Impact of the 13-valent pneumococcal conjugate vaccine on Streptococcus pneumoniae multiple serotype carriage.
Pneumococcal multiple serotype carriage is important for evolution of the species and to understand how the pneumococcal population is changing with vaccination. We aimed to determine the impact of the 13-valent pneumococcal conjugate vaccine (PCV13) on multiple serotype carriage. Nasopharyngeal samples from fully vaccinated pneumococcal carriers (4 doses of PCV13, n=141, aged 18-72months) or from non-vaccinated pneumococcal carriers (0 doses of any PCV, n=140, same age group) were analyzed. Multiple serotype carriage was evaluated by DNA hybridization with a molecular serotyping microarray that detects all known serotypes. Vaccinated children had a lower prevalence of multiple serotype carriage than the non-vaccinated group (20.6% vs 29.3%, p=0.097), and a significantly lower proportion of PCV13 serotypes (6.4% vs 38.5%, p=0.0001). PCV13 serotypes found among vaccinated children were mostly detected as a minor serotype in co-colonization with a more abundant non-vaccine serotype. Vaccinated children were colonized by a significantly higher proportion of commensal non-pneumococcal Streptococcus spp. (58.2% vs 42.8%, p=0.012). In vaccinated children there were significantly less non-vaccine type (NVT) co-colonization events than expected based on the distribution of these serotypes in non-vaccinated children. The results suggest that vaccinated children have lower pneumococcal multiple serotype carriage prevalence due to higher competitive abilities of non-vaccine serotypes expanding after PCV13 use. This might represent an additional benefit of PCV13, as decreased co-colonization rates translate into decreased opportunities for horizontal gene transfer and might have implications for the evolution and virulence of pneumococci.


Transient Monocytosis Subjugates Low Platelet Count in Adult Dengue Patients.
Dengue is one of the most important vector-borne human viral diseases globally. The kinetic changes of hematological parameters of dengue in adult Taiwanese patients have seldomly been systematically investigated and characterized. Serial laboratory data of 1,015 adult patients who were diagnosed with dengue virus serotype 2 (DENV2) and 3 (DENV3) infections in southern Taiwan were retrospectively examined. Prominent parameters were verified with specimens from a 2015 dengue outbreak. Higher absolute monocyte counts on day 5 in severe patients than mild fever subjects after the onset of fever was seen. The absolute number of monocytes was significantly greater in those with DENV2 than DENV3 infections in spite of subtle differences in laboratory tests. Platelet counts were lowest and activated partial thromboplastin time was highest on day 5 in patients with severe conditions. In addition, sudden downward platelet counts corresponding to a transient surge of monocytes on day 4 onward was observed. Fluorescence-activated cell sorting analysis of peripheral blood mononuclear cells obtained from acute dengue patients and experimental investigations revealed that phagocytic effects of innate immune cells contribute to thrombocytopenia in dengue patients. Innate phagocytic cells play an essential role in low platelet counts in adult patients with dengue virus infections.


Inflammation and implantation.
Approximately half of all human embryo implantations result in failed pregnancy. Multiple factors may contribute to this failure, including genetic or metabolic abnormalities of the embryo. However, many of these spontaneous early abortion cases are attributed to poor uterine receptivity. Furthermore, although many fertility disorders have been overcome by a variety of assisted reproductive techniques, implantation remains the rate-limiting step for the success of the in vitro fertilization (IVF) treatments. It has been demonstrated that endometrial biopsies performed either during the spontaneous, preceding cycle, or during the IVF cycle itself, significantly improve the rate of implantation, clinical pregnancies and live births. These observations suggest that mechanical injury of the endometrium may enhance uterine receptivity by provoking the immune system to generate an inflammatory reaction. In strong support of this idea, we recently found that dendritic cells (DCs), an important cellular component of the innate immune system, play a critical role in successful implantation in a mouse model. In this review, we discuss the hypothesis that the injury-derived inflammation in the biopsy-treated patients generates a focus for uterine DCs accumulation that, in turn, enhances the endometrial expression of essential molecules, which facilitate the interaction between the embryo and the uterine epithelium.


Rainbow Trout Erythrocytes ex vivo Transfection With a DNA Vaccine Encoding VHSV Glycoprotein G Induces an Antiviral Immune Response.
Fish red blood cells (RBCs), are integral in several biologic processes relevant to immunity, such as pathogen recognition, pathogen binding and clearance, and production of effector molecules and cytokines. So far, one of the best strategies to control and prevent viral diseases in aquaculture is DNA immunization. DNA vaccines (based on the rhabdoviral glycoprotein G [gpG] gene) have been shown to be effective against fish rhabdoviruses. However, more knowledge about the immune response triggered by DNA immunization is necessary to develop novel and more effective strategies. In this study, we investigated the role of fish RBCs in immune responses induced by DNA vaccines. We show for the first time that rainbow trout RBCs express gpG of viral hemorrhagic septicaemia virus (VHSV) (GVHSV) when transfected with the DNA vaccine ex vivo and modulate the expression of immune genes and proteins. Functional network analysis of transcriptome profiling of RBCs expressing GVHSV revealed changes in gene expression related to G-protein coupled receptor (GPCR)-downstream signaling, complement activation, and RAR related orphan receptor α (RORA). Proteomic profile functional network analysis of GVHSV-transfected RBCs revealed proteins involved in the detoxification of reactive oxygen species, interferon-stimulated gene 15 (ISG15) antiviral mechanisms, antigen presentation of exogenous peptides, and the proteasome. Conditioned medium of GVHSV-transfected RBCs conferred antiviral protection and induced ifn1 and mx gene expression in RTG-2 cells infected with VHSV. In summary, rainbow trout nucleated RBCs could be actively participating in the regulation of the fish immune response to GVHSV DNA vaccine, and thus may represent a possible carrier cells for the development of new vaccine approaches.


Unphosphorylated STAT1 promotes sarcoma development through repressing expression of Fas and bad and conferring apoptotic resistance.
STAT1 exists in phosphorylated (pSTAT1) and unphosphorylated (uSTAT1) forms each regulated by IFN-γ. Although STAT1 is a key mediator of the IFN-γ signaling pathway, an essential component of the host cancer immunosurveillance system, STAT1 is also overexpressed in certain human cancers where the functions of pSTAT1 and uSTAT1 are ill defined. Using a murine model of soft tissue sarcoma (STS), we show that disruption of the IFN effector molecule IRF8 decreases pSTAT1 and increases uSTAT1 in STS cells, thereby increasing their metastatic potential. We determined that the IRF8 gene promoter was hypermethylated frequently in human STS. An analysis of 123 human STS specimens revealed that high uSTAT1 levels in tumor cells was correlated with a reduction in disease-specific survival (DSS), whereas high pSTAT1 levels in tumor cells were correlated with an increase in DSS. In addition, uSTAT1 levels were negatively correlated with pSTAT1 levels in these STS specimens. Mechanistic investigations revealed that IRF8 suppressed STAT1 transcription by binding the STAT1 promoter. RNAi-mediated silencing of STAT1 in STS cells was sufficient to increase expression of the apoptotic mediators Fas and Bad and to elevate the sensitivity of STS cells to Fas-mediated apoptosis. Together, our findings show how the phosphorylation status of pSTAT1 determines its function as a tumor suppressor, with uSTAT1 acting as a tumor promoter that acts by elevating resistance to Fas-mediated apoptosis to promote immune escape.


Steric hindrance as a mechanistic probe for olefin reactivity: variability of the hydrogenic canopy over the isomeric adamantylideneadamantane/sesquihomoadamantene pair (a combined experimental and theoretical study).
Access to each C=C face of adamantylideneadamantane (AA) and sesquihomoadamantene (SA) is hindered by the hydrogenic canopy consisting of four beta-hydrogens; otherwise, these olefins have quite normal environments. X-ray crystallography and density functional (DFT) calculations show a 0.5 A larger annular opening in the protective cover of AA than that in SA. This contributes to the remarkable differences in reactivity toward various reagents, not only by limiting access to the olefin site in SA but also by inhibiting reactions which force these hydrogens closer together. Thus, AA is subject to typical olefin-addition reactions with bromine, sulfuryl chloride, m-chloroperbenzoic acid, dioxygen, and so forth, albeit sometimes at attenuated rates. On the other hand, SA is singularly unreactive under identical reaction conditions, except for the notable exceptions that include Brønsted (protonic) acids, a nitrosonium cation, and dichlorine. The exceptions are characterized as three sterically limited (electrophilic) reagents whose unique reactivity patterns are shown to be strongly influenced by steric access to the C=C center. As such, the different degrees of steric encumbrance in the isomeric donors AA and SA shed considerable light on the diverse nature of olefinic reactions. In particular, they evoke mechanistic features in electrophilic addition versus electron transfer, which are otherwise not readily discernible with other less hindered olefinic donors. Transient structures of the olefinic-reaction intermediates such as the protonated carbocations AA-H+ and SA-H+ as well as the cation radicals AA*+ and SA*+ are probed by the combination of X-ray crystallographic analyses and density functional theoretical computations.


Ecological momentary assessment of environmental and personal factors and snack food intake in African American women.
This study examined contributions of environmental and personal factors (specifically, food availability and expense, daily hassles, self-efficacy, positive and negative affect) to within-person and between-person variations in snack food intake in 100 African American women. Participants were signaled at random five times daily for seven days to complete a survey on a study-provided smartphone. Women reported consuming snack foods at 35.2% of signals. Easier food availability accounting for one's usual level was associated with higher snack food intake. Being near outlets that predominately sell snacks (e.g., convenience stores), while accounting for one's usual proximity to them, was associated with higher snack food intake. Accounting for one's usual daily hassle level, we found that on days with more frequent daily hassles snack food intake was higher. The positive association between within-person daily hassles frequency and snack food intake was stronger when foods were easily available. Public and private policies to curb ubiquitous food availability and mobile health interventions that take into account time-varying influences on food choices and provide real-time assistance in dealing with easy food availability and coping with stressors may be beneficial in improving African American women's day to day food choices.


