Mitophagy Failure in APP and Tau Overexpression Model of Alzheimer's Disease.
Mitochondrial alterations and oxidative stress are common features of Alzheimer's disease brain and peripheral tissues. Moreover, mitochondrial recycling process by autophagy has been found altered in the sporadic form of the disease. However, the contribution of the main proteins involved in this pathology such as amyloid-β protein precursor (AβPP) and tau needs to be achieved. With this aim, human unmodified fibroblasts were transduced with lentivectors encoding APP and Tau and treated with CCCP to study the mitophagy process. Both AβPP and tau separately increased autophagy flux mainly by improving degradation phase. However, in the specific case of mitophagy, labeling of mitochondria by PINK1 and PARK2 to be degraded by autophagy seemed reduced, which correlates with the long-term accumulation of mitochondria. Nevertheless, the combination of tau and AβPP was necessary to cause a mitophagy functional impairment reflected in the accumulation of depolarized mitochondria labeled by PINK1. The overexpression of Tau and APP recapitulates the mitophagy failure previously found in sporadic Alzheimer's disease.


Combining chromatin immunoprecipitation and DNA footprinting: a novel method to analyze protein-DNA interactions in vivo.
A variety of methods are available to analyze protein-DNA interactions in vivo. Two of the most prominent of these methods are chromatin immunoprecipitation (ChIP) and in vivo footprinting. Both of these procedures have specific limitations. For example, the ChIP assay fails to document where exactly a protein binds in vivo. The precipitation of a specific segment of DNA with antibodies directed against DNA-binding proteins does not necessarily indicate that the protein directly interacts with a sequence in the precipitate but could rather reflect protein-protein interactions. Furthermore, the results of in vivo footprinting studies are inconclusive if a DNA sequence is analyzed that is bound by a specific protein in only a certain fraction of cells. Finally, in vivo footprinting does not indicate which protein is bound at a specific site. We have developed a new procedure that combines the ChIP assay and DMS footprinting techniques. Using this method we show here that antibodies specific for USF1 and NF-E2 precipitate the murine beta-globin promoter in MEL cells. DMS footprinting analysis of the DNA precipitated with NF-E2 antibodies revealed a protection over a partial NF-E2-binding site in the beta-globin downstream promoter region. We believe that this novel method will generally benefit investigators interested in analyzing protein-DNA interactions in vivo.


The meaning of dignity for older adults: A meta-synthesis.
Dignified care is a central issue in the nursing care of older adults. Nurses are expected to treat older adults with dignity, and older adults wish to be treated in a dignified manner. Researchers have recommended investigating the concept of dignity based on specific contexts and population groups. This meta-synthesis study aims to explore the understandings of dignity from the perspective of older adults in the Nordic countries. Synthesising findings from qualitative studies on older adults' experiences of dignity has provided important insight into what can be essential for dignified care in a Nordic context. The importance of visibility and recognition for the experience of dignity is an overarching theme in all the studies. The participants' descriptions mostly implicated an existence dominated by a lack of recognition. The older adults do not feel valued as people or for their contribution to society and strive to tone down their illnesses in an attempt to become more visible and acknowledged as people. Toning down their illnesses and masking their needs can protect their independence. At the same time, becoming less visible can leave them without a voice. The metaphorical phrase protected and exposed by a cloak of invisibility is used to express the authors' overall interpretation of the findings. Lack of recognition and being socially invisible is a genuine threat to older adults' dignity.


New Insights into N-Doped Porous Carbons as Both Heterogeneous Catalysts and Catalyst Supports: Opportunities for the Catalytic Synthesis of Valuable Compounds.
Among the vast class of porous carbon materials, N-doped porous carbons have emerged as promising materials in catalysis due to their unique properties. The introduction of nitrogen into the carbonaceous matrix can lead to the creation of new sites on the carbon surface, often associated with pyridinic or pyrrolic nitrogen functionalities, which can facilitate various catalytic reactions with increased selectivity. Furthermore, the presence of N dopants exerts a significant influence on the properties of the supported metal or metal oxide nanoparticles, including the metal dispersion, interactions between the metal and support, and stability of the metal nanoparticles. These effects play a crucial role in enhancing the catalytic performance of the N-doped carbon-supported catalysts. Thus, N-doped carbons and metals supported on N-doped carbons have been revealed to be interesting heterogeneous catalysts for relevant synthesis processes of valuable compounds. This review presents a concise overview of various methods employed to produce N-doped porous carbons with distinct structures, starting from diverse precursors, and showcases their potential in various catalytic processes, particularly in fine chemical synthesis.


ABO, Lewis, secretor and non-secretor phenotypes in patients infected or uninfected by the Helicobacter pylori bacillus.
Epidemiological studies have demonstrated higher frequencies of the O blood group and the non-secretor phenotype of ABH antigens among patients suffering from peptic ulcers. Since Helicobacter pylori has been established as the main etiological factor in this disease, controversies about the associations of the ABO and Lewis blood group phenotypes and secretor and non-secretor phenotypes in relation to susceptibility towards infection by this bacillus have been presented. To verify the frequencies of ABO, Lewis blood group phenotypes, secretor and non-secretor phenotypes in patients infected or uninfected by H. pylori. Cross-sectional study. Outpatient clinic. One hundred and twenty patients with dyspeptic symptoms who underwent endoscopy. ABO and Lewis blood group phenotypes were determined by a standard hemagglutination test and the secretor and non-secretor phenotypes were evaluated by saliva samples using the inhibitor hemagglutination test. The diagnosis of infection, made via breath and urea tests and confirmed using polymerase chain reaction (PCR) in gastric biopsy fragments, showed the presence of H. pylori in 61.7% of the patients and absence in 38.3%. The differences between the frequencies of the ABO blood group phenotypes among infected (A 27.0%; B 12.2%; AB 4.0% and O 56.8%) and uninfected patients (A 58.7%; B 13.0%; AB 4.3% and O 24.0%) were significant. The Lewis blood type, secretor and non-secretor phenotypes showed homogeneous distribution between the groups of patients analyzed. Our results suggest that the infection of H. pylori can be related to ABO blood groups but not to the Lewis blood group nor to secretor and non-secretor phenotypes.


The fine line between Takayasu arteritis and giant cell arteritis.
The objective of this study is to describe a series of patients above the age of 50 years with large vessel arteritis and vascular involvement typical of TAK. A retrospective review of 18 patients (median age 64 years) with emphasis on clinical characteristics, laboratory values, and vascular involvement by CT, MRI, or planar angiography. Five patients fulfilled the ACR criteria for GCA, five for TAK, three both GCA and TAK, while five patients did not fulfill the criteria for either disease. The dominant presenting symptoms were constitutional, while only a few patients had cranial or peripheral symptoms. Sixty-one percent had physical signs of vascular compromise. Temporal artery biopsy showed giant cell arteritis in six out of nine biopsies. Arterial involvement: 78 % had either involvement of the ascending aorta, the aortic arch, descending or/and abdominal aorta, 9 carotid, 12 subclavian, 5 axillary, 3 renal, 7 iliac, and 2 femoral arteries; 7 mesenteric or celiac trunk. All the patients were treated with prednisone and 50 % with steroid-sparing drug. Nine out of 15 patients (60 %) achieved remission after 1 year of follow-up. No substantial differences in the distribution of vascular involvement, type of treatment, or outcome measures were observed between patients fulfilling criteria for GCA or TAK. Vascular involvement typical of TAK in patients above the age of 50 years with large vessel arteritis seems to be more frequent than previously assumed. Our findings support the assumption that TAK and GCA represent a spectrum of the same disease.


Ultrastructural organization of the alveolar-capillary unit.
As a result of its special position in the circulatory system the lung can screen and monitor the composition of the blood which comes from and is returned to all the tissues. This function, together with the exchange of gases, takes place at the level of the alveolar-capillary unit. The cellular components of the unit are: the epithelium, lining the air spaces, and the endothelium, facing the blood compartment. The epithelium is composed of two types of cells: type I--broad, squamous, highly branched cells occupying approximately 97% of the total alveolar surface; these cells seem to be involved mostly in exchange of gases; and type II--cuboidal cells containing characteristic osmiophilic lamellar bodies in their cytoplasm. The epithelial cells are connected to one another by tight junctions. A thin layer of a surface-active material--the surfactant--covers the epithelium toward the air space, where its role is to lower the surface tension. Surfactant is a mixture of lipids (approximately 75%) and proteins; dipalmitoyl-phosphatidylcholine is the major lipid component and is synthesized and secreted by type II epithelial cells. The endothelium is of continuous type and has a large population of plasmalemmal vesicles; the cells are linked together by tight junctions. Morphometric studies indicate that in humans the capillary surface area is approximately 120 m2 and the alveolar surface area is approximately 140 m2. Some of the metabolic functions ascribed to the lung have been localized to cellular components. Phospholipids needed for the constantly renewed surfactant are synthesized in type II epithelial cells. Angiotensin-converting enzyme is associated with the endothelial cell membrane and vesicles opening to the blood front. There are indications that pulmonary cells also intervene in the metabolism of circulating vasoactive substances which during their passage through the lung can be activated (angiotensin I), inactivated (bradykinin) or removed from the circulation (5-hydroxytryptamine). The lung is a metabolically active organ where the anabolism and catabolism of pharmacologically active substances and the synthesis of lipids take place and a proper balance for blood homeostasis is maintained.


Biological characterization of 2-aminothiazole-derived Cdk4/6 selective inhibitor in vitro and in vivo.
Abnormalities in the p16INK4a/ cyclin-dependent kinase (Cdk)4, 6/ Retinoblastoma (Rb) pathway frequently occur in various human cancers. Thus, Cdk4/6 is an attractive target for cancer therapy. Here we report the biological characterization of a 2-aminothiazole-derived Cdk4/6 selective inhibitor, named Compound A in vitro and in vivo. Compound A potently inhibits Cdk4 and Cdk6 with high selectivity (more than 57-fold) against other Cdks and 45 serine/threonine and tyrosine kinases. Compound A inhibits Rb protein (pRb) phosphorylation at Ser780, inhibits E2F-dependent transcription, and induces cell-cycle arrest at G1 in the T98G human glioma cell line. Among 82 human cells derived from various tissues, cell lines derived from hematological cancers (leukemia/lymphoma) tended to be more sensitive to Compound A in cell proliferation assay. Rb-negative cells tended to be insensitive to Compound A, as we had expected. In a nude rat xenograft model, Compound A inhibited pRb phosphorylation and bromodeoxyuridine (BrdU) incorporation in Eol-1 xenograft tumor at plasma concentration of 510 nM. Interestingly Compound A only moderately inhibited those pharmacodynamic and cell cycle parameters of normal crypt cells in small intestine even at 5 times higher plasma concentration. In F344 rats, Compound A did not cause immunosuppression even at 17 times higher plasma conc. These results suggest that Cdk4/6 selective inhibitors only moderately affects on the cell cycle of normal proliferating tissues and has a safer profile than pan-Cdk inhibitor in vivo.


