Demographic Patterns and Clinicopathological Analysis of Sarcomatoid Renal Cell Carcinoma in US Population.
Sarcomatoid renal cell carcinoma (RCC) is defined by the presence of any amount of sarcomatoid components admixed with other RCC histologic subtypes. Our investigation utilizes a large, diverse set of sarcomatoid RCC patients to summarize clinical, demographic, and pathological factors along with demographic disparities that may affect the prognosis and survival of sarcomatoid RCC patients. The Surveillance, Epidemiology, and End Results (SEER) database was employed to compile data from 2000 to 2018 from 2695 patients diagnosed with sarcomatoid RCC. The mean age for sarcomatoid RCC diagnosis is 62.8 years. Males (68.2%) and White patients (82.6%) were more likely to be diagnosed with sarcomatoid RCC. Among the 64.4% of tumors with known size, 35.4% were less than 7 cm, 27.6% were 7.1 to 10 cm, and 36.4% were larger than 10 cm. Among the 95.8% of patients with known stage, 15.3% were localized, 28.9% were regionalized, and 55.8% were found in distant sites. Among the 44.2% of cases with known metastases site, lung was found to be the most common metastatic site.. Surgery was the most common treatment (70.9%). While the overall 5-year survival was 18.1%, it was 27.1% among patients who underwent surgery. Independent risk factors for mortality include age > 60 years, distant stage, and tumor size > 10 cm, per our multivariate analysis. Sarcomatoid RCC most commonly affects White males in their seventh decade. Increased age, distant stage, and size > 10 cm tumor size have associations with unfavorable prognosis. Surgery is associated with better survival outcomes in localized disease and multimodal therapy (surgery with adjuvant chemoradiation was associated with better survival.).


Comparison of the different monosodium urate crystals in the preparation process and pro-inflammation.
The deposition of monosodium urate (MSU) crystals within synovial joints and tissues is the initiating factor for gout arthritis. Thus, MSU crystals are a vital tool for studying gout's molecular mechanism in animal and cellular models. This study mainly compared the excellence and worseness of MSU crystals prepared by different processes and the degree of inflammation induced by MSU crystals. MSU crystals were prepared using neutralization, alkali titration, and acid titration methods. The crystals' shape, length, quality, and uniformity were observed by polarized light microscopy and calculated by the software Image J. The foot pad and air pouch models were used to assess the different degrees of inflammation induced by the MSU crystals prepared by the three different methods at different time points. Paw swelling was evaluated by caliper. In air pouch lavage fluid, inflammatory cell recruitment was measured by hemocytometer, and the level of IL-1β, TNF-α, and IL-18 by ELISA. Inflammatory cell infiltration was assayed by immunohistochemistry of air pouch synovial slices. For the preparation of MSU crystals with the same uric acid, the quantity acquired by the alkalization method was highest, followed by neutralization, with the acid titration method being the lowest. The crystals prepared by neutralization were the longest. The swelling index of the foot pad induced by MSU crystals prepared by acid titration was significantly lower than that of the other methods at 24 h. The inflammatory cell recruitment and level of IL-1β, TNF-α, and IL-18 in air pouch lavage fluid were lowest in animals with crystals prepared by acid titration. IL-1β secretion induced by MSU crystals prepared by acid titration was significantly lower than that of the other two groups, but there was no significant difference in IL-18 secretion between the three groups in THP-1 macrophages and BMDMs. All three methods can successfully prepare MSU crystals, but the levels of inflammation induced by the crystals prepared by the three methods were not identical. The degree of inflammation induced by MSU crystals prepared by neutralization and alkalization is greater than by acid titration, but the quantity of MSU crystals obtained by the alkalization method is higher and less time-consuming. Apparently, the window of inflammation triggered by acid titration preparation is shorter compared to other forms of crystal preparation. Overall, MSU crystals prepared by the alkaline method should be recommended for studying the molecular mechanisms of gout in animal and cellular models.


Prognostic changes after sudden deafness in patients with inner ear malformations characterized by LSCC: a retrospective study.
This study aimed to investigate the clinical features and prognosis of sudden sensorineural hearing loss in patients with lateral semicircular canal (LSCC) malformation. This study enrolled patients with LSCC malformation and sudden sensorineural hearing loss (SSNHL) who were admitted to Shandong ENT Hospital between 2020 and 2022. We collected and analyzed data on examinations of audiology, vestibular function, and imaging records of patients and summarized the clinical characteristics and prognosis of these patients. Fourteen patients were enrolled. Patients with LSCC malformation was noted in 0.42% of all SSNHL cases during the same period. One patients had bilateral SSNHL and the rest had unilateral SSNHL. Of them, eight and six patients had unilateral and bilateral LSCC malformations, respectively. Flat hearing loss was noted in 12 ears (80.0%) and severe or profound hearing loss was noted in 10 ears (66.7%). After treatment, the total efficacy rate of SSNHL with LSCC malformation was 40.0%. Vestibular function was abnormal in all patients, but only five patients (35.7%) had dizziness. There were statistically significant differences in the vestibular functions between patients with LSCC malformation and matched patients without the malformation hospitalized during the same period (p < 0.05). Patients with SSNHL and LSCC malformation had flat-type and severe hearing loss and worse disease prognosis compared to those with SSNHL without LSCC malformation. Vestibular function is more likely to be abnormal; however, there was no significant difference in vestibular symptoms between patients with and without LSCC malformation. LSCC is a risk factor for the prognosis of SSNHL.


Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero.
Exposures to di-(2-ethylhexyl) phthalate (DEHP) have been shown to be associated with decreased adult testosterone (T) levels and increased Leydig cell numbers. As yet, little is known about DEHP effects in utero on fetal Leydig cells (FLC). The present study investigated effects of DEHP on FLC function. Pregnant Long-Evans female rats received vehicle (corn oil) or DEHP at 10, 100, or 750 mg/kg by oral gavage from gestational day (GD)2-20. At GD21, T production, FLC numbers and distribution, and testicular gene expression were examined. The percentage of FLC clusters containing 6-30 cells increased in all treatment groups, with 29 +/- 2% in control vs. 37 +/- 3, 35 +/- 3, and 56 +/- 4% in rats receiving 10, 100, and 750 mg/kg DEHP, respectively. In contrast, FLC numbers were 33% and 39% lower than control after exposures to 100 and 750 mg/kg DEHP, respectively. At these doses, mRNA levels of leukemia inhibitory factor (LIF) increased. LIF was found to induce cell aggregation in FLCs in vitro, consistent with the hypothesis that DEHP induced FLC aggregation. Testicular T levels were doubled by the 10 mg/kg dose and halved at 750 mg/kg. The mRNA levels of IGF-1 and c-Kit ligand (KITL) were induced by 10 mg/kg DEHP. These results, taken together, indicate that fetal exposures to DEHP have effects on FLC number, distribution, and most importantly, steroidogenic capacity and suggest that abnormal expressions of IGF1, KITL, and LIF genes may contribute to the reproductive toxicity of phthalates.


Deletion of IL-6 Exacerbates Colitis and Induces Systemic Inflammation in IL-10-Deficient Mice.
Interleukin 6 [IL-6] or its receptor is currently a candidate for targeted biological therapy of inflammatory bowel disease [IBD]. Thus, a comprehensive understanding of the consequences of blocking IL-6 is imperative. We investigated this by evaluating the effects of IL-6 deletion on the spontaneous colitis of IL-10-deficient mice [IL-10-/-]. IL-6/IL-10 double-deficient mice [IL-6-/-/IL-10-/-] were generated and analysed for intestinal inflammation, general phenotypes and molecular/biochemical changes in the colonic mucosa compared with wild-type and IL-10-/- mice. Unexpectedly, the IL-6-/-/IL-10-/- mice showed more pronounced gut inflammation and earlier disease onset than IL-10-/- mice, both locally [colon and small bowel] and systemically [splenomegaly, ulcerative dermatitis, leukocytosis, neutrophilia and monocytosis]. IL-6-/-/IL-10-/- mice exhibited elevations of multiple cytokines [IL-1β, IL-4, IL-12, TNFα] and chemokines [MCP-1 and MIG], but not IFN-γ [Th1], IL-17A and IL-17G [Th17], or IL-22 [Th22]. FOXP3 and TGF-β, two key factors for regulatory T [Treg] cell differentiation, were significantly down-regulated in the colonic mucosa, but not in the thymus or mesenteric lymph nodes, of IL-6-/-/IL-10-/- mice. CTLA-4 was diminished while iNOS was up-regulated in the colonic mucosa of IL-6-/-/IL-10-/- mice. In IL-10-/- mice, complete IL-6 blockade significantly aggravates gut inflammation, at least in part by suppressing Treg/CTLA-4 and promoting the IL-1β/Th2 pathway. In addition, the double mutant exhibits signs of severe systemic inflammation. Our data define a new function of IL-6 and suggest that caution should be exercised when targeting IL-6 in IBD patients, particularly those with defects in IL-10 signalling.


Truncation of the nuclear localization signal of polyomavirus VP1 results in a loss of DNA packaging when expressed in the baculovirus system.
Using the pBlueBacIII baculovirus transfer vector, N11-VP1, a truncated form of the polyomavirus major capsid protein VP1, was cloned for expression in the baculovirus-insect cell expression system. The N11-VP1 protein is virtually identical to full-length, wild-type VP1, except that the first 11 amino acids have been deleted from the amino terminus of the protein. The N-terminal region of VP1 has previously been shown to contain the nuclear localization signal (NLS) of the protein and contains residues essential for both nuclear transport as well as DNA-binding functions. The 5-day infected Sf9 cellular lysate from the recombinant N11-VP1 preparation was purified by cesium chloride density gradient centrifugation. Capsid-like particles were observed in the resulting preparation. The purified particle preparation was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis as well as Western blotting and was shown to have accurately expressed the N11-VP1 as cloned. Examination of the Coomassie-stained gels revealed that the capsid-like particles composed of the N11-VP1 protein did not contain any host-derived histones. The absence of the histones in the N11-VP1 capsid-like particles is indicative of the inability of these particles to package DNA, a feature which is observed when wild-type VP1 is treated in this manner. Electron microscopy of these particles substantiated this observation. To determine if the deletion of the NLS exhibited true in vivo characteristics, Sf9 insect cells were infected with the recombinant baculovirus carrying the N11-VP1 gene and examined early in infection (30 h post-infection) by indirect immunofluorescence. The N11-VP1 protein was not transported to the nucleus and remained in the cytoplasm. When the Sf9 cells were coinfected with N11-VP1 and polyomavirus VP2 and VP3 carrying baculoviruses, the N11-VP1 was transported to the nucleus by cooperation with the minor capsid proteins. These studies demonstrate that the N-terminal region of VP1, which contains the NLS and DNA-binding domains, is essential for VP1 nuclear transport and its ability to package Sf9 cellular DNA.


