Modulation of cellular proliferation alters glutamine transport and metabolism in human hepatoma cells.
The authors determined the effects of growth inhibition on glutamine transport and metabolism in human hepatoma cells. Hepatoma cells exhibit markedly higher (10- to 30-fold) glutamine uptake than normal human hepatocytes, via a disparate transporter protein with a higher affinity for glutamine. Currently, little is known about the effects of growth arrest on glutamine transport and metabolism in hepatoma cells. The authors determined proliferation rates, glutamine transport, and glutaminase activities in the human hepatoma cell lines HepG2, Huh-7, and SK-Hep, both in the presence and absence of the chemotherapeutic agents novobiocin and sodium butyrate. The transport activities for alanine, arginine, and leucine also were determined in both treated and untreated cells. Glutaminase activity was determined in normal human liver tissue and compared with that present in hepatoma cells. Glutaminase activities were similar in all three cell lines studied, despite differences in proliferation rates, and were sixfold higher than the activity in normal human liver. In contrast to normal hepatocytes, which expressed the liver-specific glutaminase, hepatomas expressed the kidney-type isoform. Sodium butyrate (1 mmol/L) and novobiocin (0.1 mmol/L) inhibited cellular proliferation and reduced both glutamine transport and glutaminase activity by more than 50% after 48 hours in the faster-growing, less differentiated SK-Hep cells. In contrast, the agents required 72 hours to attenuate glutamine uptake by 30% and 50% in the slower-growing, more differentiated HepG2 and Huh-7 cell lines, respectively. Treatment of all three cell lines with novobiocin/butyrate also resulted in a 30% to 60% attenuation of the transport of alanine, arginine, and leucine, and glutamine, indicating that inhibition of cellular proliferation similarly affects disparate amino acid transporters. Hepatocellular transformation is characterized by a marked increase in glutamine transport and metabolism. Inhibition of cellular proliferation attenuates glutamine transport and metabolism, especially in fast-growing, relatively undifferentiated hepatoma cells. Because the uptake of other amino acids is similarly reduced under cytostatic conditions, plasma membrane amino acid transport activity in hepatoma cells is regulated by the proliferation state of the cells.


Functional significance of chronotropic response during chronic amiodarone therapy.
Amiodarone, a potent antiarrhythmic agent, has been shown to depress sinus node function. Therefore, this study was undertaken to assess the effect of chronic amiodarone therapy on heart rate during graded exercise testing. 13 patients treated with amiodarone for ventricular arrhythmias were administered symptom-limited graded exercise testing before and 12 weeks after drug therapy. None of the patients had prior evidence of sinus node dysfunction. The mean resting heart rate (beats per minute; bpm) before and after amiodarone therapy was 75 +/- (SD) 13 versus 60 +/- 7 bpm, respectively (p less than 0.005), and the maximal heart rate was 135 +/- 30 versus 109 +/- 24 bpm (p less than 0.005). However, the change in heart rate from rest to maximum exercise (heart rate reserve) was not affected by the drug. Heart rate measured at comparable exercise levels before and during amiodarone therapy was 124 +/- 25 versus 104 +/- 31 (p less than 0.025). There was no change in the systolic blood pressure readings at these respective measured heart rates. Estimated maximal functional capacity before and after drug therapy was 4.9 +/- 1.8 versus 4.7 +/- 2.2 METs (p = NS). In conclusion, chronic amiodarone therapy significantly decreases heart rate at rest and during exercise without altering systolic blood pressure and functional capacity.


Evaluation of Light-Dependent Photosynthetic Reactions in Reynoutria japonica Houtt. Leaves Grown at Different Light Conditions.
The Japanese knotweed (Reynoutria japonica Houtt.) is considered as one of the most aggressive and highly successful invasive plants with a negative impact on invaded habitats. Its uncontrolled expansion became a significant threat to the native species throughout Europe. Due to its extensive rhizome system, rapid growth, and allelopathic activity, it usually forms monocultures that negatively affect the nearby vegetation. The efficient regulation of partitioning and utilization of energy in photosynthesis enables invasive plants to adapt rapidly a variety of environmental conditions. Therefore, we aimed to determine the influence of light conditions on photosynthetic reactions in the Japanese knotweed. Plants were grown under two different light regimes, namely, constant low light (CLL, 40 μmol/m2/s) and fluctuating light (FL, 0-1,250 μmol/m2/s). To evaluate the photosynthetic performance, the direct and modulated chlorophyll a fluorescence was measured. Plants grown at a CLL served as control. The photosynthetic measurements revealed better photosystem II (PSII) stability and functional oxygen-evolving center of plants grown in FL. They also exhibited more efficient conversion of excitation energy to electron transport and an efficient electron transport beyond the primary electron acceptor QA, all the way to PSI. The enhanced photochemical activity of PSI suggested the formation of a successful adaptive mechanism by regulating the distribution of excitation energy between PSII and PSI to minimize photooxidative damage. A faster oxidation at the PSI side most probably resulted in the generation of the cyclic electron flow around PSI. Besides, the short-term exposure of FL-grown knotweeds to high light intensity increased the yield induced by downregulatory processes, suggesting that the generation of the cyclic electron flow protected PSI from photoinhibition.


The prevalent genotypes of bovine viral diarrhea virus in Japan, Germany and the United States of America.
Genotypes and subgenotypes of bovine viral diarrhea virus (BVDV) field isolates from Japan, Germany and the United States of America (USA) were identified, and the prevalent pattern of BVDV in individual countries was estimated genetically. Subgenotypes were determined based on phylogenetic analyses of nucleotide sequences of a part of the E2-coding gene of BVDV. Forty-five, 61 and 56 BVDV strains were isolated from naturally infected cattle in Japan, Germany and USA, respectively, between 1980 and 2003. The most prevalent BVDV in these three countries was BVDV-1b. The second most prevalent BVDV strains were 1a, 1d and BVDV-2 in Japan, Germany and USA, respectively. The most prevalent subgenotype 1b in each country constructed individual small clusters in the subgenotype 1b branch in the phylogenetic tree. Although cattle and/or cattle products were moving among the three countries as part of international trade, the distribution of BVDV in the field in each country showed long-standing individual patterns.


NHERF1 inhibits proliferation of triple-negative breast cancer cells by suppressing GPER signaling.
G protein-coupled estrogen receptor (GPER) signaling is activated in triple-negative breast cancer (TNBC); however, the detailed mechanisms of its regulation remain unclear. The present study aimed to elucidate the molecular mechanisms involved in GPER activation in TNBC. In MDA-MB-231 cells, a TNBC cell line, NHERF1 interaction with GPER was verified by co-immunoprecipitation and immunofluorescent staining assays. Overexpression of NHERF1 in MDA-MB-231 cells inhibited GPER-mediated proliferation and phosphorylation of ERK1/2 and Akt. Furthermore, NHERF1 expression levels were negatively correlated with the gene signatures of GPER activation, ERK1/2 and Akt signaling, and cell proliferation in early stage of TNBC tumors from the TCGA data set. Taken together, NHERF1 inhibited the activation of GPER-mediated signaling and suppressed the proliferation of triple-negative breast cancer cells. Loss of NHERF1 expression may play a pivotal role in the early stage of TNBC carcinogenesis.


[A case in which XELOX plus bevacizumab chemotherapy was effective in an elderly patient with heart failure and multiple liver metastases after sigmoidectomy].
A 75-year-old woman with a chief complain of anal pain visited the emergency department. She was diagnosed as having S-colon cancer perforation accompanied by an intra-abdominal abscess. Computed tomography (CT)-guided drainage was applied to the intra-abdominal abscess. Six days after drainage, the patient's condition progressed to acute respiratory failure due to heart failure, and ventilator support was provided temporarily. The patient's cardiopulmonary function improved with conservative management. S-colon cancer was detected during colonoscopy examination, and biopsy indicated a tub2 tumor. Next, S-colon resection with D3 lymph node dissection was performed. The postoperative course was uncomplicated. Two months after surgery, liver metastases were detected on CT. Since the patient's performance status (PS) was 3, it was impossible for her to undergo chemotherapy. Four months after surgery, her PS was restored to 2 and the liver metastases were exacerbated, as seen on CT. The patient began chemotherapy (XELOX plus bevacizumab, 30% reduced dose). Eight months after the start of chemotherapy, 9 courses had been administered, the carcinoembryonic antigen (CEA)/carbohydrate antigen (CA) 19-9 level had decreased to the reference value, and the decrease in size of the liver metastases indicated a partial response (PR), as assessed by CT.


Fat oxidation, fitness and skeletal muscle expression of oxidative/lipid metabolism genes in South Asians: implications for insulin resistance?
South Asians are more insulin resistant than Europeans, which cannot be fully explained by differences in adiposity. We investigated whether differences in oxidative capacity and capacity for fatty acid utilisation in South Asians might contribute, using a range of whole-body and skeletal muscle measures. Twenty men of South Asian ethnic origin and 20 age and BMI-matched men of white European descent underwent exercise and metabolic testing and provided a muscle biopsy to determine expression of oxidative and lipid metabolism genes and of insulin signalling proteins. In analyses adjusted for age, BMI, fat mass and physical activity, South Asians, compared to Europeans, exhibited; reduced insulin sensitivity by 26% (p = 0.010); lower VO2max (40.6±6.6 vs 52.4±5.7 ml x kg(-1) x min(-1), p = 0.001); and reduced fat oxidation during submaximal exercise at the same relative (3.77±2.02 vs 6.55±2.60 mg x kg(-1) x min(-1) at 55% VO2max, p = 0.013), and absolute (3.46±2.20 vs 6.00±1.93 mg x kg(-1) x min(-1) at 25 ml O(2) x kg(-1) x min(-1), p = 0.021), exercise intensities. South Asians exhibited significantly higher skeletal muscle gene expression of CPT1A and FASN and significantly lower skeletal muscle protein expression of PI3K and PKB Ser473 phosphorylation. Fat oxidation during submaximal exercise and VO2max both correlated significantly with insulin sensitivity index and PKB Ser473 phosphorylation, with VO2max or fat oxidation during exercise explaining 10-13% of the variance in insulin sensitivity index, independent of age, body composition and physical activity. These data indicate that reduced oxidative capacity and capacity for fatty acid utilisation at the whole body level are key features of the insulin resistant phenotype observed in South Asians, but that this is not the consequence of reduced skeletal muscle expression of oxidative and lipid metabolism genes.