Adult blood lead epidemiology and surveillance--United States, second quarter, 1994.
CDC's National Institute for Occupational Safety and Health (NIOSH) Adult Blood Lead Epidemiology and Surveillance program (ABLES) monitors elevated blood lead levels (BLLs) in adults in the United States. Blood lead data from laboratory reports are transmitted to state-based lead surveillance programs and are compiled by NIOSH for quarterly reporting.


Pancreatic autoantibodies in Italian patients with newly diagnosed type 1 diabetes mellitus under the age of 20 years.
We analyzed 97 children and young persons (< 20 years of age) with newly diagnosed diabetes for antibodies to islet cells (ICAs), glutamic acid decarboxylase (GADAbs), second-islet antigen (IA2Abs), and insulin (IAAs) in order to evaluate the prevalence of immune-mediated type 1 diabetes, as well as to recognize which autoantibody combination is better associated with the disease. A positive result for one or more diabetes-related antibodies evaluated was found in 92 children (94.8%): 41 females (95.3%) and 51 males (94.4%). With regard to single autoantibody testing, ICA levels were found to be positive in 84 patients (86.6%), GADAbs in 71 (73.2%), IA2Abs in 60 (61.8%), and IAAs in 51 (52.6%) patients. Combining the determination of at least two autoantibodies, ICAs and/or GADAbs were more frequently detectable than other antibody combinations, being positive in 89 patients (91.8%). Our data indicate that the vast majority of cases of type 1 diabetes in children may be considered as immune-mediated, that multiple autoantibody analysis improves identification of the disease, and that first-level screening is provided by the combined detection of ICAs and GADAbs.


The effect of multimedia-based nursing visit on preoperative anxiety and vital signs in patients undergoing lumbar disc herniation surgery: A randomised clinical trial.
This study was a randomised clinical trial on 60 candidates undergoing lumbar disc herniation surgery. Anxiety rate and vital signs were measured before and after the intervention. There was a statistically significant difference between the two groups in terms of the preoperative anxiety, systolic and diastolic blood pressure, pulse and respiratory rate (P = 0.0001). Neurosurgery perioperative nurses can make use of multimedia in preoperative nursing visit based on the needs of patients.


Promoting the autonomy of rural older adults in active aging.
to understand how the rural older adults promote their autonomy in active aging. qualitative research through the Paulo Freire's research itinerary, consisting of three steps: area of research; encoding and decoding; and critical unveiling. Seventeen older adults living in the rural area of a municipality in Southern Brazil participated in the research. Six culture circles were conducted from July to December 2016. the investigation revealed two generating themes: joint pain and participation in groups. The understanding of autonomy promotion for the active aging of older adults is focused on the physical capacity and independence of activities of daily living. the culture circles have promoted reflection moments for the participants, especially about the advantages and difficulties related to the practice of autonomy in the exercise of citizenship for active aging in the rural area.


Atorvastatin prevents end-organ injury in salt-sensitive hypertension: role of eNOS and oxidant stress.
Statins, inhibitors of cholesterol biosynthesis, are endowed with pleiotropic effects that may contribute to their favorable clinical results. Hypertensive Dahl salt-sensitive (DS) rats have endothelial dysfunction and cardiorenal injury associated with decreased NO bioavailability and increased superoxide (O2-) production linked to a functional upregulation of angiotensin II. We investigated whether atorvastatin (30 mg/kg per day; by gavage) would prevent endothelial nitric oxide (eNOS) downregulation and the increase in O2- in DS rats, thereby reducing end-organ injury. DS rats given a high-salt diet (4% NaCl) for 10 weeks developed hypertension (systolic blood pressure [SBP] 200+/-8 versus 150+/-2 mm Hg in DS rats fed 0.5% NaCl diet [NS]; P<0.05), impaired endothelium-dependent relaxation, functional upregulation of endothelin-1, left ventricular hypertrophy (LVH; 30%), and proteinuria (167%), accompanied by downregulation of aortic eNOS activity (0.7+/-0.2 versus 1.8+/-0.3 nmol/min per gram protein in NS; P<0.05) and increased aortic O2- (2632+/-316 versus 1176+/-112 counts/min per milligram in NS; P<0.05) and plasma 8-F2alpha isoprostanes. Atorvastatin prevented the decrease in eNOS activity (1.5+/-0.3 nmol/min per gram protein) as well as the increase in O2- (1192+/-243 counts/min per milligram) and plasma 8-F2alpha isoprostanes, reduced LVH and proteinuria, and normalized endothelial function and vascular response to endothelin-1, although reduction in SBP was modest (174+/-8 mm Hg). Atorvastatin combined with removal of high salt normalized aortic eNOS activity, SBP, LVH, and proteinuria. These findings strongly suggest that concomitant prevention of vascular eNOS downregulation and inhibition of oxidative stress may contribute to the protection against end-organ injury afforded by this statin in salt-sensitive hypertension.


Posttranslational isomerization of a neuropeptide in crustacean neurosecretory cells studied by ultrastructural immunocytochemistry.
Isomerization of the third amino acid residue (a phenylalanine) of crustacean hyperglycemic hormone (CHH) has been previously reported to occur as a late step of hormone precursor maturation in a few neurosecretory cells in the X-organ-sinus gland complex of the crayfish Orconectes limosus. In the present report, using conformation-specific antisera combined with immunogold labeling, we have studied, at the ultrastructural level, the distribution of L- and D-CHH immunoreactivity in CHH-secreting cells of the crayfish Astacus leptodactylus. Two CHH-secreting cell populations were observed, the first one (L-cells), the most numerous, exhibited only labeling for L-CHH. In the second one (D-cells), four secretory granule populations were distinguished according to their labeling: unlabeled, either L- or D- exclusively or both L- and D-granules. Labeling quantification by image analysis in D-cells showed a marked increase in D-labeling from the cell body to the axon terminal. However some L- and mixed granules remain in axon terminals. Our results demonstrate that Phe3 isomerization of CHH occurs within the secretory granules of specialized neurosecretory cells and progresses as the granules migrate along the axonal tract. The observation that not all the CHH synthesized is isomerized, and the great variability in the proportion of L- and D-immunoreactivity in granules in every cell region may suggest an heterogeneous distribution of the putative enzyme involved in Phe3 isomerization, a peptide isomerase, within the secretory pathway.


Phylogeographic patterns of Lygus pratensis (Hemiptera: Miridae): Evidence for weak genetic structure and recent expansion in northwest China.
Lygus pratensis (L.) is an important cotton pest in China, especially in the northwest region. Nymphs and adults cause serious quality and yield losses. However, the genetic structure and geographic distribution of L. pratensis is not well known. We analyzed genetic diversity, geographical structure, gene flow, and population dynamics of L. pratensis in northwest China using mitochondrial and nuclear sequence datasets to study phylogeographical patterns and demographic history. L. pratensis (n = 286) were collected at sites across an area spanning 2,180,000 km2, including the Xinjiang and Gansu-Ningxia regions. Populations in the two regions could be distinguished based on mitochondrial criteria but the overall genetic structure was weak. The nuclear dataset revealed a lack of diagnostic genetic structure across sample areas. Phylogenetic analysis indicated a lack of population level monophyly that may have been caused by incomplete lineage sorting. The Mantel test showed a significant correlation between genetic and geographic distances among the populations based on the mtDNA data. However the nuclear dataset did not show significant correlation. A high level of gene flow among populations was indicated by migration analysis; human activities may have also facilitated insect movement. The availability of irrigation water and ample cotton hosts makes the Xinjiang region well suited for L. pratensis reproduction. Bayesian skyline plot analysis, star-shaped network, and neutrality tests all indicated that L. pratensis has experienced recent population expansion. Climatic changes and extensive areas occupied by host plants have led to population expansion of L. pratensis. In conclusion, the present distribution and phylogeographic pattern of L. pratensis was influenced by climate, human activities, and availability of plant hosts.


Attenuation of Red Blood Cell Storage Lesions with Vitamin C.
Stored red blood cells (RBCs) undergo oxidative stress that induces deleterious metabolic, structural, biochemical, and molecular changes collectively referred to as "storage lesions". We hypothesized that vitamin C (VitC, reduced or oxidized) would reduce red cell storage lesions, thus prolonging their storage duration. Whole-blood-derived, leuko-reduced, SAGM (saline-adenine-glucose-mannitol)-preserved RBC concentrates were equally divided into four pediatric storage bags and the following additions made: (1) saline (saline); (2) 0.3 mmol/L reduced VitC (Lo VitC); (3) 3 mmol/L reduced VitC (Hi VitC); or (4) 0.3 mmol/L oxidized VitC (dehydroascorbic acid, DHA) as final concentrations. Biochemical and rheological parameters were serially assessed at baseline (prior to supplementation) and Days 7, 21, 42, and 56 for RBC VitC concentration, pH, osmotic fragility by mechanical fragility index, and percent hemolysis, LDH release, glutathione depletion, RBC membrane integrity by scanning electron microscopy, and Western blot for β-spectrin. VitC exposure (reduced and oxidized) significantly increased RBC antioxidant status with varying dynamics and produced trends in reduction in osmotic fragility and increases in membrane integrity. VitC partially protects RBC from oxidative changes during storage. Combining VitC with other antioxidants has the potential to improve long-term storage of RBC.


Structure elucidation and phytotoxicity of ecdysteroids from Chenopodium album.
The leaves of Chenopodium album were infused in H2O/MeOH. The extract treated with cold acetone gave heavy precipitation, which was removed by centrifugation. Solid material was fractionated into acidic and neutral fractions. The acidic material was subjected to different silica-gel column chromatographies, and then it was purified by reversed-phase HPLC to afford four known ecdysteroids and the new 3beta,14alpha-dihydroxy-5beta-pregn-7-ene-2,6,20-trione that were characterized by extensive spectroscopic investigation, especially by 1D- and 2D-NMR. Their effects on germination and growth of Lactuca sativa L. have been studied. The results are reported as percentage differences of germination, root elongation and shoot elongation, from the control at concentrations ranging from 10(-4) to 10(-7) M.


