Prediction of drug adverse events using deep learning in pharmaceutical discovery.
Traditional machine learning methods used to detect the side effects of drugs pose significant challenges as feature engineering processes are labor-intensive, expert-dependent, time-consuming and cost-ineffective. Moreover, these methods only focus on detecting the association between drugs and their side effects or classifying drug-drug interaction. Motivated by technological advancements and the availability of big data, we provide a review on the detection and classification of side effects using deep learning approaches. It is shown that the effective integration of heterogeneous, multidimensional drug data sources, together with the innovative deployment of deep learning approaches, helps reduce or prevent the occurrence of adverse drug reactions (ADRs). Deep learning approaches can also be exploited to find replacements for drugs which have side effects or help to diversify the utilization of drugs through drug repurposing.


Intracardiac thrombi in acute myeloid leukemia: an echocardiographic and autopsy correlation.
Two-dimensional echocardiography is the primary diagnostic imaging modality for the evaluation of cardiac masses. We describe an adult male suffering from acute myeloid leukemia who was detected to have right atrial and right ventricular mass on echocardiography. Based on the clinical data metastasis, coincidental primary cardiac tumor, vegetation, and thrombi were considered as possible differential diagnosis. Chemotherapy for acute myeloid leukemia failed and patient succumbed to septicemia. Later, clinical autopsy confirmed the diagnosis of intracardiac thrombi. Occurrence of intracardiac thrombi in acute myeloid leukemia is extremely rare. This report also emphasises the importance of histopathological or clinical autopsy examination of the mass in certain clinical scenario with diagnostic dilema.


Methylthioadenosine phosphorylase as target for chemoselective treatment of T-cell acute lymphoblastic leukemic cells.
We analyzed the role of methylthioadenosine phosphorylase (MTAP) for chemoselective treatment of T-cell acute lymphoblastic leukemia (T-ALL). MTAP converts methylthioadenosine into adenine which serves as an alternative purine source, if de novo purine biosynthesis is inhibited by antimetabolites (i.e., methotrexate). The idea of the chemoselectivity concept is that tumors with MTAP deletion at chromosome 9p21 are more susceptible to antimetabolites than normal cells without such a deletion. First, we screened 13 T-ALL lines for 9p21 deletions by comparative genomic hybridization. Five cell lines revealed deletions at the short arm of chromosome 9, dim(9p21pter). Further analyses were performed with CEM cells in which the 9p21 deletion was corroborated by fluorescence in situ hybridization. CEM cells were transfected with an MTAP expression vector. A green fluorescent protein (GFP) plasmid was cotransfected, to monitor the transfection efficacy by flow cytometry. The response of MTAP-transfected cells to the antimetabolites methotrexate (MTX), trimetrexate (TMX), and L-alanosine (ALA) was decreased compared to mock control transfectants using growth inhibition assays. The activity of doxorubicin (DOX) which is not involved in DNA biosynthesis was not changed in MTAP transfectants. As the p16(INK4a) tumor suppressor gene resides also at 9p21, we transfected CEM cells with a p16(INK4a) expression vector. These transfectant cells were more resistant to all four drugs indicating that p16(INK4a) did not specifically affect antimetabolites. The chemoselective effect of antimetabolites in MTAP-deleted tumor cells may, however, be compensated by the development of drug resistance. To prove this possibility, we analyzed an MTX-resistant subline, CEM/MTX1500LV, in which the MTX-resistance conferring dihydrofolate reductase (DHFR) gene was amplified. While TMX exhibited considerable cross-resistance in CEM/MTX1500LV cells, ALA did not. Thus, ALA could exhibit chemoselectivity in 9p21/MTAP-deleted cells, even if DHFR amplification occurs. We conclude that ALA may be more suitable than MTX or TMX for MTAP-mediated chemoselective treatment of T-ALL. Pretherapeutical detection of 9p21 and MTAP deletion may be helpful in developing a predictive molecular chemosensitivity test for T-ALL.


Probable clonal origin of acute myeloblastic leukemia following radiation and chemotherapy of colon cancer.
A 64-yr-old female developed acute myeloblastic leukemia following radiation and drug therapy for colon carcinoma. The patient was heterozygous for glucose-6-phosphate dehydrogenase (G-6-PD) and displayed types A and B isoenzymes in nonhematopoietic tissue. In contrast, only type B G-6-PD was observed in peripheral blood white cells. In addition, a karyotypic abnormality was found in peripheral blood and marrow cells but not in skin fibroblasts. The data are consistent with a clonal origin of this leukemia.


An update on ovarian suppression/ablation.
Adjuvant ovarian function suppression is acknowledged today as effective therapy for premenopausal patients with early breast cancer. Various modalities have been applied to achieve this treatment option: First, early investigations comparing ovarian ablation with chemotherapy identified similar outcomes in terms of patients' rates of disease-free survival (DFS). Second, prospective randomized trials have more recently focused on luteinizing hormone-releasing hormone analogues (LHRHa) that induce medical ovarian suppression and avoid the morbidity and irreversibility associated with surgical ovariectomy or irradiation. These trials analyzed the value of treatment with goserelin or other LHRHa, with or without tamoxifen, as against chemotherapy. Goserelin was subsequently established as a valid alternative, and our own results demonstrated that goserelin + tamoxifen is more effective and better tolerated in hormone-responsive patients. Third, other multiple-arm studies have compared LHRHa + chemotherapy with chemotherapy alone. Addition of tamoxifen to goserelin + chemotherapy was shown to improve DFS, and significant benefits in goserelin-treated patients were seen irrespective of use of chemotherapy or tamoxifen. Finally, ongoing trials are addressing the appropriate duration of LHRHa therapy and other unresolved issues. In summary, combined ovarian suppression with adjuvant goserelin and tamoxifen is considered to be at least as effective as chemotherapy in premenopausal breast cancer patients. Published reports have demonstrated that ovarian suppression is a safe means of reducing risk of recurrence in estrogen receptor-positive women and underlined its use as a competitive alternative to chemotherapy in this patient subset.


AAV2-mediated combined subretinal delivery of IFN-α and IL-4 reduces the severity of experimental autoimmune uveoretinitis.
We previously showed that adeno-associated virus 2 (AAV2) mediated subretinal delivery of human interferon-alpha (IFN-α) could effectively inhibit experimental autoimmune uveoretinitis (EAU). In this study we investigated whether subretinal injection of both AVV2.IFN-α and AAV2.IL-4 had a stronger inhibition on EAU activity. B10RIII mice were subretinally injected with AAV2.IFN-α alone (1.5×10(7) vg), AAV2.IL-4 alone (3.55×10(7) vg), and AAV2.IFN-α combined with AAV2.IL-4. PBS, AAV2 vector encoding green fluorescent protein (AAV2.GFP) (5×10(7) vg) was subretinally injected as a control. IFN-α and IL-4 were effectively expressed in the eyes from three weeks to three months following subretinal injection of AAV2 vectors either alone or following combined administration and significantly attenuated EAU activity clinically and histopathologically. AAV2.IL-4 showed a better therapeutic effect as compared to AAV2.IFN-α. The combination of AAV2.IL-4 and AAV2.IFN-α was not significantly different as compared to AAV2.IL-4 alone. There was no difference concerning DTH (delayed-type hypersensitivity) reaction, lymphocyte proliferation and IL-17 production among the investigated treatment groups, suggesting that local retinal gene delivery did not affect the systemic immune response.


Chondrosarcoma apoplexy in thoracic spine.
Chondrosarcoma is a very uncommon malignant primary bone tumor, especially, it occurs extremely rare in the spine. A 52-year-old man was admitted to the emergency room with sudden paraplegia. Twelve hours prior to a paraplegic event, he visited an outpatient clinic with discomfort and tenderness around the medial border of the right scapular, and his neurologic status was absolutely intact. Magnetic resonance imaging showed a lobulated soft tissue mass from T3 to T5, which extended to the epidural space. Computed tomography scans showed soft tissue mass on the spinal posterior arch and osteolytic change of the adjacent bony structures. Emergent surgery was performed and the lesion was removed. Dark reddish blood and gel-like material were encountered around the dura and posterior arch during the operation. Multiple pulmonary nodules were found on a chest CT scan and a biopsy of one of them had been proven to be a metastasis of chondrosarcoma. The histologic examination showed dedifferentiated chondrosarcoma. The patient's neurologic deficit was improved slowly from ASIA A to ASIA D. Chondrosarcoma in the spine is extremely rare, even more with acute hemorrhage and sudden expansion into the epidural space. We named it chondrosarcoma apoplexy. We should consider the possibility of a hemorrhagic event when the patient's neurologic deficit worsens suddenly with spinal bone tumor.


Dietary feeding of silibinin inhibits advance human prostate carcinoma growth in athymic nude mice and increases plasma insulin-like growth factor-binding protein-3 levels.
We have reported recently the anticancer effect of flavonoid antioxidant silymarin, the major part of milk thistle extract, against advanced human prostate carcinoma DU145 cells (X. Zi et al., Cancer Res., 58: 1920-1929, 1998) and later identified that silibinin is the main active component in silymarin responsible for its effect in cell culture studies. On the basis of these observations, here we assessed in vivo growth inhibitory potential of silibinin against advanced human prostate cancer (PCA). Dietary feeding of silibinin at 0.05 and 0.1% doses (w/w) for 60 days, 24 h after s.c. DU145 tumor xenograft implantation in athymic male nude mice, significantly inhibited tumor volume by 35 and 58% (P < 0.05), and wet weight of tumor by 29 and 40% (P < 0.05), respectively. In a second experiment where mice were fed with these test diets for 3 weeks before tumor xenograft implantation and continued on these diets for a total of 63 days, tumor volume and wet weight of tumor were reduced by 53-64% (P < 0.001-0.05) and 31-52% (P < 0.05), respectively. In both studies, animals did not show weight loss or reduced food consumption. These in vivo anticancer effects of silibinin were associated with an increased accumulation (up to 5.8 fold; P < 0.05) of human insulin-like growth factor-binding protein-3 in mouse plasma. In additional studies assessing biological availability of silibinin in nude mice and its antiproliferative activity at such doses in DU145 cells in culture, silibinin levels in plasma and prostate were found to be in the range of 7-13 microg/ml and 3.7-4.6 microg/g, respectively. At these biologically achievable silibinin concentrations, increased IGFBP-3 level in DU145 cell culture medium and a strong DU145 cell growth inhibition were observed that were irreversible in the absence of silibinin in culture medium. These findings extend and translate our observations on in vitro anticancer effect of silibinin/silymarin to an in vivo preclinical PCA model, which may form the basis for a Phase I clinical trial in PCA patients.