Comparison of lymphoscintigraphy and single photon emission computed tomography with computed tomography (SPECT/CT) for sentinel lymph node detection in endometrial cancer.
Endometrial cancer is the most common gynecologic cancer, and lymph node metastasis is one of the most important prognostic factors. Increasing evidence shows that sentinel lymph node (SLN) mapping is an effective alternative to comprehensive lymphadenectomy. Single photon emission CT with computed tomography (SPECT/CT) is associated with a high SLN detection rate. To compare the clinical efficacy of SPECT/CT with that of lymphoscintigraphy in detecting SLNs in patients with endometrial cancer. Between May 2014 and October 2018, 151 patients with endometrial cancer were enrolled in this study at the Department of Obstetrics and Gynecology of the Kagoshima University Hospital. Inclusion criteria were patients with endometrial cancer, older than 18 years, and with pre-operative International Federation of Gynecology and Obstetrics (FIGO) staging of I and II. All patients underwent pre-operative CT, and patients with suspected peritoneal dissemination and lymph node metastasis were excluded from this study. Pelvic SLNs were detected by injection of tecnetium-99m-labeled phytate into the uterine cervix. The number and locations of SLNs detected using lymphoscintigraphy and SPECT/CT were evaluated. JMP software (version 14, SAS Institute Inc., Cary, North Carolina, USA) was used for statistical analysis. A total of 151 patients who underwent pre-operative lymphoscintigraphy and SPECT/CT were included in the study. The median age was 57 years (range 24-79), and the median body mass index was 24.3 kg/m2 (range 16-40). The final pathology was as follows: 135 (89%) endometrioid carcinoma, 11 (7%) serous carcinoma, one (1%) clear cell carcinoma, and four (3%) other histotypes. Based on SPECT/CT, 204 pelvic SLNs were detected. The bilateral pelvic SLN detection rate was better for SPECT/CT (43% (65/151)) than for lymphoscintigraphy (32% (48/151)) (p<0.0001). The overall pelvic SLN detection rate (at least one pelvic SLN detected) was also better with SPECT/CT (77% (16/151)) vs lymphoscintigraphy (68% (102/151)) (p<0.0001). The distribution of SLN locations detected using SPECT/CT was as follows: external iliac, 91 (45%); obturator, 61 (30%); common iliac, 28 (14%); internal iliac, 19 (9%); para-aortic, 2 (1%); parametrium, 2 (1%), and presacral, 1 (1%). The SLN detection rate using SPECT/CT was significantly worse in patients of advanced age (p<0.0001). Overall and bilateral SLN detection rate was better with SPECT/CT than with lymphoscintigraphy in patients with stage I/II endometrial cancer.


Application of Traditional Chinese Medicine in medical practice: a survey of community residents in Beijing, China.
To investigate how community residents in Beijing understood and used Traditional Chinese Medicine (TCM) in their medical practice. This was a cross-sectional study conducted on 3410 community residents from four large communities of Tongzhou district in Beijng, China. A validated, self-administered questionnaire comprised of three sections was used to gather the data. A systematic sampling procedure was applied to recruit the community residents. A total of 3410 participants completed the questionnaire survey. It showed that in highly educated residents, 33.4% (170) knew of the names of 3-10 Chinese herbals, 35.8% (182) knew of names of 3-10 traditional Chinese patent drug. Among all the respondent residents, 80.7% (2753) believed that TCM herbal therapy and TCM non-drug treatments were effective in disease treatment, health enhancement, 85.7% (2923) had taken traditional Chinese patent drug in their life, 56.8% (1937) of residents had used herbal decoction, 40.0% (1365) had received non-drug treatment of TCM, such as acupuncture, massage, cupping, auricular acupuncture. Among the elderly residents, 11.4% (98) often used Chinese patent drug and 9.8% (85) often used herbal decoction. In addition, 70.8% (2415) of residents were willing to accept knowledge and information on TCM for health enhancement and disease prevention, such as medicated diet, medicinal tea, Tai Chi and Qi Gong, although 82.8% (2825) of residents had never used them. Chinese patent drug and herbal decoction are widely used in the communities in Beijing, and there existed a possible close correlation between high educational level and better understanding of TCM. Age and occupation also correlated with the attitude to TCM therapies. The characteristics of the residents should be considered seriously in the course of promoting the understanding and application of TCM.


The molecular mechanisms of a high Ca2+-sensitivity and muscle weakness associated with the Ala155Thr substitution in Tpm3.12.
Substitution of Ala for Thr residue in 155th position in γ-tropomyosin (Tpm3.12) is associated with muscle weakness. To understand the mechanisms of this defect, we studied the Ca2+-sensitivity of thin filaments in solution and multistep changes in mobility and spatial arrangement of actin, Tpm, and myosin heads during the ATPase cycle in reconstituted muscle fibres, using the polarized fluorescence microscopy. It was shown that the Ala155Thr (A155T) mutation increased the Ca2+-sensitivity of the thin filaments in solution. In the absence of the myosin heads in the muscle fibres, the mutation did not alter the ability of troponin to switch the thin filaments on and off at high and low Ca2+, respectively. However, upon the binding of myosin heads to the thin filaments at low Ca2+, the mutant Tpm was found to be markedly closer to the open position, than the wild-type Tpm. In the presence of the mutant Tpm, switching on of actin monomers and formation of the strong-binding state of the myosin heads were observed at low Ca2+, which indicated a higher myofilament Ca2+-sensitivity. The mutation decreased the amount of myosin heads bound strongly to actin at high Ca2+ and increased the number of these heads at relaxation. It is suggested that direct binding of myosin to Tpm may be one оf the reasons for muscle weakness associated with the A155T mutation. The use of reagents that decrease the Ca2+-sensitivity of the troponin complex may not be adequate to restore muscle function in patients with the A155T mutation.


Perirhinal cortex ablation impairs visual object identification.
Impairments in both recognition memory and concurrent discrimination learning have been shown to follow perirhinal cortex ablation in the monkey. The pattern of these impairments is consistent with the hypothesis that the perirhinal cortex has a role in the visual identification of objects. In this study we compared the performance of a group of three cynomolgus monkeys with bilateral perirhinal cortex ablation with that of a group of three normal controls in two tasks designed to test this hypothesis more directly. In experiment 1 the subjects relearned a set of 40 familiar concurrent discrimination problems; the stimuli in each trial were digitized images of real objects presented in one of three different views. After attaining criterion they were tested on the same problems using similar, but previously unseen, views of the objects. In experiment 2 the subjects were tested on their ability to perform 10 of these familiar discriminations with each problem presented in the unfamiliar context of a digitized image of a unique complex scene. The subjects with ablations were significantly impaired on both tasks. These results demonstrate that the role of the perirhinal cortex is not restricted to memory, and they support the hypothesis that the perirhinal cortex is involved in visual object identification. We suggest that the perirhinal cortex is crucially involved in processing coherent concepts of individual objects. A deficit of this nature could underlie the pattern of impairments that follow perirhinal cortex damage in both visual object recognition memory and visual associative memory.


Rapid HbA1c testing in a community setting.
To determine whether the DCA 2000 analyzer provides valid and reliable HbA1c results when used under field conditions and operated by nonmedical personnel. This study was part of a community diabetes education program, the Native American Diabetes Project, in which HbA1c was measured as an indicator of average glycemic control. Two study samples were taken, the first in the spring of 1994 and the second in the spring of 1995. Seven community members in 1994 and six new community members in 1995 were trained over 2 days, using standard protocol, to operate the DCA 2000 HbA1c analyzer and to collect two capillary blood samples from participants in the Native American Diabetes Project. Duplicate DCA 2000 HbA1c measurements performed by the community workers were compared with measurements from a high-performance liquid chromatography (HPLC) system. Validity and reliability measures were calculated. Of the participants, 43 were studied in 1994 and 14 in 1995. Comparison of the mean DCA 2000 results with those of HPLC showed high validity, with the absolute relative difference between the mean DCA 2000 and the external reference of HPLC (magnitude of mean DCA 2000-HPLC magnitude of /HPLC) as 4.0 and 2.0% for 1994 and 1995, respectively. The Pearson correlation coefficients (r) between these two measures were 0.968 and 0.996 for 1994 and 1995, respectively. While the 1994 data appeared to have less validity for values > 10%, they included only one value with a 60-min warm-up of the DCA analyzer. The 1995 data, all collected after a 60-min warm-up, had good correlation throughout the range of values. The within-run reliability was excellent, with an intraclass correlation coefficient of reliability of 0.959 and 0.975 for paired samples, for 1994 and 1995 respectively. The mean coefficient of variation for these paired measures was 3.0% in 1994 and 2.8% in 1995. Both validity and reliability were improved by changing the warm-up period of the DCA 2000 analyzer from 5 to 60 min. All correlation coefficients were statistically significant (P < 0.0001). The DCA 2000 gave valid and reliable HbA1c results when operated in a community setting by nonmedical personnel. Extending the warm-up period of the device to 60 min slightly improved the validity and reliability of the test.


Elemental characterization of PM2.5 and PM10 emitted from light duty vehicles in the Washburn Tunnel of Houston, Texas: release of rhodium, palladium, and platinum.
We report the elemental composition, including Rh, Pd, and Pt, of total (i.e., tailpipe and nontailpipe) PM2.5 and PM10 emissions from predominantly gasoline-driven light-duty vehicles (LDVs) traversing the Washburn Tunnel in Houston, Texas during November and December, 2012. Using a novel sample preparation and dynamic reaction cell-quadrupole-inductively coupled plasma-mass spectrometry technique, we quantify the emission of numerous representative, transition, and lanthanoid elements. Two sets of time integrated PM samples were collected over 3-4week duration both inside the tunnel as well as from the tunnel ventilation air supply to derive accurate LDV source profiles incorporating three platinum group elements (PGEs) for the first time. Average Rh, Pd, and Pt concentrations from the tunnel ventilation air supply were 1.5, 11.1, and 4.5pgm(-3) in PM2.5 and 3.8, 23.1, and 15.1pgm(-3) in PM10, respectively. Rh, Pd, and Pt levels were elevated inside the Washburn Tunnel reaching 12.5, 91.1, and 30.1pgm(-3) in PM2.5 and 36.3, 214, and 61.1pgm(-3) in PM10, respectively. Significantly higher enrichment factors of Cu, Zr, Rh, Pd, Sb, and Pt (referenced to Ti in the upper continental crust) inside the tunnel compared with the ventilation air supply suggested that they are unique elemental tracers of PM derived from gasoline-driven LDVs. This highlights the importance of advancing methods to quantify the trace level PGE emissions as a technique to more accurately estimate LDVs' contributions to airborne PM. Using the emission profile based on PGEs and ambient quantification, mass balancing revealed that approximately half the fine PM mass in the tunnel could be attributed to tailpipe emissions, approximately one-quarter to road dust, with smaller contributions from brake (7%) and tire (3%) wear. On the other hand, PM10 mostly originated from resuspended road dust (∼50%), with progressively lower contributions from tailpipe emissions (14%), brake wear (9%), and tire wear (2%).