Proteomic applications of protein quantification by isotope-dilution mass spectrometry.
Over the decades, isotope-dilution mass spectrometry (IDMS) has been implemented extensively for accurate quantification of drugs, metabolites and peptides in body fluids and tissues. More recently, it has been extended for quantifying specific proteins in complex mixtures. In this extended methodology, proteins are subjected to endoprotease action and specific resultant peptides are quantified by using synthetic stable isotope-labeled standard (SIS) peptides and IDMS. This article outlines the utilities and applications of quantifying proteins by IDMS, emphasizing its complementary value to global survey-based proteomic studies. The potential of SIS peptides to provide quantitative insights into cell signaling is also highlighted, with specific examples. Finally, we propose several novel mass spectrometric data acquisition strategies for large-scale applications of IDMS and SIS peptides in systems biology and protein biomarker validation studies.


A Million-Cow Genome-Wide Association Study of Three Fertility Traits in U.S. Holstein Cows.
A genome-wide association study (GWAS) of the daughter pregnancy rate (DPR), cow conception rate (CCR), and heifer conception rate (HCR) using 1,001,374-1,194,736 first-lactation Holstein cows and 75,140-75,295 SNPs identified 7567, 3798, and 726 additive effects, as well as 22, 27, and 25 dominance effects for DPR, CCR, and HCR, respectively, with log10(1/p) > 8. Most of these effects were new effects, and some new effects were in or near genes known to affect reproduction including GNRHR, SHBG, and ESR1, and a gene cluster of pregnancy-associated glycoproteins. The confirmed effects included those in or near the SLC4A4-GC-NPFFR2 and AFF1 regions of Chr06 and the KALRN region of Chr01. Eleven SNPs in the CEBPG-PEPD-CHST8 region of Chr18, the AFF1-KLHL8 region of Chr06, and the CCDC14-KALRN region of Chr01 with sharply negative allelic effects and dominance values for the recessive homozygous genotypes were recommended for heifer culling. Two SNPs in and near the AGMO region of Chr04 that were sharply negative for HCR and age at first calving, but slightly positive for the yield traits could also be considered for heifer culling. The results from this study provided new evidence and understanding about the genetic variants and genome regions affecting the three fertility traits in U.S. Holstein cows.


Levels and values of inflammatory markers in patients with angina pectoris.
Inflammation plays an important pathogenic role in the initiation and progression of atherosclerotic plaque lesions. C-reactive protein (CRP), which directly participates in plaque inflammation, induces vascular cell adhesion molecule-1 (VCAM-1) expression in endothelial cells. However, the levels and values of high-sensitivity (hs)-CRP, white blood cell (WBC) count, and VCAM-1 in both stable and unstable angina pectoris (AP) have not been fully investigated. This study examines the levels and values of these inflammatory markers in patients with stable or unstable AP. From March 2003 to December 2003, a prospective cohort study was conducted in 128 consecutive patients, including unstable AP patients (class I: n = 59; combined class II and III: n = 16) and stable AP patients (n = 53) undergoing elective coronary stenting. Blood samples for hs-CRP, WBC count, and VCAM-1 were obtained in the catheterization laboratory before coronary angiography. The circulating levels of hs-CRP and VCAM-1 were also evaluated in 40 healthy volunteers. The circulating levels of these three inflammatory markers were substantially higher in patients than in healthy volunteers (all P values < 0.0001). Additionally, circulating levels of hs-CRP and the WBC count were significantly higher in patients with unstable AP than in patients with stable AP (all P value < 0.0001). However, only those patients with class II and III unstable AP had significantly higher circulating levels of VCAM-1 than patients with stable AP (P < 0.0001). On the other hand, the circulating levels of VCAM-1 did not differ between patients with class I unstable AP and patients with stable AP (P = 0.782). Multiple stepwise logistic regression analysis showed that only hs-CRP level was independently associated with unstable AP (P = 0.0002). In conclusion, circulating levels of hs-CRP, WBC count, and VCAM-1 were significantly increased in patients with AP. The circulating level of hs-CRP was strongly associated with the clinical setting of unstable AP.


The relationship between sunitinib exposure and both efficacy and toxicity in real-world patients with renal cell carcinoma and gastrointestinal stromal tumour.
Sunitinib is an oral tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). Because of the large interpatient pharmacokinetic variability and established exposure-response and exposure-toxicity relationships in clinical trial patients, therapeutic drug monitoring (TDM) seems promising for optimizing sunitinib exposure. We aimed to investigate the relationship between sunitinib exposure and treatment outcome in a real-world patient cohort. We performed a retrospective observational cohort study in 53 patients with metastatic RCC and 18 patients with metastatic GIST treated with sunitinib and receiving TDM-guided dosing. Time on treatment - as a surrogate for progression-free survival - in patients who achieved adequate sunitinib exposure was compared with patients who did not. Additionaly, the median sunitinib exposure was compared in patients with or without sunitinib-induced toxicity leading to dose reduction. The median time on treatment in patients with RCC who achieved adequate sunitinib exposure (n = 39) was 32 weeks, compared to 15 weeks in patients who did not achieve adequate sunitinib exposure (n = 12) (P = 0.244). In 29 patients (41%) with toxicity leading to dose reduction, sunitinib sum plasma trough concentration (Ctrough ) until dose reduction was significantly higher compared to patients without toxicity leading to dose reduction (median 60 ng/mL vs 44 ng/mL; P < 0.001) and reduced to comparable levels after dose reduction (44 ng/mL; P = 0.488). In our real-world patient cohort, patients with sunitinib-induced toxicity requiring dose reduction had significantly higher sunitinib exposure compared to patients without toxicity. The threshold for toxicity, however, was lower compared to that previously described in clinical trials.


From a Viewpoint of Clinical Settings: Pharmacoepidemiology as Reverse Translational Research (rTR).
Clinical pharmacology and pharmacoepidemiology research may converge in practise. Pharmacoepidemiology is the study of pharmacotherapy and risk management in patient groups. For many drugs, adverse reaction(s) that were not seen and/or clarified during research and development stages have been reported in the real world. Pharmacoepidemiology can detect and verify adverse drug reactions as reverse translational research. Recently, development and effective use of medical information databases (MID) have been conducted in Japan and elsewhere for the purpose of post-marketing safety of drugs. The Ministry of Health, Labour and Welfare, Japan has been promoting the development of 10-million scale database in 10 hospitals and hospital groups as "the infrastructure project of medical information database (MID-NET)". This project enables estimation of the frequency of adverse reactions, the distinction between drug-induced reactions and basal health-condition changes, and usefulness verification of administrative measures of drug safety. However, because the database information is different from detailed medical records, construction of methodologies for the detection and evaluation of adverse reactions is required. We have been performing database research using medical information system in some hospitals to establish and demonstrate useful methods for post-marketing safety. In this symposium, we aim to discuss the possibility of reverse translational research from clinical settings and provide an introduction to our research.


Nanomaterials and synergistic low-intensity direct current (LIDC) stimulation technology for orthopedic implantable medical devices.
Nanomaterials play a significant role in biomedical research and applications because of their unique biological, mechanical, and electrical properties. In recent years, they have been utilized to improve the functionality and reliability of a wide range of implantable medical devices ranging from well-established orthopedic residual hardware devices (e.g., hip implants) that can repair defects in skeletal systems to emerging tissue engineering scaffolds that can repair or replace organ functions. This review summarizes the applications and efficacies of these nanomaterials that include synthetic or naturally occurring metals, polymers, ceramics, and composites in orthopedic implants, the largest market segment of implantable medical devices. The importance of synergistic engineering techniques that can augment or enhance the performance of nanomaterial applications in orthopedic implants is also discussed, the focus being on a low-intensity direct electric current (LIDC) stimulation technology to promote the long-term antibacterial efficacy of oligodynamic metal-based surfaces by ionization, while potentially accelerating tissue growth and osseointegration. While many nanomaterials have clearly demonstrated their ability to provide more effective implantable medical surfaces, further decisive investigations are necessary before they can translate into medically safe and commercially viable clinical applications. The article concludes with a discussion about some of the critical impending issues with the application of nanomaterials-based technologies in implantable medical devices, and potential directions to address these.


Consumption of a diet rich in Brassica vegetables is associated with a reduced abundance of sulphate-reducing bacteria: A randomised crossover study.
We examined whether a Brassica-rich diet was associated with an increase in the relative abundance of intestinal lactobacilli and sulphate-reducing bacteria (SRB), or alteration to the composition of the gut microbiota, in healthy adults. A randomised crossover study was performed with ten healthy adults who were fed a high- and a low-Brassica diet for 2-wk periods, with a 2-wk washout phase separating the diets. The high-Brassica diet consisted of six 84 g portions of broccoli, six 84 g portions of cauliflower and six 300 g portions of a broccoli and sweet potato soup. The low-Brassica diet consisted of one 84 g portion of broccoli and one 84 g portion of cauliflower. Faecal microbiota composition was measured in samples collected following 2-wk Brassica-free periods (consumption of all Brassica prohibited), and after each diet, whereby the only Brassica consumed was that supplied by the study team. No significant changes to the relative abundance of lactobacilli were observed (p = 0.8019). The increased consumption of Brassica was associated with a reduction in the relative abundance of SRB (p = 0.0215), and members of the Rikenellaceae, Ruminococcaceae, Mogibacteriaceae, Clostridium and unclassified Clostridiales (p < 0.01). The increased consumption of Brassica vegetables was linked to a reduced relative abundance of SRB, and therefore may be potentially beneficial to gastrointestinal health.


Enhancing patency, safety and cost effectiveness of catheters.
Catheters are generally known to be the last resort for blood access in dialysis. Because of the many problems related to catheter use, catheters are banned from vascular access courses organized by professional societies and the development of catheters and catheter related equipment relies on a few interested medical doctors with limited knowledge of hydraulics and material science. Rather than accepting the need for catheters and the need for improving catheters and catheter related procedures, vascular access meetings typically begin and end with statements saying that the use of fistulas must be increased and catheters must be banned. Several small companies have developed new catheters and catheter related equipment, which potentially overcome many of the problems related to the use of catheters. The authors had the privilege of participating in one of these developments and report about basic features and clinical experience of the DIALOCK blood access port and an antimicrobial catheter locking solution (CLS) which is used with conventional catheters as well as with the DIALOCK.