Comparison of miRNA Evolution and Function in Plants and Animals.
MicroRNAs (miRNAs), as a major player in post-transcriptional regulation of gene expression, have been reported to regulate a broad variety of key biological processes, including growth, development and stress responses in both plants and animals. While the biogenesis and regulatory abilities of miRNAs have been extensively studied, the evolutionary history of miRNAs still needs more exploration. So far, several models explain the origination of plant and animal MIRNA (MIR) genes. Both inter-species and intra-species conservation and divergence of miRNAs exhibits functional adaptation to changing environments in evolution. Here we summarize recent progress in how these similarities and differences contribute to the characteristic features of miRNA evolution in the two kingdoms.


Disassembly of Subplasmalemmal Actin Filaments Induces Cytosolic Ca2+ Increases in Astropecten aranciacus Eggs.
Eggs of all animal species display intense cytoplasmic Ca2+ increases at fertilization. Previously, we reported that unfertilized eggs of Astropecten aranciacus exposed to an actin drug latrunculin A (LAT-A) exhibit similar Ca2+ waves and cortical flashes after 5-10 min time lag. Here, we have explored the molecular mechanisms underlying this unique phenomenon. Starfish eggs were pretreated with various agents such as other actin drugs or inhibitors of phospholipase C (PLC), and the changes of the intracellular Ca2+ levels were monitored by use of Calcium Green in the presence or absence of LAT-A. The concomitant changes of the actin cytoskeleton were visualized with fluorescent F-actin probes in confocal microscopy. We have shown that the LAT-A-induced Ca2+ increases are related to the disassembly of actin flaments: i) not only LAT-A but also other agents depolymerizing F-actin (i.e. cytochalasin B and mycalolide B) induced similar Ca2+ increases, albeit with slightly lower efficiency; ii) drugs stabilizing F-actin (i.e. phalloidin and jasplakinolide) either blocked or significantly delayed the LAT-A-induced Ca2+ increases. Further studies utilizing pharmacological inhibitors of PLC (U-73122 and neomycin), dominant negative mutant of PLC-ɣ, specific sequestration of PIP2 (RFP-PH), InsP3 uncaging, and quantitation of endogenous InsP3 all indicated that LAT-A induces Ca2+ increases by stimulating PLC rather than sensitizing InsP3 receptors. In support of the idea, it bears emphasis that LAT-A timely increased intracellular contents of InsP3 with concomitant decrease of PIP2 levels in the plasma membrane. Taken together, our results suggest that suboolemmal actin filaments may serve as a scaffold for cell signaling and modulate the activity of the key enzyme involved in intracellular Ca2+ signaling.


Microfluidized hemp protein isolate: an effective stabilizer for high-internal-phase emulsions with improved oxidative stability.
Hemp protein isolates (HPIs), which provide a well-balanced profile of essential amino acids comparable to other high-quality proteins, have recently garnered significant attention. However, the underutilized functional attributes of HPIs have constrained their potential commercial applications within the food and agriculture field. This study advocates the utilization of dynamic-high-pressure-microfluidization (DHPM) for the production of stable high-internal-phase emulsions (HIPEs), offering an efficient approach to fully exploit the potential of HPI resources. The findings underscore the effectiveness of DHPM in producing HPI as a stabilizing agent for HIPEs with augmented antioxidant activity. Microfluidized HPI exhibited consistent adsorption and anchoring at the oil-water interface, resulting in the formation of a dense and compact layer. Concurrently, the compression of droplets within HIPEs gave rise to a polyhedral framework, conferring viscoelastic properties and a quasi-solid behavior to the emulsion. Remarkably, HIPEs stabilized by microfluidized HPI demonstrated superior oxidative and storage stability, attributable to the establishment of an antioxidative barrier by microfluidized HPI particles. This study presents an appealing approach for transforming liquid oils into solid-like fats using HPI particles, all without the need for surfactants. HIPEs stabilized by microfluidized HPI particles hold promise as emerging food ingredients for the development of emulsion-based formulations with enhanced oxidative stability, thereby finding application in the food and agricultural industries. © 2023 Society of Chemical Industry.


Contact angle anomalies indicate that surface-active eluates from silicone coatings inhibit the adhesive mechanisms of fouling organisms.
Silicone coatings with critical surface tensions (CST) between 20 and 30 mN m-1 more easily release diverse types of biofouling than do materials of higher and lower CST. Oils added to these coatings selectively further diminish the attachment strengths of different marine fouling organisms, without significantly modifying the initial CST. In a search for the mechanisms of this improved biofouling resistance, the interfacial instabilities of four silicone coatings were characterised by comprehensive contact angle analyses, using up to 12 different diagnostic fluids selected to mimic the side chain chemistries of the common amino acids of bioadhesive proteins. The surfaces of painted steel test panels were characterised both before and after exposure to freshwater, brackish water, and seawater over periods ranging from 9 months to nearly 4 years. Contact angle measurements demonstrated significant surface activity of the oil-amended coatings both before and after long-term underwater exposure. The surface activity of the control (coating without oil) increased as a result of underwater exposure, consistent with mild surface chain scission and hydrolysis imparting a self-surfactancy to the coating and providing a weak boundary layer promoting continuing easy release of attaching foulants. Coatings with additives that most effectively reduced biofouling showed both initial and persistent contact angle anomalies for the test liquid, thiodiglycol, suggesting lower-shear biofouling release mechanisms based upon diminished bioadhesive crosslinking by interfering with hydrogen- and sulfhydryl bonds. Swelling of the silicone elastomeric coatings by hydrocarbon fluids was observed for all four coatings, before and after immersion.


Side-chain dynamics of an alpha-helical polypeptide monitored by fluorescence.
The "blob" model, developed to analyze the fluorescence decays of polymers randomly labeled with pyrene, has been applied to a series of pyrene-labeled poly(glutamic acid)s (PyPGA) in DMF and carbonated buffer solutions at pH 9. Poly(glutamic acid) (PGA) exists in the ionized form in the buffer solutions as poly(sodium glutamate) (PGNa). PGA adopts an alpha-helical conformation in DMF, whereas in aqueous solution PGNa is a random coil. Fluorescence, UV-vis absorption, and circular dichroism measurements indicate that in our studies pyrene pendants attached themselves along PGA in a clustered manner. Simulations were carried out to establish that the geometry of the PGA alpha-helix induces the high level of pyrene clustering. Since the level of pyrene clustering decreased with lower pyrene content, information about naked PGA was retrieved by extrapolating the trends obtained by fluorescence to zero pyrene content. Analysis of the fluorescence decays demonstrated that during its lifetime an excited pyrene probes a 32 amino acid section of the PGA alpha-helix. This result was supported by molecular mechanics optimizations. This study establishes that the blob model, originally used to monitor the encounters between pyrenes attached randomly onto a polymer adopting a random coil conformation, can also be applied to study the dynamics of the side chains of structured proteins. Since the blob model helps in monitoring the encounters between amino acids in the initial state (i.e., random coil) and in the final state (i.e., structured protein) of the folding pathway of a protein, it could be applicable to the study of protein folding.


Effect of growth factors on oocyte maturation and allocations of inner cell mass and trophectoderm cells of cloned bovine embryos.
This study was conducted to determine the additive effects of exogenous growth factors during in vitro oocyte maturation (IVM) and the sequential culture of nuclear transfer (NT) embryos. Oocyte maturation and culture of reconstructed embryos derived from bovine granulosa cells were performed in culture medium supplemented with either epidermal growth factor (EGF) alone or a combination of EGF with insulin-like growth factor-I (IGF-I). The maturation rates of oocytes matured in the presence of EGF or the EGF + IGF-I combination were significantly higher than those of oocytes matured in the presence of only fetal calf serum (FCS) (P 0.05). IGF-I alone or in combination with EGF in sequential embryo culture medium significantly increased the ratio of inner cell mass (ICM) to total blastocyst cells (P < 0.05). Our results showed that the addition of growth factors to IVM and sequential culture media of cloned bovine embryos increased the ICM without changing the total cell number. These unknown and uncontrolled effects of growth factors can alter the allocation of ICM and trophectoderm cells (TE) in NT embryos. A decrease in TE cell numbers could be a reason for developmental abnormalities in embryos in the cloning system.


In vivo assessment of protease dynamics in cutaneous wound healing by degradomics analysis of porcine wound exudates.
Proteases control complex tissue responses by modulating inflammation, cell proliferation and migration, and matrix remodeling. All these processes are orchestrated in cutaneous wound healing to restore the skin's barrier function upon injury. Altered protease activity has been implicated in the pathogenesis of healing impairments, and proteases are important targets in diagnosis and therapy of this pathology. Global assessment of proteolysis at critical turning points after injury will define crucial events in acute healing that might be disturbed in healing disorders. As optimal biospecimens, wound exudates contain an ideal proteome to detect extracellular proteolytic events, are noninvasively accessible, and can be collected at multiple time points along the healing process from the same wound in the clinics. In this study, we applied multiplexed Terminal Amine Isotopic Labeling of Substrates (TAILS) to globally assess proteolysis in early phases of cutaneous wound healing. By quantitative analysis of proteins and protein N termini in wound fluids from a clinically relevant pig wound model, we identified more than 650 proteins and discerned major healing phases through distinctive abundance clustering of markers of inflammation, granulation tissue formation, and re-epithelialization. TAILS revealed a high degree of proteolysis at all time points after injury by detecting almost 1300 N-terminal peptides in ∼450 proteins. Quantitative positional proteomics mapped pivotal interdependent processing events in the blood coagulation and complement cascades, temporally discerned clotting and fibrinolysis during the healing process, and detected processing of complement C3 at distinct time points after wounding and by different proteases. Exploiting data on primary cleavage specificities, we related candidate proteases to cleavage events and revealed processing of the integrin adapter protein kindlin-3 by caspase-3, generating new hypotheses for protease-substrate relations in the healing skin wound in vivo. The data have been deposited to the ProteomeXchange Consortium with identifier PXD001198.


[The role of surgical treatment in the management of nonparasitic hepatic cysts in Madagascar].
Non-parasitic liver cysts are rare in our country. We report the second case in a 61-year-old woman admitted for a painful epigastric mass. The diagnosis was suggested by ultrasound and confirmed by histological examination of the surgical specimen. Surgical treatment was performed through a right transverse subcostal incision and consisted of a maximal resection of the cystic wall. No complications followed. After 12 months, the patient was asymptomatic, and no recurrence had been observed.