Expression of corticotropin releasing hormone receptors type I and type II mRNA in suicide victims and controls.
Corticotropin-releasing hormone (CRH) is a key neuroendocrine factor implementing endocrine, immune and behavioral responses to stress. CRH exerts its action through two major receptors, CRH-R1 and CRH-R2. Recently novel non-peptidic antagonists directed against CRH-R1 or CRH-R2 have been proposed as promising agents in the treatment of depression, anxiety and eating disorder. However, so far the CRH-receptor system has not been widely studied in humans. Therefore, we employed quantitative TaqMan PCR to analyze the expression and distribution of both CRH-R1 and CRH-R2 in human brain tissue and peripheral organs. Furthermore the expression of CRH receptors was analyzed for the first time in pituitaries of suicide victims by in situ hybridization and quantitative PCR. Our data demonstrated a different expression pattern in humans as compared to rodents. Both CRH-R1 and CRH-R2 were expressed in high amounts in the brain with the strongest expression in the pituitary. As described in rodents, however the CRH-R1 in human was the predominant receptor in the brain (82.7 +/- 11.0%), whilst CRH-R2 was the predominant receptor in peripheral organs (77.0 +/- 15.8%). There was a shift in the ratio of CRH-R1/R2 in the pituitaries of suicide victims. In conclusion, both CRH-R1 and CRH-R2 are widely expressed in human tissues with a distribution substantially different from rodents. Strong expression of both CRH-R1 and CRH-R2 in human pituitaries suggests that particularly under stress, activation of the HPA axis can be maintained through both receptors.


FstSNP-HapMap3: a database of SNPs with high population differentiation for HapMap3.
The International HapMap Project has recently made available genotypes and frequency data for phase 3 (NCBI build 36, dbSNPb129) of the HapMap providing an enriched genotype dataset for approximately 1.6 million single nucleotide polymorphisms (SNPs) from 1,115 individuals with ancestry from parts of Africa, Asia, Europe, North America and Mexico. In the present study, we aim to facilitate pharmacogenetics studies by providing a database of SNPs with high population differentiation through a genomewide test on allele frequency variation among 11 HapMap3 samples. Common SNPs with minor allele frequency greater than 5 cent from each of 11 HapMap3 samples were included in the present analysis. The population differentiation is measured in terms of fixation index (Fst), and the SNPs with Fst values over 0.5 were defined as highly differentiated SNPs. Our tests were carried out between all pairs of the 11 HapMap3 samples or among subgroups with the same continental ancestries. Altogether we carried out 64 genomewide Fst tests and identified 28,215 highly differentiated SNPs for 49 different combinations of HapMap3 samples in the current database. http://FstSNP-hapmap3.googlecode.com/


Timing of first dental checkup for newly Medicaid-enrolled children with an intellectual or developmental disability.
We compared the extent to which having an intellectual or developmental disability was associated with rates at which Iowa Medicaid-enrolled children ages 3 to 8 had first dental checkups after an initial dental examination. We hypothesized that these children would have later first dental checkups than would children without an intellectual or developmental disability. Findings suggest no significant difference in the time to first dental checkup for children by intellectual or developmental disability status. Those who took over 12 months to see a dentist for their initial dental examination were 1.68 times as likely to have an earlier first dental checkup as children whose initial dental examination occurred within 4 months of being enrolled. Results suggest that having an intellectual or developmental disability is not associated with later first dental checkups for this population.


The Cradle Coast personally controlled electronic health record evaluation research.
In 2010 the Federal Government announced funding over two years to create a Personally Controlled Electronic Health Record (PCEHR) for Australians. One of the wave 2 implementation sites is the Cradle Coast in Tasmania. A PCEHR Program Benefits and Evaluation Partner (BEP) has been appointed to undertake evaluation activities with the e-health lead implementation sites. In addition to this implementation a comprehensive research plan has been developed and commenced through the Rural Clinical School at the University of Tasmania. The overarching aim of the research agenda is to evaluate the outcomes of various elements of the 4C project as it evolves and is implemented, from multiple perspectives. The research agenda is important as it expands upon the NEHTA mandated evaluation and provides an holistic overview of the PCEHR implementation process and outcomes for clinicians, patients and family members. This paper will detail the planned evaluation and its progress to date.


Mycobacterium tuberculosis CDC1551 induces a more vigorous host response in vivo and in vitro, but is not more virulent than other clinical isolates.
Mycobacterium tuberculosis CDC1551, a clinical isolate reported to be hypervirulent and to grow faster than other isolates, was compared with two other clinical isolates (HN60 and HN878) and two laboratory strains (H37Rv and Erdman). The initial (1-14 days) growth of CDC1551, HN60, HN878, and H37Rv was similar in the lungs of aerosol-infected mice, but growth of Erdman was slower. Thereafter, the growth rate of CDC1551 decreased relative to the other strains which continued to grow at comparable rates up to day 21. In the lungs of CDC1551-infected mice, small well-organized granulomas with high levels of TNF-alpha, IL-6, IL-10, IL-12, and IFN-gamma mRNA were apparent sooner than in lungs of mice infected with the other strains. CDC1551-infected mice survived significantly longer. These findings were confirmed in vitro. The growth rates of H37Rv and CDC1551 in human monocytes were the same, but higher levels of TNF-alpha, IL-10, IL-6, and IL-12 were induced in monocytes after infection with CDC1551 or by exposure of monocytes to lipid fractions from CDC1551. CD14 expression on the surface of the monocytes was up-regulated to a greater extent by exposure to the lipids of CDC1551. Thus, CDC1551 is not more virulent than other M. tuberculosis isolates in terms of growth in vivo and in vitro, but it induces a more rapid and robust host response.


Sexual selection and the adaptive evolution of mammalian ejaculate proteins.
An elevated rate of substitution characterizes the molecular evolution of reproductive proteins from a wide range of taxa. Although the selective pressures explaining this rapid evolution are yet to be resolved, recent evidence implicates sexual selection as a potentially important explanatory factor. To investigate this hypothesis, we sought evidence of a high rate of adaptive gene evolution linked to postcopulatory sexual selection in muroid rodents, a model vertebrate group displaying a broad range of mating systems. Specifically, we sequenced 7 genes from diverse rodents that are expressed in the testes, prostate, or seminal vesicles, products of which have the potential to act in sperm competition. We inferred positive Darwinian selection in these genes by estimation of the ratio of nonsynonymous (d(N), amino acid changing) to synonymous (d(S), amino acid retaining) substitution rates (omega = d(N)/d(S)). Next, we tested whether variation in this ratio among lineages could be attributed to interspecific variation in mating systems, as inferred from the variation in these rodents' relative testis sizes (RTS). Four of the 7 genes examined (Prm1, Sva, Acrv1, and Svs2, but not Svp2, Msmb, or Spink3) exhibit unambiguous evidence of positive selection. One of these, the seminal vesicle-derived protein Svs2, also shows some evidence for a concentration of positive selection in those lineages in which sperm competition is common. However, this was not a general trend among all the rodent genes we examined. Using the same methods, we then reanalyzed previously published data on 2 primate genes, SEMG1 and SEMG2. Although SEMG2 also shows evidence of positive selection concentrated in lineages subject to high levels of sperm competition, no such trend was found for SEMG1. Overall, despite a high rate of positive selection being a feature of many ejaculate proteins, these results indicate that the action of sexual selection potentially responsible for elevated evolutionary rates may be difficult to detect on a gene-by-gene basis. Although the extreme diversity of reproductive phenotypes exhibited in nature attests to the power of sexual selection, the extent to which this force predominates in driving the rapid molecular evolution of reproductive genes therefore remains to be determined.


Atomically-thin molecular layers for electrode modification of organic transistors.
Atomically-thin molecular layers of aryl-functionalized graphene oxides (GOs) were used to modify the surface characteristics of source-drain electrodes to improve the performances of organic field-effect transistor (OFET) devices. The GOs were functionalized with various aryl diazonium salts, including 4-nitroaniline, 4-fluoroaniline, or 4-methoxyaniline, to produce several types of GOs with different surface functional groups (NO2-Ph-GO, F-Ph-GO, or CH3O-Ph-GO, respectively). The deposition of aryl-functionalized GOs or their reduced derivatives onto metal electrode surfaces dramatically enhanced the electrical performances of both p-type and n-type OFETs relative to the performances of OFETs prepared without the GO modification layer. Among the functionalized rGOs, CH3O-Ph-rGO yielded the highest hole mobility of 0.55 cm(2) V(-1) s(-1) and electron mobility of 0.17 cm(2) V(-1) s(-1) in p-type and n-type FETs, respectively. Two governing factors: (1) the work function of the modified electrodes and (2) the crystalline microstructures of the benchmark semiconductors grown on the modified electrode surface were systematically investigated to reveal the origin of the performance improvements. Our simple, inexpensive, and scalable electrode modification technique provides a significant step toward optimizing the device performance by engineering the semiconductor-electrode interfaces in OFETs.


Holographic interferometry with an injection seeded Nd:YAG laser and two reference beams.
The performance of twin injection seeded Nd:YAG lasers is compared with the performance of an argon-ion laser for recording dual-reference-beam holograms in Agfa 8E56 emulsion. Optical heterodyning is used to measure interference and the results are expressed in terms of heterodyning signal level and intensity signal to noise. The Nd:YAG laser system is to be used for optical inspections of structures for cracks, defects, gas leaks, and structural changes.


Gastric bypass reduces biochemical cardiac risk factors.
Coronary artery disease (CAD) is the leading cause of death in the United States, with obesity as a leading preventable risk factor for CAD. Certain biochemical markers have demonstrated strong prediction for cardiovascular events. We hypothesized that in addition to weight reduction, gastric bypass will also induce a salutary effect on the biochemical cardiac risk factors. At a single academic institution, from 2003 to 2004, we measured the biochemical cardiac risk factors in gastric bypass patients preoperatively and at 3, 6, and 12 months postoperatively. These risk factors included total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, total cholesterol/HDL cholesterol ratio, triglyceride/HDL cholesterol ratio, triglycerides, lipoprotein A, high-sensitivity C-reactive protein, and homocysteine. The data were analyzed using the Wilcoxon signed rank test. The mean age of the 356 patients was 43 years; 84% were women; the mean body mass index was 47 kg/m(2); 33% were diabetic; 50% were hypertensive; 23% were taking lipid-lowering medications; and 2% had known CAD. Significant improvement occurred in the biochemical cardiac factors from preoperatively to 12 months. The beneficial changes were as follows: total cholesterol, 192 mg/dL preoperatively to 166 mg/dL at 12 months; HDL cholesterol, 46 mg/dL preoperatively to 54 mg/dL at 12 months; low-density lipoprotein, 125 mg/dL preoperatively to 88 mg/dL at 12 months; total cholesterol/HDL cholesterol ratio, 4 preoperatively to 3 at 12 months; triglyceride/HDL cholesterol ratio, 3 preoperatively to 2 at 12 months; triglycerides, 133 mg/dL preoperatively to 92 mg/dL at 12 months; lipoprotein A, 14 mg/dL preoperatively to 13 mg/dL at 12 months; high-sensitivity C-reactive protein, 8 mg/L preoperatively to 1 mg/L; and homocysteine, 10 mumol/L preoperatively to 8 mumol/L at 12 months. The results of our study have shown that gastric bypass significantly improves all biochemical markers of CAD risk, particularly C-reactive protein, which had an 80% reduction. As a result, gastric bypass decreases the cardiac risk by both weight loss and advantageous alterations of biochemical cardiac risk factors.