Differences in non-MHC alloantigens promote tissue rejection but fail to mediate allogeneic co-operation and autoimmunity in mice neonatally injected with semi-allogeneic F1 B cells.
Mice injected at birth with semi-allogeneic lymphoid cells develop a lupus-like autoimmune syndrome in which donor B cells are polyclonally activated by host alloreactive CD4+ T cells, producing autoantibodies and immune complex-mediated glomerulonephritis. It has been demonstrated that the recognition of major histocompatibility complex (MHC) class II alloantigens triggers the development of a complete disease. But differences in either MHC class I molecules or Mls-1 antigens are not sufficient to induce production of autoantibodies. Here we have investigated whether differences in other non-MHC alloantigens could induce a similar autoimmune disease and whether the maternal environment could modulate the T-B allogeneic co-operation in this model. For this purpose (BALB/c x BC20)F1 hybrid females were backcrossed with BC20 males. R2 mice obtained in this backcross were neonatally injected with 10(8) (C57BL/6 x BALB.Igb)F1 spleen cells and the tolerance against maternal derived BALB/c alloantigens as well as the development of autoimmune manifestations were subsequently evaluated. In contrast to R2 mice injected at birth with (C57BL/6 x BALB.Igb)F1 cells, control R2 mice rejected skin grafts from BALB/c mice and B cells from (C57BL/6 x BALB.Igb)F1 mice, independently of their H-2 haplotype (H-2b/d or H-2b/b). Nevertheless, after neonatal injection of (C57BL/6 x BALB.Igb)F1 cells, none of 19 H-2b/d R2 injected mice presented autoimmune manifestations, in contrast with the typical autoimmune disease observed in all neonatally injected H-2b/b R2 mice (26 mice). These results support that the development of autoimmunity in this model depends exclusively upon differences in MHC class II alloantigens and that the relationship between mother and fetus, through the pregnancy or the breast suckling, is not sufficient to inhibit cytolytic and allo-helper responses against non-inherited maternal-derived alloantigens.


Autologous bone marrow transplantation for non-Hodgkin lymphoma.
Non-Hodgkin lymphomas (NHLs) are a group of malignant disorders that can be cured with chemotherapy and/or radiotherapy in 30% to 50% of cases. For those who fail initial therapy, cure is rarely achieved with standard dose chemotherapy; therefore higher doses of chemotherapy have been used with autologous bone marrow support. This major medical center has performed 74 autologous bone marrow transplants (ABMT) for patients with non-Hodgkin lymphoma who had failed initial therapy between 1984 and 1993. Preparatory regimens included high doses of chemotherapy with or without radiotherapy. There were 14 patients with low grade, 41 with intermediate grade, and 18 with high grade histologies. Among patients with low grade histologies, 90% responded and 50% are relapse-free between 1 and 33 months post-ABMT. Among patients with intermediate and high grade histologies, 25% are relapse-free between 2 and 80 months post-ABMT. Autologous bone marrow transplantation is effective in patients with relapsed non-Hodgkin lymphoma and should be considered an important therapeutic option.


Retrospective Review of Atypical Femoral Fracture in Metastatic Bone Disease Patients Receiving Denosumab Therapy.
Denosumab therapy is used to reduce skeletal-related events in metastatic bone disease (MBD). There have been reports of atypical femoral fracture (AFF) in osteoporotic patients treated with denosumab but none in the context of higher dose and more frequent denosumab therapy for MBD. The goal of this study was to assess the incidence of AFF in MBD. We conducted a retrospective review of 253 patients who received a minimum of 12 doses of denosumab at 120 mg each for MBD. To identify patients with asymptomatic atypical stress reactions in the lateral subtrochanteric femur (which precede fractures), we reviewed the skeletal images of 66 patients who had received at least 21 doses of denosumab for AFF features. These patients received a median of 17 doses, with a median treatment duration of 23 months. There was 1 case of undiagnosed clinical AFF detected after chart review and 2 cases of subclinical atypical femoral stress reaction observed on imaging review after 23 doses of denosumab over 33 months, 28 doses over 27 months, and 21 doses over 21 months, respectively. Scout computed tomography films showed diffuse cortical thickening of diaphysis with localized periosteal reaction of lateral femoral cortex. Bone scan and magnetic resonance imaging scan of 2 patients with stress reactions confirmed the diagnosis. The incidence of clinical AFF in this context is 0.4% (1/253; 95% confidence interval [CI] 0.1%-2.2%), and the incidence of atypical femoral stress reaction based on imaging review is 4.5% (3/66; 95% CI 1.6%-12.5%). Clinicians should be aware of the clinical prodrome (which may or may not be present) and antecedent imaging changes associated with AFF. The Oncologist 2017;22:438-444Implications for Practice: Among patients with metastatic bone disease treated with denosumab, cases of clinical and subclinical atypical femoral fracture (AFF) are rare. The one detected case of clinical fracture went unrecognized despite prodromic symptoms. Clinicians should be aware of (a) the potential prodrome of anterior thigh/groin pain and (b) subclinical imaging changes in the lateral femur, both of which may precede clinical AFF.


Triple therapy in metastatic hormone-sensitive prostate cancer.
Over the last years, there have been striking changes in the management of metastatic hormone-sensitive prostate cancer (mHSPC) based on survival advantage of combining either a new hormonal agent (NHA) or docetaxel (D) with androgen deprivation therapy (ADT). Some of these studies primarily assessing doublet treatment included men who underwent concomitant or sequential treatment with D. Most recently, prospective randomized evidence emerged on this triplet strategy too. We aimed to outline the current data and ongoing trials evaluating the usage of the triplet therapy in male individuals with mHSPC. Phase III trials PEACE-1 and ARASENS showed that the upfront triplet treatment with ADT+D and either abiraterone acetate or darolutamide outperformed ADT+D in terms of survival, while severe toxicity was mainly driven by D. Importantly, prospective evidence comparing triplet vs. ADT+NHA is still lacking. Men with de novo high-volume disease benefit most from the triplet, while in cases with metachronous and/or low-volume disease, survival advantage is still disputable. As efficacy of ADT+NHA does not appear to be substantially amplified by combination with D, those men with a more favorable underlying tumor biology might mostly benefit from this doublet, also taking quality-adjusted survival into account.


A capability perspective on sustainable employability: A Dutch focus group study on organizational, work and personal conversion factors.
In the field of work, there is a shift towards more value-based approaches to study the sustainable employability of the present-day worker. The capability approach offers a value based and innovative conceptualisation and framework of sustainable employability characterized by contextuality, normativity and diversity. The capabilities of Dutch employees have been established and validated, yet it is not known which conversion factors on a personal, work and organizational level enable employees to achieve value in work in different Dutch occupational sectors. Our qualitative approach included seven focus groups in different occupational sectors including elderly care, higher education, insurance work, facility management and the oil-, car- and chemical industry. Each focus group included 5-11 participants and took approximately one and a half hour. A qualitative content analysis was used to analyse the data, by combining deductive and inductive coding respectively. Deductive coding involved assigning themes to the conversion of resources into capabilities at the organizational, work and personal level. On the organizational conversion level, important themes were cultural aspects, power relations, shortage of personnel and policies for self-management. On the work conversion level, social contacts, communication and workload, tasks and schedules were identified. Social contacts were described as a work value in itself, but also conditional for achieving other work values. On the personal conversion level, experienced work stress, motivation and the ability to achieve values informally within the company. From our findings it follows that focus groups are sensitive to identify conversion factors on all three levels of conversion. In addition, companies and their employees might effectively increase work capabilities by being sensitive to all three conversion levels simultaneously. Further research is necessary to study the effect of a capability-based intervention at the work floor.


Assessing clinical pragmatism.
"Clinical pragmatism" is an important new method of moral problem-solving in clinical practice. This method draws on the pragmatic philosophy of John Dewey and recommends an experimental approach to solving moral problems in clinical practice. Although the method may shed some light on how clinicians and their patients ought to interact when moral problems are at hand, it nonetheless is deficient in a number of respects. Clinical pragmatism fails to explain adequately how moral poblems can be solved experimentally, it underestimates the relevance and importance of judgment in clinical ethics, and it presents a questionable account of the role that moral principles should play in moral problem solving.


Radiological and pathological evaluation of the spinal cord in a rat model of electrical injury-induced myelopathy.
No study has reported an animal-based experimental model of electrical injury to the spinal cord. This paper presents the first systematic establishment of an animal model of electrical injury to the spinal cord with subsequent pathophysiologic analysis. The voltage required for the electrical shock was generated by an electroconvulsive therapy apparatus (57800 ECT unit; UGO BASILE, Italy). We used one side ear as the entry site and the contralateral hind limb as the exit site. Seven electrical shock (frequency, 120 Hz; pulse width, 0.9 ms; duration, 3 s; current, 99 mA) was applied to each rat and used rat showing hind limb weakness. Radiologic and histologic evaluations were performed at one day, one, two and four weeks after injury. Twelve rats showed the hind limb weakness among the total 18 rats. Manganese-enhanced magnetic resonance imaging showed interruption of spinal cord enhancement in the thoracic area. Histological examination showed a greater decrease in the number of neurons in the ventral horn versus the dorsal horn. This study demonstrates a novel design and analysis of an animal-based experimental model of spinal cord injury by electrical etiology. This model is useful for experimental studies of injuries to the spinal cord.


Hormonal regulation of postnatal chicken preadipocyte differentiation in vitro.
This study was designed to develop a culture system from the stromal-vascular fraction of chicken adipose tissue that can be used to characterize hormones that promote preadipocyte differentiation. Abdominal adipose tissue was excised from 2 to 4-week-old male broilers (Gallus domesticus) by sterile dissection. The stromal-vascular cell fraction from the adipose tissue was isolated by collagenase digestion, filtration, and subsequent centrifugation. These preadipocytes were seeded in six well culture plates and proliferated to confluency in 10% fetal bovine serum in DMEM/F12 (50:50) medium. At confluency, experiments were initiated to determine hormonal requirements for differentiation. Insulin (100 nM) stimulated expression of citrate lyase and sn-glycerol-3-phosphate dehydrogenase relative to lactate dehydrogenase in the presence of 2.5% chicken serum (P<0.05), but not with 10% chicken serum (P>0.05). Triiodothyronine (T(3), 1 nM) and insulin-like growth factor 1 (100 ng/ml) had no effect on differentiation. Dexamethasone (Dex, 1 microM) stimulated differentiation in 2.5 or 10% chicken serum (P<0.05). Insulin, Dex and 2.5% chicken serum stimulated enzymatic differentiation to the extent of 10% chicken serum, but heparin (10 U/ml) addition, in combination with insulin and Dex was necessary to stimulate lipid filling of adipocytes.