Education modifies the relationship between height and cognitive function in a cross-sectional population-based study of older adults in Rural South Africa.
We aimed to estimate the relationship between height (a measure of early-life cumulative net nutrition) and later-life cognitive function among older rural South African adults, and whether education modified this relationship. Data were from baseline in-person interviews with 5059 adults ≥ 40 years in the population-based "Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa" (HAALSI) study in Agincourt sub-district, South Africa, in 2015. Linear regression was used to estimate the relationship between height quintile and latent cognitive function z-score (representing episodic memory, time orientation, and numeracy), with adjustment for life course covariates and a height-by-education interaction. Mean (SD) height was 162.7 (8.9) cm. Nearly half the sample had no formal education (46%; 2307/5059). Mean age- and sex-adjusted cognitive z-scores increased from - 0.68 (95% CI: - 0.76 to - 0.61) in those with no education in the shortest height quintile to 0.62 (95% CI: 0.52-0.71) in those with at least 8 years of education in the tallest height quintile. There was a linear height disparity in cognitive z-scores for those with no formal education (adjusted β = 0.10; 95% CI: 0.08-0.13 per height quintile), but no height disparity in cognitive z-scores in those with any level of education. Short stature is associated with poor cognitive function and may be a risk factor for cognitive impairment among older adults living in rural South Africa. The height disparity in cognitive function was negated for older adults who had any level of education.


The diagnosis and pathological value of combined detection of HE4 and CA125 for patients with ovarian cancer.
To evaluate the value of individual and combined measurement of human epididymis protein 4 (HE4) and cancer antigen 125 (CA-125) in the diagnosis of ovarian cancer. A clinical case-control study was performed in which the levels of serum HE4 and CA-125 of subjects with malignant, borderline, benign ovarian tumors and healthy women were measured before surgery. An immunohistochemistry method was used to measure the expression of HE4 in different tissues. Statistical analysis was performed to determine the relationship between the level of HE4 and the pathologic type as well as the stage of the ovarian tumors. The level of HE4 in the serum was significantly elevated in the malignant ovarian cancer group compared with other groups. Women with benign ovarian tumors and non-neoplastic lesions, and healthy women were designated as references. When the level of HE4 in the serum was 58.66 pmol/L, the sensitivity and specificity of HE4 in diagnosing malignant ovarian tumors was 82.35% and 96.03%, respectively. The level of HE4 was negatively correlated with the differentiation extent of the tumors whereas positively correlated to the clinical staging. In the groups of malignant and borderline tumors, the levels of HE4 were higher than the other groups. The expression of HE4 was significant higher in the serous types of ovarian tumors than that of the mucous types (P<0.05). The level of HE4 in the serum and tissues were positively correlated with each other. HE4 can be used as a novel clinical biomarker for predicting malignant ovarian tumors and its expression was closely related with the clinical pathological features of malignant ovarian tumors.


[A case of scheduled mitral valve replacement for mitral regurgitation caused by papillary muscle rupture after acute myocardial infarction].
Mitral regurgitation caused by papillary muscle rupture after acute myocardial infarction has poor prognosis, and it is the usual course for such cases in cardiogenic shock to be performed early mitral valve replacement. However, we recently experienced a case of successful scheduled mitral valve replacement for mitral regurgitation caused by rupture of the posterior papillary muscle after acute inferior myocardial infarction. The patient was a 63-year-old woman who admitted to a hospital with back pain and dyspnea and was diagnosed as pulmonary edema due to mitral regurgitation after acute myocardial infarction. She was treated with dopamine and diuretic agents effectively, but not weaned from these drugs. Then, she was transferred to our hospital. At the admission, she was in the NYHA class II due to mitral regurgitation and inferior myocardial infarction with papillary muscle rupture revealed by transesophageal echocardiography. Cardiac catheterization demonstrated total occlusion of the proximal right coronary artery (segment #2) and mitral regurgitation in Sellers III. The patient underwent a successful scheduled mitral valve replacement with SJM 27M concomitant with coronary artery bypass grafting 47 days after the onset of acute mitral regurgitation. There are few reports that successful surgical treatment for papillary muscle rupture was done more than 4 weeks after the onset of mitral regurgitation in Japan.


Receptor-associated protein: a specialized chaperone and antagonist for members of the LDL receptor gene family.
Members of the LDL receptor gene family mediate cellular uptake of various extracellular ligands, including lipoprotein particles. Ligand interactions with these receptors can be antagonized by a 39 kDa receptor-associated protein. Recent biochemical, cellular, and genetic studies have shown that receptor-associated protein is a molecular chaperone/escort protein for LDL receptor-related protein, a member of the LDL receptor gene family that binds multiple ligands. These studies indicate that receptor-associated protein interacts with LDL receptor-related protein at multiple sites and assists the proper folding and disulfide bond formation of LDL receptor-related protein within the endoplasmic reticulum. Following the completion of folding, receptor-associated protein remains associated with the receptor during its subsequent trafficking along the early secretory pathway, thereby preventing premature ligand interaction with the receptor. The ability of receptor-associated protein to universally inhibit ligand interactions with members of the LDL receptor gene family underscores the use of this protein as a tool in the study of ligand-receptor interactions.


Downregulation of JWA expression in human esophageal squamous cell carcinoma and its clinical significance.
JWA is involved in the regulation of many cellular processes. Recent studies have indicated a potential role for altered JWA expression and function in tumor development and progression. The purpose of this study was to investigate the expression and prognostic significance of JWA in human esophageal squamous cell carcinoma (ESCC). Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot assays were performed to detect the expression of JWA mRNA or protein in paired sample tissues from 20 ESCC patients. Expression levels of JWA protein in archival 292 formalin-fixed, paraffin-embedded specimens were also analyzed by immunohistochemistry. Finally, the correlation between JWA expression, clinicopathological factors, and patient survival was evaluated. RT-qPCR results showed that the levels of JWA mRNA were significantly lower in tumor tissue specimens than in the matched nontumor tissues. This finding was supported by Western blot analysis. Immunohistochemical staining data indicated that JWA protein level was correlated closely with the tumor cell differentiation, tumor invasion, lymph node metastasis, and distant metastasis. Kaplan-Meier survival analysis showed that low expression level of JWA resulted in a significantly poor prognosis of ESCC patients. Cox regression analysis revealed that the JWA expression level was an independent prognostic parameter for the overall survival rate of ESCC patients. In conclusion, our data suggest that JWA plays an important role in the occurrence and progress of human ESCC and that high expression level of JWA may predict a favorable prognosis in ESCC patients.


Quantitative analysis of skeletal muscle mass in patients with rheumatic diseases under glucocorticoid therapy--comparison among bioelectrical impedance analysis, computed tomography, and magnetic resonance imaging.
To determine the availability of bioelectrical impedance analysis (BIA), computed tomography (CT), and magnetic resonance imaging (MRI) for measurement of skeletal muscle mass in patients with rheumatic diseases and quantitatively assess skeletal muscle loss after glucocorticoid (GC) treatment. The data from 22 patients with rheumatic diseases were retrospectively obtained. The muscle mass of body segments was measured with a BIA device in terms of skeletal muscle mass index (SMI). Cross-sectional area (CSA) was obtained from CT and MRI scans at the mid-thigh level using the image analysis program. We further assessed the data of three different measurements before and after GC treatment in 7 patients with rheumatic diseases. SMI of whole body was significantly correlated with estimated muscle volume and mid-thigh muscle CSA with CT and MRI (p < 0.01). Significant correlations between SMI and mid-thigh muscle CSA of each leg were also found (p < 0.01). All the three measurements were negatively correlated with GC dosage (p < 0.01). Significant decline in mid-thigh muscle CSA with CT and MRI was found after GC treatment in 7 patients (p < 0.02). Those patients showed significant decline in SMI of whole body after GC treatment, but not in SMI of each leg. On the other hand, significant correlations between mid-thigh muscle CSA with CT and MRI were found before and after GC treatment (p < 0.01). GC-related skeletal muscle loss could be quantitatively assessed with BIA, CT, or MRI in patients with rheumatic diseases, and CT and MRI appeared to be more accurate than BIA.


Relationship mindfulness, negative relationship quality, and physical health.
Romantic relationships have the potential to be a great source of support or a significant stressor depending on the quality of the relationship. Given the importance of these relationships, it is important to explore possible predictors of relationship quality, primarily if such predictors can be targeted in a clinical setting. Relationship mindfulness, or the propensity to be mindful in the setting of a romantic relationship, is one such option. The current study explored the associations between relationship mindfulness, negative relationship quality, and physical health. An online assessment was completed by 116 middle-aged different-sex couples that measured the variables of interest. In addition, an Actor-Partner Interdependence Mediation Model was utilized to determine significant associations between relationship mindfulness, negative relationship quality, and physical health for both actors and partners. The clinical implications are that relationship mindfulness may help to decrease negative relationship quality and subsequently benefit individual physical health.


Cartilaginous abrasion and debridement: correlation between type of cartilaginous injury and results in patients with a 4 to 9-year follow-up.
It is the purpose of this study to verify whether or not there is a correlation between some parameters for cartilaginous injury (width, depth, and type of injury), analyzed separately, and the medium to long-term prognosis of the same. Thus, the parameters were analyzed, correlating them individually with the results obtained when a self-evaluation form was used, and the Lysholm-Gillquist score system. The small number of patients (because of the strict criteria for inclusion) does not allow for a statistically valid analysis of the results obtained. At any rate, the following considerations may be made: the depth parameter for the injury may be a valid element alone in determining a medium- to long-term prognosis; this agrees with what is reported in the literature. The parameter for width of the injury, based on our results, does not appear to be a sufficient element to determine a correlation with future prognosis. As for the type of lesion parameter, this could be correlated with the prognosis. Studies conducted in this sense with higher numbers of patients could determine the type of injury with the worst prognosis.


Man in his 50s with chest pain and dyspnoea.
A man in his 50s with sudden-onset chest pain and dyspnoea was transferred to the emergency room. He had a history of aortic valve replacement due to aortic regurgitation with a mechanical valve 6 years previously. Heart rate was 90 bpm, and blood pressure was too low to measure. In the emergency room, he presented with severe dyspnoea and a chest X-ray showed severe lung congestion (figure 1A). ECG showed complete left bundle branch block. His respiratory status rapidly worsened, and he went into cardiopulmonary arrest. After cardiopulmonary resuscitation, transthoracic echocardiography was performed (figure 1B, online supplementary video 1).DC1SP110.1136/heartjnl-2017-312477.supp1Supplementary file 1 heartjnl;104/10/868/F1F1F1Figure 1(A) Chest X-ray. (B) Colour Doppler image from apical five-chamber view. What is the most likely cause of the patient's cardiopulmonary arrest?Myocardial infarction in left main trunkAortic dissectionProsthetic valve thrombosisProsthetic valve embolisationPulmonary embolism.