Psychometric properties and measurement invariance of the 7-item game addiction scale (GAS) among Chinese college students.
The 7-item Gaming Addiction Scale (GAS) has been used as a screening tool for addictive game use worldwide, and this study aimed to examine its psychometric properties and measurement invariance among college students in China. Full-time students from multiple colleges in China were recruited. A total of 1040 completed questionnaires were used in the final analysis. Reliability of the GAS was assessed by internal consistency and split-half reliability. Validity of the GAS was assessed by structural validity, convergent validity, discriminant validity, and concurrent validity. A series of Multigroup Confirmatory Factor Analysis (MG-CFA) were conducted to test and establish measurement invariance across gender, class standing, family income and parental educational level. Exploratory factor analysis revealed a unidimensional structure of the GAS. The GAS exhibited excellent internal consistency (Cronbach's α = 0.951, theta coefficient = 0.953, omega coefficient = 0.959) and structural validity (χ2 /df = 0.877 (p < 0.05), CFI = 0.999, TIL = 0.996, RMSEA =0.000). Concurrent validity of the GAS was confirmed by its correlation with problematic internet use, sleep quality, nine dimensions of psychiatric symptoms, and substance use. The GAS also demonstrated measurement invariance across father's educational level (Δχ2 (df) = 19.128 (12), ΔCFI = - 0.009, ΔRMSEA = 0.010 for weak factorial model; Δχ2 (df) = 50.109 (42), ΔCFI = - 0.010, ΔRMSEA = 0.007 for strict factorial model.) and mother's educational level (Δχ2 (df) = 6.679 (12), ΔCFI = 0.007, ΔRMSEA = - 0.010 for weak factorial model; Δχ2 (df) =49.131 (42), ΔCFI = - 0.009, ΔRMSEA = - 0.004 for strict factorial model), as well as partial measurement invariance across gender (except for item 2), class standing (except for item 7) and family income (except for item 5). The Chinese version of the 7-item GAS can be an adequate assessment tool to assess internet gaming disorder among the college student population in China.


Acute Effects of Foam Rolling, Static Stretching, and Dynamic Stretching During Warm-ups on Muscular Flexibility and Strength in Young Adults.
Foam rolling has been proposed to improve muscle function, performance, and joint range of motion (ROM). However, whether a foam rolling protocol can be adopted as a warm-up to improve flexibility and muscle strength is unclear. To examine and compare the acute effects of foam rolling, static stretching, and dynamic stretching used as part of a warm-up on flexibility and muscle strength of knee flexion and extension. Crossover study. University research laboratory. 15 male and 15 female college students (age 21.43 ± 1.48 y, weight 65.13 ± 12.29 kg, height 166.90 ± 6.99 cm). Isokinetic peak torque was measured during knee extension and flexion at an angular velocity of 60°/second. Flexibility of the quadriceps was assessed by the modified Thomas test, while flexibility of the hamstrings was assessed using the sit-and-reach test. The 3 interventions were performed by all participants in random order on 3 days separated by 48-72 hours. The flexibility test scores improved significantly more after foam rolling as compared with static and dynamic stretching. With regard to muscle strength, only knee extension peak torque (pre vs. postintervention) improved significantly after the dynamic stretching and foam rolling, but not after static stretching. Knee flexion peak torque remained unchanged. Foam rolling is more effective than static and dynamic stretching in acutely increasing flexibility of the quadriceps and hamstrings without hampering muscle strength, and may be recommended as part of a warm-up in healthy young adults.


Remdesivir potently inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA polymerase in mice.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 as the causative agent of the novel pandemic viral disease COVID-19. With no approved therapies, this pandemic illustrates the urgent need for safe, broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV), a monophosphoramidate prodrug of an adenosine analog, potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC 50 = 0.01 μM). Weaker activity was observed in Vero E6 cells (EC 50 = 1.65 μM) due to their low capacity to metabolize RDV. To rapidly evaluate in vivo efficacy, we engineered a chimeric SARS-CoV encoding the viral target of RDV, the RNA-dependent RNA polymerase, of SARS-CoV-2. In mice infected with chimeric virus, therapeutic RDV administration diminished lung viral load and improved pulmonary function as compared to vehicle treated animals. These data provide evidence that RDV is potently active against SARS-CoV-2 in vitro and in vivo , supporting its further clinical testing for treatment of COVID-19.


Solution structure of Delta 5-3-ketosteroid isomerase complexed with the steroid 19-nortestosterone hemisuccinate.
The solution structure of the ketosteroid isomerase homodimer complexed with the product analogue 19-nortestosterone hemisuccinate (19-NTHS) was solved by heteronuclear multidimensional NMR methods using 1647 distance restraints, 77 dihedral angle (phi) restraints, and 67 hydrogen bond restraints per monomer. The refined secondary structure of each subunit consists of three alpha-helices, eight beta-strands, four turns, and two beta-bulges. The beta-strands form a mixed beta-sheet. One of the five proline residues, Pro-39, is cis and begins a nonclassical turn. A self-consistent ensemble of 15 tertiary/quaternary structures of the enzyme dimer-steroid complex, with no distance violations greater than 0.35 A, was generated by simulated annealing and energy minimization with the program X-PLOR. The mean pairwise RMSD of the secondary structural elements was 0.63 A for the average subunit and 1.25 A for the dimer. Within each subunit, the three alpha-helices are packed onto the concave surface of the beta-sheet with a groove between them into which the steroid binds at a site defined by 14 intermolecular distances. In the productive complex, Tyr-14, from alpha-helix 1, approaches both Asp-99 and the 3-keto group of 19-NTHS while, from beta-strand 1, the carboxylate of Asp-38 approaches the beta-face of the steroid near C4 and C6, between which it transfers a proton during catalysis. Thus the solution structure of the isomerase-steroid complex can accommodate the catalytic diad mechanism in which Asp-99 donates a hydrogen bond to Tyr-14 which in turn is hydrogen bonded to the 3-oxygen of the steroid. While direct hydrogen bonding of Asp-99 to the steroid oxygen is less likely, it cannot be excluded. All other interactions of the steroid with the enzyme are hydrophobic. The dimer interface, which is between the convex surfaces of the beta-sheets, is defined by 28 intersubunit NOEs between hydrophobic residues in the 13C-filtered NOESY-HSQC spectrum of a 13C/12C-heterolabeled dimer. Both hydrophobic and polar interactions occur at the dimer interface which contains no space that would permit additional steroid binding. Comparison of the complexed enzyme with the solution structure of the free enzyme [Wu et al. (1997) Science 276, 415-418] reveals that the three helices change position in the steroid complex, becoming more closely packed onto the concave surface of the beta-sheet, thus bringing Tyr-14 closer to Asp-99 and the substrate. Comparison of the enzyme-steroid complex in solution with the free enzyme in the crystalline state reveals similar differences between the positions of the helices.


Comprehensive identification of arginine methylation in primary T cells reveals regulatory roles in cell signalling.
The impact of protein arginine methylation on the regulation of immune functions is virtually unknown. Here, we apply a novel method—isomethionine methyl-SILAC—coupled with antibody-mediated arginine-methylated peptide enrichment to identify methylated peptides in human T cells by mass spectrometry. This approach allowed the identification of 2,502 arginine methylation sites from 1,257 tissue-specific and housekeeping proteins. We find that components of T cell antigen receptor signal machinery and several key transcription factors that regulate T cell fate determination are methylated on arginine. Moreover, we demonstrate changes in arginine methylation stoichiometry during cellular stimulation in a subset of proteins critical to T cell differentiation. Our data suggest that protein arginine methyltransferases exert key regulatory roles in T cell activation and differentiation, opening a new field of investigation in T cell biology.


The effect of immediate breast reconstruction on adjuvant chemotherapy.
Immediate breast reconstruction is being increasingly offered to patients requiring mastectomy for breast cancer. An audit was carried out to determine whether it affected time to initiation of chemotherapy, delays during chemotherapy, percentage intended dose and need for support with antibiotics or granulocyte-colony stimulating factor. A total of 44 patients undergoing a variety of reconstructive procedures followed by chemotherapy were identified and patient records were reviewed. These were compared with a control group of 49 patients undergoing mastectomy alone and chemotherapy in the same 4-year period and institution. Patients undergoing transverse rectus abdominis myocutaneous flap reconstruction experienced an average of 5 more days delay to chemotherapy initiation than controls with the commonest reason being poor wound healing. Percentage intended dose, delays during chemotherapy and need for support with granulocyte-colony stimulating factor or antibiotics were comparable in all groups.


The rgg gene of Streptococcus pyogenes NZ131 positively influences extracellular SPE B production.
Streptococcus pyogenes produces several extracellular proteins, including streptococcal erythrogenic toxin B (SPE B), also known as streptococcal pyrogenic exotoxin B and streptococcal proteinase. Several reports suggest that SPE B contributes to the virulence associated with S. pyogenes; however, little is known about its regulation. Nucleotide sequence data revealed the presence, upstream of the speB gene, of a gene, designated rgg, that was predicted to encode a polypeptide similar to previously described positive regulatory factors. The putative Rgg polypeptide of S. pyogenes NZ131 consisted of 280 amino acids and had a predicted molecular weight of 33,246. To assess the potential role of Rgg in the production of SPE B, the rgg gene was insertionally inactivated in S. pyogenes NZ131, which resulted in markedly decreased SPE B production, as determined both by immunoblotting and caseinolytic activity on agar plates. However, the production of other extracellular products, including streptolysin O, streptokinase, and DNase, was not affected. Complementation of the rgg mutant with an intact rgg gene copy in S. pyogenes NZ131 could restore SPE B production and confirmed that the rgg gene product is involved in the production of SPE B.