Emerging structure of the nicotinic acetylcholine receptors.
The conversion of acetylcholine binding into ion conduction across the membrane is becoming more clearly understood in terms of the structure of the receptor and its transitions. A high-resolution structure of a protein that is homologous to the extracellular domain of the receptor has revealed the binding sites and subunit interfaces in great detail. Although the structures of the membrane and cytoplasmic domains are less well determined, the channel lining and the determinants of selectivity have been mapped. The location and structure of the gates, and the coupling between binding sites and gates, remain to be established.


Complementary competencies: public health and health sciences librarianship.
The authors sought to identify opportunities for partnership between the communities of public health workers and health sciences librarians. The authors review competencies in public health and health sciences librarianship. They highlight previously identified public health informatics competencies and the Medical Library Association's essential areas of knowledge. Based on points of correspondence between the two domains, the authors identify specific opportunities for partnership. The points of correspondence between public health and health sciences librarianship are reflected in several past projects involving both communities. These previous collaborations and the services provided by health sciences librarians at many public health organizations suggest that some health sciences librarians may be considered full members of the public health workforce. Opportunities remain for productive collaboration between public health workers and health sciences librarians. Drawing on historical and contemporary experience, this paper presents an initial framework for forming collaborations between health sciences librarians and members of the public health workforce. This framework may stimulate thinking about how to form additional partnerships between members of these two communities.


Signatures of brain plasticity supporting language recovery after perinatal arterial ischemic stroke.
Brain imaging methods such as functional Magnetic Resonance Imaging (fMRI) and Diffusion Tensor Imaging (DTI) have already been used to decipher the functional and structural brain changes occurring during normal language development. However, little is known about the differentiation of the language network after an early lesion. While in adults, stroke over the left hemisphere generally induces post-stroke aphasia, it is not always the case when a stroke occurs in the perinatal period, thus revealing a remarkable plastic power of the language network during early development. In particular, the role of perilesional tissues, as opposed to undamaged brain areas in the functional recovery of language functions after an early insult, remains unclear. In this review article, we provide an overview of the extant literature using functional and structural neuroimaging data revealing the signatures of brain plasticity underlying near-normal language development.


A tale of two centuries: voices of the past and present.
This article compares the reported experiences of children and adolescents receiving inpatient treatment in contemporary psychiatric hospital settings with those of women institutionalized in mental hospitals from 1840 to 1945. Qualitative data include case study material from former psychiatrically hospitalized patients and archival narratives. Analysis includes matching themes from in-depth interviews with archival narratives. Nine representative experiences emerged and are presented in a typology under broader themes of structure, process, and outcome. Similarity of patient experiences over two centuries leads to questions about the meaning of advances in understanding mental illnesses in the context of attitudes, biases, and staff behavior toward patients that remains disturbingly unchanged.


The current status of composite materials and adhesive systems. Part 1: Composite resins--review and recent developments.
This series of articles reviews the current status, clinical techniques and developments in tooth coloured restorative materials and adhesive systems.


Facial Tightening Effects, Following Focused and Radial Acoustic Wave Therapy Assessment, Using a Three-Dimensional Digital Imaging.
Acoustic wave therapy is a novel facial tightening technique that involves nonthermal penetration of the skin and subcutaneous tissue, affecting cells and their metabolism, and resulting in an increased release of unwanted fat and activation of blood and lymphatic flow in tissues. The objective of this study was to investigate the effectiveness of acoustic wave therapy. A total of 333 patients underwent multiple facial tightening treatment sessions using focused and radial acoustic waves. Each patient received 2,000-3,000 pulses of focused acoustic waves at a power of 0.45-0.88 mJ/mm2 with a pulse frequency of 3-5 Hz and 4,000 pulses of radial acoustic waves at 4-bar power at a frequency of 21 Hz. These sessions were performed more than three times, and treatments were repeated at 1-month intervals. Digital photographs superimposed three-dimensional volumetric assessments, and three-dimensional skin surface displacement calculations using vectors were used to evaluate the results 12 months after the last treatment. Patients also evaluated the results using a 5-point Likert scale. Improvements in skin texture, clarity, and laxity were observed in digital photographs. Superimposed three-dimensional color images showed marked volumetric reduction and/or formative modification for even contour toward the lower mid-face. Most vectors showed three-dimensional skin surface displacement at the lateral sides of the temples, cheeks, and chin, in an upward direction. These results were obtained and sustained for up to 12 months without edematous reactions. Almost all patients reported improvement, with 79% reporting "good" or "excellent" improvement. Complications were minor and transitory. Persistent side effects were not observed. Acoustic wave therapy could be used as a standard facial tightening treatment, with skin rejuvenation effects shown on digital photographs and three-dimensional quantification assessments. This noninvasive acoustic wave approach was found to be a safe, long-lasting, and effective method for facial tightening. Lasers Surg. Med. 00:00-00, 2020. © 2020 Wiley Periodicals LLC.


"Design of Experiments" as a Method to Optimize Dynamic Disulfide Assemblies: Cages and Functionalizable Macrocycles.
Cyclophanes are a venerable class of macrocyclic and cage compounds that often contain unusual conformations, high strain, and unusual properties. However, synthesis of complex, functional derivatives remains difficult due to low functional group tolerance, high dilution, extreme reaction conditions, and sometimes low yields using traditional stepwise synthetic methods. "Design of experiments" (DOE) is a method employed for the optimization of reaction conditions, and we showcase this approach to generate a dramatic increase in the yield of specific targets from two different self-assembling systems. These examples demonstrate that DOE provides an additional tool in tuning self-assembling, dynamic covalent systems.


Reclassification of the current tumor, node, metastasis staging in pT3 renal cell carcinoma.
Although the tumor, node, metastasis (TNM) staging classification of renal cell carcinoma (RCC) was last modified in 2002, pT3 staging has continued to be debated. It has been suggested that direct adrenal gland involvement and pT3b with pT3a should be reclassified. This study accordingly explores reclassification of the current 2002 TNM staging in pT3 RCCs. A total of 111 patients with pT3 RCC who underwent radical nephrectomy at our institution between March 1972 and February 2006 were enrolled in this study. Histological samples were reviewed by a single pathologist. Disease-specific survival was compared according to reclassification as pT3a with perirenal fat involvement only (pT3a-fat), pT3a with adrenal gland involvement (pT3a-ad), pT3b without pT3a factors (pT3b-only), pT3b with pT3a factors (pT3b with pT3a), or pT3c. Seven patients were identified as having pT3a-ad and 20 patients as having pT3b with pT3a. The mean disease-specific survival times in pT3a-fat and pT3b-only were significantly longer: 124.1 +/- 13.2 (SE) months and 70.9 +/- 9.1 (SE) months, respectively, compared with 24.7 +/- 6.7 (SE) months in pT3a-ad (P = 0.0004 and 0.0010, respectively), and 25.0 +/- 4.4 (SE) months in pT3b with pT3a (P = 0.0009 and 0.0032, respectively). On multivariate analysis, the presence of direct ipsilateral adrenal gland involvement was recognized as a predictor of poor prognosis (P = 0.0331). Direct ipsilateral adrenal gland involvement for patients with pT3a, and perirenal fat or adrenal gland involvement for patients with pT3b should be reclassified nearly to pT4.


AVT is involved in the regulation of ion transport in the intestine of the sea bream (Sparus aurata).
The intestine of marine fish plays a crucial role in ion homeostasis by selective processing of ingested fluid. Although arginine vasotocin (AVT) is suggested to play a role in ion regulation in fish, its action in the intestine has not been demonstrated. Thus, the present study investigated in vitro the putative role of AVT in intestinal ion transport in the sea bream (Sparus aurata). A cDNA encoding part of an AVT receptor was isolated and phylogenetic analysis revealed it clustered with the V1a2-type receptor clade. V1a2 transcripts were expressed throughout the gastrointestinal tract, from esophagus to rectum, and were most abundant in the rectum regardless of long-term exposure to external salinities of 12, 35 or 55p.p.t. Basolateral addition of AVT (10(-6)M) to the anterior intestine and rectum of sea bream adapted to 12, 35 or 55p.p.t. mounted in Ussing chambers produced rapid salinity and region dependent responses in short circuit current (Isc), always in the absorptive direction. In addition, AVT stimulation of absorptive Isc conformed to a dose-response curve, with significant effects achieved at 10(-8)M, which corresponds to physiological values of plasma AVT for this species. The effect of AVT on intestinal Isc was insensitive to the CFTR selective inhibitor NPPB (200μM) applied apically, but was completely abolished in the presence of apical bumetanide (200μM). We propose a role for AVT in the regulation of ion absorption in the intestine of the sea bream mediated by an absorptive bumetanide-sensitive mechanism, likely NKCC2.


RAISING is a high-performance method for identifying random transgene integration sites.
Both natural viral infections and therapeutic interventions using viral vectors pose significant risks of malignant transformation. Monitoring for clonal expansion of infected cells is important for detecting cancer. Here we developed a novel method of tracking clonality via the detection of transgene integration sites. RAISING (Rapid Amplification of Integration Sites without Interference by Genomic DNA contamination) is a sensitive, inexpensive alternative to established methods. Its compatibility with Sanger sequencing combined with our CLOVA (Clonality Value) software is critical for those without access to expensive high throughput sequencing. We analyzed samples from 688 individuals infected with the retrovirus HTLV-1, which causes adult T-cell leukemia/lymphoma (ATL) to model our method. We defined a clonality value identifying ATL patients with 100% sensitivity and 94.8% specificity, and our longitudinal analysis also demonstrates the usefulness of ATL risk assessment. Future studies will confirm the broad applicability of our technology, especially in the emerging gene therapy sector.


