Heterologous prion-forming proteins interact to cross-seed aggregation in Saccharomyces cerevisiae.
The early stages of protein misfolding remain incompletely understood, as most mammalian proteinopathies are only detected after irreversible protein aggregates have formed. Cross-seeding, where one aggregated protein templates the misfolding of a heterologous protein, is one mechanism proposed to stimulate protein aggregation and facilitate disease pathogenesis. Here, we demonstrate the existence of cross-seeding as a crucial step in the formation of the yeast prion [PSI +], formed by the translation termination factor Sup35. We provide evidence for the genetic and physical interaction of the prion protein Rnq1 with Sup35 as a predominant mechanism leading to self-propagating Sup35 aggregation. We identify interacting sites within Rnq1 and Sup35 and determine the effects of breaking and restoring a crucial interaction. Altogether, our results demonstrate that single-residue disruption can drastically reduce the effects of cross-seeding, a finding that has important implications for human protein misfolding disorders.


High weight loss during radiation treatment changes the prognosis in under-/normal weight nasopharyngeal carcinoma patients for the worse: a retrospective analysis of 2433 cases.
Although weight loss is common in nasopharyngeal carcinoma (NPC) patients receiving radiotherapy, the prognostic influence of weight loss and its impact modified by body mass index (BMI) are still unclear. 2433 NPC patients receiving radical radiotherapy at Sun Yat-sen University Cancer Center from November, 2000 to December, 2004 were enrolled. Weight change during radiation treatment was categorized into high weight loss (HWL) and low weight loss (LWL). The associations of HWL with overall survival (OS) and disease-specific survival (DSS) were analyzed by Cox regression. Among underweight patients, HWL was independently associated with poor OS (hazard ratio [HR], 2.06; 95% CI 1.36-3.11) and DSS (HR, 2.27; 95% CI 1.38-3.73), as compared with LWL, after adjusting for covariates. In normal weight patients, the impact of HWL on OS (HR, 1.47; 95% CI 1.19-1.80) and DSS (HR, 1.59; 95% CI 1.24-2.03) was moderate. Among overweight/obese patients, no significant association between HWL and OS (HR, 1.22; 95% CI 0.95-1.55), or DSS (HR, 1.23; 95% CI 0.93-1.64) was found. Except for overweight/obese patients, high weight loss during radiation treatment was independently associated with poor survival in NPC. This impact was more prominent in the underweight patient group.


The C. elegans dosage compensation complex mediates interphase X chromosome compaction.
Dosage compensation is a specialized gene regulatory mechanism which equalizes X-linked gene expression between sexes. In Caenorhabditis elegans, dosage compensation is achieved by the activity of the dosage compensation complex (DCC). The DCC localizes to both X chromosomes in hermaphrodites to downregulate gene expression by half. The DCC contains a subcomplex (condensin I(DC)) similar to the evolutionarily conserved condensin complexes which play fundamental roles in chromosome dynamics during mitosis and meiosis. Therefore, mechanisms related to mitotic chromosome condensation have been long hypothesized to mediate dosage compensation. However experimental evidence was lacking. Using 3D FISH microscopy to measure the volumes of X and chromosome I territories and to measure distances between individual loci, we show that hermaphrodite worms deficient in DCC proteins have enlarged interphase X chromosomes when compared to wild type. By contrast, chromosome I is unaffected. Interestingly, hermaphrodite worms depleted of condensin I or II show no phenotype. Therefore X chromosome compaction is specific to condensin I(DC). In addition, we show that SET-1, SET-4, and SIR-2.1, histone modifiers whose activity is regulated by the DCC, need to be present for the compaction of the X chromosome territory. These results support the idea that condensin I(DC), and the histone modifications regulated by the DCC, mediate interphase X chromosome compaction. Our results link condensin-mediated chromosome compaction, an activity connected to mitotic chromosome condensation, to chromosome-wide repression of gene expression in interphase.


A rare case report of tracheal leech infestation in a 40-year-old woman.
Leeches are the very rare types of airway foreign body. Here we report a rare case of a 40-year-old woman with tracheal leech infestation. A 40-year-old woman presented 2-month history of dyspnea, occasional haemoptysis. There were foreign body sensation in throat, cough and hoarseness. Computed Tomography (CT) revealed some soft tissue shadow in the upper trachea. Eventually a 5 cm long living leech was smoothly removed from trachea by rigid bronchoscopy under sevoflurane general anesthesia. The airway leech infestation should be kept in mind especially in patients presenting with unexplained haemoptysis, dyspnea, hoarseness and a foreign body sensation in the throat and a history of drinking infested water from streams, pools and spring. General anesthesia might be necessary for the removal of the leech.


Intravenous glomus tumour of the upper arm.
Glomus tumours are rare, benign tumours of the glomus body, most frequently located in the subungual region of digits, palms and soles, but they have been reported throughout the body. Our patient is a 65-year-old man who presented with a 3-year history of a very painful area on his left upper arm. The overlying skin was normal and there was no lesion to palpate, but the symptoms were very striking, warranting further investigation. An exploratory operation identified a prominent vein with a noticeable bulge in the vessel wall. The vein was ligated and excised. On dissection of the vein, a tumour was present within its lumen. Histological examination and immune profile of the tumour confirmed an intravascular glomus tumour. Following surgical excision, symptoms resolved.


Education and training in occupational hygiene in the United Kingdom.
Occupational hygiene education and training is undergoing rapid changes both in the United Kingdom and elsewhere, developing closer links with safety and environmental matters whilst retaining the essential and well developed links with occupational medicine. At the same time major developments in the role of professional accreditation bodies including BEBOH are being reviewed. This paper identifies recurring themes on the scope of professionalism, accreditation and the requisite education and training for occupational hygienists.


Influence of composite flour constituents and extrusion temperature in the production of analog rice.
This study was conducted to determine the effect of composite flour (CF) constituents and different extrusion temperatures on the production of analog rice and community perceptions about the produced rice. CF was produced by mixing modified cassava flour (Mocaf) and snakehead fish flour (SF) in the following ratios: 100:0; 97:3; 94:6; 91:9; and 88:12. Analog rice was then extruded from CF at the following temperatures: 50, 70, and 90°C. The analog rice was tested for physical properties (bulk density and cooking time), chemical properties (nutrient content), and organoleptic properties. The results showed that CF and extrusion temperature affect the nutrient content of analog rice. The best analog rice formulation constituted of CF with Mocaf:SF ratio of 91:9 and extrusion temperature of 70°C, and contained 14.34% water, 0.85% ash, 71.83% carbohydrate, 11.24% protein, 1.12%, calcium 1,113 ppm, and 2.43% dietary fiber. This study included 42 respondents aged 20-23 years, including 20 males and 22 females. All the respondents showed acceptance for the analog rice, suggesting that it could substitute ordinary rice as a staple food.


Immunobiology of Norwalk virus.
Clinical immunity to Norwalk virus in inoculated human volunteers appears to be unusual for gastroenteritis viruses, as certain individuals are repeatedly ill on long-term virus rechallenge and others remain persistently well. In these volunteers there is a paradoxical inverse correlation between the prechallenge serum (and jejunal fluid) Norwalk antibody level (measured by radioimmunoassay) and resistance to illness, suggesting that non-immunological factors, perhaps genetic, may be important in determining resistance. Most reported naturally occurring Norwalk disease outbreaks in developed nations also show that humoral antibody fails to correlate with immunity to infection. The unusual pattern of clinical immunity to Norwalk virus indicates a need for caution in the development of vaccines against this agent as well as a need for additional information on its immunobiological characteristics. The virus is known to contain a single protein, like the caliciviruses. Recently we have found evidence for at least a one-way serological cross-relatedness between Norwalk virus and human calicivirus. Twelve of 20 paired sera from ill patients in outbreaks due to calicivirus strain UK4 seroconverted to Norwalk virus by radioimmunoassay and two of eight paired sera from UK2 outbreaks showed seroconversion. Future studies of outbreaks caused by various calicivirus strains should be designed to correlate acute-phase serum antibody titres to Norwalk virus with clinical susceptibility and immunity to infection.


Influence of modification of Na2O in a glass matrix on the strength of leucite-containing porcelains.
The desirable thermal properties of matrix glass to the strength of feldspar porcelain with leucite crystal were investigated. Five kinds of feldspar glasses, each with different a content of Na2O, were prepared for the matrix glasses of the leucite-containing porcelains. The specimens were arranged by mixing each glass powder with high-purity natural leucite crystals (0, 20 and 40%) followed by firing. The thermal properties of the glass and the transformation temperature of the leucite were measured. A three-point bending test was performed to measure the flexural strength of the porcelains. The glass transition temperature and deformation temperature of the glass-only porcelains were decreased as the Na2O content increased. The Na2O-modified glasses were substantially strengthened by the leucite dispersion. However, the strength of the porcelains was affected by the relation between the transformation temperature of the leucite and the thermal properties of the glass matrix. It was concluded that control of the residual stress in the composite porcelain is an important factor in developing high strength porcelain containing leucite.


Somatic cell nuclear transfer: recent progress and challenges.
Somatic cell nuclear transfer (NT) offers new and exciting opportunities in many areas of research and biotechnology. However, the field as a whole is still in its infancy, with continuing inefficiencies in the process proving many early expectations premature. The technical steps of NT are complex, and success is highly susceptible to minor variations. Furthermore, the biological process of reprogramming is not fully understood, making it difficult to optimize the protocols for providing ideal recipient oocytes and donor cells. In this paper, we describe recent advances and novel approaches, which resulted in progress during the last year, including the birth of cloned piglets and farm animals with precise genetic changes. Key problems hindering further progress are addressed.


Quality of life associated with varying degrees of chronic lower limb ischaemia: comparison with a healthy sample.
To assess quality of life in patients with varying degrees of ischaemia in comparison with controls, and to determine whether the degree of lower limb ischaemia and sense of coherence were associated with quality of life. 168 patients, including 93 claudicants and 75 patients with critical ischaemia and 102 controls were studied. Quality of life was assessed using the Nottingham Health Profile in addition to the Sense of Coherence scale. Patients with lower limb ischaemia scored significantly reduced quality of life in all aspects compared to controls. Pain, physical mobility and emotional reactions were the significant independent factors when using logistic regression analysis. The grade of disease and low sense of coherence were significantly associated with low quality of life. Increasing lower limb ischaemia significantly conferred worse pain, sleeping disturbances and immobility. This study showed that the quality of life was impaired among patients with lower limb ischaemia, in all investigated respects. The degree to which quality of life was affected seems to represent an interplay between the grade of ischaemia and the patient's sense of coherence. This suggests the need for a multidimensional assessment prior to intervention.