Asymmetric diversification of mating pheromones in fission yeast.
In fungi, mating between partners depends on the molecular recognition of two peptidyl mating pheromones by their respective receptors. The fission yeast Schizosaccharomyces pombe (Sp) has two mating types, Plus (P) and Minus (M). The mating pheromones P-factor and M-factor, secreted by P and M cells, are recognized by the receptors mating type auxiliary minus 2 (Mam2) and mating type auxiliary plus 3 (Map3), respectively. Our recent study demonstrated that a few mutations in both M-factor and Map3 can trigger reproductive isolation in S. pombe. Here, we explored the mechanism underlying reproductive isolation through genetic changes of pheromones/receptors in nature. We investigated the diversity of genes encoding the pheromones and their receptor in 150 wild S. pombe strains. Whereas the amino acid sequences of M-factor and Map3 were completely conserved, those of P-factor and Mam2 were very diverse. In addition, the P-factor gene contained varying numbers of tandem repeats of P-factor (4-8 repeats). By exploring the recognition specificity of pheromones between S. pombe and its close relative Schizosaccharomyces octosporus (So), we found that So-M-factor did not have an effect on S. pombe P cells, but So-P-factor had a partial effect on S. pombe M cells. Thus, recognition of M-factor seems to be stringent, whereas that of P-factor is relatively relaxed. We speculate that asymmetric diversification of the two pheromones might be facilitated by the distinctly different specificities of the two receptors. Our findings suggest that M-factor communication plays an important role in defining the species, whereas P-factor communication is able to undergo a certain degree of flexible adaptation-perhaps as a first step toward prezygotic isolation in S. pombe.


Biological roles of RNA m5C modification and its implications in Cancer immunotherapy.
Epigenetics including DNA and RNA modifications have always been the hotspot field of life sciences in the post-genome era. Since the first mapping of N6-methyladenosine (m6A) and the discovery of its widespread presence in mRNA, there are at least 160-170 RNA modifications have been discovered. These methylations occur in different RNA types, and their distribution is species-specific. 5-methylcytosine (m5C) has been found in mRNA, rRNA and tRNA of representative organisms from all kinds of species. As reversible epigenetic modifications, m5C modifications of RNA affect the fate of the modified RNA molecules and play important roles in various biological processes including RNA stability control, protein synthesis, and transcriptional regulation. Furthermore, accumulative evidence also implicates the role of RNA m5C in tumorigenesis. Here, we review the latest progresses in the biological roles of m5C modifications and how it is regulated by corresponding "writers", "readers" and "erasers" proteins, as well as the potential molecular mechanism in tumorigenesis and cancer immunotherapy.


Inhibition of rat sexual behavior by antisense oligonucleotides to the progesterone receptor.
To test further the idea that sexual behavior in rodents is mediated via the progesterone receptor (PR) in the ventromedial nucleus of the hypothalamus, antisense and sense oligonucleotides to progesterone receptor were administered intracerebroventricularly into the third cerebral ventricle of ovariectomized estrogen-primed animals. Progesterone-facilitated sexual behavior was inhibited in animals treated with antisense oligonucleotides, with proceptive and receptive responses being minimal or completely suppressed. Sexual behavior was not altered by control sense oligonucleotides. In vitro binding assays of the cytosol progesterone receptors demonstrated a 52.2% reduction of PRs in the hypothalamus of animals that received antisense oligonucleotides, suggesting a reduction in PR synthesis. These data suggest that a threshold level of estrogen-induced hypothalamic PR is critical in the regulation of progesterone-facilitated sexual behavior in female rats.


Inheritance of brachydactyly type D.
Inheritance of brachydactyly type D (BD-D) was studied in two unreported Caucasian family pedigrees and in 36 previously reported family pedigrees. The inheritance pattern was characteristic of a single autosomal dominant gene with incomplete penetrance. Using the proportion of individuals exhibiting the trait as the index, penetrance was sex influenced, being complete in females and approximately 62 percent in males. Expression of BD-D in both females and males was bilateral (both thumbs) for approximately three-fourths and unilateral (either right or left thumb) for approximately one-fourth of the individuals.


Detecting Suicide-Related Emergency Department Visits Among Adults Using the District of Columbia Syndromic Surveillance System.
Limited studies have examined the usefulness of syndromic surveillance to monitor emergency department (ED) visits involving suicidal ideation or attempt. The objectives of this study were to (1) examine whether syndromic surveillance of chief complaint data can detect suicide-related ED visits among adults and (2) assess the added value of using hospital ED data on discharge diagnoses to detect suicide-related visits. The study data came from the District of Columbia electronic syndromic surveillance system, which provides daily information on ED visits at 8 hospitals in Washington, DC. We detected suicide-related visits by searching for terms in the chief complaints and discharge diagnoses of 248 939 ED visits for which data were available for October 1, 2015, to September 30, 2016. We examined whether detection of suicide-related visits according to chief complaint data, discharge diagnosis data, or both varied by patient sex, age, or hospital. The syndromic surveillance system detected 1540 suicide-related ED visits, 950 (62%) of which were detected through chief complaint data and 590 (38%) from discharge diagnosis data. The source of detection for suicide-related ED visits did not vary by patient sex or age. However, whether the suicide-related terms were mentioned in the chief complaint or discharge diagnosis differed across hospitals. ED syndromic surveillance systems based on chief complaint data alone would underestimate the number of suicide-related ED visits. Incorporating the discharge diagnosis into the case definition could help improve detection.


Review: The use of bull breeding soundness evaluation to identify subfertile and infertile bulls.
Efficient and economical herd management depends a great deal on maintaining a short, well-defined calving season. This requires highly fertile females and bulls. Low pregnancy rates are very noticeable, however; potentially greater economic loss may be due to delayed conception. Many studies showed that approximately one of every five bulls had inadequate semen quality, physical soundness, or both, but when evaluation of serving capacity is included about one in four bulls is unsatisfactory. Due mainly to the time and expense that the market will bear, usually only physical soundness and semen quality are evaluated. Breeding soundness evaluation is a useful, low-cost screening method for reducing the risk of using low fertility bulls. The biggest problem with breeding soundness evaluations is not our lack of knowledge or ability, but in the willingness of veterinary schools to provide adequate equipment and training in this area, a lack of diagnostic laboratories equipped to handle the more difficult cases and, most importantly, the weaknesses of human nature that result in negligent testing procedure.


Intense 2.89 μm emission from Dy³⁺/Yb³⁺-codoped PbF₂ crystal by 970 nm laser diode pumping.
A novel Dy(3+)/Yb(3+) co-doped PbF2 mid-IR laser crystal was successfully grown using the vertical Bridgman method. Efficient emission at around 3 μm from the crystal was observed under excitation of a conventional 970 nm laser diode (LD). The energy transfer efficiency from Yb(3+) to Dy(3+) in Dy(3+)/Yb(3+):PbF2 crystal is as high as (97.7±0.3)%. It is also found that the Dy(3+)/Yb(3+):PbF2 crystal possesses long fluorescence lifetime (15.4±0.2) ms, high quantum efficiency (95.0±0.3)%, and large emission cross section (1.37±0.11)×10(-20) cm2 corresponding to the stimulated emission of Dy(3+):(6)H(13/2)→(6)H(15/2) transition. Additionally, the phonon energy of the crystal was analyzed by the Raman spectrum. These results indicate that Dy(3+)/Yb(3+):PbF2 crystal may become a promising material for 3 μm solid state lasers under a conventional 970 nm LD pump.


Global ischemia activates nuclear factor-kappa B in forebrain neurons of rats.
After global ischemia, brain levels of hydrogen peroxide, oxygen radicals, and the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) are increased. Oxygen radicals, TNF-alpha, and IL-1 beta are known to activate nuclear factor-kappa B (NF-kappa B) in vitro. The present study was performed to determine whether NF-kappa B was activated in vivo by global ischemia in hippocampal CA1 neurons. Adult male rats were subjected to 30 minutes of four-vessel occlusion and killed 72 hours later. Levels of NF-kappa B p50 and p65 subunits in hippocampus were determined by immunocytochemistry, Western blot, and gel-shift analysis. Specific labeling of DNA strand breaks was demonstrated by means of an Apoptag apoptosis detection kit. Labeling of DNA strand breaks was present at 72 hours. Chromatin compaction and segregation, a characteristic of apoptosis, was observed in sections stained with hematoxylin and eosin. NF-kappa B p50 and p65 immunoreactivity localized only to nuclei of CA1 neurons at 72 hours after reperfusion. Induction of the activated p50 and p65 subunits was confirmed by Western blot and electromobility shift analysis. The results demonstrate that NF-kappa B is activated selectively in hippocampal CA1 neurons at 72 hours after four-vessel occlusion, which is at the approximate time of CA1 neuronal cell death. Transient forebrain ischemia resulted in a marked activation of nuclear NF-kappa B in the highly vulnerable CA1 sector. Intense nuclear localization of NF-kappa B was associated only with dying neurons; regions of the hippocampus that were not vulnerable to four-vessel occlusion did not exhibit nuclear NF-kappa B localization. The elevation of NF-kappa B in degenerating CA1 neurons may be associated mechanistically with apoptotic or necrotic cell death.


Deuterium for estimating total body water and turnover rates in turkeys exposed to different incubation treatments.
Total water intake (TWI) in poultry can be influenced by various factors. Recommendations for water requirements are usually reported on a flock basis without considering individual variation. In the present study, a total of 18 turkeys were used to measure water intake over a 1-wk period starting at 15 wk of age by applying the deuterium dilution technique. Poults originated from eggs exposed to different incubation treatments, with eggs incubated at normal temperature (37.5 degrees C) and eggs subjected to 38.5 degrees C at embryonic d 9 to 12. Experimental birds were kept in flocks of 22 to 30 birds separated by sex and treatment. Feed and water were provided ad libitum. Incubation treatment had no significant effect on any of the parameters investigated (BW, daily gain, water turnover rate, total body water, TWI), whereas sex exerted a significant effect on nearly all traits. Total body water ranged between 60 and 65% of BW, with significantly (P < 0.05) greater values for toms (63.2%) than for hens (60.9%). Males had approximately 30% greater water influxes than females (1,054 +/- 198 vs. 742 +/- 153 mL/d, mean +/- SD). However, the significant influence of sex was eliminated (P = 0.464) when TWI was expressed as grams per kilogram of BW (76 +/- 18 vs. 70 +/- 12 mL/kg of BW; males vs. females). Water consumed averaged 837 mL in male and 569 mL per day in female birds. The present results suggest that the isotope dilution method offers a viable method to measure individual water intake, which can be used for establishing reference values for water consumption in group-housed turkeys.