Projector Augmented Wave Method Incorporated into Gauss-Type Atomic Orbital Based Density Functional Theory.
The Projector Augmented Wave (PAW) method developed by Blöchl is well recognized as an efficient, accurate pseudopotential approach in solid-state density functional theory (DFT) calculations with the plane-wave basis. Here we present an approach to incorporate the PAW method into the Gauss-type function (GTF) based DFT implementation, which is widely used for molecular quantum chemistry calculations. The nodal and high-exponent GTF components of valence molecular orbitals (MOs) are removed or pseudized by the ultrasoft PAW treatment, while there is elaborate transparency to construct an accurate and well-controlled pseudopotential from all-electron atomic description and to reconstruct an all-electron form of valence MOs from the pseudo MOs. The smoothness of the pseudo MOs should benefit the efficiency of GTF-based DFT calculations in terms of elimination of high-exponent primitive GTFs and reduction of grid points in the numerical quadrature. The processes of the PAW method are divided into basis-independent and -dependent parts. The former is carried out using the previously developed PAW libraries libpaw and atompaw. The present scheme is implemented by incorporating libpaw into the conventional GTF-based DFT solver. The details of the formulations and implementations of GTF-related PAW procedures are presented. The test calculations are shown for illustrating the performance. With the near-complete GTF basis at the cc-pVQZ level, the total energies obtained using our PAW method with suited frozen core treatments converge to those with the conventional all-electron GTF-based method with a rather small absolute error.


Intratumoral depletion of regulatory T cells using CD25-targeted photodynamic therapy in a mouse melanoma model induces antitumoral immune responses.
Tumor immunotherapy aims to overcome the immunosuppressive microenvironment within tumors, and various approaches have been developed. Tumor-associated T regulatory cells (Tregs) suppress the activation and expansion of tumor antigen-specific effector T cells, thus, providing a permissive environment for tumor growth. Therefore, optimal strategies need to be established to deplete tumor-infiltrated Tregs because systemic depletion of Tregs can result in reduced anti-tumor effector cells and autoimmunity. Here, to selectively deplete Tregs in tumors, we intratumorally injected anti-CD25 antibodies conjugated to Chlorin e6 (Ce6), a photosensitizer that absorbs light to generate reactive oxygen species. Local depletion of tumor-associated Tregs with photodynamic therapy (PDT) inhibited tumor growth, which was likely due to the altered tumor immune microenvironment that was characterized by increased infiltration of CD8+ effector T cells and the expression of IFN-γ and CD107a, which is a cytolytic granule exocytosis marker in tumor tissues. Furthermore, PDT-induced intratumoral Treg depletion did not influence adaptive immune responses in a murine influenza infection model. Thus, our results show that intratumoral Treg-targeted PDT could specifically modulate tumor microenvironments by depleting Tregs and could be used as a novel cancer immunotherapy technique.


Rifampicin prevents the aggregation and neurotoxicity of amyloid beta protein in vitro.
The aggregation and cerebral deposition of amyloid beta protein (A beta), which is a major component of senile plaques in Alzheimer's disease (AD) brains, is believed to be involved in the pathogenesis of AD. Inhibition of A beta aggregation would seem to be a promising strategy for the treatment of AD. Here, we show that rifampicin, which is an antibiotic widely used in the treatment of tuberculosis and leprosy, inhibited the aggregation and fibril formation of synthetic A beta 1-40 peptide in a dose-dependent manner at reasonable concentrations. Furthermore, rifampicin was found to prevent A beta 1-40-induced neurotoxicity on rat pheochromocytoma PC12 cells. Rifampicin may have therapeutic potential as an agent for inhibiting the initial step of amyloid formation in AD.


Anti-Phosphatidylserine/Prothrombin antibodies in patients with Polyarteritis Nodosa.
Anti-phosphatidylserine/prothrombin (aPS/PT) antibodies have been described in cutaneous Polyarteritis Nodosa (PAN) in association with specific manifestations. To determine aPS/PT antibodies in patients with PAN and its correlation with clinical manifestations. Cross-sectional comparative study including PAN patients and 20 controls (10 Microscopic Polyangiitis [MPA] and 10 Behçet's disease [BD]). Clinical and demographic variables, treatment, serological markers, prognosis, activity and damage indexes were evaluated. aPS/PT, anti-cardiolipin (aCL), anti-beta 2 glycoprotein 1 (anti-B2GP1) antibodies, and lupus anticoagulant (LA) were determined. Fourteen patients with PAN were included, 11 (79%) women, with disease duration of 207 months, and mostly inactive disease. Only one patient with PAN and one with BD were positive for aPS/PT IgG. LA was the most frequent antibody identified. One patient with MPA and one with BD were positive for aCL IgM; one with MPA for anti-B2GP1 IgG, and one with PAN for anti-B2GP1 IgM. aPS/PT antibodies are not frequent in patients with longstanding inactive PAN.


Synthesis of disaccharide modified berberine derivatives and their anti-diabetic investigation in zebrafish using a fluorescence-based technology.
Berberine is a naturally occurring isoquinoline alkaloid and has been used as an important functional food additive in China due to its various pharmacological activities. Berberine exhibits great potential for developing anti-diabetic agents against type 2 diabetes mellitus (T2DM), as it can reduce the blood glucose level in many animal models. However, the low anti-diabetic activity and poor bioavailability of berberine (below 5%) by oral administration significantly limit its practical applications. To solve these problems, this article focuses on the structural modification of berberine using some disaccharide groups, because the carbohydrate moiety has been proved to improve the bioavailability and enhance the receptor-binding affinity of drugs. Anti-diabetic investigation of the synthesized compounds was performed in a zebrafish model using a fluorescently labelled glucose analog 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-d-glucose (2-NBDG) as a glucose tracker. The results indicated that the modification of berberine with carbohydrate groups could give derivatives with improved anti-diabetic activity, in particular the diglucose modified berberine derivative 1 which could dramatically promote the uptake of 2-NBDG in both zebrafish larvae and their eyes even at very low concentrations. Furthermore, the fluorescence-based anti-diabetic investigation method in zebrafish shows great potential for anti-diabetic drug screening.


Inferential social learning: cognitive foundations of human social learning and teaching.
Social learning is often portrayed as a passive process of copying and trusting others. This view, however, does not fully capture what makes human social learning so powerful: social information is often 'curated' by helpful teachers. I argue that both learning from others (social learning) and helping others learn (teaching) can be characterized as probabilistic inferences guided by an intuitive understanding of how people think, plan, and act. Consistent with this idea, even young children draw rich inferences from evidence provided by others and generate informative evidence that helps others learn. By studying social learning and teaching through a common theoretical lens, inferential social learning provides an integrated account of how human cognition supports acquisition and communication of abstract knowledge.


A Quantitative Proteomics Approach to Clinical Research with Non-Traditional Samples.
The proper handling of samples to be analyzed by mass spectrometry (MS) can guarantee excellent results and a greater depth of analysis when working in quantitative proteomics. This is critical when trying to assess non-traditional sources such as ear wax, saliva, vitreous humor, aqueous humor, tears, nipple aspirate fluid, breast milk/colostrum, cervical-vaginal fluid, nasal secretions, bronco-alveolar lavage fluid, and stools. We intend to provide the investigator with relevant aspects of quantitative proteomics and to recognize the most recent clinical research work conducted with atypical samples and analyzed by quantitative proteomics. Having as reference the most recent and different approaches used with non-traditional sources allows us to compare new strategies in the development of novel experimental models. On the other hand, these references help us to contribute significantly to the understanding of the proportions of proteins in different proteomes of clinical interest and may lead to potential advances in the emerging field of precision medicine.


Blood and intestinal parasites of squirrels (Rodentia: Sciuridae) in Amazonian Brazil.
We report the result of an examination for blood and intestinal protozoa in 12 specimens of the red squirrel Sciurus spadiceus (Rodentia: Sciuridae) from Birroque, municipality of Placido de Castro, state of Acre, Brazil. No parasites were detected in thin, Giemsa-stained blood films of the animals, but culture of the blood of three in Difco B45 medium blood-agar slants gave rise to isolates of epimastigotes. Inoculation of one isolate into laboratory mice resulted in the appearance of Trypanosoma cruzi-like trypomastigotes in their peripheral blood, and the other two isolates gave rise to transient infections with a T. lewisi-like parasite in inoculated mice and hamsters. The failure of the latter parasite to develop in the triatomine bug Rhodnius robustus suggests that it is probably not T. rangeli. This appears to be the first record of a T. lewisi-like trypanosome in neotropical squirrels. Oocysts of an Eimeria sp., were detected in the faeces of 10 animals (83.3%). The parasite develops in the epithelial cells of the intestine, where it may cause severe damage and sometimes results in death of the animal. No oocysts were detected in bile.


Complete remission through icotinib treatment in Non-small cell lung cancer epidermal growth factor receptor mutation patient with brain metastasis: A case report.
Brain metastasis (BM) has been universally recognized as a poor prognostic factor in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown efficacy in treating BM with an EGFR mutation. This paper reports a case of BM patient with EGFR-mutated NSCLC. According to the findings, a complete remission (CR) of the BM was achieved by icotinib treatment without conducting a radiotherapy, which was followed by a resection of the primary lung cancer lesion and lymph nodes. After one-year follow-up, the disease progressed to liver metastasis and liver lesion biopsy showed a T790M mutation. The patient responded well to the combination treatment of AZD9291 and icotinib after the failure of transcatheter arterial chemoembolization (TACE). This case report suggests that icotinib has a sustainable anticancer response to BM and the combination with icotinib and AZD9291 is effective for liver metastasis with T790M.


[Evaluation of therapeutics in psychiatry: clinical trials and evaluation of psychotherapies].
Clinical trial methodology is well established in the field of somatic disorders, but what about psychiatric treatments? The situation is relatively clear in the case of psychotropics but opinions diverge when it comes to psychotherapeutic approaches. The author considers four key methodological issues in this setting. What are the treatments to be compared? Which patients should be enrolled? How to evaluate treatment effectiveness? and how to ensure the treatment groups are comparable? The evaluation of treatments used in psychiatry, whether drug-based or psychotherapeutic, should follow a methodology very similar to that used for somatic diseases. Particularly strong similarities exist with the approaches used to evaluate surgical treatments.


Pathogenesis of ankylosing spondylitis and related disorders: future perspectives.
A review mainly based on Norwegian cases of ankylosing spondylitis and allied disorders is given. This concludes that it is a question of one or more syndromes which may frequently overlap. It is suggested that a clinical descriptive name like ankylosing spondylitis for the whole group may be misleading since the symptoms are so variable. The conditions are due to genetically determined patterns of reactions caused by different trigger mechanisms.


