non diagnostic scan. Twenty-three scans were ranked in group A. In all these patients, scintigraphy diagnosed both the side and the localization of the adenoma correctly. Sonography made the correct diagnosis in 21/23 individuals and showed false-positive results in 2/23 cases. Group B included 10 scans. In 7/10 individuals, both the side and the localization of the adenoma were diagnosed correctly, whereas in 2/10 patients only the side was diagnosed. The scan of a single patient with hyperplasia of all 4 parathyroid glands was falsely interpreted as "consistent with a left caudal single gland disease". Sonography made the correct diagnosis in 8/10 cases, two individuals were diagnosed as false positive and false negative, respectively. No scan was interpreted as multiple gland disease (group C) and two scans were non diagnostic (group D). Both patients of the last group were correctly diagnosed by sonography. These findings suggest that in case of typical scintigraphic findings of single gland disease, scintigraphy but not sonography should be the primary localization technique for minimally invasive parathyroidectomy.


Genetic characterisation and breed assignment in Austrian sheep breeds using microsatellite marker information.
Samples from 717 sheep of 11 Austrian sheep breeds were genotyped for 25 microsatellite loci. Twenty-one loci showing no deviation from Hardy-Weinberg equilibrium were used to calculate pairwise genetic distances (Nei's minimum distance and Reynolds' distance). All breeds could be clearly distinguished through these genetic distances. The shortest genetic distance was found between Alpines Steinschaf (AS) and Waldschaf (WS). Within the so-called 'Steinschaf' group [AS, Montafoner Steinschaf (MS), Krainer Steinschaf (KS) and Tiroler Steinschaf (TS)] the MS adopted an extreme status with the largest distance to the other breeds in the group. This finding resulted in the decision to consider the MS no longer as subpopulation of Alpines Steinschaf but as an independent breed. A correct breed assignment using a Bayesian approach was possible for only 66% of all individuals belonging to Alpines Steinschaf, but for at least 90% of individuals for all other breeds investigated.


Ischemic Stroke Following Calloselasma rhodostoma Snakebite: A Rare Case Report.
Ischemic stroke following a snakebite is a rare case. Snake venom consists of multiple components which can cause various symptoms and consequences. We report a case of ischemic stroke following Calloselasma rhodostoma snakebite, and this study was the first to report a case of ischemic stroke after snakebite in Indonesia. A 72-year-old Mongoloid male presented with a history of snakebite one day before hospital admission with a swollen right lower leg with no history of hypertension, diabetes mellitus, or heart disease. The patient was conscious. His temperature was 36.5°C, pulse rate was 90 beats per minute, respiration rate was 30 breaths per minute, and blood pressure was 162/109 mmHg. The neurological examination showed left-side weakness and headache, with blood laboratory results showing prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), leucocytosis, thrombocytopenia, and low haemoglobin. A computerized tomogram (CT) scan of the brain was taken, which revealed a sign of infarct in the pericallosal of the right lateral periventricular anterior horn. Although ischemic stroke following a snakebite is uncommon, it must be considered and monitored.


Molecular subtyping of gastric cancer according to ACRG using immunohistochemistry - Correlation with clinical parameters.
Gastric cancer (GC) is a very heterogenous disease necessitating further stratification for prognostic and therapeutic aspects. Based on the recommendation of The Asisan Cancer Research Group (ACRG) recently established four molecular subtypes (MSI, MSS/EMT, MSS/TP53+, MSS/TP53-) which require molecular expression analysis. The technology required for comprehensive molecular analysis is expensive and not applicable for routine diagnostics. Thus, in this study we established a classification system utilizing immunohistochemistry and morphology-based analyses as surrogate markers in order to reproduce the ACRG molecular subtypes of gastric cancer. To clarify the clinical relevance of the novel classification system, we performed a correlation with established clinical parameters. The study cohort consisted of 189 patients with GC (UICC III and IV). Using immunohistochemistry, the following markers were analysed: MLH1, MSH2, MSH6, PMS2 (as a surrogate for microsatellite status), p53, SOX9. We assessed tumor budding as a surrogate for EMT to distinguish between MSS/EMT and MSS/non-EMT groups. Immunohistochemical and morphologic subtyping classified cases as follows: 10% MSI, 35% MSS/EMT, 16% MSS/TP53 + and 39% MSS/TP53-. Subtypes significantly correlated with the Lauren classification, tumor stage, venous invasion and SOX9 expression (p < .05). There was no significant correlation between molecular subtype and lymph node growth pattern. We propose a simple algorithm for molecular subtyping of GC using universally available immunohistochemistry, which correlates with clinical parameters and is cost-effective and applicable in diagnostic routine. This classification might prospectively help to determine patient prognosis, optimize patient care and homogenize patient cohorts for clinical trials.


Effect of Telehealth Treatment by Lay Counselors vs by Clinicians on Depressive Symptoms Among Older Adults Who Are Homebound: A Randomized Clinical Trial.
Older adults who are homebound and have low income have limited access to psychosocial treatments because of their homebound state and geriatric mental health workforce shortages. To evaluate clinical effectiveness of a brief, aging service-integrated, videoconferenced behavioral activation (tele-BA) treatment delivered by lay counselors compared with videoconferenced problem-solving therapy (tele-PST) delivered by licensed clinicians and attention control (AC; telephone support calls). This 3-group randomized clinical trial using a randomization prior to consent approach included individuals aged 50 years or older who were homebound and had 24-item Hamilton Depression Rating Scale (HAMD) scores of 15 or greater between February 15, 2016, and April 15, 2019. Tele-BA and tele-PST participants received 5 weekly treatment sessions. Assessments were performed at baseline and 12, 24, and 36 weeks after baseline. Intention-to-treat statistical analyses were performed from January 1, 2020, to February 15, 2020. Tele-BA participants were taught 5 steps for reinforcing healthy behaviors to improve mood, physical functioning, and social engagement. Tele-PST participants were taught a 7-step approach for problem solving coping skills. The primary outcome was the 24-item HAMD scores. Response (ie, ≥50% reduction in HAMD) and remission (ie, HAMD <10) rates and effect sizes for clinically meaningful differences were examined. Secondary outcomes were disability, social engagement and activity frequency, and satisfaction with participation in social roles. A total of 277 participants were enrolled, including 193 (69.7%) women, 83 (30.0%) who were Black, 81 (29.2%) who were Hispanic, and 255 (92.1%) with income of $35 000 or less. The mean (SD) age was 67.5 (8.9) years. Among these, 90 participants were randomized to tele-BA, 93 participants were randomized to tele-PST, and 94 participants were randomized to the AC. Compared with participants in the AC group, participants in the tele-BA and tele-PST groups had significantly higher response and remission rates and medium to large effect sizes (tele-BA: raw growth modeling analysis d = 0.62 [95% CI, 0.35 to 0.89]; P < .001; tele-PST: raw growth modeling analysis d = 1.00 [95% CI, 0.73 to 1.26]; P < .001) for HAMD scores. While tele-PST was significantly more effective than tele-BA for reducing HAMD scores (t258 = -2.79; P = .006), there was no difference between tele-BA and tele-PST on secondary outcomes. In this randomized clinical trial, participants who received tele-BA by lay counselors achieved statistically and clinically meaningful changes in depressive symptoms. Given shortages of licensed mental health clinicians, tele- and lay counselor-delivered services may help improve access to evidence-based depression treatment for large numbers of underserved older adults. ClinicalTrials.gov Identifier: NCT02600754.