Genetic linkage mapping of chromosome 17 markers and neurofibromatosis type I.
The von Recklinghausen neurofibromatosis (NF1) gene has been localized to the pericentromeric region of chromosome 17. We have screened six multigenerational families with multiple, tightly linked markers to aid in mapping this region of the chromosome. More than 150 members in six families were typed with probes including HHH202, D17Z1, EW203, EW206, EW207, EW301, pA10-41, D17S37, and D17S36. Two-point lod scores for NF1 versus all markers were calculated. HHH202 demonstrated the tightest linkage to NF1 with theta = .0, z = 3.86 (95% confidence limits [CL] of theta = .0-.13), suggesting that HHH202 be considered as a potential candidate marker for use in carrier detection and prenatal diagnosis. Pairwise marker-to-marker lod scores were used in examining the most likely order of subsets of the markers. Of those tested, the most likely order was (pter)-pA10-41-EW301-D17Z1-HHH202-NF1-E W206-EW207-EW203-(qter). In addition, we have ascertained an NF1 x NF1 half-cousin mating in which there are four affected family members who are potentially homozygous for the disease gene. Two of these four individuals have been sampled and typed for marker loci. When their D17Z1 genotypes are considered, the probability that both these individuals are heterozygous is 85%.


Ex vivo expansion of CD4+CD25+FoxP3+ T regulatory cells based on synergy between IL-2 and 4-1BB signaling.
Naturally occurring CD4(+)CD25(+)FoxP3(+) T regulatory (Treg) cells require three distinct signals transduced via TCR, CD28, and IL-2R for their development and maintenance. These requirements served as the basis for several recently developed ex vivo expansion protocols that relied on the use of solid support-bound Abs to CD3 and CD28 in the presence of high dose IL-2. We report in this study that Treg cells up-regulate the expression of inducible costimulatory receptor 4-1BB in response to IL-2, and stimulation using this receptor via a novel form of 4-1BB ligand (4-1BBL) fused to a modified form of core streptavidin (SA-4-1BBL) was effective in expanding these cells up to 110-fold within 3 wk. Expanded cells up-regulated CD25, 4-1BB, and membranous TGF-beta, suppressed T cell proliferation, and prevented the rejection of allogeneic islets upon adoptive transfer into graft recipients. Importantly, SA-4-1BBL rendered CD4(+)CD25(-) T effector cells refractive to suppression by Treg cells. This dual function of signaling via 4-1BB, vis-à-vis Treg cell expansion and licensing T effector cells resistant to Treg cell suppression, as well as the up-regulation of 4-1BB by IL-2 may serve as important regulatory mechanisms for immune homeostasis following antigenic challenge. Stimulation using a soluble form of SA-4-1BBL represents a novel approach to expand Treg cells with potential therapeutic applications in autoimmunity and transplantation.


Development of a multichannel Fourier transform spectrometer.
We devised a novel type of multichannel Fourier transform spectrometer (MCFTS) that incorporates a Wollaston prism, polarizing interferometer combined with two Savart plates and a phase-retarding plate. This original MCFTS produces a number of lines of folded interferograms recorded with a two-dimensional imaging detector such as a CCD detector. In the present type of MCFTS, the total incident light is available except for a small amount of reflection loss. It is possible to enhance the signal-to-noise ratio. The enhancement of the resolving power is also expected by the connection of the interferograms with a newly developed method.


Increased loss of chromosome 9p21 but not p16 inactivation in primary non-small cell lung cancer from smokers.
Epidemiological studies have demonstrated a causal association between tobacco use and carcinoma of the lung, and some genetic targets of the carcinogens in cigarette smoke have been defined recently. We further examined the effect of cigarette smoking on the frequency of allelic losses on chromosome 9p21 and the incidence of p16 inactivation. Chromosomal loss at 9p21-24 was determined by microsatellite analysis using 14 markers in 47 patients with non-small cell lung cancer. In addition, p16 gene inactivation was determined by DNA sequence analysis, methylation-specific PCR, and immunohistochemistry. Tumors from a group of nonsmokers (n = 14) were compared with tumors from a group of smokers (n = 33) matched for cell type, tumor stage, and gender. Allelic loss encompassing the p16 locus was present significantly (P = 0.01) more often in smokers (23 of 33 smokers, 70%) than in nonsmokers (4 of 14 nonsmokers, 28%). No significant differences in the frequency of p16 inactivation were observed between smokers and nonsmokers (45% versus 36%). However, homozygous deletion of the p16 gene locus and point mutation of p16 gene were only observed in tumors from smokers, whereas the p16 gene was inactivated in tumors from nonsmokers only through promoter hypermethylation. Thus, inactivation of the p16 gene is a common event in all non-small cell lung cancer, but the mechanism of gene alteration differs between smokers and nonsmokers. The significant link between tobacco and loss of the p16 locus identifies additional genetic targets of smoking in the pathogenesis of lung cancer.


Evaluation of the pathogenicity and virulence of three strains of Salmonella organisms in calves and pigs.
To assess in pigs the pathogenicity and virulence of 3 strains of Salmonella spp capable of causing atypical salmonellosis in cattle. 36 Holstein calves and 72 pigs experimentally infected with Salmonella spp. Representative Salmonella strains associated with 3 new disease phenotypes (protozoa-mediated hypervirulence, multisystemic cytopathicity, and encephalopathy) that have been characterized in cattle during the past 10 years were orally inoculated into pigs. Clinical manifestations were compared with those observed in cattle. Samples were collected from various tissues, and the presence of Salmonella organisms was assessed qualitatively and quantitatively by use of Salmonella-selective media. Of the 3 unique Salmonella disease phenotypes observed in cattle, only protozoa-mediated hypervirulence was observed in pigs. Hypervirulence was related to a more rapid onset of disease and higher pathogen burden in pigs than in cattle. This phenotype was observed in pigs inoculated with multiresistant Salmonella enterica serotypes Typhimurium or Choleraesuis bearing the Salmonella genomic island 1 (SGI1) integron. Salmonella hypervirulence was identified in pigs noculated with SGI1-bearing strains exposed to free-living protozoa. Additionally, an SGI1-bearing strain of Salmonella Choleraesuis was detected that resulted in augmented virulence in pigs. Therefore, it appeared that protozoa-associated salmonellosis was analogous in pigs and cattle. Salmonella-mediated encephalopathy and multisystemic cytopathicity did not appear to be relevant diseases in pigs.


Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine.
Circulatory shock is a life-threatening syndrome resulting in multiorgan failure and a high mortality rate. The aim of this consensus is to provide support to the bedside clinician regarding the diagnosis, management and monitoring of shock. The European Society of Intensive Care Medicine invited 12 experts to form a Task Force to update a previous consensus (Antonelli et al.: Intensive Care Med 33:575-590, 2007). The same five questions addressed in the earlier consensus were used as the outline for the literature search and review, with the aim of the Task Force to produce statements based on the available literature and evidence. These questions were: (1) What are the epidemiologic and pathophysiologic features of shock in the intensive care unit? (2) Should we monitor preload and fluid responsiveness in shock? (3) How and when should we monitor stroke volume or cardiac output in shock? (4) What markers of the regional and microcirculation can be monitored, and how can cellular function be assessed in shock? (5) What is the evidence for using hemodynamic monitoring to direct therapy in shock? Four types of statements were used: definition, recommendation, best practice and statement of fact. Forty-four statements were made. The main new statements include: (1) statements on individualizing blood pressure targets; (2) statements on the assessment and prediction of fluid responsiveness; (3) statements on the use of echocardiography and hemodynamic monitoring. This consensus provides 44 statements that can be used at the bedside to diagnose, treat and monitor patients with shock.


Evidence for an inherited predisposition to lumbar disc disease.
A genetic predisposition for the development of symptomatic lumbar disc disease has been suggested by several twin sibling studies and subsequent genetic marker studies. The purpose of the present study was to define population-based familial clustering among individuals with a diagnosis of, or treated for, lumbar disc herniation or disc degeneration. The Utah Population Database allows analysis of combined health and genealogic data for over one million Utah residents. We used the International Classification of Diseases, Ninth Revision, diagnosis codes entered in patient records to identify patients with a diagnosis of either lumbar disc herniation or lumbar disc degeneration and genealogic data. The hypothesis of excess relatedness (familial clustering) was tested with use of the Genealogical Index of Familiality, which compares the average relatedness of affected individuals with expected population relatedness. Relative risks in relatives were estimated by comparing rates of disease in relatives with expected population rates (estimated from the relatives of matched controls). This methodology has been previously reported for other disease conditions but not for spinal diseases. The Genealogical Index of Familiality test for 1264 patients with lumbar disc disease showed a significant excess relatedness (p < 0.001). Relative risk in relatives was significantly elevated in both first-degree (relative risk, 4.15; p < 0.001) and third-degree relatives (relative risk, 1.46; p = 0.027). Excess relatedness of affected individuals and elevated risks to both near and distant relatives was observed, strongly supporting a heritable contribution to the development of symptomatic lumbar disc disease.


A Rare Cause of Hemoptysis in Childhood: Tracheal Capillary Hemangioma.
Hemangiomas are benign tumors most frequently seen in childhood and are mostly associated with cutaneous and mucosal surfaces. Tracheal capillary hemangiomas are extremely rare. The most common presenting symptom is hemoptysis, ranging from minor to major and chronic cough. We present the case of a 12-year-old boy with recurrent hemoptysis due to tracheal capillary hemangioma, who was treated with interventional bronchoscopy.


Testing for a Debt-Threshold Effect on Output Growth.
Using the Reinhart-Rogoff dataset, we find a debt threshold not around 90 per cent but around 30 per cent, above which the median real gross domestic product (GDP) growth falls abruptly. Our work is the first to formally test for threshold effects in the relationship between public debt and median real GDP growth. The null hypothesis of no threshold effect is rejected at the 5 per cent significance level for most cases. While we find no evidence of a threshold around 90 per cent, our findings from the post-war sample suggest that the debt threshold for economic growth may exist around a relatively small debt-to-GDP ratio of 30 per cent. Furthermore, countries with debt-to-GDP ratios above 30 per cent have GDP growth that is 1 percentage point lower at the median.


Sympathetic hyperactivity, respiratory failure, pruritus, and anesthesia after unintentional epidural injection of potassium chloride: case report.
A combination of epidural and general anesthesia has been widely used to attenuate the surgical stress response and to provide postoperative analgesia. This case report illustrates the use of this anesthetic technique. Analgesia was induced with local anesthetic in the immediate postoperative period using unintentional 19.1% potassium chloride (KCl) as diluent. An ASA I male patient was scheduled for surgical correction of idiopathic megaesophagus under continuous epidural anesthesia combined with general anesthesia. In the postoperative period, while preparing 10 mL 0.125% bupivacaine to be administered through the epidural catheter for pain control, 5 mL 19.1% KCl was unintentionally used as diluent, resulting in a 9.55% potassium solution concentration. The patient developed warmness of the lower limbs, tachycardia, hypertension, intense pruritus on the chest, agitation, exacerbation of sensory and motor blocks, and respiratory failure secondary to pulmonary edema, requiring ventilatory support. Total recovery was observed after 24 hours. Epidurally injected potassium leads to severe clinical manifestations caused by autonomic dysfunction, spinal cord irritation, and possible release of histamine. Despite continuous recommendations, ampule misidentification still happens in hospitals, frequently leading to serious accidents.


