Extramedullary plasmacytoma of the salivary gland in two Syrian hamsters (Mesocricetus auratus).
Two Syrian hamsters developed marked swelling of the ventral neck. Histologic examination of both masses revealed that the submaxillary salivary glands were effaced by large numbers of neoplastic plasma cells. In one hamster, neoplastic cells had infiltrated the adjacent lymph node. The neoplastic cells expressed CD79a antigen and were negative for CD3, lambda, and kappa light chains. Ultrastructural features of neoplastic cells in the salivary gland of one hamster included abundant cytoplasmic rough endoplasmic reticulum profiles, and peripherally displaced nuclei that contained marginated heterochromatin, consistent with plasma cells. Salivary gland plasmacytomas are extremely rare in humans and have not previously been reported in nonhuman species. The occurrence of such neoplasms in two hamsters suggests that this species may be predisposed to developing tumors of this type.


LncRNA HAGLROS accelerates the progression of lung carcinoma via sponging microRNA-152.
The aim of this study was to analyze the expression profiling of long non-coding RNA (lncRNA) HAGLROS and microRNA-152 in lung carcinoma (LCa), and to explore their regulatory effects on the malignant progression of LCa. The expression of HAGLROS in 44 paired LCa tissues and matched adjacent tissues was determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The correlation between HAGLROS expression and clinical indexes of LCa patients was analyzed. Furthermore, HAGLROS expression in LCa cell lines was detected as well. The HAGLROS over-expression and knockdown models were established in A549 and SPC-A1 cells by transfection of pcDNA-HAGLROS and anti-HAGLROS, respectively. The biological influences of HAGLROS on LCa cells were evaluated through a series of functional experiments. Furthermore, the potential relationship between HAGLROS and microRNA-152 was analyzed. HAGLROS was highly expressed in LCa tissues compared with adjacent normal tissues. LCa patients with a higher expression of HAGLROS presented significantly worse tumor stage, a higher rate of lymphatic metastasis, and a lower survival. The knockdown of HAGLROS significantly attenuated the proliferative and migratory abilities of LCa cells. Meanwhile, HAGLROS over-expression obtained the opposite results. MicroRNA-152 was negatively correlated with HAGLROS in LCa. Rescue experiments showed that the knockdown of microRNA-152 reversed the regulatory effects of HAGLROS on proliferative and migratory abilities of LCa cells. HAGLROS expression is correlated with tumor stage and lymphatic metastasis of LCa patients. Furthermore, HAGLROS accelerates proliferation and migration of LCa cells by regulating microRNA-152.


Preclinical Evaluation of Ureidosulfamate Carbonic Anhydrase IX/XII Inhibitors in the Treatment of Cancers.
Carbonic anhydrases (CAs) are a family of enzymes involved in the pH regulation of metabolically active cells/tissues. Upregulation of the CAIX/XII isoforms is associated with hypoxic tumours and clinically linked with malignant progression, treatment resistance and poor prognosis. The elucidation of the crystal structure of the catalytic domains of CAIX/XII provided the basis for the generation of CAIX/XII selective inhibitors based on the sulfonamide, sulfamate and coumarins chemical structures. Ureido-substituted benzenesulfonamide CAIX/XII inhibitors have shown significant potential, with U-104 (SLC-0111) currently present in clinical Phase I/II. Ureido-substituted sulfamate CAIX/XII inhibitors have received less attention despite encouraging preclinical test results. In triple-negative breast cancer (TNBC), ureidosulfamates revealed a significant antitumour (FC9-398A) and antimetastatic potential (S4). In small cell lung cancer (SCLC), a cancer cell type very sensitive to a dysregulation in CAIX signaling, S4 treatment was particularly effective when combined with cisplatin with no evidence of acquired cisplatin-resistance. These successful anticancer strategies should provide a solid basis for future studies on ureido-substituted sulfamates.


Redox properties of the disulfide bond of human Cu,Zn superoxide dismutase and the effects of human glutaredoxin 1.
The intramolecular disulfide bond in hSOD1 [human SOD1 (Cu,Zn superoxide dismutase 1)] plays a key role in maintaining the protein's stability and quaternary structure. In mutant forms of SOD1 that cause familial ALS (amyotrophic lateral sclerosis), this disulfide bond is more susceptible to chemical reduction, which may lead to destabilization of the dimer and aggregation. During hSOD1 maturation, disulfide formation is catalysed by CCS1 (copper chaperone for SOD1). Previous studies in yeast demonstrate that the yeast GSH/Grx (glutaredoxin) redox system promotes reduction of the hSOD1 disulfide in the absence of CCS1. In the present study, we probe further the interaction between hSOD1, GSH and Grxs to provide mechanistic insight into the redox kinetics and thermodynamics of the hSOD1 disulfide. We demonstrate that hGrx1 (human Grx1) uses a monothiol mechanism to reduce the hSOD1 disulfide, and the GSH/hGrx1 system reduces ALS mutant SOD1 at a faster rate than WT (wild-type) hSOD1. However, redox potential measurements demonstrate that the thermodynamic stability of the disulfide is not consistently lower in ALS mutants compared with WT hSOD1. Furthermore, the presence of metal cofactors does not influence the disulfide redox potential. Overall, these studies suggest that differences in the GSH/hGrx1 reaction rate with WT compared with ALS mutant hSOD1 and not the inherent thermodynamic stability of the hSOD1 disulfide bond may contribute to the greater pathogenicity of ALS mutant hSOD1.


Identification of swine H1N2/pandemic H1N1 reassortant influenza virus in pigs, United States.
In October and November 2010, novel H1N2 reassortant influenza viruses were identified from pigs showing mild respiratory signs that included cough and depression. Sequence and phylogenetic analysis showed that the novel H1N2 reassortants possesses HA and NA genes derived from recent H1N2 swine isolates similar to those isolated from Midwest. Compared to the majority of reported reassortants, both viruses preserved human-like host restrictive and putative antigenic sites in their HA and NA genes. The four internal genes, PB2, PB1, PA, and NS were similar to the contemporary swine triple reassortant viruses' internal genes (TRIG). Interestingly, NP and M genes of the novel reassortants were derived from the 2009 pandemic H1N1. The NP and M proteins of the two isolates demonstrated one (E16G) and four (G34A, D53E, I109T, and V313I) amino acid changes in the M2 and NP proteins, respectively. Similar amino acid changes were also noticed upon incorporation of the 2009 pandemic H1N1 NP in other reassortant viruses reported in the U.S. Thus the role of those amino acids in relation to host adaptation need to be further investigated. The reassortments of pandemic H1N1 with swine influenza viruses and the potential of interspecies transmission of these reassortants from swine to other species including human indicate the importance of systematic surveillance of swine population to determine the origin, the prevalence of similar reassortants in the U.S. and their impact on both swine production and public health.


Molecular inhibition mechanisms of cell migration and invasion by coix polysaccharides in A549 NSCLC cells via targeting S100A4.
S100 calcium binding protein A4 (S100A4) promotes extracellular signal transduction, intercellular adhesion, motility and mobility. Different extracts from Coix lachryma-jobi have been used for the treatment of various types of cancer in Asia. In our previous study, the polysaccharide fraction extact, CP1, induced cell apoptosis of non‑small cell lung cancer cells. In the current study, CP1 inhibited migration and invasion of A549 cells in a scratch wound healing assay and matrigel invasion assay, respectively. Furthermore, reverse transcription‑polymerase chain reaction and western blotting demonstrated that CP1 downregulated the gene and protein expression levels of S100A4. In silico docking analysis demonstrated that polysaccharides may not interfere with dimerization, whereas, the affinity of polysaccharides for an S100A4‑NMIIA pocket was margnially greater than at the dimerization sites. Thus, CP1 inhibited A549 cell migration and invasion potentially via downregulation of S100A4, and may also interact with the binding site of S100A4‑NMIIA, which indicated that CP1 has potential as an alternative cancer chemotherapeutic by targeting S100A4.


Pharmacotherapy of Bulimia Nervosa.
This review article summarizes the progress that has been made over the past 14 years in the drug treatment of bulimia nervosa, an eating disorder characterized by recurrent binge eating and purging that has continued for 3 months with a regularity of at least twice a week. This recently described eating disorder has been the subject of intensive research scrutiny with regard to both pharmacotherapy and psychotherapy, and results indicate a role for both types of treatment. The linkage of bulimia to major depressive illness is reflected in the overlap that is seen in neurotransmitter dysregulations--including similarities in serotonin disturbances--as well as in shared symptomatology, longitudinal risk and comorbidity, and prominent history of affective illness in the families of bulimic probands. The observed relationship between these disorders acted as a catalyst for the early pharmacotherapy studies documenting the use of antidepressant medications in the treatment of bulimia. Among the drugs documented to reduce bulimia are tricyclic antidepressants, monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors. The sequencing and integration of pharmacotherapy and psychotherapy require further study, but current research has yielded a variety of therapeutic options for the clinician to reduce both the disturbed eating behavior and the dysfunctional eating attitudes of patients with bulimia nervosa.


Hydrogen gas sensing using aluminum doped ZnO metasurfaces.
Hydrogen (H2) sensing is crucial in a wide variety of areas, such as industrial, environmental, energy and biomedical applications. However, engineering a practical, reliable, fast, sensitive and cost-effective hydrogen sensor is a persistent challenge. Here we demonstrate hydrogen sensing using aluminum-doped zinc oxide (AZO) metasurfaces based on optical read-out. The proposed sensing system consists of highly ordered AZO nanotubes (hollow pillars) standing on a SiO2 layer deposited on a Si wafer. Upon exposure to hydrogen gas, the AZO nanotube system shows a wavelength shift in the minimum reflectance by ∼13 nm within 10 minutes for a hydrogen concentration of 4%. These AZO nanotubes can also sense the presence of a low concentration (0.7%) of hydrogen gas within 10 minutes. Their rapid response time even for a low concentration, the possibility of large sensing area fabrication with good precision, and high sensitivity at room temperature make these highly ordered nanotube structures a promising miniaturized H2 gas sensor.