Treatment of refractory metastatic breast cancer with 5-fluorouracil plus levofolinic acid as continuous venous infusion: a phase II study.
Effective palliation of metastatic breast carcinoma (MBC) after the failure of front-line chemotherapy for advanced disease, often based on the use of anthracyclines and taxanes, is quite difficult to achieve due to the development of dominant neoplastic cellular clones highly resistant to further therapy. Therefore the therapeutic index of second and third line chemotherapeutic treatments is usually quite low. Thirty patients with MBC with progressive disease after anthracycline-based chemotherapy as first line therapy were treated with l-FA 100 mg/m2/day and 5FU 1000 mg/m2/day ad continuous venous infusion for 96 hours every 4 weeks. Most patients (60%) had multiple sites of disease at entry and had visceral lesions as the dominant site of disease. Twenty-eight patients were evaluated for objective response: two patients had clinically progressive disease before restaging after the third cycle of chemotherapy. These patients were considered progressive disease since all patients were included in an intent-to-treat analysis. Nine patients achieved partial response for an overall response rate of 30% (intent-to-treat analysis) with a median duration of 9.5+ months (range 4.0/14.0 months), and disease stability was obtained in 10 cases (33%) with a median duration of 5.5 months (5-11). Progressive disease was recorded in 9 patients. After a median follow-up of 11 months, the overall median survival time of the whole series of patients was 14.0+ months. Objective responses were recorded both at visceral and bone sites. Chemotherapeutic treatment was generally quite well tolerated. No toxic deaths were recorded. Among gastrointestinal side-effects grade 3 stomatitis was noted in 30% of patients, and grade 3 diarrhea in 10% of cases. Grade 3-4 leukopenia was observed in 23% of patients, but significant episodes of febrile neutropenia were limited (2 patients). Grade 3 thrombocytopenia was seen only occasionally in 1 patient. Grade 1 anemia was recorded in 10% of patients. Hand-foot syndrome was noted in 2 patients (7%). Cardiotoxicity was minimal. The combination of 5FU and high-dose I-FA given as 96 hour continuous venous infusion was active, at least in terms of the overall response rate, against anthracycline refractory metastatic breast carcinoma. These results compare favourably with bolus 5FU/FA or other salvage regimens in terms of antineoplastic activity, and is well tolerated both subjectively and objectively by most patients.


Interleukin-4, interleukin-13, signal transducer and activator of transcription factor 6, and allergic asthma.
Interleukin (IL)-4 and IL-13 share many biological activities. To some extent, this is because they both signal via a shared receptor, IL-4Ralpha. Ligation of IL-4Ralpha results in activation of Signal Transducer and Activator of Transcription factor 6 (STAT6) and Insulin Receptor Substrate (IRS) molecules. In T- and B-cells, IL-4Ralpha signaling contributes to cell-mediated and humoral aspects of allergic inflammation. It has recently become clear that IL-4 and IL-13 produced in inflamed tissues activate signaling in normally resident cells of the airway. The purpose of this review is to critically evaluate the contributions of IL-4- and IL-13-induced tissue responses, especially those mediated by STAT6, to some of the pathologic features of asthma including eosinophilic inflammation, airway hyperresponsiveness, subepithelial fibrosis and excessive mucus production. We also review the functions of some recently identified IL-4- and/or IL-13-induced mediators that provide some detail on molecular mechanisms and suggest an important contribution to host defense.


A novel putative reductase (Cpd1p) and the multidrug exporter Snq2p are involved in resistance to cercosporin and other singlet oxygen-generating photosensitizers in Saccharomyces cerevisiae.
Phytopathogenic Cercospora species produce cercosporin, a photoactivated perylenequinone toxin that belongs to a family of photosensitizers which absorb light energy and produce extremely cytotoxic, reactive oxygen species. In this work, we used Saccharomyces cerevisiae as a model system for the identification and cloning of genes whose products mediate cercosporin detoxification. Two genesexpressed in high-copy number vectors conferred cercosporin resistance to an otherwise sensitive strain. One gene codes for Snq2p, a well-characterized multidrug, ABC-type, efflux protein. The other, designated CPD1 (Cercosporin Photosensitizer Detoxification), encodes a novel protein with significant similarity to the FAD-dependent pyridine nucleotide reductases. We showed that over-expression of either of these proteins can also mediate resistance to other singlet oxygen-generating compounds. The involvement of Snq2p and Cpd1p in photosensitizer detoxification reinforces previous observations which suggested that singlet oxygen acts on membrane lipids and that cellular resistance to cercosporin is mediated by a mechanism involving toxin efflux and/or toxin reduction.


Whispering gallery mode lasing in mesomorphic liquid crystal microdroplets.
In recent years, investigation on the non-display applications of liquid crystals has increased considerably. One of the emerging applications is whispering gallery mode (WGM) lasing. Here, we report experimental studies on the morphology and WGM lasing in nematic (N), smectic-A (SmA) and smectic-C (SmC) microdroplets dispersed in a highly transparent and low refractive index perfluopolymer. The mesomorphic microdroplets, obtained by varying the temperature, exhibit radial director configuration. The SmA microdroplets are found to be highly stable and robust against mechanical stress compared to the N and SmC microdroplets. We study lasing properties such as intensity, threshold pump energy and linewidth, and show that overall the SmA microdroplets are superior to the N and SmC microdroplets. The experimental results are discussed based on the orientation of the dye molecules, director fluctuations and tilting at the interface.


Resonance frequency of fluid-filled and prestressed spherical shell-A model of the human eyeball.
An acoustic tonometer that measures shifts in resonance frequencies associated with intraocular pressure (IOP) could provide an opportunity for a type of tonometer that can be operated at home or worn by patients. However, there is insufficient theoretical background, especially with respect to the uncertainty in operating frequency ranges and the unknown relationships between IOPs and resonance frequencies. The purpose of this paper is to develop a frequency function for application in an acoustic tonometer. A linear wave theory is used to derive an explicit frequency function, consisting of an IOP and seven other physiological parameters. In addition, impulse response experiments are performed to measure the natural frequencies of porcine eyes to validate the provided function. From a real-time detection perspective, explicitly providing a frequency function can be the best way to set up an acoustic tonometer. The theory shows that the resonance oscillation of the eyeball is mainly dominated by liquid inside the eyeball. The experimental validation demonstrates the good prediction of IOPs and resonance frequencies. The proposed explicit frequency function supports further modal analysis not only of the dynamics of eyeballs, but also of the natural frequencies, for further development of the acoustic tonometer.