Early modern "citation index"? Medical authorities in academic treatises on plague (1480-1725).
The paper deals with the problem of early modern scientific citations. It attempts to establish a measure of scientific popularity in a specific area of the academic medicine in a way which resembles a modern evaluation of scientific activity (citation index). For this purpose an analysis of a series of plague treatises written between 1480 and 1725 in Europe was conducted. Citations for various historical medical authorities (Hippocrates, Galen, etc.) are given in Tables which reflect a long time development of popularity. The authorities from various groups (Ancient, Medieval, Arabic, Early Modern) are linked together, and "generic authorities" are explained and discussed.


Effects of weaning on plasma levels of prolactin, oxytocin, insulin, glucagon, glucose, gastrin and somatostatin in sows.
The effect of total weaning (all piglets were weaned at 35 days of lactation) and fractionated weaning (the heavier half of the litter was weaned on day 33 of lactation and the remainder 2 days later) on plasma levels of prolactin, oxytocin, insulin, glucagon, glucose, gastrin and somatostatin in primiparous sows was studied. Twelve crossbred sows were grouped into six pairs according to farrowing data and litter size. The litter of one sow in each pair was weaned in two stages (treatment), and the other was conventionally weaned (control). Blood samples were collected via a permanent jugular vein catheter every 3 hours from 9 a.m. to 9 p.m. from day 31 of lactation until the third day of final weaning. In response to total weaning (studied in the six control sows), plasma prolactin, glucagon and gastrin decreased significantly, whereas plasma insulin and somatostatin significantly increased. Basal concentrations of plasma oxytocin and glucose remained unchanged after weaning. Fractionated weaning did not result in any significant differences in the hormonal and glucose levels as compared with the total weaning. The possible role of prolactin in modulating insulin, glucagon and glucose concentrations as well as the possibility that oxytocin affects gastrin and somatostatin levels following weaning are discussed.


Microcomputer-based image analysis systems for two-dimensional electrophoresis gels.
The intent of this overview is to provide the readers, especially those who are currently conducting two-dimentional electrophoresis, a basic understanding in the construction and use of microcomputer-based systems for the analysis of protein profiles generated by two-dimensional gel electrophoresis. In addition, a microcomputer-based system, employing fixed-point operations and effective algorithms, has been evaluated. The validity of this system has been demonstrated by using the two-dimensional silver-stained gels and fluorograms derived from the rat prostate. It is concluded that the present system can be used to aid the analysis of two-dimensional electrophoresis gels. An overall consideration of hardware and software components of a computer-based system is briefly discussed.


Regulation of the homologous two-component systems KvgAS and KvhAS in Klebsiella pneumoniae CG43.
In Klebsiella pneumoniae CG43, deletion of the sensor gene kvgS reduced the kvgAS expression in M9 medium with 0.2 mM paraquat, 0.2 mM 2,2-dihydropyridyl, or 300 mM NaCl. This result shows an autoregulatory role of KvgS and a stress-responsive expression of the two-component system (2CS). The kvgS deletion also appeared to decrease the expression of kvhAS, paralogous genes of kvgAS. Additionally, measurements of the promoter activity in kvgA(-) mutant revealed that KvgA is probably an activator for the expression of kvgAS and kvhAS. The subsequent electrophoretic mobility shift assay, indicating a specific binding of the recombinant KvgA to the putative promoters P(kvgAS) and P(kvhAS), also supported an interacting regulation between the 2CSs. In P(kvgAS) and P(kvhAS), the presence of RpoS binding elements suggested an RpoS-dependent regulation. Nevertheless, the rpoS deletion reduced the expression of kvgAS but increased that of kvhAS. Moreover, the kvgA deletion reduced the expression of katG and sodC. The overexpression of KvhA altered the susceptibility to fosfomycin and an increasing activity of UDP-N-acetylglucosamine enolpyruvyl transferase, the target protein of fosfomycin, which suggesting a regulation by KvhA. Taken together, these indicated that the two 2CSs probably belong to different regulatory circuits of the RpoS regulon.


[Inhibition of liver metastases in rabbits by arterial infusion of angiogenesis inhibitor, TNP-470].
We examined the prevention of liver metastases by arterial infusion of the angiogenesis inhibitor, TNP-470, in Japanese White Rabbits; 1.0 x 10(6) of VX2 carcinoma cells were injected into the mesenteric vein for tumor inoculation. Then the rabbits were divided into the following two groups. Group 1: 2 ml of distilled water was continuously injected into the common hepatic artery of control for 7 days. Group 2: 50 mg of TNP-470 solved in 2 ml of distilled water was continuously administered into the common hepatic artery for 7 days. On day 14, the number of metastases on each liver surface was counted. The mean number of metastases were 237.0 +/- 133.26 and 24.4 +/- 15.05 in Group 1 and 2, respectively. There was a significant difference between the two groups (p < 0.05). We found no side effects of TNP-470 such as body weight loss or liver disfunction. Microphil was injected into the common hepatic artery to observe the neovasculature. The proliferation of tumor vessels was suppressed in Group 2. We considered that arterial infusion of TNP-470 is effective to prevent liver metastases, because the blood supply to liver metastases is well developed from the hepatic artery, and TNP-470 is directly effective on the endothelium itself, and inhibits neovascularization.


Effects of synthetic human gastric inhibitory polypeptide on splanchnic circulation in dogs.
Changes in blood flow in the celiac artery, superior mesenteric artery, and pancreas in response to an intravenous injection of synthetic human gastric inhibitory polypeptide (GIP) were determined simultaneously and continuously in anesthetized dogs, using a transit-time ultrasonic flowmeter and a laser-Doppler flowmeter. Injection of GIP significantly increased superior mesenteric arterial flow in a dose-related manner (by 9%, 43%, and 139% at 30 s after an injection at the doses of 3, 50, and 800 pmol/kg, respectively). In contrast, celiac arterial flow was not significantly altered by GIP at any of the three doses. Calculated vascular resistance in the superior mesenteric artery decreased after GIP infusion, whereas that in the celiac artery was not changed by GIP. Pancreatic blood flow decreased significantly after GIP injection at the doses of 50 and 800 pmol/kg (by 11% and 17%, respectively). Our data indicate that there is a substantial difference in the hemodynamic responses to GIP among splanchnic organs, and suggest that GIP acts specifically on the mesenteric vasculature.


The factor structure of the internet addiction tool with university students in Jordan.
Internet addiction is a growing phenomenon affecting people in varying ways around the globe. This study examined the factor structure and internal reliability of the Internet Addiction Test (IAT) with a heterogeneous sample of university students in Jordan. The study used a cross-sectional design, and all the questionnaires were completed in classrooms. A sample of 587 students from seven universities in Jordan was obtained. The exploratory and confirmatory factor analyses of the 20-item IAT revealed that a four-factor solution offered the most parsimonious explanation of the data. The IAT reliably assesses distinct domains of Internet addiction. These domains are Excessive Use, Loss/Suffer, Attached To, and Impaired Social Relations. Thus, it is recommended to use the obtained four factors when assessing Internet addiction among a similar population.


Phytoextraction of Cd-Contaminated Soils: Current Status and Future Challenges.
Cadmium (Cd) is one of the most toxic and widely distributed pollutants in the environment. Cadmium contamination of soils has posed a serious threat to safe food production in many parts of the world. The authors present a comprehensive review of present status of phytoextraction technology for cleaning up Cd-contaminated soils, based primarily on the data resulting from both laboratory and field-scale studies that have been conducted to assess or improve the Cd phytoextraction potential of various plant species in the past decade. The encouraging results of field-scale studies have provided a fundamental basis to usher phytoextraction technology into practical use to remediate slightly to moderately Cd-contaminated soils in Europe and Asia, although this technology is not yet ready for widespread application. Chelators and microorganisms tested so far seem not to contribute to the applicability of Cd phytoextraction. The major challenges for the large-scale application of Cd phytoextraction are (a) how to further improve the efficiency of Cd phytoextraction, (b) how to cut the overall costs of Cd phytoextraction, and (c) how to get greater stakeholders' acceptance of Cd phytoextraction as a reliable option.


NMR Study on Ion Dynamics and Phase Behavior of a Piperidinium-Based Room-Temperature Ionic Liquid: 1-Butyl-1-methylpiperidinium Bis(fluorosulfonyl)amide.
By use of pulse NMR methods, the temperature dependences of the longitudinal and transverse relaxation times for (1)H and (19)F were measured for the three phases of 1-butyl-1-methylpiperidinium bis(fluorosulfonyl)amide ([Pip1,4][FSA]), i.e., liquid or supercooled liquid, Cryst-α, and Cryst-β, to investigate the ion dynamics and phase behavior related to the dynamics. Since the cations and anions in the room-temperature ionic liquid have (1)H and (19)F nuclei, respectively, the dynamics of the [Pip1,4] cation and [FSA] anion can be independently observed and the relation between them can be evaluated. The relevant local motions of the ions are fluctuational motion around the chair form of the piperidinium ring, libration or rotation of the alkyl groups, and libration or rotation of the SO2F groups around the N-S axes. Each phase preferentially exhibits these motions. In the Cryst-β phase, it is thought that O atoms in the SO2F groups form strong hydrogen bonds with the H atoms in the piperidinium ring. As a result, the motions of the SO2F groups and the piperidinium ring are restricted. In the liquid or supercooled liquid states and Cryst-α phase, the motion of the anion is more significant than that of the cation and the former works as a trigger for phase changes. Particularly, the motion of the SO2F groups in the Cryst-α phase becomes very significant with rising temperature and is directly related to the melting phase transition.


Regional anaesthesia for bilateral upper limb surgery: a review of challenges and solutions.
Regional anaesthesia for bilateral upper limb surgery can be challenging, yet surgeons are becoming increasingly interested in performing bilateral procedures at the same operation. Anaesthetists have traditionally avoided bilateral brachial plexus block due to concerns about local anaesthetic toxicity, phrenic nerve block and pneumothorax. We discuss these three concerns and review whether advances in ultrasound guidance and nerve catheter techniques should make us reconsider our options. A search of Medline and EMBASE from 1966 to January 2009 was conducted using multiple search terms to identify techniques of providing anaesthesia or analgesia for bilateral upper limb surgery and potential side-effects. Ultrasound imaging and nerve catheter techniques have led to a reduction in dose requirements for effective blocks without side-effects. Effective regional anaesthesia can be performed for bilateral surgery while remaining within recommended safe dose limits. Spacing blocks apart in time can further reduce potential toxicity issues, such that peak absorption rates for each block do not coincide. Since phrenic nerve block remains an issue even with low doses of local anaesthesia, bilateral interscalene blocks are still not recommended. Peripheral nerve blocks have excellent safety profiles and are ideal for ultrasound guidance. Regional anaesthesia can be a suitable option for bilateral upper limb surgery.