Intravitreal anti-VEGF injections for treating wet age-related macular degeneration: a systematic review and meta-analysis.
Age-related macular degeneration (AMD) is the main cause of blindness. Anti-vascular endothelial growth factor is used to prevent further neovascularization due to wet AMD. The purpose of this systematic review was to investigate the effect and protocol of anti-vascular endothelial growth factor treatment on wet AMD. A comprehensive literature search was performed in PubMed, Embase, the Cochrane Library, CNKI, and reference lists. Meta-analysis was performed using Stata12.0 software, best corrected visual acuity (BCVA), retinal thickness, and lesion size were evaluated. Twelve randomized controlled trials spanning from 2010 to 2014 and involving 5,225 patients were included. A significant difference was observed between the intravitreal ranibizumab (IVR) group and the intravitreal bevacizumab group (standard mean difference = -0.14, 95% confidence interval [CI] = -0.23 to -0.05). No significant differences were observed in best corrected VA, retinal thickness, or lesion size between IVR and the intravitreal aflibercept group. Compared to monthly injection, IVR as-needed injections (PRN) can raise VA by 1.97 letters (weighted mean difference = 1.97, 95% CI = 0.14-3.794). Combination therapy of IVR and photodynamic therapy can significantly raise VA by 2.74 letters when combined with IVR monotherapy (weighted mean difference = 2.74, 95% CI = 0.26-5.21). The superiority remains unclear between IVR and intravitreal bevacizumab in the treatment of neovascular AMD. Intravitreal aflibercept dosed every 2 months required fewer injection times, but produced similar efficacy as monthly IVR. IVR PRN could significantly increase VA. Combined with photodynamic therapy, IVR therapy could also increase VA effectively.


Polymeric nanomedicines for the treatment of hepatic diseases.
The liver is an important organ in the human body and performs many functions, such as digestion, detoxification, metabolism, immune responses, and vitamin and mineral storage. Therefore, disorders of liver functions triggered by various hepatic diseases, including hepatitis B virus infection, nonalcoholic steatohepatitis, hepatic fibrosis, hepatocellular carcinoma, and transplant rejection, significantly threaten human health worldwide. Polymer-based nanomedicines, which can be easily engineered with ideal physicochemical characteristics and functions, have considerable merits, including contributions to improved therapeutic outcomes and reduced adverse effects of drugs, in the treatment of hepatic diseases compared to traditional therapeutic agents. This review describes liver anatomy and function, and liver targeting strategies, hepatic disease treatment applications and intrahepatic fates of polymeric nanomedicines. The challenges and outlooks of hepatic disease treatment with polymeric nanomedicines are also discussed.


Efficacy of Duddingtonia flagrans (Bioverm®) on the biological control of buffalo gastrointestinal nematodes.
We evaluated the efficacy of Bioverm®, a commercial product containing Duddingtonia flagrans, on the control of buffalo (Bubalus bubalis) gastrointestinal nematodes. We randomly divided 12 buffaloes into two groups of six animals. In the treated group, each animal received a Bioverm®`s single dose of 1g (105 chlamydospores of D. flagrans) to 10 kg of live weight; in the control group, each animal received 1g of corn bran for each 10 kg of live weight as a placebo. Fecal samples were individually collected from 12, 24, 36, 48, 60 and 72 h after treatments. To examine 1) viability of chlamydospores passed through the gastrointestinal tract, 2 g of faeces and 1000 infective larvae (L3) were added to Petri dishes with 2% water-agar, and 2) to examine larval predation by D. flagrans during fecal cultures, 2000 L3 were added. In the Petri dishes, were observed significant reductions (p < 0.01) in the treated group after 48 (56.7%) and 60 h (91.5%). In the fecal cultures, significant reductions (p < 0.01) occurred in the treated group from 36 h (75%), with larval reduction up to 72 h. High larval predation rate occurred 60 h after Bioverm® administration. Bioverm® maintained viability and predation capacity after passage through the buffalo's gastrointestinal tract, showing efficacy on gastrointestinal nematodes.


High G9a Expression in DLBCL and Its Inhibition by Niclosamide to Induce Autophagy as a Therapeutic Approach.
Diffuse large B-cell lymphoma (DLBCL) is a malignant lymphoid tumor disease that is characterized by heterogeneity, but current treatment does not benefit all patients, which highlights the need to identify oncogenic genes and appropriate drugs. G9a is a histone methyltransferase that catalyzes histone H3 lysine 9 (H3K9) methylation to regulate gene function and expression in various cancers. TCGA and GTEx data were analyzed using the GEPIA2 platform. Cell viability under drug treatment was assessed using Alamar Blue reagent; the interaction between G9a and niclosamide was assessed using molecular docking analysis; mRNA and protein expression were quantified in DLBCL cell lines. Finally, G9a expression was quantified in 39 DLBCL patient samples. The TCGA database analysis revealed higher G9a mRNA expression in DLBCL compared to normal tissues. Niclosamide inhibited DLBCL cell line proliferation in a time- and dose-dependent manner, reducing G9a expression and increasing p62, BECN1, and LC3 gene expression by autophagy pathway regulation. There was a correlation between G9a expression in DLBCL samples and clinical data, showing that advanced cancer stages exhibited a higher proportion of G9a-expressing cells. G9a overexpression is associated with tumor progression in DLBCL. Niclosamide effectively inhibits DLBCL growth by reducing G9a expression via the cellular autophagy pathway; therefore, G9a is a potential molecular target for the development of therapeutic strategies for DLBCL.


Epidemiology, etiology, and diagnosis of hospital-acquired pneumonia and ventilator-associated pneumonia in Asian countries.
Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are significant public health issues in Asian countries, as they are worldwide. Mortality attributable to HAP and especially VAP can be very high. The present review aims to determine whether the incidence and prevalence of HAP and VAP are higher in Asian countries than in Western countries, whether the organisms causing these nosocomial infections differ etiologically, and whether they are more difficult to treat (ie, demonstrate greater resistance). The implementation of available guidelines can be best achieved through an understanding of local epidemiology, etiology, and resistance patterns, which can facilitate optimal treatment choices. The current review presents data on epidemiology, etiology, and diagnosis of HAP and VAP drawn from an expert panel of clinicians representing 10 Asian countries.


[Electronic coding of death certificates].
About half of all German death certificates are processed electronically by regional statistical offices to select the underlying cause of death in accordance with the instructions from the World Health Organization. This paper illustrates electronic coding and its importance for cause of death statistics.The electronic coding kernel MUSE was added a few years ago to the international coding system Iris, which is maintained by the Iris Core Group.A new module assigns, as far as possible, ICD-10 codes to medical terms documented in death certificates. It takes into account syntactical specifics of the German language. In addition, automatic text correction is implemented. Unrecognised text parts are highlighted and coded manually.Despite these efforts, improvement of data quality is the greatest challenge of German cause-of-death statistics. All involved stakeholders (physicians, local health authorities, and regional statistical offices) can cope with this task by a common effort.The process of electronic coding provides valuable hints for improving the quality of death certificates. In future, the coding system could generate feedback to local health authorities indicating medical documentation problems.


Tex19 and Sectm1 concordant molecular phylogenies support co-evolution of both eutherian-specific genes.
Transposable elements (TE) have attracted much attention since they shape the genome and contribute to species evolution. Organisms have evolved mechanisms to control TE activity. Testis expressed 19 (Tex19) represses TE expression in mouse testis and placenta. In the human and mouse genomes, Tex19 and Secreted and transmembrane 1 (Sectm1) are neighbors but are not homologs. Sectm1 is involved in immunity and its molecular phylogeny is unknown. Using multiple alignments of complete protein sequences (MACS), we inferred Tex19 and Sectm1 molecular phylogenies. Protein conserved regions were identified and folds were predicted. Finally, expression patterns were studied across tissues and species using RNA-seq public data and RT-PCR. We present 2 high quality alignments of 58 Tex19 and 58 Sectm1 protein sequences from 48 organisms. First, both genes are eutherian-specific, i.e., exclusively present in mammals except monotremes (platypus) and marsupials. Second, Tex19 and Sectm1 have both duplicated in Sciurognathi and Bovidae while they have remained as single copy genes in all further placental mammals. Phylogenetic concordance between both genes was significant (p-value < 0.05) and supported co-evolution and functional relationship. At the protein level, Tex19 exhibits 3 conserved regions and 4 invariant cysteines. In particular, a CXXC motif is present in the N-terminal conserved region. Sectm1 exhibits 2 invariant cysteines and an Ig-like domain. Strikingly, Tex19 C-terminal conserved region was lost in Haplorrhini primates while a Sectm1 C-terminal extra domain was acquired. Finally, we have determined that Tex19 and Sectm1 expression levels anti-correlate across the testis of several primates (ρ = -0.72) which supports anti-regulation. Tex19 and Sectm1 co-evolution and anti-regulated expressions support a strong functional relationship between both genes. Since Tex19 operates a control on TE and Sectm1 plays a role in immunity, Tex19 might suppress an immune response directed against cells that show TE activity in eutherian reproductive tissues.


Cell vesiculation and immunopathology: implications in cerebral malaria.
Microparticles are plasma membrane fragments that are generated and released under physiological conditions. They are also released when tissue and/or systemic homeostasis is disrupted. These microparticles display different physiological features of the cells from which they originate. They are detected in some pathological conditions, but rarely suspected of participating in the disease's pathogenesis. In the present review, we summarise data about the production of the microparticles, their biological significance and potential role during microorganism-driven processes, especially in cerebral malaria.


Parasites detect host spatial pattern and density: a field experimental analysis.
A common assumption in mathematical models of parasitism is that the susceptibility to parasitism of an individual host increases both with host density and the degree of host spatial aggregation. To determine whether this assumption is correct in nature, we developed a factorial field experiment with the parasitic marine isopod Hemioniscus balani and its barnacle host Chthamalus dalli. Our factorial design enabled evaluation of the separate effects on parasitism of the two factors (host density and host spatial pattern) and also to assess the host density-spatial pattern interaction effect. Both host density and spatial aggregation were found to lead to increased parasitism, and the interaction effect was nonsignificant. These findings are the first experimental field demonstration that these processes occur in nature, as widely assumed in ecological theory.


[Current state, goals and quality standards of outpatient care in rheumatology: position paper of the Professional Association of German Rheumatologists (BDRh)].
Even in the era of modern guidelines, the treatment of rheumatic diseases is only as good as the framework of rheumatological care within which the treatment is carried out. The access to high-quality medical treatment for all patients is therefore essentially decisive for the prognosis of the patients. This article describes the current state of outpatient treatment in rheumatology and demonstrates which quality projects, such as treatment contracts, outpatient specialized medical treatment (ASV), digitalization and training as specialized rheumatological assistant (RFA), have been created in order to ensure the treatment of our patients. Furthermore, standards are defined that can guarantee a contemporary and guideline-conform treatment in outpatient rheumatological units. As an example it is an affirmation of the Professional Association of German Rheumatologists (BDRh) for ensuring optimal care for all rheumatology patients through early or emergency rheumatology clinics, treat to target, appropriate delegation of medical duties and diversification of treatment, thus an assurance of the quality and comprehensive treatment in rheumatology. The important topic of safeguarding the next generation of rheumatologists, which is indispensable for this, is also discussed.