A false negative by planar scintigraphy liver hemangioma, diagnosed by technetium-99m-red blood cells and technetium-99m-sulfur colloid single photon emission tomography scan.
We present a 42-year-old patient who was examined in the Gastroenterology Department of Gaziantep University for chronic abdominal pain, nausea and vomiting. Ultrasonography showed a 4.7 cm solid hepatic mass on the right lateral side of the right lobe of the liver. The patient was then sent to the Nuclear Medicine Department of Gaziantep University for liver scan. After injecting autologous red blood cells labeled with 740 MBq of technetium-99m ((99m)Tc-RBC), early and delayed anterior planar images of the liver showed no significant findings because of the right kidney shine through the liver. Two days later, after injecting again 740 MBq of (99m)Tc-RBC, we performed a single photon emission tomography (SPET) scan but still this scan was nondiagnostic even in the delayed images of the liver. Three days later, after the iv injection of 185 MBq of technetium-99m-sulphur colloid ((99m)Tc-SC), we observed in the delayed SPET images of the liver, a mismatch defect with decreased focal uptake of (99m)Tc-SC at 60 min while the uptake of (99m)Tc-RBC at the same area was normal or slightly increased. The patient was then operated due to bleeding in the abdominal cavity. A cavernous hemangioma was found, confirmed by histology. The absorbed dose from all three diagnostic scanning procedures was: 4 mSv. In conclusion, the mismatch of the SPET delayed images between the (99m)Tc-RBC and the (99m)Tc-SC scans indicated that this procedure was effective for the diagnosis of liver cavernous hemangioma located in this unusual position.


Gastrointestinal digestion of Bet v 1-homologous food allergens destroys their mediator-releasing, but not T cell-activating, capacity.
Food allergy to apples, hazelnuts, and celery is frequent in individuals with birch pollen allergy because IgE antibodies specific for the major birch pollen allergen, Bet v 1, cross-react with structurally related allergens in these foods. In addition, T lymphocytes specific for Bet v 1 also cross-react with these dietary proteins. We sought to evaluate the effects of simulated gastrointestinal degradation of Bet v 1-related food allergens on their mediator-releasing and T cell-activating capacity. Recombinant Mal d 1, Cor a 1.04, and Api g 1 were incubated separately with pepsin and trypsin. Binding of IgE was tested in immunoblots. After successive incubation with both enzymes, allergens were tested in mast cell mediator release assays and used to stimulate PBMCs and Bet v 1-specific T-cell lines and clones. Proteolytic fragments of allergens were analyzed and sequenced by means of mass spectrometry. Pepsin completely destroyed IgE binding of all allergens within 1 second, and trypsin completely destroyed IgE binding of all allergens within 15 minutes, except for the major hazelnut allergen, which remained intact for 2 hours of trypsinolysis. Allergens after gastrointestinal digestion did not induce basophil activation but induced proliferation in PBMCs from allergic and nonallergic individuals. Digested Mal d 1 and Cor a 1.04 still activated Bet v 1-specific T cells, whereas digested Api g 1 did not. Different proteolytic fragments of Mal d 1 and Cor a 1.04 matching relevant Bet v 1 T-cell epitopes were found. Gastrointestinal degradation of Bet v 1-related food allergens destroys their histamine-releasing, but not T cell-activating, property. Our data emphasize that birch pollen-related foods are relevant activators of pollen-specific T cells.


Scope of cardiovascular complications in patients with kidney disease.
Approximately 6 million Americans have combined chronic cardiovascular and kidney disease with growing epidemics of heart and kidney failure. This clinical intersection presents unique risks to the patient and unique challenges to the clinician. Observational studies have provided quantitative methods for estimating the risk of acute renal failure in patients undergoing percutaneous intervention and bypass surgery procedures. Fortunately, for the general cardiovascular population, these risks are small. On the other hand, patients with chronic kidney disease have increased risks of accelerated atherosclerosis, nonfatal myocardial infarction, congestive heart failure, atrial and ventricular arrhythmias, and cardiac death. Chronic kidney disease presents difficult scenarios in using conventional cardioprotective therapy. However, there are increasing bodies of evidence to suggest the kidney and the heart can be targeted with lines of therapy, specifically with renin-angiotensin system antagonism, which benefit both systems with respect to reduction in the progression of disease, and the prevention of hard kidney and cardiac endpoints. This paper will address the scope of cardiovascular complications in patients with chronic kidney disease and discuss the rationale for expanded basic and clinical investigation of the cardiorenal patient population.


Breeding Potentials of Bambara Groundnut for Food and Nutrition Security in the Face of Climate Change.
Constant production of quality food should be a norm in any community, but climate change, increasing population, and unavailability of land for farming affect food production. As a result, food scarcity is affecting some communities, especially in the developing world. Finding a stable solution to this problem is a major cause of concern for researchers. Synergistic application of molecular marker techniques with next generation sequencing (NGS) technologies can unlock the potentials hidden in most crop genomes for improving yield and food availability. Most crops such as Bambara groundnut (BGN), Winged bean, and African yam bean are underutilized. These underutilized crops can compete with the major crops such as cowpea, soybean, maize, and rice, in areas of nutrition, ability to withstand drought stress, economic importance, and food production. One of these underutilized crops, BGN [Vigna subterranea (L.), Verdc.], is an indigenous African legume and can survive in tropical climates and marginal soils. In this review, we focus on the roles of BGN and the opportunities it possesses in tackling food insecurity and its benefits to local farmers. We will discuss BGN's potential impact on global food production and how the advances in NGS technologies can enhance its production.


Design of an Integrated Acceptance Framework for Older Users and eHealth: Influential Factor Analysis.
eHealth and telehealth play a crucial role in assisting older adults who visit hospitals frequently or who live in nursing homes and can benefit from staying at home while being cared for. Adapting to new technologies can be difficult for older people. Thus, to better apply these technologies to older adults' lives, many studies have analyzed the acceptance factors for this particular population. However, there is not yet a consensual framework that can be used in further development and to search for solutions. This paper aims to present an integrated acceptance framework (IAF) for older users' acceptance of eHealth based on 43 studies selected through a systematic review. We conducted a 4-step study. First, through a systematic review in the field of eHealth from 2010 to 2020, the acceptance factors and basic data for analysis were extracted. Second, we conducted a thematic analysis to group the factors into themes to propose an integrated framework for acceptance. Third, we defined a metric to evaluate the impact of the factors addressed in the studies. Finally, the differences among the important IAF factors were analyzed according to the participants' health conditions, verification time, and year. Through a systematic review, 731 studies were found in 5 major databases, resulting in 43 (5.9%) selected studies using the PRISMA (Preferred Reporting Item for Systematic Reviews and Meta-Analyses) methodology. First, the research methods and acceptance factors for eHealth were compared and analyzed, extracting a total of 105 acceptance factors, which were grouped later, resulting in an IAF. A total of 5 dimensions (ie, personal, user-technology relational, technological, service-related, and environmental) emerged, with a total of 23 factors. In addition, we assessed the quality of evidence and then conducted a stratification analysis to reveal the more appropriate factors depending on the health condition and assessment time. Finally, we assessed the factors and dimensions that have recently become more important. The result of this investigation is a framework for conducting research on eHealth acceptance. To elaborately analyze the impact of the factors of the proposed framework, the criteria for evaluating the evidence from the studies that have the extracted factors are presented. Through this process, the impact of each factor in the IAF has been presented, in addition to the framework proposal. Moreover, a meta-analysis of the current status of research is presented, highlighting the areas where specific measures are needed to facilitate eHealth acceptance.