Hot tar burns: twenty-seven hospitalized cases.
Between July 1, 1984, and December 31, 1991, 27 consecutive patients required admission to the Grady Memorial Hospital Burn Unit for care of hot tar burns. This group represented 1.4% of all admissions to this burn unit. Injuries occurred at the workplace and occurred mostly during the summer. They most commonly involved the patient slipping while carrying a bucket of hot tar. Ninety-six percent were male. The mean age was 33.7 years. Mean burn size was 13.1% total body surface area. Burn topography centered on the upper extremities and hands. Forty-one percent required a surgical procedure for their burn. Mean hospitalization time for survivors was 16.6 days. The survival rate was 92.6%. Both of the patients who died had large burns and/or preexisting medical problems. Hot tar burns occur under predictable circumstances, appear to be preventable, and have accounted for only a small fraction of all admissions to this burn unit.


Optical Ion Sensing Platform Based on Potential-Modulated Release of Enzyme.
We report here on an optical ion sensing platform, in which a polymeric membrane ion-selective electrode (ISE) serves as not only a potentiometric transducer for ion activities in the sample solution but also a reference electrode for the potential-modulated release of enzyme from an iron-alginate-horseradish peroxidase (HRP) thin film modified working electrode. The ISE and working electrode are physically separated by a salt bridge. The dissolution of the HRP-embedded thin film can be triggered by the reduction of Fe3+, which is modulated by the potential response of the ISE to the target ion in the sample. The released enzyme induces the oxidation of its substrate mediated by H2O2 to produce a visual color change. With this setup, an optical ion sensing platform for both cations (e.g., NH4+) and anions (e.g., Cl-) can be obtained. The proposed platform provides a general and versatile visual-sensing strategy for ions and allows optical ion sensing in colored and turbid solutions.


[The background factors influencing loss of sexual intercourse after transurethral resection of the prostate (TUR-P)--A study using the Sapporo Medical University-Questionnaire].
Sexual dysfunction after transurethral resection of the prostate (TUR-P) depends on multiple factors including preoperative erectile function itself. Using the Sapporo Medical University-questionnaire, we analyzed background factors contributing to loss of sexual intercourse after the operation. We sent the self-administered questionnaires to 1,000 patients who had received TUR-P. Answers to questions were ranked as scores. Multiple regression analysis was used to identify factors significant for loss intercourse after TUR-P. The response rate was 63.5%. Patient with incomplete answers and those having diseases affecting voiding or sexual function and antiandrogen medication were excluded from the study. Leaving 536 patients for the final analysis. Scores for sexual desire and erectile function in the patients who received TUR-P were lower than those of age-matched healthy males. When we divided the patients according to frequency of sexual intercourse before and after TUR-P, there was distinct differences in age, scores for sensory disturbance, depression, the cooperative value of the sexual partner, sexual desire, erectile function, nocturia, residual sensation and urgency between those maintaining sexual intercourse and those having lost it. Multiple regression analysis using these factors indicated that the scores of erectile function was the most significant determinant for maintaining sexual intercourse after TUR-P in patients aged from 50 to 69 years, followed by the cooperative value of the sexual partner, residual sensation and sensory disturbance. In those 70 old and older, the score for erectile function was the most significant determinant, followed by the cooperative value of sexual partner. Our results suggest that, irrespective of age, the cooperation of the patient's sexual partner as well as erectile function significantly influence the maintenance of sexual intercourse after TUR-P. In addition, voiding condition and psychological status after TUR-P may affect the maintenance of sexual intercourse in patients in their fifties and sixties.


The differential regulation of microRNAs is associated with oral cancer.
Oral squamous cell carcinoma (OSCC), is the most frequently occurring malignant head and neck tumor, generally it exhibits a poor prognosis, and metastasis is the main cause of death in these cancer patients. The discovery of reliable prognostic indicators for tumors progression would greatly improve clinical treatments. MicroRNAs (miRNAs) play a critical role in the degradation of mRNA and the inhibition of protein synthesis. The miRNAs function either as tumor suppressors or as oncogenes in tumorigenesis, and little is known about the clinical significance of miRNA expression profiles in oral cancers. In the present study, we investigated the expression profiles of miR-375, miR-204 and miR-196a in 39 healthy and tumor tissue pairs of oral cancer patients using TaqMan real-time quantitative polymerase chain reaction (qPCR). The predicted target genes for miR-375, miR-204 and miR-196a were confirmed using luciferase reporter-based assays and western blot analyses. In oral cancer tissue, the expression of miR-375 and miR-204 decreased, whereas the expression of miR-196a was significantly elevated. In OSCC, HOXB8 and p27 (CDKN1B) were the direct target genes of miR-196a, whereas HMGA2 was the direct target gene of miR-204. HOXB8 and p27 (CDKN1B) protein expression levels were inhibited by miR-196a, whereas the protein expression level of HMGA2 was inhibited by miR-204. Furthermore, the miR-196a inhibitor blocked cell proliferation. Our results indicate that the combined expression signatures of miR-375, miR-204 and miR-196a are promising biomarkers for the diagnosis, prognosis and treatment of OSCC.


Downregulation of ubiquitin-specific protease 2 possesses prognostic and diagnostic value and promotes the clear cell renal cell carcinoma progression.
Clear cell renal cell carcinoma (ccRCC), characterized by high mortality, invasion, metastasis, recurrence and drug resistance, is the most common malignant tumor of the urinary system. A clear understanding of the underlying molecular mechanisms and its role during tumorigenesis of RCC can contribute to development of prognostic and targeted therapies. We analyzed datasets from the public database, TCGA, Oncomine, for differential expression of ubiquitin-specific protease 2 (USP2), and further investigated its relationship with the clinical stage, pathological grade and prognosis of renal cancer. We used real-time quantitative PCR and western blot analysis to validate USP2 expression in clinical samples and renal cancer cell lines. Finally, we used CCK-8 and transwell assays to determine its effects on biological functions in cells. We observed significantly lower levels of USP2 mRNA in renal cancer, relative to normal, tissues across the four datasets from the Oncomine database (P<0.001), 533 cases from TCGA database (P<0.0001) and 30 pairs of clinical samples (P<0.0001). Similarly, a decreased USP2 protein expression in ccRCC was detected following immunohistochemical (IHC) and western blot analyses. Furthermore, the aberrant expression of USP2 resulted in significant relationship with clinical stage, pathological grade and lower USP2 mRNA expression was interrelated to poor prognosis of renal cell carcinoma. USP2 acted as an independent factor for ccRCC diagnosis, with an AUC of 0.8888 (95% CI: 0.8529 to 0.9246; P<0.0001). Exogenous restoration of USP2 in ccRCC cells resulted in repression of cell proliferation, migration, and invasion. Overall, these results show that USP2 acts as an anti-oncogene and an independent factor for ccRCC prognosis. Positive modulation of USP2 might lead to development of a novel strategy for ccRCC treatment.


Publicly available data reveals association between asthma hospitalizations and unconventional natural gas development in Pennsylvania.
Since the early 2000s, unconventional natural gas development (UNGD) has rapidly grown throughout Pennsylvania. UNGD extracts natural gas using a relatively new method known as hydraulic fracturing (HF). Here we addressed the association of HF with asthma Hospitalization Admission Rates (HAR) using publicly available data. Using public county-level data from the Pennsylvania Department of Health (PA-DOH) and the Pennsylvania Department of Environmental Protection for the years 2001-2014, we constructed regression models to study the previously observed association between asthma exacerbation and HF. After considering multicollinearity, county-level demographics and area-level covariables were included to account for known asthma risk factors. We found a significant positive association between the asthma HAR and annual well density for all the counties in the state (3% increase in HAR attributable to HF, p<0.001). For a sensitivity analysis, we excluded urban counties (urban counties have higher asthma exacerbations) and focused on rural counties for the years 2005-2014 and found a significant association (3.31% increase in HAR attributable to HF in rural counties, p<0.001). An even stronger association was found between asthma hospitalization admission rates (HAR) and PM2.5 levels (7.52% increase in HAR attributable to PM2.5, p<0.001). As expected, asthma HAR was significantly higher in urban compared to rural counties and showed a significant racial disparity. We conclude that publicly available data at the county-level supports an association between an increase in asthma HAR and UNGD in rural counties in Pennsylvania.


Adaptive Gaze Behavior and Decision Making of Penalty Corner Strikers in Field Hockey.
In recent years, studies have increasingly dealt with the interaction of gaze behavior and decision making of team sports athletes. However, there is still a variety of important game situations, for example, in the case of penalty corners in field hockey, in which this interaction has not been investigated in detail yet. Penalty corners present a meaningful goal scoring opportunity by providing a relatively free shot. This paper considers two studies. The first study investigated a possible connection between the gaze behavior and the quality of decisions of experienced field hockey players and evaluated the level of success of different gaze strategies. A preliminary study (Study 1) was designed as a survey questionnaire with the aim of preparing for the main study by obtaining subjective assessments of the individual gaze behavior and decision making of professional athletes. In the second and the main study (Study 2), the gaze behavior of experienced field hockey players was recorded using mobile eye-tracking systems to analyze different strategical approaches in associated gaze behavior and decision making. Study 1 showed that players consider reacting to the defenders' behavior during a penalty corner a promising avenue for improving success at penalty corner attempts. It also indicated that such defense-dependent strategies are currently only rarely employed. Study 2 demonstrated how gaze behavior differs between different strategical approaches of the offense. It was shown that the gaze direction on the ball, the stopper, and the goal area is important to allow for a more optimal adaptation to the tactical behavior of defense. It can be concluded that adaptive decision making (i.e., choosing which variation will be carried out just after the "injection" of the ball) seems promising but requires further training to improve the success rate of penalty corner.


[Combined antithrombin deficiency and factor VLeiden in a Danish family].
Factor VLeiden (FVL) and antithrombin (AT) deficiency are both known genetic risk factors for venous thromboembolism (VTE). The combination is rare and leads to significantly increased risk for VTE. In this case we present a 22-year-old woman with VTE while treated with oral contraceptives. Laboratory investigation of the patient and her relatives showed co-segregation of FVL and AT deficiency. This is the first Danish family reported with co-segregated FVL and AT deficiency, and this clarifies the importance for thorough laboratory screening of patients presenting VTE while treated with oral contraceptives.