Tolerance and resistance of myocardium to anoxia: experimental studies.
We shall emphasize the notion of wide variability in the tolerance and resistance to anoxia of the myocardium, although the most important parameters are temperature and time. They can be modified widely by accompanying physical or biochemical conditions: --Cardiac distension and drugs inducing cardiac arrest; --Resuscitative perfusion; --The effect of some biochemical components is more likely explained by their possible action on the mitochondriae (glyoxilic acid-Isoproterenol). The study of the mitochondriae alone can explain the different behaviours of hearts subjected to anoxia in various situations.


PAK1 and CtBP1 Regulate the Coupling of Neuronal Activity to Muscle Chromatin and Gene Expression.
Acetylcholine receptor (AChR) expression in innervated muscle is limited to the synaptic region. Neuron-induced electrical activity participates in this compartmentalization by promoting the repression of AChR expression in the extrasynaptic regions. Here, we show that the corepressor CtBP1 (C-terminal binding protein 1) is present on the myogenin promoter together with repressive histone marks. shRNA-mediated downregulation of CtBP1 expression is sufficient to derepress myogenin and AChR expression in innervated muscle. Upon denervation, CtBP1 is displaced from the myogenin promoter and relocates to the cytoplasm, while repressive histone marks are replaced by activating ones concomitantly to the activation of myogenin expression. We also observed that upon denervation the p21-activated kinase 1 (PAK1) expression is upregulated, suggesting that phosphorylation by PAK1 may be involved in the relocation of CtBP1. Indeed, preventing CtBP1 Ser158 phosphorylation induces CtBP1 accumulation in the nuclei and abrogates the activation of myogenin and AChR expression. Altogether, these findings reveal a molecular mechanism to account for the coordinated control of chromatin modifications and muscle gene expression by presynaptic neurons via a PAK1/CtBP1 pathway.


Acquired Resistance of MET-Amplified Non-small Cell Lung Cancer Cells to the MET Inhibitor Capmatinib.
Amplified mesenchymal-epithelial transition factor, MET, is a receptor tyrosine kinase (RTK) that has been considered a druggable target in non-small cell lung cancer (NSCLC). Although multiple MET tyrosine kinase inhibitors (TKIs) are being actively developed for MET-driven NSCLC, the mechanisms of acquired resistance to MET-TKIs have not been well elucidated. To understand the mechanisms of resistance and establish therapeutic strategies, we developed an in vitro model using the MET-amplified NSCLC cell line EBC-1. We established capmatinib-resistant NSCLC cell lines and identified alternative signaling pathways using 3' mRNA sequencing and human phospho-RTK arrays. Copy number alterations were evaluated by quantitative polymerase chain reaction and cell proliferation assay; activation of RTKs and downstream effectors were compared between the parental cell line EBC-1 and the resistant cell lines. We found that EBC-CR1 showed an epidermal growth factor receptor (EGFR)‒dependent growth and sensitivity to afatinib, an irreversible EGFR TKI. EBC-CR2 cells that had overexpression of EGFR-MET heterodimer dramatically responded to combined capmatinib with afatinib. In addition, EBC-CR3 cells derived from EBC-CR1 cells that activated EGFR with amplified phosphoinositide-3 kinase catalytic subunit α (PIK3CA) were sensitive to combined afatinib with BYL719, a phosphoinositide 3-kinase α (PI3Kα) inhibitor. Our in vitro studies suggested that activation of EGFR signaling and/or genetic alteration of downstream effectors like PIK3CA were alternative resistance mechanisms used by capmatinib-resistant NSCLC cell lines. In addition, combined treatments with MET, EGFR, and PI3Kα inhibitors may be effective therapeutic strategies in capmatinib-resistant NSCLC patients.


Fucoxanthin Attenuates Oxidative Damage by Activating the Sirt1/Nrf2/HO-1 Signaling Pathway to Protect the Kidney from Ischemia-Reperfusion Injury.
Oxidative stress is a key component of renal ischemia/reperfusion (I/R) injury. Fucoxanthin (Fx), a marine carotenoid with enhanced antioxidant capacity, acts as a ROS inhibitor in diseases such as ischemic stroke and acute lung injury. We hypothesized that fucoxanthin could attenuate renal I/R-induced oxidative damage. C57BL/6 mice (n = 30) were randomly assigned to sham, IR, IR + DMSO, and IR + Fx (25, 50, and 100 mg/kg) groups. The renal I/R injury was induced by clamping the left kidney nephron tip in mice. Fucoxanthin was injected intraperitoneally 24 hours before surgery. Compared with the IR group, pretreatment with fucoxanthin significantly improved renal dysfunction and tissue structural damage and inhibited ROS levels and apoptosis. Consistent results were observed in HK-2 cells. Besides, we found that renal I/R resulted in decreased expression of Sirt1, Nrf2, and HO-1, while fucoxanthin upregulated the expression of Sirt1, Nrf2, and HO-1. The protective effects of fucoxanthin were significantly reversed by EX527 (a selective inhibitor of Sirt1) or si-Sirt1. In conclusion, our study investigated the protective effect of fucoxanthin against renal I/R injury, and the underlying mechanism may be related to the activation of the Sirt1/Nrf2/HO-1 signaling pathway by fucoxanthin to attenuate oxidative stress-induced apoptosis.


Re-revisiting the Utilities of Health States Worse than Dead: The Problem Remains.
In valuation studies of the EQ-5D-5L instrument, the composite time tradeoff method (cTTO) is often used to elicit preferences. In cTTO, some health states are considered worse than dead (WTD) and are assigned negative utility values. However, these negative values correlate poorly with state severity, which suggests that cTTO is insufficiently sensitive. A recent threshold explanation has been offered to account for the lack of correlation: because the severity threshold beyond which a state is considered WTD differs between respondents, the correlation should be studied for individual respondents clustered by the number of WTD states. The results obtained in such a threshold approach were interpreted to disprove the insensitivity of the cTTO method. To scrutinize the threshold explanation and test whether it indeed refutes the insensitivity of cTTO. The study uses data from the EQ-5D-5L Polish valuation study, which includes cTTO responses from 1,510 participants, each of whom evaluated 10 EQ-5D-5L states. The correlation analysis and threshold approach are repeated to confirm the results from previous studies. The data are then modified in 2 contrasting ways. First, negative utilities are randomly reshuffled to test whether the threshold approach can capture cTTO insensitivity. Second, individual-level regressions are used to simulate negative values to ensure they correlate with severity at the individual respondent level, verifying whether the overall severity-utility correlation should be observed. First, reshuffling negative utilities does not change the results of the threshold approach. Hence, the threshold explanation fails to prove cTTO sensitivity. Second, when sensitivity was introduced on an individual level, a significant overall correlation between severity and negative utility arose. cTTO is insensitive to severity for WTD states. For the composite time tradeoff method, the utility values of health states worse than dead correlate poorly with state severity, which suggests that cTTO has insufficient sensitivity.Recently, a so-called threshold explanation was offered for the lack of correlation.I show why the threshold explanation fails and why the composite time tradeoff is indeed insensitive for worse-than-dead states.


A systematic review on physical mutagens in rice breeding in Southeast Asia.
In the 1920s, Lewis Stadler initiated the introduction of permanent improvements to the genetic makeup of irradiated plants. Since then, studies related to breeding mutations have grown, as efforts have been made to expand and improve crop productivity and quality. Stadler's discovery began with x-rays on corn and barley and later extended to the use of gamma-rays, thermal, and fast neutrons in crops. Radiation has since been shown to be an effective and unique method for increasing the genetic variability of species, including rice. Numerous systematic reviews have been conducted on the impact of physical mutagens on the production and grain quality of rice in Southeast Asia. However, the existing literature still lacks information on the type of radiation used, the rice planting materials used, the dosage of physical mutagens, and the differences in mutated characteristics. Therefore, this article aims to review existing literature on the use of physical mutagens in rice crops in Southeast Asian countries. Guided by the PRISMA Statement review method, 28 primary studies were identified through a systematic review of the Scopus, Science Direct, Emerald Insight, Multidisciplinary Digital Publishing, and MDPI journal databases published between 2016 and 2020. The results show that 96% of the articles used seeds as planting materials, and 80% of the articles focused on gamma-rays as a source of physical mutagens. The optimal dosage of gamma-rays applied was around 100 to 250 Gy to improve plant development, abiotic stress, biochemical properties, and nutritional and industrial quality of rice.


Involvement of amygdalar protein kinase A, but not calcium/calmodulin-dependent protein kinase II, in the reconsolidation of cocaine-related contextual memories in rats.
Contextual control over drug relapse depends on the successful reconsolidation and retention of context-response-cocaine associations in long-term memory stores. The basolateral amygdala (BLA) plays a critical role in cocaine memory reconsolidation and subsequent drug context-induced cocaine-seeking behavior; however, less is known about the cellular mechanisms of this phenomenon. The present study evaluated the hypothesis that protein kinase A (PKA) and calcium/calmodulin-dependent protein kinase II (CaMKII) activation in the BLA is necessary for the reconsolidation of context-response-cocaine memories that promote subsequent drug context-induced cocaine-seeking behavior. Rats were trained to lever-press for cocaine infusions in a distinct context, followed by extinction training in a different context. Rats were then briefly re-exposed to the previously cocaine-paired context or an unpaired context in order to reactivate cocaine-related contextual memories and initiate their reconsolidation or to provide a similar behavioral experience without explicit cocaine-related memory reactivation, respectively. Immediately after this session, rats received bilateral microinfusions of vehicle, the PKA inhibitor, Rp-adenosine 3',5'-cyclic monophosphorothioate triethylammonium salt (Rp-cAMPS), or the CaMKII inhibitor, KN-93, into the BLA or the posterior caudate putamen (anatomical control region). Rats were then tested for cocaine-seeking behavior (responses on the previously cocaine-paired lever) in the cocaine-paired context and the extinction context. Intra-BLA infusion of Rp-cAMPS, but not KN-93, following cocaine memory reconsolidation impaired subsequent cocaine-seeking behavior in a dose-dependent, site-specific, and memory reactivation-dependent fashion. PKA, but not CaMKII, activation in the BLA is critical for cocaine memory re-stabilization processes that facilitate subsequent drug context-induced instrumental cocaine-seeking behavior.


A new one-dimensional radiative equilibrium model for investigating atmospheric radiation entropy flux.
A new one-dimensional radiative equilibrium model is built to analytically evaluate the vertical profile of the Earth's atmospheric radiation entropy flux under the assumption that atmospheric longwave radiation emission behaves as a greybody and shortwave radiation as a diluted blackbody. Results show that both the atmospheric shortwave and net longwave radiation entropy fluxes increase with altitude, and the latter is about one order in magnitude greater than the former. The vertical profile of the atmospheric net radiation entropy flux follows approximately that of the atmospheric net longwave radiation entropy flux. Sensitivity study further reveals that a 'darker' atmosphere with a larger overall atmospheric longwave optical depth exhibits a smaller net radiation entropy flux at all altitudes, suggesting an intrinsic connection between the atmospheric net radiation entropy flux and the overall atmospheric longwave optical depth. These results indicate that the overall strength of the atmospheric irreversible processes at all altitudes as determined by the corresponding atmospheric net entropy flux is closely related to the amount of greenhouse gases in the atmosphere.