Preliminary X-ray crystallographic studies of the short form of the human TRAF4 TRAF domain.
TNF (tumour necrosis factor) receptor-associated factor 4 (TRAF4) is a unique TRAF protein that participates in morphogenetic and developmental function and cell migration. TRAF-family proteins contain a TRAF domain for target interaction. In this study, the short form of the human TRAF4 TRAF domain, corresponding to amino acids 290-462, was overexpressed in Escherichia coli using engineered C-terminal His tags. The short form of the TRAF4 TRAF domain was purified to homogeneity and crystallized at 293 K. Finally, X-ray diffraction data were collected to a resolution of 4.2 Å from a crystal belonging to the hexagonal space group P3₂, with unit-cell parameters a = b = 147.17, c = 202.69 Å.


Effect of high-speed rolling on herpes simplex virus detection and replication.
We examined the effect of high-speed rolling on herpes simplex virus replication. Inoculated cultures were rolled at 2, 96, or 383 rpm, while stationary cultures served as controls. At 24 h, inoculated cultures rolled at 96 rpm had a 6.8-fold increase in foci when compared with stationary cultures (P less than 0.01) and a 2.8-fold increase over cultures rolled at 2 rpm (P less than 0.05). Cultures rolled at 2 rpm had a 2.4-fold increase in foci over stationary cultures (P less than 0.05). Viral yield results correlated with focus results. Significantly more virus was present in cultures rolled at 96 rpm (7.3-fold) than in stationary cultures. Cultures rolled at 2 rpm produced 2.9-fold more virus than stationary cultures (P less than 0.05). Of 37 cultures rolled at 96 rpm, 33 (89%) were cytopathic effect positive at 96 h, while 18 of 40 (45%) were positive at 2 rpm and only 2 of 37 (5%) were positive for stationary cultures (P less than 0.01). Cultures rolled at 96 rpm produced maximum viral yields 2 days sooner than stationary cultures. Rolling of inoculated cultures should be used in the clinical laboratory to aid in the rapid detection of herpes simplex virus.


A Useful Synthesis of 2-Acylamino-1,3,4-oxadiazoles from Acylthiosemicarbazides Using Potassium Iodate and the Discovery of New Antibacterial Compounds.
A useful method for the synthesis of 2-acylamino-1,3,4-oxadiazoles was developed. By using potassium iodate as an oxidant in water at 60 °C, a wide range of 2-acylamino-1,3,4-oxadiazoles were afforded in moderate to excellent yields within two hours. This method could provide a facile shortcut to generate a series of 2-acylamino-1,3,4-oxadiazoles in medicinal chemistry. Interestingly, some highly potent antibiotic compounds were found through this synthetic method, and some of them displayed a significant improvement in activity compared with the corresponding 1,4-diacylthiosemicarbazides. Compound 2n was the most active against Staphylococcus aureus with MIC (minimum inhibitory concentration) of 1.56 mg/mL, and compounds 2m and 2q were the most active against Bacillus subtilis with MIC of 0.78 mg/mL. The preliminary cytotoxic activities of the most potent compounds 2m, 2n, and 2q against the androgen-independent (PC-3) prostate cancer cell line were more than 30 μM (IC50 > 30 μM).


Comparison of an imaging heel quantitative ultrasound device (DTU-one) with densitometric and ultrasonic measurements.
The purpose of this study was to evaluate a new imaging ultrasound scanner for the heel, the DTU-one (Osteometer MediTech, Denmark), by comparing quantitative ultrasound (QUS) results with bone mineral density (BMD) of the heel and femur from dual X-ray absorptiometry (DXA), and by comparing the DTU-one with another QUS device, the UBA 575+. The regions of interest in the DXA heel scan were matched with the regions evaluated by the two QUS devices. 134 healthy and 16 osteoporotic women aged 30-84 years old were enrolled in the study. In vivo short-term precision of the DTU-one for broadband ultrasound attenuation (BUA) and speed of sound (SOS) was 2.9% and 0.1%, respectively, and long-term precision was 3.8% and 0.2%, respectively. Highest correlations (r) between QUS and BMD measurements were achieved when comparing DTU-one results with BMD in matched regions of the DXA heel scan. Correlation coefficients (r) were 0.81 for BUA and SOS. Highest correlations with the UBA 575+ were 0.68 and 0.72, respectively. The comparison of BMD in different femoral sites with BUA and SOS (DTU-one) varied from 0.62 to 0.69 when including the entire study population. The correlation between BMD values within different sites of the femur tended to be higher (from r = 0.81 to 0.93). When comparing BUA with BUA and SOS with SOS on the two QUS devices, the absolute QUS values differed significantly. However, correlations were relatively high, with 0.76 for BUA and 0.82 for SOS. In conclusion, the results of the new quantitative ultrasound device, the DTU-one, are highly correlated (r = 0.8) with results obtained using the UBA 575+ and with BMD in the heel. The precision of the DTU-one is comparable to other QUS devices for BUA and is high for SOS.


The burden of emergency department use for sickle-cell disease: an analysis of the national emergency department sample database.
It is estimated that there are 100,000 people living with sickle-cell disease (SCD) in the United States [1]. The most common manifestation of SCD is vaso-occlusive crisis, which is characterized by intermittent, unexpected episodes of excruciating pain. As these episodes often come on suddenly, much of the care for these crises occurs within emergency departments (EDs). Several studies have examined ED use and costs for certain groups of patients with SCD [2-4]. For example, in 1997, Woods et al. [2] found that 85.7% of 7,202 hospital admissions for SCD in Illinois were for patients that came through the ED, and the total charges for sickle-cell admissions in Illinois were found to be $30 million a year. A recent study of healthcare use by children with SCD demonstrated that children insured by Medicaid had higher ED utilization than those with private insurance (57% vs.45%) [5]. The purpose of our study was to provide national level estimates of ED utilization by SCD patients, which have not previously been available.


Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease.
The history, physical examination, chest radiograph, electrocardiogram and blood gases were evaluated in patients with suspected acute pulmonary embolism (PE) and no history or evidence of pre-existing cardiac or pulmonary disease. The investigation focused upon patients with no previous cardiac or pulmonary disease in order to evaluate the clinical characteristics that were due only to PE. Acute PE was present in 117 patients and PE was excluded in 248 patients. Among the patients with PE, dyspnea or tachypnea (greater than or equal to 20/min) was present in 105 of 117 (90 percent). Dyspnea, hemoptysis, or pleuritic pain was present in 107 of 117 (91 percent). The partial pressure of oxygen in arterial blood on room air was less than 80 mm Hg in 65 of 88 (74 percent). The alveolar-arterial oxygen gradient was greater than 20 mm Hg in 76 of 88 (86 percent). The chest radiograph was abnormal in 98 of 117 (84 percent). Atelectasis and/or pulmonary parenchymal abnormalities were most common, 79 of 117 (68 percent). Nonspecific ST segment or T wave change was the most common electrocardiographic abnormality, in 44 of 89 (49 percent). Dyspnea, tachypnea, or signs of deep venous thrombosis was present in 107 of 117 (91 percent). Dyspnea or tachypnea or pleuritic pain was present in 113 of 117 (97 percent). Dyspnea or tachypnea or pleuritic pain was present in 113 of 117 (97 percent). Dyspnea or tachypnea or pleuritic pain or atelectasis or a parenchymal abnormality on the chest radiograph was present in 115 of 117 (98 percent). In conclusion, among the patients with pulmonary embolism that were identified, only a small percentage did not have these important manifestations or combinations of manifestations. Clinical evaluation, though nonspecific, is of considerable value in the selection of patients in whom there is a need for further diagnostic studies.


Follicular fluid stimulation of 3 beta-hydroxysteroid dehydrogenase activity in vitro.
Follicular fluid from porcine antral follicles stimulates progesterone secretion by porcine granulosa cells from small antral follicles in vitro. Fluid from large (6-12 mm) follicles has more stimulatory activity than fluid from smaller follicles. In this study, we have examined the action of charcoal-treated and filtered follicular fluid on 3 beta-hydroxysteroid dehydrogenase activity (3 beta-HSD) and the ability of exogenous pregnenolone to increase progesterone secretion. Granulosa cells cultured with 30% follicular fluid in TC 199 (v/v) for 3 days were less dependent on the presence of exogenous pregnenolone to enhance their progesterone secretion and exhibited more 3 beta-HSD activity than control cells incubated in 30% serum in TC 199. The apparent Vmax of 3 beta-HSD was increased 80% in follicular fluid-treated cells over that observed in controls (4.8 vs. 2.6 nM/min/100 mg protein) whereas the apparent Kms for 3 beta-HSD were similar (1.3 +/- 0.34 microM) in both experimental and control cells.


Impact and prevention of severe exacerbations of COPD: a review of the evidence.
Severe exacerbations of COPD, ie, those leading to hospitalization, have profound clinical implications for patients and significant economic consequences for society. The prevalence and burden of severe COPD exacerbations remain high, despite recognition of the importance of exacerbation prevention and the availability of new treatment options. Severe COPD exacerbations are associated with high mortality, have negative impact on quality of life, are linked to cardiovascular complications, and are a significant burden on the health-care system. This review identified risk factors that contribute to the development of severe exacerbations, treatment options (bronchodilators, antibiotics, corticosteroids [CSs], oxygen therapy, and ventilator support) to manage severe exacerbations, and strategies to prevent readmission to hospital. Risk factors that are amenable to change have been highlighted. A number of bronchodilators have demonstrated successful reduction in risk of severe exacerbations, including long-acting muscarinic antagonist or long-acting β2-agonist mono- or combination therapies, in addition to vaccination, mucolytic and antibiotic therapy, and nonpharmacological interventions, such as pulmonary rehabilitation. Recognition of the importance of severe exacerbations is an essential step in improving outcomes for patients with COPD. Evidence-based approaches to prevent and manage severe exacerbations should be implemented as part of targeted strategies for disease management.


Changes in Enzyme Regulation during Growth of Maize: III. Intracellular Localization of Homoserine Dehydrogenase in Chloroplasts.
Extracts of leaf tissue of Zea mays L. seedlings were fractionated on nonlinear sucrose gradients to separate subcellular organelles. Homoserine dehydrogenase (EC 188.8.131.52) was identified in those fractions containing intact chloroplasts, as judged by the presence of chlorophyll and triosephosphate isomerase activity. Neither enzyme activity was detected in fractions containing ruptured chloroplasts, mitochondria, or microbodies. Quantitative measurements of enzyme activity and chlorophyll, and electron microscopic analysis of plastid preparations support the conclusion that maize mesophyll chloroplasts contain a significant fraction of the total cellular content of homoserine dehydrogenase.A survey of representative kinetic, regulatory, and physical properties did not reveal any significant differences between enzyme released from isolated, undamaged chloroplasts and that obtained from soluble cellular fractions.Examination of enzyme prepared from chloroplasts of different age seedlings indicated that the sensitivity of homoserine dehydrogenase to inhibition by the feedback modifier l-threonine was progressively diminished during growth of the plants. This systematic change in regulatory properties of the enzyme occurred to the same extent for the enzymes obtained from chloroplasts and soluble fractions.


[Sperm centrifugation in azoospermia?].
In cases of azoospermia especially after vasectomy the investigation of the seminal sediment investigation is necessary. Exclusive on this way it is possible to find some side dispersed spermatozoa. The described case deals with a pregnancy about 48 days following vasectomy. Postoperative the sperm sediment investigation was not performed. In the following judicial hearing the doctor justified himself, that there do'nt exist any special direction in different textbooks of andrology as well as of urology. But this case demonstrates the necessary of the seminal sediment, which is the most important andrological investigation after vasectomy. For this it is not necessary to find special directions, this is common use.


Effect of colchicine on schistosoma-induced renal amyloidosis in Syrian golden hamsters.
Seventy Syrian golden hamsters were infected with Schistosoma haematobium, and 10 uninfected hamsters served as negative controls. Of the schistosome-infected hamsters, 10 served as positive controls (infected but untreated) and the rest (60 hamsters) received treatment. In 30 hamsters treatment was given 9 weeks after infection (before the appearance of renal amyloidosis) and in the other 30 it was given after the appearance of amyloid deposits, 15 weeks after infection. Each treatment group was subdivided into 3 groups (10 hamsters each) in which treatment was either anti-schistosomal alone, combined anti-schistosomal and colchicine, or colchicine alone. Eighteen weeks after infection half of the animals in each group were sacrificed, while the rest were sacrificed 24 weeks after infection. Kidney specimens were evaluated semiquantitatively for renal amyloid deposits. Significant reductions in renal amyloid deposits and proteinuria were observed when combined treatment was given. This was nearly complete with early treatment and only partial when treatment was given late. When colchicine was given alone, a partial but significant reduction in proteinuria with no recognizable effect on renal amyloid deposits was observed. We conclude that colchicine is effective for the prevention and cure of schistosome-related renal amyloidosis in golden hamsters.