Three-phase partitioning for efficient extraction and separation of polysaccharides from Corbicula fluminea.
Three-phase partitioning (TPP), which is a simple, efficient, and green bioseparation technique, was used to extract and separate polysaccharides from Corbicula fluminea (CFPS). The optimal parameters with a high yield of 9.32% were as follows: mass fraction of (NH4)2SO4, 20.0% (w/v); amount of t-butanol, 9.8mL; temperature, 35.3°C; extraction time, 30min; and pH 6.0. The purified CFPS after TPP consisted of d-glucose, d-glucosamine, and d-mannose in a molar ratio of 57.1: 5.6:1.0 with high purity (86.5%) and different molecular weights (1311.1 and 41.5-92.8kDa). Amino acid analysis, UV-vis absorption and Fourier transform-infrared spectra indicated that the purified CFPS was a proteoglycan with O-glycosidic bonds. Moreover, the purified CFPS possessed strong free-radical scavenging abilities and antioxidant activities in vitro. The obtained Trolox equivalent antioxidant capacity and ferric-reducing ability of plasma values were 95.01μmol Trolox/g sample and 38.30μmol Fe2+/g sample, respectively.


Fluticasone propionate/formoterol for COPD management: a randomized controlled trial.
To evaluate fluticasone propionate/formoterol (FP/FORM) in COPD. COPD patients with forced expiratory volume in 1 s (FEV1) ≤50% predicted and ≥1 moderate/severe COPD exacerbation in the last 12 months were randomized to FP/FORM 500/20 or 250/10 µg bid, or formoterol (FORM) 12 µg bid for 52 weeks. The primary outcome was the annualized rate of moderate/severe COPD exacerbations. In total, 1,765 patients were randomized. There were fewer discontinuations with FP/FORM 500/20 µg (20.6%) and 250/10 µg (24.0%) compared with FORM (26.1%). None of the two FP/FORM doses reduced the moderate/severe exacerbation rate versus FORM (rate ratios [RR]: 0.93; P≤0.402). There was a trend toward a lower moderate/severe exacerbation rate with FP/FORM 500/20 µg versus FORM in patients with ≥2 exacerbations in the preceding year (RR: 0.79; P=0.084). Pre- and post-dose FEV1 and forced vital capacity were greater with FP/FORM 500/20 µg versus FORM (P≤0.039). There was a trend toward a lower EXAcerbations of Chronic pulmonary disease Tool (EXACT) exacerbation rate with FP/FORM 500/20 µg versus FORM (RR: 0.87; P=0.077). There were more St George's Respiratory Questionnaire for COPD (SGRQ-C) responders with FP/FORM 500/20 µg than FORM (odds ratios [OR] at weeks 6, 23 and 52 ≥1.28; P≤0.054). EXACT-respiratory symptoms total and breathlessness scores were lower with both FP/FORM 500/20 µg and 250/10 µg versus FORM (P≤0.066). Acute β2-agonist-induced effects and 24-hour Holter findings were similar for all treatments. Mean 24-hour urinary cortisol was similarly reduced with both FP/FORM doses. Radiologically confirmed pneumonia was seen in 2.4%, 3.2% and 1.5% of FP/FORM 500/20 µg, FP/FORM 250/10 µg and FORM-treated patients, respectively. Adverse events were otherwise similar across treatment groups. FP/FORM did not reduce exacerbation rates versus FORM. Numerical benefits were observed with FP/FORM 500/20 µg versus FORM for secondary variables, including lung function, EXACT exacerbations, SGRQ-C and EXACT-respiratory symptoms total and breathlessness scores. Few efficacy differences were evident between FP/FORM 250/10 µg and FORM. Pneumonia was more frequent in FP/FORM-treated patients, although the absolute difference was low. Adverse events were otherwise similar between treatments.


Comparing Symptom Burden in Patients with Metastatic and Nonmetastatic Cancer.
Symptoms of patients with advanced cancer have been extensively studied, but less attention has been paid to the symptomatology of patients with localized disease. We compared the symptom burden of outpatients with cancer, either metastatic or localized disease, seen in a palliative care comanagement clinic. We conducted a retrospective, cross-sectional study assessing patient symptoms with multiple patient surveys, including a modified Edmonton Symptom Assessment Survey (to assess pain, fatigue, anxiety, depression, and nausea), along with a spiritual well-being screen and questions about relationships and quality of life. Consecutive patients at a comprehensive cancer center completed the surveys prior to their first visit to an outpatient palliative care clinic providing palliative care concurrently with the patients' oncologic treatments. Patients were referred by their oncologist, radiation oncologist, oncologic surgeon, or primary care physician without respect to their stage or prognosis. Statistical analyses used were χ(2), Fisher's exact test, Student's t test, and multivariate linear regression. Significance was taken as p<0.05. Two hundred and five patients were included in this study. One hundred and twenty-seven patients (62%) had metastatic cancer and 78 (38%) had nonmetastatic cancer. The characteristics of the two study groups were similar with regard to age, sex, ethnicity, language, religion, partnership status, and insurance status. Patients with metastatic disease and localized disease had similar mean symptom burden and mean individual symptom intensity for all symptoms evaluated except for nausea, which was worse in patients with metastatic disease (3.4 versus 2.5, p=0.0028). Nausea was also worse in younger patients. Among patients referred to a cancer center outpatient palliative care clinic, symptom burden is similar in patients with localized and metastatic disease. Even patients with relatively good prognoses may nevertheless have significant symptom burdens in physical, emotional, and existential domains. The palliative care needs of all patients must be assessed, regardless of stage or prognosis.


Neuromuscular junction abnormalities in DNM2-related centronuclear myopathy.
Dynamin-2-related centronuclear myopathy (DNM2-CNM) is a clinically heterogeneous muscle disorder characterized by muscle weakness and centralized nuclei on biopsy. There is little known about the muscle dysfunction underlying this disorder, and there are currently no treatments. In this study, we establish a novel zebrafish model for DNM2-CNM by transiently overexpressing a mutant version of DNM2 (DNM2-S619L) during development. We show that overexpression of DNM2-S619L leads to pathological changes in muscle and a severe motor phenotype. We further demonstrate that the muscle weakness seen in these animals can be significantly alleviated by treatment with an acetylcholinesterase inhibitor. Based on these results, we reviewed the clinical history of five patients with two different DNM2-CNM mutations (S619L and E368K) and found electrophysiological evidence of abnormal neuromuscular transmission in two of the individuals. All five patients showed improved muscle strength and motor function, and/or reduced fatigability following acetylcholinesterase inhibitor treatment. Together, our results suggest that deficits at the neuromuscular junction may play an important role in the pathogenesis of DNM2-CNM and that treatments targeting this dysfunction can provide an effective therapy for patients with this disorder.


Transplanting Cells for Spinal Cord Repair: Who, What, When, Where and Why?
Cellular transplantation for repair of the injured spinal cord has a rich history with strategies focused on neuroprotection, immunomodulation, and neural reconstruction. The goal of the present review is to provide a concise overview and discussion of five key themes that have become important considerations for rebuilding functional neural networks. The questions raised include: (i) who are the donor cells selected for transplantation, (ii) what is the intended target for repair, (iii) when is the optimal time for transplantation, (iv) where should the cells be delivered, and lastly (v) why does cell transplantation remain an attractive candidate for promoting neural repair after injury? Recent developments in neurobiology and engineering now enable us to start addressing these questions with multidisciplinary expertise and methods.


Inflammation in the pathogenesis of depression: a disorder of neuroimmune origin.
There are several hypotheses concerning the underlying pathophysiological mechanisms of major depression, which centre largely around adaptive changes in neuronal transmission and plasticity, neurogenesis, and circuit and regional connectivity. The immune and endocrine systems are commonly implicated in driving these changes. An intricate interaction of stress hormones, innate immune cells and the actions of soluble mediators of immunity within the nervous system is described as being associated with the symptoms of depression. Bridging endocrine and immune processes to neurotransmission and signalling within key cortical and limbic brain circuits are critical to understanding depression as a disorder of neuroimmune origins. Emergent areas of research include a growing recognition of the adaptive immune system, advances in neuroimaging techniques and mechanistic insights gained from transgenic animals. Elucidation of glial-neuronal interactions is providing additional avenues into promising areas of research, the development of clinically relevant disease models and the discovery of novel therapies. This narrative review focuses on molecular and cellular mechanisms that are influenced by inflammation and stress. The aim of this review is to provide an overview of our current understanding of depression as a disorder of neuroimmune origin, focusing on neuroendocrine and neuroimmune dysregulation in depression pathophysiology. Advances in current understanding lie in pursuit of relevant biomarkers, as the potential of biomarker signatures to improve clinical outcomes is yet to be fully realised. Further investigations to expand biomarker panels including integration with neuroimaging, utilising individual symptoms to stratify patients into more homogenous subpopulations and targeting the immune system for new treatment approaches will help to address current unmet clinical need.


Pharmacological Basis for Use of Selaginella moellendorffii in Gouty Arthritis: Antihyperuricemic, Anti-Inflammatory, and Xanthine Oxidase Inhibition.
This study was aimed at evaluating the effects of Selaginella moellendorffii Hieron. (SM) on gouty arthritis and getting an insight of the possible mechanisms. HPLC method was developed for chemical analysis. The paw oedema, the neutrophil accumulation, inflammatory mediators, lipid peroxidation, and histopathological changes of the joints were analyzed in gouty arthritis rat model, and the kidney injury and serum urate were detected in hyperuricemic mice. Pharmacokinetic result demonstrated that the main apigenin glycosides might be quantitatively transformed into apigenin in the mammalian body. Among these compounds, the apigenin exhibited the strongest effect on xanthine oxidase (XOD). SM aqueous extract has proved to be active in reducing hyperuricemia in dose-dependent manner, and the levels of blood urea nitrogen (BUN) and creatinine (Cr) in high dose group were decreased significantly as compared with hyperuricemic control group (P < 0.01). The high dose of SM extract could significantly prevent the paw swelling, reduce gouty joint inflammatory features, reduce the release of IL-1β and TNF-α, lower malondialdehyde (MDA) and myeloperoxidase (MPO) levels, and increase superoxide dismutase (SOD) level (P < 0.01). For the first time, this study provides a rational basis for the traditional use of SM aqueous extract against gout in folk medicine.