The ivory tower from outside and in: a survey of Minnesota surgeons.
Increasing competition has eroded the patient base of many university hospitals and may jeopardize their teaching programs. We questioned all private surgeons (PS), university surgeons (US), and resident surgeons (RS) in our state. Chi-squared analysis was used. Most PS, US, and RS, respectively, answered "yes" when asked to respond to the following items: whether teaching hospitals were the best way to educate new surgeons (77% versus 96% versus 87%), whether surgery residencies should be based at a university hospital (72% versus 96% versus 91%), and whether PS should refer complicated clinical cases for teaching purposes (75% versus 87% versus 68%). Differences appeared when the groups were asked whether the university should take the lead in guaranteeing the quality of surgical care in the state (67% versus 100% versus 77%, p = 0.002) and whether PS are better teachers of surgery than US (40% versus 4% versus 59%, p = 0.0001). An unexpected and disturbing trend was observed in RS when groups were asked whether practicing surgeons had any obligation to the state's university (57% versus 74% versus 22%, p = 0.0001) and whether surgeons had an obligation to repay society for their education (77% versus 83% versus 56%, p = 0.005). Despite recent changes in medical economics, most PS still feel residency programs should be university based. A significantly smaller percentage of RS feel an obligation to their university and to society than do either PS or US.


Bladder reconstruction in the surgical management of bladder cancer.
As the preceding discussion has demonstrated, a number of ingenious yet relatively practical approaches have been proposed for urinary reconstruction following partial or total cystectomy for bladder cancer. Ileal conduit diversion and ureterosigmoidostomy are the only procedures for which there is adequate clinical experience to judge their relative advantages and disadvantages. Neither is an ideal form of diversion but both are practical solutions to the problem of urinary drainage following radical cystectomy. Until effective alternatives are developed, these procedures will remain the standard therapies in the management of bladder cancer. The ideal bladder substitute which needs to be developed must be continent, able to evacuate completely, have minimal physiologic consequences, and be stomaless. Ureteroiliourethrostomy comes closest to fulfilling these criteria, but there is persistent skepticism about the ability of the ileal bladder to empty effectively. Further clinical trials of this procedure are necessary before any definitive statements are possible regarding its eventual role in patients with bladder cancer. The major consideration in urinary reconstruction in the management of bladder cancer is the possibility of tumor recurrence in an adjacent urinary segment. Partial rather than total bladder reconstruction is usually precluded by this factor, but may be feasible in carefully selected patients. Staged urinary reconstruction, such as initial conduit diversion and later reestablishment of urinary continuity once tumor recurrence has been ruled out, is an attractive but relatively untried solution to this problem. The quality of life of the patient must improve to an extent which warrants the operative risks involved. To minimize these risks, a flexible, reliable, and uncomplicated procedure must be developed and must withstand prolonged clinical scrutiny. Advances in urinary reconstruction in the management of bladder cancer are eagerly anticipated by surgeons and patients alike.


Synthesis and characterization of novel polyurethane cationomers with dipeptide sequences and alkylammonium groups.
A synthetic approach to polyurethane cationomers containing S-pyroglutamyl-S-glutamic acid dipeptide (S-PyGlu-S-Glu) and alkylammonium groups is presented. Two segmented polycations, based on polycaprolactone diol, isophorone diisocyanate and dipeptide together with N-methyldiethanolamine, subsequently quaternized with dodecylbromide, were synthesized and characterized by IR spectroscopy, GPC, DSC and reduced viscosity measurements. Such polycations exhibited excellent film forming properties and their soft elastomeric nature provides adequate physical properties. Optical rotation varying from +10 (monomer) to -15 (polycation) could be associated with a configuration pertubation through the asymmetric carbon atoms of glutamic residues. Susceptibility of the cationic surface to heparinization and then to blood-polymer interaction suggested an anticoagulant activity of the heparinized polymeric films.


Research agenda: emerging issues in the management of health and illness.
Today, in our capitalistic society, demographics, economics, and quality assessments are major systemwide drivers of research in the management of health and illness. Future trends promise a continued emphasis on outcomes, with a likely focus on rationing of care. Changes in quality definitions and changing acceptance of the levels and locations of care, with continued cost shifting into a broadened form of tax-supported health care, are anticipated. Concomitant and reflexive with these macroscopic trends are more microscopic organizational and professional trends and research agendas.


Quantitative analysis of the distribution of the myenteric plexus in the rabbit large intestine.
Rabbit large intestine has a segment-specific morphology and motility. However, the morphological features of the myenteric plexus, which controls intestinal motility, have not been characterized in each large intestinal segment. We investigated the myenteric plexus morphology in the rabbit large intestine using protein gene product 9.5 immunohistochemistry in whole-mount preparations. The tenial part of the first and second segments of the proximal colon had the most well developed myenteric plexus, while the caecum had the least. These findings suggest different neuronal control over the motility of each intestinal segment, thereby providing a fundamental understanding of the rabbit enteric nervous system.


Seedless Growth of Palladium Nanocrystals with Tunable Structures: From Tetrahedra to Nanosheets.
Despite the great success that has been accomplished on the controlled synthesis of Pd nanocrystals with various sizes and morphologies, an efficient approach to systematic production of well-defined Pd nanocrystals without seed-mediated approaches remains a significant challenge. In this work, we have developed an efficient synthetic method to directly produce Pd nanocrystals with a highly controllable feature. Three distinct Pd nanocrystals, namely, Pd nanosheets, Pd concave tetrahedra, and Pd tetrahedra, have been selectively prepared by simply introducing a small amount of ascorbic acid (AA) and/or water without the other synthesis conditions changed. We found that the combined use of AA and water is of importance for the successful production of the unique Pd nanosheets. Detailed catalytic investigations showed that all the obtained Pd nanocrystals exhibit higher activity in the formic acid electrooxidation and styrene hydrogenation with respect to the Pd black, and their activities are highly shape-dependent with Pd nanosheets demonstrating a higher activity than both the Pd concave tetrahedra and Pd tetrahedra, which is likely due to the simple yet important feature of ultrathin thickness of Pd nanosheets. The present work highlights the importance of structures in tuning the related properties of metallic nanocrystals.


Withdrawal and tolerance as related to compulsive sexual behavior disorder and problematic pornography use - Preregistered study based on a nationally representative sample in Poland.
The addiction model of compulsive sexual behavior disorder (CSBD) and problematic pornography use (PPU) predicts the presence of withdrawal symptoms and increased tolerance for sexual stimuli in the disorder phenotype. However, clear empirical evidence supporting this claim has largely been lacking. In the preregistered, nationally representative survey (n = 1,541, 51.2% women, age: M = 42.99, SD = 14.38), we investigated the role of self-reported withdrawal symptoms and tolerance with respect to CSBD and PPU severity. Both withdrawal and tolerance were significantly associated with the severities of CSBD (β = 0.34; P < 0.001 and β = 0.38; P < 0.001, respectively) and PPU (β = 0.24; P < 0.001 and β = 0.27; P < 0.001, respectively). Of the 21 withdrawal symptom types investigated, the most often reported symptoms were frequent sexual thoughts that were difficult to stop (for participants with CSBD: 65.2% and with PPU: 43.3%), increased overall arousal (37.9%; 29.2%), difficult to control level of sexual desire (57.6%; 31.0%), irritability (37.9%; 25.4%), frequent mood changes (33.3%; 22.6%), and sleep problems (36.4%; 24.5%). Changes related to mood and general arousal noted in the current study were similar to the cluster of symptoms in a withdrawal syndrome proposed for gambling disorder and internet gaming disorder in DSM-5. The study provides preliminary evidence on an understudied topic, and present findings can have significant implications for understanding the etiology and classification of CSBD and PPU. Simultaneously, drawing conclusions about clinical importance, diagnostic utility and detailed characteristics of withdrawal symptoms and tolerance as a part of CSBD and PPU, as well as other behavioral addictions, requires further research efforts.


Targeting NAD+ regeneration enhances antibiotic susceptibility of Streptococcus pneumoniae during invasive disease.
Anaerobic bacteria are responsible for half of all pulmonary infections. One such pathogen is Streptococcus pneumoniae (Spn), a leading cause of community-acquired pneumonia, bacteremia/sepsis, and meningitis. Using a panel of isogenic mutants deficient in lactate, acetyl-CoA, and ethanol fermentation, as well as pharmacological inhibition, we observed that NAD(H) redox balance during fermentation was vital for Spn energy generation, capsule production, and in vivo fitness. Redox balance disruption in fermentation pathway-specific fashion substantially enhanced susceptibility to killing in antimicrobial class-specific manner. Blocking of alcohol dehydrogenase activity with 4-methylpyrazole (fomepizole), an FDA-approved drug used as an antidote for toxic alcohol ingestion, enhanced susceptibility of multidrug-resistant Spn to erythromycin and reduced bacterial burden in the lungs of mice with pneumonia and prevented the development of invasive disease. Our results indicate fermentation enzymes are de novo targets for antibiotic development and a novel strategy to combat multidrug-resistant pathogens.


Ideal cardiovascular health metrics and the risks of ischemic and intracerebral hemorrhagic stroke.
Previous studies showed an inverse association between ideal cardiovascular health (CVH) metrics and the total risk of cardiovascular diseases and stroke. This study aimed to investigate the relationship between ideal CVH metrics and the risks of ischemic and hemorrhagic stroke, respectively. We collected information on the 7 ideal CVH metrics (including smoking status, body mass index, dietary intake, physical activity, blood pressure, total cholesterol, and fasting blood glucose) among 91 698 participants from the Kailuan study, China (72 826 men and 18 872 women between the ages of 18 and 98 years), free of myocardial infarction and stroke at baseline (2006-2007). Cox proportional hazards models were used to estimate stroke risk. During the 4-year follow-up, we identified 1486 incident stroke events (1057 ischemic, 386 intracerebral hemorrhagic, and 43 subarachnoid hemorrhagic). The hazard ratios (95% confidence interval) for total stroke with adherence to 0 (reference), 1, 2, 3, 4, 5, and 6/7 ideal CVH metrics were: 1, 0.92 (0.69-1.23), 0.69 (0.52-0.92), 0.52 (0.39-0.68), 0.38 (0.28-0.51), 0.27 (0.18-0.40), and 0.24 (0.11-0.54), respectively (P trend <0.01), after adjusting for age, sex, education, income, and hospital. Similar inverse associations were observed for both ischemic and intracerebral hemorrhagic stroke (both P trend <0.01). We observed a clear inverse gradient relationship between the number of ideal CVH metrics and the risk of stroke in a Chinese population, supporting the importance of ideal health behaviors and factors in stroke prevention.