[Epidemiological studies on the symptoms due to strawberry culture in the vinyl-house. 2. An analysis of clinical examinations with emphasis on allergic response (author's transl)].
Clinical mass surveys were carried out on the residents to whom questionnaires on symptoms with reference to strawberry culture in the vinyl-house had been delivered. Two hundred and eleven persons attended at the first survey in September, 1976 (off the season of strawberry culture) and the 58 attended at the second survey in March, 1977 (within the season). The participants of the first survey consisted of three groups, i.e. farmers with and without strawberry culture and people without farming. The participants of the second survey consisted only of farmers with strawberry culture. Results are summarized as follows. 1) There were no difference of incidence of various clinical findings detected by an ophthalmologist and otolaryngologists among the three groups. 2) There were also no difference of incidence of abnormal findings in urine tests, liver functions, respiratory test, blood examinations and blood pressure test among the three groups. However, the comparison of persons in charge of strawberry culture and attended at both tof the first and the second surveys, such changes were detected as increases in the value of GOT (within normal limits), of stab neutrophiles, lymphocytes and of monocytes within the season of strawberry culture. 3) Increases of positive rates in skintest by extracts of house dust and Candida sp. were observed in the farmers with and without strawberry culture. Positive rates of skintest by strawberry pollen and honey bee extracts among the farmers with strawberry culture were markedly higher than the allergic patients in Dokkyo Hospital having no relation to this culture. This positive rate was markedly elevated among the persons who complained the symptom of rhinorrea within the season.


Retroperitoneal laparoscopic nephrectomy and other procedures in the upper retroperitoneum using a balloon dissection technique.
This article describes a hydraulic balloon dissection technique. The retroperitoneum is developed via a small lumbodorsal incision between the edges of the musculus latissimus dorsi and musculus obliquus externus and then after visualization of its correct position the balloon catheter is filled with 500-1,200 ml of warm normal saline (according to patient size). The device consists of the finger of a surgeon's glove ligated around the end of a rigid bladder catheter. The balloon insufflation is maintained for 5 min to guarantee adequate hemostasis. Recently, we have replaced the balloon catheter by a balloon trocar sheath allowing direct endoscopic control of the hydraulic dissection. After retrieval of the balloon the CO2 insufflator is connected to the first trocar. All secondary trocars are placed under endoscopic control. The hydraulic dissection techniques also enable optimal creation of an effective pneumoperitoneum in children. Until now, we have used this technique for twelve procedures in the upper retroperitoneum including five nephrectomies, two nephroureterectomies, one tumor nephrectomy, one nephropexy, one renal cyst marsupialization and two renal biopsies. Up to now we have encountered no major complications. Three of the nephrectomized patients had undergone multiple previous abdominal surgical interventions. The retroperitoneal approach allows the surgeon to apply similar dissecting techniques as used in respective open procedures. It has become the routine approach for laparoscopic procedures in benign renal disease. This procedure can be performed even in cases with previous abdominal surgery.


Knowledge of prostate cancer among African American men: A systematic review.
Recent studies indicate that many African American men may not be making informed decisions about prostate cancer early detection. This is partly due to patients having limited knowledge about early detection of the disease. The present review is based upon bibliographic searches in PubMed and CINAHL and relevant search terms. Articles (n = 235) published in English from 1993 through July 31, 2020 were identified using the following MESH search terms and Boolean algebra commands: prostate cancer and knowledge and African Americans. Forty-two articles were eligible for inclusion. The results of this literature review indicate that many African American men have inadequate knowledge of prostate cancer and prostate cancer early detection. Studies indicate that knowledge of prostate cancer is particularly low among older, less-educated, lower-income, and unmarried men, along with those who lack a regular physician or health insurance. Many African American men are unaware that they are at increased risk of prostate cancer because of their age or race. Culturally appropriate educational efforts are needed to inform African- American men about the pros and cons of prostate cancer early detection and about risk factors for the disease so that they can make an informed decision about whether prostate cancer early detection is right for them. Of particular concern is the prostate cancer knowledge of low-income and less-educated men, along with those who lack health care insurance or a regular provider.


Labor pain at the time of epidural analgesia and mode of delivery in nulliparous women presenting for an induction of labor.
To assess whether the degree of labor pain at the initiation of neuraxial analgesia is associated with mode of delivery. Nulliparous women who presented to the labor department for an induction of labor, who were between 37 and 41 weeks of gestation, and who requested labor epidural analgesia with a pain score of 0-3 (low pain) and a cervical dilatation less than 4 cm were assessed retrospectively. Maternal and neonatal outcome including mode of delivery and duration of labor were compared with a similar group of women with pain scores of 4-6 (moderate pain), and 7-10 (severe pain). Assessing whether there was an association between pain level at the time of epidural and operative delivery rates was analyzed using a chi test for trend and by logistic regression to include potentially relevant covariates. We found 185 nulliparous women with low pain and compared them with a randomly selected equal number of women in each of the other pain groups. There was no significant association between pain groups in terms of duration of the first or second stage of labor or mode of delivery. Women with low pain had an operative delivery rate (instrumental assisted vaginal delivery plus cesarean delivery) of 49%, compared with 45% and 45% in those with moderate and severe pain, respectively (P=.40). We did not find an association between the degree of labor pain at initiation of epidural analgesia and mode of delivery or duration of labor. II.


A simple DNA extraction method suitable for PCR detection of genetically modified maize.
The polymerase chain reaction (PCR) is a powerful tool that is being increasingly used for detection of transgenic DNA. PCR requires only a minute quantity of template, but sensitive and accurate testing requires DNA of sufficient purity and free from inhibitors such as plant polysaccharides. Several standard protocols are available for this purpose, but they usually involve several steps, imply destruction of the maize kernel, or are time-consuming. Our aim was to develop a fast and simple extraction method to isolate a raw DNA-containing solution from maize tissues suitable for use as a template in a PCR-based detection assay with specific oligonucleotides directed to the identification of event MON810. The NaOH-based DNA extraction method we report here is time-saving (5 min) and can be used to isolate DNA-containing solutions from a small maize leaf portion (down to 1 mg) or from a single overnight-germinated kernel. PCR performed with selected primers yielded reproducible detection of transgenic DNA. The main advantages of the procedure are the quick extraction step, the possibility of non-destructive testing of maize kernels, and the robustness of the PCR-based detection, a consequence of the selection of MON810-matching oligonucleotides yielding intense and highly specific amplicons. Copyright © 2007 Society of Chemical Industry.


Sobering challenges faced by the brewing industry in a warming world.
Barley (Hordeum vulgare), a vital crop to the food and beverage industry, is highly vulnerable to unstable conditions on the climatic horizon. An article in this special issue of Physiologia Plantarum by Mahalingam and Bregitzer (2019) describes the impact that individual and combined stresses linked to climate change could have on the agronomic source of one of our favourite libations, as well as offering achievable solutions that will be needed if crop yield and quality are to be maintained.


Improving prediction accuracy for WSN data reduction by applying multivariate spatio-temporal correlation.
This paper proposes a method based on multivariate spatial and temporal correlation to improve prediction accuracy in data reduction for wireless sensor networks (WSN). Prediction of data not sent to the sink node is a technique used to save energy in WSNs by reducing the amount of data traffic. However, it may not be very accurate. Simulations were made involving simple linear regression and multiple linear regression functions to assess the performance of the proposed method. The results show a higher correlation between gathered inputs when compared to time, which is an independent variable widely used for prediction and forecasting. Prediction accuracy is lower when simple linear regression is used, whereas multiple linear regression is the most accurate one. In addition to that, our proposal outperforms some current solutions by about 50% in humidity prediction and 21% in light prediction. To the best of our knowledge, we believe that we are probably the first to address prediction based on multivariate correlation for WSN data reduction.


Identification of alpha 2-adrenergic receptors in chicken pineal gland using [3H]rauwolscine.
The norepinephrine-induced inhibition of avian pineal N-acetyltransferase activity appears to be mediated by alpha 2-adrenergic receptors. In this study, alpha 2-adrenergic receptors in the chicken pineal gland were directly identified by radioligand binding. Membrane preparations of pineal glands from chickens from 1 to 6 weeks of age were examined using [3H]rauwolscine, a selective alpha 2-adrenergic receptor antagonist, to characterize the binding sites. The results indicate no ontological change in either the affinity (KD) or density of receptor binding sites (Bmax) during the time span examined. The binding was saturable and of high affinity with a mean KD of 0.27 +/- 0.01 nM and a mean Bmax of 242 +/- 12 fmol/mg protein. Further characterization of these binding sites indicated that the alpha 2-adrenergic receptor is of the alpha 2A subtype, since prazosin and ARC-239 bound with low affinities and oxymetazoline bound with high affinity.


Radioimmunotherapy of human colorectal carcinoma xenografts using 90Y-labeled monoclonal antibody CO17-1A prepared by two bifunctional chelate techniques.
Monoclonal antibody CO17-1A, which has specificity for colorectal and pancreatic carcinomas, was radiolabeled with the pure beta emitter, 90Y, by either the cyclic diethylenetriaminepentaacetic acid (DTPA) anhydride technique or by a site-specific bifunctional chelate technique using 1-(p-aminobenzyl)DTPA (p-NH2-Bz-DTPA). Female nude mice bearing SW 948 human colorectal carcinoma xenografts were given injections i.v. of 90Y-labeled monoclonal antibody CO17-1A at dosages of 100, 150, and 200 muCi/25 g body weight. Unlabeled CO17-1A (100 micrograms/25 g body weight) was coadministered. In animals receiving 90Y-CO17-1A prepared by the cyclic DTPA anhydride technique, tumor volume was unchanged from base line at a dose of 200 microCi/25 g. As the dosage of 90Y-CO17-1A increased, the rate of tumor growth decreased, but all experimental animals in this group died between 14 and 21 days. In contrast, CO17-1A radiolabeled with 90Y by the site-specific p-NH2-Bz-DTPA bifunctional chelate technique produced a maximum tumor volume reduction of 87% in the 200 microCi/25 g group by day 15, and no deaths were noted in any of the 90Y-CO17-1A-treated groups for 71 days. Dose-response curves again showed increased tumoricidal effects with increased dosages of 90Y-CO17-1A. S-2-(3-Aminopropylamino)ethylphosphorothioic acid, commonly known as WR-2721, is a radioprotective drug which has been shown to protect against bone marrow depression in irradiated humans. No protection was observed when WR-2721 was used as an adjunct to treatment with 90Y-CO17-1A prepared by either the cyclic DTPA anhydride technique or the site-specific p-NH2-Bz-DTPA technique. When the site-specific p-NH2-Bz-DTPA technique was used, the reduction in WBC and hemoglobin levels correlated with increasing bone marrow toxicity at higher doses. We conclude that CO17-1A labeled with 90Y via the site-specific p-NH2-Bz-DTPA technique has potential for radioimmunotherapy of human colorectal carcinoma.