QuantiFERON-TB Gold: state of the art for the diagnosis of tuberculosis infection?
Tuberculosis (TB) remains a major threat to global health. The recently launched Global Plan to Stop Tuberculosis 2006-2015 highlights the need for accurate, simple and low-cost diagnostic tests for the detection of TB infection. For the first time in decades, new diagnostic tools have emerged that may facilitate this goal. The discovery of Mycobacterium tuberculosis-specific immunodominant antigens has led to the development of interferon gamma-release assays that have been shown to have high sensitivity and specificity for TB disease. This review focuses on the QuantiFERON-TB Gold tests and addresses the potential strengths and limitations of the current assays, summarizes the available evidence for their use and identifies areas of future research and development. Although representing an advance in TB diagnostics, with the potential to have a significant impact on global TB control, many issues remain unanswered. The cost of the tests and laboratory requirements may limit their use in developing countries. Most importantly, additional studies are needed in TB-endemic regions, particularly in high-risk persons such as children and individuals who are also co-infected with HIV.


What About the Different Shortened Versions of the Mindful Attention Awareness Scale?
Given the mixed conclusions on the psychometric properties of the Mindful Attention Awareness Scale (MAAS) and the variety of subsets of items identified as abbreviated forms, the current study aimed to (a) further investigate the performance of single items and different combinations of items of the MAAS from within an Item Response Theory framework, (b) to expand upon existing knowledge about the coverage of the construct of the scale and its shortened versions. A sample of 914 participants (67.6% women; mean age 23.28, SD = 4.77) completed the MAAS. To fulfill the second aim of the study, of the total sample, two subsamples (N = 156 and N = 158, respectively) were administered a battery of self-report questionnaires. Analyses attested that four items of the MAAS have weak psychometric properties and that the reliability of the scale remains unchanged when these items are excluded. The relationships with several constructs (consciousness, present-time attitude, emotional intelligence, alexithymia, emotion regulation strategies, behavioral inhibition and activation, affect, anxiety, and depression) provided evidence that the scale adequately reflects the operationalization of the construct, although some facets of the construct are only partially covered. The current findings confirm that the MAAS might be slightly shortened without reducing its reliability and validity, but drastically abbreviated forms, such as the proposed five-item version, fail to maintain adequate psychometric properties.


Monitoring glaucomatous visual field progression: the effect of a novel spatial filter.
To assess the impact of a novel visual field spatial filtering technique on the detection of glaucomatous progression. One hundred ninety-eight ocular hypertensive (OHT) and 21 control subjects were examined prospectively (1994-2001) with regular full-threshold Humphrey visual field (VF) testing. VF progression was assessed by point-wise linear regression (PLR) of sensitivity/time in Progressor for Windows software modified to include a novel spatial filter. Standard progression criteria (slope > -1 dB/year, P < 0.01) were applied to both "raw" (unfiltered) and "filtered" VF series. Three-omitting confirmatory VF criteria were also applied to unfiltered VF series. Specificity was estimated as the proportion of progressing control subjects and as the proportion of significantly improving subjects (both OHT and control) at the end of the study period. Applying standard PLR, specificity was estimated at 91.8% to 97.5% using unfiltered standard PLR, compared with 93.5% to 98.4% using filtered standard PLR and 95.4% to 99.3% using unfiltered three-omitting PLR. The rate of identified VF progression in the OHT cohort was 32.3% with unfiltered standard PLR, 28.7% with filtered standard PLR, and 18.6% with unfiltered three-omitting PLR. There was no significant difference in time to detected progression between filtered and unfiltered standard PLR. The use of confirmatory tests resulted in improved specificity using unfiltered data; however, application of the spatial filter resulted in similar specificity but with a higher rate of detected progression. This filter may therefore be useful in the monitoring of glaucomatous progression as it may reduce the dependence on confirmatory testing, although it has yet to be applied to longitudinal SITA data.


Preservation of embryonic kidneys for transplantation.
Long-term storage of embryonic kidneys is crucial for the organization of transplantation and organ banking. In this study, we investigated the effects of controlled-rate freezing and ice-free vitrification on metanephroi (MN) viability. Metanephroi isolated from 15-day (E15) timed pregnant Lewis rats were either: (i) frozen, using a DMSO/FCS/RPMI solution and a controlled freezing rate of -0.3 degrees C/min, from -10 degrees to -40 degrees C; or (ii) cryopreserved in an ice-free state by rapid cooling to -100 degrees C in cryoprotectant (VS55), followed by vitrification to -120 degrees C. After cryopreservation, the metanephroi were stored at -135 degrees C for 48 hours. After storage the MN were rewarmed, resuspended in culture media, and their viability was assessed using the AlamarBlue assay and histology (light microscopy, TEM, and cryosubstitution). There was statistically no difference in embryonic kidney metabolic activity of either of the cryopreserved MN groups relative to the control untreated group. However, cryosubstitution demonstrated the presence of significant ice formation during controlled-rate freezing, yet in contrast the amount of ice was significantly reduced by vitrification. This was confirmed by TEM, where vacuolation of the cytoplasm of controlled-rate frozen metanephroi was observed, whereas vitrified metanephroi had little cytoplasmic disruption. However, vitrified metanephroi showed mitochondrial and nuclear injury at the cellular level. There is a need for long-term storage of organs to make MN transplantation a reality. This study demonstrates that standard freezing methods are unsuitable for this purpose. Vitrification yielded more promising results, but further development is required.


Agonist-dependent internalization of the human melanocortin-4 receptors in human embryonic kidney 293 cells.
A chimeric protein comprised of melanocortin-4 receptor (MC4R) and the green fluorescent protein (GFP) was created for studying receptor/ligand localization and trafficking. The ligand binding affinities and second messenger stimulation induced by MC4R-GFP closely resembled those of the wild-type receptor, suggesting functional integrity of the chimeric protein. As observed with a confocal microscope, in human embryonic kidney (HEK)-293 cells MC4R/GFP was distributed evenly along the cell membrane. Addition of [Nle4-d-Phe7]-alpha-melanocyte-stimulating hormone (NDP-MSH), a peptide MC4R agonist, induced receptor translocation into intracellular compartments in a time- and concentration-dependent manner. [Ac-Nle-c[Asp-His-d-Nal(2')-Arg-Trp-Lys]-NH2] (SHU9119), a potent MC4R antagonist, completely inhibited NDP-MSH-mediated internalization. MC4R-GFP internalization was unaffected by a protein kinase A inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89), but was impaired by pretreatment with inhibitors of endocytosis through clathrin-coated pits, hypertonic sucrose, or concanavalin A. Time-dependent colocalization of MC4R-GFP with rhodamine-transferrin, an early endosome marker, and with LysoTraker, a lysosome marker, was observed after short-term (45 min) and prolonged (20 h) agonist exposure, respectively. Rhodamine-[AcNle-c[Asp-His-d-Phe-Arg-Trp-Lys]-NH2] (MTII), a fluorescent derivative of an MC4R agonist, was found to cointernalize with MC4R-GFP into intracellular vesicles. No significant receptor recycling or segregation from the ligand was observed 60 min after removal of the agonist. In contrast, an antagonist rhodamine-Ac-Cys-Glu-His-(d-Nal)-Arg-Trp-Gly-Cys-Pro-Pro-Lys-Asp-NH2 (HS014) bound to and colocalized with MC4R-GFP on the cell surface and did not stimulate receptor internalization. In sum, these results suggest that MC4R is subject to agonist-dependent endocytosis via clathrin-coated pits. Prolonged agonist exposure directs MC4R into lysosomes, possibly for degradation. Receptor and ligand recycling is not efficient for MC4R in HEK-293 cells.


Identity of the residues responsible for the species-restricted complement inhibitory function of human CD59.
The membrane-anchored glycoprotein CD59 inhibits assembly of the C5b-9 membrane attack complex (MAC) of human complement. This inhibitory function of CD59 is markedly selective for MAC assembled from human complement components C8 and C9, and CD59 shows little inhibitory function toward MAC assembled from rabbit and many other non-primate species. We have used this species selectivity of CD59 to identify the residues regulating its complement inhibitory function: cDNA of rabbit CD59 was cloned and used to express human/rabbit CD59 chimeras in murine SV-T2 cells. Plasma membrane expression of each CD59 chimera was quantified by use of a 5'-TAG peptide epitope, and each construct was tested for its ability to inhibit assembly of functional MAC from human versus rabbit C8 and C9. These experiments revealed that the species selectivity of CD59 is entirely determined by sequence contained between residues 42 and 58 of the human CD59 polypeptide, whereas chimeric substitution outside this peptide segment has little effect on the MAC inhibitory function of CD59. Substitution of human CD59 residues 42-58 into rabbit CD59 resulted in a molecule that was functionally indistinguishable from native human CD59, whereas the complementary construct (corresponding residues of rabbit CD59 substituted into human CD59) was functionally indistinguishable from rabbit CD59. Based on the solved solution structure of CD59, these data suggest that selectivity for human C8 and C9 resides in a cluster of closely spaced side chains on the surface of CD59 contributed by His44, Asn48, Asp49, Thr51, Thr52, Arg55, and Glu58 of the polypeptide.


Safety and efficacy of doxorubicin-eluting superabsorbent polymer microspheres for the treatment of liver metastases from neuroendocrine tumours: preliminary results.
The aim of the study was to retrospectively evaluate the symptom control, tumour response, and complication rate in patients with liver-predominant metastatic neuroendocrine tumours treated with transarterial chemoembolization using doxorubicin-eluting superabsorbent polymer (SAP) microspheres. Patients with neuroendocrine liver metastases who underwent hepatic transarterial chemoembolization using doxorubicin-eluting SAP-microspheres (50-100 μm Hepasphere/Quadrasphere Microsphere® particles, Merit Medical, South Jordan, Utah, USA) were included in this study. Pre-and post-procedure imaging studies were evaluated to assess short and intermediate-term tumour response using modified RECIST criteria. Symptom relief and procedure-related complications were evaluated. A total of 27 embolization procedures were performed on 17 patients. Twelve of 17 patients (70%) were symptomatic, including carcinoid syndrome (n = 8) and severe, uncontrollable hypoglycemia (n = 4). Eight of 12 patients (67%) had complete symptom relief, and the remaining 4 (33%) had partial relief. One patient developed ischemic cholecystitis (6%). No other hepatobiliary complications occurred. Short-term and intermediate-term imaging follow-up was available for 15/17 patients (88%) and 12/14 patients (86%) respectively. At short-term follow-up (< 3 months), 14 patients (93%) showed partial response and the remaining patient had progressive disease (7%). At intermediate-term imaging follow-up (> 3 months), partial response, stable disease and progressive disease were found respectively in 7 (58%), 3 (25%) and 2 (17%) patients. Chemoembolization with doxorubicin-eluting SAP-microspheres is a safe and effective treatment option for neuroendocrine liver metastases and is associated with a low complication rate. In particular, no clinically evident liver necrosis or bile duct complications were encountered.