Profound analgesia is associated with a truncated peptide resulting from tissue specific alternative splicing of DRG CA8-204 regulated by an exon-level cis-eQTL.
Carbonic anhydrase-8 (CA8) is an intracellular protein that functions as an allosteric inhibitor of inositol trisphosphate receptor-1 (ITPR1) critical to intracellular Ca++ release, synaptic functions and neuronal excitability. We showed previously that murine nociception and analgesic responses are regulated by the expression of this gene in dorsal root ganglion (DRG) associated with a cis-eQTL. In this report, we identify an exon-level cis-eQTL (rs6471859) that regulates human DRG CA8 alternative splicing, producing a truncated 1,697bp transcript (e.g., CA8-204). Our functional genomic studies show the "G" allele at rs6471859 produces a cryptic 3'UTR splice site regulating expression of CA8-204. We developed constructs to study the expression and function of the naturally occurring CA8-204G transcript (G allele at rs6471859), CA8-204C (C allele at rs6471859 reversion mutation) and CA8-201 (full length transcript). CA8-204G transcript expression occurred predominantly in non-neuronal cells (HEK293), while CA8-204C expression was restricted to neuronal derived cells (NBL) in vitro. CA8-204G produced a stable truncated transcript in HEK293 cells that was barely detectable in NBL cells. We also show CA8-204 produces a stable peptide that inhibits pITPR1 and Ca++ release in HEK293 cells. These results imply homozygous G/G individuals at rs6471859, which are common in the general population, produce exclusively CA8-204G that is barely detectable in neuronal cells. CA8 null mutations that greatly impact neuronal functions are associated with severe forms of spinal cerebellar ataxia, and our data suggest G/G homozygotes should display a similar phenotype. To address this question, we show in vivo using AAV8-FLAG-CA8-204G and AAV8-V5-CA8-201 gene transfer delivered via intra-neural sciatic nerve injection (SN), that these viral constructs are able to transduce DRG cells and produce similar analgesic and anti-hyperalgesic responses to inflammatory pain. Immunohistochemistry (IHC) examinations of DRG tissues further show CA8-204G peptide is expressed in advillin expressing neuronal cells, but to a lesser extent compared to glial cells. These findings explain why G/G homozygotes that exclusively produce this truncated functional peptide in DRG evade a severe phenotype. These genomic studies significantly advance the literature regarding structure-function studies on CA8-ITPR1 critical to calcium signaling pathways, synaptic functioning, neuronal excitability and analgesic responses.


Optical imaging of neuronal populations during decision-making.
We investigated decision-making in the leech nervous system by stimulating identical sensory inputs that sometimes elicit crawling and other times swimming. Neuronal populations were monitored with voltage-sensitive dyes after each stimulus. By quantifying the discrimination time of each neuron, we found single neurons that discriminate before the two behaviors are evident. We used principal component analysis and linear discriminant analysis to find populations of neurons that discriminated earlier than any single neuron. The analysis highlighted the neuron cell 208. Hyperpolarizing cell 208 during a stimulus biases the leech to swim; depolarizing it biases the leech to crawl or to delay swimming.


Observations on sporulation of Eimeria bovis (Apicomplexa: Eimeriidae) from the European bison Bison bonasus: effect of temperature and potassium dichromate solution.
The present study was designed to determine the influence of temperature and the addition of potassium dichromate solution (K2Cr2O7) on the efficiency of sporulation of Eimeria bovis (Zublin, 1908), a coccidian species most commonly diagnosed in European bison Bison bonasus (Linnaeus). Sporulation under conventional conditions (2.5% dichromate solution, 23 °C) was completed on the fourth day of incubation (control), whereas the oocyst development took two days more at the temperature of 18 °C, and two days less at 28 °C. Additionally, experimental sporulation of E. bovis at the temperature of 23 °C in the environment of sterilised tap water (without any preservation) took 9 days more compared to control. Finally, oocyst development took 16 weeks when the faces were stored in the refrigerator (3-5 °C) without any special additives. Overall, our results indicate that K2Cr2O7, besides the temperature, plays a crucial role in the process of sporulation of oocysts under laboratory conditions, as the longest delay in sporogony was observed when the faeces were stored without any other additives in the temperature of the refrigerator.


Community-acquired vs. nosocomial spontaneous bacterial peritonitis in patients with liver cirrhosis.
Spontaneous bacterial peritonitis (SBP) is a common complication in patients with end-stage liver disease, but reports comparing community-acquired SBP (CA-SBP) with nosocomial SBP (N-SBP) are rare. This study compared the clinical characteristics, microbiological characteristics, and treatment outcomes of patients with CA-SBP and N-SBP. Records for 248 patients (173 men, 75 women) with cirrhosis who experienced SBP were retrospectively reviewed. The study population included 202 (81.5%) patients with CA-SBP and 46 (18.5%) patients with N-SBP. Patients with CA-SBP or N-SBP showed no significant differences in baseline or microbiological characteristics, except for a high frequency of previous SBP history in the N-SBP population (P=0.020). During hospitalization, antibiotic switching and in-hospital mortality were significantly higher for patients with N-SBP than CA-SBP (35.6% vs. 8.9%; P=0.001 and 30.4% vs. 12.9%; P=0.028). There were 202 (81.5%) deaths during the follow-up period, with longer overall survival time in patients with CA-SBP (7.9 vs. 3.9 months; P=0.041). However, time to recurrence was not significantly different between the two groups (4.7 vs. 3.6 months; P=0.910). N-SBP was significantly associated with increased antibiotic switching, higher in-hospital mortality and shorter overall survival. Third-generation cephalosporin may be inappropriate as first-line empirical antibiotics for patients with N-SBP.


Lack of access to clean fuel and piped water and children's educational outcomes in rural India.
Investments in clean fuel and piped water are often recommended in developing countries on health grounds. This paper examines an alternative channel, the relationship between piped water and access to liquefied petroleum gas (LPG) and children's educational outcomes. Results based on the second round of the India Human Development Survey (2011-12) for rural India show that children aged 6-14 years, living in households that rely on free collection of water and cooking fuel, have lower mathematics scores and benefit from lower educational expenditures than children living in households that do not collect water and fuel. Moreover, gender inequality in this unpaid work burden also matters. In households where the burden of collection is disproportionately borne by women, child outcomes are significantly lower, particularly for boys. The endogeneity of choice to collect or purchase water and cooking fuel are modeled via Heckman selection and the entropy balancing method.


Reconsidering the moral hazard-risk avoidance tradeoff.
The received model for optimal demand-side cost sharing trades off moral hazard and risk avoidance. This model appears to lie behind recent increases in initial cost sharing, such as those embodied in Health Savings Accounts and Health Reimbursement Accounts. At the same time there is evidence that lower cost sharing for certain drugs can reduce future total health care costs and/or improve future health, and this may be true of other medical services as well. To the degree that individuals remain in the same common insurance pool, lower cost sharing that induces increases in certain services that reduce total costs, including future costs, represents a classic case for a subsidy and will minimize an employer's labor costs. Even if total costs increase, the value of a change in health could increase more. In that case such a subsidy is consistent with recent work in behavioral economics for those with self-control problems.


Efficacy of Telerehabilitation for Adults With Traumatic Brain Injury: A Systematic Review.
To identify and appraise studies evaluating the efficacy of telerehabilitation for adults with traumatic brain injury (TBI). A systematic search of Cochrane Library, MEDLINE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and PsycINFO databases was conducted from January 1980 to April 23, 2017, for studies evaluating the efficacy of telerehabilitation for adults with TBI. Two reviewers independently assessed articles for eligibility and rated methodological quality using 16 criteria related to internal validity, descriptive, and statistical characteristics. The review yielded 13 eligible studies, including 10 randomized controlled trials and 3 pre-/postgroup studies (n ≥ 10). These evaluated the feasibility and/or efficacy of telephone-based (10 studies) and Internet-based (3 studies) interventions. Overall, the evidence of efficacy was somewhat mixed. The most common study design evaluated the efficacy of telephone-based interventions relative to usual care, for which 4 of 5 randomized controlled trials reported positive effects at postintervention (d = 0.28-0.51). For these studies, improvements in global functioning, posttraumatic symptoms and sleep quality, and depressive symptoms were reported. The feasibility of Internet-based interventions was generally supported; however, the efficacy could not be determined because of insufficient studies. Structured telephone interventions were found to be effective for improving particular outcomes following TBI. Controlled studies of Internet-based therapy and comparisons of the clinical and cost-effectiveness of in-person and telerehabilitation formats are recommended for future research.


Excited state dynamics of symmetric and asymmetric Cr3(dpa)4Cl2 measured using femtosecond transient absorption spectroscopy.
Herein, the excited-state dynamics of an extended metal atom chain complex, Cr3(dpa)4Cl2 (dpa = dipyridylamide), in tetrahydrofuran solution were investigated using femtosecond transient absorption spectroscopy. Upon excitation at a wavelength of 330 nm, two distinct excited-state absorption species with varied dynamics were identified and assigned to the symmetric (s-) and unsymmetric (u-) Cr3(dpa)4Cl2. The major species is s-Cr3(dpa)4Cl2 that undergoes rapid conversion at less than 100 fs from the ligand-centred π-π* state, which is the initially accessed state, to the metal-centred d-d state and then vibrational cooling accompanying the structural relaxation at a time constant ∼2.2 ps. Most of the s-form is recovered to the ground state at ∼200 ps. For u-Cr3(dpa)4Cl2, a similar rapid conversion to d-d states is observed, and the geometric/vibrational relaxation is ∼0.8 ps. The second recovery of the ground state with approximately equal amplitude is observed at a time constant of ∼5 ns. This might be because many d-d states exist and about half of them inefficiently couple with the ground state surface.


Artificial intelligence in diabetic retinopathy: A natural step to the future.
Use of artificial intelligence in medicine in an evolving technology which holds promise for mass screening and perhaps may even help in establishing an accurate diagnosis. The ability of complex computing is to perform pattern recognition by creating complex relationships based on input data and then comparing it with performance standards is a big step. Diabetic retinopathy is an ever-increasing problem. Early screening and timely treatment of the same can reduce the burden of sight threatening retinopathy. Any tool which can aid in quick screening of this disorder and minimize requirement of trained human resource for the same would probably be a boon for patients and ophthalmologists. In this review we discuss the current status of use of artificial intelligence in diabetic retinopathy and few other common retinal disorders.