Planning to reduce 30-day adverse events after discharge of frail elderly patients with acute heart failure: design and rationale for the DEED FRAIL-AHF trial.
To demonstrate the efficacy of a system for comprehensive care transfer (Multilevel Guided Discharge Plan [MGDP]) for frail older patients diagnosed with acute heart failure (AHF) and to validate the results of MGDP implementation under real clinical conditions. The MGDP seeks to reduce the number of adverse outcomes within 30 days of emergency department (ED) discharge. We will enroll frail patients over the age of 70 years discharged home from the ED with a main diagnosis of AHF. The MGDP includes the following components: 1) a checklist of clinical recommendations and resource activations, 2) scheduling of an early follow-up visit, 3) transfer of information to the primary care doctor, and 4) written instructions for the patient. Phase 1 of the study will be a matched-pair cluster-randomized controlled trial. Ten EDs will be randomly assigned to the intervention group and 10 to the control group. Each group will enroll 480 patients, and the outcomes will be compared between groups. Phase 2 will be a quasi-experimental study of the intervention in 300 new patients enrolled by the same 20 EDs. The outcomes will be compared to those for each Phase-1 group. The main endpoint at 30 days will be a composite of 2 outcomes: revisits to an ED and/for hospitalization for AHF or cardiovascular death. The study will assess the efficacy and feasibility of comprehensive MGDP transfer of care for frail older AHF patients discharged home.


Active CMV and EBV infections in renal transplant recipients with unexplained fever and elevated serum creatinine.
Proper identification of active cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections are helpful for monitoring antiviral treatment in transplant recipients. Qualitative and quantitative CMV, EBV DNA PCR techniques in the context of serological tests are performed for early detection and differentiation of active and latent CMV and EBV infections in renal transplantation. Basically, 129 renal transplanted recipients monitored carefully and hospitalized for unexplained elevated creatinine levels or high fever and 21 of their donors were studied. CMV DNA was detected in 63.5% of the febrile episodes following transplantation and in 46.42% of readmitted patients using qualitative PCR method. In the first group, 15% of the patients and in the second group 42.85% of the patients had copy numbers more than cutoff point (900 copies/mL). Cutoff point had 100% sensitivity and 82.5% specificity for active and symptomatic CMV infection. Only 15.5% of the subjects were positive for EBV infection by qualitative PCR method. Among them 5% had >2000 copies/mL and were symptomatic. One subject with a history of three times hospitalization had higher EBV viral load and developed post-transplant lymphoproliferative disorder. CMV load was significantly correlated with elevated creatinine levels (OR = 3.1, p = 0.006), abnormal heart sounds (OR = 4.7; p = 0.02) and hypertension (OR = 3.6; p = 0.03). Only qRT-PCR could differentiate between latent and active infections and might be clinically useful for monitoring symptomatic CMV and EBV infections and initiation of the antiviral therapy. Elevated creatinine levels, hypertension, and abnormal heart sounds could be considered as main manifestations of HCMV infection in kidney recipients.


Electrical dry needling versus conventional physiotherapy in the treatment of active and latent myofascial trigger points in patients with nonspecific chronic low back pain.
Chronic low back pain is considered to be one of the main causes of absenteeism from work and primary and specialized consultations. The symptoms of nonspecific chronic low back pain may be accompanied by the activation of myofascial trigger points in the muscles, together with local and/or referred pain. Electrical dry needling is increasingly used in the treatment of lumbar myofascial pain. Conventional physiotherapy, however, is a popular approach to chronic pathologies, and there is evidence of different modalities of physiotherapy being used in the treatment of chronic low back pain. The aim of this study has been to determine the effectiveness of electrical dry needling versus conventional physiotherapy when applied to active and latent myofascial trigger points in patients with nonspecific chronic low back pain. This is a controlled, randomized, two-arm, double-blind study. A total of 92 patients with chronic low back pain (time to onset ≥ 3 months, Roland Morris Disability Questionnaire score ≥ 4) will be recruited from the University of Almería. Participants will be divided into two study groups (n = 40) to receive treatment of low back pain with electrical dry needling and conventional physiotherapy (ischaemic compression, analytic stretching and postural education training dossier). A total of 6 sessions will be administered once a week for 6 weeks. Pain intensity, disability, fear of movement, quality of life, quality of sleep, anxiety and depression, pressure pain threshold, abdominal strength and lumbar mobility will be recorded at 6 weeks (post-immediate) and 2 months after the end of treatment. We believe that an approach including electrical dry needling to chronic low back pain dysfunction will be more effective in these patients. The results of this study will inform clinicians on which type of treatment is more beneficial for patients with chronic low back pain. ClinicalTrials.gov NCT04804228. Registered on 14 January 2021.


Tas-102 for Refractory Metastatic Colorectal Cancer: A Multicenter Retrospective Cohort Study.
Trifluridine/tipiracil (TAS-102) is an oral chemotherapy approved for the treatment of metastatic colorectal cancer. The efficacy and tolerability of TAS-102 were shown in phase II-III clinical trials and in several real-life studies. The elderly and other special subgroups are underrepresented in published literature. We conducted a retrospective multicenter study to assess the effectiveness and safety of TAS-102 in consecutive patients with pretreated mCRC. In particular, we estimated the effectiveness and safety of TAS-102 in elderly patients (aged ≥70, ≥75 and ≥80 years) and in special subgroups, e.g., patients with concomitant heart disease. One hundred and sixty patients were enrolled. In particular, 71 patients (44%) were 70 years of age or older, 50 (31%) were 75 years of age or older, and 23 (14%) were 80 years of age or older. 19 patients (12%) had a concomitant chronic heart disease, three (2%) patients were HIV positive, and one (<1%) patient had a DPYD gene polymorphism. In 115 (72%) cases TAS-102 was administered as a third-line treatment. The median overall survival (OS) in the overall population was 8 months (95% confidence interval [CI], 6-9), while the median progression-free survival (PFS) was 3 months (95% CI, 3-4). No significant age-related reduction in effectiveness was observed in the subpopulations of elderly patients included. The toxicity profile was acceptable in both the whole and subgroups' population. Our study confirms the effectiveness and safety of TAS-102 in patients with pretreated mCRC, suggesting a similar risk-benefit profile in the elderly.


The Effect of Autochthonous Starter Culture, Sugars and Temperature on the Fermentation of Slavonian Kulen.
In this study, the effect of an isolated and well-characterised autochthonous starter culture, glucose and maltodextrin (w=0.8%) and temperatures of 12 and 20 °C on fermentation and quality of Slavonian kulen produced using the traditional technology and recipe were investigated. Physicochemical and microbiological analyses were carried out after 20 days of fermentation. Upon the completion of the production process (90 days), a sensory analysis was carried out. Furthermore, pH value was continuously measured throughout the twenty-day fermentation period. The addition of an autochthonous starter culture and sugars and different fermentation temperatures significantly (p<0.05) affected the instrumental colour and texture parameters of the Slavonian kulen. The fermentation was most intense in the samples with added autochthonous starter culture and 0.8% glucose, and fermented at 20 °C. Microbiological analysis showed that samples with added autochthonous starter culture and fermented at higher temperature contained a higher number of lactic acid bacteria and coagulase-negative staphylococci and were safe. Sensory evaluation confirmed the outcomes of physicochemical and microbiological analyses and showed differences among samples fermented at two different temperatures and with added glucose or maltodextrin and an autochthonous starter culture.


MarH, a Bifunctional Enzyme Involved in the Condensation and Hydroxylation Steps of the Marineosin Biosynthetic Pathway.
A novel bifunctional enzyme, MarH, has been identified, and its key functional role in the marineosin biosynthesis successfully probed. MarH catalyzes (1) a condensation step between 4-methoxy-2,2'-bipyrrole-5-carboxaldehyde (MBC) and 2-undecylpyrrole (UP) to form undecylprodiginine (UPG) and (2) hydroxylation of the alkyl chain of UPG to form the (S)-23-hydroxyundecylprodiginine (HUPG), which is essential for MarG catalyzed bicyclization toward the formation of an unusual spiro-tetrahydropyran-aminal ring of marineosins. The final enigmatic steps in the marineosin biosynthesis have now been deciphered.


G protein mediated signaling pathways in lysophospholipid induced cell proliferation and survival.
Agonist activation of a subset of G protein coupled receptors (GPCRs) stimulates cell proliferation, mimicking the better known effects of tyrosine kinase growth factors. Cell survival or apoptosis is also regulated via pathways initiated by stimulation of these same GPCRs. This review focuses on aspects of signaling by the lysophospholipid mediators, lysophosphatidic acid (LPA), and sphingosine 1 phosphate (S1P), which make these agonists uniquely capable of modulating cell growth and survival. The general features of GPCR coupling to specific G proteins, downstream effectors and signaling cascades are first reviewed. GPCR coupling to G(i) and Ras/MAPK or to G(q) and phospholipase generated second messengers are insufficient to regulate cell proliferation while G(12/13)/Rho engagement provides additional complementary signals required for cell proliferation. Survival is best predicted by coupling to G(i) pathways that regulate PI3K and Akt, but other signals generated through different G protein pathways are also implicated. The unique ability of LPA and S1P to concomitantly stimulate G(i), G(q), and G(12/13) pathways, given the proper complement of expressed LPA or S1P receptors, allows these receptors to support cell survival and proliferation. In pathophysiological situations, e.g., vascular disease, cancer, brain injury, and inflammation, components of the signaling cascade downstream of lysophospholipid receptors, in particular those involving Ras or Rho, may be altered. In addition, up or downregulation of LPA or S1P receptor subtypes, altering their ratio, and increased availability of the lysophospholipid ligands at sites of injury or inflammation, likely contribute to disease and may be important targets for therapeutic intervention.


Design, biological evaluation and 3D QSAR studies of novel dioxin-containing pyrazoline derivatives with thiourea skeleton as selective HER-2 inhibitors.
A series of novel dioxin-containing pyrazoline derivatives with thiourea skeleton have been designed, synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. A majority of them displayed selective HER-2 inhibitory activity against EGFR inhibitory activity. Compound C20 displayed the most potent activity against HER-2 and MDA-MB-453 human breast cancer cell line (IC50 = 0.03 μM and GI50 = 0.15 μM), being slightly more potent than the positive control Erlotinib (IC50 = 0.16 μM and GI50 = 1.56 μM) and comparable with Lapatinib (IC50 = 0.01 μM and GI50 = 0.03 μM). It is a more exciting result that C20 was over 900 times more potent against HER-2 than against EGFR while this value was 0.19 for Erlotinib and 1.00 for Lapatinib, indicating high selectivity. The results of docking simulation indicate that the dioxin moiety occupied the exit of the active pocket and pushed the carbothioamide deep into the active site. QSAR models have been built with activity data and binding conformations to begin our work in this paper as well as to provide a reliable tool for reasonable design of EGFR/HER-2 inhibitors in future.