Differential effect of IP- and IV-injected nitrogen mustard on subsequently-irradiated intestinal crypts: implications for 'dose-effect factors' predicted by experimental, combined modality therapy.
In experimental chemotherapy-radiotherapy, cytotoxic drugs are almost invariably injected by the intraperitoneal (IP) route. This contrasts with normal clinical practice, which is to employ the intravenous (IV) route. We have used a clonogenic assay of gastrointestinal (GI) injury in mice to show that a given administered dose of nitrogen mustard (HN2), injected IP, results in a much greater reduction in the subsequent radiation dose required to achieve an isoeffect, than if the drug is injected IV. At an administered dose of 3.5 mg kg-1 of HN2 (the animal LD10/30 for IP injection), the radiation dose-reduction factor for 10% survival of intestinal crypts, was 1.94 for IP HN2 and only 1.28 for IV HN2. Even the grossly-equitoxic (mouse LD10/30) dose of IV HN2 resulted in a smaller predicted radiation dose reduction for GI injury, by a factor of 1.45. The validity of using the IP route in combined chemotherapy-radiotherapy studies designed to generate quantitative estimates of toxicity is discussed.


Intermittent chemotherapy with trichlorfon (metrifonate) reverses proteinuria, hematuria, and leukocyturia in urinary schistosomiasis: results of a three-year field study.
Trichlorfon (metrifonate) was given intermittently to 37 schoolboys with urinary schistosomiasis living in a hyperendemic area of the Sudan. Patients were followed up for three years. Initially, 10 mg of trichlorfon/kg of body weight was administered; this dosage was repeated 14 days and 16 months later. Patients still excreting eggs after 24 months received a fourth dose. At month 24, 61% and at month 36, 56% of the patients had no detectable egg excretion; the others showed severe reduction of egg output. The number of ova excreted was always paralleled by a combined scale of hematuria, leukocyturia , and proteinuria, as assessed by urine analysis reagent strips. Quantitative urine analysis at month 36 revealed pathological findings in only eight individuals. Thus, trichlorfon given three or four times in a dose of 10 mg/kg of body weight spaced over a period of two years was highly effective in reducing parasite load and disease in children living under hyperendemic conditions.


Sodium-hydrogen antiporter: its possible role in the genesis of diabetic nephropathy.
The epidemiological evidence that only a subset of diabetic patients are susceptible to renal damage and the demonstration of clear familiar clustering of diabetic nephropathy are consistent with the possibility that genetic factors may explain the liability to or protection from renal disease of diabetic patients. A predisposition to hypertension and cardiovascular disease may be an important determinant of susceptibility to renal disease and its cardiovascular complications in diabetes since raised blood pressure [1] and an increased frequency of cardiovascular disease [2] are more prevalent in parents of diabetic patients with nephropathy. These results have raised growing interest in the search for intermediate phenotypes significantly associated with diabetic nephropathy, poorly influenced by environment, stable with age, easy to quantify and possibly dependent upon a single major gene effect. Such intermediate phenotypes can be useful for early diagnosis and would help clarify the molecular mechanisms leading to diabetic nephropathy. An elevation of Na+/H+ antiporter activity has consistently been associated with diabetic renal disease both in insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) patients, making this cell membrane exchanger system an ideal intermediate phenotype for the study of diabetic nephropathy.


Neurological surgery during the Great War: the influence of Colonel Cushing.
Despite von Bergmann's work in the Franco-Prussian War and Makins' experiences in the Boer conflict, military surgeons in World War I were unprepared for the nature and extent of intracranial injuries. Poor triage, disorganized transportation, incomplete surgery, and sepsis resulted in a mortality of over 50%. In 1915, as a volunteer to the Ambulance Américaine near Paris, Harvey Cushing spent 5 weeks observing the Allied medical system. He quickly recognized the technical importance of early, definitive intracranial surgery and the logistical requirements for a unified triage system located along the main lines of traffic. Cushing returned to France in 1917 as director of Base Hospital #5, known as the Harvard Unit. Immediately detached to the British Expeditionary Force, he operated at a smaller casualty clearing station close to the Belgian front. The patients treated during the third battle of Ypres (Passchendaele) formed the basis of his technical reports. He standardized intracranial injuries into nine categories with separate mortality rates. In addition, he recommended the surgical techniques of en bloc bone resection under local anesthesia with suction debridement and primary two-layer closure. Shell fragments were removed by magnets when possible; dichloramine-T was used as an antiseptic. By reducing infection and secondary complications, Cushing halved the earlier mortality rates. In September 1918, as senior consultant to the American Expeditionary Force, Cushing was in charge of organizing the neurosurgical care for the St. Mihiel and Meuse-Argonne offensives. His instruction of individual surgeons in operative techniques and the creation of identified hospital centers with suitable equipment and trained personnel helped to establish neurological surgery as a military specialty.


Rapid assessment of cataract surgical services in age group 50 years and above in Lower Dir District Malakand, Pakistan.
To assess the rapid assessment of cataract blindness and surgical services in age group 50 years and above. A cross-sectional survey. This survey was conducted in District Lower Dir, Malakand Division, NWFP, Pakistan, from March 9-23, 2003. A community-based survey was carried out with systematic cluster random sampling. The survey was preceded by a pilot study in which the proforma and operational methods were field-tested and refined. One thousand, one hundred and fifty eligible adults of 50 years and older were selected by systematic random sampling from the whole lower Dir district of Malakand, Pakistan. A total of 1076 subjects (93.6%) were examined. The visual acuity of each eye was assessed using tumble Snellen's E Card method at 6 and 3 meters. Any subject having visual acuity <3/60 with or without obvious lens opacity or with aphakia (removal of lens) or pseudophakia (removal of cataract lens and implantation of artificial lens) was examined in detail. The surgical services were assessed by measuring the prevalence of pseudophakia, surgical outcome of visual acuity and also the effect of place of surgery on outcome. Prevalence of total bilateral blindness was 2.6%, and unilateral blindness 2.46%. Total prevalence of aphakia was 2.4%, which was almost equal in both sexes, male 2.3% and female 2.4%. Prevalence of unilateral aphakia was 0.3 % in females being slightly higher than males, 0.16 %. The prevalence of bilateral aphakia was 2.2% and 2% in males and females respectively. Prevalence of total pseudophakic eyes was 2.74%. Surgical outcome showed good, borderline and poor visual acuity of 40.5%, 22% and 14.3% respectively. Surgical outcome was also seemed to be better in private hospitals as compared to field camps. It is concluded that to reduce the prevalence of blindness there was a need to improve the quality of services in mobile camps and fixed facilities. At the same time the visual outcome of surgery could be improved by expanding the number of Intraocular lens procedures and routine monitoring of cataract outcome.


Restoration of the extracellular matrix in human osteoarthritic articular cartilage by overexpression of the transcription factor SOX9.
Human osteoarthritis (OA) is characterized by a pathologic shift in articular cartilage homeostasis toward the progressive loss of extracellular matrix (ECM). The purpose of this study was to investigate the ability of rAAV-mediated SOX9 overexpression to restore major ECM components in human OA articular cartilage. We monitored the synthesis and content of proteoglycans and type II collagen in 3-dimensional cultures of human normal and OA articular chondrocytes and in explant cultures of human normal and OA articular cartilage following direct application of a recombinant adeno-associated virus (rAAV) SOX9 vector in vitro and in situ. We also analyzed the effects of this treatment on cell proliferation in these systems. Following SOX9 gene transfer, expression levels of proteoglycans and type II collagen increased over time in normal and OA articular chondrocytes in vitro. In situ, overexpression of SOX9 in normal and OA articular cartilage stimulated proteoglycan and type II collagen synthesis in a dose-dependent manner. These effects were not associated with changes in chondrocyte proliferation. Notably, expression of the 2 principal matrix components could be restored in OA articular cartilage to levels similar to those in normal cartilage. These data support the concept of using direct, rAAV-mediated transfer of chondrogenic genes to articular cartilage for the treatment of OA in humans.


How do parents influence their adolescents' use of over-the-counter analgesics: A review of the current literature.
Continuous use of over-the-counter analgesics (OTCAs) may prevent adolescents from learning healthier options and might lead to lifelong use of such medicines. It is possible that parents' own use of OTCAs might influence adolescents, but little is known about this issue. Our research questions were; "What are the main factors leading to a high use of OTCAs among adolescents and how can health professionals support these adolescents in their pain management?" Frequent consumption of OTCAs may cause health problems such as drug-induced headache and liver failure. Some adolescents frequently use non-prescribed pain medication and their attitudes towards the use of OTCAs vary from responsible to careless. A "systematic search and review" was conducted between March 2017 and May 2018. Quantitative and qualitative studies were included. We used the PRISMA Statement checklist, the PRISMA flow diagram and The Critical Appraisal Skills Programme for quality appraisal. Our search identified 3,386 possible sources, 2,043 articles were selected for title examination, and 70 articles underwent abstract review. Fourteen articles were reviewed entirety. Ten articles were of acceptable quality. The importance of parental influence on adolescent use of OTCAs is significant. These findings seem to be independent of country and culture. Parents are the most important source of information regarding the use of OTCAs; further, they are the main supplier of the medicine. A broad understanding of human development, health, pain and use of pain medication is needed to develop targeted information and support adolescents with high consumption of non-prescription pain medication. Information from professionals such as school nurses is important. Professionals must consider the physical, social and psychological aspects influencing the use of OTCAs. Information should be made available to adolescents, parents and society in general.