Naphthalimide-Based Fluorescent Probe for Profiling of Aldehydes during Oxidation of Unsaturated Lipids.
A lipophilic naphthalimide hydrazine fluorescent probe was successfully developed in this study for profiling aldehyde oxidation products. Dodecyl amine was applied to afford lipophilicity of the fluorescent probe for lipids. Investigation of fluorescence properties of the probe and condensation products with typical aldehydes including MDA and hexanal revealed significant enhancement of fluorescence intensity after condensation due to the inhibition of photo-induced electron transfer. MDA and hexanal could be differentiated by the probe through emission of different fluorescence colors (blue, MDA; green, hexanal). Eight major oxidation components including seven aldehydes were detected by the fluorescent probe coupled with high-performance liquid chromatography-mass spectrometry during aerobic oxidation of typical unsaturated lipids. Formation of these aldehyde oxidation products was rationalized through the radical oxidation mechanism. Detection of representative aldehyde products demonstrated the generality in the application of this fluorescent probe for profiling of aldehydes after lipid oxidation.


Giant cell arteritis among Hispanic Americans.
To compare the prevalence and clinical course of giant cell arteritis (GCA) among Hispanic and non-Hispanic patients. Comparative case series. Two hundred fifty-seven consecutive patients who underwent temporal artery biopsy in our institution from 1996 to 2002 were studied. A prospective telephone survey was conducted to determine race and Hispanic origin separately by means of methodology of the US Census Bureau. One hundred thirty-four patients completed the interview, with 65 (49%) identifying themselves as Hispanic and 69 (51%) as non-Hispanic. Of the 32 respondents with biopsy-proven GCA, all identified themselves racially as white, and 13 (41%) were Hispanic and 19 (59%) were non-Hispanic (P = .32). Statistically significant differences in age, presenting symptoms, and final visual acuity were not observed among Hispanic and non-Hispanic patients with GCA. Although GCA has been reported to be rare in Hispanics, we found the prevalence and clinical course of GCA to be similar in Hispanic and non-Hispanic patients.


The health impact of intimate partner violence.
Research suggests that between 960,000 to 4 million individuals are victims of intimate partner violence (IPV) each year and of these about 85 percent are women. In a recent survey conducted by the Commonwealth Fund, it was estimated that approximately one-third of American women will become a victim of IPV at some point in their life. The literature reports 36 percent to 95 percent of battered women suffer injuries to the face, neck or head. Women who have been abused by a partner report significantly lower self assessments of health, increased disabilities and increased chronic health conditions than non-abused women. When direct costs to the health care system are combined with indirect costs to society, total health care costs of IPV can escalate into the billions. Intimate partner violence erodes the health of patients, consumes healthcare dollars, compromises the health and safety of children and communities, and represents a liability exposure for the healthcare clinician who turns their head. Healthcare providers, especially dental professionals, must gain experience in the diagnosis and management of IPV so that identification occurs earlier and intervention follows established protocols.


[Macroprolactin as etiology of hyperprolactinemia. Method for detection and clinical characterization of the entity in 39 patients].
The presence of serum macroprolactin is a relatively frequent situation that can lead to expensive explorations and ineffective treatments. The precipitation with polyethylene glycols permits its detection rapidly, trustworthily, and inexpensively. The objective of the present work has been to assess the incidence of macroprolactin in patients with hyperprolactinemia through its identification with polyethylene glycols, as well as the clinical and radiological findings, and the response in these patients to the treatment. For it the clinical history of all the cases in which there was detected macroprolactinemia, some of them with several years of previous follow-up, was reviewed exhaustively. Of the 1505 patients in which prolactin level was determined, 195 (13%) showed values higher than 40 microg/l. In 39 (20%) of them the presence of macroprolactin was detected. After observing the evolution of these patients, spontaneously or under treatment with dopaminergic agonists, a clear relationship of causality between the presence of macroprolactin and the clinical manifestations was not found, except in a case of galactorrhea. In 27 cases nuclear magnetic resonance was done; in 4 of them a picture was observed compatible with small microadenoma or microcyst and in no patient a macroadenoma was detected. We conclude that the macroprolactinemia is a relatively frequent and easily detected entity through precipitation with polyethylene glycols. It has a limited relation with the clinical findings and there should always be sought other possible causes of this situation. It is an apparently benign situation and its identification can avoid unnecessary explorations and treatments.


Gene-coexpression network analysis identifies specific modules and hub genes related to cold stress in rice.
When plants are subjected to cold stress, they undergo a series of molecular and physiological changes to protect themselves from injury. Indica cultivars can usually withstand only mild cold stress in a relatively short period. Hormone-mediated defence response plays an important role in cold stress. Weighted gene co-expression network analysis (WGCNA) is a very useful tool for studying the correlation between genes, identifying modules with high phenotype correlation, and identifying Hub genes in different modules. Many studies have elucidated the molecular mechanisms of cold tolerance in different plants, but little information about the recovery process after cold stress is available. To understand the molecular mechanism of cold tolerance in rice, we performed comprehensive transcriptome analyses during cold treatment and recovery stage in two cultivars of near-isogenic lines (9311 and DC907). Twelve transcriptomes in two rice cultivars were determined. A total of 2509 new genes were predicted by fragment splicing and assembly, and 7506 differentially expressed genes were identified by pairwise comparison. A total of 26 modules were obtained by expression-network analysis, 12 of which were highly correlated with cold stress or recovery treatment. We further identified candidate Hub genes associated with specific modules and analysed their regulatory relationships based on coexpression data. Results showed that various plant-hormone regulatory genes acted together to protect plants from physiological damage under short-term low-temperature stress. We speculated that this may be common in rice. Under long-term cold stress, rice improved the tolerance to low-temperature stress by promoting autophagy, sugar synthesis, and metabolism. Through WGCNA analysis at the transcriptome level, we provided a potential regulatory mechanism for the cold stress and recovery of rice cultivars and identified candidate central genes. Our findings provided an important reference for the future cultivation of rice strains with good tolerance.


[Captopril in the treatment of congestive heart failure in acute myocardial infarct].
The extent of affection of the heart muscle by infarction with subsequent left-ventricular dilatation, remodelling and congestive failure is the decisive prognostic indicator of mortality. Inhibitors of ACE influence congestive heart failure in a favourable way and captopril reduces the morbidity and mortality in patients with still asymptomatic left ventricular dysfunction. The authors administered to a group of 23 patients with acute myocardial infarction and congestive heart failure (grade II according to Killip) small doses of captopril (4 x 6.25 mg/day)for a period of 10 days from the 1st-4th day after the onset of the disease). From ACE serum levels the effectiveness of these doses was assessed in keeping with data in the literature. As compared with a control group of 26 patients with similar haemodynamic conditions the authors did not find significant differences as regards improvement of the decompensation and in the mortality (à 3 patients in both groups). As to undesirable effects, arterial hypotension was recorded three times, twice minor proteinuria, once asymptomatic thrombocytopenia. Decisive for future therapeutic decision making are above all the results of the SAVE study which prefers captopril in patients with a yet asymptomatic left ventricular dysfunction. The authors are not quite convinced on the necessity to administer larger doses of captopril (up to 3 x 50 mg/day) in this indication.


Emergency Risk Communication: Lessons Learned from a Rapid Review of Recent Gray Literature on Ebola, Zika, and Yellow Fever.
A rapid review of gray literature from 2015 to 2016 was conducted to identify the lessons learned for emergency risk communication from recent outbreaks of Ebola, Zika, and yellow fever. Gray literature databases and key websites were searched and requests for documents were posted to expert networks. A total of 83 documents met inclusion criteria, 68 of which are cited in this report. This article focuses on the 3 questions, out of 12 posed by World Health Organization as part of a Guideline development process, dealing most directly with communicating risk during health emergencies: community engagement, trust building, and social media. Documents were evaluated for credibility using an Authority, Accuracy, Coverage, Objectivity, Date, Significance (AACODS) checklist? and if the document contained a study, a method-specific tool was applied. A rapid content analysis of included sources was undertaken with relevant text either extracted verbatim or summarized and mapped against the questions. A database subset was created for each question and citations were assigned to the subset(s) for which they contained relevant information. Multiple designations per document were common. Database subsets were used to synthesize the results into a coherent narrative. The gray literature strongly underlines the central importance of local communities. A one-size-fits-all approach does not work. For maximum effectiveness, local communities need to be involved with and own emergency risk communication processes, preferably well before an emergency occurs. Social media can open new avenues for communication, but is not a general panacea and should not be viewed as a replacement for traditional modes of communication. In general, the gray literature indicates movement toward greater recognition of emergency risk communication as a vitally important element of public health.


A Novel Method for the Synthesis of MOF-199 for Sensing and Photocatalytic Applications.
Multifunctional Cu (II)-based Metal Organic Framework (MOF) [Cu3(BTC)2] has been synthesized by a facile electrochemical method. Crystallographic and morphological characterizations of synthesized MOF have been done using Powder X-ray Diffractometer and Scanning Electron Microscope (SEM), respectively, whereas Fourier Transform Infrared Spectroscopy (FT-IR), Energy Dispersive X-ray Spectroscopy (EDS), UV-Vis Absorption Spectroscopy and Energy Resolved Luminescence Spectroscopic studies have been used for the detailed qualitative, quantitative as well as optical analyses. Sharp PXRD peaks indicate the formation of highly crystalline MOF with face centered cubic (fcc) structure. Flakes (average length = 0.71 µm and width = 0.10 µm) and rods (average aspect ratio = ((0.1:8.3) µm) like morphologies have been observed in SEM micrographs. The presence of C, O and Cu has been confirmed by EDS analysis. Photocatalytic activity potential of the synthesized MOF has been tested using methylene blue dye (MB) as a test contaminant in aqueous media under sunlight irradiation. Selective and sensitive fluorescent sensing of different Nitroaromatic compounds (NACs) like 4-Nitroaniline (4-NA), 2-Nitroaniline (2-NA), 3-Nitroaniline (3-NA), 4-Nitrotoulene (4-NT), 2,4-Dinitrotoulene (2,4-DNT), 1,3-Dinitrobenzene (1,3-DNB), 2,6- Dinitrotoulene (2,6-DNT) has been done by exploring the photoluminescent behaviour of chemically stable Cu3(BTC)2. Synthesized MOF is extremely sensitive towards 4-NA, which is having PL quenching efficiency of 82.61% with highest quenching rate till reported. Indeed, a large quenching coefficient KSV = 34.02 × 10-7 M-1 and correlation coefficient R2 = 0.9962 in KSV plot have been elucidated with limit of detection (LOD) = 0.7544 ppb. The possible ways of luminescence quenching are successfully explained by the combination of Photoinduced Electron Transfer (PET) and Resonance Energy Transfer (RET) mechanisms. Additionally, the Density Functional Theory (DFT) calculations have been employed to support the experimental results. Cu3(BTC)2 fully demonstrates the power of a multi component MOF, which provides a feasible pathway for the design of novel material towards fast responding luminescence sensing and photocatalytic degradation of pollutants.