Hexavalent chromium responsible for lung lesions induced by intratracheal instillation of chromium fumes in rats.
Lung toxicity of chromium fumes (Cr fumes) was examined by a single intratracheal instillation into rats of 10.6 mg and 21.3 mg Cr fumes/kg body weight and by repeated (3 times) instillations of 10.8 mg and 21.7 mg Cr fumes/kg. The pathological changes were compared with those induced by single administrations of 3.2 mg and 19.2 mg Na2CO3 solution-insoluble fraction of Cr fumes (Cr-Fr)/kg and 20.8 mg commercially available chromium (III) oxide powder (Cr (III) oxide)/kg. Single and repeated administrations of Cr fumes suppressed growth rate in a dose-dependent manner, but administrations of Cr-Fr and Cr (III) oxide did not. A single administration of Cr fumes produced granulomas in the entire airways and alveoli with progressive fibrotic changes, as well as severe mobilization and destruction of macrophages and foamy cells. Those histopathological changes were aggravated by the repeated administration of Cr fumes. On the other hand, single administrations of Cr-Fr and Cr (III) oxide produced no remarkable histopathological changes. Cr fumes were found to be composed of 73.5% chromium (III) oxide and 26.5% chromium (VI) oxide. The primary particles of Cr fumes and Cr-Fr were similar, 0.02 micron in size (sigma g: 1.25), and Cr (III) oxide particles were 0.30 micron in size (sigma g: 1.53), measured by analytical electron microscopy (ATEM). Diffuse clusters of the primary particles in Cr fumes were identified as Cr (VI) oxide. The present results suggested that the lung toxicity of Cr fumes was mainly caused by these Cr (VI) oxide (CrO3) particles in Cr fumes.


Independent prognostic factors in patients with liver cirrhosis.
Evaluation of the urgency of the liver transplantation in individual patients may help to prioritize patients at risk of death. Consequently we undertook the search for independent prognostic factors in patients with liver cirrhosis. The study group was composed of 219 patients with liver cirrhosis, treated in our Department, from 1996 to 2005. Patients' files were examined for details of physical findings, results of laboratory examinations, and patients' survival. Prognostic significance of 15 variables was analyzed. All prognostic factors which turned out to be statistically significant in univariate analysis were included in the Cox proportional hazard model. Child-Turcotte-Pugh (CTP) score B (p<0.001; hazard ratio (HR): 13.33), CTP score C (p<0.001; HR=7.45), presence of hepato-renal syndrome (p<0.001; HR=3.54), history of esophageal bleeding (p=0.048; HR=1.63) and presence of peripheral edema (p=0.034; HR=1.61) were found to be independently associated with survival. Model of End-stage Liver Disease score, etiology of cirrhosis, sex, ascites, bacterial spontaneous peritonitis, encephalopathy, serum creatinine concentration, INR and serum bilirubin concentration were shown to be significantly associated with patients' prognosis, however not independently. Analysis of presence of common clinical symptoms is crucial for evaluation of patients' prognosis.


Trial of telemedicine for patients on home ventilator support: feasibility, confidence in clinical management and use in medical decision-making.
We investigated whether telemedicine (videoconferencing) was feasible in patients with special care needs on home ventilation, whether it affected the confidence of families about the clinical management of their child, and whether it supported clinical decision-making. Videoconferencing software was provided free for 14 families who had a computer and webcam. Families completed questionnaires about clinical management before the addition of telemedicine and 2-3 months after they had used telemedicine. They also completed a questionnaire about their experience with videoconferencing. There were 27 telemedicine encounters during the 9-month study. Families reported higher confidence in clinical care with telemedicine compared to telephone. They also reported that the videoconferencing was high-quality, easy to use, and did not increase their telecommunication costs. The telemedicine encounters supported clinical decision-making, especially in patients with active clinical problems or when the patient was acutely ill. The telemedicine encounters prevented the need for 23 clinic visits, three emergency room visits, and probably one hospital admission. Although the study was small, videoconferencing appears useful in the management of medically fragile patients on home ventilator support, producing high levels of family confidence in clinical management and value to clinicians in their decision-making.


Three-dimensional analysis of structural coloration by a slanted dielectric grating.
The stripe of the tropical freshwater fish "neon tetra" consists of many iridophores, in which tilted reflecting platelets are periodically arranged. The neon tetra has structural coloration and changes the color of a stripe in response to the surrounding conditions. The mechanism of the color change is thought to be controlling a slant angle of the platelets and changing the spacing between the platelets. This paper considers a slanted dielectric grating modeled on an iridophore of neon tetra, and formulates the matrix eigenvalues method as an analytical method for the three-dimensional scattering problem of a slanted grating having a grating vector. Calculating the reflection spectrum using the matrix eigenvalues method, the chromatic coordinates in standard red-green-blue color space, and the xy chromaticity coordinates for a slanted grating, it is shown that the color changes depending on the slant angles numerically.


Ligand-based molecular modeling study on a chemically diverse series of cholecystokinin-B/gastrin receptor antagonists: generation of predictive model.
Pharmacophore hypotheses were developed for six structurally diverse series of cholecystokinin-B/gastrin receptor (CCK-BR) antagonists. A training set consisting of 33 compounds was carefully selected. The activity spread of the training set molecules was from 0.1 to 2100 nM. The most predictive pharmacophore model (hypothesis 1), consisting of four features, namely, two hydrogen bond donors, one hydrophobic aliphatic, and one hydrophobic aromatic feature, had a correlation (r) of 0.884 and a root-mean-square deviation of 1.1526, and the cost difference between null cost and fixed cost was 81.5 bits. The model was validated on a test set consisting of six different series of 27 structurally diverse compounds and performed well in classifying active and inactive molecules correctly. This validation approach provides confidence in the utility of the predictive pharmacophore model developed in this work as a 3D query tool in the virtual screening of drug-like molecules to retrieve new chemical entities as potent CCK-BR antagonists. The model can also be used to predict the biological activities of compounds prior to their costly and time-consuming synthesis.


Role of the central nervous system in hemodynamic and sympathoadrenal responses to cocaine in rats.
These studies were undertaken to examine the contribution of central nervous system mechanisms to the cardiovascular and sympathoadrenal effects of cocaine. Changes in systolic and diastolic blood pressure, heart rate and plasma catecholamine concentrations were determined in response to cocaine injected i.a. or i.c.v. in conscious unrestrained rats. Systemically administered cocaine produced brisk, transient dose-related increases in systolic and diastolic pressure at doses of 0.05 to 5 mg/kg i.a. Plasma catecholamine concentrations increased in a dose-related manner, reaching peak levels at 5 to 10 min after i.a. cocaine injection. Only the higher doses of cocaine induced reflex vagal bradycardia that was blocked by atropine (0.4 mg/kg i.a.). Propranolol (1 mg/kg i.a.) prolonged the duration of cocaine-induced hypertension and bradycardia. Ganglionic blockade with chlorisondamine (7.5 mg/kg i.a.) antagonized completely the cardiovascular and sympathoadrenal effects of cocaine, indicating that intact ganglionic transmission is required for full expression of the autonomic responses. Antagonist drugs selective for the D-1 or D-2 dopamine receptors attenuated effects of cocaine on plasma catecholamine concentrations but not on cardiovascular parameters. Intracerebroventricular injection of cocaine (50-250 micrograms) increased systolic pressure and plasma catecholamine concentrations, providing direct evidence for an action of cocaine in the central nervous system. These results demonstrate that cocaine acts centrally to increase sympathetic outflow leading to hypertension and reflex bradycardia in conscious rats.