A study of immunoglobulin G glycosylation in monoclonal and polyclonal species by electrospray and matrix-assisted laser desorption/ionization mass spectrometry.
N-linked oligosaccharides were released from human and bovine polyclonal immunoglobulin G (IgG) obtained from commercial sources and also from a monoclonal IgG(1) secreted by murine B-lymphocyte hybridoma cells (CC9C10) grown under different serum-free conditions. These conditions differed according to their steady-state dissolved oxygen concentrations. This work is based on a previous quantitative study where released glycans were characterized by fluorophore-assisted carbohydrate electrophoresis (FACE) and high-pH anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) (J. P. Kunkel, D. C. H. Jan, J. C. Jamieson, and M. Butler, 1998, J. Biotechnol. 62, 55-71). In the present article, peptide-N-glycosidase F-released glycans from different species of polyclonal IgG and murine monoclonal IgG were characterized qualitatively by high-performance liquid chromatography (HPLC) coupled to electrospray ionization mass spectrometry (ESI-MS). The glycans were also analyzed by matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS). The MALDI mass spectrometer used allowed acquisition of MS and tandem MS data, which were useful in structural investigations at a more detailed level than allowed by FACE and HPAEC-PAD. Predominant N-linked structures, as determined by all techniques, were core-fucosyl asialyl biantennary chains with varying galactosylation. Minor amounts of afucosyl, bisected, and monosialyl oligosaccharides were also detected. In contrast to FACE and HPAEC-PAD, MALDI-double quadrupole/time-of-flight MS and HPLC/ESI-MS also detected low-abundance high-mannose and hybrid structures in some of the species under investigation.


Differentiation of nestin‑negative human hair follicle outer root sheath cells into neurons in vitro.
A specialized quiescent population of hair follicle stem cells, residing in the hair follicle outer root sheath cells (ORSCs), has previously demonstrated pluripotency for differentiation into neural stem cells (NSCs). A previous study indicated that nestin‑positive hair follicle ORSCs are able to differentiate into neurons. However, little has been reported on the isolation of nestin‑negative human ORSCs and whether they can successfully differentiate into neurons in vitro. In the present study, nestin‑positive ORSCs were significantly reduced with a prolonged incubation time in vitro. Following 9 days of primary culture, nestin‑expressing ORSCs disappeared entirely, and ORSCs remained nestin‑negative following 5 days of subculture. Notably, nestin was identified in ORSCs following a three‑step process of neuro‑induction. In addition, neruodevelopmental markers were detected in the ORSC‑derived nestin‑positive spherical cell mass, including the induction of the neuronal specific markers growth associated protein‑43, neurotensin receptor‑3 and p75 neurotrophin receptor, and also the gliocyte markers, glial fibrillary acidic protein and S100. These sphere‑forming cells did not express the mature neuron‑associated markers neurofilament medium, neuronal nuclei and neuron‑specific enolase, which suggested that sphere‑forming cells may preferentially differentiate into neural stem cell‑like cells as opposed to mature neurons or neurogliocyte. In conclusion, ORSC‑driven neural differentiation may be a suitable treatment strategy for neurodegenerative diseases and may possess an important value in regenerative medicine.


[Model experiments for quantitative cytophotometry using protein films (author's transl)].
The usefulness of protein films denaturated and fixed with ethanol/ether as cytochemical model systems was investigated. Kinetics of staining with amido black 10B were analyzed as well as the spectroscopic properties of the protein-dye complex. The absorption coefficient of the complex was estimated. Data obtained so far are compared with both stained cells and the protein-dye complex in solution. Discussion focuses on the influence of fixation and the possibilities to use the films as systems for calibrating cytochemical stainings.


Effectiveness of problem-solving therapy for older, primary care patients with depression: results from the IMPACT project.
We compared a primary-care-based psychotherapy, that is, problem-solving therapy for primary care (PST-PC), to community-based psychotherapy in treating late-life major depression and dysthymia. The data here are from the IMPACT study, which compared collaborative care within a primary care clinic to care as usual in the treatment of 1,801 primary care patients, 60 years of age or older, with major depression or dysthymia. This study is a secondary data analysis (n = 433) of participants who received either PST-PC (by means of collaborative care) or community-based psychotherapy (by means of usual care). Older adults who received PST-PC had more depression-free days at both 12 and between 12 and 24 months (beta = 47.5, p <.001; beta = 47.0, p <.001), and they had fewer depressive symptoms and better functioning at 12 months (beta(dep) = -0.36, p <.001; beta(func) = -0.94, p <.001), than those who received community-based psychotherapy. We found no differences at 24 months. Results suggest that PST-PC as delivered in primary care settings is an effective method for treating late-life depression.


Regulation of respiration in sleeping dogs.
We have examined the respiratory changes that occur during physiological sleep in three dogs with exteriorized cervical vagal loops. Sleep stage was determined by behavioral and EEG criteria. During non-REM (NREM) sleep breathing was slower (mean change, 23%),deeper (mean change, 18%), and less variable (coefficients of variation, 0.05-0.10) than during wakefulness (W); minute volume of ventilation (Ve) decreased (mean change, 14%) and alveolar CO2 pressure (PAco2) increased slightly (mean change, 1.3 mmHg). In addition, the rate of O2 consumption and ventilatory response to hypercapnia were decreased. In contrast, REM sleep was characterized by rapid, shallow, and considerably more irregular (coefficients of variation, 0.18-0.30) breathing; Ve increased markedly and PAco2 decreased (mean change, 5.2 mmHg). Blockade of both cervical vagus nerves produced comparable changes in each stage of sleep (W, NREM, REM): breathing became slower and deeper, but the differences between stages and the marked irregularity in REM sleep persisted. In contrast, the Hering-Breuer inflation reflex (HBIR) was strong in W and NREM sleep, but weak in REM sleep. The results indicate that changes in respiratory control and stability during sleep are not due to fluctuations in vagal influence despite the fact that one vagal reflex (HBIR) was sleep-state dependent.


Expression of the gene for the alpha-subunit of inhibin in human adrenocortical tumours.
To determine whether the pathogenesis of human adrenocortical tumours is associated with variations of inhibin expression, we assayed the mRNA of the alpha-subunit of inhibin in 5 normal adrenals and 48 adrenocortical tumours, including 10 paediatric tumours. mRNA of alpha-subunit of inhibin was detected in all adrenocortical tissues. It was similarly abundant in the three pathological groups of adult tumours (benign, suspect and malignant) and in normal adrenal tissues, irrespective of the hormonal pattern. However, in paediatric tumours, the levels of the mRNA for the alpha-subunit of inhibin were significantly higher than those in adult tumours (p < 0.01). Inhibin is more abundant in the foetal than in the adult adrenal cortex and therefore these data suggest that the paediatric tumours may have a foetal pattern.


Induction of a suppressive serum factor, prevention of sensitization, and prolongation of kidney graft survival in rats by transfusion with antibody-coated blood cells.
Transfusion with antibody-coated allogeneic blood cells suppresses the cytotoxic antidonor antibody response in a strongly incompatible rat combination (BN----LEW). Cell coating with homologous recipient antidonor antiserum, rat monoclonal antibodies against MHC class I donor antigens, or rabbit antirat lymphocyte serum all were effective. The suppression was not abrogated by repeated booster transfusions with untreated donor blood. Moreover, the suppression extended to antibody-uncoated antigens present on the same donor cell. Not only the antibody response but also the Graft-versus-host reaction against donor antigens was suppressed. The serum of pretreated animals contained suppressive activity. It suppressed the cytotoxic antibody response as well as the cellular immune response (GVH) when transferred into syngeneic recipients. A weaker suppression of antibody response was obtained by transferring spleen cells of pretreated animals into syngeneic recipients. The transfer data suggest that broadly reactive serum factor(s) were mainly responsible for the suppressive effect. Transfusion with LEW-anti-BN-coated donor cells before transplantation induced markedly prolonged kidney graft survival in the BN----LEW combination without additional immunosuppression (untreated controls: 8.4 +/- 0.4, pretreated recipients: 124 +/- 36 days, P less than 10(-4)).


New Efforts to Demonstrate the Successful Use of TRH as a Therapeutic Agent.
Thyrotropin-releasing hormone (TRH) is a tripeptide that regulates the neuroendocrine thyroid axis. Moreover, its widespread brain distribution has indicated that it is a relevant neuromodulator of behaviors such as feeding, arousal, anxiety, and locomotion. Importantly, it is also a neurotrophic peptide, and thus may halt the development of neurodegenerative diseases and improve mood-related disorders. Its neuroprotective actions on those pathologies and behaviors have been limited due to its poor intestinal and blood-brain barrier permeability, and because it is rapidly degraded by a serum enzyme. As new strategies such as TRH intranasal delivery emerge, a renewed interest in the peptide has arisen. TRH analogs have proven to be safe in animals and humans, while not inducing alterations in thyroid hormones' levels. In this review, we integrate research from different approaches, aiming to demonstrate the therapeutic effects of TRH, and to summarize new efforts to prolong and facilitate the peptide's actions to improve symptoms and the progression of several pathologies.


Corticosteroid plus glycyrrhizin therapy for chronic drug- or herb-induced liver injury achieves biochemical and histological improvements: a randomised open-label trial.
Treatment of chronic drug-induced liver injury (DILI) or herb-induced liver injury(HILI) is an important and unresolved challenge. There is no consensus regarding the indications for corticosteroids for chronic DILI/HILI. To investigate the efficacy and safety of corticosteroid plus glycyrrhizin for patients with chronic DILI/HILI. This was a randomised open-label trial. Eligible patients with causality assessment using the updated RUCAM were randomly assigned (1:1) either to the steroid treatment group (48-week stepwise dose reduction of methylprednisolone plus glycyrrhizin) or control group (glycyrrhizin alone). Liver biopsies were performed at baseline and at the end of the 48-week treatment period. The primary outcome was the proportion of patients with sustained biochemical response (SBR). The secondary outcomes were improvement in liver histology, time to biochemical normalisation and safety. Of 80 participants, 70 (87.5%) completed the trial. The patients were predominantly female (77.5%), aged >40 years (77.5%) and had a hepatocellular injury pattern of DILI (71.2%). Compared to the control group, the treatment group showed a higher proportion of SBR (94.3% vs. 71.4%, p = 0.023), shorter biochemical normalisation time and histological improvements in both histological activity and fibrosis. The DILI and HILI subgroups, as well as the autoimmune hepatitis (AIH)-like DILI and non-AIH-like subgroups, showed comparable responses. No severe adverse events were observed during the trial. This study provides the first clinical evidence that corticosteroid plus glycyrrhizin therapy for chronic DILI with or without AIH-like features can achieve both biochemical response and histological improvements with good safety. (ClinicalTrials.gov, NCT02651350).