The Cambridge Anti-myopia Study: variables associated with myopia progression.
To identify variables associated with myopia progression and to identify any interaction between accommodative function, myopia progression, age, and treatment effect in the Cambridge Anti-Myopia Study. Contact lenses were used to improve static accommodation by altering ocular spherical aberration, and vision training was performed to improve dynamic accommodation. One hundred forty-two subjects, aged 14-21 years, were recruited who had a minimum of -0.75D of myopia. Subjects were assigned to contact lens treatment only, vision training only, contact lens treatment and vision training, or control group. Spherical aberration, lag of accommodation, accommodative convergence/accommodation (AC/A) ratio, accommodative facility, ocular biometry, and refractive error were measured at regular intervals throughout the 2-year trial. Ninety-five subjects completed the 24-month trial period. There was no significant difference in myopia progression between the four treatment groups at 24 months. Age, lag of accommodation, and AC/A ratio were significantly associated with myopia progression. There was a significant treatment effect at 12 months in the contact lens treatment group in younger subjects, based on a median split, aged under 16.9 years (p = 0.005). This treatment effect was not maintained over the second year of the trial. Younger subjects experienced a greater reduction in lag of accommodation with the treatment contact lens at 3 months (p = 0.03), compared to older contact lens treatment and control groups. There was no interaction between AC/A ratio and contact lens treatment effect. Age, lag of accommodation, and AC/A ratio were significantly associated with myopia progression. Although there was no significant treatment effect at 24 months, an interaction between age and contact lens treatment suggests younger subjects may be more amenable, at least in the short term, to alteration of the visual system using optical treatments.


Evaluation of filtering blebs using the 'Wuerzburg bleb classification score' compared to clinical findings.
To determine the agreement between intraocular pressure and the 'Wuerzburg bleb classification score', as well as between single items of the score and intraocular pressure. Interobserver variability was analyzed. 57 post-trabeculectomy eyes were included. Colour photographs were used to score the filtering bleb in accordance to the Wuerzburg bleb classification score by two different examiners. At the same visit, clinical data such as intraocular pressure, best corrected visual acuity, slit lamp biomicroscopy and medical history were obtained by another examiner. After trabeculectomy, 42 out of 57 eyes (73.7%) reached the target pressure (≤ 21mmHg, and intraocular pressure reduction of at least 20%, without antiglaucoma medication, and without any additional intervention). Fair agreement was found between intraocular pressure and Wuerzburg bleb classification score ≥ 8 points and ≥ 7 points (kappa 0.24 and 0.27, respectively). Analyzing the subgroups of the morphological criteria, best agreement was found between occurrence of microcysts and target intraocular pressure (к 0.22-0.34). Evaluating filtering blebs after trabeculectomy by using the Wuerzburg bleb classification score is a good technique for predicting intraocular pressure control in eyes attaining a minimum score of seven points. The presence of microcysts on the filtering bleb predicts that the eye is likely to attain target pressure.


Microbial pathway prediction: a functional group approach.
We have developed a system to predict microbial catabolism, using the University of Minnesota Biocatalysis/Biodegradation Database (UM-BBD, http://umbbd.ahc.umn.edu/) as a knowledge base. The present system, available on the Web (http://umbbd.ahc.umn.edu/predict/), can predict biodegradation of most of the major aliphatic and aromatic organic functional groups containing C, H, N, O, and halogens. It can duplicate at least one known biodegradation pathway for 60% of the compounds in a 84-member validation set; most pathways that did not completely duplicate known metabolism could plausibly occur in nature. Users are encouraged, and have begun, to submit additional biotransformation rules and comment on existing rules; the system will further develop under the direction of the scientific community.


Taxonomic revision and cladistic analysis of the tarantula genera Tapinauchenius Ausserer, 1871, Psalmopoeus Pocock, 1985, and Amazonius n. gen. (Theraphosidae, Psalmopoeinae).
The genera Psalmopoeus Pocock, 1895, Tapinauchenius Ausserer, 1871 and Pseudoclamoris Hsser, 2018 are revised and cladistics analyses carried out including most species of these genera. In order to test the monophyly of Aviculariinae and Psalmopoeinae, species of all genera in these two subfamilies were included, as well as of Harpactirinae, Selenocosmiinae, Theraphosinae, Stromatopelmatinae, Ischnocolinae, Schismatothelinae, Poecilotherinae, and a barychelid was used to root the cladogram. The matrix with 50 terminal taxa, 1 continuous and 85 discrete characters was analysed with TNT 1.5. The results show a monophyletic Psalmopoeinae as sister group of Aviculariinae. Psalmopoeus comprises 9 species: Psalmopoeus cambridgei Pocock, 1895 (type species), Psalmopoeus ecclesiasticus Pocock, 1903, Psalmopoeus emeraldus Pocock, 1903, Psalmopoeus irminia Saager, 1994, Psalmopoeus langenbucheri Schmidt, Bullmer Thierer-Lutz, 2006, Psalmopoeus plantaris Pocock, 1903, Psalmopoeus pulcher Petrunkevitch, 1925, Psalmopoeus reduncus (Karsch, 1880), and Psalmopoeus victori Mendoza, 2014. Psalmopoeus intermedius Chamberlin, 1940 is considered a junior synonym of P. reduncus. Psalmopoeus copanensis Gabriel Sherwood, 2020, P. sandersoni Gabriel Sherwood, 2020 and P. petenensis Gabriel Sherwood, 2020 are considered junior synonyms of P. victori. Psalmopoeus maya Witt, 1996 is considered nomen nudum. Tapinauchenius comprises 8 species: Tapinauchenius plumipes (C. L. Koch, 1842) (type species), Tapinauchenius sanctivincenti (Walckenaer, 1837), Tapinauchenius latipes L. Koch, 1875, Tapinauchenius brunneus Schmidt, 1995, Tapinauchenius cupreus Schmidt Bauer, 1996, Tapinauchenius polybotes Hsser, 2018, Tapinauchenius rasti Hsser, 2018, and T. gretae n. sp. The female of T. brunneus is described for first time. Tapinauchenius violaceus (Mello-Leito, 1930), T. purpureus Schmidt, 1995, T. concolor (Caporiaccco, 1947), and T. gigas Caporiacco, 1954 are considered junior synonyms of T. plumipes. With the synonymy of T. gigas (type species of Pseudoclamoris Hsser, 2018), it was necessary to describe a new genus for the two species formerly included in it. Thus, the new genus Amazonius n. gen. is erected to include A. elenae (Schmidt, 1994) n. comb., A. burgessi (Hsser, 2018) n. comb. as well as two new species A. giovaninii n. gen. n. sp. and A. germani n. gen. n. sp. A discussion on the relationship of Psalmopoeinae and Aviculariinae and maps with the distributions of all species are provided.


Assessment of the Quality and Reliability of Information on Nutrition After Bariatric Surgery on YouTube.
YouTube™ is a platform that many people, including patients, use to access health information. Recent studies have revealed that videos on YouTube™ are misleading or that medical videos may not contain appropriate information. This study aimed to assess the quality and reliability of videos on nutrition after bariatric surgery. The keywords "after bariatric surgery diet" and "weight loss surgery postop diet" were used, and the first 100 videos for each keyword on YouTube™ were analyzed by considering the source, duration, content, and the number of likes of the video. The popularity of the video was calculated using the video power index (VPI) and view rate. The educational quality of the videos was evaluated using the DISCERN score, the Journal of the American Medical Association (JAMA) score, the Global Quality Score (GQS), the usefulness score, and a novel postoperation nutrition score (PONS). One hundred fourteen patients were included in the study. The mean duration and number of views were 12.51 min and 87,558.46, respectively. The DISCERN score, JAMA score, GQS, and usefulness score of the physicians or dietician-based videos were significantly higher than those of the patient-based videos (p < 0.001). Positive correlations were found between the VPI and view ratio, as well as between the duration and number of likes. Additionally, the DISCERN score was significant correlated with the duration and number of likes. Significantly positive correlations were found between the usefulness score and duration, usefulness score and number of likes, and PONS and duration (p < 0.01). Informational videos on nutrition after bariatric surgery on YouTube™ are of low quality. Although the videos uploaded by physicians and dieticians have higher quality, only a few are available. Additionally, patients prefer to watch low-quality videos.


Surface-plasmon-polariton whispering-gallery mode analysis of the graphene monolayer coated InGaAs nanowire cavity.
In this article, we proposed and numerically studied the surface plasmon polariton whispering gallery mode properties of the graphene coated InGaAs nanowire cavity. The quality factor and the mode area were investigated as a function of the chemical potential, the cavity radius and the wavelength. A high cavity quality factor of 235 is predicted for a 5 nm radius cavity, accompanied by a mode area as small as3.75×10(-5)(λ(0))(2), when the chemical potential is 1.2 eV. The proposed structure offers a potential solution to high density integration of the nanophotonic devices with an ultra-compact footprint.


7 Mb de novo deletion within 8q21 in a patient with distal arthrogryposis type 2B (DA2B).
We report on a 7 11/12 years old male patient with normal mental development, club feet, ulnar deviation and mild camptodactyly as well as facial dysmorphism including high forehead, small mouth, broad nasal bridge, epicanthus, high palate, brachycephalus, short neck, and dysplastic ears consistent with distal arthrogryposis type 2B (DA2B). Mutational analysis of the genes MYH3, TNNI2, TNNT3 and TPM2, known to cause DA2B revealed no apparent disease causing mutation. Molecular karyotyping using a 250 K SNP array revealed a heterozygous de novo 7 Mb deletion of 8q21.11-8q21.13 containing 23 genes. Prioritisation of possible candidate genes using the bioinformatics tool ENDEAVOUR revealed three favoured genes, HEY1, FABP5 and FABP4 as potential causes of the phenotype. We propose that the 8q21 region contains a further locus which contributes to the genetically heterogeneous DA2B.


Implementation of a prioritized scoring tool to improve time to pharmacist intervention.
The implementation of a prioritized scoring tool to improve time to pharmacist intervention is described. At the Ohio State University Wexner Medical Center, pharmacists are accepted providers of therapeutic drug monitoring of vancomycin and aminoglycosides. At the onset of this initiative and despite the implementation of an integrated electronic medical record (EMR), management of pharmacokinetically monitored medications was conducted using a paper monitoring form. The potential for transcription errors during this process provided an opportunity for improvement. For these reasons, the department of pharmacy focused its initial efforts for a patient scoring system on the pharmacokinetics scoring module. Adjustment of associated medications based on pharmacokinetic values was a core function of pharmacists of the institution and was expected to be conducted without fail. Vancomycin was used as the index surrogate pharmacokinetically monitored medication within the module for testing and validation because of the clear expectations and standardized resources available to pharmacists to complete the task. The pharmacokinetics scoring module was designed specifically for the function of dosing management, searching throughout the EMR and concisely displaying the information a pharmacist needs to make a clinical decision. Importantly, integration of the scoring module reduced the time to intervention from hours to minutes. The median time to intervention was reduced to within a clinical working shift (8 hours) with the scoring module versus 24 hours or longer with the paper monitoring system. The implementation of an internally developed pharmacokinetics scoring module built into the EMR substantially reduced the time to clinical intervention for pharmacokinetic monitoring of vancomycin drug levels.