Novel three-dimensional bioglass functionalized gelatin nanofibrous scaffolds for bone regeneration.
The clinical use of FDA-approved bone morphogenetic proteins (BMPs) are impeded by high costs, super-high dosage requirement, short half-life, and other undesirable side effects. Therefore, designing a biomaterial that can promote new bone formation without using exogenous BMPs is highly desirable in clinical applications. In the present work, a new kind of nanofibrous scaffold composed of gelatin and 45S5 bioglass (GF/45S5 BG) was prepared through thermally induced phase separation method together with the particle leach technique (TIPS&P). In addition to the significantly higher mechanical strength, the composite scaffolds (GF/45S5 BG) significantly increased osteogenic differentiation of human mesenchymal stem cells (hMSCs) in vitro compared with the neat scaffold (GF) without adding other biological agents, for example, BMPs or hormones. Most importantly, our in vivo studies also indicated that GF/45S5 BG scaffolds could directly promote ectopic bone regeneration in SD rats without exogenous BMP2. In summary, both in vitro and in vivo results indicated that the novel 45S5 bioglass functionalized GF nanofibrous scaffold is a promising alternative for bone tissue engineering.


Prior experience of captivity affects behavioural responses to 'novel' environments.
Information ecology theory predicts that prior experience influences current behaviour, even if the information is acquired under a different context. However, when individuals are tested to quantify personality, cognition, or stress, we usually assume that the novelty of the test is consistent among individuals. Surprisingly, this 'gambit of prior experience' has rarely been explored. Therefore, here we make use of a wild population of great tits (Parus major) to test if prior experience of handling and captivity influences common measures of exploration (open field tests in two novel contexts: room and cage arenas), social response (simulated using a mirror), and behavioural stress (breathing rate). We found that birds with prior experience of captivity (caught previously for unrelated learning and foraging experiments) were more exploratory, but this depended on age: exploration and captivity experience (in terms of both absolute binary experience and the length of time spent in captivity) were associated more strongly in young (first-winter) birds than in adults. However, there was no association of prior experience of captivity with social response and breathing rate, and nor did the measures of exploration correlate. Together our results suggest that re-testing of individuals requires careful consideration, particularly for younger birds, and previous experiences can carry over and affect behaviours differently.


Tissue specific disruption of photosynthetic electron transport rate in pigeonpea (Cajanus cajan L.) under elevated temperature.
Nutritional rich pigeonpea (Cajanus cajan [L.]), a perennial shrub member of family Fabaceae is the sixth most important grain legume of the world. Continuous rise of temperature and current global climate scenario limits plant growth and performance but photosynthetic machineries are adversely affected. The aim of this study was the analysis of tissue specific photosynthetic pigments and photosynthetic electron transport rate under elevated temperature. Two different stages of both leaf (young and mature), and pod (young and mature) were chosen, and photosynthetic pigment and J-I-P tests were measured. Leaves and pods were detached and incubated in normal temperature (25°C) for 24 h in two different condition one light irradiance (100 µmol m-2 s-1) and another darkness as control, and treated with high temperature 45°C for 24 h and repeated previous measurements were taken. Tissue specific photosynthetic pigments variation were observed; J-I-P parameters clearly revealed that elevated temperature has greater influence on photosystem II (PSII) electron transport than photosystem I (PSI), and significant changes were observed in pods than leaves. Young tissues were adversely affected by elevated temperature. In addition, the J-I-P tests and energy pipeline model indicated that PSI electron transport rate of leaves and pods appeared to be more thermo-tolerance than those in PSII. Only a minor drop in pigments pool and photosynthetic performance was observed after 24 h of darkness. O-J-I-P transients can be used as a sensitive, nondestructive method for measuring heat stress damage and a special tool for investigating action sites of high temperature stress. Findings of this study will contribute to basic understanding of photosynthetic performance, and to screen potential thermo-tolerant genotypes of pigeonpea to sustain in either current scenario of climate change or/and erratic future climatic conditions.


Directionalities of magnetic fields and topographic scaffolds synergise to enhance MSC chondrogenesis.
Mesenchymal stem cell (MSC) chondrogenesis is modulated by diverse biophysical cues. We have previously shown that brief, low-amplitude pulsed electromagnetic fields (PEMFs) differentially enhance MSC chondrogenesis in scaffold-free pellet cultures versus conventional tissue culture plastic (TCP), indicating an interplay between magnetism and micromechanical environment. Here, we examined the influence of PEMF directionality over the chondrogenic differentiation of MSCs laden on electrospun fibrous scaffolds of either random (RND) or aligned (ALN) orientations. Correlating MSCs' chondrogenic outcome to pFAK activation and YAP localisation, MSCs on the RND scaffolds experienced the least amount of resting mechanical stress and underwent greatest chondrogenic differentiation in response to brief PEMF exposure (10 min at 1 mT) perpendicular to the dominant plane of the scaffolds (Z-directed). By contrast, in MSC-impregnated RND scaffolds, greatest mitochondrial respiration resulted from X-directed PEMF exposure (parallel to the scaffold plane), and was associated with curtailed chondrogenesis. MSCs on TCP or the ALN scaffolds exhibited greater resting mechanical stress and accordingly, were unresponsive, or negatively responsive, to PEMF exposure from all directions. The efficacy of PEMF-induced MSC chondrogenesis is hence regulated in a multifaceted manner involving focal adhesion dynamics, as well as mitochondrial responses, culminating in a final cellular response. The combined contributions of micromechanical environment and magnetic field orientation hence will need to be considered when designing magnetic exposure paradigms.


Altered expression of transcription factors IRF4 and IRF8 in peripheral blood B cells is associated with clinical severity and circulating plasma cells frequency in patients with myasthenia gravis.
Previous studies have shown that interferon regulatory factor-4 (IRF4) and IRF8 play critical but distinct roles in the differentiation of B cells into plasma cells (PCs). In the present study, we aimed to measure the expression levels of IRF4 and IRF8 in B cells from patients with myasthenia gravis (MG) and to investigate whether the expression of IRF4 and IRF8 associates with pathogenesis of MG. A total of 35 anti-acetylcholine receptor (AChR) antibody (Ab)-positive patients with MG [20 generalized MG (GMG) and 15 ocular MG (OMG) and 25 healthy donors were recruited in this study. The quantitative myasthenia gravis score (QMGS) was used to evaluate the clinical severity. Real-time PCR and Western blot were used to measure the levels of IRF4 and IRF8 expressed in peripheral blood B cells. Peripheral blood CD138+ PCs were assayed by flow cytometry. Our data demonstrated that the mRNA/protein levels of IRF4 and IRF8 were significantly higher and lower, respectively, in patients with OMG/GMG groups compared with healthy controls. In addition, IRF4 expression was significantly higher and IRF8 expression was significantly lower in GMG group than in OMG group. Pearson's correlation analysis revealed that IRF8 expression was negatively correlated with clinical severity, PCs frequency and anti-AChR Ab levels, while IRF4 expression and IRF4/IRF8 ratio was positively correlated with these parameters in two MG subgroups. Finally, glucocorticoid treatment can relieve the imbalance of IRF4/IRF8 in peripheral blood B cells, and this restoration is accompanied by reduced PCs frequency and clinical symptoms. These evidences suggest that IRF4 and IRF8 are important in the counter-balancing mechanisms controlling differentiation of PCs in MG. The disruption of the balanced IRF4/IFR8 ratio in B cells may play important roles in the pathogenesis of MG and offer a promising therapeutic target for the development of novel immunotherapy for MG patients.