Hemodynamic Findings of Severe Subacute Aortic Regurgitation.
The hemodynamic features of subacute aortic regurgitation include equalization of the left ventricular pressure and the aortic pressure during diastole, a mildly increased pulse pressure, and systemic hypotension. These findings are distinct from the hemodynamics of chronic aortic regurgitation.


Synthesis, Structure Characterization, and Evaluation in Microglia Cultures of Neuromelanin Analogues Suitable for Modeling Parkinson's Disease.
In the substantia nigra of human brain, neuromelanin (NM) released by degenerating neurons can activate microglia with consequent neurodegeneration, typical of Parkinson's disease (PD). Synthetic analogues of NM were prepared to develop a PD model reproducing the neuropathological conditions of the disease. Soluble melanin-protein conjugates were obtained by melanization of fibrillated β-lactoglobulin (fLG). The melanic portion of the conjugates contains either eumelanic (EufLG) or mixed eumelanic/pheomelanic composition (PheofLG), the latter better simulating natural NMs. In addition, the conjugates can be loaded with controlled amounts of iron. Upon melanization, PheofLG-Fe conjugates maintain the amyloid cross-β protein core as the only structurally organized element, similarly to human NMs. The similarity in composition and structural organization with the natural pigment is reflected by the ability of synthetic NMs to activate microglia, showing potential of the novel conjugates to model NM induced neuroinflammation. Thus, synthetic NM/microglia constitute a new model to develop anti-Parkinson drugs.


Modeling and analyzing respondent-driven sampling as a counting process.
Respondent-driven sampling (RDS) is an approach to sampling design and analysis which utilizes the networks of social relationships that connect members of the target population, using chain-referral. RDS sampling will typically oversample participants with many acquaintances. Naïve estimators, such as the sample average, will thus be biased towards the state of the most highly connected individuals. Current methodology cannot estimate population size from RDS, and promotes inverse probability weighted estimators for population parameters such as HIV prevalence. We propose to use the timing of recruitment, typically collected and discarded, in order to estimate the population size via a counting process model. Once population size and degree frequencies are made available, prevalence can be debiased in a post-stratified framework. We adapt methods developed for inference in epidemiology and software reliability to estimate the population size, degree counts and frequencies. A fundamental advantage of our approach is that it makes the assumptions of the sampling design explicit. This enables verification of the assumptions, maximum likelihood estimation, extension with covariates, and model selection. We develop large-sample theory, proving consistency and asymptotic normality. We further compare our estimators to other estimators in the RDS literature, through simulation and real-world data. In both cases, we find our estimators to outperform current methods. The likelihood problem in the model we present is separable, and thus efficiently solvable. We implement these estimators in an accompanying R package, chords, available on CRAN.


MiR-144 Inhibits Tumor Growth and Metastasis in Osteosarcoma via Dual-suppressing RhoA/ROCK1 Signaling Pathway.
Several microRNAs (miRNAs) have been found expressed differentially in osteosarcoma (OS), so they may function in the onset and progression of OS. In this study, we found that miR-144 significantly suppresses osteosarcoma cell proliferation, migration, and invasion ability in vitro and inhibited tumor growth and metastasis in vivo. Mechanically, we demonstrated that Ras homolog family member A (RhoA) and its pivotal downstream effector Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) were direct targets of miR-144. Moreover, the negative correlation between down-regulated miR-144 and up-regulated ROCK1/RhoA was verified in both OS cell lines and clinical patients' specimens. Functionally, RhoA with or without ROCK1 co-overexpression resulted a rescue phenotype on miR-144 inhibited cell growth, migration, and invasion abilities whereas individual overexpression of ROCK1 had no statistical significance compared with controls in miR-144-transfected SAOS2 and U2-OS cells. Taken together, this study demonstrates that miR-144 inhibited tumor growth and metastasis in OS via dual-suppressing of RhoA and ROCK1, which could be a new therapeutic approach for the treatment of OS.


Coalescence of drops in a 2D microchannel: critical transitions to autocatalytic behaviour.
A single coalescence event in a 2D concentrated emulsion in a microchannel can trigger an avalanche of similar events that can destabilize the entire assembly of drops. The sensitive dependence of the process on numerous parameters makes the propagation dynamics appear probabilistic. In this article, a stochastic simulation framework is proposed to understand this collective behavior in a system employing a large number of drops. We discover that the coalescence propagation dynamics exhibit a critical behavior where two outcomes are favored: no avalanche and large avalanches. Our analysis reveals that this behavior is a result of the inherent autocatalytic nature of the process. The effect of the aspect ratio of the drop assembly on the propagation dynamics is studied. We generate a parametric plot that shows the region of the parameter space where the propagation, averaged over the ensemble, is autocatalytic: where the possibility of near destabilization of the drop assembly appears.


The effect of neurospecific knockdown of candidate genes for locomotor behavior and sound production in Drosophila melanogaster.
Molecular mechanisms underlying the functioning of central pattern generators (CPGs) are poorly understood. Investigations using genetic approaches in the model organism Drosophila may help to identify unknown molecular players participating in the formation or control of motor patterns. Here we report Drosophila genes as candidates for involvement in the neural mechanisms responsible for motor functions, such as locomotion and courtship song. Twenty-two Drosophila lines, used for gene identification, were isolated from a previously created collection of 1064 lines, each carrying a P element insertion in one of the autosomes. The lines displayed extreme deviations in locomotor and/or courtship song parameters compared with the whole collection. The behavioral consequences of CNS-specific RNAi-mediated knockdowns for 10 identified genes were estimated. The most prominent changes in the courtship song interpulse interval (IPI) were seen in flies with Sps2 or CG15630 knockdown. Glia-specific knockdown of these genes produced no effect on the IPI. Estrogen-induced knockdown of CG15630 in adults reduced the IPI. The product of the CNS-specific gene, CG15630 (a predicted cell surface receptor), is likely to be directly involved in the functioning of the CPG generating the pulse song pattern. Future studies should ascertain its functional role in the neurons that constitute the song CPG. Other genes (Sps2, CG34460), whose CNS-specific knockdown resulted in IPI reduction, are also worthy of detailed examination.


Risk factors for severe neutropenia induced by combination therapy of S-1 and cisplatin in patients with advanced/recurrent gastric cancer.
S-1 and cisplatin therapy (SP therapy) is widely used as the first-line of advanced/recurrent gastric cancer. However, severe neutropenia is often observed (40%) during this therapy. Therefore, the risk management of neutropenia is important. From September 2014 to April 2017, we investigated 76 patients who underwent SP therapy as primary treatment for advanced/recurrent gastric cancer at Ogaki Municipal Hospital. Risk factors for grade 3/4 neutropenia were examined by univariate and multivariate analyses. In SP therapy, 19 patients (25%) experienced grade 3/4 neutropenia. The results of multivariate analysis of factors with p <0.05 in the univariate analysis indicated that less than 10.6 g/dL of the haemoglobin value before the course at the lowest neutrophil count (odds ratio: 7.900; 95% CI: 1.280-48.60; p = 0.026), more than six courses of the total course (odds ratio: 9.13; 95% CI: 2.13-39.1; p = 0.003), and less than 3140 m2 neutrophil counts (odds ratio: 5.33; 95% CI: 1.47-19.3; p = 0.011) before chemotherapy were risk factors of grade 3/4 neutropenia. A low haemoglobin value before the course at the lowest neutrophil count was revealed as a risk factor causing severe neutropenia in SP therapy.


Development of a Gestational and Lactational Physiologically Based Pharmacokinetic (PBPK) Model for Perfluorooctane Sulfonate (PFOS) in Rats and Humans and Its Implications in the Derivation of Health-Based Toxicity Values.
There is a great concern on potential adverse effects of exposure to perfluorooctane sulfonate (PFOS) in sensitive subpopulations, such as pregnant women, fetuses, and neonates, due to its reported transplacental and lactational transfer and reproductive and developmental toxicities in animals and humans. This study aimed to develop a gestational and lactational physiologically based pharmacokinetic (PBPK) model in rats and humans for PFOS to aid risk assessment in sensitive human subpopulations. Based upon existing PBPK models for PFOS, the present model addressed a data gap of including a physiologically based description of basolateral and apical membrane transporter-mediated renal reabsorption and excretion in kidneys during gestation and lactation. The model was calibrated with published rat toxicokinetic and human biomonitoring data and was independently evaluated with separate data. Monte Carlo simulation was used to address the interindividual variability. Model simulations were generally within 2-fold of observed PFOS concentrations in maternal/fetal/neonatal plasma and liver in rats and humans. Estimated fifth percentile human equivalent doses (HEDs) based on selected critical toxicity studies in rats following U.S. Environmental Protection Agency (EPA) guidelines ranged from 0.08 to 0.91μg/kg per day. These values are lower than the HEDs estimated in U.S. EPA guidance (0.51-1.6μg/kg per day) using an empirical toxicokinetic model in adults. The results support the importance of renal reabsorption/excretion during pregnancy and lactation in PFOS dosimetry and suggest that the derivation of health-based toxicity values based on developmental toxicity studies should consider gestational/lactational dosimetry estimated from a life stage-appropriate PBPK model. This study provides a quantitative tool to aid risk reevaluation of PFOS, especially in sensitive human subpopulations, and it provides a basis for extrapolating to other per- and polyfluoroalkyl substances (PFAS). All model codes and detailed tutorials are provided in the Supplemental Materials to allow readers to reproduce our results and to use this model. https://doi.org/10.1289/EHP7671.