The Ca2+ channel ORAI1 is a regulator of oral cancer growth and nociceptive pain.
Oral cancer causes pain associated with cancer progression. We report here that the function of the Ca2+ channel ORAI1 is an important regulator of oral cancer pain. ORAI1 was highly expressed in tumor samples from patients with oral cancer, and ORAI1 activation caused sustained Ca2+ influx in human oral cancer cells. RNA-seq analysis showed that ORAI1 regulated many genes encoding oral cancer markers such as metalloproteases (MMPs) and pain modulators. Compared with control cells, oral cancer cells lacking ORAI1 formed smaller tumors that elicited decreased allodynia when inoculated into mouse paws. Exposure of trigeminal ganglia neurons to MMP1 evoked an increase in action potentials. These data demonstrate an important role of ORAI1 in oral cancer progression and pain, potentially by controlling MMP1 abundance.


Agreement among dentists' restorative treatment planning thresholds for primary occlusal caries, primary proximal caries, and existing restorations: findings from The National Dental Practice-Based Research Network.
The aim of this study was to quantify the agreement among individual National Dental Practice-Based Research Network dentists' self-reported treatment decisions for primary occlusal caries, primary proximal caries, and existing restorations. Five hypothetical clinical scenarios were presented: primary occlusal caries; primary proximal caries; and whether three existing restorations should be repaired or replaced. We quantified the probability that dentists who recommended later restorative intervention for primary caries were the same ones who recommended that existing restorations be repaired instead of replaced. Dentists who recommended later restorative treatment of primary occlusal caries and proximal caries at a more-advanced stage were significantly more likely to recommend repair instead of replacement. Agreement among dentists on a threshold stage for the treatment of primary caries ranged from 40 to 68%, while that for repair or replacement of existing restorations was 36 to 43%. Dentists who recommended repair rather than replacement of existing restorations were significantly more likely to recommend later treatment of primary caries. Conversely, dentists who recommended treatment of primary caries at an earlier stage were significantly more likely to recommend replacement of the entire restoration. Between-dentist agreement for primary caries treatment was better than between-dentist agreement for repair or replacement of existing restorations. These findings suggest consistency in how individual dentists approach the treatment of primary caries and existing restorations. However, substantial variation was found between dentists in their treatment decisions about the same teeth.


Chlamydial infection in women.
Infections caused by Chlamydia trachomatis are the most common sexually transmitted diseases occurring in developed countries. Among women, chlamydia-mediated diseases include urethritis, cervicitis, endometritis, and salpingitis. Sequelae include infertility, pelvic pain, ectopic pregnancy, and perinatal infection. Aspects of epidemiology, pathogenesis, diagnosis, treatment, and prevention are discussed.


Comparative proteomic analysis of the Arabidopsis cbl1 mutant in response to salt stress.
Many environmental stimuli, including light, biotic and abiotic stress factors, induce changes in cellular Ca(2+) concentrations in plants. Such Ca(2+) signatures are perceived by sensor molecules such as calcineurin B-like (CBL) proteins. AtCBL1, a member of the CBL family which is highly inducible by multiple stress signals, is known to function in the salt stress signal transduction pathway and to positively regulate the plant tolerance to salt. To shed light into the molecular mechanisms of the salt stress response mediated by AtCBL1, a two-dimensional DIGE proteomic approach was applied to identify the differentially expressed proteins in Arabidopsis wild-type and cbl1 null mutant plants in response to salt stress. Seventy-three spots were found altered in expression by least 1.2-fold and 50 proteins were identified by MALDI-TOF/TOF-MS, including some well-known and novel salt-responsive proteins. These proteins function in various processes, such as signal transduction, ROS scavenging, energy production, carbon fixation, metabolism, mRNA processing, protein processing and structural stability. Receptor for activated C kinase 1C (RACK1C, spot 715), a WD40 repeat protein, was up-regulated in the cbl1 null mutant, and two rack1c mutant lines showed decreased tolerance to salt stress, suggesting that RACK1C plays a role in salt stress resistance. In conclusion, our work demonstrated the advantages of the proteomic approach in studies of plant biology and identified candidate proteins in CBL1-mediated salt stress signaling network.


Legonaridin, a new member of linaridin RiPP from a Ghanaian Streptomyces isolate.
Linaridins are rare linear ribosomally-synthesized and post-translationally modified peptides (RiPPs) and only two, cypemycin and SGR-1832, in this family have been identified so far. Legonaridin 1 has been discovered as a new member of linaridins through chemical isolation, peptidogenomics, comprehensive 1- and 2-D NMR and advanced Marfey's analyses from the soil bacterium Streptomyces sp. CT34, an isolate collected from Legon, Ghana. Bioinformatics analysis of the gene cluster suggested that the biosynthesis of legonaridin 1 is different from those of cypemycin and SGR-1832. Consistent with bioinformatics and peptidogenomics analyses, 1 has a total of nine post-modifications, 8 dehydrobutyrine residues and a N,N-dimethylated N-terminus with a carboxylic acid at the C-terminus. Legonaridin 1 is structurally different from the two known linaridins comprising a new subfamily. This is the first time that NMR spectroscopy is used to establish the 2-D structure of a linaridin RiPP.


Differences in Hip and Knee Running Moments across Female Pubertal Development.
This study aimed to investigate whether knee and hip running moments differ across stages of female pubertal development. This was a cross-sectional study comparing the barefoot running moments of 91 prepubertal (n = 31, Tanner stage I), early/midpubertal (n = 30, Tanner stages II and III), and late/postpubertal (n = 30, Tanner stages IV and V) girls. External peak moments for knee abduction (KAbM), knee adduction (KAM), knee flexion (KFM), and knee internal rotation (KIRM) were analyzed. Secondary measures of hip adduction moment at the time of peak KAbM and hip flexion moment at the time of peak KFM were also derived. Between-group differences were analyzed using a series of one-way ANOVAs and ANCOVAs. At the knee, the late/postpubertal girls displayed a higher peak KFM and KAM compared with the prepubertal group (P < 0.05), and the early/midpubertal group exhibited a higher peak KFM than the prepubertal group (P = 0.034). No between-group differences were found for peak KAbM or KIRM (P > 0.05). At the hip, both the late/postpubertal (P = 0.03) and early/midpubertal girls (P = 0.039) ran with a lower hip adduction moment at the time of peak KAbM than the prepubertal girls. The hip flexion moment at the time of peak KFM in late/postpubertal girls was also significantly lower than both the early/mid- and prepubertal girls (P < 0.001). Girls at the latter stages of puberty exhibit higher peak external knee flexion and adduction moments, but not abduction or internal rotation moments. This may be partly attributed to a lower hip flexion but higher hip abduction moment at the time of peak knee moments. Future research should examine whether these differences in knee kinetics between pubertal stages have implications for knee injuries such as patellofemoral pain syndrome.


Management of crown root fracture by interdisciplinary approach.
Fracture of tooth after trauma is distressing to a person because of the discomfort and pain due to pulpal injury. Crown root fractures of anterior teeth cause concomitant periodontal injury and there will be concern about appearance, and aesthetics. Management of pulpal and periodontal tissue relieves pain and restoration of tooth form regains patients confidence. Restoration of fractured tooth will be accepted readily if it is minimally invasive, less expensive, and aesthetically acceptable. Reattachment is an option for restoration of anterior teeth compared to other artificial replacements because of its appearance as natural. This method is favourable when the fractured fragment is intact and available. Utilization of pulp space for retention of fragment is achieved by the insertion of a dentine bonding post. This case report describes a case of tooth reattachment after trauma in which the pulp space is utilized to bond a fiber-reinforced post for retention after periodontal tissue management.


Protective effects of Arctium lappa L. roots against hydrogen peroxide-induced cell injury and potential mechanisms in SH-SY5Y cells.
Accumulated evidence has shown that excessive reactive oxygen species (ROS) have been implicated in neuronal cell death related with various chronic neurodegenerative disorders. This study was designed to explore neuroprotective effects of ethyl acetate extract of Arctium lappa L. roots (EAL) on hydrogen peroxide (H2O2)-induced cell injury in human SH-SY5Y neuroblastoma cells. The cell viability was significantly decreased after exposure to 200 μM H2O2, whereas pretreatment with different concentrations of EAL attenuated the H2O2-induced cytotoxicity. Hoechst 33342 staining indicated that EAL reversed nuclear condensation in H2O2-treated cells. Meanwhile, TUNEL assay with DAPI staining showed that EAL attenuated apoptosis was induced by H2O2. Pretreatment with EAL also markedly elevated activities of antioxidant enzyme (GSH-Px and SOD), reduced lipid peroxidation (MDA) production, prevented ROS formation, and the decrease of mitochondrial membrane potential. In addition, EAL showed strong radical scavenging ability in 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) assays. Furthermore, EAL inhibited H2O2-induced apoptosis by increases in the Bcl-2/Bax ratio, decreases in cytochrome c release, and attenuation of caspase-3, caspase-9 activities, and expressions. These findings suggest that EAL may be regarded as a potential antioxidant agent and possess potent neuroprotective activity against H2O2-induced injury.


Is ice-rafted sediment in a North Pole marine record evidence for perennial sea-ice cover?
Ice-rafted sediments of Eurasian and North American origin are found consistently in the upper part (13 Ma BP to present) of the Arctic Coring Expedition (ACEX) ocean core from the Lomonosov Ridge, near the North Pole (≈88° N). Based on modern sea-ice drift trajectories and speeds, this has been taken as evidence of the presence of a perennial sea-ice cover in the Arctic Ocean from the middle Miocene onwards (Krylov et al. 2008 Paleoceanography 23, PA1S06. (doi:10.1029/2007PA001497); Darby 2008 Paleoceanography 23, PA1S07. (doi:10.1029/2007PA001479)). However, other high latitude land and marine records indicate a long-term trend towards cooling broken by periods of extensive warming suggestive of a seasonally ice-free Arctic between the Miocene and the present (Polyak et al. 2010 Quaternary Science Reviews 29, 1757-1778. (doi:10.1016/j.quascirev.2010.02.010)). We use a coupled sea-ice slab-ocean model including sediment transport tracers to map the spatial distribution of ice-rafted deposits in the Arctic Ocean. We use 6 hourly wind forcing and surface heat fluxes for two different climates: one with a perennial sea-ice cover similar to that of the present day and one with seasonally ice-free conditions, similar to that simulated in future projections. Model results confirm that in the present-day climate, sea ice takes more than 1 year to transport sediment from all its peripheral seas to the North Pole. However, in a warmer climate, sea-ice speeds are significantly faster (for the same wind forcing) and can deposit sediments of Laptev, East Siberian and perhaps also Beaufort Sea origin at the North Pole. This is primarily because of the fact that sea-ice interactions are much weaker with a thinner ice cover and there is less resistance to drift. We conclude that the presence of ice-rafted sediment of Eurasian and North American origin at the North Pole does not imply a perennial sea-ice cover in the Arctic Ocean, reconciling the ACEX ocean core data with other land and marine records.