Design and Applications of Metastable-State Photoacids.
Proton transfer is one of the most common processes in nature, and many chemical, material, and biological processes are sensitive to proton concentration, from acid-catalyzed reactions to the activities of many enzymes. Photoacids that reversibly undergo proton dissociation upon irradiation promise remote spatial and temporal control over proton-sensitive processes and could provide a way to convert photoenergy into other types of energy. The recently discovered metastable-state photoacids can produce a large proton concentration with high efficiency and good reversibility. A reversible pH change of over 2 units has been demonstrated using an aqueous solution of a metastable-state photoacid. Additionally, moderate-intensity visible light, for example, from LEDs and sunlight, can be used to activate this type of photoacid. This photocontrolled proton release occurs in aqueous and nonaqueous solutions and in polymeric materials. Therefore, this type of photoacid can be conveniently incorporated into different systems to control various proton transfer processes. Metastable-state photoacids are generally designed by linking an electron-accepting moiety and a weakly acidic nucleophilic moiety with a double bond. Photoinduced trans-cis isomerization of the double bond allows a nucleophilic cyclization reaction to occur between the two moieties. The tandem reaction generates a highly acidic metastable form, which releases a proton. In the dark, the metastable form relaxes to the original form and takes back the proton. Several electron-accepting and nucleophilic moieties have been used to construct different types of metastable-state photoacids for different applications. The advantages and disadvantages of these photoacids in terms of their photoacidity, dark acidity, reversibility, stability, etc. will be discussed in this Account. Metastable-state photoacids have been used to catalyze bond formation and bond-breaking reactions in which the reactions can be activated and stopped by turning on and off irradiation, respectively. They have been used to reversibly protonate molecules to affect the ionic and hydrogen bonding between molecules or between different moieties of a molecule. Protonation can also alter the electronic configuration of molecules to change their electronic and optical properties. Since a proton has a positive charge, photoacids have been used to control ion exchange processes. Applying metastable-state photoacids to control Fisher esterification, volume-changing hydrogels, the killing of bacteria, odorant release, the color of materials, the formation of nanoparticles, and polymer conductivity has been reported by our group. Metastable-state photoacids have also been utilized to control supramolecular assemblies, molecular switches, microbial fuel cells, cationic sensors, nanoparticle aggregation, and ring-opening polymerizations. The future prospects of this research area will be discussed at the end of this Account.


The discriminatory performance of body mass index, waist circumference, waist-to-hip ratio and waist-to-height ratio for detection of metabolic syndrome and their optimal cutoffs among Iranian adults.
The superiority of either of body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) for prediction of metabolic syndrome (MetS) is remained controversial in Asian population. The objective of this study was to compare the discriminative capacity of either of these measures in prediction of non-adipose components of MetS. In this population-based cross sectional study, 1000 representative samples of adults were recruited in Babol, northern Iran. The demographic, anthropometric measures and blood pressure were determined by standard method. Fasting plasma glucose (FPG), triglycerides (TG), total cholesterol (CHL), high density lipoprotein (HDL) cholesterol levels were measured with enzymatic methods by an auto analyzer. The presence of two or more any of four non-obese components were considered as MetS. The diagnostic accuracies (AUCs) of four different measures were rather similar. While AUC for BMI (AUC=0.684; 95% CI: 0.633, 0.736) slightly tended to be higher than that of WC (AUC=0.640; 95% CI: 0.587, 0.693) and WHtR (AUC=0.649; 95% CI: 0.596, 0.701) in men but the accuracy of WC (equivalently WHtR (AUC=0.708; 95% CI: 0.664, 0.751) is tended to be greater than that of BMI in women. The optimal cut-off value for WC was higher in men compared with women. Overall, BMI, WC and WHtR were significant predictors of MetS equally but WC (equivalently WHtR) was a better predictor than BMI and WHR in women. The optimal cut-offs of WC are lower compared with western population for men but not for women.


Ground and surface water developmental toxicity at a municipal landfill: description and weather-related variation.
Contaminated groundwater poses a significant health hazard and may also impact wildlife such as amphibians when it surfaces. Using FETAX (Frog Embryo Teratogenesis Assay-Xenopus), the developmental toxicity of ground and surface water samples near a closed municipal landfill at Norman, OK, were evaluated. The groundwater samples were taken from a network of wells in a shallow, unconfined aquifer downgradient from the landfill. Surface water samples were obtained from a pond and small stream adjacent to the landfill. Surface water samples from a reference site in similar habitat were also analyzed. Groundwater samples were highly toxic in the area near the landfill, indicating a plume of toxicants. Surface water samples from the landfill site demonstrated elevated developmental toxicity. This toxicity was temporally variable and was significantly correlated with weather conditions during the 3 days prior to sampling. Mortality was negatively correlated with cumulative rain and relative humidity. Mortality was positively correlated with solar radiation and net radiation. No significant correlations were observed between mortality and weather parameters for days 4-7 preceding sampling.


Effect of processing parameters for electrocatalytic properties of SnO(2) thin film matrix for uric acid biosensor.
RF sputtered tin oxide (SnO2) thin film matrix has been efficiently exploited for the detection of uric acid. The deposition parameters for SnO2 thin film have been optimized to yield better electrocatalytic properties. A correlation between its electrocatalytic properties with the structural and electrical properties has been made. SnO2 thin film prepared under optimized growth parameter (70% argon in reactive gas ambient of Ar and O2) exhibits higher mobility of charge carrier and high carrier concentration thereby resulting in enhanced charge transfer characteristics. High surface coverage of uricase onto SnO2 thin films (4.28 × 10(-4) mole cm(-2)), low value of Michaelis-Menten constant (km) 0.18 mM, good linearity in detection of uric acid in the range 0.05-1.00 mM and a fast response of 5 s are attractive features of prepared SnO2 thin film based bioelectrodes for efficient detection of uric acid. The nanoporous and rough surface morphology of SnO2 thin film besides its high carrier mobility in comparison to that of ITO is responsible for the obtained enhanced sensitivity (∼700 μA mM(-1)) and improved sensing response characteristics towards uric acid.


[Guidelines for caring for HIV-infected adults and post-exposure prophylaxis of HIV infection].
Presented are general principles of care for HIV-infected persons following their admission to an AIDS care center, initiation of antiretroviral therapy and follow-up. Scientific research, drug development and new clinical data in recent years have led to a change in certain therapeutic perspectives and preferences for the treatment of HIV infection. Certain conditions are better specified, which affect the choice of antiretroviral regimens. Procedures and criteria for monitoring the effect of treatment and indication of post-exposure prophylaxis are specified. The development of this document was based on the latest updates of the most prominent international and European recommendations. It also reflects some of the new scientific information published in recent months. However, general recommendations cannot fully cover all the possible alternatives. They only state basic principles based on current clinical studies, clinical observation and practice. The present document should be the basic source of information for physicians involved in the treatment of patients with HIV infection and should provide a quick reference when selecting treatment regimens in terms of modern pharmacotherapy as well as information on the pitfalls of this treatment. Finally, it should be a support for negotiations between the professional society, state authorities and health care payers.This updated version of the guidelines follows the 2012 edition; once again, they are supplemented by a modified tabular overview.


Temperature-Dependent Electric Field Poling Effects in CH3NH3PbI3 Optoelectronic Devices.
Organo-lead halide perovskites show excellent optoelectronic properties; however, the unexpected inconsistency in forward-backward I-V characteristics remains a problem for fabricating solar panels. Here we have investigated the reasons behind this "hysteresis" by following the changes in photocurrent and photoluminescence under electric field poling in transverse CH3NH3PbI3-based devices from 300 to 10 K. We found that the hysteresis disappears at cryogenic temperatures, indicating the "freeze-out" of the ionic diffusion contribution. When the same device is cooled under continuous poling, the built-in electric field from ion accumulation brings significant photovoltaic effect even at 10 K. From the change of photoluminescence upon polling, we found a second dipole-related mechanism which enhances radiative recombination upon the alignment of the organic cations. The ionic origin of hysteresis was also verified by applying a magnetic field to affect the ion diffusion. These findings reveal the coexistence of ionic and dipole-related mechanisms for the hysteresis in hybrid perovskites.


Effective and creative surveillance and reporting of surgical wound infections.
Surgical wound infections offer a major challenge to hospital infection control programs. Surgical procedures and host factors are independent variables which markedly influence the risk of infection. Frequently used categories of surgical procedures (clean, contaminated, and infected) are inadequate to identify the special risks and problems of individual procedures. In 1976, in conjunction with the practicing surgeons of a large, referral hospital, the Infections Control Committee instituted surveillance of selected clean surgical procedures and deep-versus-superficial wound infections. Major problems associated with the cleaning of sternal saws and the timing of the administration of prophylactic antibiotics have been detected by these methods. Conventional surveillance undoubtedly would have overlooked these problems. Effective surveillance and control of surgical wound infections requires a willingness to modify surveillance activities to meet the local needs, and a determination to include the operating surgeons in the planning of surveillance activities.


Effect of different kinds of complex iron on the growth of Anabaena flos-aquae.
As a necessary micronutrient for algal growth, iron (Fe) has important effects on the physiological metabolism and enzymatic reactions of algae. In this study, a series of experiments were designed to compare the effects of different kinds of iron on the growth of Anabaena flos-aquae. Results showed that the promotion of iron species on algae growth was in order of ferric ammonium citrate > EDTA-Fe > iron ions > iron oxalate. When the concentration of iron is in the range of 0.1-0.8 mg/L, iron species have more significant influences on Anabaena bloom compared with iron concentration. Our experiments also revealed that A. flos-aquae has the strongest adsorption capacity for iron ion among the four iron sources and further induced. This leads to the toxicity of the iron ion group to algal cells at low concentration.


How I monitor long-term and late effects after blood or marrow transplantation.
Blood or marrow transplantation (BMT) is used with curative intent for hematologic malignancies. Conditional on surviving the first 2 years after BMT, 5-year survival generally exceeds 70%. However, the cumulative therapeutic exposures lead to premature onset of chronic health conditions, such that the 15-year cumulative incidence of severe or life-threatening chronic health conditions exceeds 40%, resulting in premature mortality. The high burden of morbidity, coupled with a long latency between BMT and the development of chronic health conditions necessitates life-long risk-based monitoring of the BMT survivors. The issues of how and when to screen BMT survivors for therapy-related complications and exacerbation of preexisting conditions are important and largely unanswered questions. For BMT survivors, screening recommendations must incorporate risks associated with pre-BMT therapy as well as risks related to transplant conditioning and graft-versus-host disease. Here, we describe our approach to monitoring BMT survivors for risk-based screening and early detection of key late-occurring or long-term complications using patient scenarios to illustrate our discussion.