Revealing the Nature of Singlet Fission under the Veil of Internal Conversion.
Singlet fission (SF) holds the potential to boost the maximum power conversion efficiency of photovoltaic devices. Internal conversion (IC) has been considered as one of the major competitive deactivation pathways to transform excitation energy into heat. Now, using time-resolved spectroscopy and theoretical calculation, it is demonstrated that, instead of a conventional IC pathway, an unexpected intramolecular singlet fission (iSF) process is responsible for excited state deactivation in isoindigo derivatives. The 1 TT state could form at ultrafast rate and nearly quantitatively in solution. In solid films, the slipped stacked intermolecular packing of a thiophene-functionalized derivative leads to efficient triplet pair separation, giving rise to an overall triplet yield of 181 %. This work not only enriches the pool of iSF-capable materials, but also contributes to a better understanding of the iSF mechanism, which could be relevant for designing new SF sensitizers.


Effect of turmeric and its active principle curcumin on t(3)-induced oxidative stress and hyperplasia in rat kidney: a comparison.
The present study was designed to compare the potential of turmeric and its active principle curcumin on T(3)-induced oxidative stress and hyperplasia. Adult male Wistar strain rats were rendered hyperthyroid by T(3) treatment (10 μg · 100 g(-1) · day(-1) intraperitoneal for 15 days in 0.1 mM NaOH) to induce renal hyperplasia. Another two groups were treated similarly with T(3) along with either turmeric or curcumin (30 mg kg(-1) body weight day(-1) orally for 15 days). The results indicate that T(3) induces both hypertrophy and hyperplasia in rat kidney as evidenced by increase in cell number per unit area, increased protein content, tubular dilation and interstitial edema. These changes were accompanied by increased mitochondrial lipid peroxidation and superoxide dismutase activity without any change in catalase activity and glutathione content suggesting an oxidative predominance. Both turmeric and curcumin were able to restore the level of mitochondrial lipid peroxidation and superoxide dismutase activity in the present dose schedule. T(3)-induced histo-pathological changes were restored with turmeric treatment whereas curcumin administration caused hypoplasia. This may be due to lower concentration of curcumin in the whole turmeric. Thus it is hypothesized that regulation of cell cycle in rat kidney by T(3) is via reactive oxygen species and curcumin reveres the changes by scavenging them. Although the response trends are comparable for both turmeric and curcumin, the magnitude of alteration is more in the later. Turmeric in the current dose schedule is a safer bet than curcumin in normalizing the T(3)-induced hyperplasia may be due to the lower concentration of the active principle in the whole spice.


Laboratory tests in adults with monoarticular arthritis: can they rule out a septic joint?
It is difficult to differentiate septic arthritis from other causes of monoarticular arthritis solely with a history and physical examination. The clinician must rely on ancillary tests to make a diagnosis, such as the white blood cell count of peripheral blood (WBC), the erythrocyte sedimentation rate (ESR), and the white blood cell count of the joint fluid (jWBC) obtained from arthrocentesis. Although it is known that septic arthritis is associated with abnormalities in these tests, the majority of the data are based on studies in the pediatric population. In addition, although several emergency medicine texts indicate that a jWBC greater than 50,000 cells/mm(3) is "positive," it is known that septic arthritis can occur in patients with low jWBCs. To determine whether specific ancillary tests have sufficiently high sensitivities to rule out septic arthritis in adults. This was a retrospective consecutive case series of patients from an urban emergency department (ED). Patients at least 18 years old who had septic arthritis confirmed by positive arthrocentesis culture or operative findings were included in the study. WBC greater than 11,000 cells/mm(3), ESR greater than 30 mm/hr, and jWBC greater than 50,000 cells/mm(3) were considered elevated. Seventy-three patients met the inclusion criteria. The sensitivities of an elevated WBC, ESR, or jWBC in adults who had septic arthritis were 48%, 96%, and 64%, respectively. There were broad ranges of WBC, ESR, or jWBC among the patients. More than one third of adult patients with septic arthritis had jWBCs less than 50,000 cells/mm(3). All patients had an abnormality in at least one of these tests. The WBC, ESR, and jWBC are extremely variable in adults with septic arthritis. Laboratory tests do not rule out septic arthritis with accuracy.


Recombinant Fv immunotoxins and Fv fragments as novel agents for cancer therapy and diagnosis.
Recombinant immunotoxins are new agents being developed for cancer therapy. They are composed of Fv fragments of antibodies that bind to cancer cells fused to a truncated form of a very potent bacterial toxin. The antibody moiety directs the toxin to cancer cells, which are killed, while normal cells are not recognized and thus survive. The excellent preclinical results in vitro and in vivo have led to the initiation of several clinical trials.


Design of a novel quantitative PCR (QPCR)-based protocol for genotyping mice carrying the neuroprotective Wallerian degeneration slow (Wlds) gene.
Mice carrying the spontaneous genetic mutation known as Wallerian degeneration slow (Wlds) have a unique neuroprotective phenotype, where axonal and synaptic compartments of neurons are protected from degeneration following a wide variety of physical, toxic and inherited disease-inducing stimuli. This remarkable phenotype has been shown to delay onset and progression in several mouse models of neurodegenerative disease, suggesting that Wlds-mediated neuroprotection may assist in the identification of novel therapeutic targets. As a result, cross-breeding of Wlds mice with mouse models of neurodegenerative diseases is used increasingly to understand the roles of axon and synapse degeneration in disease. However, the phenotype shows strong gene-dose dependence so it is important to distinguish offspring that are homozygous or heterozygous for the mutation. Since the Wlds mutation comprises a triplication of a region already present in the mouse genome, the most stringent way to quantify the number of mutant Wlds alleles is using copy number. Current approaches to genotype Wlds mice are based on either Southern blots or pulsed field gel electrophoresis, neither of which are as rapid or efficient as quantitative PCR (QPCR). We have developed a rapid, robust and efficient genotyping method for Wlds using QPCR. This approach differentiates, based on copy number, homozygous and heterozygous Wlds mice from wild-type mice and each other. We show that this approach can be used to genotype mice carrying the spontaneous Wlds mutation as well as animals expressing the Wlds transgene. We have developed a QPCR genotyping method that permits rapid and effective genotyping of Wlds copy number. This technique will be of particular benefit in studies where Wlds mice are cross-bred with other mouse models of neurodegenerative disease in order to understand the neuroprotective processes conferred by the Wlds mutation.


Paediatric post-traumatic cortical defects of the distal radius.
Paediatric post-traumatic cortical defects, although rare, are predominately seen affecting the distal radius following a greenstick or torus fracture. We review the literature and present a further two cases supported by CT and MRI. Images from an acute greenstick fracture are also presented to help understand the pathogenesis. Defects are typically solitary on plain radiographs and are usually noticed late, proximal to the site of compression. They are non-expansile in an otherwise healthy child. CT and MRI may reveal smaller multiple subperiosteal defects. Typical defects require no further management other than reassurance and advice that they may occasionally cause discomfort but resolve with time.


Does fasting during Ramadan influence the therapeutic effect of warfarin?
The changes in the therapeutic effect of warfarin during Ramadan fasting are controversial. Hence, we carried out the present study to assess if there are any alterations in the anticoagulation response to warfarin and identify the associated risk factors. Patients receiving warfarin for at least 1 year were included in the present study. Their demographic details, warfarin doses, prothrombin time-international normalized ratio (PT-INR) values and concomitant diseases/drugs were retrieved. The dates of Ramadan periods for the calendar years were obtained, and these periods were considered as Ramadan periods. One month before the start dates of Ramadan was considered as pre-Ramadan, and 1 month later than the last dates was considered as post-Ramadan periods. Warfarin sensitivity index (WSI), PT-INR category and time spent in therapeutic range (TTR) were assessed. National Institute of Clinical Health Excellence (NICE) criteria for anticoagulation status were adhered to where TTR (%) <65 was considered as poor anticoagulation. One hundred and eighty-three patients were recruited. No significant differences were observed in warfarin doses between the study participants between pre-Ramadan, Ramadan and post-Ramadan periods. Significantly more numbers of PT-INR tests were carried out during Ramadan compared with pre- and post-Ramadan periods. A higher WSI was akin to PT-INR, and lower intra-individual variability was observed in middle-aged and older adults in the post-Ramadan period. Significantly fewer patients had their PT-INR in the therapeutic range and more in the subtherapeutic range during Ramadan periods. Greater proportion of patients had PT-INR in the supratherapeutic range during post-Ramadan periods, particularly the elderly. Although 38.3% had poor anticoagulation status overall, 92.4% met the NICE criteria for poor anticoagulation during the 3 months (pre-Ramadan, Ramadan and post-Ramadan periods). Ramadan fasting influences the therapeutic effect of warfarin in terms of lowered TTR (%), reduced proportion of patients achieving therapeutic PT-INR and increased risk of poor anticoagulation control. Greater caution is required during the post-Ramadan period, particularly in the elderly category as they are more prone for over-anticoagulation and consequently the risk of bleeding.


[The expression and significance of myocardial cathepsin L in dilated cardiomyopathy].
To clarify the expression of myocardial cathepsin L and its significance in the pathogenesis of dilated cardiomyopathy (DCM). Myocardial tissue specimens derived from 20 patients undergoing orthotopic cardiac transplantation and 5 normal myocardium samples collected at autopsy from sudden death as controls were studied. The expression of cathepsin L was detected with immunohistochemistry, real time PCR and Western Blotting, respectively. At the same time, the relationship between the Cathepsin L mRNA expressional levels and the myocardial function (ejection fraction, EF) was investigated. The expression levels of cathepsin L mRNA and protein in DCM group were markedly elevated compared with those in control group and the expression levels of cathepsin L mRNA had significantly negative correlation with the myocardial function (ejection fraction, EF). Cathepsin L is markedly elevated in DCM myocardial tissue and it may participate in the pathogenesis of DCM.