Dangerous curves. A perspective on exercise, lactate, and the anaerobic threshold.
A number of general observations can be made from these recent studies. Lactate is a ubiquitous substance that is produced and removed from the body at all times, even at rest, both with and without the availability of oxygen. It is now recognized that lactate accumulates in the blood for several reasons, not just the fact that oxygen supply to the muscle is inadequate. Lactate production and removal is a continuous process; it is a change in the rate of one or the other that determines the blood lactate level. Rather than a specific threshold, there is most likely a period of time during which lactate production begins to exceed the body's capacity to remove it (through buffering or oxidation in other fibers). It may be appropriate to replace the term "anaerobic threshold" to a more functional description, since the muscles are never entirely anaerobic nor is there always a distinct threshold ("oxygen independent glycolysis" among others has been suggested) Lactate plays a major role as a metabolic substrate during exercise, is the preferred fuel for slow-twitch muscle fibers, and is a precursor for liver gluconeogenesis. The point at which lactate begins to accumulate in the blood, causing an increase in ventilation, is important to document clinically. Irrespective of the underlying mechanism or specific model that describes the process, the physiologic changes associated with lactate accumulation have significant import for cardiopulmonary performance. These include metabolic acidosis, impaired muscle contraction, hyperventilation, and altered oxygen kinetics, all of which contribute to an impaired capacity to perform work. Thus, any delay in the accumulation of blood lactate which can be attributed to an intervention (drug, exercise training, surgical, etc) may add important information concerning the efficacy of the intervention. A substantial body of evidence is available demonstrating that lactate accumulation occurs later (shifting to a higher percentage of Vo2max) after a period of endurance training. In athletes, the level of work that can be sustained prior to lactate accumulation, visually determined, is an accurate predictor of endurance performance. Presumably, these concepts have implications related to vocation/disability among patients with cardiovascular and pulmonary disease, but few such applied studies have been performed outside the laboratory. Blood lactate during exercise and its associated ventilatory changes maintain useful and interesting applications in both the clinical exercise laboratory and the sport sciences. However, the mechanism, interpretation, and application of these changes continue to rely more on tradition and convenience than science.


In vivo diffuse correlation spectroscopy investigation of the ocular fundus.
Diffuse correlation spectroscopy (DCS) measurements in vivo recorded from rabbits' ocular fundus are presented. Despite the complexity of these ocular tissues, we provide a clear and simple demonstration of the DCS abilities to analyze variations in physiological quantities of clinical interest. Indeed, the reported experimental activities demonstrate that DCS can reveal both choroidal-flow and temperature variations and detect nano- and micro-aggregates in ocular fundus circulation. Such abilities can be of great interest both in fundamental research and practical clinical applications. The proposed measuring system can be useful in: (a) monitoring choroidal blood flow variations, (b) determining the end-point for photo-dynamic therapy and transpupillary thermo therapy and, (c) managing the dye injection and determining an end-point for dye-enhanced photothrombosis. Moreover, it could allow both diagnoses when the presence of nano- and micro-aggregates is related to specific diseases and verifying the effects of nanoparticle injection in nanomedicine. Even though the reported results demonstrate the applicability of DCS to investigate ocular fundus, a detailed and accurate investigation of the limits of detection is beyond the scope of this article.


Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights.
Genome-wide association studies (GWAS) have identified over 100 risk loci for schizophrenia, but the causal mechanisms remain largely unknown. We performed a transcriptome-wide association study (TWAS) integrating a schizophrenia GWAS of 79,845 individuals from the Psychiatric Genomics Consortium with expression data from brain, blood, and adipose tissues across 3,693 primarily control individuals. We identified 157 TWAS-significant genes, of which 35 did not overlap a known GWAS locus. Of these 157 genes, 42 were associated with specific chromatin features measured in independent samples, thus highlighting potential regulatory targets for follow-up. Suppression of one identified susceptibility gene, mapk3, in zebrafish showed a significant effect on neurodevelopmental phenotypes. Expression and splicing from the brain captured most of the TWAS effect across all genes. This large-scale connection of associations to target genes, tissues, and regulatory features is an essential step in moving toward a mechanistic understanding of GWAS.


Insights into the quantification and reporting of model-related uncertainty across different disciplines.
Quantifying uncertainty associated with our models is the only way we can express how much we know about any phenomenon. Incomplete consideration of model-based uncertainties can lead to overstated conclusions with real-world impacts in diverse spheres, including conservation, epidemiology, climate science, and policy. Despite these potentially damaging consequences, we still know little about how different fields quantify and report uncertainty. We introduce the "sources of uncertainty" framework, using it to conduct a systematic audit of model-related uncertainty quantification from seven scientific fields, spanning the biological, physical, and political sciences. Our interdisciplinary audit shows no field fully considers all possible sources of uncertainty, but each has its own best practices alongside shared outstanding challenges. We make ten easy-to-implement recommendations to improve the consistency, completeness, and clarity of reporting on model-related uncertainty. These recommendations serve as a guide to best practices across scientific fields and expand our toolbox for high-quality research.


Differential diagnosis and management of an older runner with an atypical neurodynamic presentation: a case for clinical reasoning.
Case Report. The purpose of this case report is to describe the clinical reasoning process involved with the differential diagnosis and management of a 69 year-old male runner reporting a six month history of insidious onset of left sided low back and buttock pain of low to medium degree of irritability. The case presented describes the utilization of clinical reasoning by a clinician in fellowship training when a patient with atypical adverse neurodynamic dysfunction related to running was encountered. The patient's physical examination was relatively unremarkable. Assessment of the patient's subjective history, self-report measures [Oswestry Disability Index (ODI), global rating of change scale (GROC)], objective findings, and tests and measures led to a working diagnosis of atypical adverse peripheral neurodynamic dysfunction. The lumbar spine, sacroiliac joint, hip joint and lower extremity were ruled out by a comprehensive subjective and objective examination. The diagnosis of adverse neurodynamic dysfunction became a diagnosis of exclusion. Returning two and a half weeks after initial evaluation the patient reported no pain with running. Twelve weeks after the initiation of physical therapy, the patient was contacted via email. He was sent, and asked to fill out an ODI. The patient demonstrated an improvement in ODI from 10% to 2%. He also reported that he continued to run after treatment without pain. Determining the source of a patient complaint can occasionally be an arduous undertaking. Pathological sources of a patient's symptoms may not be easily determined. Development of differential diagnosis and clinical reasoning skills is imperative. Improving clinical reasoning skills requires deliberate practice through reflective thinking before, during, and after patient interactions. Refinement of these skills leads to the primary goal of identifying the patient's clinical presentation, thus matching it with the most effective treatment approach. Level 4.


Bias, discrimination, and obesity.
This article reviews information on discriminatory attitudes and behaviors against obese individuals, integrates this to show whether systematic discrimination occurs and why, and discusses needed work in the field. Clear and consistent stigmatization, and in some cases discrimination, can be documented in three important areas of living: employment, education, and health care. Among the findings are that 28% of teachers in one study said that becoming obese is the worst thing that can happen to a person; 24% of nurses said that they are "repulsed" by obese persons; and, controlling for income and grades, parents provide less college support for their overweight than for their thin children. There are also suggestions but not yet documentation of discrimination occurring in adoption proceedings, jury selection, housing, and other areas. Given the vast numbers of people potentially affected, it is important to consider the research-related, educational, and social policy implications of these findings.


Gate-tunable electroluminescence in Aviram-Ratner-type molecules: Kinetic description.
A theoretical study of the mechanisms of electroluminescence (EL) generation in photoactive molecules with donor and acceptor centers linked by saturated σ-bonds (molecules of the Aviram-Ratner-type) is presented. The approach is based on the kinetics of single-electron transitions between many-body molecular states. This study shows that the EL polarity arises due to asymmetric coupling of molecular orbitals of the photochromic part of the molecule to the electrodes. The gate voltage controls the power of the EL through the occupancy of the excited singlet state. The shifting of the orbital energies forms a resonant or a non-resonant path for the transmission of electrons through the molecule. The action of the gate voltage is reflected in specific critical voltages. An analytical dependence of the critical voltages on the energies of molecular states involved in the formation of EL, as well as on the gate voltage, was derived for both positive and negative polarities. Conditions under which the gate voltage lowers the absolute value of the bias voltage that is responsible for the activation of the resonance mechanism of EL formation were also established. This is an important factor in control of EL in molecular junctions.


Validation of the "L-DOPA test" for diagnosis of restless legs syndrome.
We developed and validated a standardized test procedure to evaluate the accuracy of the supportive diagnostic criterion "response to dopaminergic treatment" in restless legs syndrome (RLS). Forty-eight patients who fulfilled at least three of the four essential criteria for RLS, thus including uncertain clinical cases for a nonexpert, were recruited. Patients received a preliminary diagnosis of RLS or non-RLS. All patients underwent a polysomnography (PSG) and were then asked to perform the diagnostic L-DOPA test at home, which consisted in the application of one single dose of 100/25 mg L-DOPA/benserazide and a subsequent observational period of 2 hours. Before, and in 15-minute intervals after, drug intake, the patients rated the severity of the "symptoms in the legs" and the "urge to move the legs" using a 100-mm visual analogue scale. Considering a 50% improvement as a positive test result, we found a sensitivity of 88% ("symptoms in the legs") and 80% ("urge to move the legs") with a specificity of 100% for both test items. A rate of 90% or 83% of all patients could be correctly diagnosed by the L-DOPA test. Both scales were able to predict the response to dopaminergic agents in the subsequent course of the treatment by 100%. The periodic leg movements arousal index as assessed by polysomnography was less appropriate for the prediction of the correct diagnosis. We recommend the L-DOPA test for diagnostic decision making in all patients with an unclear RLS diagnosis according to the essential diagnostic criteria of the International RLS Study Group.