[Factors related with pathological complete response of neoadjuvant chemotherapy in primary breast cancer].
To assess the effect of neoadjuvant chemotherapy and the factors related with pathological complete response (pCR) of neoadjuvant chemotherapy in breast cancer. The data of 159 primary breast cancer patients who had received neoadjuvant chemotherapy and operation with complete MRI data and histopathology evaluation in this center from January 2009 to December 2011 was analyzed. All the patients were female, aging from 28 to 70 years with a median of 50 years. The neoadjuvant chemotherapy regimens were based on anthracyclines or taxanes, and trastuzumab was used in almost half of the human epidermalgrowth factor receptor 2 positive patients. The response of neoadjuvant chemotherapy was comprehensively evaluated based on RECIST 1.1 and Miller-Payne grading system. SPSS 18.0 was used for statistical analysis. Among the 159 patients, 10.1% patients had achieved complete response according to the MRI evaluation, and the rate of partial response, stable disease, and progressive disease was 65.4%, 24.5%, and 0 respectively. According to the Miller-Payne grading system, 27.7% patients had pathological response evaluated as G5 (pCR), and the response evaluated as G4, G3, G2, and G1 were 28.3%, 18.9%, 12.6%, and 12.6% respectively. The higher histological grade were correlated with pCR statistically (Z = -2.820, P = 0.005). Meanwhile strong expression of Ki67 (Z = -1.989, P = 0.047) and p53 (Z = -2.457, P = 0.014) were related to pCR in a significant statistically way. The response of neoadjuvant chemotherapy can be predicted. The histological grade and the immunohistochemistry results of Ki67 and p53 are related to pCR of neoadjuvant chemotherapy for primary breast cancer. Basal-like breast cancer had a higher pCR statistically.


Ammonium tolerance in the cyanobacterium Synechocystis sp. strain PCC 6803 and the role of the psbA multigene family.
Ammonium is one of the major nutrients for plants, and a ubiquitous intermediate in plant metabolism, but it is also known to be toxic to many organisms, in particular to plants and oxygenic photosynthetic microorganisms. Although previous studies revealed a link between ammonium toxicity and photodamage in cyanobacteria under in vivo conditions, ammonium-induced photodamage of photosystem II (PSII) has not yet been investigated with isolated thylakoid membranes. We show here that ammonium directly accelerated photodamage of PSII in Synechocystis sp. strain PCC6803, rather than affecting the repair of photodamaged PSII. Using isolated thylakoid membranes, it could be demonstrated that ammonium-induced photodamage of PSII primarily occurred at the oxygen evolution complex, which has a known binding site for ammonium. Wild-type Synechocystis PCC6803 cells can tolerate relatively high concentrations of ammonium because of efficient PSII repair. Ammonium tolerance requires all three psbA genes since mutants of any of the three single psbA genes are more sensitive to ammonium than wild-type cells. Even the poorly expressed psbA1 gene, whose expression was studied in some detail, plays a detectable role in ammonium tolerance.


Double-strand DNA cleavage by copper complexes of 2,2'-dipyridyl with guanidinium/ammonium pendants.
Two ligands with guanidinium/ammonium groups were synthesized and their copper complexes, [Cu(L1)Cl2](ClO4)2.H2O (1) and [Cu(L2)Cl2](ClO4)2 (2) (L1 = 5,5'-di[1-(guanidyl)methyl]-2,2'-bipyridyl cation and L2 = 5,5'-di[1-(amino)methyl]-2,2'-bipyridyl cation), were prepared to serve as nuclease mimics. X-Ray analysis revealed that Cu(II) ion in 1 has a planar square CuN2Cl2-configuration. The shortest distance between the nitrogen of guanidinium and copper atoms is 6.5408(5) A, which is coincident with that of adjacent phosphodiesters in DNA (ca. 6 A). In the absence of reducing agent, supercoiled plasmid DNA cleavage by the complexes were performed and their hydrolytic mechanisms were demonstrated with radical scavengers and T4 ligase. The pseudo-Michaelis-Menten kinetic parameters (kcat, KM) were calculated to be 4.42 h(-1), 7.46 x 10(-5) M for 1, and 4.21 h(-1), 1.07 x 10(-4) M for 2, respectively. The result shows that their cleavage efficiency is about 10-fold higher than the simple analogue [Cu(bipy)Cl2] (3) (0.50 h(-1), 3.5 x 10(-4) M). The pH dependence of DNA cleavage by 1 and its hydroxide species in solution indicates that mononuclear [Cu(L1)(OH)(H2O)]3+ ion is the active species. Highly effective DNA cleavage ability of is attributed to the effective cooperation of the metal moiety and two guanidinium pendants with the phosphodiester backbone of nucleic acid.


Community mental health centers and family service agencies.
This study presents documentation that compares community mental health centers and family service agencies. Although these are complementary in function, their degree of interaction is less than optimal. This paper compares the characteristics of the two systems, using data regarding staff, finances and expenditures, clients, and programs.


Tuberculous lymphadenitis as a cause of obstructive jaundice.
Obstructive jaundice secondary to abdominal tuberculosis is extremely rare. We present a patient with jaundice secondary to compression of the common bile duct by TB lymphadenitis. A 49-year-old woman was admitted to our department for nausea,epigastric pain and jaundice. Abdominal ultrasonography and computer tomography scan were suggestive of stenosis of the distal common bile duct caused by a retro pancreatic mass. At laparotomy, an enlarged lymph node behind the head of the pancreas was found, causing compression and stenosis of the distal parts of the choledochus. The lymph node frozen section analysis showed epithelioid granuloma with caseous necrosis,strongly suggesting tuberculous origin. Choledochoduodenal anastomosis was performed. Definitive pathohistological examination confirmed TB lymphadenitis. ATB should be considered as a potential cause of jaundice especially in immuno compromised patients and endemic areas. Diagnosing abdominal tuberculosis can be a challenging task. No satisfactory diagnostic gold standard is available so that in most cases the diagnosis cannot be reached before exploratory laparotomy.Early detection enables successful conservative treatment and eliminates the necessity of surgery.