Pretreatment levels of circulating Th1 and Th2 cytokines, and their ratios, are associated with ER-negative and triple negative breast cancers.
Immune signatures in breast tumors differ by estrogen receptor (ER) status. The purpose of this study was to assess associations between ER phenotypes and circulating levels of cytokines that co-ordinate cell-mediated [T-helper type 1 (Th1)] and humoral [T-helper type 2 (Th2)] immunity. We conducted a case-case comparison of 523 women with newly diagnosed breast cancer to evaluate associations between 27 circulating cytokines, measured using Luminex XMap technology, and breast cancer phenotypes [ER(-) vs. ER(+); triple negative breast cancer (TNBC) vs. luminal A (LumA)]. Ratios of Th1 to Th2 cytokines were also evaluated. Levels of interleukin (IL)-5, a Th-2 cytokine, were higher in ER(-) than in ER(+) tumors. The highest tertile of IL-5 was more strongly associated with ER(-) (OR = 2.33, 95 % CI 1.40-3.90) and TNBCs (OR = 2.78, 95 % CI 1.53-5.06) compared to ER(+) and LumA cancers, respectively, particularly among premenopausal women (OR = 4.17, 95 % CI 1.86-9.34, ER(-) vs. ER(+); OR = 5.60, 95 % CI 2.09-15.01, TNBC vs. LumA). Elevated Th1 cytokines were also detected in women with ER(-) and TNBCs, with women in the highest tertile of interferon α2 (OR = 2.39, 95 % CI 1.31-4.35) or tumor necrosis factor-α (OR = 2.27, 95 % CI 1.21-4.26) being twice as likely to have TNBC versus LumA cancer. When cytokine ratios were examined, women with the highest ratios of Th1 cytokines to IL-5 levels were least likely to have ER(-) or TNBCs compared to ER(+) or LumA cancers, respectively. The strongest associations were in premenopausal women, who were up to 80 % less likely to have TNBC than LumA cancers (IL-12p40/IL-5, OR = 0.19, 95 % CI 0.07-0.56). These findings indicate that immune function is associated with ER(-) and TNBC and may be most relevant among younger women, who are likely to be diagnosed with these aggressive phenotypes.


Infant recognition of mother's voice.
Each of a group of one-month-old infants was reinforced, contingent upon nonutritive sucking, with its mother's voice and the voice of a stranger. In this experiment, two conditions were applied. Under the first, the mother's speech was aimed at communicating with the infant, while, under the second, the mother's speech lacked prosodic and intonational aspects of normal speech. It was shown that infants will suck more for their mother's voices under the intonanted condition only. It was concluded that a young infant prefers its own mother's voice provided the mother speaks normally.


[Evaluation of remaining performance capacity in patients with alveolitis and pulmonary fibrosis].
In patients with alveolitis or interstitial fibrosis of the lungs reduction of physical work capacity is the consequence of cardiopulmonary functional impairment. On the basis of the results of the evaluation of investigation in 493 patients with alveolitis and fibrosis a decision matrix for quantifying different degrees of impairment is recommended.


Liberalization of donor criteria in lung and heart-lung transplantation.
Since March 1986, we have performed 26 heart-lung transplantations, 42 single-lung transplantations, 9 bilateral single-lung transplantations, and 1 double-lung transplantation. The original lung donor requirements were as follows: age less than 40 years, no smoking history; no gram-negative rods or fungus on sputum Gram stain; arterial oxygen tension greater than 140 mm Hg on an inspired oxygen fraction of 0.40; no infiltrate or pneumothorax on the chest radiograph; and donor height within 15 cm (6 inches) of recipient height. As the number of potential recipients increased, so did the waiting time. To counter this delay, during the past year we have liberalized our donor criteria. We now accept lung donors up to age 60 years. Any kind of smoking history is acceptable unless there is chronic obstructive pulmonary disease or pulmonary fibrosis on the chest radiograph. Sputum must be free from fungus, but gram-negative rods are treated with appropriate antibiotics. The arterial oxygen tension on an inspired oxygen fraction of 0.40 should be greater than 100 mm Hg, and a small pulmonary infiltrate is not worrisome. This liberalization of the donor pool for lung and heart-lung transplantation has not adversely affected early outcome.


3-Methyl-4-{(E)-[4-(methyl-sulfan-yl)benzyl-idene]amino}-1H-1,2,4-triazole-5(4H)-thione.
In the title mol-ecule, C11H12N4S2, the dihedral angle between the triazole and benzene rings is 21.31 (5)°. A weak intra-molecular C-H⋯S hydrogen bond generates an S(6) ring motif. In the crystal, pairs of N-H⋯S hydrogen bonds form inversion dimers. In addition, π-π inter-actions are observed between the benzene rings, with a centroid-centroid separation of 3.7599 (11) Å.


Phenotyping jasmonate regulation of root growth.
Root architecture is a complex and highly plastic feature of higher plants. Direct treatments with jasmonates and alterations in jasmonate signaling have been shown to elicit a range of root phenotypes. Here, we describe a fast, noninvasive, and semiautomatic method to monitor root architectural responses to environmental stimuli using plant tissue culture and the software tool EZ-RHIZO.


Prothrombin complex concentrate versus recombinant factor VIIa for reversal of coumarin anticoagulation.
Prothrombin complex concentrate (PCC) is recommended for emergency reversal of oral coumarin anticoagulation. Recently, recombinant factor VIIa (rFVIIa) has also been investigated for this purpose, although no direct comparison of PCC and rFVIIa has been reported. This study was designed to compare the effectiveness of PCC and rFVIIa for reversal of both acute and sustained coumarin anticoagulation. In the acute model, rats received 2.5 mg.kg(-1) phenprocoumon, and reversal of anticoagulation by 4.88 mL.kg(-1) saline, 100 microg.kg(-1) rFVIIa (NovoSeven) or 50 U.kg(-1) PCC (Beriplex P/N) was assessed at 16 h. For the sustained model, a second phenprocoumon dose was administered at 24 h and anticoagulation reversal evaluated at 48 h. Study endpoints were activated partial thromboplastin time (aPTT), prothrombin time (PT) and tail tip bleeding. Acute anticoagulation raised median PT to 4.3 fold the normal level. This elevation was nearly completely reversed both by rFVIIa and PCC. aPTT increase was minor. Effects of sustained anticoagulation were more severe and pervasive, with aPTT, PT and blood loss increasing to 7.7, 51 and 30 fold the control levels, respectively. In the sustained model, rFVIIa substantially reduced and PCC fully normalized PT. In this model, PCC also diminished aPTT (p<0.01), fully normalized blood loss (p<0.01) and shortened bleeding time (p=0.008), while rFVIIa was without significant effect on these endpoints. In a sustained anticoagulation animal model designed to simulate standard long-term oral coumarin therapy in patients, PCC was more effective than rFVIIa in restoring hemostatic function.


Evaluation of the thermal coefficient of the resistance to fluorophore rotation in model membranes.
The thermal coefficient of the frictional resistance to fluorophore rotation (b), a parameter related to the change in the local viscosity with temperature, was determined for anthroyloxy-fatty acid probes in micelles and dimyristoyl lecithin (DMPC) and dioleoyl lecithin (DOPC) unilamellar and multilamellar vesicles. The value of b and the percent change in anisotropy with temperature (%dA/dT) remained constant with membrane depth and only depended on composition. These parameters were also the same when either in-plane, or in-plane and out-of-plane fluorophore motions were observed. This result indicates that the membranes expand isotropically. The magnitude of b was found to be primarily dependent on the packing of the hydrocarbon chains with higher b values relating to more closely-packed chains. b was responsive to the gel to liquid crystal phase transition of DMPC and the bilayer to hexagonal phase transition of egg-phosphatidylethanolamine. When the enthalpy values for the fluorophore transfer from one phase to another are calculated, the values are larger than those measured by calorimetry and reflect a discrepancy between the microscopic enthalpy experienced by the fluorophore due to a change in environment versus the macroscopic enthalpy of the system as a whole.


Use-dependent inhibition of the skeletal muscle ryanodine receptor by the suramin analogue NF676.
The skeletal muscle Ca2+ release channel, the ryanodine receptor, is activated by the trypanocidal drug suramin via the calmodulin-binding site. As calmodulin activates and inhibits the ryanodine receptor depending on whether Ca2+ is absent or present, suramin analogues were screened for inhibition of the ryanodine receptor. Up to 300 microM, the novel suramin analogue, 4,4'-(carbonyl-bis(imino-4,1-phenylene-(2,5-benzimidazolylene)carbonylimino))-bis-benzenesulfonic acid disodium salt (NF676) was not able to significantly inhibit the basal [3H]ryanodine binding. However, kinetic analysis of the high affinity [3H]ryanodine binding elucidates a time-dependent increment of inhibition by NF676, which is indicative for an open channel blocker. Moreover, the ryanodine receptor was much more sensitive towards inhibition by NF676 when preactivated with caffeine or the nonhydrolysable ATP analogue, adenylyl-imidodiphosphate. Nonetheless, the suramin activated ryanodine receptor was not susceptible towards high-affinity NF676 inhibition, indicating an allosteric hindrance between the binding sites of suramin and NF676. In the line of this finding, NF676 per se was not capable to elute the purified ryanodine receptor from a calmodulin-Sepharose, but it prevented the elution by suramin. Other than suramin, NF676 did not inhibit the Ca2+ ATPase of the sarcoplasmic reticulum. However, suramin-induced Ca2+ release from sarcoplasmic reticulum was completely abrogated by preincubation with NF676. Taken together, we conclude from these data that NF676 represents a novel lead compound as a potent use-dependent blocker of the skeletal muscle ryanodine receptor via an allosteric interaction with the suramin-binding site.


Evaluation of the biological effects of amelogenin on human oral keratinocytes.
Amelogenins are clinically used in periodontal regeneration as main components of root surface modifying agents, even without specifically preventing the premature colonization of the healing tissue defect by means of a physical barrier membrane. The objective of this study was to investigate the effects of human amelogenin on the proliferation, migration, and morphology of Immortalized Human Oral Keratinocytes (iHOKs). Immortalized Human Oral Keratinocytes were expanded in Keratinocyte Growth Medium-2 (KGM-2). Full-length recombinant amelogenin protein was diluted in KGM-2 in five concentrations (10 ng/ml, 100 ng/ml, 1.000 ng/ml, 5.000 ng/ml and 10.000 ng/ml). iHOKs were cultured in medium supplemented with the amelogenin dilutions. Samples without amelogenin served as control. Cell metabolism and cell proliferation together with cell migration were evaluated at day 7, 14, 21. At day 7, iHOKs treated with 10,000 ng/ml showed a significant decrease in keratinocytes´ proliferation. The metabolic activity at this timepoint was significantly lower for concentrations ≥ 1000 ng/ml. At days 14 and 21, both the addition of 5000 ng/ml and even more 10,000 ng/ml amelogenin reduced significantly the proliferation of keratinocytes. The effects on the metabolic activity for these timepoints were visible already with 100 ng/ml. Treatment of iHOKs with amelogenin of ≥ 1000 ng/ml led to inhibitory effects on cell migration already after 24 h. The full-length recombinant amelogenin has a significant biological impact on iHOKs. The increasing dose dependent inhibitory effects of amelogenin shown on iHOKs might explain the disruption of the apical migration of the junctional epithelium during regenerative healing. Amelogenin, presents time- and dose-dependent inhibitory effects on the growth of keratinocytes, which might explain the biological rationale behind its application in periodontal regeneration.