Analysis of epistatic interactions and fitness landscapes using a new geometric approach.
Understanding interactions between mutations and how they affect fitness is a central problem in evolutionary biology that bears on such fundamental issues as the structure of fitness landscapes and the evolution of sex. To date, analyses of fitness landscapes have focused either on the overall directional curvature of the fitness landscape or on the distribution of pairwise interactions. In this paper, we propose and employ a new mathematical approach that allows a more complete description of multi-way interactions and provides new insights into the structure of fitness landscapes. We apply the mathematical theory of gene interactions developed by Beerenwinkel et al. to a fitness landscape for Escherichia coli obtained by Elena and Lenski. The genotypes were constructed by introducing nine mutations into a wild-type strain and constructing a restricted set of 27 double mutants. Despite the absence of mutants higher than second order, our analysis of this genotypic space points to previously unappreciated gene interactions, in addition to the standard pairwise epistasis. Our analysis confirms Elena and Lenski's inference that the fitness landscape is complex, so that an overall measure of curvature obscures a diversity of interaction types. We also demonstrate that some mutations contribute disproportionately to this complexity. In particular, some mutations are systematically better than others at mixing with other mutations. We also find a strong correlation between epistasis and the average fitness loss caused by deleterious mutations. In particular, the epistatic deviations from multiplicative expectations tend toward more positive values in the context of more deleterious mutations, emphasizing that pairwise epistasis is a local property of the fitness landscape. Finally, we determine the geometry of the fitness landscape, which reflects many of these biologically interesting features. A full description of complex fitness landscapes requires more information than the average curvature or the distribution of independent pairwise interactions. We have proposed a mathematical approach that, in principle, allows a complete description and, in practice, can suggest new insights into the structure of real fitness landscapes. Our analysis emphasizes the value of non-independent genotypes for these inferences.


Epidural injection of depot corticosteroids. Australian Pain Society Limited.
This position statement is for general information and discussion only and is not intended as medical advice. Its purpose is to review the current literature on a controversial subject so as to assist medical practitioners who have an interest in pain management. The epidural injection of depot corticosteroids is one of a number of treatment techniques for chronic pain, and it is the view of the directors of the Australian Pain Society Limited that patients with chronic pain require assessment and treatment within multidisciplinary pain management programs. This statement does not encourage or discourage medical practitioners from using epidural steroid injections as a treatment modality. While this review of the pertinent literature may be of assistance to practitioners, no responsibility can be accepted by the Australian Pain Society Limited, or its directors, for any inaccuracy contained in studies referred to therein. All liability is expressly disclaimed for any loss or damage which may arise from any person acting on any statement or information contained herein.


Evolution of an RNP assembly system: a minimal SMN complex facilitates formation of UsnRNPs in Drosophila melanogaster.
In vertebrates, assembly of spliceosomal uridine-rich small nuclear ribonucleoproteins (UsnRNPs) is mediated by the SMN complex, a macromolecular entity composed of the proteins SMN and Gemins 2-8. Here we have studied the evolution of this machinery using complete genome assemblies of multiple model organisms. The SMN complex has gained complexity in evolution by a blockwise addition of Gemins onto an ancestral core complex composed of SMN and Gemin2. In contrast to this overall evolutionary trend to more complexity in metazoans, orthologs of most Gemins are missing in dipterans. In accordance with these bioinformatic data a previously undescribed biochemical purification strategy elucidated that the dipteran Drosophila melanogaster contains an SMN complex of remarkable simplicity. Surprisingly, this minimal complex not only mediates the assembly reaction in a manner very similar to its vertebrate counterpart, but also prevents misassembly onto nontarget RNAs. Our data suggest that only a minority of Gemins are required for the assembly reaction per se, whereas others may serve additional functions in the context of UsnRNP biogenesis. The evolution of the SMN complex is an interesting example of how the simplification of a biochemical process contributes to genome compaction.


Determining whether managed care formularies meet the needs of pediatric patients.
This activity is designed for healthcare providers making formulary decisions for managed care organizations. To help clinicians determine whether managed care formularies meet the needs of pediatric patients. 1. List general considerations for establishing a pediatric drug formulary. 2. Understand the importance of growth and development when selecting drug therapy for pediatric patients. 3. Discuss potential difficulties with administering medications during school hours. 4. Identify specific medications within the drug classes of antibiotics, asthma medications, endocrine, and gastrointestinal agents that should be available on a pediatric drug formulary.


The therapy of relapsed acute leukaemia in adults.
Although the cure of acute leukaemia has improved significantly, many patients will still relapse and die. The unraveling of the molecular pathogenesis of acute leukaemia has lead to the identification of new prognostic factors and improved the detection of minimal residual disease. The treatment of relapsed acute leukaemia with chemotherapy remains unsatisfactory. Allogeneic or autologous blood and marrow transplant (BMT) can cure a subset of patients with relapsed acute leukaemia. The identification of the graft-vs-leukaemia (GVL) effect has lead to the development of donor lymphocyte infusions to re-induce remission in patients with relapsed leukaemia after allogeneic BMT and also stimulated the development of the less toxic nonmyeloablative allogeneic transplant approach. The identification of molecular targets of therapy and the development of monoclonal antibody-directed therapy has generated optimism. It is possible that combinations of chemotherapy, molecularly directed therapy, and immunotherapy may be combined to cure an increasing proportion of patients with acute leukaemia.


The cysteines of catalase HPII of Escherichia coli, including Cys438 which is blocked, do not have a catalytic role.
Site-directed mutagenesis of the katE gene of Escherichia coli was used to change, individually and in combination, Cys438 and Cys669 to serine in catalase HPII. The Cys438-->Ser mutation caused a 30% reduction in the specific activity of the enzyme, whereas the Cys669-->Ser mutation did not affect enzyme activity. The titration of free sulfhydryl groups in HPII revealed that Cys669 was reactive whereas Cys438 was unreactive. Properties of the modification on Cys438 included alkali lability, insensitivity to methylamine, hydroxylamine or reducing agents, and a mass determined by mass spectrometry to be approximately 43 +/- 2 Da. A hemithioacetal structure is consistent with these properties. Although free sulfhydryl groups do not play a significant role in the stability or catalytic mechanism of HPII, the sulfhydryl agent 2-mercaptoethanol caused a 50% inactivation of HPII along with an irreversible change in the absorption spectrum of the protein. Other sulfhydryl agents, including dithiothreitol, cysteine and glutathione, and the organic peroxide, t-butylhydroperoxide, which cannot directly access the active site, do not affect HPII activity, but they do cause a small reversible change in the absorption spectrum, possibly by a mechanism involving superoxide.


Catheter-Related Complications in Children With Cancer Receiving Parenteral Nutrition: Change in Risk Is Moderated by Catheter Type.
Although central venous catheters (CVCs) are essential to pediatric cancer care, complications are common (eg, occlusion, central line-associated bloodstream infection [CLABSI]). Parenteral nutrition (PN) and external CVCs are associated with an increased complication risk, but their interaction is unknown. A retrospective matched cohort study of pediatric oncology patients who received PN through subcutaneous ports or external CVCs. Complication rates were compared between CVC types during PN and non-PN periods (log-negative binomial model). Risk of CLABSI was higher during PN for children with ports (relative risk [RR] = 39.6; 95% confidence interval, 5.0-309) or external CVCs (RR = 2.9; 95% confidence interval, 1.1-7.4). This increased risk during PN was greater for ports than for external CVCs (ratio of relative risks = 13.6). Occlusion risk was higher during PN in both groups (RR = 10.0 for ports; RR = 2.0 for external CVCs), and the increase was significantly greater in ports (ratio of relative risks, 4.9). Overall, complication rates for ports were much lower than for external CVCs during the non-PN period but similar during the PN period. Children with cancer who receive PN have increased risk of CLABSI and occlusion. The risk increase is greatest in children with ports: a 40- and 10-fold increase in infection risk and occlusion, respectively, resulting in similar complication rates during PN regardless of CVC type and negating the usual benefits of ports. Children with cancer who will require PN should have primary insertion of external CVCs where possible.


Neuronal protein kinase signaling cascades and excitotoxic cell death.
Perturbation of normal survival mechanisms may play a role in a large number of disease processes. Glutamate neurotoxicity, particularly when mediated by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, has been hypothesized to underlie several types of acute brain injury, including stroke. Several neurological insults linked to excessive release of glutamate and neuronal death result in tyrosine kinase activation, including p44/42 mitogen activated protein (MAP) kinase. To further explore a role for MAP kinase activation in excitotoxicity, we used a novel tissue culture model to induce neurotoxicity. Removal of the endogenous blockade by Mg2+ of the NMDA receptor in cultured hippocampal neurons triggers a self perpetuating cycle of excitotoxicity, which has relatively slow onset, and is critically dependent on NMDA receptors and activation of voltage gated Na+ channels. These injury conditions led to a rapid phosphorylation of p44/42 that was blocked by MAP kinase kinase (MEK) inhibitors. MEK inhibition was associated with protection against synaptically mediated excitotoxicity. Interestingly, hippocampal neurons preconditioned by a sublethal exposure to Mg(2+)-free conditions were rendered resistant to injury induced by a subsequently longer exposure to this insult; the preconditioning effect was MAP kinase dependent. The MAP kinase signaling pathway can also promote polypeptide growth factor mediated neuronal survival. MAP kinase regulated pathways may act to promote survival or death, depending upon the cellular context in which they are activated.


Gastrin cell responses to acidification of the achlorhydric rat stomach.
In the rat, gastrin cells are normally exposed to the stimulatory effects of food and the inhibitory influences of acid in the gastric lumen. We have studied the effects of intragastric acid on gastrin cell function in animals in which the tonic inhibitory action of acid was removed by prior treatment with the proton pump blocker omeprazole. In fasted rats with gastric fistula treated with omeprazole, instillation of acid into the stomach produced a prompt decrease in plasma gastrin, but gastrin mRNA abundance showed a modest transient increase over a period of 2 h and thereafter no change; there was also a transient increase in tissue concentrations of the gastrin precursor progastrin that was compatible with increased gastrin synthesis. Concentrations of tissue gastrins, in general, increased after acid instillation, which can be attributed to continued synthesis in the presence of suppressed gastrin release. In rats fed ad libitum, a single dose of omeprazole (which produces achlorhydria for 24-30 h) produced an increase in plasma gastrin that peaked after 24 h and declined to control levels over the following 48 h; in contrast, gastrin mRNA abundance peaked 48 h after omeprazole before declining to control levels. The results indicate that whereas gastrin release might be promptly inhibited by intragastric acid, the changes in gastrin mRNA abundance are much slower: achlorhydria increases gastrin mRNA within 24 h, but acid takes longer to depress gastrin mRNA abundance. Over periods of a few hours, gastrin release and synthesis need not, therefore, change in parallel.