Ectopic differentiation of melanocyte stem cells is influenced by genetic background.
Hair graying in mouse is attributed to the loss of melanocyte stem cell function and the progressive depletion of the follicular melanocyte population. Single-gene, hair graying mouse models have pointed to a number of critical pathways involved in melanocyte stem cell biology; however, the broad range of phenotypic variation observed in human hair graying suggests that additional genetic variants involved in this process may yet be discovered. Using a sensitized approach, we ask here whether natural genetic variation influences a predominant cellular mechanism of hair graying in mouse, melanocyte stem cell differentiation. We developed an innovative method to quantify melanocyte stem cell differentiation by measuring ectopically pigmented melanocyte stem cells in response to the melanocyte-specific transgene Tg(Dct-Sox10). We make the novel observation that the production of ectopically pigmented melanocyte stem cells varies considerably across strains. The success of sensitizing for melanocyte stem cell differentiation by Tg(Dct-Sox10) sets the stage for future investigations into the genetic basis of strain-specific contributions to melanocyte stem cell biology.


ZmmiR169q/ZmNF-YA8 is a module that homeostatically regulates primary root growth and salt tolerance in maize.
In response to salt stress, plants alter the expression of manifold gene networks, enabling them to survive and thrive in the face of adversity. As a result, the growth and development of plant roots could be drastically altered, with significant inhibition of the growth of root meristematic zones. Although it is known that root growth is primarily regulated by auxins and cytokinins, the molecular regulatory mechanism by which salt stress stunts root meristems remains obscure. In this study, we found that the ZmmiR169q/ZmNF-YA8 module regulates the growth of maize taproots in response to salt stress. Salt stress downregulates ZmmiR169q expression, allowing for significant upregulation of ZmNF-YA8, which, in turn, activates ZmERF1B, triggering the upregulation of ASA1 and ASA2, two rate-limiting enzymes in the biosynthesis of tryptophan (Trp), leading to the accumulation of auxin in the root tip, thereby inhibiting root growth. The development of the maize root is stymied as meristem cell division and meristematic zone expansion are both stifled. This study reveals the ZmmiR169q/ZmNF-YA8 module's involvement in maintaining an equilibrium in bestowing plant salt tolerance and root growth and development under salt stress, providing new insights into the molecular mechanism underlying the homeostatic regulation of plant development in response to salt stress.


A hybrid zone comprising staggered chromosomal clines in the house mouse (Mus musculus domesticus).
In the vicinity of John o'Groats (Caithness, Scotland) there is a small karyotypic race of the house mouse (Mus musculus domesticus) characterized by a diploid number of 32 chromosomes, including the metacentrics 4.10, 9.12, 6.13 and 11.14. This race forms a hybrid zone with the standard British race (fully acrocentric chromosomes, 2n = 40). Although hybrid zones normally consist of several (or many) narrow character clines at the same position, this zone is unusual in that the chromosomal clines do not coincide. The cline for arm combination 11.14 is staggered relative to the 6.13 cline and both are separate from the clines for 4.10 and 9.12 (which may or may not coincide). A variety of explanations for the structure of the hybrid zone are discussed. It is possible that this may be a case of 'zonal raciation'.


Prediction of human papilloma virus antigen in cervical squamous epithelium by koilocyte nuclear morphology and "wart scores": confirmation by immunoperoxidase.
Koilocytes (balloon cells) in cervical squamous epithelium can be distinguished by their nuclear morphology as members of two populations A and B. The proposition that population A was infected with human papilloma virus (HPV) and population B was not, was examined immunohistologically. A peroxidase-antiperoxidase technique using polyclonal HPV antibody failed to support the hypothesis and showed small fractions of both populations to be infected with the virus (A = 5 of 25; B = 2 of 19). Nuclear morphology alone is thus inadequate to distinguish infected from non-infected koilocytes, or balloon cells. When a number of well established histological changes in squamous epithelia infected with HPV were examined, graded, and summated to obtain a "wart score," however, a reasonably accurate prediction of HPV infection emerged.


The association between the cervical spine, the stomatognathic system, and craniofacial pain: a critical review.
Craniofacial pain is a term that encompasses pain in the head, face, and related structures. Multiple etiologies and factors may be related to craniofacial pain; however, the association between the cervical spine and its related structures and craniofacial pain is still a topic of debate. The objective of this critical review was to present and analyze the evidence of the associations between the cervical spine, stomatognathic system, and craniofacial pain. A search of the databases Medline, PubMed, Embase, Web of Sciences, Cochrane Library, Cinahl, and HealthStar was conducted for all publications related to the topic in the English and Spanish languages. Relevant information was also derived from reference lists of the retrieved publications. The key words used in the search were cervical spine, cervical vertebrae, neck pain, neck injuries, neck muscles, craniofacial pain, orofacial pain, facial pain, temporomandibular joint pain, and temporomandibular joint disorders. The search provided information referring to the biomechanical, anatomical, and pathological association between craniofacial pain, the stomatognathic system and the cervical spine. The information provided by this review suggests an association between the cervical spine, stomatognathic system, and craniofacial pain, but most of this information is not conclusive and was derived from poor-quality studies (levels 3b, 4, and 5 based on Sackett's classification). Better designed studies are needed in order to clarify the real influence that the cervical spine has in relation to the stomatognathic system and craniofacial pain.


Non-histone proteins Nhp6A and Nhp6B are required for the regulated expression of SUC2 gene of Saccharomyces cerevisiae.
Transcription of the SUC2 gene that encodes invertase enzyme is controlled by glucose repression and derepression mechanisms in Saccharomyces cerevisiae. Several regulatory factors such as Mig1p complex, Gcr1p, Hxk2p, nucleosomes, and the Snf1p kinase complex have been identified as the regulators of SUC2 transcription. The results presented in this study indicate that the non-histone proteins Nhp6A and Nhp6B were also required for the regulated expression of SUC2 gene. Expression of the SUC2 gene reduced to one-fiftieth-one-tenth in the Deltanhp6A Deltanhp6B double mutant strain depending on the growth conditions. Moreover, SUC2 expression and invertase synthesis became constitutive after long-term derepression, and decreased to a low level in Deltanhp6A Deltanhp6B double deletion mutant. A time course analysis of the invertase synthesis revealed that both the repression and derepression rates were very slow in the Deltanhp6A Deltanhp6B double mutant yeast. These results indicate that the architectural transcription factors Nhp6A and Nhp6B play a very critical role in the regulation of SUC2 gene expression.


Criterion Validity, Reliability and Usefulness of a Judo-Specific Maximal Aerobic Power Test.
To evaluate criterion validity, reliability and usefulness of a test to measure maximal aerobic power using judo-specific movements (UKtest). 12 judokas performed five graded exercise tests (GETs) in 4 sessions. In sessions 1 and 2, upper-body (UBtest), lower-body (LBtest) and familiarization UKtest. GETs were randomly performed and separated by at least 48 hours. In sessions 3 and 4, test and retest UKtest were performed (7-day apart). For all GETs, peak oxygen consumption (V̇O2peak), maximal heart rate (HRmax), peak blood lactate concentration ([Lapeak]), maximal aerobic intensity and rating of perceived exertion (RPE) were determined. Another group of 12 judokas performed the UKtest and one confirmation test (20-min after the UKtest), at 105% of maximal aerobic speed (MAS) until exhaustion, to confirm if maximal responses were achieved. V̇O2peak did not differ (P>.05) between UKtest (46.04±5.34 mL.kg-1.min-1) and LBtest (44.78±5.98 mL.kg-1.min-1), but was higher (P<.05) than UBtest (37.03±7.16 mL.kg-1.min-1). Total duration (551±60s) and [Lapeak] (7.10±1.76 mmol.L-1) in the UKtest were different (P<.05) from UBtest (416±47s, 9.93±2.15 mmol.L-1, respectively) and LBtest (433±54s, 10.29±2.23 mmol.L-1, respectively). Very large relationships between V̇O2peak in UKtest with UBtest (r=0.78, P=.003) and LBtest (r=0.87, P<.001) were found. Maximal values were achieved for the UKtest V̇O2peak, HRmax, [Lapeak], RPE and MAS, with no difference between test and retest (P>.05). In addition, very large intraclass correlation coefficients (ICC) for the V̇O2peak (ICC=0.86), HRmax (ICC=0.90) and MAS (ICC=0.81) were found. UKtest can be considered a valid, reliable and useful test to measure maximal aerobic power using judo-specific movements.


Habitat preferences of Boros schneideri (Coleoptera: Boridae) in the natural tree stands of the Białowieża Forest.
We analyzed habitat requirements of Boros schneideri (Panzer, 1796) (Coleoptera: Boridae) in the natural forests of the continental biogeographical region, using data collected in the Białowieża Forest. This species has been found on the six host trees, but it preferred dead, standing pine trees, characterized by large diameter, moderately moist and moist phloem but avoided trees in sunny locations. It occurred mostly in mesic and wet coniferous forests. This species demonstrated preferences for old tree stands (over 140-yr old), and its occurrence in younger tree-stand age classes (minimum 31-40-yr old) was not significantly different from random distribution. B. schneideri occupied more frequently locations distant from the forest edge, which were less affected by logging. Considering habitat requirements, character of occurrence, and decreasing number of occupied locations in the whole range of distribution, this species can be treated as relict of primeval forests.


Potentially Important Extracolonic Findings at Screening CT Colonography: Incidence and Outcomes Data From a Clinical Screening Program.
The effect of detection of extracolonic findings at screening CT colonography (CTC) remains controversial. Our objective is to analyze the incidence and outcomes of unsuspected potentially significant (CT Colonography Reporting and Data System [C-RADS] extracolonic category E4) findings in a population undergoing clinical CTC screening. Over the course of 99 months (April 1, 2004, through June 30, 2012), 7952 consecutive asymptomatic adults (3675 men and 4277 women; mean [± SD] age, 56.7 ± 7.3 years) underwent first-time screening CTC. Examinations were prospectively interpreted by radiologists within our abdominal imaging section, and extracolonic findings were recorded and categorized. Potentially significant (i.e., C-RADS extracolonic category E4) findings were retrospectively reviewed with additional analysis of follow-up (range, 2-10 years) and ultimate clinical outcome. Overall, 2.5% (202/7952) of patients had a potentially significant (C-RADS category E4) extracolonic finding for which further imaging (56%; 113/202) or clinical follow-up (44%; 89/202) was recommended. No patients had multiple category E4 findings. Twenty-two patients were lost to follow-up. Of the remaining 180 patients, 68% (123/180) proved to have clinically significant disease, including 23% (42/180) with malignant or potentially malignant neoplasms and 32% (57/180) with abdominal aortic or other visceral artery aneurysms requiring treatment or surveillance. The most commonly involved organs and systems included the vascular system (26%; 53/202), the genitourinary system (18%; 36/202), the liver (15%; 30/202), the gastrointestinal system (9.9%; 20/202), the lungs (9.4%; 19/202), and the gynecologic system (6.9%; 14/202). Potentially significant extracolonic findings in asymptomatic adults at screening CTC are uncommon (2-3% of cases). However, most of these findings (68%) will prove to be clinically significant, including a number of malignancies and aneurysms requiring treatment or surveillance.