Growth inhibitory effects of 3'-nitro-3-phenylamino nor-beta-lapachone against HL-60: a redox-dependent mechanism.
In this study, the cytotoxicity, genotoxicity and early ROS generation of 2,2-dimethyl-(3H)-3-(N-3'-nitrophenylamino)naphtho[1,2-b]furan-4,5-dione (QPhNO(2)) were investigated and compared with those of its precursor, nor-beta-lapachone (nor-beta), with the main goal of proposing a mechanism of antitumor action. The results were correlated with those obtained from electrochemical experiments held in protic (acetate buffer pH 4.5) and aprotic (DMF/TBABF(4)) media in the presence and absence of oxygen and with those from dsDNA biosensors and ssDNA in solution, which provided evidence of a positive interaction with DNA in the case of QPhNO(2). QPhNO(2) caused DNA fragmentation and mitochondrial depolarization and induced apoptosis/necrosis in HL-60 cells. Pre-treatment with N-acetyl-l-cysteine partially abolished the observed effects related to the QPhNO(2) treatment, including those involving apoptosis induction, indicating a partially redox-dependent mechanism. These findings point to the potential use of the combination of pharmacology and electrochemistry in medicinal chemistry.


A New Scoring System Using Preoperative Factors and Contour Mapping for Predicting Postoperative Complications of Laparoscopic Gastrectomy.
Surgical risk assessment is becoming more important in the field of laparoscopic gastrectomy given the increasing complexity and technical demands of oncological procedures undertaken. However, no validated method for preoperative risk (PR) assessment has been reported. Two-hundred fourteen patients who underwent laparoscopic gastrectomy between October 2011 and August 2014 were reviewed. Independent risk factors were examined by multivariate analysis and a PR score model was established. Thirty-six (16.8%) patients experienced postoperative complications. Multivariate analysis revealed that age ≥75 years, American Society of Anesthesiologists score ≥2, severe pulmonary disease, Brinkman index ≥600, history of upper abdominal surgery and body mass index (BMI) were independent factors. Among these, BMI was strongly correlated with postoperative morbidity rate (r = 0.960). To permit risk prediction using BMI and the remaining 5 factors, a new PR score was established using 5 categorical variables. The new score was significantly correlated with the postoperative complication rate (r = 0.948), and its predictive value was superior to conventional risk scores such as E-PASS and POSSUM. A contour map was then created using BMI and this new PR score to more accurately stratify patients according to surgical risk prior to laparoscopic gastrectomy. A 2-dimensional risk estimation model was created to better estimate surgical risk and is a promising new tool for adequate surgical management.


PAH intermediates: Links between the atmosphere and biological systems.
China is now the world's largest emitter of polycyclic aromatic hydrocarbons (PAHs). In addition, PAHs, and their reactive intermediates, undergo trans-Pacific atmospheric transport to the Western U.S. The objectives of our research are to predict, identify and quantify novel PAH intermediates in the atmosphere and biological systems, using computational methods, as well as laboratory and field experiments. Gaussian is used to predict the thermodynamic properties of parent structure PAHs, as well as the associated nitro-, oxy-, and hydroxy-PAH intermediates. Based on these predictions, state-of-the-art analytical chemistry techniques are used to identify and quantify these potential intermediates on Asian particulate matter before and after reaction in a continuous flow photochemical reactor. These same techniques are used to identify the relative proportion of PAH intermediates in PAH source regions (such as Beijing, China) and during long-range atmospheric transport to the Western U.S. PAH personal exposure studies in China and the Confederated Tribes of the Umatilla Indian Reservation in Oregon will be used to assess the similarities and differences in the PAH intermediates in biological systems relative to the atmosphere.


Determination of specific alpha-emitting radionuclides (uranium, plutonium, thorium and polonium) in water using [Ba+Fe]-coprecipitation method.
The indicative dose (ID) is one of the parameters established in the current European directive for water intended for human consumption. To determine the ID, it is necessary to know the activity concentration of: 238U, 234U, 226Ra, 210Po, 239,240Pu and 241Am. The existing methods to determine these radionuclides involve complex radiochemical separations (ionic exchange columns, extraction chromatography, etc.), followed by measurements with a semiconductor detector, laboratory procedures that are time-consuming and costly. As a lower cost alternative that reduces measuring and preparation times, avoids the need for a self-absorption correction and the use of tracers, and above all that can be used in any laboratory, methods based on liquid-liquid extraction and selective co-precipitation were developed. These methodologies offer high separation recovery and selectivity, and the measurements are made using a gas proportional counter or a solid ZnS(Ag) scintillation counter. The separation factor ranged between 91.4% and 100.0% for all alpha-emitting radionuclides across the different methods. The activity concentration for each method was computed through linear equations that represent the relationship between the activity and selectivity of the different alpha-emitting radionuclides. This mathematical procedure simplifies the radiochemical separations and provides more accurate activity concentrations. The results of the internal and external validation studies proved that the proposed method is suitable for determining 241Am, 226Ra, uranium, plutonium, thorium and 210Po in water samples.


Sub-classification of borderline changes into diffuse or focal and its impact on long-term renal transplant outcomes.
Borderline changes (BL) with stable renal function is a controversial category in renal transplantation, given its contradictory outcomes. The aim of this study was to compare the clinical outcomes of BL in patients with stable renal function classified as focal and diffuse according to the extent of tubulitis. Patients with no history of rejection with a surveillance graft biopsy at 3 or 12 months showing BL (n = 40), acute cellular rejection (n = 20) or normal biopsies (n = 20), were included in this study. Biopsies with BL were divided into diffuse BL (BLD) and focal BL (BLF) according to the extent of tubulitis. Because of the low frequency of subclinical ACR (ACRND) (n = 12), biopsies with ACR and graft dysfunction (ACRD) (n = 8) were also included. A composite outcome that included the presence of rejection in subsequent biopsies, graft loss, patient death, decrease in GFR ≥30% or presence of de novo DSA (dnDSA) during the first year of follow-up was evaluated. The primary composite outcome occurred in five patients of each of the Normal, BLF and ACRND, eight patients with BLD and six patients with ACRD (p = 0.105). A trend towards more rejection episodes was observed in the ACRND and ACRD. Also, a shorter time to rejection in the BLD, ACRND and ACRD groups compared to BLF and Normal groups (p = 0.039) was observed. During the first year of follow-up, no patient in the ACRND group developed dnDSA, compared to 15-25% in the other groups. The median time of dnDSA development in the BLF group was 45 months, and in the BLD group was 10 months (p = 0.020). Classifying BL biopsies with stable renal function into focal and diffuse categories, is a simple and feasible strategy that helps to differentiate between BLD with a phenotype that shows a trend towards worse outcomes, and BLF that behaves more similar to normal biopsies.


Method validation and determination of enantiomers and conformers in tofisopam drug substances and drug products by chiral high-performance liquid chromatography and kinetic and thermodynamic study of the interconversion of the conformers.
1-(3,4-Dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine (tofisopam) contains one chiral center, so two enantiomeric forms exist. The ring system of tofisopam possesses two sterically stable boat structures, leading to two distinct conformers for each enantiomer. A method was developed for the separation of these enantiomers and conformers in the drug substances and drug products. Separation was achieved with a separation factor of at least 3.9 for any adjacent peaks. Validation of the method challenged linearity, limit of detection, limit of quantification, specificity, accuracy, repeatability, intermediate precision, robustness, and stability of standard and sample solutions, and all validation results met the acceptance criteria. A study of accuracy at 80%, 100%, and 120% levels gave recoveries of 100 +/- 1%. The RSD of six sample injections for repeatability was less than 0.5%. The detection limit of tofisopam enantiomer was as low as 0.12 microg/mL. The kinetics and thermodynamics of the interconversion of tofisopam conformers were also investigated, and the kinetic and equilibrium constants of the interconversion process were determined at 15 degrees C, 25 degrees C, and 35 degrees C.


The influence of patent branches on in situ vein graft haemodynamics.
The effect of patent graft branches on intra-operative graft flow and pressure has been studied in 50 patients undergoing in situ vein femoro-distal arterial bypass. In 35 grafts in which patent branches in the calf and thigh were preserved as arteriovenous fistulae, release of temporary branch occlusion increased mean proximal graft flow by 178.6% in 32, and reduced distal graft flow by 49.7% in 30. Seventeen limbs had thigh fistulae only: release of temporary fistula occlusion produced a fall in distal graft flow in only three. We identified three types of fistula: (a) cutaneous branches usually found in the thigh, which do not affect graft flow; (b) perforator branches which increase graft inflow but have no effect on distal graft flow: (c) perforator branches which increase graft inflow and decrease graft outflow, and are most frequently found in the calf. Discrimination between these haemodynamically differing branches at operation proved difficult. Since patent branches never improve distal graft flow and may reduce it, we recommend that all fistulae are ligated at operation.


Update on Clinical Ex Vivo Hematopoietic Stem Cell Gene Therapy for Inherited Monogenic Diseases.
Gene transfer into autologous hematopoietic stem progenitor cells (HSPCs) has the potential to cure monogenic inherited disorders caused by an altered development and/or function of the blood system, such as immune deficiencies and red blood cell and platelet disorders. Gene-corrected HSPCs and their progeny can also be exploited as cell vehicles to deliver molecules into the circulation and tissues, including the central nervous system. In this review, we focus on the progress of clinical development of medicinal products based on HSPCs engineered and modified by integrating viral vectors for the treatment of monogenic blood disorders and metabolic diseases. Two products have reached the stage of market approval in the EU, and more are foreseen to be approved in the near future. Despite these achievements, several challenges remain for HSPC gene therapy (HSPC-GT) precluding a wider application of this type of gene therapy to a wider set of diseases while gene-editing approaches are entering the clinical arena.