Impaired discourse content in aphasia is associated with frontal white matter damage.
Aphasia is a common consequence of stroke with severe impacts on employability, social interactions and quality of life. Producing discourse-relevant information in a real-world setting is the most important aspect of recovery because it is critical to successful communication. This study sought to identify the lesion correlates of impaired production of relevant information in spoken discourse in a large, unselected sample of participants with post-stroke aphasia. Spoken discourse (n = 80) and structural brain scans (n = 66) from participants with aphasia following left hemisphere stroke were analysed. Each participant provided 10 samples of spoken discourse elicited in three different genres, and 'correct information unit' analysis was used to quantify the informativeness of speech samples. The lesion correlates were identified using multivariate lesion-symptom mapping, voxel-wise disconnection and tract-wise analyses. Amount and speed of relevant information were highly correlated across different genres and with total lesion size. The analyses of lesion correlates converged on the same pattern: impaired production of relevant information was associated with damage to anterior dorsal white matter pathways, specifically the arcuate fasciculus, frontal aslant tract and superior longitudinal fasciculus. Damage to these pathways may be a useful biomarker for impaired informative spoken discourse and informs development of neurorehabilitation strategies.


Effect of calcium levels on structure and function of mitochondria in yeast under high glucose fermentation.
In this study, the effects of calcium levels on structure and function of mitochondria under high glucose environment were studied. In the high glucose environment, yeast growth capacity was inhibited, and intracellular reactive oxygen species (ROS) content was increased from 6 h to 12 h, while ROS content was reduced in group with 1 × 10-1 and 1 g/L CaCl2 level from 24 h to 36 h. Exogenous calcium addition had a significant effect on the elevation of intracellular Ca2+ and cytochrome C content in yeast from 6 h to 12 h; mitochondrial membrane potential decreased with the increase of CaCl2 level under high glucose levels. Mitochondrial swelling of yeast was influenced by high glucose levels and showed a regulatory dynamic change by Ca2+ levels. Isocitrate dehydrogenase activity increased in 1 × 10-3 g/L CaCl2 level from 6 h to 12 h, α-ketoglutarate dehydrogenase activity increased with an increase in CaCl2 level from 6 h to 24 h. Calcium affected the structure and function of mitochondria by regulating the intracellular signal, enzymes in tricarboxylic acid cycle, and cytochrome system of yeast under high glucose stress.


Tissue-specific impact of stem-loops and quadruplexes on cancer breakpoints formation.
Chromosomal rearrangements are the typical phenomena in cancer genomes causing gene disruptions and fusions, corruption of regulatory elements, damage to chromosome integrity. Among the factors contributing to genomic instability are non-B DNA structures with stem-loops and quadruplexes being the most prevalent. We aimed at investigating the impact of specifically these two classes of non-B DNA structures on cancer breakpoint hotspots using machine learning approach. We developed procedure for machine learning model building and evaluation as the considered data are extremely imbalanced and it was required to get a reliable estimate of the prediction power. We built logistic regression models predicting cancer breakpoint hotspots based on the densities of stem-loops and quadruplexes, jointly and separately. We also tested Random Forest models varying different resampling schemes (leave-one-out cross validation, train-test split, 3-fold cross-validation) and class balancing techniques (oversampling, stratification, synthetic minority oversampling). We performed analysis of 487,425 breakpoints from 2234 samples covering 10 cancer types available from the International Cancer Genome Consortium. We showed that distribution of breakpoint hotspots in different types of cancer are not correlated, confirming the heterogeneous nature of cancer. It appeared that stem-loop-based model best explains the blood, brain, liver, and prostate cancer breakpoint hotspot profiles while quadruplex-based model has higher performance for the bone, breast, ovary, pancreatic, and skin cancer. For the overall cancer profile and uterus cancer the joint model shows the highest performance. For particular datasets the constructed models reach high predictive power using just one predictor, and in the majority of the cases, the model built on both predictors does not increase the model performance. Despite the heterogeneity in breakpoint hotspots' distribution across different cancer types, our results demonstrate an association between cancer breakpoint hotspots and stem-loops and quadruplexes. Approximately for half of the cancer types stem-loops are the most influential factors while for the others these are quadruplexes. This fact reflects the differences in regulatory potential of stem-loops and quadruplexes at the tissue-specific level, which yet to be discovered at the genome-wide scale. The performed analysis demonstrates that influence of stem-loops and quadruplexes on breakpoint hotspots formation is tissue-specific.


Decreased Expression of Serine/Arginine-Rich Splicing Factor 1 in T Cells From Patients With Active Systemic Lupus Erythematosus Accounts for Reduced Expression of RasGRP1 and DNA Methyltransferase 1.
T cells from systemic lupus erythematosus (SLE) patients have reduced protein levels of RasGRP1, a guanine nucleotide exchange factor for Ras, and increased transcript of alternatively spliced (AS) forms lacking exon 11. Serine/arginine-rich splicing factor 1 (SRSF1) binds pre-messenger RNA (pre-mRNA) to regulate AS forms of several genes, including CD3ζ in SLE T cells. This study was undertaken to assess whether SRSF1 controls the expression of RasGRP1 in T cells from patients with SLE. We studied T cells from 45 SLE patients and 18 healthy subjects. Expression levels of SRSF1, wild-type (WT) RasGRP1, and DNA methyltransferase 1 (DNMT1) were assessed by quantitative polymerase chain reaction. Direct binding of SRSF1 to exon 11 of RasGRP1 mRNA was evaluated with an oligonucleotide-protein pulldown assay. Healthy T cells and SLE T cells were treated with SRSF1-specific small interfering RNA or SRSF1 expression vector, respectively, and then evaluated for mRNA/protein expression. SRSF1 expression levels were significantly lower in T cells from SLE patients compared to those from healthy subjects, and correlated inversely with disease activity and positively with levels of RasGRP1-WT and DNMT1. SRSF1 bound directly to exon 11 of RasGRP1 mRNA. Silencing of SRSF1 in human T cells led to increased ratios of RasGRP1-AS to RasGRP1-WT and decreased levels of RasGRP1 protein, whereas overexpression of SRSF1 in SLE T cells caused recovery of RasGRP1, which in turn induced DNMT1/interleukin-2 expression. SRSF1 controls the alternative splicing of RasGRP1 and subsequent protein expression. Our findings extend evidence that alternative splicing plays a central role in the aberrant T cell function in patients with SLE by controlling the expression of multiple genes.


Tibialis Posterior Tenosynovitis: A Unique Musculoskeletal Manifestation of Gout.
Extra-articular manifestations of gout can present in several ways, including tenosynovitis. We present a rare case of acute tibialis posterior gouty tenosynovitis. An 82-year-old man with a history of well-controlled gout presented with acute onset of left ankle pain, occurring without inciting event. The medial ankle was slightly erythematous with moderate dorsal-medial swelling and mild dorsal-lateral swelling, with severe tenderness to palpation over the medial retro-malleolar region. Range of motion and manual muscle testing were pain limited throughout. Ultrasound examination revealed a left posterior tibialis tendon sheath tenosynovitis with effusion and overlying soft tissue edema. Tendon sheath aspirate revealed sodium urate crystals and a white blood cell count of 6400/μL. Tendon sheath injection with a mixture of 1% lidocaine and dexamethasone 4 mg resulted in symptom resolution. Repeat ultrasound examination demonstrated no evidence of tibialis posterior tendon sheath effusion. This case is unique not only because acute gouty posterior tibialis tenosynovitis is very rare, particularly in a normouricemic individual, but also because the sonographic evidence of gouty infiltration into the posterior tibialis tendon and overlying subcutaneous tissue considerably aided in arriving at the correct diagnosis in a timely manner.


Protein Tyrosine Phosphatase δ Mediates the Sema3A-Induced Cortical Basal Dendritic Arborization through the Activation of Fyn Tyrosine Kinase.
Leukocyte common antigen-related (LAR) class protein tyrosine phosphatases (PTPs) are critical for axonal guidance; however, their relation to specific guidance cues is poorly defined. We here show that PTP-3, a LAR homolog in Caenorhabditis elegans, is involved in axon guidance regulated by Semaphorin-2A-signaling. PTPδ, one of the vertebrate LAR class PTPs, participates in the Semaphorin-3A (Sema3A)-induced growth cone collapse response of primary cultured dorsal root ganglion neurons from Mus musculus embryos. In vivo, however, the contribution of PTPδ in Sema3A-regualted axon guidance was minimal. Instead, PTPδ played a major role in Sema3A-dependent cortical dendritic growth. Ptpδ-/- and Sema3a-/- mutant mice exhibited poor arborization of basal dendrites of cortical layer V neurons. This phenotype was observed in both male and female mutants. The double-heterozygous mutants, Ptpδ+/-; Sema3a+/-, also showed a similar phenotype, indicating the genetic interaction. In Ptpδ-/- brains, Fyn and Src kinases were hyperphosphorylated at their C-terminal Tyr527 residues. Sema3A-stimulation induced dephosphorylation of Tyr527 in the dendrites of wild-type cortical neurons but not of Ptpδ-/- Arborization of cortical basal dendrites was reduced in Fyn-/- as well as in Ptpδ+/-; Fyn+/- double-heterozygous mutants. Collectively, PTPδ mediates Sema3A-signaling through the activation of Fyn by C-terminal dephosphorylation.SIGNIFICANCE STATEMENT The relation of leukocyte common antigen-related (LAR) class protein tyrosine phosphatases (PTPs) and specific axon guidance cues is poorly defined. We show that PTP-3, a LAR homolog in Caenorhabditis elegans, participates in Sema2A-regulated axon guidance. PTPδ, a member of vertebrate LAR class PTPs, is involved in Sema3A-regulated cortical dendritic growth. In Sema3A signaling, PTPδ activates Fyn and Src kinases by dephosphorylating their C-terminal Tyr residues. This is the first evidence showing that LAR class PTPs participate in Semaphorin signaling in vivo.