β-Cyclodextrin Stabilized Nanoceria for Hydrolytic Cleavage of Paraoxon in Aqueous and Cationic Micellar Media.
Beta-cyclodextrin (β-CD) stabilized cerium oxide nanoparticles (β-CD@CeO2 NPs) were synthesized through a hydrothermal route. The electronic properties, surface functional group, surface composition, size, and morphologies of the as-synthesized β-CD@CeO2 NPs were characterized using UV-visible spectroscopy, FTIR analysis, high resolution X-ray photoelectron spectroscopy (HRXPS), high resolution transmission electron microscopy (HRTEM), and field emission scanning electron microscopy (FESEM). The pH-dependent variation of the ζ-potential of β-CD@CeO2 NPs and the catalytic activity of the NPs for the hydrolysis of paraoxon were investigated. The observed pseudo-first-order rate constant (kobs) for the hydrolysis of paraoxon is increased with increasing pH and the ζ-potential of β-CD@CeO2 NPs. The kinetics and mechanism of hydrolysis of paraoxon in the aqueous and cationic micellar media have been discussed.


Hybrid Broussonetia papyrifera Fermented Feed Can Play a Role Through Flavonoid Extracts to Increase Milk Production and Milk Fatty Acid Synthesis in Dairy Goats.
In order to explore the effect of hybrid Broussonetia papyrifera fermented feed on milk production and milk quality of dairy goats, and to compare with alfalfa hay, three dairy goat diets were designed based on the principle of equal energy and equal protein. The goats in the control group were fed a basic TMR diet (CG group), and the other two groups were supplemented with 10% alfalfa hay (AH group) and 10% hybrid B. papyrifera fermented feed (BP group). The results showed that the dry matter intake and milk production of BP group increased significantly. The total amount of amino acids and the content of each amino acid in the milk of AH group and BP group were lower than those of CG group. The content of saturated fatty acids in the milk of BP group decreased while the content of unsaturated fatty acids increased. The contents of prolactin, estrogen and progesterone in BP goat serum were generally higher than those of AH goat and CG goat. Subsequently, this study separated and cultured mammary epithelial cells from breast tissue, and added flavone extracted from the leaves of hybrid B. papyrifera and alfalfa to their culture medium for comparison, which is one of their important bioactive components. The results showed that low-dose alfalfa flavone (AH) and hybrid B. papyrifera flavone (BP) can increase cell viability. They also can increase the accumulation of intracellular triglyceride and the formation of lipid droplets. Both AH flavone and BP flavone significantly up-regulated the expression of genes related to milk fat synthesis, including genes related to fatty acid de novo synthesis (ACACA, FASN, and SCD1), long-chain fatty acid activation and transport related genes (ACSL1), and genes related to transcription regulation (SREBP1). The three genes related to triglyceride synthesis (DGAT1, DGAT2, and GPAM) were all significantly increased by BP flavone. Both AH flavone and BP flavone significantly increased the protein expression of progesterone receptor and estrogen receptor in mammary epithelial cells but had no effect on prolactin receptor.


A customized long acting formulation of the kisspeptin analog C6 triggers ovulation in anestrus ewe.
The modulation of the kisspeptin system holds promise as a treatment for human reproductive disorders and for managing livestock breeding. The design of analogs has overcome some unfavorable properties of the endogenous ligands. However, for applications requiring a prolongation of drug activity, such as ovulation induction in the ewe during the non-breeding season, additional improvement is required. To this aim, we designed and tested three formulations containing the kisspeptin analog C6. Two were based on polymeric nanoparticles (NP1 and NP2) and the third was based on hydrogels composed of a mixture of cyclodextrin polymers and dextran grafted with alkyl side chains (MD/pCD). Only the MD/pCD formulation prolonged C6 activity, as shown by monitoring luteinizing hormone (LH) plasma concentration (elevation duration 23.4 ± 6.1, 13.7 ± 4.7 and 12.0 ± 2.4 h for MD/pCD, NP1 and NP2, respectively). When compared with the free C6 (15 nmol/ewe), the formulated (MD/pCD) doses of 10, 15 and 30 nmol/ewe, but not the 90 nmol/ewe dose, provided a more gradual release of C6 as shown by an attenuated LH release during the first 6 h post-treatment. When tested during the non-breeding season without progestogen priming, only, the formulated 30 nmol/ewe dose triggered ovulation (50% of ewes). Hence, we showed that a formulation with an adapted action time would improve the efficacy of C6 with respect to inducing ovulation during the non-breeding season. This result suggests that formulations containing a kisspeptin analog might find applications in the management of livestock reproduction but also point to the possibility of their use for the treatment of some human reproductive pathologies.


Incidence, etiology and timing of infections following azacitidine therapy for myelodysplastic syndromes.
We examine the infective complications occurring during azacitidine (AZA) therapy in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). A retrospective review of patients receiving ≥1 cycle of AZA for MDS or AML was performed. Patient demographics, infection prophylaxis/episodes and outcomes were evaluated. Sixty eight patients received 884 AZA cycles. Bacterial infections occurred in 25% of cycle-1 and 27% of cycle-2 AZA therapy. Febrile neutropenia complicated 5.3% of AZA cycles, bacteremia 2% and invasive Aspergillosis 0.3%. Using Poisson modeling, a very high IPSS-R (RR 10.26, 95% CI 1.20, 87.41, p= .033) was identified as an independent risk factor for infection. Infection-related attributable mortality was 23%. The burden of infection is high in AZA-treated patients, associated with high attributable mortality. Over 25% of AZA cycles 1 and 2 were complicated by infection, predominantly bacterial, rates dropping to <10% after cycle-5.


Experimental manipulation of uncanny feeling does not increase adherence to conspiracy theories.
Research over the past decade has shown that endorsement of conspiracy theories (CTs) is shaped by motivated cognition processes. Accordingly, CTs are theorized to stem from compensatory processes, as individuals attempt to cope with existential threats (i.e., uncertainty, loss of control). Based on the meaning maintenance model, we investigated whether this compensatory effect could follow from epistemic threats in domains unrelated to CTs in the form of uncanniness. Feelings of uncanniness were experimentally manipulated through exposure to absurdist art and literature in a set of five studies, followed by a mini meta-analysis (Ntotal = 1,041). We conducted a final, preregistered sixth study (N = 266) manipulating uncanniness through autobiographical recall. No robust evidence for a compensatory effect was found. We discussed methodological and conceptual limitations of the meaning maintenance model, as well as boundary conditions under which conspiracy theories could have a compensatory function to deal with threats.


Effect of prophylactic ondansetron on postoperative nausea and vomiting in patients on preoperative steroids undergoing craniotomy for supratentorial tumors.
The exact incidence of postoperative nausea and vomiting (PONV) in patients on steroids undergoing neurosurgical procedures is not known. This prospective randomized double-blind study was planned to know the efficacy of prophylactic ondansetron in the prevention of PONV in patients on steroids as compared with placebo. Seventy adult patients of either sex who had received preoperative steroids (dexamethasone) for at least 24 hours and were scheduled to undergo craniotomy for supratentorial tumors were included. Patients were randomly allocated using a randomization chart to 1 of the 2 groups to receive either ondansetron 4 mg (group O) or 0.9% saline (group S) intravenously at the time of dural closure. Numeric Rating Scale score for nausea and pain intensity was recorded preoperatively and till 24 hours postoperatively. The 6-hour postoperative nausea score was significantly lower in group O [median, 0; interquartile range (IQR), 0 to 20] than in group S (median, 20; IQR, 0 to 20) (P<0.05). The incidence of vomiting was lower in group O (23%) than in group S (46%) (P<0.05). The total number of emetic episodes, the number of doses of rescue antiemetics given in the first 6 postoperative hours, and the total number of rescue antiemetics given were significantly lower in group O than in group S (P<0.05). Intravenous administration of 4 mg of ondansetron at the time of dural closure was effective in reducing the incidence of PONV and the rescue antiemetics requirement in patients on preoperative steroids undergoing craniotomy for supratentorial tumors.


Analytical Methods for Triamcinolone Acetonide: An Exploratory Literature Review.
An artificial glucocorticoid with anti-inflammatory and immunosuppressive properties is triamcinolone acetonide. It is abundantly used to treat redness, itching, and many other skin conditions like itching and psoriasis. As a result, there are several different triamcinolone acetonide formulations available. Each of these formulations must go through the correct phases of development and validation in order to identify the medications and other additives for safer use. This review article is just a representation of all the methods reported for the development and validation of triamcinolone acetonide in pure form to break down contaminants, in addition to other medications, and even in biological samples. The International Council for Harmonization (ICH) technical requirements for human use suggestions, which include a number of analytical parameters, have been followed in the validation of all the procedures. The present study also clarified the most significant drug combination.


NINQ: Name-Integrated Query Framework for Named-Data Networking of Things.
Information-Centric Networking (ICN) is a paradigm shift from host-to-host Internet Protocol (IP)-based communication to content-based communication. In ICN, the content-retrieval process employs names that are given through different naming schemes such as hierarchical, flat, attribute, and hybrid. Among different ICN architectures, Named-Data Networking (NDN) has gained much interest in the research community and is actively being explored for the Internet of Things (IoT) and sensor networks, and follows a hierarchical naming format. NDN protocol follows a pull-based communication model where the content consumer gets content irrespective of the location of the content provider. The content provider in NDN and sensor networks can be considered to be a distributed database that monitors or controls the environment and caches the sensed data or controls information into their memory. The proposed Name-INtegrated Query (NINQ) framework for NDN-based IoT provides a flexible, expressive, and secure query mechanism that supports content retrieval as well as control and configuration command exchange among various nodes in a smart building. Different use cases are presented in this paper that expand on the behavior of proposed query framework in different scenarios. Simulation results of data collection and exchange of control commands show that proposed query framework significantly improves Interest Satisfaction Rate (ISR), Command Satisfaction Rate (CSR), energy efficiency, and average delay. Moreover, it is evident from the simulation results that proposed query framework significantly reduces the number of transmissions in the network in both data collection and exchange of control command scenarios, which improves the network performance.


Ghrelin gene expression is age-dependent and influenced by gender and the level of circulating IGF-I.
Ghrelin activates GH release and is implicated in growth and metabolic regulation. The regulation of its biosynthesis has not been well studied. The current investigation was designed to examine some of the factors that may influence ghrelin gene expression in the stomach. Thus, in C57BL/6 mice, ghrelin mRNA was detectable by Northern blots throughout the age groups studied, but the levels changed markedly over time. Levels were low at E18.5 and increased rapidly after birth to 6-fold at P14 before peaking to 8-fold at P21. The levels then exhibited a gradual decline at P60 (75% of the peak level) and at 6 months (67%) and a drastic decrease as the animals aged to 19 months (only 5%). Furthermore, sexual dimorphic gene expression, the effect of liver-derived IGF-I deficiency, as well as ghrelin secretion were studied. Our results support a role of ghrelin in growth/metabolism in juvenile and young adult mice of both sexes and in sexually dimorphic regulation of GH secretion in aged mice.