Use of complementary and integrative health in Finland: a cross-sectional survey.
Population based studies have shown large differences in the estimated prevalence of complementary and integrative health (CIH) usage between studies. This is in part due to there being no golden standard definition for CIH. In Finland, an updated and internationally comparable study on the prevalence of CIH usage is needed. In the present study, a modified Finnish version of the International Questionnaire to Measure Use of Complementary and Alternative Medicine (I-CAM-QFI) was utilised to examine prevalence of use of different CIH modalities and their experienced helpfulness in the general Finnish population. Respondents aged 16 and above were invited to take part in this descriptive cross-sectional study through an online panel in December 2022. The usage of CIH and the experienced helpfulness were calculated with SPSS (v28) as the proportion of users per each modality. The data were weighted based on gender, age and place of residence. A total of 3244 respondents completed the survey. CIH was used by 51.1% (95%CI: 49.4-52.8) of the respondents in the 12 months prior to the survey. Self-help practices were the most used category of CIH (28.8%; 95%CI: 27.3-30.4). The prevalence of usage of CIH natural remedies excluding vitamins and minerals was 27.0% (95%CI: 25.5-28.6). CIH providers were visited by 20.4% of the respondents (95%CI: 19.0-21.8). Getting help for a long-term illness or improvement of well-being were often mentioned as the most important reason for the use of different CIH modalities. CIH was generally used more by women compared to men. The large majority found the modalities they used helpful. The results increase current understanding on CIH usage in Finland. As the majority of users experience CIH as helpful, there is a need to study CIH in the context of public health policies. The estimates of CIH usage are highly dependent on what is considered as CIH, and this should be paid attention to in future studies.


Opinion of gastroenterologists towards quality assurance in endoscopy.
Quality assurance has become an important issue. Many societies are adopting quality assurance programs in order to monitor and improve quality of care. To assess the opinion of gastroenterologists towards quality assurance on the endoscopy department. A survey was sent to all gastroenterologists (n=319) in the Netherlands. It assessed their opinion on a quality assurance program for endoscopy units, including its design, logistics, and content. 200 gastroenterologists (63%) completed the questionnaire. 95% had a positive opinion towards quality assurance and 67% supposed an increase in quality. 28% assumed a negative impact on the time available for patient contact by introducing a quality assurance program and 35% that the capacity would decrease. A negative attitude towards disclosure of results to insurance companies (23%) and media (53%) was reported. Female gastroenterologists were less positive to share the results with other stakeholders (p<0.05). Most important quality measurements were assessment of complications (97%), standardised reporting (96%), and adequate patient information (95%). Gastroenterologists have a positive attitude towards quality assurance. However, concerns do exist about time investment and disclosure of results to others. Information provision and procedure characteristics were considered the most important aspects of quality assurance.


Radial bias alters high-level motion perception.
The visual system involves various orientation and visual field anisotropies, one of which is a preference for radial orientations and motion directions. By radial, we mean those directions coursing symmetrically outward from the fovea into the periphery. This bias stems from anatomical and physiological substrates in the early visual system. We recently reported that this low-level visual anisotropy can alter perceived object orientation. Here, we report that radial bias can also alter another higher-level system, the perceived direction of apparent motion. We presented a bistable apparent motion quartet in the center of the screen while participants fixated on various locations around the quartet. Participants (N = 22) were strongly biased to see the motion direction that was radial with respect to their fixation, controlling for any biases with center fixation. This was observed using a vertical-horizontal quartet as well as an oblique quartet (45° rotated quartet). The latter allowed us to rule out the contribution of the hemisphere effect where motion across the midline is perceived less often. These results extend our earlier findings on perceived object orientation, showing that low-level structural aspects of the visual system alter yet another higher-level visual process, that of apparent motion perception.


Determination of terbacil in soil by gas-liquid chromatography with 63Ni electron capture detection.
A method is described for the determination of terbacil residue in soil. The herbicide residue is extracted with 1.5% NaOH, partitioned into an organic phase and subsequently cleaned up by passing through a Florisil column. Extract is analyzed by gas-liquid chromatography using a 63Ni electron capture detector. The procedure has a sensitivity of about 0.01 ppm, based on a 20 g sample. The method was used for the analysis of terbacil residues in the field treated soil samples.


Attitudes of adolescents and parents of adolescents concerning condom advertisements on television.
The major television networks have considered airing condom advertisements. A Louis-Harris poll entitled "Attitudes About Television, Sex and Contraceptive Advertising" conducted in early 1987 concluded that at least 60% of adult Americans were in favor of such advertisements. To better understand the attitudes of adolescents and parents of adolescents in a private practice setting toward contraceptive advertisement on television, the present study was performed. Between March and June 1987, 108 parents of adolescents, 100 adolescent females, and 90 adolescent males filled out a questionnaire asking their opinions of such advertisements. Eighty-three percent of the parents, 89% of adolescent females, and 92% of adolescent males approved of such advertisements. The data suggest that a majority of adults and adolescents approve of condom advertisements on television. The use of the media to take advantage of the present opportunity to educate and promote birth control and disease prevention to our adolescent population may be beneficial.


Dose-dependent effects of peroxisome proliferator-activated receptors β/δ agonist on systemic inflammation after haemorrhagic shock.
PPARβ/δ agonists are known to modulate the systemic inflammatory response after sepsis. In this study, inflammation modulation effects of PPARβ/δ are investigated using the selective PPARβ/δ agonist (GW0742) in a model of haemorrhagic shock (HS)-induced sterile systemic inflammation. Blood pressure-controlled (35±5mmHg) HS was performed in C57/BL6 mice for 90min. Low-dose GW0742 (0.03mg/kg/BW) and high-dose GW0742 (0.3mg/kg/BW) were then administered at the beginning of resuscitation. Mice were sacrificed 6h after induction of HS. Plasma levels of IL-6, IL-1β, IL-10, TNFα, KC, MCP-1, and GM-CSF were determined by ELISA. Myeloperoxidase (MPO) activity in pulmonary and liver tissues was analysed with standardised MPO kits. In mice treated with high-dose GW0742, plasma levels of IL-6, IL-1β, and MCP-1 were significantly increased compared to the control group mice. When compared to mice treated with low-dose GW0742 plasma levels of IL-6, IL-1β, GM-CSF, KC, and MCP-1 were significantly elevated in high-dose-treated mice. Low-dose GW0742 treatment was associated with a non-significant downtrend of inflammatory factors in mice with HS. No significant changes of MPO activity in lung and liver were observed between the control group and the GW0742 treatment groups. This study identified dose-dependent effects of GW0742 on systemic inflammation after HS. While high-dose GW0742 substantially enhanced the systemic inflammatory response, low-dose GW0742 led to a downtrend of pro-inflammation cytokine expression. The exact mechanisms are yet unknown and need to be assessed in further studies.


Obstetric impact of anaemia in pregnant women in United Arab Emirates.
Our objective was to determine the effect of anaemia during pregnancy on maternal and perinatal outcome. A retrospective case-control study was conduced on 100 anaemic (haemoglobin level < 11g/dl) and 100 non-anaemic, pregnant women with singleton pregnancies who received antenatal care and delivered vaginally in our hospital. The maternal characteristics of both groups were not different. The causes of anaemia were iron deficiency (91%), beta-thalassaemia trait (8%) and folate deficiency (1%). There was no significant difference in the mean gestational age at delivery (38.9 +/- 2.0 vs 39.6 +/- 1.6 weeks), 5-minute Apgar score (7.8 +/- 0.8 vs 7.9 +/- 0.1) and birth weight (3,150 +/- 530 vs 3,230 +/- 430 g) between both groups. Post-partum haemorrhage (3%), pre-term delivery (4%) and fetal growth restriction (6%) were more frequent in anaemic women but the difference was not significant. Anaemia, therefore, had no significant obstetric adverse effects in our pregnant hospital-population.


Erratum to The effect of mesenchymal stem cells improves the healing of burn wounds: A phase 1 dose-escalation clinical trial.
[This corrects the article DOI: 10.1177/20595131211070783.].


Function of shrimp STAT during WSSV infection.
JAK/STAT signaling pathway plays key roles in the antiviral immunity of mammals, fish and insect. However, limited knowledge is known about the function of JAK/STAT signaling pathway in the antiviral immunity of shrimp although virus disease has caused severe mortality in shrimp aquaculture. In order to understand the function of JAK/STAT signaling pathway in the antiviral immunity of shrimp, dsRNA interfering technique was used to silence the expression of STAT gene in Litopenaeus vannamei, and the mortality of shrimp was detected after WSSV infection. Furthermore, the expressions of some potential target genes regulated by STAT or genes related to RNA interfering pathway were detected in STAT silenced shrimp during WSSV infection. The WSSV copy number in STAT silenced shrimp was 10(2)-10(3) copies/ng DNA which was much lower than that in the control. The mortality in STAT silenced shrimp caused by WSSV infection decreased very significantly compared to their controls. The function of STAT was verified in vitro cultured cells of hematopoietic tissue of crayfish Cherax quadricarinatus by adding specific inhibitor of STAT3(S3I-201), and the cultured cells treated with S3I-201 showed much less WSSV copy number than their controls, which further suggested that STAT might be helpful for the replication of WSSV. Expression analysis on the potential STAT target genes and genes in RNA interfering pathway provide important information for understanding the functional mechanism of STAT in antiviral immunity of shrimp.


The effect of prostaglandins of cultured lapine articular chondrocytes.
The effect of B protaglandins (PG) on growth and sulfate incorportation by monolayer and spinner-cultured rabbit articular chondrocytes has been measured. PGA1, PGB1, PGE1 and PGE2 reduced synthesis of sulfated glycosaminoglycans (GAG) but the PGF series did not. PGA1 was the most potent, being effective at a concentration of 2.5 microng/ml [6.8 micronM] while the others required 25 microng/ml. These compounds had no effect on degradation of GAG. All 8 PGs augmented growth slightly but significantly at 2.5 microng/ml. At the higher concentration, PGA1 was highly cytotoxic, and PGB1 as well as PGE2 reduced cell growth. The cytotoxicity of PGA1 was also observed in two additional types of cultured connective tissue cells, but the inhibition of sulfated-GAG synthesis by PGA1 and PGB1 was confined to the chondrocytes. The response of cultured chondrocytes to exogenous PGs, albeit at apparently unphysiologically high concentrations, together with other evidence, suggests that these compounds may conceivably play a direct role in cartilage metabolism in vivo.