Thermoelectric detection of ferromagnetic resonance of a nanoscale ferromagnet.
We present thermoelectric measurements of the heat dissipated due to ferromagnetic resonance of a Permalloy strip. A microwave magnetic field, produced by an on-chip coplanar strip waveguide, is used to drive the magnetization precession. The generated heat is detected via Seebeck measurements on a thermocouple connected to the ferromagnet. The observed resonance peak shape is in agreement with the Landau-Lifshitz-Gilbert equation and is compared with thermoelectric finite-element modeling. Unlike other methods, this technique is not restricted to electrically conductive media and is therefore also applicable to for instance ferromagnetic insulators.


Sexuality in early childhood: pediatric nurses' attitudes, knowledge, and clinical practice.
This exploratory study assessed pediatric nurses' attitudes, knowledge, and patient care practices related to the sexuality of hospitalized preschool and early school-age children. Sexuality was defined as the sum of the physical, emotional, and psychologic attributes that are expressed in gender identity and behavior. For this study, a questionnaire containing 24 attitude, 20 knowledge, and 29 nursing practice Likert-scale items was used to survey 45 pediatric nurses in a southeastern tertiary care teaching hospital. Results indicated that, in general, the nurses surveyed had positive attitudes, sound knowledge, and appropriate practice with regard to the sexuality-related needs of their patients. However, there appeared to be some attitudinal biases and knowledge gaps that could adversely affect nursing practice. These findings were used to alter the content in pediatric nursing education at the study institution.


Spectrum of Beta Globin Gene Mutations in Egyptian Children with β-Thalassemia.
The molecular defects resulting in a β-thalassemia phenotype, in the Egyptian population, show a clear heterogenic mutations pattern. PCR-based techniques, including direct DNA sequencing are effective on the molecular detection and characterization of these mutations. The molecular characterization of β-thalassemia is necessary for carrier screening, genetic counseling, and to offer prenatal diagnosis. was to evaluate the different β-globin gene mutations in two hundred β-thalassemic Egyptian children. This study was carried out on two hundred β-thalassemic Egyptian children covering most Egyptian Governorates including 158 (79%) children with thalassemia major (TM) and 42 (21%) children with thalassemia intermedia(TI). All patients were subjected to meticulous history taking, clinical examination, complete blood count, hemoglobin electrophoresis, serum ferritin and direct fluorescent DNA sequencing of the β-globin gene to detect the frequency of different mutations. The most common mutations among patients were IVS I-110(G>A) 48%, IVS I-6(T>C) 40%, IVS I-1(G>A) 24%, IVS I-5(G>C)10%, IVS II-848 (C>A) 9%, IVS II-745(C>G) 8%, IVS II-1(G>A) 7%, codon "Cd"39(C> T) 4%, -87(C>G) 3% and the rare mutations were: Cd37 (G>A), Cd8 (-AA), Cd29(-G), Cd5 (-CT), Cd6(-A), Cd8/9(+G), Cd 106/107(+G), Cd27(C>T), IVS II-16(G> C), Cd 28 (-C), Cap+1(A>C), -88(C>A), all of these rare mutations were present in 1%. There was a considerable variation in phenotypic severity among patients resulting from the interaction of different β(∘) and β+mutations. Furthermore, no genotype-phenotype association was found both among the cases with thalassemia major and the cases with thalassemia intermedia. Direct DNA sequencing provides insights for the frequency of different mutations in patients with β-thalassemia including rare and/or unknown ones. The most common mutations in Egyptian children with beta thalassemia were IVS I-110(G>A) 48%, IVS I-6(T>C) 40%, IVS I-1(G>A)24%, IVS I-5(G>C)10%, IVS II-848 (C>A) 9%, IVS II-745(C>G) 8%, IVS II-1(G>A) 7%.


Electrochemical Detection of Gallic Acid-Capped Gold Nanoparticles Using a Multiwalled Carbon Nanotube-Reduced Graphene Oxide Nanocomposite Electrode.
Recently, a plethora of ecofriendly methods have been developed for the synthesis of AuNPs using a multitude of biogenic agents. Polyphenols from plants are particularly attractive for producing AuNPs because in addition to helping with the synthesis of AuNPs, the polyphenol capping of the NPs can be used as a platform for versatile applications. Polyphenol-capped AuNPs could also make the detection of AuNPs possible, should they be released into the environment. Because polyphenols are redox-active, they can be used as a probe to detect AuNPs using electrochemical techniques. In this work, we have developed an MWCNT-rGO nanocomposite electrode for the sensitive detection of AuNPs capped with gallic acid (GA, a green-tea-derived polyphenol) using differential pulse voltammetry (DPV). The reduction of gallic acid-capped AuNPs was used as the quantification signal, and the calibration curve displayed a detection limit of 2.57 pM. Using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), we have shown that the modification of the electrode surface with an MWCNT-rGO hybrid nanocomposite resulted in a 10-fold increase in current response leading to the sensitive detection of GA-AuNPs compared to unmodified electrodes. We have also demonstrated the applicability of the electrochemical sensor in detecting GA-AuNPs in various analytical matrixes such as human serum and natural creek water (Highland Creek, ON) with good recovery.


Comprehensive diagnosis and treatment of alveolar echinococcosis: A single-center, long-term observational study of 312 patients in Germany.
Alveolar echinococcosis (AE) is the most Iethal human helminthic infection. The malignancy-like disease is rare, but morbidity and treatment costs are high. Objective of the study was to identify factors at baseline and during specific AE therapy influencing the long-term outcome of the disease. All patients with AE seen at the specialized treatment unit in Ulm between January 1992 and December 2011 were included in the analysis. The data of 312 patients were analyzed; 108 were diagnosed before 2000 (series A), 204 since 2000 (series B); 290 received specific AE treatment. Patients of series B were more often symptom-free at diagnosis (44.1% vs. 21.3%), had lower disease stages (50.0% vs. 34.2%) and more complete resections (57.7% vs. 20.0%), but higher rates of side effects and drug toxicity (54.1% vs. 40.8%). In series B, more patients remained relapse- or progression-free after 5 years (90.5% vs. 82.8%); after 10 years, the ratio of relapses converged (70.3% vs. 66.9%, p=0.0507). Relapses or progression occurred more often after incomplete surgery or long treatment pauses. The 5-year and 10-year survival rates were 96.9% and 90.6%, respectively, and 17% of the patients were cured. We observed a shift towards early diagnosis, earlier initiation of specific therapy and more complete resections after 2000. Although diagnosis and treatment of AE pose a challenge, with an individual interdisciplinary management 88.8% of the patients have a favorable outcome.


Observation of the d3Pi(g)<--c3Sigma(u)+ band system of C2.
A new band system of C(2), d (3)Pi(g)<--c (3)Sigma(u) (+) is observed by laser induced fluorescence spectroscopy, constituting the first direct detection of the c (3)Sigma(u) (+) state of C(2). Observations were made by laser excitation of c (3)Sigma(u) (+)(v(")=0) C(2), produced in an acetylene discharge, to the d (3)Pi(g)(v(')=3) level, followed by detection of Swan band fluorescence. Rotational analysis of this band yielded rotational constants for the c (3)Sigma(u) (+)(v(")=0) state: B(0)=1.9218(2) cm(-1), lambda(0)=-0.335(4) cm(-1) and gamma(0)=0.011(2) cm(-1). The vibrational band origin was determined to be nu(3-0)=15861.28 cm(-1).


Optically active bis(aminophenols) and their metal complexes.
Optically active C2-symmetric bis(aminophenols) based on (R)-2,2'-diaminobinaphthyl (BiniqH4) and (R,R)-2,3-butanediyldianthranilate (BdanH4) have been prepared by condensation of the diamines with 3,5-di-tert-butylcatechol. Group 10 bis(iminosemiquinone) complexes (R)-(Biniq)M (M = Pd, Pt) and (C,R,R)-(Bdan)Pd have been prepared by oxidatively metalating the corresponding ligands. In (R)-(Biniq)M, the C2 axis passes through the approximate square plane of the bis(iminosemiquinone)metal core, while in (C,R,R)-(Bdan)Pd the C2 axis is perpendicular to this plane. In the latter compound, the (R,R)-butanediyl strap binds selectively over one enantioface of the metal complex in a conformation where the methyl groups are anti to one another. Osmium oxo complexes with the intrinsically chiral OsO(amidophenoxide)2 chromophore are obtained by metalation of OsO(OCH2CH2O)2 with (R,R)-BdanH4. Both the (A,R,R) and (C,R,R) diastereomers can be observed, with metalation in refluxing toluene selectively giving the latter isomer. The electronic structures of the complexes are illuminated by the circular dichroism spectra, in conjuction with the optical spectra and TDDFT calculations.


The use of mannan antigen and anti-mannan antibodies in the diagnosis of invasive candidiasis: recommendations from the Third European Conference on Infections in Leukemia.
Timely diagnosis of invasive candidiasis (IC) remains difficult as the clinical presentation is not specific and blood cultures lack sensitivity and need a long incubation time. Thus, non-culture-based methods for diagnosing IC have been developed. Mannan antigen (Mn) and anti-mannan antibodies (A-Mn) are present in patients with IC. On behalf of the Third European Conference on Infections in Leukemia, the performance of these tests was analysed and reviewed. The literature was searched for studies using the commercially available sandwich enzyme-linked immunosorbent assays (Platelia™, Bio-Rad Laboratories, Marnes-la-Coquette, France) for detecting Mn and A-Mn in serum. The target condition of this review was IC defined according to 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. Sensitivity, specificity and diagnostic odds ratios (DOR) were calculated for Mn, A-Mn and combined Mn/A-Mn testing. Overall, 14 studies that comprised 453 patients and 767 controls were reviewed. The patient populations included in the studies were mainly haematological and cancer cases in seven studies and mainly intensive care unit and surgery cases in the other seven studies. All studies but one were retrospective in design. Mn sensitivity was 58% (95% confidence interval [CI], 53-62); specificity, 93% (95% CI, 91-94) and DOR, 18 (95% CI 12-28). A-Mn sensitivity was 59% (95% CI, 54-65); specificity, 83% (95% CI, 79-97) and DOR, 12 (95% CI 7-21). Combined Mn/A-Mn sensitivity was 83% (95% CI, 79-87); specificity, 86% (95% CI, 82-90) and DOR, 58 (95% CI 27-122). Significant heterogeneity of the studies was detected. The sensitivity of both Mn and A-Mn varied for different Candida species, and it was the highest for C. albicans, followed by C. glabrata and C. tropicalis. In 73% of 45 patients with candidemia, at least one of the serological tests was positive before the culture results, with mean time advantage being 6 days for Mn and 7 days for A-Mn. In 21 patients with hepatosplenic IC, 18 (86%) had Mn or A-Mn positive test results at a median of 16 days before radiological detection of liver or spleen lesions. Mn and A-Mn are useful for diagnosis of IC. The performance of combined Mn/A-Mn testing is superior to either Mn or A-Mn testing.