Morse Taper Implants Immediately Loaded in Fresh Extraction Sockets: A Prospective Cohort Study.
To evaluate survival rate and bone response around immediate loaded Morse taper implants installed in fresh sockets on the anterior area of the maxilla. The sample comprised 16 patients in whom 16 single implants were installed. All the teeth were extracted in a flapless surgery. Radiographic and tomographic evaluations were performed immediately after surgery (T1) and after 12 months (T2). The variables studied were height of the buccal wall (HBW), buccal wall width (BW) at 3 levels, and proximal bone height at 2 different areas: the alveolar crest level (CLH) and at the point where bone tissue meets the implant surface (BIS). Statistically significant differences were observed. The buccal plate showed bone loss in height (HBW = -0.50 ± 0.42 mm) and in width (BW-1 = -0.71 ± 0.48 mm; BW-2 = -0.48 ± 0.34 mm; BW-3 = -0.48 ± 0.34 mm). In the proximal areas, there was also bone loss in height (CLH-M = -0.85 ± 0.89 mm; BIS-M = -0.91 ± 0.70 mm; CLH-D = -0.64 ± 0.57 mm; and BIS-D = -0.68 ± 0.62 mm). There was 100% survival rate after a 12-month period, but bone loss was observed in all evaluated areas.


Sodium-dependent organic anion transporter (Slc10a6-/-) knockout mice show normal spermatogenesis and reproduction, but elevated serum levels for cholesterol sulfate.
The sodium-dependent organic anion transporter SOAT (gene name SLC10A6 in man and Slc10a6 in mice) is a plasma membrane transporter for sulfated steroids, which is highly expressed in germ cells of the testis. SOAT can transport biologically inactive sulfated steroids into specific target cells, where they can be reactivated by the steroid sulfatase (STS) to biologically active, unconjugated steroids known to regulate spermatogenesis. Significantly reduced SOAT mRNA expression was previously found in different forms of impaired spermatogenesis in man. It was supposed that SOAT plays a role for the local supply of steroids in the testis and consequently for spermatogenesis and fertility. Thus, an Slc10a6-/- Soat knockout mouse model was established by recombination-based target deletion of the Slc10a6 gene to elucidate the role of Soat in reproduction. However, the Slc10a6-/- knockout mice were fertile, produced normal litter sizes, and had normal spermatogenesis and sperm vitality. This phenotype suggests that the loss of Soat can be compensated in the knockout mice or that Soat function is not essential for reproduction. In addition to reproductive phenotyping, a comprehensive targeted steroid analysis including a set of 9 un-conjugated and 12 sulfo-conjugated steroids was performed in serum of Slc10a6-/- knockout and Slc10a6+/+ wildtype mice. Only cholesterol sulfate, corticosterone, and testosterone (only in the males) could be detected in considerable amounts. Interestingly, male Slc10a6-/- knockout mice showed significantly higher serum levels for cholesterol sulfate compared to their wildtype controls. As cholesterol sulfate has a broader impact apart from the testis, further analysis of this phenotype will include other organs such as skin and lung, which also show high Soat expression in the mouse.


Characteristics And Outcome Of Patients With Diffuse Large B Cell Lymphoma-Treated With Chemotherapy Or Chemo-Immunotherapy.
Diffuse large-B-cell lymphoma, is the most common subtype of Non-Hodgkin lymphoma. Aim of this study was to look at the characteristics and outcome of DLBCL patients who were treated with chemotherapy or chemotherapy plus rituximab at our institution. Data of 750 patients, who got registered at our institute between 2007 and 2014, was reviewed retrospectively. After appropriate exclusions, 337 were included. Disease free survival (DFS) and overall survival (OS) were compared between patients who received rituximab plus CHOP (Cyclophosphamide, Doxorubicine, Vincristine, Prednisolon) (R-Ch) and standard chemotherapy- CHOP (S-Ch). Males and females were 216 (64%) and 121 (36%) respectively, with median age 38 years (Range 18-80 yrs.). R-Ch and S.Ch was received by 129(38.3%) and 197(58.4%) patients, respectively. Complete remission (CR) was achieved by 81 (62.8%) vs. 105 (53.3%) patients in R-Ch vs. S-Ch cohorts, respectively. In subset analysis CR was seen in 34 (63.0%) and 45 (58.4%) (p=0.01) in R-Ch/XRT and S-Ch/XRT, respectively. At three years, DFS was 85.3% vs. 74% (p=0.04) and OS was 82.2% vs. 72.6% (p=0.02) in R-Ch and S-Ch cohorts respectively. Deaths observed were 9 Vs.13 in R-Ch/XRT and S-Ch/XRT, respectively. Based on our study, onset of DLBCL is at younger age in our population with male predominance. Addition of rituximab to CHOP resulted in better DFS and OS in patients with DLBCL. In developing countries, due to cost, large number of patients do not have access to rituximab. Efforts should be made to reduce the price of targeted therapies so that more and more patients are benefitted from these newer agents.


A perspective on environmental health in the USSR: research and practice.
Under the auspices of the US-USSR agreement for cooperative research in environmental health, Soviet methods for setting and enforcing standards for environmental pollutants were observed. Since all industry is government owned, the Soviet government is the principal polluter of the environment, the regulator of environmental degradation, and supporter of research on environmental quality control. The Sanitary Epidemiological Service, a subdivision of the Ministry of Health, coordinates the activities of many of the research institutes involved in environmental research as well as a large network of Sanepid Stations for maintaining and controlling environmental quality at the local level. The Soviet Union's distinctive view of a pollutant standard has greatly influenced the environmental research that is undertaken. The centralized absolute power of the government to enforce pollution abatement has led to some improvements in environmental quality.


Efficient Isolation of Dihydropyranocoumarins and Simple Coumarins from Mutellina purpurea Fruits.
For the first time, the separation of coumarin derivatives from the petroleum ether extract of the fruits of Mutellina purpurea through high-performance countercurrent chromatography (HPCCC) is described. Four compounds, pteryxin (1; 2.72 mg), hyuganin C (2; 7.94 mg), osthol (3; 4.30 mg), and hyuganin A (4; 3.09 mg), were obtained in a single run following the injection of crude extract (300 mg). Additionally, auraptenol (5) and hyuganin D (6) were identified using LC-ESI-(Q)TOF-MS. The structures of the isolated compounds were elucidated through spectroscopic (NMR and MS) methods. This is apparently the first report of the identification of dihydropyranocoumarins in this plant, and the first time that HPCCC was used to separate them.


From brain to blood: alternative splicing evidence for the cholinergic basis of Mammalian stress responses.
Three principal features of mammalian stress responses are that they span peripheral and CNS changes, modify blood cell composition and activities, and cover inter-related alterations in a large number of gene products. The finely tuned spatiotemporal regulation of these multiple events suggests the hierarchic involvement of modulatory neurotransmitters and modified process(es) in the pathway of gene expression that together would enable widely diverse stress responses. We report evidence supporting the notion that acetylcholine (ACh) acts as a stress-response-regulating transmitter and that altered ACh levels are variously associated with changes in the alternative splicing of pre-mRNA transcripts in brain neurons and peripheral blood cells. We used acetylcholinesterase (AChE) gene expression as a case study and developed distinct probes for its alternative splice variants at the mRNA and protein levels. In laboratory animals and human-derived cells, we found stress-induced changes in the alternative splicing patterns of AChE pre-mRNA, which attributes to this gene and its different protein products diverse stress responsive functions that are associated with the enzymatic and noncatalytic properties of AChE. Together, these approaches provide a conceptually unified view of the studied pathways for controlling stress responses in brain and blood.


[Concentration of piperacillin in bone].
Eighteen patients received 2.0 grams of piperacillin sodium (PIPC) intravenously. The concentrations of PIPC in serum, cancellous bone, and cortical bone were measured approximately 30 minutes after injection. Serum concentrations ranged from 9.10 to 167.0 micrograms/ml (mean 95.61 +/- 10.03 micrograms/ml). Cortical bone concentrations varied between 0 and 17.5 micrograms/g (mean 4.58 +/- 1.03 micrograms/g). The levels measured in cancellous bone ranged from 0.62-13.1 micrograms/g (mean 8.07 +/- 1.43 micrograms/g). PIPC achieved high concentrations in bone.


Carvedilol: use in chronic heart failure.
Carvedilol is a beta-adrenergic antagonist with vasodilatory properties (alpha1-antagonism), which has been extensively evaluated in the treatment of patients with heart failure. In patients with chronic heart failure carvedilol improves left-ventricular (LV) ejection fraction over 6 to 12 months of treatment, and attenuates LV remodelling. Large-scale randomised, placebo controlled trials involving more than 4000 patients with chronic heart failure have demonstrated that carvedilol improves survival and reduces hospitalizations. Comparative studies with metoprolol in patients with heart failure have suggested that carvedilol may be associated with greater survival benefit although differences in the preparation of metoprolol have left uncertainty in this area. Carvedilol has a high safety profile and the clinical benefits appear maintained across a wide range of patients with comorbidities such as diabetes and renal failure. Carvedilol has also been shown to attenuate LV remodeling and improve clinical outcomes in patients with LV dysfunction and/or heart failure following acute myocardial infarction. As a result of these data, carvedilol is recommended for treatment of patients with heart failure in heart-failure guidelines. This evidence-based treatment should be widely implemented to ensure that patients with heart failure receive appropriate medical therapy.


[Experimental study of the anti-tumor activity of direct current--an effective adjuvant therapy in irradiation].
The anti-tumor activity of direct current combined with radiation was studied. The experiments were performed with fibrosarcomas (FSA, NFSA) syngenetic to C3H mice. Direct current (0.6mA, 120min) alone was effective to reduce the tumor sizes, but could not cure the tumors. When the direct current therapy (DC therapy) was combined with radiation, the DC therapy following radiation was more effective than that before radiation. Using TCD50 assay, the DC therapy enhanced the effect of a single dose of radiation with the dose-modifying factor of 1.2. However, tumor control rates by the combination therapy were more improved at the smaller doses of radiation than at the larger ones. When the single DC therapy (0.6mA, 120min) was applied immediately after the first radiation of fractionated one the combination therapy still showed the enhanced effect. However, both DC therapy and the radiation therapy were divided in three fractions, and the DC therapy (0.6mA, 40min) was applied after each radiation. Tumor growth retardation by the combination therapy was no different from that by radiation alone. This result suggests that there might be a minimum required dose of coulombs to show the effect of the combination therapy.