Determination of RNA orientation during translocation through a biological nanopore.
We investigate single-molecule electrophoretic translocation of A(50), C(50), A(25)C(50), and C(50)A(25) RNA molecules through the alpha-hemolysin transmembrane protein pore. We observe pronounced bilevel current blockages during translocation of A(25)C(50) and C(50)A(25) molecules. The two current levels observed during these bilevel blockages are very similar to the characteristic current levels observed during A(50) and C(50) translocation. From the temporal ordering of the two levels within the bilevel current blockages, we infer whether individual A(25)C(50) and C(50)A(25) molecules pass through the pore in a 3'-->5' or 5'-->3' orientation. Correlation between the level of current obstruction and the inferred A(25)C(50) or C(50)A(25) orientation indicates that 3'-->5' translocation of a poly C segment causes a significantly deeper current obstruction than 5'-->3' translocation. Our analysis also suggests that the 3' ends of C(50) and A(25)C(50) RNA molecules are more likely to initiate translocation than the 5' ends. Orientation dependent differences in a smaller current blockage that immediately precedes many translocation events suggest that this blockage also contains information about RNA orientation during translocation. These findings emphasize that the directionality of polynucleotide molecules is an important factor in translocation and demonstrate how structure within ionic current signals can give new insights into the translocation process.


Inter-Tissue and Intra-Tissue Co-Expression Networks in Human Metabolism: Morphological Evaluation of the Link Between Transcription Factors ERβ and NFAT in Morbid Obesity.
Estrogen receptor β (ERβ) plays an important role in human metabolism and some of its metabolic actions are mediated by a positive "cross-talk" with Nuclear Factor of Activated T cells (NFAT) and the key metabolic transcriptional coregulator Transcriptional Intermediary Factor 2 (TIF2). Our study is an "in situ" morphological evaluation of the communication between ERβ, NFAT and TIF2 in morbid obesity. Potential correlations with clinicopathological parameters and with the presence of diabetes and non-alcoholic fatty liver disease (NAFLD) were also explored. The aim of the present study was to determine the role of ERβ and NFAT in the underlying pathophysiology of obesity and related comorbidities. We have investigated the expression of specific proteins using immunochemistry methodologies. Our population consists of 50 morbidly obese patients undergoing planned bariatric surgery, during which biopsies were taken from visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), skeletal muscle (SM), extramyocellular adipose tissue (EMAT) and liver and the differential protein expression was evaluated by immunohistochemistry. We demonstrated an extensive intra- and inter-tissue co-expression network, which confirms the tissue-specific and integral role of each one of the investigated proteins in morbid obesity. Moreover, a beneficial role of ERβ and NFATc1 against NAFLD is implicated, whereas the distinct roles of TIF2 still remain an enigma. We believe that our findings will shed light on the complex underlying mechanisms and that the investigated biomarkers could represent future targets for the prevention and therapy of obesity and its comorbidities.


[Design, synthesis and activity assessment of aryl-substituent benzyl acid targeting HIV gp41].
To synthesize novel aryl-substituent benzyl acid compounds targeting HIV gp41 and characterize their anti-HIV activities. Twelve analogues of aryl-substituent benzyl acid were designed and synthesized by Suzuki- Miyaura cross-coupling and Knoevenagel condensation reactions using halo-benzyl acid or 3-carboxybenzeneboronic acid as the raw material. The inhibitory activities of these compounds on gp41 six-helix bundle formation were tested by ELISA, and their anti-HIV activities were determined using a luciferase assay. The structures of the compounds were characterized by nuclear magnetic resonance and mass spectrography. Among the 12 compounds, 5 (7b, 7c, 7d, 7e, and 7g) could inhibit the gp41 six-helix bundle formation, and 7d showed the most potent effect, and could also inhibit the replication of HIV-1 SF33 strain with an IC(50) of 20 µmol/L. The synthesized aryl-substituent benzyl acid compound 7d could inhibit HIV replication by blocking the gp41 six-helix bundle formation.


[IBL-like T cell lymphoma associated with early gastric cancer: a case report].
A 67-year-old man was admitted in October 1987 with complaints of nausea, headache, dizziness and speech disturbance. Hematological examination showed pancytopenia. Bone marrow aspiration failed with a dry tap. A month later, the second aspiration showed hypocellular marrow containing 18.2% of lymphoma cells. Physical examination showed splenomegaly and lymph node swelling. Polyclonal hypergammaglobulinemia was not observed. A lymph node biopsy exhibited typical histology of immunoblastic lymphadenopathy (IBL)-like T cell lymphoma. Surface marker CD3 and CD4 positive cells were dominant. The patient complained of epigastric pain and occult blood was positive in stool. Gastrofiberscopic examination disclosed well differentiated adenocarcinoma in situ located on a polyp, and polypectomy was performed. Lymphoma was treated with cyclophosphamide, doxorubicin, vinblastine and prednisolone. Splenomegaly and lymph node swelling were reduced in size but the effect was temporary. Thereafter the patient has been treated with cyclophosphamide, doxorubicin, vindesine, prednisolone and etoposide every 3 weeks. This is our first case report of IBL-like T cell lymphoma associated with early gastric cancer.


The morbidity and mortality of vermiculite miners and millers exposed to tremolite-actinolite: Part I. Exposure estimates.
The vermiculite ore and concentrate of a mine and mill near Libby, Montana, was found to be contaminated with fibrous tremolite-actinolite. Of 599 fibers (length greater than 5 microns and width greater than 0.45 micron) counted in eight airborne membrane filter samples, 96% had an aspect ratio greater than 10 and 16% had an aspect ratio greater than 50. Additionally, 73% of the fibers were longer than 10 microns, 36% were longer than 20 microns, and 10% were longer than 40 microns. Estimates of exposure before 1964 in the dry mill were 168 fibers/cc for working areas, 182 fibers/cc for sweepers, 88 fibers/cc for skipping, and 13 fibers/cc for the quality control laboratory. In 1964-1971, exposure estimates for these areas were 33, 36, 17, and 3 fibers/cc, respectively. Estimates of exposures in the mine before 1971 ranged from 9-23 fibers/cc for drillers and were less than 2 fibers/cc for nondrilling jobs. All 8-hr TWA job exposure estimates decreased from 1972-1976, and from 1977-1982 were less than 1 fiber/cc.


Provision of first-trimester medication abortion in 2019: Results from the Canadian abortion provider survey.
To explore the Canadian first-trimester medication abortion (MA) workforce and their clinical care following the introduction of mifepristone in 2017, updated national clinical practice guidelines and government approval of nurse practitioners (NPs) as first-trimester MA providers. We conducted a national, self-administered, cross-sectional survey of abortion providers in 2019. Our bilingual (French/English) survey collected information on demographics, abortion number, and clinical care characteristics. The true number of abortion providers is unknown thus we cannot calculate a survey response rate. To maximize identification of possibly eligible respondents, we widely distributed the survey between July and December 2020 through health professional organizations, using a modified Dillman technique. We used descriptive statistics to characterize the workforce and clinical practices. Four-hundred-sixty-five clinicians responded, of whom 388 provided first-trimester MA. Physicians (n = 358) and NPs (n = 30) reported providing 13,429 first-trimester MAs in 2019 which represented 27.7% of all reported abortions in the survey. The majority of first-trimester MA respondents were primary care physicians (n = 245, 63.1%), had less than five years' experience (n = 223, 61.3%) and practiced outside of hospitals (n = 228, 66.5%). Forty-three percent (n = 165) practiced rurally, and 44.0% (n = 136) used telemedicine for some abortion care. Ninety-nine percent (n = 350) used a guideline-recommended mifepristone/misoprostol regimen while 14.5% (n = 51) sometimes used methotrexate. Patients most commonly received mifepristone/misoprostol at community pharmacies (median 100.0%; interquartile range 50.0%-100.0%). Our results suggest that there are many new first-trimester MA providers, an increase in the proportion of MAs since 2012 and a shift to primary care settings. Respondents widely adopted mifepristone. Our results highlight that, following mifepristone introduction, many new primary care practitioners started providing first-trimester medication abortion throughout Canada, including the first non-physicians. This increased access to abortion particularly in rural and underserved communities. These results could inform future directions in policy, guidelines, and abortion access initiatives.


Clinical utility of contrast-enhanced echocardiography.
Over the past three decades, echocardiography has become a major diagnostic tool in the arsenal of clinical cardiology for real-time imaging of cardiac dynamics. More and more, cardiologists' decisions are based on images created from ultrasound wave reflections. From the time ultrasound imaging technology provided the first insight into a human heart, our diagnostic capabilities have increased exponentially as a result of our growing knowledge and developing technologies. One of the most intriguing developments that brought about a decade-long combination of expectations and disappointments was the introduction of echocardiographic contrast agents. Despite repeated waves of controversy regarding the readiness of this technology for clinical use, it has overcome multiple hurdles and currently provides useful clinical information that helps cardiologists to diagnose heart disease accurately. Since the initial reports on the use of ultrasound contrast media such as agitated saline or renografin, the major advances in the field of contrast echocardiography have included (1) the development of stable perfluorocarbon-filled microbubbles, frequently referred to as second-generation contrast agents; and (2) the development of contrast-targeted nonlinear imaging modes, such as harmonic imaging, pulse inversion, and power modulation, which allow consistent real-time visualization of these agents. These contrast agents in conjunction with the new imaging technology constitute powerful tools that improve our ability to evaluate left ventricular function and myocardial perfusion, and allow differential diagnosis of thrombi and intravascular masses. In this manuscript, we briefly review some of the literature that has provided the scientific basis for the use of echocardiographic contrast agents in the context of these important variables.