Myocardial Metastasis of Tongue Cancer: A Rare Localization.
BACKGROUND Cardiac metastases of head and neck tumors are extremely rare, and antemortem diagnosis is even rarer. In most cases, patients show symptoms or electrocardiographic abnormalities and expected survival is considerably low. CASE REPORT A 72-year-old man was admitted to our cardiology ward with suspected endocarditis 2 months after a right hemiglossectomy for a squamous cell carcinoma. He was asymptomatic and showed no electrocardiogram abnormalities. Echocardiography showed an iso-ipoechogenic round-shaped formation at the right ventricle apex that was suspected to be a metastasis owing to 2 cardiac magnetic resonance imaging examinations showing a significant increase in its volume over 14 days. The patient was evaluated by a multidisciplinary team and referred for first-line chemotherapy with carboplatin, 5-fluoruracil, and cetuximab. He died after almost 4 months of follow-up. CONCLUSIONS This case presents a very rare diagnosis as well as some unique features, including the intramyocardial localization, the absence of symptoms, and electrocardiogram abnormalities. Our report shows the relevance of imaging techniques in defining even the most unusual clinical findings, and it emphasizes the significance of early recognition of cardiac masses in order to identify the appropriate medical or surgical therapy for patients.


Quantifying the three-dimensional facial morphology of the laboratory rat with a focus on the vibrissae.
The morphology of an animal's face will have large effects on the sensory information it can acquire. Here we quantify the arrangement of cranial sensory structures of the rat, with special emphasis on the mystacial vibrissae (whiskers). Nearly all mammals have vibrissae, which are generally arranged in rows and columns across the face. The vibrissae serve a wide variety of important behavioral functions, including navigation, climbing, wake following, anemotaxis, and social interactions. To date, however, there are few studies that compare the morphology of vibrissal arrays across species, or that describe the arrangement of the vibrissae relative to other facial sensory structures. The few studies that do exist have exploited the whiskers' grid-like arrangement to quantify array morphology in terms of row and column identity. However, relying on whisker identity poses a challenge for comparative research because different species have different numbers and arrangements of whiskers. The present work introduces an approach to quantify vibrissal array morphology regardless of the number of rows and columns, and to quantify the array's location relative to other sensory structures. We use the three-dimensional locations of the whisker basepoints as fundamental parameters to generate equations describing the length, curvature, and orientation of each whisker. Results show that in the rat, whisker length varies exponentially across the array, and that a hard limit on intrinsic curvature constrains the whisker height-to-length ratio. Whiskers are oriented to "fan out" approximately equally in dorsal-ventral and rostral-caudal directions. Quantifying positions of the other sensory structures relative to the whisker basepoints shows remarkable alignment to the somatosensory cortical homunculus, an alignment that would not occur for other choices of coordinate systems (e.g., centered on the midpoint of the eyes). We anticipate that the quantification of facial sensory structures, including the vibrissae, will ultimately enable cross-species comparisons of multi-modal sensing volumes.


Induction of DNA synthesis by cholera toxin in the temperature-sensitive cell-cycle mutants of rat 3Y1 fibroblasts at a restrictive temperature.
Four temperature-sensitive mutants of rat 3Y1 fibroblasts representing separate complementation groups (3Y1tsD123, 3Y1tsF121, 3Y1tsG125 and 3Y1tsH203) are arrested at a restrictive temperature of 39.8 degrees C mainly with a G1-phase DNA content (temperature arrest). Cholera toxin (CT) (3 micrograms ml-1) induced DNA synthesis at 39.8 degrees C in the temperature-arrested cultures of two mutants (3Y1tsD123 and 3Y1tsG125). This effect of CT was not mimicked by other agents known to elevate the cellular level of cyclic AMP, such as dibutyryl-cyclic AMP, prostaglandin E1 and forskolin, suggesting that the elevation of cellular cyclic AMP level per se is not responsible for the induction of DNA synthesis by CT. Addition of the B subunit of CT to the temperature-arrested cultures of 3Y1tsD123 and 3Y1tsG125 did not induce DNA synthesis at 39.8 degrees C, indicating that the binding of CT to the cell surface alone is insufficient for the induction. The CT-treated cell membrane fraction prepared from temperature-arrested 3Y1tsG125 cells had similar activity for [32P]ADP-ribosylation of the 45 X 10(3) Mr protein to that prepared from cells proliferating at a permissive temperature of 33.8 degrees C. All these results suggest that 3Y1tsG125 cells utilize a CT-responsive signal transduction pathway, different from adenylate cyclase cascade, for preparation for entry into S phase in the temperature-arrested 3Y1tsG125.(ABSTRACT TRUNCATED AT 250 WORDS)


The Influence of Alexithymia on Alcohol Craving, Health-Related Quality of Life and Gender in Alcohol-Dependent Outpatients.
Alexithymia is a vulnerability factor for physical and mental illness that can significantly influence the daily function of alcohol-dependent patients. The aim of this study was to examine the indirect effect of obsessive thoughts and compulsive behaviors involving alcohol craving on the relationship between alexithymia, quality of life (QoL) of psychological well-being and health status. Three hundred and eighty-one outpatients (263 males and 118 females) in treatment for alcohol dependence completed self-report measures of alexithymia, alcohol craving, GHQ-28 (QoL-psychological well-being) and SF-36 (QoL-health status). Males scored significantly higher than females on aspects of alexithymia, and females reported significantly higher levels of alcohol craving. Path analysis showed an indirect effect of alcohol craving on the relationship between alexithymia, QoL-psychological well-being and self-reported QoL-health status for males only. The current study provides important new information about impaired self-reported health status and well-being among male alcohol-dependent treatment seekers with alexithymia.


Diagnostic possibilities from a serum sample-Clinical value of new methods within small animal reproduction, with focus on anti-Müllerian hormone.
During the last decade, analysis of anti-Müllerian hormone (AMH), highly conserved between mammalian species, has contributed to new information in reproductive endocrinology, due to clinically available diagnostic assays. AMH is produced solely in the gonads, in the Sertoli cells of testes and granulosa cells of the ovary, and thus offers possibilities to diagnose physiologic and pathologic conditions involving these organs. This article reviews indications for AMH analysis in cats and dogs, including diagnosing the presence of gonads, and granulosa or Sertoli cell tumours. Diagnostic challenges are addressed. One specific organ, the prostate, is commonly affected by pathologic changes in older dogs. A commercial assay for analysing canine prostatic specific esterase (CPSE) enables analysis of CPSE in clinical practice, of potential value in the workup of benign prostatic hyperplasia in male dogs. This is described in this review, as is a new method for analysis of steroids: liquid chromatography-tandem mass spectrometry LC-MS/MS. Steroids have since long been analysed in studies on reproduction, and LC-MS/MS has the advantage of allowing analysis of panels of multiple steroids from small sample volumes. Altogether, these available methods may give new insights into small animal reproduction and are valuable tools for the practicing veterinarian.


Insect prothoracicotropic hormone: evidence for two molecular forms.
In an insect, the tobacco hornworm Manduca sexta, the cerebral neuropeptide prothoracicotropic hormone (PTTH), the primary effector of postembryonic development, exists as two molecular forms. These two PTTH's elicit characteristic in vitro dose responses of activation of prothoracic glands from different developmental stages, an indication that during development the glands change in their sensitivity to the neurohormones. Both PTTH's are active in a specific in situ bioassay. Since they may be released in situ at stage-specific times to evoke distinctly different developmental responses, the PTTH neuroendocrine axis appears to be an effective system for determining the functions of molecular forms of a neurohormone in the regulation of growth and development.


β-Hydroxybutyrate Detection with Proton MR Spectroscopy in Children with Drug-Resistant Epilepsy on the Ketogenic Diet.
The ketogenic diet, including both classic and modified forms, is an alternative to antiepileptic medications used in the treatment of drug-resistant epilepsy. We sought to evaluate the utility of proton MR spectroscopy for the detection of β-hydroxybutyrate in a cohort of children with epilepsy treated with the ketogenic diet and to correlate brain parenchymal metabolite ratios obtained from spectroscopy with β-hydroxybutyrate serum concentrations. Twenty-three spectroscopic datasets acquired at a TE of 288 ms in children on the ketogenic diet were analyzed with LCModel using a modified basis set that included a simulated β-hydroxybutyrate resonance. Brain parenchymal metabolite ratios were calculated. Metabolite ratios were compared with serum β-hydroxybutyrate concentrations, and partial correlation coefficients were calculated using patient age as a covariate. β-hydroxybutyrate blood levels were highly correlated to brain β-hydroxybutyrate levels, referenced as either choline, creatine, or N-acetylaspartate. They were inversely but more weakly associated with N-acetylaspartate, regardless of the ratio denominator. No strong concordance with lactate was demonstrated. Clinical MR spectroscopy in pediatric patients on the ketogenic diet demonstrated measurable β-hydroxybutyrate, with a strong correlation to β-hydroxybutyrate blood levels. These findings may serve as an effective tool for noninvasive monitoring of ketosis in this population. An inverse correlation between serum β-hydroxybutyrate levels and brain tissue N-acetylaspartate suggests that altered amino acid handling contributes to the antiepileptogenic effect of the ketogenic diet.


Diagnostic, clinicopathologic, therapeutic and prognostic value of Plasma Heat Shock Protein 90 levels in patients with advanced Gastrointestinal Carcinoma.
Purpose: Heat shock protein 90 (HSP90) is a critical molecular chaperone for protein folding, intracellular disposition and regulation of tumor biological behavior in the extracellular space. HSP90 has received much attention due to its specific effect in gastrointestinal cancer. This clinical study sought to determine whether HSP90 in plasma may serve as a biomarker in patients with advanced gastrointestinal carcinoma. Methods: Using human plasma samples of advanced gastrointestinal carcinoma, we investigated the specific value of HSP90 in gastrointestinal cancer from a clinical perspective. Results: In summary, plasma levels of HSP90 were shown to be higher in patients with gastric cancer (GC) or colorectal cancer (CRC) than in controls with benign gastrointestinal diseases. In both GC and CRC patients, HSP90 was significantly associated with live metastasis. Higher HSP90 levels were more frequent in CRC patients with hazardous or harmful alcohol consumption habits. Patients with RAS mutations had higher HSP90 levels in CRC. Compared with Carcinoembryonic Antigen (CEA) and Carbohydrate Antigen 19-9 (CA19-9), HSP90 benefited patients by enhancing diagnostic sensitivity and the Youden index. The levels of HSP90 were inversely associated with short-term efficacy in GC patients who had received fluorouracil/platinum-based advanced first-line treatment. When first-line therapy failed, plasma HSP90 levels in patients with GC were significantly increased. In terms of progression-free survival (PFS), patients with GC or CRC who had low levels of HSP90 were not significantly different from those with high levels of HSP90. Univariate and multivariate analyses demonstrated that HSP90 was not an independent prognostic predictor for GC and CRC patients with PFS. However, RAS mutation was an independent prognostic factor for poor PFS in CRC patients. Conclusions: Plasma HSP90 levels have potential diagnostic value in advanced gastrointestinal carcinoma and therapeutic predictive value in GC.