The effects of propranolol on spontaneous and experimental hypertension in the rat.
1. The hypotensive effect of propranolol and its correlation with the changes in heart rate, plasma volume and plasma renin activity produced by this drug were studied in normotensive rats and in rats with spontaneous, renovascular and deoxycorticosterone-induced hypertension. 2. No correlation was found between the fall in arterial pressure and the reduction in heart rate and plasma volume. On the contrary, a direct correlation was found between the hypotensive response and plasma renin activity: rats with high renin showed the maximum response, those with low renin no response. 3. Studies on blood volume distribution in different organs and the direct measurement of blood flow in the splanchnic bed demonstrated a significant correlation between the effect of propranolol on capillary permeability and the haemodynamic changes which it causes, namely a significant increase in portal venous pressure.


Histologic healing following tooth extraction with ridge preservation using mineralized versus combined mineralized-demineralized freeze-dried bone allograft: a randomized controlled clinical trial.
Mineralized and demineralized freeze-dried bone allografts (FDBAs) are used in alveolar ridge (AR) preservation; however, each material has advantages and disadvantages. Combinations of allografts aimed at capitalizing on the advantages each offers are available. To date, there is no evidence to indicate if a combination allograft is superior in this application. The primary objective of this study is to histologically evaluate and compare healing of non-molar extraction sites grafted with either mineralized FDBA or a 70:30 mineralized:demineralized FDBA combination allograft in AR preservation. The secondary objective is to compare dimensional changes in ridge height and width after grafting with these two materials. Forty-two patients randomized into two equal groups received ridge preservation with either 100% mineralized FDBA (active control group) or the combination 70% mineralized: 30% demineralized allograft (test group). Sites were allowed to heal for 18 to 20 weeks, at which time core biopsies were obtained and dental implants were placed. AR dimensions were evaluated at the time of extraction and at implant placement, including change in ridge width and change in buccal and lingual ridge height. Histomorphometric analysis was performed to determine percentage of vital bone, residual graft, and connective tissue/other non-bone components. There was no significant difference between groups in AR dimensional changes. Combination allograft produced increased vital bone percentage (36.16%) compared to the FDBA group (24.69%; P = 0.0116). The combination allograft also had a significantly lower mean percentage of residual graft particles (18.24%) compared to FDBA (27.04%; P = 0.0350). This study provides the first histologic evidence showing greater new bone formation with a combination mineralized/demineralized allograft compared to 100% mineralized FDBA in AR preservation in humans. Combination allograft results in increased vital bone formation while providing similar dimensional stability of the AR compared to FDBA alone in AR preservation.


Recovery from contrast adaptation matches ideal-observer predictions.
Recovery from contrast adaptation was studied in psychophysical experiments. We measured detection thresholds for a test pulse presented on a photopic background as a function of the time after the offset of a high-contrast flicker of the background. The decrease of thresholds with time is well described by a power-law function. Thresholds for tests presented at 640 ms after the offset of the background contrast are still significantly elevated above the threshold measured when the observers have completely adapted to a steady background. We compare the psychophysical data with contrast estimates of ideal-observer models. A match between the results for human and ideal observers can be obtained when the ideal observer is limited by noise. For a quantitative match, we assume that the ideal observer performs a Bayesian calculation on its noise-perturbed input, sampled every 10-20 ms. For the Bayesian calculation we assume a prior probability distribution function for the input contrast that has a lower cutoff at the standard deviation of the noise.


Patients with obsessive-compulsive disorder vs depression have comparable health care costs: a retrospective claims analysis of Florida Medicaid enrollees.
The health care burden of obsessive-compulsive disorder (OCD) is relatively unknown. To compare the health care burden of patients with OCD vs depression. This retrospective claims analysis compared the 2-year median per-patient health care claims and costs for Florida Medicaid adult enrollees (1997 to 2006) newly diagnosed with "pure OCD" (P-OCD; OCD without comorbid major depression, bipolar disorder, psychosis, organic mental disorder, pervasive developmental disorder, nonpsychotic brain damage, developmental delay, or mental retardation) with matched patients newly diagnosed with "pure depression" (P-D; similar to P-OCD but excluding OCD instead of depression). Eighty-five newly diagnosed P-OCD patients were matched with 14,906 P-D patients. Although median per-patient total health care costs were comparable across groups, patients with P-D incurred significantly higher median outpatient medical costs ($1,928 vs $363, P = .003), while those with P-OCD incurred almost three-fold greater psychiatric costs ($2,028 vs $759, P < .0001). The latter was due primarily to significantly higher costs of psychotropic medications among those with P-OCD ($4,307 vs $2,317, P = .0006) rather than to psychiatric outpatient care. Patients with P-D and P-OCD carry a similar burden in overall health care costs. However, the burden of those with P-D was largely attributable to outpatient medical costs while that of those with P-OCD was due to higher costs of psychotropic medications.


Risk perception, preventive behaviors, and vaccination coverage in the Korean population during the 2009-2010 pandemic influenza A (H1N1): comparison between high-risk group and non-high-risk group.
This study was carried out to estimate the vaccination coverage, public perception, and preventive behaviors against pandemic influenza A (H1N1) and to understand the motivation and barriers to vaccination between high-risk and non-high-risk groups during the outbreak of pandemic influenza A (H1N1). A cross-sectional nationwide telephone survey of 1,650 community-dwelling Korean adults aged 19 years and older was conducted in the later stage of the 2009-2010 pandemic influenza A (H1N1) outbreak. The questionnaire identified the demographics, vaccination status of participants and all household members, barriers to non-vaccination, perceived threat, and preventive behaviors. In Korea, the overall rate of pandemic influenza vaccination coverage in the surveyed population was 15.5%; vaccination coverage in the high-risk group and non-high-risk group was 47.3% and 8.0%, respectively. In the high-risk group, the most important triggering event for vaccination was receiving a notice from a public health organization. In the non-high-risk group, vaccination was more strongly influenced by previous experience with influenza or mass media campaigns. In both groups, the most common reasons for not receiving vaccination was that their health was sufficient to forgo the vaccination, and lack of time. There was no significant difference in how either group perceived the threat or adopted preventive behavior. The predictive factors for pandemic influenza vaccination were being elderly (age ≥ 65 years), prior seasonal influenza vaccination, and chronic medical disease. With the exception of vaccination coverage, the preventive behaviors of the high-risk group were not different from those of the non-high-risk group during the 2009-2010 pandemic. For future pandemic preparedness planning, it is crucial to reinforce preventive behaviors to avoid illness before vaccination and to increase vaccination coverage in the high-risk group.


T670X KIT mutations in gastrointestinal stromal tumors: making sense of missense.
Chronic myeloid leukemia, gastrointestinal stromal tumors (GISTs), and idiopathic hypereosinophilic syndrome are associated with pathological deregulation of the tyrosine kinases BCR-ABL, KIT, and PDGFRA, respectively. Patients who become resistant to imatinib treatment often develop secondary mutations, the most common of which results in a substitution of isoleucine for threonine at the same location in the ATP-binding domain in all three kinases (in KIT this occurs at amino acid 670). We sought to determine why Thr is always replaced by Ile. All possible point mutations in the DNA triplet codon that could result in amino acid substitutions at Thr670 (Thr670Arg, Thr670Ile, Thr670Lys, Thr670Ala, Thr670Ser, Thr670Pro) were introduced by site-specific mutagenesis of the complementary DNA for a constitutively active, imatinib-sensitive form of the KIT receptor, Delta559/KIT. The resulting mutant KIT proteins were transiently expressed in COS1 African green monkey kidney cells grown with and without imatinib, and cell extracts were analyzed for KIT activation by immunoprecipitation and immunoblotting to determine autophosphorylation levels. We also performed molecular modeling to estimate the relative affinities of wild-type (Thr670) KIT and the KIT mutants for ATP and imatinib. Like the parental strain, Thr670Ala, Thr670Ser, and Thr670Lys mutants were inhibited by 5 microM imatinib, but in comparison, they were only weakly active and Thr670Pro and Thr670Arg were not active at all. Only the Thr670Ile mutant was fully active (autophosphorylated) and resistant to imatinib. These findings were consistent with computer modeling predictions that ranked these mutants Thr - Ile > Ala, Ser > Lys >> Pro according to their affinity for ATP but Thr > Ala, Ser > Lys >Pro - Arg - Ile according to their affinity for imatinib. This combination of in vitro and molecular modeling analyses shows why, among all possible amino acid substitutions at position 670 of KIT, only Ile is naturally selected as a resistance mutant in imatinib-treated GIST patients.


Extension of Survival in Bilaterally Adrenalectomized Mice by Implantation of SF-1/Ad4BP-Induced Steroidogenic Cells.
Mesenchymal stroma/stem cells (MSCs) exist in adult tissues, such as adipose tissue and bone marrow, and differentiate into cells of multiple lineages. In previous studies, we found that MSCs differentiate into steroidogenic cells by forced expression of steroidogenic factor 1 (SF-1)/adrenal 4 binding protein (Ad4BP), the master regulator of steroidogenesis and differentiation of pituitary gonadotrophs, adrenal glands, and gonads. In this study, SF-1/Ad4BP-induced steroidogenic cells derived from mouse adipose tissue-derived MSCs (ADSCs) were implanted under the kidney capsule of bilateral adrenalectomized (bAdx) mice. bAdx mice did not survive after 7 days. However, 4 of 9 bAdx mice implanted with SF-1/Ad4BP-induced steroidogenic cells, 1 of 10 bAdx mice transplanted with control ADSCs, and bAdx mice transplanted with an adrenal gland survived for 30 days. Plasma corticosterone levels in bAdx mice implanted with SF-1/Ad4BP-induced steroidogenic cells and control ADSCs were 5.41 ± 2.26 ng/mL (mean ± SEM) and undetectable at 7 days after implantation, respectively. After removal of the kidney bearing the graft from the surviving mice at 30 days after implantation, plasma corticosterone was not detected in any of the samples. Immunohistochemical staining revealed SF-1/Ad4BP-positive cells under the capsule of the kidney. Although we performed an adrenocorticotropin (ACTH) loading test on bAdx mice implanted with SF-1/Ad4BP-induced steroidogenic cells, ACTH responsiveness was not observed. Implantation of steroidogenic cells derived from ADSCs into bAdx mice increased the basal plasma corticosterone level and extended the survival of bAdx mice, suggesting the capability of restoring steroidogenic cells by cell transplantation therapy for adrenal insufficiency.