[Bronchial carcinoid tumors: a prospective study].
We report the results of a study performed in the thoracic surgery department of Hospital General Universitario of Valencia from October 1989 to December 1996. Of the 621 patients diagnosed of lung cancer during this period, 320 underwent the usual surgical excision, 18 were confirmed histologically as bronchial carcinoid tumors, indicating an incidence of 5.6% of all pulmonary neoplasms resected in our department. The symptoms most often reported were recurring infection (44.5%) and chest pain (33.3%). Only one patient presented carcinoid syndrome. The most common radiologic presentation was solitary pulmonary nodule (50%). The tumor was visible by fiberoptic bronchoscopy in 9 cases. Diagnosis was by bronchial biopsy in four cases. Confirmation was by immunohistochemical analysis of the specimen in all cases. Electron microscopy and immunohistochemical techniques using neuroendocrine panmarkers is considered fundamental for differentiating between neuroendocrine neoplasms and typical and atypical carcinoid tumors. Thirteen (72.2%) of the 18 patients studied were diagnosed of typical carcinoids and 5 (27.8%) of atypical carcinoids. Neuroendocrine marking showed neurospecific enolase in 15 patients and chromogranin positivity in 10.


[A CASE OF PULMONARY MYCOBACTERIUM ABSCESSUS INFECTION SUCCESSFULLY TREATED WITH SHORT-TERM CAM, AMK, AND IPM/cs FOLLOWED BY LONG-TERM ORAL CAM AND LVFX].
A 78-year-old woman who had been treated for two years with ITCZ for chronic pulmonary aspergillosis associated with prior pulmonary tuberculosis was admitted to our hospital because of general fatigue and hemosputum along with deterioration of her chest radiographic findings. Mycobacterium abscessus had been isolated once from her sputum one year before admission. We performed fiberoptic bronchoscopy (FOB) in order to help establish a final diagnosis. Sputum aspirated from her bronchus on FOB stained positive for acid-fast bacilli and was negative for Tbc and MAC using PCR. From these results, we diagnosed the patient with pulmonary M. abscessus infection. Chemotherapy with AMK, IPM/cs, and CAM was initiated. Because her symptoms rapidly improved, we switched the chemotherapy to long-term oral CAM and LVFX, and she has been in a good condition at 12 months after the initiation of the therapy. Recently, subtypes of M. abscessus complex, such as M. massiliense, have been recognized, which are more sensitive to chemotherapy. Considering the good response to therapy, there is a possibility that is the patient in the current case had a M. massiliense infection.


The role of clean air in wound infection acquired during operation.
A wound isolator was used to perform 109 total arthroplasties of the hip, while 108 similar operations were done in a plenum ventilated operating room. Extensive bacteriologic studies of all patients were carried out before, during and after operation. Despite sterility of the air around the wound in the isolator group of patients, two major wound infections occurred in each of the two groups. Five minor wound infections occurred in the isolator and three in the nonisolator group of patients. All wound infections appeared to be secondarily acquired. No evidence was obtained to indicate that primary wound infection occurred during operation. The need for ultraclean air in operating rooms is deemed to be less urgent than the need to prevent secondary infection after operation.


Librarians Promoting Changes in the Health Care Delivery System through Systematic Assessment.
Patient engagement in health care decisions largely depends on a patient's health literacy and the health literacy attributes of the health care organization. Librarians have an established role in connecting patients with health information in the context of their care. However, librarians can play a larger role in helping to make changes in their organization's health literacy attributes. This article discusses one medical library's process of leading systematic assessment of their organization's health literacy attributes. Included in this discussion is the institutional support, timeline, assessment tool, the results for five areas of health literacy, marketing and the event-planning process to disseminate results. The systematic assessment process described employs the Health Literacy Environment of Hospitals and Health Centers document, which provides assessment tools for Print Communication, Oral Communication, Navigation, Technology, and Policies and Protocols.


Zebrafish Database: Customizable, Free, and Open-Source Solution for Facility Management.
Zebrafish Database is a web-based customizable database solution, which can be easily adapted to serve both single laboratories and facilities housing thousands of zebrafish lines. The database allows the users to keep track of details regarding the various genomic features, zebrafish lines, zebrafish batches, and their respective locations. Advanced search and reporting options are available. Unique features are the ability to upload files and images that are associated with the respective records and an integrated calendar component that supports multiple calendars and categories. Built on the basis of the Joomla content management system, the Zebrafish Database is easily extendable without the need for advanced programming skills.


Comparison of Outcomes of Patients with vs without Previous Coronary Artery Bypass Graft Surgery Presenting with ST-Segment Elevation Acute Myocardial Infarction.
The outcomes of patients with previous coronary bypass graft surgery (CABG) presenting with ST-segment elevation acute myocardial infarction (STEMI) have received limited study. We compared the clinical and procedural characteristics and outcomes of STEMI patients with and without previous CABG in a contemporary multicenter STEMI registry between 2003 and 2020. The primary outcomes of the study were mortality and major cardiac adverse events (MACE: death, MI or stroke). Survival curves were derived using the Kaplan-Meier method and compared with the log-rank test. Of the 13,893 patients included in the analyses, 7.2% had previous CABG. Mean age was 62.4 ± 13.6 years, most patients (71%) were men and 22% had diabetes. Previous CABG patients were older (69.0 ± 11.7 vs 61.9 ± 13.6 years, p <0.001) and more likely to have diabetes (40% vs 21%, p <0.001) compared with patients without previous CABG. Previous CABG patients had higher mortality and MACE at 5 years (p <0.001). Outcomes were similar with saphenous vein graft vs native coronary culprits. Previous CABG remained associated with mortality from discharge to 18 months (p = 0.044) and from 18 months to 5 years (p <0.001) after adjusting for baseline characteristics. Long term outcomes after STEMI were worse among patients with previous CABG compared with patients without previous CABG, even after adjustment for baseline characteristics.


Determining the clinical significance of co-colonization of vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus in the intestinal tracts of patients in intensive care units: a case-control study.
The emergence of vancomycin-resistant Staphylococcus aureus (VRSA) has become a global concern for public health. The proximity of vancomycin-resistant enterococcus (VRE) and methicillin-resistant S. aureus (MRSA) is considered to be one of the foremost risk factors for the development of VRSA. This study aimed to determine the incidence, risk factors, and clinical outcomes of intestinal co-colonization with VRE and MRSA. A case-control study was conducted in 52-bed intensive care units (ICUs) of a university-affiliated hospital from September 2012 to October 2017. Active surveillance using rectal cultures for VRE were conducted at ICU admission and on a weekly basis. Weekly surveillance cultures for detection of rectal MRSA were also conducted in patients with VRE carriage. Patients with intestinal co-colonization of VRE and MRSA were compared with randomly selected control patients with VRE colonization alone (1:1). Vancomycin minimum inhibitory concentrations (MICs) for MRSA isolates were determined by the Etest. Of the 4679 consecutive patients, 195 cases and 924 controls were detected. The median monthly incidence and duration of intestinal co-colonization with VRE and MRSA were 2.3/1000 patient-days and 7 days, respectively. The frequency of both MRSA infections and mortality attributable to MRSA were higher in the case group than in the control group: 56.9% vs. 44.1% (P = 0.011) and 8.2% vs. 1.0% (P = 0.002), respectively. Independent risk factors for intestinal co-colonization were enteral tube feeding (odds ratio [OR], 2.09; 95% confidence interval [CI] 1.32-3.32), metabolic diseases (OR, 1.75; 95% CI 1.05-2.93), male gender (OR, 1.62; 95% CI 1.06-2.50), and Charlson comorbidity index < 3 (OR, 3.61; 95% CI 1.88-6.94). All MRSA isolates from case patients were susceptible to vancomycin (MIC ≤ 2 mg/L). Our study indicates that intestinal co-colonization of VRE and MRSA occurs commonly among patients in the ICU with MRSA endemicity, which might be associated with poor clinical outcomes.


Reduction of Medication Errors: A Unique Approach.
Medication errors are a source of serious patient harm. A unique approach, Socio-Technical Probabilistic Risk Assessment, was used to analyze historical errors in this setting. The goal was to identify a minimal number of steps that would establish increased reliability and decrease errors if these steps were used every time. Three steps were identified that should be taken with every intravenous medication or fluid administration. Preliminary analysis revealed a 22% reduction in errors when using these 3 steps.


Thiophene-fused dithiaoctaphyrins: π-system switching between cross-conjugated and macrocyclic π-networks.
We synthesized for the first time octaphyrins with a dithieno[3,4-b:3',4'-d]thiophene core as thiophene-fused dithiaoctaphyrins with a cross-conjugated structure. The octaphyrins revealed cross-conjugated and macrocyclic 36π-electron networks.


[Study of immunological parameters in radiography and excretory urography].
Some immunological parameters (levels of serum complement, content of circulating immune complexes, and serum concentrations of immunoglobulins) were examined in patients after excretory urography by using triombrast and after X-ray studies without applying any contrast substance. Some changes were found in the activity of complement and in the concentration of immunoglobulins following intravenous triombrast injection. In addition, the above parameters were evaluated in patients with adverse reactions during the contrast study. The findings are discussed in terms of the immunotropic effects of triombrast.


Adsorbate motions induced by inelastic-tunneling current: theoretical scenarios of two-electron processes.
We discuss how the excitation of high-frequency modes in adsorbed molecules may result in motion (e.g., rotation, translation, or dissociation) of the molecules. Our study is based on rate equations and considers one- and two-vibrational excitation processes, corresponding to linear and quadratic dependences of the reaction rate on the tunneling current in the case the scanning tunneling microscopy is used to excite the vibrations (inelastic tunneling). From the results reported in this paper it should be possible to obtain intramolecular transition rates directly from the experimental data, and gain some understanding on how these important quantities depend on the modes involved and on the substrate.


Examination of microcystin neurotoxicity using central and peripheral human neurons.
Microcystins (MC) are a group of cyanobacterial toxins that comprises MC-LF and other cyclic heptapeptides, best known as potent hepatotoxicants. Cell culture and epidemiological studies suggest that MC might also affect the nervous system when there is systemic exposure, e.g., via drinking water or food. We asked whether in vitro studies with human neurons could provide estimates on the neurotoxicity hazard of MC-LF. First, we used LUHMES neurons, a well-established test system for neurotoxicants and neuropathological processes. These central nervous system cells express OATP1A2, a presumed carrier of MC-LF, and we observed selective neurite toxicity in the μM range (EC20 = 3.3 μM ≈ 3.3 μg/mL). Transcriptome changes pointed towards attenuated cell maintenance and biosynthetic processes. Prolonged exposure for up to four days did not increase toxicity. As a second model, we used human dorsal root ganglia-like neurons. These peripheral nervous system cells represent parts of the nervous system not protected by the blood-brain barrier in humans. Toxicity was observed in a similar concentration range (EC20 = 7.4 μM). We conclude that MC-LF poses a potential neurotoxic hazard in humans. The adverse effect concentrations observed here were orders of magnitude higher than those presumed to be encountered after normal nutritional or environmental exposure. However, the low μM concentrations found to be toxic are close to levels that may be reached after very excessive algae supplement intake.