The Ca2+-pumping ATPase in skeletal muscle sarcolemma. Calmodulin dependence, regulation by cAMP-dependent phosphorylation, and purification.
A Ca2+-pumping ATPase has been shown to be an integral component of skeletal muscle sarcolemma. The enzyme is stimulated by calmodulin and inhibited by micromolar concentrations of vanadate. The presence of calmodulin results in the transition of the AT-Pase to a high Ca2+ affinity state; removal of calmodulin reverses this effect. The Ca2+-ATPase and the Ca2+ uptake associated with it are also regulated by a specific cAMP-dependent phosphorylation system. The phosphorylation of the membrane enhances the Ca2+-ATPase activity. The effect is reversible. Three sarcolemmal proteins (Mr 35,000, 28,000, and 26,000) were identified as specific substrates of the cAMP-dependent phosphorylation system. The sarcolemmal Ca2+-ATPase was isolated by means of a calmodulin affinity chromatography column as a protein band of Mr of about 140,000, which could be eluted from the column by EDTA. The band possesses Ca2+-ATPase activity and is phosphorylated with [gamma-32P]ATP in a Ca2+-dependent manner. The membrane of the transverse tubules does not contain the calmodulin-sensitive Ca2+-ATPase. It contains only one cAMP-dependent phosphoprotein (Mr 30,000).


COPD in patients after heart transplantation is associated with a prolonged hospital stay, early posttransplant atrial fibrillation, and impaired posttransplant survival.
COPD is associated with reduced physical activity, an increased risk for pulmonary infections, and impaired survival in nontransplant patients. The aim of this study was to investigate the influence of COPD in patients after heart transplantation (HTX). We performed an observational retrospective single-center study of 259 patients receiving HTX at Heidelberg University Hospital between 2003 and 2012. Patients were stratified by the Tiffeneau index (forced expiratory volume in 1 second/forced vital capacity [FEV1/FVC]) <0.70 before HTX. The analysis included demographics, posttransplant medication, length of the initial hospital stay after HTX, early posttransplant atrial fibrillation (AF), mortality, and causes of death. In total, 63 (24.3%) patients had an FEV1/FVC <0.70. These patients showed a prolonged hospital stay after HTX (52.0 days vs 43.4 days, mean difference (MD) = 8.6 days, 95% CI: 0.2, 17.0 days), a higher rate of early posttransplant AF (19.0% vs 8.2%, MD = 10.8%, 95% CI: 0.4%, 21.2%), and an increased 30-day mortality (9.5% vs 2.6%, HR = 3.79, 95% CI: 1.16, 12.40). Kaplan- Meier analysis showed a significant inferior 5-year survival in patients with an FEV1/FVC <0.70, along with a higher percentage of death due to transplant failure and infection/sepsis. In addition, a multivariate analysis for mortality within 5 years after HTX indicated an FEV1/FVC <0.70 as a significant risk factor for impaired 5-year posttransplant survival (HR =4.77, 95% CI: 2.76, 8.22). COPD in patients after HTX is associated with a prolonged hospital stay, early posttransplant AF, and impaired posttransplant survival.


A Core-Shell Nanoreinforced Ion-Conductive Implantable Hydrogel Bioelectronic Patch with High Sensitivity and Bioactivity for Real-Time Synchronous Heart Monitoring and Repairing.
To achieve synchronous repair and real-time monitoring the infarcted myocardium based on an integrated ion-conductive hydrogel patch is challenging yet intriguing. Herein, a novel synthetic strategy is reported based on core-shell-structured curcumin-nanocomposite-reinforced ion-conductive hydrogel for synchronous heart electrophysiological signal monitoring and infarcted heart repair. The nanoreinforcement and multisite cross-linking of bioactive curcumin nanoparticles enable well elasticity with negligible hysteresis, implantability, ultrahigh mechanoelectrical sensitivity (37 ms), and reliable sensing capacity (over 3000 cycles) for the nanoreinforced hydrogel. Results of in vitro and in vivo experiments demonstrate that such solely physical microenvironment of electrophysiological and biomechanical characteristics combining with the role of bioactive curcumin exert the synchronous benefit of regulating inflammatory microenvironment, promoting angiogenesis, and reducing myocardial fibrosis for effective myocardial infarction (MI) repair. Especially, the hydrogel sensors offer the access for achieving accurate acquisition of cardiac signals, thus monitoring the whole MI healing process. This novel bioactive and electrophysiological-sensing ion-conductive hydrogel cardiac patch highlights a versatile strategy promising for synchronous integration of in vivo real-time monitoring the MI status and excellent MI repair performance.


Gadolinium(III)-based Polymeric Magnetic Resonance Imaging Agents for Tumor Imaging.
Contrast agents (CAs) are widely used to improve the signal-noise ratio in the magnetic resonance imaging (MRI) examinations. The majority of MRI CAs used in clinic are gadolinium( III) (Gd(III)) chelates with low molecular weight. Compared with these small-molecule CAs, Gd(III)-based polymeric magnetic resonance imaging agents (i.e. macromolecular contrast agents, mCAs), prepared by conjugating small-molecule Gd(III) chelates onto macromolecules, possess high relaxivity and relative long blood circulation time, which are favorable for MRI examinations. In last decades, increasing attention was paid to the design of mCAs with various structures, and further evaluation of the MRI performance both in vitro and in vivo. Herein, we focus on the recent progress of mCAs, including structures, properties and applications. Meanwhile, this review also highlights the emerging MRI mCAs with smart response and multi-function: tumor microenvironment- stimulated MRI, multi-mode imaging and MRI-based theranostics.


Androgen deprivation therapy and depression in the prostate cancer patients: review of risk and pharmacological management.
Purpose: Despite the effectiveness of androgen deprivation therapy in advanced prostate cancer, serious neuropsychiatric consequences in androgen deprivation therapy (ADT)-treated patients, mainly depression, have been concerning and gained more attention recently. This narrative review aims to shed light on the risk and pharmacological management of ADT-induced depression in PCa patients.Methods: We searched PubMed, Scopus and Google Scholar databases using MESH keywords "Prostate cancer OR prostate neoplasm" AND "Depression" AND "Androgen Deprivation Therapy" AND "antidepressants". Search was limited to English and studies conducted on humans. Studies' titles and abstracts were screened, and further information were obtained from the text, if necessary, to decide whether studies are to be included in this review.Results: Our review revealed 23 studies confirming the occurrence and worsening of depressive symptoms in ADT-treated patients, which frequently require pharmacological interventions; whereas 10 studies indicated otherwise. All studies were prospective, retrospective, cross-sectional or case reports. Based on the incidence of depression provided by the observational studies, the average among ADT-treated patients was 18.23% (range: 2.1-46.9%), while it was 8.42% (range: 1.4-23.3%) in the non-ADT patients. Although several treatments have been used for depression in cancer patients, current knowledge lacks observational and controlled studies as well as clinical guidelines that demonstrate efficacy and safety of antidepressants and guide clinicians to the appropriate treatment in these patients, respectively. On the other side, a few clinical studies have been published regarding the efficacy of selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors and/or saftey on other ADT associated adverse effects.Conclusions: Our work supports the recent attention towards mood issues as an adverse effect of ADT, and that greater awareness of this is warranted among clinicians. Clinical studies published regarding the use of antidepressants for other ADT associated adverse effects established the foundation that can be adopted to examine these therapies on ADT-induced depression.


The role of dental professionals in identifying, reporting, and supporting domestic violence victims.
Domestic violence is a pervasive social issue affecting individuals across all demographics and has severe consequences for both the victims and society. Domestic violence is commonly defined as the exertion of power by one individual over another within a relationship, aiming to establish a sense of fear, control, and authority. The connection between domestic violence and oral health is established, with common oral health issues associated with domestic violence, such as dental trauma, head and neck bruises and injuries as well as facial fractures. Dental professionals play a crucial role in detecting signs of domestic violence by closely examining the head and neck region and the oral cavity during routine examinations. The significance of approaching patients suspected of experiencing domestic violence with sensitivity and empathy is of utmost importance. Recommendations include establishing trust, maintaining confidentiality, using open-ended questions, and providing information about local resources. Legal and ethical considerations are paramount, highlighting the obligations of dental professionals in cases of suspected domestic violence, including mandatory reporting laws and the balance between patient autonomy and safety. Challenges faced by dental professionals in reporting and intervening are discussed as well in this narrative review, emphasizing the importance of collaboration with other healthcare professionals and support services. This review underscores the vital role of dental care providers in recognizing signs of domestic violence, promoting intervention and support, and contributing to the well-being and safety of individuals impacted by domestic violence.


Quantitative kinetics of development of N-2-fluorenylacetamide-induced, altered (hyperplastic) hepatocellular foci resistant to iron accumulation and of their reversion or persistence following removal of carcinogen.
For study of the behavior of previously described carcinogen-induced foci of hepatocytes refractory to iron accumulation, iron deposition was induced in all hepatocytes of rat livers by feeding 8-hydroxyquinoline and ferrous gluconate to the animals for 3 months. The kinetics of development of the altered foci of hepatocytes free of stainable iron was then quantified for each lobe of liver for as long as 13 weeks of feeding of the carcinogen N-2-fluorenylacetamide and for 6 months following cessation of carcinogen exposure. The foci increased slowly in number and size for the first 12 weeks of carcinogen administration and then grew rapidly between weeks 12 and 13. At week 13, they corresponded to altered foci that have been observed in sections stained with hematoxylin and eosin, and they also displayed abnormal glycogen storage. After the carcinogen was discontinued, the foci disappeared by a reversion back to iron storage while temporarily retaining the nuclear abnormalities of altered cells. Over 95% of altered foci at this stage underwent reversion by 6 months following removal of the carcinogen. More advanced lesions developed in the lobes that displayed the greatest incidence and persistence of foci.