Post-operative complications in elderly onset inflammatory bowel disease: a population-based study.
IBD diagnosed after the age of 60 is increasing. Data on post-operative complications in elderly onset IBD are scarce. To describe the incidence of and factors associated with post-operative complications in elderly onset IBD, diagnosed after the age of 60. Using EPIMAD Cohort (1988-2006), among 841 incident IBD patients, 139 (17%) underwent intestinal surgery, including 100 Crohn's disease (CD) and 39 ulcerative colitis (UC). After a median post-operative follow-up of 6 years (2-10), 50 (36%) patients experienced at least 1 complication with a total of 69. During the first 30 post-operative days, the mortality rate was 4%. Thirty-two early complications (<30 days) were observed in 23 patients (17%), with 15 infectious, without significant difference between CD and UC. More than half early post-operative complications (n = 19, 59%) were severe (>grade 2) without significant difference between CD and UC (P = 0.28). Thirty-seven long-term adverse effects of surgical therapy (≥30 days) were observed in 33 patients (24%). Multivariate analysis found (1) acute severe colitis (OR = 7.84 [2.15-28.52]) and emergency surgery (OR = 4.46 [1.75-11.36]) were associated with early post-operative complications, and (2) Female gender (HR = 2.10 [1.01-4.37]) and delay before surgery >3 months (HR = 2.09 [1.01-4.31]) with long-term adverse effects of surgical therapy. One-third of elderly IBD patients experienced at least 1 post-operative complication. Half of the early complications were severe, and infectious. Emergency surgery was the key driver for post-operative complication.


Extreme inbreeding in a European ancestry sample from the contemporary UK population.
In most human societies, there are taboos and laws banning mating between first- and second-degree relatives, but actual prevalence and effects on health and fitness are poorly quantified. Here, we leverage a large observational study of ~450,000 participants of European ancestry from the UK Biobank (UKB) to quantify extreme inbreeding (EI) and its consequences. We use genotyped SNPs to detect large runs of homozygosity (ROH) and call EI when >10% of an individual's genome comprise ROHs. We estimate a prevalence of EI of ~0.03%, i.e., ~1/3652. EI cases have phenotypic means between 0.3 and 0.7 standard deviation below the population mean for 7 traits, including stature and cognitive ability, consistent with inbreeding depression estimated from individuals with low levels of inbreeding. Our study provides DNA-based quantification of the prevalence of EI in a European ancestry sample from the UK and measures its effects on health and fitness traits.


Cadmium-Sensitive Mutants of Arabidopsis thaliana.
A screening procedure for identifying Cd-sensitive mutants of Arabidopsis thaliana is described. With this procedure, two Cd-sensitive mutants were isolated. These represent independent mutations in the same locus, referred to as CAD1. Genetic analysis has shown that the sensitive phenotype is recessive to the wild type and segregates as a single Mendelian locus. Crosses of the mutant to marker strains showed that the mutation is closely linked to the tt3 locus on chromosome 5. In addition to Cd, the mutants are also significantly more sensitive to mercuric ions and only slightly more sensitive to Cu and Zn, while being no more sensitive than the wild type to Mn, thus indicating a degree of specificity in the mechanism affected by the mutation. Undifferentiated callus tissue is also Cd sensitive, suggesting that the mutant phenotype is expressed at the cellular level. Both wild-type and mutant plants showed increased sensitivity to Cd in the presence of buthionine sulfoximine, an inhibitor of the biosynthesis of the cadmium-binding (gamma-glutamylcysteine)(n)-glycine peptides, suggesting that the mutant is still able to synthesize these peptides. However, the effects of a cad1 mutation and buthionine sulfoximine together on cadmium sensitivity are essentially nonadditive, indicating that they may affect different aspects of the same detoxification mechanism. Assays of Cd uptake by intact plants indicate that the mutant is deficient in its ability to sequester Cd.


Expression patterns of nociceptin in rats following experimental tooth movement.
To determine the expression levels of nociceptin following experimental tooth movement. A total of 72 male Sprague-Dawley rats were divided into two groups: sham and experimental groups. For the experimental group, closed coil springs were used to mimic orthodontic force (80 g) between upper incisors and first molars, and the rats were killed at 0 hours, 4 hours, 12 hours, 1 day, 2 days, 5 days, 7 days, 10 days, and 14 days. All of these procedures were similar for the sham group, except for that no force was applied. The four rats killed at 0 hours without any intervention were used as the baseline control in each group. Trigeminal nucleus caudalis from both the ipsilateral and contralateral sides of force applications were obtained for immunostaining. Nociceptin was expressed in both the ipsilateral and contralateral sides of each group. Its expression levels started to increase on day 2, peaked on day 7, and returned to baseline on day 10 in the experimental group, while expression levels started to decrease on day 1 and returned to baseline on day 10 in the sham group. Moreover, the expression levels were similar between the ipsilateral and contralateral sides in each group. The expression levels of nociceptin were elevated following experimental tooth movement. The anesthetic agent used in this study (chloral hydrate) may have an antagonism with nociceptin. Due to bilateral innervation of anterior teeth and bilateral projection of nerve fibers, the expression levels of nociceptin were similar between ipsilateral and contralateral sides.


A simple analytical expression for the gradient induced potential on active implants during MRI.
During magnetic resonance imaging, there is an interaction between the time-varying magnetic fields and the active implantable medical devices (AIMD). In this study, in order to express the nature of this interaction, simplified analytical expressions for the electric fields induced by time-varying magnetic fields are derived inside a homogeneous cylindrical volume. With these analytical expressions, the gradient induced potential on the electrodes of the AIMD can be approximately calculated if the position of the lead inside the body is known. By utilizing the fact that gradient coils produce linear magnetic field in a volume of interest, the simplified closed form electric field expressions are defined. Using these simplified expressions, the induced potential on an implant electrode has been computed approximately for various lead positions on a cylindrical phantom and verified by comparing with the measured potentials for these sample conditions. In addition, the validity of the method was tested with isolated frog leg stimulation experiments. As a result, these simplified expressions may help in assessing the gradient-induced stimulation risk to the patients with implants.


Fast separations by capillary electrophoresis hyphenated to electrospray ionization time-of-flight mass spectrometry as a tool for arsenic speciation analysis.
Fast capillary electrophoresis (CE) hyphenated to time-of-flight mass spectrometry (TOF-MS) of four organoarsenic species (glycerol oxoarsenosugar, sulfate oxoarsenosugar, arsenobetaine, arsenocholine) are presented using short length CE capillaries under high electric field strengths of up to 1.3 kV cm(-1) with small inner diameter (ID). The separation of arsenosugars by CE is demonstrated for the first time. An aqueous formic acid solution was employed as the background electrolyte (BGE) for the separation. Various acid concentrations were evaluated for their influence on migration times, separation efficiency as well as with regard to controlling the charge of the arsenic species. A 0.1 M formic acid/ammonium formate buffer (pH 2.8) proved to be suitable for the separation of the four species. A non-aqueous BGE was tested as an alternative buffer system for fast speciation analysis. Separation of arsenobetaine and arsenocholine could even be achieved within 10 s by pressure-assisted CE. Application of the optimized method for the analysis of extracts of a seagrass and a Wakame algae sample as well as the brown algae homogenate reference material IAEA-140/TM revealed a clear signal for the glycerol arsenosugar.


An anatomic study of the quadratus plantae in relation to tendinous slips of the flexor hallucis longus for gait analysis.
The aim of this study was to demonstrate the morphology of the quadratus plantae (QP) in relation to the tendinous slips of the flexor hallucis longus (FHL) and their surrounding structures, thereby providing data to understand function of the QP during gait, and for analyzing the movements of the foot and designing postoperative rehabilitation programs. The QP was investigated in 50 specimens of embalmed adult cadavers. The QP inserted into the tendon of the flexor digitorum longus (FDL) and the tendinous slips of the FHL in 96%, and only to the tendon of the FDL in 4%. The tendinous slip of the FHL targeted the tendon for the second toe in 4 of the 50 specimens (8%). The tendinous slip divided into two separate slips to the tendons for the second and third toes in 32 specimens (64%), and for the second, third, and fourth toes in 14 specimens (28%). Thus, the tendon and tendinous slips of the FHL may distribute the load of the great toe to the second toe to the third or fourth toe in the forefoot, especially during toe-off. In addition, the main attachment of the QP to the tendinous slips of the FHL may provide more efficient control of the long flexor tendons in comparison with that of the QP to the tendon of the FDL.


Specific binding of chromosomal protein HMG1 to DNA damaged by the anticancer drug cisplatin.
The mechanism of action of the anticancer compound cis-diamminedichloroplatinum(II) (cisplatin) involves covalent binding to DNA. In an effort to understand the tumor-specific cytotoxicity of such DNA damage, the interactions of these lesions with cellular proteins have been studied. One such protein has been identified as the high-mobility group protein HMG1. Recombinant rat HMG1 binds specifically (dissociation constant 3.7 +/- 2.0 x 10(-7) molar) to DNA containing cisplatin d(GpG) or d(ApG) intrastrand cross-links, which unwind and bend DNA in a specific manner, but not to DNA modified by therapeutically inactive platinum analogs. These results suggest how HMG1 might bind to altered DNA structures and may be helpful in designing new antitumor drugs.


Explaining the Process of Spiritual healing of Critically-ill Patients: A Grounded Theory Study.
Spiritual healing is one of the most intriguing category of alternative and complementary medicine. The aim of this study was to explain the process of spiritual healing in patients with refractory diseases in Iran. This grounded theory study was conducted in Iran from 2018 to 2019. The participants were 14 patients with refractory diseases and 4 healers whom were first selected through purposeful and then theoretical sampling. Semi-structured interviews were used to collect data on patients and healers. All the interviews were transcribed verbatim. Data were coded and grouped under specific categories and analyzed using the Strauss and Corbin's approach (2008). Four main categories emerged from data analysis including: I) frustration to initial acceptance II) disbelief to trust III) evaluation to action and IV) doubt to certainty. The results of our study provide context-specific factors affecting the complex and multifactorial nature of spiritual healing process in patients with refractory diseases. Health care professional can use these findings in designing and implementing appropriate interventions to integrate spiritual healing into their holistic practices of care.