Nodding syndrome in Uganda: field observations, challenges and research agenda.
This article summarizes observations made in Northern Uganda and a lecture given at the Nodding Syndrome Workshop in Nagasaki September 2013. The objective of the manuscript is to summarize the current knowledge on nodding syndrome and to provide an agenda for investigations into the epidemiology, pathophysiology, diagnosis and care management of nodding syndrome in Uganda.


Subsets of activated monocytes and markers of inflammation in incipient and progressed multiple sclerosis.
Multiple sclerosis (MS) is an immune mediated, inflammatory and demyelinating disease of the central nervous system (CNS). Substantial evidence points toward monocytes and macrophages playing prominent roles early in disease, mediating both pro- and anti-inflammatory responses. Monocytes are subdivided into three subsets depending on the expression of CD14 and CD16, representing different stages of inflammatory activation. To investigate their involvement in MS, peripheral blood mononuclear cells from 40 patients with incipient or progressed MS and 20 healthy controls were characterized ex vivo. In MS samples, we demonstrate a highly significant increase in nonclassical monocytes (CD14+CD16++), with a concomitant significant reduction in classical monocytes (CD14++CD16-) compared with healthy controls. Also, a significant reduction in the surface expression of CD40, CD163, and CD192 was found, attributable to the upregulation of the nonclassical monocytes. In addition, significantly increased levels of human endogenous retrovirus (HERV) envelope (Env) epitopes, encoded by both HERV-H/F and HERV-W, were specifically found on nonclassical monocytes from patients with MS; emphasizing their involvement in MS disease. In parallel, serum and cerebrospinal fluid (CSF) samples were analyzed for soluble biomarkers of inflammation and neurodegeneration. For sCD163 versus CD163, no significant correlations were found, whereas highly significant correlations between levels of soluble neopterine and the intermediate monocyte (CD14++CD16+) population was found, as were correlations between levels of soluble osteopontin and the HERV Env expression on nonclassical monocytes. The results from this study emphasize the relevance of further focus on monocyte subsets, particularly the nonclassical monocytes in monitoring of inflammatory diseases.


Patients with learning difficulties: outcome on peritoneal dialysis.
In the present study, we identified patients who had difficulties learning the minimum knowledge and skills required to carry out peritoneal dialysis (PD), and we compared the outcomes in this subgroup of patients with outcomes in the general PD population. We calculated the mean learning sessions needed by our total PD population during the training period. We then assigned patients to one of two groups according to the number of learning sessions they needed. Patients who required a number of sessions equal to or less than the mean were placed in the "standard learning" group; patients who required more sessions but who reached the minimum knowledge and skills were placed in the "learning difficulties " group. We compared these two groups in terms of age, sex, diabetes status, autonomy to perform PD, family support, education level, residual renal function, and Charlson comorbidity index. Outcomes on PD included time to first peritonitis episode, peritonitis rate, percentage of patients free of peritonitis during follow-up, survival time on PD, and transfer to hemodialysis. Patients with learning difficulties were older and had more comorbidities. Outcomes on PD in the learning difficulties group were similar to those in the standard learning group, except for time to first peritonitis.


Sympathetic nervous system synchrony: An exploratory study of its relationship with the therapeutic alliance and outcome in couple therapy.
In previous research, we found that sympathetic nervous system synchrony, measured via electrodermal activity (EDA), occurs between participants at the start of couple therapy. The aim now was to test whether this synchrony changes during the therapy process, and how any changes may be related to clients' and therapists' evaluations of the working alliance, and the outcome of therapy. Twelve different couple therapy processes were analyzed (24 clients, plus 10 therapists, working in pairs; hence, 4 persons per session) using EDA concordance indices and questionnaires (Outcome Rating Scale, Session Rating Scale, and Clinical Outcomes in Routine Evaluation-Outcome Measure). EDA synchrony between the couples increased from the beginning to the end of therapy. This seemed to be connected to a positive linear trend in female clients' well-being during the therapy process. There were no statistically significant changes in the EDA synchrony between the cotherapists, or between the clients and the therapists. We found specific changes in the EDA synchrony to be related to changes in the therapeutic alliance, and/or changes in the clients' well-being. Heightened EDA synchrony was frequently related to a better outcome; nevertheless, there was one instance in which decreasing synchrony seemed to be more beneficial. It appears that couple therapy can bring spouses closer together also on a physiological level, which could be especially important for the well-being of women. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Heterodyne frequency measurements of (13)CO(2) laser hot band transitions.
The frequencies of twenty-eight lines in the P-branch of the 01(1)1-[11(1)0,03(1)0](I) band of (13)C(16)O(2), observed in laser emission, and three lines in the R-branch, observed in absorption with a diode laser, have been carefully measured with stabilized CO(2) lasers. A significant improvement in the ro-vibrational constants has been obtained from a least squares fit to these data. The laser lines stabilized by saturated absorption techniques provide convenient, accurate (uncertainty <0.1 MHz) frequency references near 11.7 microm.


The effects of substance P and acetylcholine on human tenocyte proliferation converge mechanistically via TGF-β1.
Previous in vitro studies on human tendon cells (tenocytes) have demonstrated that the exogenous administration of substance P (SP) and acetylcholine (ACh) independently result in tenocyte proliferation, which is a prominent feature of tendinosis. Interestingly, the possible link between SP and ACh has not yet been explored in human tenocytes. Recent studies in other cell types demonstrate that both SP and ACh independently upregulate TGF-β1 expression via their respective receptors, the neurokinin 1 receptor (NK-1R) and muscarinic ACh receptors (mAChRs). Furthermore, TGF-β1 has been shown to downregulate NK-1R expression in human keratocytes. The aim of this study was to examine if TGF-β1 is the intermediary player involved in mediating the proliferative pathway shared by SP and ACh in human tenocytes. The results showed that exogenous administration of SP and ACh both caused significant upregulation of TGF-β1 at the mRNA and protein levels. Exposing cells to TGF-β1 resulted in increased cell viability of tenocytes, which was blocked in the presence of the TGFβRI/II kinase inhibitor. In addition, the proliferative effects of SP and ACh on tenocytes were reduced by the TGFβRI/II kinase inhibitor; this supports the hypothesis that the proliferative effects of these signal substances are mediated via the TGF-β axis. Furthermore, exogenous TGF-β1 downregulated NK-1R and mAChRs expression at both the mRNA and protein levels, and these effects were negated by simultaneous exposure to the TGFβRI/II kinase inhibitor, suggesting a negative feedback loop. In conclusion, the results indicate that TGF-β1 is the intermediary player through which the proliferative actions of both SP and ACh converge mechanistically.


Bayesian Neighborhood Component Analysis.
Learning a distance metric in feature space potentially improves the performance of the nearest neighbor classifier and is useful in many real-world applications. Many metric learning (ML) algorithms are, however, based on the point estimation of a quadratic optimization problem, which is time-consuming, susceptible to overfitting, and lacks a natural mechanism to reason with parameter uncertainty-a property useful especially when the training set is small and/or noisy. To deal with these issues, we present a novel Bayesian ML (BML) method, called Bayesian neighborhood component analysis (NCA), based on the well-known NCA method, in which the metric posterior is characterized by the local label consistency constraints of observations, encoded with a similarity graph instead of independent pairwise constraints. For efficient Bayesian inference, we explore the variational lower bound over the log-likelihood of the original NCA objective. Experiments on several publicly available data sets demonstrate that the proposed method is able to learn robust metric measures from small size data set and/or from challenging training set with labels contaminated by errors. The proposed method is also shown to outperform a previous pairwise constrained BML method.


Diabetes Prevalence and Incidence Inequality Trends Among U.S. Adults, 2008-2021.
This study examined national trends in age, sex, racial and ethnic, and socioeconomic inequalities for diagnosed diabetes prevalence and incidence among U.S. adults from 2008 to 2021. Adults (aged ≥18 years) were from the National Health Interview Survey (2008-2021). The annual between-group variance (BGV) for sex, race, and ethnicity; and the slope index of inequality (SII) for age, education, and poverty-to-income ratio along with the average annual percentage change (AAPC) were estimated in 2023 to assess trends in inequalities over time in diabetes prevalence and incidence. For BGV and SII, a value of 0 represents no inequality, whereas a value further from 0 represents greater inequality. On average over time, poverty-to-income ratio inequalities in diabetes prevalence worsened (SII= -8.24 in 2008 and -9.80 in 2021; AAPC for SII= -1.90%, p=0.003), whereas inequalities in incidence for age (SII=17.60 in 2008 and 8.85 in 2021; AAPC for SII= -6.47%, p<0.001), sex (BGV=0.09 in 2008, 2.05 in 2009, 1.24 in 2010, and 0.27 in 2021; AAPC for BGV= -12.34%, p=0.002), racial and ethnic (BGV=4.80 in 2008 and 2.17 in 2021; AAPC for BGV= -10.59%, p=0.010), and education (SII= -9.89 in 2008 and -2.20 in 2021; AAPC for SII=8.27%, p=0.001) groups improved. From 2008 to 2021, age, sex, racial and ethnic, and education inequalities in the incidence of diagnosed diabetes improved but persisted. Income-related diabetes prevalence inequalities worsened over time. To close these gaps, future research could focus on identifying the factors driving these trends, including the contribution of morbidity and mortality.


Large-scale production of recombinant Saw1 in Escherichia coli.
Saccharomyces cerevisiae Saw1 is an essential gene in single-strand annealing - the DNA repair pathway that repairs double-strand breaks when they occur between homologous repeats. Saw1 interacts with the structure-specific nuclease Rad1-Rad10 and this results in the recruitment of this nuclease to 3' non-homologous DNA tailed recombination intermediates. Saw1 is unstable in the absence of the Rad1-Rad10 nuclease and, hence, it has been difficult to study its specific function in vitro. In the present work, we present the combination of dynamic light scattering and differential scanning fluorimetry techniques to optimize the stability and homogeneity of recombinant Saw1. The protein expression and purification conditions identified in this study allow for higher recovery of soluble Saw1 and enable the biochemical characterization of the protein.