Features of hospital and emergency medical service in out-of-hospital cardiac arrest patients with shockable rhythm.
Predicting the outcome of out-of-hospital cardiac arrest (OHCA) patients is crucial. We examined hospital characteristics and parameters of emergency medical service (including scene time interval and direct ambulance delivery to intensive heart hospitals) as survival or outcome predictors. Data from 546 consecutive OHCA shockable patients treated between January 2012 and December 2015 in Taoyuan City (Taiwan, ROC) were collected. In addition to demographic data, location of arrest, initial rhythm, availability of a hospital with or without 24/7 percutaneous coronary intervention (PCI), emergency medical service (EMS) time, provision of cardiopulmonary resuscitation by a bystander, presence of a witness at collapse, and level of life support were analysed. Multivariate analysis showed that hospitalisation with immediate PCI availability was an independent predictor (OR: 4.32; 95% CI: 1.27-14.70) solely for the outcome of survival until discharge. The presence of a witness while collapsing (OR: 3.52; 95% CI: 1.03-11.98), EMS response time (OR: 0.83; 95% CI: 0.70-0.98), and scene time interval (STI; OR: 0.89; 95% CI: 0.81-0.99) were valuable for predicting the neurological outcome. Direct ambulance delivery to intensive heart hospitals that had 24/7 PCI availability was associated with a higher probability of surviving until discharge in OHCA patients with shockable rhythms. Similarly, a witnessed collapse was correlated with being discharged alive from hospital and recovering with good cerebral performance. In addition, longer response time and scene time interval indicated poorer survival and neurological outcome.


Effect of the standardized Cimicifuga foetida extract on Hsp 27 expression in the MCF-7 cell line.
Cimicifuga foetida, an Asian Cimicifuga species, has been employed as a cooling and detoxification agent in traditional Chinese medicine since ancient times. For this herb, two cycloartane triterpene glycosides isolated from the rhizomes have demonstrated cytotoxicity on rat tumor and human cancer cell lines. Since human Hsp27 is increased in various human cancers and exhibits cytoprotective activity that affects tumorigenesis and the susceptibility of tumours to cancer treatment, the purpose of this research was to study the expression of this protein in MCF-7 breast cancer cells. To accomplish this aim, MCF-7 cells were exposed to different concentrations of Cimicifuga foetida extract showing a reduction in cell number measured by the sulforhodamine assay. In addition, the expression of Hsp-27 mRNA detected by RT-PCR and Hsp-27 protein detected by immnofluorescence was present in all conditions, except when using the highest concentration of Cimicifuga foetida extract (2,000 jig /L). We conclude that Hsp 27 expression at 2,000 jig /L Cimicifuga foetida extract is diminished. This is the first report showing the Hsp-27 expression after exposure to Cimicifuga foetida extract in MCF-7 cells.


Nebulized lidocaine in the treatment of refractory tussive syncope.
Tussive syncope is a rare condition that often responds to treatment of the underlying cause of coughing. Therefore, the workup and diagnosis of the cause is essential. However, at times, the cough is refractory to conventional treatment. The use of nebulized lidocaine in such instances may be an important adjunctive therapy.


Tafasitamab combined with idelalisib or venetoclax in patients with CLL previously treated with a BTK inhibitor.
Patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) whose treatment failed with a Bruton's tyrosine kinase inhibitor have poor outcomes. We investigated tafasitamab plus idelalisib (cohort A) or venetoclax (cohort B) in this patient population in a phase II study (NCT02639910). In total, 24 patients were enrolled (cohort A: n = 11, median time on study, 7.4 months; cohort B: n = 13, median time on study, 15.6 months). The most common treatment-emergent adverse event (TEAE) in cohort A was anemia (63.6%) and in cohort B was infusion-related reaction (53.8%). The most common severe TEAE was neutropenia (cohort A: 45.5%; cohort B: 46.2%). The best overall response rate was 90.9% (cohort A) and 76.9% (cohort B). Undetectable minimal residual disease in peripheral blood was achieved in 2/8 patients (cohort A) and 6/7 patients (cohort B). Overall, these results suggest that anti-CD19 antibody-based combinations may be important in the treatment of patients with CLL.


A modified method for isolating mouse islets of an adequate quality, quantity, and purity.
Mouse islets are widely used in diabetes research. Thus an adequate quality, quantity, and purity of islets are needed for high-quality investigations. We performed a combination of filtration and density gradient separation and optimized many steps in the islet isolation procedure, including perfusion, digestion, and purification. Our results show that an increased quality, quantity, and purity of isolated islets can be achieved using these modifications. Moreover, this method can guarantee maximal recovery and purity of the isolated islets and is easy to perform with practice.


Design and Performance of a Metal-Shielded Piezoelectric Sensor.
In certain circumstances when acoustic measurements are required in the presence of explosive atmospheres the sensor must be placed inside a Faraday Cage. Piezoelectric active materials are suitable for this purpose as they do not need an electrical power supply, although the metal shielding can considerably reduce sensor sensitivity, which is already low at the acoustic frequency range (<20 kHz). This paper describes a metal-shielded piezoelectric sensor designed to work in the range of frequencies between 1 and 2 kHz and in these environmental conditions. The main idea was to add a thin material layer to the front face of the piezoelectric ceramic in order to force the system to vibrate in flexure mode at low frequencies. The resonant frequency and sensitivity of the system was studied as a function of the radius, thickness, and material of the thin layer. The study includes a comparison of theoretical model, FEM simulation, and real data measured using three aluminum and three steel prototypes of different sizes.


Infant disorganized attachment: Clarifying levels of analysis.
Lack of clarity regarding the infant disorganized attachment classification has caused confusion in the clinical, forensic, and research contexts in which it is used. This article offers distinctions to clarify the concept with the goal of increasing understanding and identifying potential misapplications. In particular, attention is drawn to the fact that there are many indices used to code "disorganized attachment," and that so far they have been validated as a set rather than individually; and it is noted that the construct validation of disorganization in naturalistic settings is partially finished. Clinicians and social workers should be cautious in their interpretations of such behavior.


Population database on nine STR loci of the AmpFlSTR Profiler kit in Koreans.
Allele frequencies for nine STR loci included in the AmpFlSTR Profiler Kit (D3S1358, vWA, FGA, TH01, TPOX, CSF1PO, D5S818, D13S317 and D7S820), were obtained from a sample of 1206 unrelated individuals living in the central region of Korea.


Arcticiflavibacter luteus gen. nov., sp. nov., a member of the family Flavobacteriaceae isolated from intertidal sand.
A yellow-pigmented, rod-shaped, non-flagellated, aerobic and Gram-reaction-negative bacterium, designated strain SM1212T, was isolated from intertidal sand of Kongsfjorden, Svalbard. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain SM1212T constituted a distinct lineage within the family Flavobacteriaceae. It shared highest 16S rRNA gene sequence similarities with the type strains of Bizionia echini (96.0 %), Lacinutrix jangbogonensis (95.8 %) and Psychroserpens damuponensis (95.7 %) and < 95.6 % sequence similarity with other recognized species in the family Flavobacteriaceae. The strain grew at 4-35 °C and with 0-6.0 % (w/v) NaCl. It hydrolysed gelatin, DNA, starch and Tween 80 but did not reduce nitrate to nitrite. The major cellular fatty acids were anteiso-C15 : 0, iso-C15 : 0, iso-C15 : 1 G, anteiso-C15 : 1 A, iso-C15 : 0 3-OH, C17 : 0 2-OH and iso-C17 : 0 3-OH and the major respiratory quinone was menaquinone MK-6. Polar lipids included phosphatidylethanolamine, one unidentified phospholipid, one unidentified aminophospholipid, three unidentified aminolipids and nine unidentified lipids. The genomic DNA G+C content of strain SM1212T was 36.6 mol%. On the basis of data from this polyphasic study, strain SM1212T represents a novel species in a new genus in the family Flavobacteriaceae, for which the name Arcticiflavibacter luteus gen. nov., sp. nov. is proposed. The type strain of Arcticiflavibacter luteus is SM1212T ( = MCCC 1K00234T = KCTC 32514T).


Non-steroidal anti-inflammatory drugs vs. Paracetamol: drug availability, patients' preference and knowledge of toxicity.
Self-medication is a common practice which is influenced by level of education, society factors and health care facilities availability. In our region, Pakistan, it is very common and awareness regarding prescription implementation needs to be ensured. Hence the current study highlights the preference, availability and knowledge of toxicity of non-steroidal antiinflammatory medications and paracetamol in Pakistan. It was a Descriptive, cross sectional, conducted in Rawalpindi and Islamabad, Pakistan from May to august 2012. A total of 1000 questionnaires comprising of 21 questions were distributed to the persons with age groups from 18 years to 40 years. Non-probability convenience sampling technique was used for results deduction. Data was analysed using descriptive statistics. The most commonly used medicine was Mefenamic acid (n=191, 40.8%). Paracetamol was second on the priority list (n=146, 31.3%). About 178 out of 467(38.1%) used these medications for headache. Very few responders knew about the toxic doses of the medicines they used. Only 52 (11%) were aware of the raised bleeding tendency being the most common side effect of acetylsalicylic acid and 129 (28%) were aware of liver damage by paracetamol toxicity. In Pakistan, common people take NSAIDs and Paracetamol without prescription and majority of them are unaware of the side effects of these medicines. This is the reason it is important to make the general public aware of the problems they may face if they misuse or over use the drugs without the prescription.


Implications of permeation through intrinsic defects in graphene on the design of defect-tolerant membranes for gas separation.
Gas transport through intrinsic defects and tears is a critical yet poorly understood phenomenon in graphene membranes for gas separation. We report that independent stacking of graphene layers on a porous support exponentially decreases flow through defects. On the basis of experimental results, we develop a gas transport model that elucidates the separate contributions of tears and intrinsic defects on gas leakage through these membranes. The model shows that the pore size of the porous support and its permeance critically affect the separation behavior, and reveals the parameter space where gas separation can be achieved regardless of the presence of nonselective defects, even for single-layer membranes. The results provide a framework for understanding gas transport in graphene membranes and guide the design of practical, selectively permeable graphene membranes for gas separation.