The effect of cervical rotation on blood flow in the contralateral vertebral artery.
Twenty asymptomatic volunteers (mean age 33 years, range 26 - 54 years) underwent investigation using duplex Doppler ultrasound with real-time imaging and colour flow enhancement. With the subjects seated, peak velocity at C1-2 and volume flow rate at C5-6 were measured in the artery contralateral to the direction of rotation, in the four positions of neutral, 45 degrees and end range rotation, plus a subsequent neutral position. No change in peak velocity at C1-2 between the initial neutral measurement and the measurements at 45 degrees and end range rotation was found (P>0.05). Peak velocity was less in both vertebral arteries on return to the neutral position as compared with end range rotation, however the difference was significant for the left vertebral artery only (P=0.005). This lends support for the rest period, which is taken between cervical movement tests when conducting pre-manipulative testing, to allow for any latent effect on blood flow of the tests themselves. There was no change in volume flow rate between any of the test positions (P=0.349). There was no indication of a cumulative effect of the test procedure (P>0.05).


Recent advances in polysaccharides stabilized emulsions for encapsulation and delivery of bioactive food ingredients: A review.
Many bioactive food ingredients were encapsulated in different forms to improve their stability and bioavailability. Emulsions have showed excellent properties in encapsulation, controlled release, and targeted delivery of bioactives. Polysaccharides are widely available and have different structures with different advantages including non-toxic, easily digested, biocompatible and can keep stable over a wide range of pH and temperatures. In this review, the most common polysaccharides and polysaccharide based complexes as emulsifiers to stabilize emulsions in recent ten years are described. The close relationships between the types and structures of polysaccharides and their emulsifying capacities are discussed. In addition, the absorption and bioavailability of bioactive food components loaded in polysaccharide stabilized emulsions are summarized. The main goal of the review is to emphasize the important roles of polysaccharides in stabilizing emulsions. Moreover, speculations regarded to some issues for the further exploration and possible onward developments of polysaccharides stabilized emulsions are also discussed.


Role of serum renin and aldosterone in animal adaptation to high-altitude conditions.
Adaptation to high-altitude conditions in rats with experimental renal failure is associated with shifts in the rennin-angiotensin-aldosterone system, which manifested in different serum levels of renin and aldosterone in response to water and salt loads depending on the stage of the compensation processes.


Look before you leap: the importance of ECG in management of out-of-hospital cardiac arrest.
Graphical abstractReconstructed pre-hospital ECG, 25 mm/s 10 mm/mV.


Willing to Work But Not to Wait: Individuals with Greater Alcohol Use Disorder Show Increased Delay Discounting Across Commodities and Less Effort Discounting for Alcohol.
Delay discounting refers to the devaluation of a reward given increasing delays to delivery. Similarly, effort discounting refers to the devaluation of a reward given increasing effort required to obtain it. Individuals with substance use disorder show higher rates of delay discounting, exacerbating short-term positive reinforcement at the expense of long-term consequences. This study explores how effort discounting compares to delay discounting behavior among alcohol users as well as how these preferences change between monetary and alcohol rewards. A total of 100 participants completed an online survey through Amazon Mechanical Turk. Participant alcohol use was evaluated using DSM-5 and the Alcohol Use Disorders Identification Test criteria. All participants completed 4 randomized discounting tasks involving delay or effort discounting, in which the reward was money or alcohol. A follow-up experiment (n = 423) added the alcohol purchase task to assess alcohol valuation. Individuals with greater alcohol use disorder (AUD) severity discounted future money and alcohol significantly more than those with less AUD. However, individuals meeting more DSM-5 criteria were only willing to perform more effort for alcohol. The follow-up experiment replicated these findings and demonstrated that individuals with greater AUD also showed an increased valuation of alcohol and alcohol value-mediated effort discounting. These results suggest that individuals with greater AUD were less willing to wait for money or alcohol. While all participants were willing to work for money regardless of AUD severity, individuals with greater AUD showed increased valuation of alcohol drinks and were willing to exert more effort to obtain alcohol. Together, these results paint a picture of individuals with increased AUD as both more impulsive and willing to work to obtain alcohol, contributing to our understanding of decision making among individuals who abuse substances.


Isolated rat kidney perfused with dextran and bovine serum albumin: a stable model for investigating renal drug handling.
The rat isolated perfused kidney (IPK) preparation is a very useful model for pharmacokinetic and pharmacologic studies. Bovine serum albumin (BSA) is the oncotic agent used most commonly in IPK models, but the protein is expensive and varies significantly in quality. The present study evaluated the use of dextran to replace a large proportion of BSA as the oncotic agent, to establish a more reliable and economic IPK model for pharmacokinetic studies. The right kidneys of male Sprague-Dawley rats were isolated and perfused in recirculating mode with Krebs-Henseleit pH 7.4 buffer containing amino acids, glucose and 65 g/l BSA (BSA group, n=11) or 6.5 g/l BSA plus 36 g/l dextran (dextran/BSA group, n=6). (14)C-Inulin was added to the perfusate to permit estimation of glomerular filtration rate (GFR). An antiviral guanosine analogue, AM188, was administered to the IPK perfusate to investigate its renal disposition. During the 130-min experimental period, urine was collected in 10-min intervals and perfusate was collected at the midpoint of these intervals. The kidney functional parameters were generally better and more stable in the dextran/BSA IPKs when compared to the BSA group. At a similar perfusate flow rate, the IPKs in the dextran/BSA group exhibited lower renal artery perfusion pressure, a higher GFR, and more extensive tubular reabsorption of water, glucose, and sodium. These functional parameters were acceptable and stable throughout the whole experimental period in the dextran/BSA group. The renal clearance of AM188 was higher in the dextran/BSA group compared with that in the BSA group. Using a large proportion of dextran and a small proportion of BSA as oncotic agent in perfusate provides an improved IPK preparation. This offers a reliable and economic rat IPK model for pharmacokinetic studies.


Found in the crystal: phospholipid ligands for nuclear orphan receptors.
Phospholipids are important components of cellular membranes, contributing to their structural integrity and regulatory functions. Because of these functional properties, phospholipids are often the subject of cell biology and signal transduction studies. Proteins that bind and transport phospholipids between membranes have been described and investigated but few scientists would have entertained the thought of phospholipids acting as ligands for transcription factors. However, the surprising results of recent crystallization studies revealed phospholipid ligands in the binding pockets of members of the nuclear orphan receptor family 5. Their ability to alter transcriptional activity by acting as bona fide ligands has been inspirational not only for the transcription factor community, but also for phospholipid researchers.


Epiphyseal lymphoid infiltrates of the knee in adolescents.
We present three adolescents with focal lesions of the distal femur that were shown to be benign aggregates of small lymphocytes and plasma cells of unknown origin. The patients were within the age of 12 and 14 years. All lesions presented with similar MRI findings and provided the same histopathological findings in the biopsy. Although all lesions increased in size, only one patient remained symptomatic and underwent subsequent tumor resection. To our best knowledge, tumor or pseudotumoral epiphyseal lymphoid infiltrates as seen in these three patients have not previously been described. We recommend a biopsy to rule out a malignant tumor or an infection. Observation, without further invasive testing in asymptomatic patients, is recommended until the resolution of the lesions. However, if a lesion becomes symptomatic, surgical resection should be considered.


Instability of ovine babesiosis in an endemic area in Turkey.
This study was designed to determine the endemic status of Babesia ovis in sheep in Turkey. A total of 2000 sheep, from different age groups (i.e. 0-3, 4-6, 6-9, 10-12, and >12 months), were selected randomly from 132 sheep flocks. The presence of specific antibodies against B. ovis was diagnosed by indirect fluorescent antibody test (IFAT). A total of 843 (42.15%) serum samples were determined to be positive. The seropositivity rates in the age groups stated above were 31.90, 31.64, 47.69, 40.22, and 52.99%, respectively. The endemic status of the disease was determined by calculating the inoculation rate (h) of each group. The h value for each group was determined to be lower than 0.005, which revealed that the endemic status of B. ovis was instable. This report may indicate the necessity of vaccination.


Chronaxie and accommodation index in the diagnosis of muscle denervation.
To determine the sensitivity of the combined measurement of chronaxie and the accommodation index in the qualitative diagnosis of muscle denervation with needle electromyography and to compare quantitative diagnoses. Ninety-three neurogenic muscles diagnosed by needle electromyography were consecutively included for measurement of chronaxie and the accommodation index in this prospective study. The sensitivity of qualitative diagnosis was assessed for all muscles, separately for the acute and subacute-chronic denervation phase and for the complete and partial denervation. The combined measurement of chronaxie and the accommodation index showed a 90% sensitivity to needle electromyography for qualitative diagnosis of muscle denervation for all muscles. A 100% sensitivity was found for the acute denervation phase and for complete denervation. The subacute-chronic denervation phase revealed a 86% sensitivity, and partial denervation had a 88% sensitivity. The kappa coefficients did not show satisfactory agreement in quantitative diagnosis, and Bowker's test revealed a statistically significant underestimation of muscle denervation for measurement of chronaxie. The combined measurement of chronaxie and the accommodation index can be recommended for the screening of neurogenic lesions in the acute denervation phase.


High concentrations of pamidronate in bone weaken the mechanical properties of intact femora in a rat model.
Bisphosphonates have been used to treat osteoporosis for more than ten years. However, complications associated with long-term administration of bisphosphonates, such as nonunion after pelvic insufficiency fracture or osteonecrosis of the jaw, have been recently reported in the literature. We investigated the relationships among the mechanical properties of the intact rat femur as well as healing fracture calluses and the intraosseous concentration of pamidronate (ICP), after long-term administration of pamidronate in a rat osteoporosis model. We performed bilateral ovariectomy in 25 3-month-old female Sprague-Dawley rats. Beginning three months after ovariectomy, disodium pamidronate (0.5 mg/kg) was injected every month. After the six-month administration period, the left femoral shaft was fractured using the closed fracture technique. Five weeks after fracture, 23 rats were euthanized and both femora were removed. We checked the mechanical properties of the intact (right) and fractured (left) femora using a three-point bending technique. Intraosseous concentration of pamidronate was checked by high-performance liquid chromatography. The mean ICP was 61.8+/-15.7 ng/mg of bone. High ICP decreased the ultimate load to failure, stiffness, and ultimate stress of the intact femora (p=0.015, 0.027, 0.039, respectively). There was a tendency to decrease the ultimate load to failure in the healing callus when the ICP increased (p= 0.183). High ICP decreased the bone mineral density of the femoral head (p=0.005). High concentrations of pamidronate in intact bone decreased the bone mineral density and weakened the mechanical strength of the rat femora. The mechanical strength of the early healing callus was not correlated with concentration of pamidronate in the bone.